article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "Seizures are a recognized and potentially serious complication of recreational drug use. This study examined a large international data set of presentations to Emergency Departments with acute recreational drug toxicity, the European Drug Emergencies Plus (Euro-DEN Plus) Network, to compare presentations with and without seizures and estimate incidence and associated drugs. Amongst 23,947 presentations between January 2014 and December 2017, there were 1013 (4.2%) with reported seizures. Clinical and demographic features were similar between individuals who had a seizure and those who did not, although rates of coma, cardiac arrest, intubation, intensive care admission, and death were significantly higher in those with seizures. There was a significant association between specific drugs and a higher seizure incidence, including fentanyl (odds ratio 2.63, 95% confidence interval 1.20-5.80), and synthetic cannabinoids (OR 2.90, 95% CI 2.19-3.84). Other drugs were associated with a lower seizure incidence, including heroin (OR 0.46, 95% CI 0.35-0.61), clonazepam (OR 0.22, 95% CI 0.06-0.91), and cannabis (OR 0.65, 95% CI 0.50-0.86). This substantiates observations that the synthetic cannabinoids as a group of novel psychoactive substances are clinically different in consequence of intoxication than cannabis, and that individuals who suffer a seizure in the context of recreational drug intoxication are likely to have worse outcomes overall. Utilising this information of what substances have a greater risk of seizures, could provide tailored harm reduction and education strategies to users to reduce the risk of seizures and their associated complications.",
"affiliations": "Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK. Electronic address: caitlin.wolfe@gstt.nhs.uk.;Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK; Clinical Toxicology, Faculty of Life Sciences and Medicine, King's College London, London, UK.;Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.;Clinical and Experimental Epilepsy, Queen Square Institute of Neurology, University College London, London, UK.;Emergency Department and Clinical Toxicology Unit, Hospital Universitari Son Espases, Mallorca, Spain.;The Norwegian CBRNe Centre of Medicine, Oslo University Hospital, Oslo, Norway.;The Norwegian CBRNe Centre of Medicine, Oslo University Hospital, Oslo, Norway.;European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal.;Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK; Clinical Toxicology, Faculty of Life Sciences and Medicine, King's College London, London, UK.",
"authors": "Wolfe|Caitlin E|CE|;Wood|David M|DM|;Dines|Alison|A|;Whatley|Benjamin P|BP|;Yates|Christopher|C|;Heyerdahl|Fridtjof|F|;Hovda|Knut Erik|KE|;Giraudon|Isabelle|I|;Dargan|Paul I|PI|;|||",
"chemical_list": "D002186:Cannabinoids; D013287:Illicit Drugs; D009292:Narcotic Antagonists; D011619:Psychotropic Drugs",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.neuro.2019.04.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0161-813X",
"issue": "73()",
"journal": "Neurotoxicology",
"keywords": "Acute toxicity; New psychoactive substances; Recreational drug; Seizure; Synthetic cannabinoid",
"medline_ta": "Neurotoxicology",
"mesh_terms": "D000328:Adult; D001831:Body Temperature; D002186:Cannabinoids; D005060:Europe; D005260:Female; D006439:Hemodynamics; D006801:Humans; D013287:Illicit Drugs; D015994:Incidence; D008297:Male; D009292:Narcotic Antagonists; D009293:Opioid-Related Disorders; D011379:Prognosis; D011619:Psychotropic Drugs; D012119:Respiration; D018570:Risk Assessment; D012307:Risk Factors; D012640:Seizures; D019966:Substance-Related Disorders",
"nlm_unique_id": "7905589",
"other_id": null,
"pages": "183-187",
"pmc": null,
"pmid": "30974132",
"pubdate": "2019-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Seizures as a complication of recreational drug use: Analysis of the Euro-DEN Plus data-set.",
"title_normalized": "seizures as a complication of recreational drug use analysis of the euro den plus data set"
} | [
{
"companynumb": "GB-JNJFOC-20200602410",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nWe describe an immune reconstitution syndrome (IRS)-like entity in the course of evolution of Cryptococcus neoformans infection in organ transplant recipients.\n\n\nMETHODS\nThe study population comprised a cohort of 83 consecutive organ transplant recipients with cryptococcosis who were observed for a median of 2 years in an international, multicenter study.\n\n\nRESULTS\nIn 4 (4.8%) of the 83 patients, an IRS-like entity was observed a median of 5.5 weeks after the initiation of appropriate antifungal therapy. Worsening of clinical manifestations was documented, despite cultures being negative for C. neoformans. These patients were significantly more likely to have received tacrolimus, mycophenolate mofetil, and prednisone as the regimen of immunosuppressive therapy than were all other patients (P = .007). The proposed basis of this phenomenon is reversal of a predominantly Th2 response at the onset of infection to a Th1 proinflammatory response as a result of receipt of effective antifungal therapy and a reduction in or cessation of immunosuppressive therapy.\n\n\nCONCLUSIONS\nThis study demonstrated that an IRS-like entity occurs in organ transplant recipients with C. neoformans infection. Furthermore, this entity may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy in such cases.",
"affiliations": "University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. nis5+@pitt.edu",
"authors": "Singh|Nina|N|;Lortholary|Olivier|O|;Alexander|Barbara D|BD|;Gupta|Krishan L|KL|;John|George T|GT|;Pursell|Kenneth|K|;Munoz|Patricia|P|;Klintmalm|Goran B|GB|;Stosor|Valentina|V|;del Busto|Ramon|R|;Limaye|Ajit P|AP|;Somani|Jyoti|J|;Lyon|Marshall|M|;Houston|Sally|S|;House|Andrew A|AA|;Pruett|Timothy L|TL|;Orloff|Susan|S|;Humar|Atul|A|;Dowdy|Lorraine|L|;Garcia-Diaz|Julia|J|;Kalil|Andre C|AC|;Fisher|Robert A|RA|;Husain|Shahid|S|;|||",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D011241:Prednisone; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1086/430606",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "40(12)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D015331:Cohort Studies; D003453:Cryptococcosis; D005260:Female; D006801:Humans; D007154:Immune System Diseases; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D016377:Organ Transplantation; D011241:Prednisone; D016559:Tacrolimus",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1756-61",
"pmc": null,
"pmid": "15909263",
"pubdate": "2005-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients.",
"title_normalized": "an immune reconstitution syndrome like illness associated with cryptococcus neoformans infection in organ transplant recipients"
} | [
{
"companynumb": "US-PFIZER INC-2019431564",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
... |
{
"abstract": "We describe a case of a 36-year-old woman with severe hypertriglyceridemia likely caused by double heterozygosity of a known pathogenic APOA5 nonsense variant (p.Q275X) and a novel CREB3L3 nonsense variant (p.C296X) on a background of very strong polygenic susceptibility. Her clinical course worsened with development of eruptive xanthomata after oral administration of 2 mg estradiol twice daily for 2 weeks as part of a medical protocol for intrauterine embryo transfer following in vitro fertilization. Her triglyceride levels decreased to baseline and xanthomata resolved without treatment after discontinuation of hormonal therapy, which also resulted in termination of pregnancy. Before undergoing a second embryo transfer using her natural cycle and no exogenous hormones, the patient started combination therapy with eicosapentaenoic acid ethyl ester and gemfibrozil, leading to an ∼80% decrease in triglyceride levels. She continued treatment throughout pregnancy, which progressed to term with the delivery of healthy twins.",
"affiliations": "Department of Family Medicine, Oregon Health & Science University, Portland, OR, USA. Electronic address: wojcikc@ohsu.edu.;Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.;Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.",
"authors": "Wójcik|Cezary|C|;Fazio|Sergio|S|;McIntyre|Adam D|AD|;Hegele|Robert A|RA|",
"chemical_list": "D000072040:Apolipoprotein A-V; C533813:CREB3L3 protein, human; D018389:Codon, Nonsense; D017362:Cyclic AMP Response Element-Binding Protein; D004967:Estrogens",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacl.2018.05.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4789",
"issue": "12(5)",
"journal": "Journal of clinical lipidology",
"keywords": "APOA5; CREB3L3; Eruptive xanthoma; Estrogen; Gene mutation; Hypertriglyceridemia; In vitro fertilization; Pregnancy",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D000328:Adult; D000072040:Apolipoprotein A-V; D018389:Codon, Nonsense; D017362:Cyclic AMP Response Element-Binding Protein; D004967:Estrogens; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D015228:Hypertriglyceridemia; D011247:Pregnancy",
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "1146-1150",
"pmc": null,
"pmid": "29954705",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Co-occurrence of heterozygous CREB3L3 and APOA5 nonsense variants and polygenic risk in a patient with severe hypertriglyceridemia exacerbated by estrogen administration.",
"title_normalized": "co occurrence of heterozygous creb3l3 and apoa5 nonsense variants and polygenic risk in a patient with severe hypertriglyceridemia exacerbated by estrogen administration"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US00363",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMFIBROZIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP.\n\n\nMETHODS\nA retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected.\n\n\nRESULTS\nA total of 193 patients (57% female and 64% Crohn's disease) were included, with a median daily TG dose of 20 mg (range: 20-40 mg), a median treatment duration of 23 months (IQR 10-47) and a median follow-up of 36 months (IQR 22-53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145-1761) and 47 mu/L (IQR 34.5-96).\n\n\nCONCLUSIONS\nLong-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.",
"affiliations": "Department of Gastroenterology and Hepatology, Amsterdam UMC, VU University Medical Centre, Amsterdam, The Netherlands. a.b.bayoumy@amsterdamumc.nl.;Department of Gastroenterology and Hepatology, Amsterdam UMC, VU University Medical Centre, Amsterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Amsterdam UMC, VU University Medical Centre, AG&M Research Institute, Amsterdam, The Netherlands.;Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Gastroenterology, Queen Elizabeth Hospital, Woolwich, UK.;Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Gastroenterology, Surrey and Sussex NHS, Easy Surrey Hospital, Surrey, UK.;Department of Gastroenterology and Hepatology, Amsterdam UMC, VU University Medical Centre, AG&M Research Institute, Amsterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Amsterdam UMC, VU University Medical Centre, Amsterdam, The Netherlands.;Department of Gastroenterology, Surrey and Sussex NHS, Easy Surrey Hospital, Surrey, UK.",
"authors": "Bayoumy|Ahmed B|AB|http://orcid.org/0000-0002-5302-9312;van Liere|Elsa L S A|ELSA|;Simsek|Melek|M|;Warner|Ben|B|;Loganayagam|Aathavan|A|;Sanderson|Jeremy D|JD|;Anderson|Simon|S|;Nolan|Jonathan|J|;de Boer|Nanne K|NK|;Mulder|Chris J J|CJJ|;Ansari|Azhar|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D004364:Pharmaceutical Preparations; D015122:Mercaptopurine; D013866:Thioguanine; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1186/s12876-020-01441-6",
"fulltext": "\n==== Front\nBMC Gastroenterol\nBMC Gastroenterol\nBMC Gastroenterology\n1471-230X BioMed Central London \n\n32917155\n1441\n10.1186/s12876-020-01441-6\nResearch Article\nEfficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom\nhttp://orcid.org/0000-0002-5302-9312Bayoumy Ahmed B. a.b.bayoumy@amsterdamumc.nl 1234 van Liere Elsa L. S. A. 1234 Simsek Melek 5 Warner Ben 2 Loganayagam Aathavan 3 Sanderson Jeremy D. 2 Anderson Simon 2 Nolan Jonathan 4 de Boer Nanne K. 5 Mulder Chris J. J. 1 Ansari Azhar 4 1 grid.16872.3a0000 0004 0435 165XDepartment of Gastroenterology and Hepatology, Amsterdam UMC, VU University Medical Centre, Amsterdam, The Netherlands \n2 grid.420545.2Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK \n3 Department of Gastroenterology, Queen Elizabeth Hospital, Woolwich, UK \n4 Department of Gastroenterology, Surrey and Sussex NHS, Easy Surrey Hospital, Surrey, UK \n5 grid.16872.3a0000 0004 0435 165XDepartment of Gastroenterology and Hepatology, Amsterdam UMC, VU University Medical Centre, AG&M Research Institute, Amsterdam, The Netherlands \n11 9 2020 \n11 9 2020 \n2020 \n20 2966 3 2020 3 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\nThioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP.\n\nMethods\nA retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected.\n\nResults\nA total of 193 patients (57% female and 64% Crohn’s disease) were included, with a median daily TG dose of 20 mg (range: 20–40 mg), a median treatment duration of 23 months (IQR 10–47) and a median follow-up of 36 months (IQR 22–53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145–1761) and 47 mu/L (IQR 34.5–96).\n\nConclusions\nLong-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.\n\nKeywords\nThioguanineThiopurinesIBDCrohn’s diseaseUlcerative colitisDrug repositioningDrug survivalissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nThe classic thiopurines mercaptopurine (MP), and its licenced and more widely used prodrug azathioprine (AZA), are still first line immunosuppressives for treating inflammatory bowel diseases (IBD). In recent times, their role is increasingly being questioned because of their relative poor performance, mainly due to treatment and dosage limiting adverse events, when compared to biologics [1–3]. Nonetheless, a sizable subgroup of individuals experience a positive response (30–50%) with meaningful clinical outcomes such as sustained steroid sparing/ free remission combined with a reduced need for hospitalisation, surgery and biologic agents [4–10]. There is an emerging interest in small molecules, as they have advantages over biologicals (e.g. oral administration, lower costs, no antibody formation and therefore sustained efficacy) [11]. The thiopurines are well-established classical small molecules and hence share these benefits. However, the conventional thiopurines (AZA/MP) have been well described and accepted shortcomings include slow onset of action, relatively high rate of adverse events and subsequent frequent need for monitoring and/or dose optimisation. These time-consuming and often distressing problems have resulted in an increase of early use of biological therapy [12, 13].\n\nThioguanine (TG) was introduced in 1950 as treatment for leukaemia and about five decades later, clinicians started using it for treating IBD. Modern cases series suggest that TG offers better outcomes in terms of efficacy (51–60%) as rescue therapy, low incidence of adverse events and possibly a more rapid onset of action compared to conventional thiopurines [14–16]. However, its widespread use has been hampered due to concerns about hepatotoxicity (nodular regenerative hyperplasia [NRH]) but this is thought to be dose-dependent [17–19]. Other long-term risks of TG might be the development of lymphoma and skin malignancy, as has been shown with AZA/MP and anti-TNF therapies [20, 21].\n\nHaving considered these potential risks, the benefits of TG remain important in the treatment of patients with IBD [22]. For this reason, a few centres continue to use TG but only at a lowered dose (10–40 mg/day). Reports of outcomes from these centres in the United Kingdom (UK), The Netherlands and Australia confirm a good efficacy and lack of hepatotoxicity [14, 15, 23–25]. Moreover, in the Netherlands, TG has been provisional licenced for IBD since a few years [26, 27]. At the moment an estimated 6000 Dutch IBD use TG as rescue treatment for IBD [28].\n\nFor the reasons outlined, it is important to evaluate the long-term outcomes of a low dose TG approach. The aim of this study was to investigate the long-term efficacy and safety of low dose TG in a large IBD cohort failing conventional thiopurines, derived from three UK centres.\n\nMethods\nStudy design and patient population\nA retrospective, multicentre cohort study was performed in three centres in the UK (St. Thomas’ Hospital, Queen Elizabeth Hospital and East Surrey Hospital). Patients were identified by using local hospital pharmacy dispensing records dating from 2003 to 2019, as TG is only dispensed through the hospital pharmacy. Patients were included if they were diagnosed with Crohn’s Disease (CD), ulcerative colitis (UC) or IBD-unclassified (IBD-U) according to clinical, endoscopic and/or histological criteria and if they were treated with TG, either as monotherapy or concomitant therapy. Montreal classification were used to classify the IBD patients [29]. Patients without complete documented follow-up were excluded.\n\nData collection\nPatient and disease characteristics, drug history and clinical, biochemical, radiological and histopathological data were reviewed using the patients’ medical records. Laboratory data were taken at 3 months prior to TG initiation, at 6 months after initiation and at final follow-up. Laboratory parameters included haemoglobin, white blood cell count (WBC), platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl-transferase (GGT), bilirubin, albumin and 6-thioguanine nucleotides (6-TGNs). Most recent abdominal ultrasonography, magnetic resonance imaging (MRI) and liver biopsies were assessed.\n\nSafety assessment\nSafety of TG therapy was assessed by evaluating 1) haematological parameters for myelotoxicity and NRH (through alkaline phosphatase) and 2) radiological, histopathological and biochemical parameters for liver toxicity. Histopathological liver biopsy reports were assessed and the pathologists’ findings and conclusions were used to assess the occurrence of NRH. Patients were categorized into ‘signs of NRH’ when minimal focal hyperplasia was present. Emphasis has been put on signs or findings of non-cirrhotic portal hypertension (NCPHT) (e.g. hepato- or splenomegaly, nodular abnormalities, ascites, varices). The occurrence of adverse events and reasons for withdrawal during the entire follow-up were recorded. Adverse events were defined as laboratory abnormalities and signs or symptoms that occurred after initiation of TG, and were listed according to the common terminology criteria for adverse events (CTCAE) (Version 5.0, released November 27, 2017) [30].\n\nEfficacy assessment\nA positive clinical response was defined as: no (re)initiation of corticosteroids, (re)initiation of biological therapy or IBD-related surgery. CRP and ESR levels were collected to determine biochemical response. TG use at final follow-up was evaluated to assess long-term beneficial effect. Primary resistance was assigned when criteria for clinical effectiveness were not met within the first 6 months of therapy. Lastly, 6-TGN levels were collected to evaluate a possible correlation with clinical response.\n\nStatistical analysis\nData was presented as numbers with percentages, medians with interquartile range (IQR) or means with standard deviations. Depending on the kind of parameter, distribution, parametric or nonparametric tests including the Mann-Whitney U test, Wilcoxon signed-rank test, Kruskal Wallis, and the student t-test or chi-square test were used to test for differences within and between groups. A Kaplan-Meier plot was performed to assess the TG attrition rate. The survival curves were compared using the Mantel-Cox test. This study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology statement [31]. IBM SPSS Statistics V.25 was used for the statistical analysis. A p-value less than 0.05 was accepted as statistically significant.\n\nEthical considerations\nAccording to the guidelines of the UK Health Research Authority, as the data were collected as part of routine clinical care and were evaluated retrospectively, the study was considered a review of clinical practice and ethical approval was not required [32]. This study was conducted in accordance with the Declaration of Helsinki [33]. All data in this study was anonymised.\n\nResults\nPatient characteristics\nIn total, 209 IBD patients treated with TG were identified. Sixteen patients were excluded due to incomplete follow-up data, leading to a total number of 193 patients whom were included in the study. Of these, 110 patients were female (57%), 123 had CD (64%), 64 UC (33%) and 6 IBD-U (3%). Perianal disease was diagnosed in 23 patients (12%). Median age at IBD diagnosis and initiation of TG was 32 (IQR 21–44) and 43 years (IQR 33–56), respectively. Sixty-three patients (33%) had a history of bowel resection prior to TG therapy. Patient and disease characteristics are shown in Table 1.\nTable 1 Patient and disease characteristics of the entire cohort (n = 193)\n\nVariable\tResults\t\nMale/female\t83/110\t\nAge at diagnosis, median (IQR)\t32 (21–44)\t\nAge at initiation TG, median (IQR)\t43 (33–56)\t\nHospital\t\n ▪ St. Thomas’ Hospital\t87 (45%)\t\n ▪ East Surrey Hospital\t67 (35%)\t\n ▪ Queen Elizabeth Hospital\t39 (20%)\t\nCrohn’s disease (Montreal classification)\t123 (64%)\t\nAge at diagnosis\t\n ▪ < 17 (A1)\t16 (19%)\t\n ▪ 17–40 (A2)\t71 (58%)\t\n ▪ > 40 (A3)\t29 (24%)\t\nLocation\t\n ▪ Ileal (L1)\t38 (31%)\t\n ▪ Colonic (L2)\t15 (15%)\t\n ▪ Ileocolonic (L3)\t62 (50%)\t\n ▪ Upper gastrointestinal disease (L4)\t4 (3%)\t\nBehaviour\t\n ▪ Nonstricturing, nonpenetrating (B1)\t45 (40%)\t\n ▪ Stricturing (B2)\t36 (33%)\t\n ▪ Penetrating (B3)\t26 (27%)\t\n ▪ Perianal disease (p)\t23 (12%)\t\nUlcerative colitis (Montreal classification)\t64 (33%)\t\nExtent\t\n ▪ Proctitis (E1)\t18 (30%)\t\n ▪ Left-sided (E2)\t24 (37%)\t\n ▪ Pancolitis (E3)\t21 (33%)\t\nSeverity\t\n ▪ Asymptomatic (S0)\t9 (14%)\t\n ▪ Mild (S1)\t15 (24%)\t\n ▪ Moderate (S2)\t18 (28%)\t\n ▪ Severe (S3)\t22 (34%)\t\nIBD unclassified\t6 (3%)\t\nDrug failure prior to thioguanine initiation\t193 (100%)\t\n ▪ Azathioprine\t123 (58%)\t\n ▪ Mercaptopurine\t11 (5%)\t\n ▪ Azathioprine and mercaptopurine\t59 (27%)\t\n ▪ Azathiopurine and allopurinol\t76 (39%)\t\n ▪ Anti-tumour necrosis factor\t77 (40%)\t\n ▪ Methotrexate\t36 (19%)\t\n ▪ Tacrolimus\t8 (4%)\t\nGastrointestinal surgery prior to thioguanine initiation\t63 (33%)\t\nFollow-up in months, median (IQR)\t36 (22–53)\t\nTreatment duration of thioguanine (months, IQR)\t23 (10–47)\t\n\n\nPrior to TG initiation, AZA was used in 123 patients (58%), MP in 11 patients (5%) and both AZA and MP in 59 patients (27%). Seventy-six of 193 patients (39%) had used co-therapy with allopurinol to optimise AZA (AZA-Allo). The median daily dosages of AZA and MP were 100 mg (range: 75–200 mg) and 100 mg (range: 50–150). The dosage used for AZA-Allo was 50 mg for AZA and 100 mg for allopurinol. The most commonly reported reason for prior thiopurine failure was intolerance to thiopurines, which occurred in 150 patients (78%). Intolerances to thiopurines mostly recorded were nausea (22%), pancreatitis (21%) and arthralgia/myalgia (6%). Resistance to thiopurines occurred in 18 patients (9%). Twelve of those 18 resistant patients (67%) were primary non-responders. The rest of the patients were switched to TG for reasons such as patients’ preference, suboptimal 6-TGN levels and non-compliance.\n\nFurthermore, 77 patients (40%) had a history of biological therapy (see Table 1). Sixty-one patients (79%) had loss of response on biologicals, six patients (8%) suffered from rash, five (6%) had infusion site reactions, two (3%) suffered from tonsillar abscess and three patients (4%) had psoriatic skin abnormalities.\n\nThe median daily dose for TG was 20 mg; 107 patients (55%) were treated with 20 mg once daily and 86 patients (45%) with 20 mg twice daily. Patients of East Surrey Hospital were commenced on 20 mg twice daily and after 6 months the lowest effective dose was achieved by reducing to 20 mg/day. At St. Thomas’ Hospital most patients were started on 20 mg once daily although some received 40 mg/day (20 mg twice daily) with the desire to reduce to 20 mg once daily if response allowed. At Queen Elizabeth Hospital, all patients received 20 mg once daily. The median treatment duration of TG was 23 months (IQR 10–47) and the median follow-up time of 36 months (IQR 22–53). Thirty-three patients (18%) started TG along with biological therapy; adalimumab (40 mg, two weekly) was started in 18 patients, infliximab (5 mg/kg, eight weekly) in 13 patients, ustekinumab (90 mg, eight weekly) in one patient and vedolizumab in one patient (300 mg, eight weekly). The median duration of follow-up was 12 months (IQR 7–15), in which 22 out of 33 patients (67%) were still using biologicals along with TG. The reasons to stop biologicals were due to loss of response and side-effects (i.e. infusion reactions).\n\nEfficacy\nClinical response at 6 and 12 months of TG therapy was seen in 71% (n = 137) and 65% (n = 125) of patients, respectively. The proportion of patients who continued TG therapy is depicted in a Kaplan-Meier survival curve (Fig. 1). Of the entire cohort, 153 (79%), 137 (71%) and 104 (54%) were still using TG at respectively 12 and 24 months after initiation, and at final follow-up. Drug survival did not depend on age, gender, type of IBD, bowel resection history, short bowel syndrome or IBD behavior. No statistical significant difference was observed between using a dosage of 20 or 40 mg per day (Fig. 2).\nFig. 1 Drug survival of TG in 193 patients, showing the time to TG withdrawal/censoring in months per hospital. Median treatment duration of TG was 23 months. The differences between the curves were not significantly different (p = 0.12, Mantel-Cox test)\n\nFig. 2 Drug survival curve of TG of patients receiving 20 mg TG per day compared to 40 mg/day. No significant differences were found between both curves (p = 0.57, Mantel-Cox test)\n\n\n\nThioguanine was discontinued in 89 patients (46%) during follow-up. Forty-three patients (22%) stopped TG due to intolerance, 15 (8%) due to resistance, 3 (2%) due to malignancy (melanoma, diffuse large B-cell lymphoma, recurrent breast cancer), 7 (4%) due to pregnancy, 4 (2%) due to non-compliance, 6 (3%) due to complete remission and 11 (5%) due to miscellaneous reasons. The median time till cessation of therapy due to intolerance or resistance was 9 (IQR 2–20) and 12 months (IQR 10–14), respectively. Of the 150 patients who failed prior thiopurine therapy due to intolerance, 112 patients (75%) did not experience any intolerances while on TG. Of these 150 patients, 92 patients (61%) were still using TG at final follow-up. Furthermore, of the 18 patients (9%) who were primary (n = 12) or secondary (n = 6) resistant to conventional thiopurines, 14 patients (78%) had a positive response to TG at 12 months. Of the primary resistant patients, nine out of 12 (75%) were responding to TG at 12 months.\n\nSafety\nSeventy-one adverse events occurred in a total of 28% (n = 54) of patients. Overall, 22% of patients had to stop TG therapy due to intolerance. No deaths occurred in our cohort study related to TG therapy. Adverse events to TG are shown in Table 2. Laboratory abnormalities occurred in 13% (elevated liver function tests or myelotoxicity) and signs/symptoms in 23% (mainly rash). Pancreatitis occurred in 1 of 30 patients with a history of conventional thiopurine-induced pancreatitis. Malignancies occurred in three patients (2%): two patients developed moderate graded (i.e. requiring minimal, local or non-invasive intervention; melanoma and recurrent breast cancer) and one patient severe graded malignancy (diffuse large B-cell lymphoma). The latter was diagnosed on surgical specimen following excision of enterocutaneous fistula and redo of ileocolic anastomosis after 4 years of TG treatment. This patient was previously treated with both anti-TNF therapy and methotrexate.\nTable 2 Adverse events (n = 71) during a median follow up of 36 months of TG therapy\n\n\tGrade 1 (mild)\n(n = 59)\tGrade 2 (moderate)\n(n = 9)\tGrade 3 (severe)\n(n = 3)\t\nGeneral, neurological and psychological\tFlu-like symptoms\t7\t–\t\t–\t\t\nBlood, lymphatic and vascular disorders\tBone marrow suppression\t12\tBone-marrow suppression\t2\t–\t\t\nMusculoskeletal and skin disorders\tAlopecia\t5\t–\t\t–\t\t\nRash\t9\t\nArthralgia/myalgia\t8\t\nHepatobiliary disorders\tDILI\t9\tDILI\t3\tPortal hypertension\t2\t\nGastrointestinal disorders\tNausea\t5\tDiarrhea\t1\tPancreatitis\t1\t\nAbdominal pain\t4\t\nInfections and infestations\t–\t\tEBV infection\t1\tHerpetic eye infection\t1\t\nNeoplasm benign and malign\t–\t\tMelanoma\t1\tDiffuse large B-cell lymphoma\t1\t\nRecurrent breast cancer\t1\t\nDILI Drug-induced liver injury, DILI grade 1 is defined as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 1.25 and ≤ 3 upper limit of normal (ULN) and total bilirubin > 1.25 and ≤ 2 ULN, grade 2 is defined as ALT and AST > 3 and ≤ 5 ULN and total bilirubin > 2 and ≤ 3 ULN. Bone marrow suppression: grade 1 < =25% reduction from normal cellularity for age, grade 2: > 25 - < 50% reduction from normal cellularity for age, grade 3: > 50 - < =75% reduction cellularity from normal for age\n\n\n\nNon-cirrhotic portal hypertension (NCPHT) occurred in two patients (1%). The first patient was between 50 and 60 years old and diagnosed with Crohn’s disease who started TG therapy in 2011 after poor response to both AZA and low dose AZA with allopurinol afterwards. TG was initiated at 20 mg twice daily (40 mg/day) and gradually reduced to 20 mg on alternate days with occasional complete breaks in treatment. In January 2016, the TG was stopped after the patient had been established on anti-TNF therapy for 12 months combined with recurrent episodes of pancytopenia. Anti-TNF therapy was ceased in July 2016 due to loss of response and a severe psoriatic reaction. In December 2017, the patient was admitted with ascites and features of portal hypertension. Investigations (within 8 weeks) determined normal portal pressures and a liver biopsy was reported as normal. The further work up for chronic liver disease and coagulopathy was negative. A clinical diagnosis on NCPHT was established and therapy was discontinued. Symptoms improved with conservative measures such as spironolactone treatment.\n\nThe second case of NCPHT was between 60 and 70 years old, diagnosed with Crohn’s disease and had three ileocecal resections prior to using TG. TG was started after not tolerating AZA and failure of both infliximab and adalimumab. Azathioprine was discontinued because of mild fibrosis and steatosis observed in the liver biopsy performed due to abnormal liver enzymes. During TG therapy, no follow-up liver biopsy was performed. After using TG 20 mg twice daily (40 mg/day) for 5 years, the patient presented with abdominal pain. Gastroscopy revealed gastric fundal varices and a CT-scan showed widespread intra-abdominal non-haemorrhagic varices and small volume ascites. TG was discontinued and the patient was given atenolol for primary prevention of variceal bleeding. No varices bleeding occurred over time.\n\nBiochemistry\nLaboratory parameters at initiation of therapy and 6 months of treatment are depicted in Table 3. Among the entire cohort, alanine transaminase (ALAT) and alkaline phosphatase (AP) levels prior to TG initiation did not differ from levels at 6 months. However, a statistically significant increase in bilirubin concentration (8 to 9 μmol/L) and a decrease in platelets (313 to 275 × 109/L) was observed (p < 0.05). The platelet level was lower in the response group compared to the non-response group but still within the normal range (259 versus 305 × 109/L, p < 0.05). Regarding efficacy, a biochemical response at 6 months was observed in the patients experiencing a positive clinical response as their CRP level was statistically significantly lower compared to the non-responders (9 versus 26 mg/L, p = 0.02). There was no statistical difference in erythrocyte sedimentation rate (ESR) level between responders and non-responders (P > 0.05).\nTable 3 Laboratory parameters at initiation of TG (T0) and 6 months of treatment (T6), shown as mean (SD). Levels of response and non-response group at T6 are compared, as are levels at T0 and T6 of the entire cohort\n\nParameter\tT0, Response\tT6, Response\tT0, Non-Response\tT6, Non-Response\tT0, Total\tT6, Total\t\nHaemoglobin\t131 (14)\t136 (17)*\t128 (21)\t132 (16)*\t131 (16)\t135 (18)*\t\nPlatelets\t305 (87)\t259 (95)*\t332 (116)\t309 (90)\t313 (95)\t275 (97)*\t\nBilirubin\t8 (6)\t9 (9)\t7 (4)\t8 (4)\t8 (6)\t9 (8)*\t\nALAT\t24 (19)\t25 (14)\t20 (12)\t20 (14)\t23 (17)\t24 (14)\t\nAP\t74 (30)\t81 (38)\t90 (31)\t94 (58)\t79 (32)\t84 (41)\t\nAlbumin\t44 (5)\t44 (5)\t44 (4)\t44 (3)\t44 (4)\t44 (5)\t\nCRP\t12 (32)\t9 (20)\t9 (11)\t26 (65)*\t11 (29)\t13 (36)\t\nESR\t17 (20)\t13 (12)\t18 (15)\t17 (14)\t17 (16)\t15 (12)\t\nALAT Alanine aminotransferase, AP Alkaline phosphatase, CRP C-reactive protein, ESR Erythrocyte sedimentation rate\n\n*: statistical significantly different (P < 0.05)\n\n\n\nTPMT measurements were performed in 87 patients (45%), the median TPMT level was 47 mu/L (IQR 34.5–96). In total, three patients (2%) had low TPMT activity (< 25 mu/L) and 37 patients (19%) had high TPMT activity (> 65 mu/L). All patients in the low activity group suffered from mild side-effects (e.g. myalgias, nausea and rash) on thiopurines. In the high TPMT activity group, 49% of patients discontinued TG, while in the normal TPMT activity group 32% of patients discontinued TG during follow-up (P = 0.13). However, if a cut-off level of 44 mu/L (based on the rate of TG discontinuation) was used, 54% of patients above this cut-off level discontinued TG while 23% of patients below this level discontinued TG (P = 0.01, Chi-Square test). Eleven patients above this cut-off value stopped TG due to non-response, while no patients stopped due to non-response under this cut-off level (P = 0.001, Chi Square test). In these 11 patients, the mean TPMT level was 91.6 ± 26.9 mu/L.\n\nMedian steady-state 6-TGN concentrations during the first 12 months of TG therapy were available in 48 patients (25%). The median 6-TGN concentration was 953 pmol/8 × 105 RBC (IQR 145–1761). Median 6-TGN metabolite levels were not significantly higher in clinical responders compared to non-responders (966 [IQR 705–1489] versus 764 [IQR 418–1265], p = 0.32). No significant differences were found between quartile 6-TGN levels (Fig. 3, p = 0.47). The response rate at 12 months was 67% in patients with a 6-TGN cut-off level below 771 pmol/8 × 105 RBC, whereas the response rate was 87% in patients with a cut-off above 771 pmol/8 × 105 RBC. This difference was not statistically significant.\nFig. 3 Correlation between 6-TGN concentration and clinical response rate within 12 months. No significant difference was found between the four quartiles (p = 0.47, Pearson Chi Square). At a cut-off level of 771 pmol/8 × 105 RBC no significant difference was found below and above the cut-off level (P = 0.09, T-test)\n\n\n\nRadiology and liver biopsy\nImaging and/or biopsies of the liver were performed in case of suspicion of NCPHT or as part of routine screening. An ultrasound was performed in 58 patients (30%) at a median of 28 months (IQR 14–41). Thirty-six patients (62%) had no abnormalities, 9 (16%) borderline splenomegaly, 16 (28%) signs of steatosis and one (2%) other unrelated abnormalities. Four patients demonstrated both steatosis and splenomegaly. Eighty-three patients (43%) underwent an magnetic resonance imaging (MRI) at a median follow-up of 37 months (IQR 21–60), showing no abnormalities in 58 patients (70%), borderline splenomegaly in seven (8%), steatosis in nine (11%), focal nodular hyperplasia in one (1%), hepatomegaly in 2 (2%) and other abnormalities (all liver cysts) in seven (8%).\n\nLiver biopsies were performed in 33 patients (17%) during TG treatment, at a median follow-up of 18 months (IQR 11–31). NRH was histologically diagnosed in two patients, signs of possible NRH were found in five patients and normal histology was found in the remaining 26 patients. One NRH patient used 20 mg once daily, the other NRH patient 20 mg twice daily. All five patients with signs of NRH were started on 40 mg/day, which was reduced to 20 mg on alternate days in one patient. The first NRH patient, also diagnosed with primary sclerosing cholangitis, suffered from varices grade I on gastroscopy for which this patient underwent band ligation. NRH was detected 5 months after cessation of TG, which had been used for 10 months. The second NRH patient was asymptomatic and developed NRH after 17 months of TG therapy. Both patients with NRH had a history of methotrexate therapy and side-effects on thiopurines.\n\nAll five patients with signs of NRH on liver biopsy were asymptomatic and did not develop clinical features of NCPHT during follow-up. Four of those five (80%) were able to continue TG until final follow-up. Nine of the 14 patients (64%) demonstrating abnormalities (spleno- or hepatomegaly) on ultrasound and/or MRI underwent a liver biopsy. Three patients of the remaining five patients who did not receive a liver biopsy were still using TG at final follow-up without signs of NCPHT. Two remaining patients who did not receive liver biopsy discontinued TG. One patient discontinued due to persistent thrombocytopenia and elevated liver function enzymes, and the other patient (known with cirrhotic liver disease) discontinued because of elevated liver enzymes and perisplenic and gastro-oesophageal varices. The latter had portal hypertension which developed due to postoperative portal vein thrombosis after a right hemicolectomy, which was performed 2 years before TG initiation.\n\nDiscussion\nThis retrospective, multicentre study sought to look at the real-world outcomes of TG from three large UK IBD units (over 4000 IBD patients per unit). A complete data capture was achieved through a search of local TG databases (prescriptions and IBD databases). This yielded 193 patients with a median follow up of 3 years and a median dose of 20 mg/day. Thioguanine can be started at its therapeutic dose as it is well tolerated, resulting in a positive clinical response of 71% at 6 months and 65% at 12 months as demonstrated in our study. Following this initial positive response, most patients continued to tolerate the treatment long-term with an overall efficacy at final follow-up of 54%. In our study, no correlation was found between 6-TGN levels and clinical response.\n\nMeijer et al. published a systematic review on the efficacy of TG in IBD. They reported results of 11 studies, comprising of 353 patients who were treated with a median TG starting dose of 20 mg/day after failing prior conventional thiopurine therapy. Clinical improvement in terms of decreased disease activity score or the ability to cease/decrease corticosteroid use was observed in 65% of patients (n = 228) [34]. Recently, Simsek et al. published the largest TG cohort consisting of 274 IBD patients, with a long-term follow-up of 4 years. They found that TG was tolerated in 79% of patients, 66% was responding at 6 months and 51% showed sustained clinical effectiveness. Although 40% of patients developed adverse events (65% mild, 30% moderate and 5% severe), only 11% overall discontinued due to intolerance. These authors also provided a meta-analysis of 483 IBD patients on at least 12 months of TG treatment. They reported that 231 patients achieved a positive clinical effect (pooled proportion: 44, 95% CI: 34–55%) [14]. The results described above are broadly in line with the outcomes of our cohort.\n\nIn our study there were two patients with histological features of NRH in their liver biopsies. Five patients had histological characteristics suspicious of NRH during liver biopsy, but none of them developed clinical signs of NCPHT. Only one patient, who did not respond to AZA and AZA-allo, discontinued TG during follow-up also due to poor-response. Additionally, two other patients (1%) were diagnosed with NCPHT in this cohort, without NRH-related characteristics in their liver biopsies. As compared to historical data from Dubinsky et al. (2003) in which high rates of NRH were described: 16 of 26 liver biopsies demonstrated features of NRH (62%), our numbers are comparable to the background incidence of NRH (6%). The worrying high NRH rate in Dubinsky’s study is not completely understood, but may be associated with the used higher doses of TG (median 45 mg/day, with an undocumented doses in the subgroup of patients who developed liver toxicity) and/or a selection bias as TG was used in patients with hepatotoxicity during AZA/MP therapy [35].\n\nMore recently, van Asseldonk et al. assessed the occurrence rate of NRH during TG therapy in 111 IBD patients. These patients had at least one liver biopsy, a mean daily TG dose of 21 mg (SD 5 mg) and a median treatment duration of 20 months. In this group only seven patients (6%) were histologically diagnosed with NRH and none had complications [36]. Ward et al. evaluated 54 patients treated with a mean TG dose of 27 mg/day in a group of patients intolerant or resistant to conventional thiopurines or methotrexate. No NRH was observed in their study [16]. Pavlidis et al. investigated a similar sized cohort of 62 IBD patients who received a median TG dose of 20 mg twice daily. The findings included mild NRH in one patient who was procoagulant due to antiphospholipid syndrome (1.6%), resulting in a portal vein thrombosis with complications. This group also had a patient with signs of NRH that resolved after dose reduction of TG to 20 mg once daily [15]. To determine the background incidence of NRH, de Boer et al. did 83 liver biopsies (during gastrointestinal surgery) in a thiopurine-naive IBD cohort and detected a NHR prevalence of 6% [37]. Furthermore, Wanless et al, reported 64 cases (2.6%) of NRH among 2500 consecutive autopsies in the general population [38]. These observations suggest that patients treated with low dose TG (not exceeding 25 mg/day) do not have a considerable higher risk of developing NRH when compared to non-TG receiving patients. Furthermore, it is important to note that the conventional thiopurines (AZA/MP) can cause NRH as well and were used in all our patients [39, 40]. Moreover, both of our NRH cases in our study were previously treated with methotrexate and one was also diagnosed with primary sclerosing cholangitis. Regarding the two NCPHT patients, one of them presented with signs of NCPHT (with a normal liver biopsy) almost 2 years after TG cessation. The other patient had already steatosis and fibrosis on liver biopsy while still on AZA. It is therefore important to state that we cannot determine which of the NRH and NCPHT patients of our study may have actually developed NRH and NCPHT due to other causes.\n\nFurthermore, van Asseldonk et al. demonstrated that although vascular liver abnormalities of any degree are commonly observed (27%) in TG treated IBD patients, they rarely become progressive or are of any clinical relevance [41, 42]. It was found by Morris et al. that NRH survival is highly variable and mostly related to age and underlying disease [43]. Seven patients in this study withdrew TG due to pregnancy, as the current UK guidelines do not allow this treatment in pregnancy, as compared to AZA/MP. Theoretically, there should be no difference between TG and AZA/MP. Thiopurines are not associated with any congenital abnormalities in men or women [44, 45]. Although data about safety of TG during pregnancy is scare, there is no evidence demonstrating negative effects. There is one case series published on 19 pregnancies in 13 IBD patients who were treated with low dose TG (20 mg/day). All patients conceived healthy new-borns, supporting the safe use of TG during pregnancy [46].\n\nTo our knowledge, the present study is the second largest study evaluating the safety and efficacy of TG in IBD patients. Patients from three different hospitals were included, which created the possibility of assessing slightly different low-dose TG treatment regimens. Secondly, the patients of our study have a long follow-up period, allowing us to assess the long-term effects of TG treatment. As a result of the retrospective design of the study, we acknowledge a few limitations. Firstly, it was difficult to compare the laboratory and imaging results between patients, as these were not regularly performed at fixed time intervals. Secondly, splenomegaly, hepatomegaly and signs of NRH were not defined using a standardised definition, therefore it was complicated to objectify and compare these parameters. Thirdly, it was not possible to assess mucosal response and clinical symptoms, as too limited endoscopic reports and disease activity indices (Simple Clinical Colitis Activity Index or Harvey-Bradshaw Index) were available. Furthermore, faecal calprotectin was not routinely measured and therefore not evaluated by us. Lastly, 6- TGN and TPMT levels were not available in the majority of our patients what led to calculating the correlation of 6-TGN level and clinical response using a relatively small number of patients. Also, the 6-TGN data is likely to be affected by selection bias as metabolite levels are mostly performed in patients having an insufficient response to TG. A 6-TGN cut-off level above 700 pmol/8 × 108 RBC seems to be associated with better clinical effectiveness [14]. In our study, patients having 6-TGN levels above 771 pmol/8 × 105 RBC had a response rate of 87%, while patients who had 6-TGN levels under this cut-off level had a response rate of 67%. This difference in response, although not statistically significant, might suggest that 6-TGN levels above 700 pmol/8 × 108 RBC can be associated with better clinical effectiveness as demonstrated by Simsek et al. [14]. One of the causes of low 6-TGN levels might be the result of drug incompliance. So, 6-TGN levels can be used to assess drug compliance in IBD patients treated with TG. Furthermore, 11 out of 15 patients who stopped TG due to non-response had TPMT levels above the cut-off level of 44 mu/L. This is in line with results that were found in literature for AZA treated IBD patients.\n\nAnsari et al. [47] found that high TPMT activity (> 14 u/mL) was significantly associated with non-response in AZA-treated IBD patients (OR 0.21, 95% CI 0.07–0.68). It seems that high TPMT activity might also be associated with non-response in TG-treated IBD patients. Although, the numbers in this study are small, it might indicate that further optimization of TG dosing might be useful by measuring the TPMT level.\n\nThe outcomes of this study are in a subset of difficult-to-treat patients who all have failed prior thiopurine therapy. Moreover, a substantial number of patients in our study were already unsuccessfully treated with biologicals and/or allopurinol co-therapy (40 and 39% respectively). Still, in this heavily treated group of patients, TG has shown to be an effective and well-tolerated therapy. A prospective study is needed to establish the role of TG as a rescue therapy for IBD patients who fail conventional thiopurine or other immunomodulation therapy (biological therapy, AZA-allo, methotrexate, tacrolimus, tofacitinib), and as first-line maintenance therapy for IBD.\n\nConclusions\nLong-term follow-up in this English cohort of 193 difficult-to-treat IBD patients suggests that low-dose TG (≤ 40 mg/day) can be effective and well-tolerated in more than half of patients who had failed prior thiopurine therapy and other immunomodulation or biological therapy. Hepatotoxicity was not common and the incidence rate of NRH was similar to the background incidence of NRH in IBD. There were no differences between 20 and 40 mg/day in terms of efficacy and safety, but we recommend to use the lowest possible effective dose of 20 mg/day or lower. A prospective trial is recommended to further establish the role of TG in IBD patients as first-line or rescue treatment.\n\nAbbreviations\nNRHNodular regenerative hyperplasia\n\nTGThioguanine\n\nIBDInflammatory bowel disease\n\nAZAAzathioprine\n\nMPMercaptopurine\n\nCDCrohn’s disease\n\nUCUlcerative colitis\n\n6-TGN6-thioguanine nucleotides\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAhmed B. Bayoumy and Elsa L.S.A. van Liere share first-authorship.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nAB collected and analyzed the data, wrote and conceptualized the manuscript. EL analyzed the data, wrote and conceptualized the manuscript. MS established the database, wrote and reviewed the manuscript. BW, AL, JS, SA, JN, NB, CM reviewed and commented on the manuscript. AA established the study, wrote and conceptualized the manuscript. All authors have read and approved the manuscript.\n\nFunding\nNo funding was obtained for the study.\n\nAvailability of data and materials\nThe datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nAccording to the guidelines of the UK Health Research Authority, as the data were collected as part of routine clinical care and were evaluated retrospectively, the study was considered a review of clinical practice and ethical approval was not required [32]. This study was conducted in accordance with the Declaration of Helsinki [33].\n\nConsent for publication\nNot Applicable.\n\nCompeting interests\nAB Bayoumy and ELSA van Liere received travel grants from TEVA. A Ansari has nothing to declare. M Simsek has received an unrestricted research grant from TEVA Pharma.\n\nCJJ Mulder has served as consultant and principal investigator for TEVA Pharma B.V. He has served as consultant and principal investigator for Takeda and TEVA Pharma B.V. He has received a (unrestricted) research grant from Dr. Falk and Takeda.\n\nNKH de Boer has served as a speaker for AbbVie and MSD and as a consultant and principal investigator for TEVA Pharma BV and Takeda. He has received unrestricted research grants from Dr. Falk, TEVA Pharma BV and Takeda.\n==== Refs\nReferences\n1. Colombel JF Sandborn WJ Reinisch W Infliximab, azathioprine, or combination therapy for Crohn’s disease N Engl J Med 2010 362 15 1383 1395 20393175 \n2. Hanauer SB Sandborn WJ Lichtenstein GR Evolving considerations for thiopurine therapy for inflammatory bowel diseases-a clinical practice update: commentary Gastroenterology 2019 156 1 36 42 30195449 \n3. Rogler G Sandborn WJ Is there still a role for thiopurines in Crohn’s disease? Gastroenterology 2013 145 4 714 716 23973853 \n4. Blackwell J Saxena S Pollok RC Role of thiopurines as disease-modifying agents in Crohn’s disease Gut 2018 67 12 2229 2230 29298871 \n5. Chatu S Subramanian V Saxena S Pollok RC The role of thiopurines in reducing the need for surgical resection in Crohn’s disease: a systematic review and meta-analysis Am J Gastroenterol 2014 109 1 23 34 24322839 \n6. Chhaya V Pollok RCG Cecil E Impact of early thiopurines on surgery in 2770 children and young people diagnosed with inflammatory bowel disease: a national population-based study Aliment Pharmacol Ther 2015 42 8 990 999 26271196 \n7. Qiu Y Chen BL Feng R Prolonged azathioprine treatment reduces the need for surgery in early Crohn’s disease J Gastroenterol Hepatol 2018 33 3 664 670 28940780 \n8. Ramadas AV Gunesh S Thomas GAO Williams GT Hawthorne AB Natural history of Crohn’s disease in a population-based cohort from Cardiff (1986–2003): a study of changes in medical treatment and surgical resection rates Gut 2010 59 9 1200 1206 20650924 \n9. Vidigal FM de Souza GS Chebli LA Azathioprine is more effective than mesalazine at preventing recurrent bowel obstruction in patients with ileocecal Crohn’s disease Med Sci Monit 2014 20 2165 2170 25370731 \n10. Lakatos PL Golovics PA David G Has there been a change in the natural history of Crohn’s disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977-2009 Am J Gastroenterol 2012 107 4 579 588 22233693 \n11. Olivera P Danese S Peyrin-Biroulet L Next generation of small molecules in inflammatory bowel disease Gut 2017 66 2 199 209 27856614 \n12. Lim SZ Chua EW Revisiting the role of thiopurines in inflammatory bowel disease through pharmacogenomics and use of novel methods for therapeutic drug monitoring Front Pharmacol 2018 9 1107 30349479 \n13. de Boer NK van Bodegraven AA Jharap B de Graaf P Mulder CJ Drug insight: pharmacology and toxicity of thiopurine therapy in patients with IBD Nat Clin Pract Gastroenterol Hepatol 2007 4 12 686 694 18043678 \n14. Simsek M Deben DS Horjus CS Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies Aliment Pharmacol Ther 2019 50 1 54 65 31094013 \n15. Pavlidis P Ansari A Duley J Oancea I Florin T Splitting a therapeutic dose of thioguanine may avoid liver toxicity and be an efficacious treatment for severe inflammatory bowel disease: a 2-center observational cohort study Inflamm Bowel Dis 2014 20 12 2239 2246 25230165 \n16. Ward MG, Patel KV, Kariyawasam VC, et al. Thioguanine in inflammatory bowel disease: long-term efficacy and safety. United European Gastroenterol J. 2017;5(4):563–70.\n17. De Bruyne R Portmann B Samyn M Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia J Hepatol 2006 44 2 407 410 16226335 \n18. Ravikumara M Hill FG Wilson DC 6-Thioguanine-related chronic hepatotoxicity and variceal haemorrhage in children treated for acute lymphoblastic leukaemia--a dual-centre experience J Pediatr Gastroenterol Nutr 2006 42 5 535 538 16707977 \n19. Ferlitsch A Teml A Reinisch W 6-thioguanine associated nodular regenerative hyperplasia in patients with inflammatory bowel disease may induce portal hypertension Am J Gastroenterol 2007 102 11 2495 2503 17894846 \n20. Lemaitre M Kirchgesner J Rudnichi A Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease JAMA 2017 318 17 1679 1686 29114832 \n21. Beigel F Steinborn A Schnitzler F Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies Pharmacoepidemiol Drug Saf 2014 23 7 735 744 24788825 \n22. Bayoumy AB, Simsek M, Seinen ML, et al. The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review. Expert Opin Drug Metab Toxicol. 2020;16(2):111–23. 10.1080/17425255.2020.1719996.\n23. Seinen ML van Asseldonk DP Mulder CJ de Boer NK Dosing 6-thioguanine in inflammatory bowel disease: expert-based guidelines for daily practice J Gastrointestin Liver Dis 2010 19 3 291 294 20922194 \n24. Ansari A Elliott T Fong F Further experience with the use of 6-thioguanine in patients with Crohn’s disease Inflamm Bowel Dis 2008 14 10 1399 1405 18521912 \n25. Omer O, Salehi S, Loganayagam A. PTH-079 6-thioguanine as an alternative therapy in inflammatory bowel disease? - experience in a London district general hospital. Gut. 2016;65:A258.\n26. Simsek M de Boer NKH Mulder CJJ Continued development of drugs: the path of thioguanine Ned Tijdschr Geneeskd 2018 162 D1757 29350120 \n27. Bayoumy AB de Boer NKH Ansari AR Crouwel F Mulder CJJ Unrealized potential of drug repositioning in Europe during COVID-19 and beyond: a physician’s perspective J Pharm Policy and Pract 2020 13 1 45 32695427 \n28. Simsek M Meijer B van Bodegraven AA de Boer NKH Mulder CJJ Finding hidden treasures in old drugs: the challenges and importance of licensing generics Drug Discov Today 2018 23 1 17 21 28867540 \n29. Satsangi J Silverberg MS Vermeire S Colombel JF The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications Gut 2006 55 6 749 753 16698746 \n30. U.S. Department Of Health And Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed 4 Jan 2020.\n31. 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 J Clin Epidemiol 2008 61 4 344 349 18313558 \n32. National Health Service of UK. http://www.hra-decisiontools.org.uk/research/. Accessed 1 Mar 2019.\n33. Morris K Revising the Declaration of Helsinki Lancet (London, England) 2013 381 9881 1889 1890 \n34. Meijer B Mulder CJ Peters GJ van Bodegraven AA de Boer NK Efficacy of thioguanine treatment in inflammatory bowel disease: a systematic review World J Gastroenterol 2016 22 40 9012 9021 27833392 \n35. Dubinsky MC Vasiliauskas EA Singh H 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients Gastroenterology 2003 125 2 298 303 12891528 \n36. van Asseldonk DP Jharap B Verheij J The prevalence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with thioguanine is not associated with clinically significant liver disease Inflamm Bowel Dis 2016 22 9 2112 2120 27482972 \n37. De Boer NK Tuynman H Bloemena E Histopathology of liver biopsies from a thiopurine-naive inflammatory bowel disease cohort: prevalence of nodular regenerative hyperplasia Scand J Gastroenterol 2008 43 5 604 608 18415755 \n38. Wanless IR Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules Hepatology (Baltimore, Md) 1990 11 5 787 797 \n39. Vernier-Massouille G Cosnes J Lemann M Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine Gut 2007 56 10 1404 1409 17504943 \n40. Musumba CO Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy Aliment Pharmacol Ther 2013 38 9 1025 1037 24099468 \n41. van Asseldonk DP Simsek M de Boer NKH Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients Scand J Gastroenterol 2019 54 6 753 760 31203688 \n42. Simsek M Meijer B Ramsoekh D Clinical course of nodular regenerative hyperplasia in Thiopurine treated inflammatory bowel disease patients Clin Gastroenterol Hepatol 2019 17 3 568 570 29775790 \n43. Morris JM Oien KA McMahon M Nodular regenerative hyperplasia of the liver: survival and associated features in a UK case series Eur J Gastroenterol Hepatol 2010 22 8 1001 1005 20075739 \n44. Akbari M Shah S Velayos FS Mahadevan U Cheifetz AS Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease Inflamm Bowel Dis 2013 19 1 15 22 22434610 \n45. Simsek M, Lambalk CB, Wilschut JA, Mulder CJJ, de Boer NKH. The associations of thiopurines with male fertility and paternally exposed offspring: a systematic review and meta-analysis. Hum Reprod Update. 2018;24(2):192–206. 10.1093/humupd/dmx034.\n46. van den Berg SA de Boer M van der Meulen-de Jong AE Safety of tioguanine during pregnancy in inflammatory bowel disease J Crohns Colitis 2016 10 2 159 165 26503525 \n47. Ansari A Hassan C Duley J Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease Aliment Pharmacol Ther 2002 16 10 1743 1750 12269967\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-230X",
"issue": "20(1)",
"journal": "BMC gastroenterology",
"keywords": "Crohn’s disease; Drug repositioning; Drug survival; IBD; Thioguanine; Thiopurines; Ulcerative colitis",
"medline_ta": "BMC Gastroenterol",
"mesh_terms": "D001379:Azathioprine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D008297:Male; D015122:Mercaptopurine; D004364:Pharmaceutical Preparations; D012189:Retrospective Studies; D013866:Thioguanine; D016896:Treatment Outcome; D006113:United Kingdom",
"nlm_unique_id": "100968547",
"other_id": null,
"pages": "296",
"pmc": null,
"pmid": "32917155",
"pubdate": "2020-09-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "16698746;20393175;24322839;17504943;20922194;20650924;23973853;26271196;29114832;25370731;16707977;29190351;12269967;23734387;28940780;29298871;27833392;32695427;18415755;20075739;24788825;29350120;18521912;30349479;26503525;27482972;18043678;17894846;18313558;28588888;24099468;27856614;12891528;22233693;31203688;30195449;2189821;22434610;28867540;31094013;25230165;32090622;29775790;16226335",
"title": "Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom.",
"title_normalized": "efficacy safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease a retrospective multi centre study in the united kingdom"
} | [
{
"companynumb": "NL-MYLANLABS-2020M1097347",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Preeclampsia is a hypertensive disorder of pregnancy that can involve dangerous neurological symptoms such as spontaneous seizures (eclampsia). Despite being diseases specific to the pregnant state, preeclampsia and eclampsia have long-lasting neurological consequences later in life, including changes in brain structure and cognitive decline at relatively young ages. However, the effects of preeclampsia on brain regions central to memory and cognition, such as the hippocampus, are unclear. Here, we present a case reporting the progressive and permanent cognitive decline in a woman that had eclamptic seizures in the absence of evidence of brain injury on MRI. We then use rat models of normal pregnancy and preeclampsia to investigate mechanisms by which eclampsia-like seizures may disrupt hippocampal function. We show that experimental preeclampsia causes delayed memory decline in rats and disruption of hippocampal neuroplasticity. Further, seizures in pregnancy and preeclampsia caused acute memory dysfunction and impaired neuroplasticity but did not cause acute neuronal cell death. Importantly, hippocampal dysfunction persisted 5 weeks postpartum, suggesting seizure-induced injury is long lasting and may be permanent. Our data provide the first evidence of a model of preeclampsia that may mimic the cognitive decline of formerly preeclamptic women, and that preeclampsia and eclampsia affect hippocampal network plasticity and impair memory.",
"affiliations": "Dept. of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT, 05405, USA. Electronic address: Abbie.Johnson@med.uvm.edu.;Dept. of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT, 05405, USA. Electronic address: zhaojin.li@med.uvm.edu.;Dept. of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Electronic address: JAMES.ORFILA@CUANSCHUTZ.EDU.;Dept. of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; Dept. of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Electronic address: PACO.HERSON@CUANSCHUTZ.EDU.;Dept. of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT, 05405, USA; Dept. of Pharmacology, University of Vermont Larner College of Medicine, Burlington, VT, 05405, USA; Dept. of Ob/Gyn & Repro Sciences, University of Vermont Larner College of Medicine, Burlington, VT, 05405, USA. Electronic address: Marilyn.Cipolla@med.uvm.edu.",
"authors": "Johnson|Abbie C|AC|;Li|Zhaojin|Z|;Orfila|James E|JE|;Herson|Paco S|PS|;Cipolla|Marilyn J|MJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.pneurobio.2020.101938",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0082",
"issue": "199()",
"journal": "Progress in neurobiology",
"keywords": "Early-onset dementia; Eclamptic seizures; Hippocampal neuroplasticity; Preeclampsia; Pregnancy",
"medline_ta": "Prog Neurobiol",
"mesh_terms": null,
"nlm_unique_id": "0370121",
"other_id": null,
"pages": "101938",
"pmc": null,
"pmid": "33130230",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "31088235;18495165;26949992;28894390;22703533;16904707;27830035;21778438;19641122;28235810;27555797;26241030;30858526;26402108;24495666;17725510;27878553;29705580;27815419;11566964;26203257;28322777;22510460;20028732;20174493;28320269;14615299;7819845;16540568;25409522;17785184;19772866;29283314;20164351;9663798;18382865;11275024;26218425;10536256;29995746;23171682;30587515;17904961;24094294;25012371;15217342;18667149;29740398;23230281;29288747;18843184;19104003;22701110;23313318;9011608;26103801;25228809;25452021;12583607;24267647;17610586;30571227;31285847;19398652;2908124;20598363;14715912;15143284;11978838;22728575;22561640",
"title": "Hippocampal network dysfunction as a mechanism of early-onset dementia after preeclampsia and eclampsia.",
"title_normalized": "hippocampal network dysfunction as a mechanism of early onset dementia after preeclampsia and eclampsia"
} | [
{
"companynumb": "US-TEVA-2021-US-1928819",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
"drugadditional": "3",
... |
{
"abstract": "In patients with renal insufficiency or hypersensitivity to iodinated contrast material, carbon dioxide gas (CO2) is generally considered a safe alternative contrast media for digital subtraction angiography. However, we herein report a previously undescribed fatal complication of CO2 angiography in a patient with acute renal dysfunction and congestive heart failure. The possible pathogenetic mechanisms of this complication are discussed.",
"affiliations": "Department of Radiology, Westchester County Medical Center, Valhalla, NY 10595, USA.",
"authors": "Rundback|J H|JH|;Shah|P M|PM|;Wong|J|J|;Babu|S C|SC|;Rozenblit|G|G|;Poplausky|M R|MR|",
"chemical_list": "D003287:Contrast Media; D002245:Carbon Dioxide",
"country": "United States",
"delete": false,
"doi": "10.1016/s0741-5214(97)70198-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-5214",
"issue": "26(2)",
"journal": "Journal of vascular surgery",
"keywords": null,
"medline_ta": "J Vasc Surg",
"mesh_terms": "D000368:Aged; D000792:Angiography; D002245:Carbon Dioxide; D003287:Contrast Media; D017809:Fatal Outcome; D006801:Humans; D007238:Infarction; D007422:Intestines; D008297:Male; D012206:Rhabdomyolysis; D017445:Skin Diseases, Vascular",
"nlm_unique_id": "8407742",
"other_id": null,
"pages": "337-40",
"pmc": null,
"pmid": "9279324",
"pubdate": "1997-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Livedo reticularis, rhabdomyolysis, massive intestinal infarction, and death after carbon dioxide arteriography.",
"title_normalized": "livedo reticularis rhabdomyolysis massive intestinal infarction and death after carbon dioxide arteriography"
} | [
{
"companynumb": "US-ALSI-201800235",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBON DIOXIDE"
},
"drugadditional": null,
... |
{
"abstract": "Valproic acid (VPA) is a commonly used agent in the management of seizures and psychiatric disorders. Hyperammonemia is a common complication of VPA with 27.8% of patients having elevated levels - that is unrelated to hepatotoxicity and normal transaminases. Common side effects include obesity, insulin resistance, metabolic disorder and severe forms of hepatotoxicity. Other rare and idiosyncratic reactions have been reported, one of which is presented in our case. A 27-year old patient presented with hyperammonemia and encephalopathy as a consequence of idiosyncratic VPA reaction causing drug-induced liver injury (DILI) with severely elevated transaminases. DILI is commonly overlooked when investigating encephalopathy in the setting of VPA. Physicians should consider DILI in the context of hyperammonemia and transaminitis.",
"affiliations": "Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USA.;Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USA.;Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USA.;Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USA.;Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USA.;Department of Medicine, Wayne State University/Detroit Medical center, Detroit, MI, USA.",
"authors": "Gayam|Vijay|V|0000-0001-5194-9134;Mandal|Amrendra Kumar|AK|;Khalid|Mazin|M|0000-0003-4868-4299;Shrestha|Binav|B|0000-0002-6839-4726;Garlapati|Pavani|P|;Khalid|Mowyad|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/20009666.2018.1514933",
"fulltext": "\n==== Front\nJ Community Hosp Intern Med PerspectJ Community Hosp Intern Med PerspectZJCHzjch20Journal of Community Hospital Internal Medicine Perspectives2000-9666Taylor & Francis 151493310.1080/20009666.2018.1514933Case ReportValproic acid induced acute liver injury resulting in hepatic encephalopathy- a case report and literature review V. GAYAM ET AL.JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVEShttp://orcid.org/0000-0001-5194-9134Gayam Vijay aMandal Amrendra Kumar ahttp://orcid.org/0000-0003-4868-4299Khalid Mazin ahttp://orcid.org/0000-0002-6839-4726Shrestha Binav aGarlapati Pavani aKhalid Mowyad ba Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USAb Department of Medicine, Wayne State University/Detroit Medical center, Detroit, MI, USACONTACT Vijay Gayam vgayam@interfaithmedical.comDepartment of Medicine, Interfaith Medical Center, Brooklyn, NY, 11213, USA2018 15 10 2018 8 5 311 314 08 5 2018 14 8 2018 © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.2018The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nValproic acid (VPA) is a commonly used agent in the management of seizures and psychiatric disorders. Hyperammonemia is a common complication of VPA with 27.8% of patients having elevated levels – that is unrelated to hepatotoxicity and normal transaminases. Common side effects include obesity, insulin resistance, metabolic disorder and severe forms of hepatotoxicity. Other rare and idiosyncratic reactions have been reported, one of which is presented in our case. A 27-year old patient presented with hyperammonemia and encephalopathy as a consequence of idiosyncratic VPA reaction causing drug-induced liver injury (DILI) with severely elevated transaminases. DILI is commonly overlooked when investigating encephalopathy in the setting of VPA. Physicians should consider DILI in the context of hyperammonemia and transaminitis.\n\nKEYWORDS\nValproic aciddrug-induced liver injuryliver failurehyperammonemiahepatic encephalopathy\n==== Body\n1. Introduction\nValproic acid (VPA) is a commonly used agent in the management of seizures and psychiatric disorders [1, 2]. VPA has a well-studied side effect profile, including obesity, insulin resistance, metabolic disorder and severe forms of hepatotoxicity [3]. Elevated transaminase levels have been reported in up to 5–10% of patients while hyperammonemia is more common with 27.8% of patients [3–5]. Hyperammonemia appears to be unrelated to hepatotoxicity with most patients having normal transaminases. We present a 27-year old patient who presented with hyperammonemia and encephalopathy as a consequence of an acute drug-induced liver injury (DILI) with severely elevated transaminases. VPA is a simple eight carbon branched-chain carboxylic acid with properties of a weak acid; which has been attributed to blocking the voltage-gated sodium channels and increasing brain levels of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter [6].\n\n2. Case presentation\nA 27-year-old male of African descent was brought to the emergency department for altered mental status. He complained of increased sleepiness for three days, which was associated with fatigue and anorexia. The patient denied any complaints of fever, chills, nausea, vomiting, headaches, abdominal pain/tenderness, diarrhea or constipation. His documented past medical history included asthma, chronic marijuana use, chronic tobacco use, bipolar disorder, schizoaffective disorder, and multiple suicide attempts. Haloperidol, benztropine, and aripiprazole were his regular home medications. He was discharged on oral VPA from a psychiatric facility one week before his presentation.\n\nVitals signs at presentation included a temperature of 98.2 degrees Fahrenheit, blood pressure of 117/82 mmHg, heart rate of 70 beats per minute and a respiratory rate of 20 beats per minute. The physical examination was notable for somnolence with ataxic gait, scleral icterus, and prominent asterixis. There was no lymphadenopathy, organomegaly, palmar erythema, gynecomastia, shifting dullness, or spider angioma. Kernig’s and Brudzinski’s signs were negative. Remarkable labs included an aspartate aminotransferase (AST) level of 12,000 IU/L (8–48 IU/L), alanine aminotransferase (ALT) of 7,000 IU/L (7–55 IU/L), ammonia of 184µmol/L (15–45 µmol/L), an alkaline phosphatase (ALP) of 96 IU/L (45–115 IU/L) and total bilirubin of 1.5 mg/dL (0.1–1.2 mg/dL). The patient had thrombocytopenia of 87,000 µL (150 to 450 µL) and coagulopathy with INR 2.40. Abdominal ultrasound and computed tomography of the head were both unremarkable. All viral hepatitis serology and toxicology panel including acetaminophen were negative except for a blood ethyl alcohol level of 9 mg/dl (0–5 mg/dl); which was also reflected in urine toxicology with the absence of other commonly tested substances.\n\nGiven the patient presentation, we suspected an adverse drug reaction (ADR) to VPA. Hence, we discontinued VPA and started on lactulose for hyperammonemia. On further exploration of his history, he reported previous use of VPA which was discontinued as he did not tolerate it, but no specific diagnoses or drug reaction was documented. After the second day of discontinuing VPA, liver function tests (LFTs) were trending downward (Figure 1) and his clinical symptomology of hyperammonemia had improved; expressed by marked improvement of his mental status with minimal asterixis. By the eighth day, his ALT and AST levels dropped to 634 and 61 respectively, and his total bilirubin was within the reference range at 0.8 mg/dL. Platelet count and INR returned to normal levels. Based on his clinical course and laboratory values, a final diagnosis of VPA induced DILI resulting in hepatic encephalopathy was made. In our case, the temporal relation of the drug history and the clinical profile was strongly suggestive of adverse drug reaction to VPA and thereafter no further evaluation for any other etiologies was required.10.1080/20009666.2018.1514933-F0001Figure 1. Serum transaminase levels during hospitalization.\n\n\n\n3. Discussion\nVPA has been used for seizure disorders, mood disorders, and migraine since the 1960s because of its efficacy and safety profile. However, it is not without side effects including hepatotoxicity, whose precise mechanism is still not established. Oxidative stress and some genetic factors have been speculated widely as the key mechanisms for hepatotoxicity [7]. Microvesicular hepatosteatosis is a typical feature of VPA toxicity and is suggestive of mitochondrial involvement especially involving the β-oxidation [8]. The recent study by Komulainen et al. showed the effects of VPA on mitochondria using the HepG2 cell in vitro model and further suggested an essential role of mitochondria; VPA inhibited mitochondrial respiration resulting in mitochondrial dysfunction, oxidative stress, and increased cell death [9,10]. Other speculated mechanisms are lysosomal membrane leakiness, inhibition of pyruvate uptake, carnitine deficiency, drug-induced coenzyme A deficiency and rapid hepatocyte glutathione (GSH) depletion [11–13]. Syndromes like Alpers-Huttenlocher syndrome (AHS), a neurometabolic disorder resulting from the mutation in mitochondrial DNA polymerase gamma (POLG), is associated with increased risk of developing VPA associated hepatotoxicity [14,15].\n\nThere are two types of Drug-i+nduced liver injury (DILI) Type I and Type II. Type I being dose-dependent toxicity with transient elevation of the liver function tests and VPA can be safely used if the levels are moderately increased. Our case is consistent with type II DILI in which there is idiosyncratic drug reaction with delayed onset of weeks to months following initial exposure.\n\nHyperammonemia is one of the common side effects of VPA which is thought to be due to inhibition of carbamoylphosphate synthetase-I, which commences the urea cycle [16]. Although asymptomatic, hyperammonemia is common and was reported as high as 51.2% by Raja et al. and Azzoni et al. VPA induced hyperammonemic encephalopathy (VHE) is unusual. VHE is thought to be mediated by inhibition of in glutamate uptake by astrocytes which lead to cerebral edema [16–18]. Glutamine production is increased but their release is inhibited in astrocyte exposed to ammonia [19].\n\nDILI, on the other hand, is also a rare etiology which also presents in very similar clinical symptoms. DILI in psychiatric patients is a clinically challenging diagnosis due to multiple medications. Clinicians must be vigilant and maintain a high level of suspicion when encountered with abnormal liver function tests in patients taking psychiatry mediations. In cases presenting with abnormal LFTs, like in ours, DILI should be among top differentials. Most of the cases presenting as VHE have been reported with normal or near normal LFTs [20–22].While hyperammonemia can be attributed to other causes, such as polypharmacy since our patient was also on haloperidol, benztropine, and aripiprazole; but the elevated LFTs make the diagnosis of DILI more likely.\n\nAs an essential part of adverse drug reaction (ADR), causality assessment was done using the Naranjo scale and RHUCAM score [23,24]. Naranjo scale concluded a definitive ADR with a score of 10 (> 9 is definitive) as shown in (Table 1). The RHUCAM score was calculated in our study with the following scores. Hepatocellular, second exposure, onset of < 5 days(+ 1), time from withdrawal of drug until reaction onset < 15 days (+ 1), risk factors being alcohol (+ 1), age < 55 (0), > 50% improvement in 8 days (+ 3), no concomitant therapy (0), excluded non drug-related causes: rule out (+ 2), response to re-administration positive (+ 3) with total score of 11 indicating ‘Highly Probable’ (> 8).10.1080/20009666.2018.1514933-T0001Table 1. Naranjo nomogram for determining likelihood whether ADR is due to VPA rather than a result of other factors.\n\nComponents\tScore\t\n1. Previous conclusive reports on this reaction\t1\t\n2. Transaminases increase (> 100x) after the suspected drug was administered\t2\t\n3. Improvement in Transaminase levels when the drug was discontinued\t1\t\n4. The reappearance of the adverse event when the drug was re‐administered\t2\t\n5. Any alternative causes for the reaction\t2\t\n6. Placebo given\t0\t\n7. Drug detected in blood (or other fluids) in concentrations known to be toxic\t0\t\n8. The reaction more severe when the dose was increased or less severe when the dose was decreased\t0\t\n9. Any similar reaction to the same or similar drugs in any previous exposure\t1\t\n10. Adverse event confirmed by any objective evidence\t1\t\nSCORE\t9\t\n\n\nVPA in our patient was immediately stopped leading to the normalization of laboratory findings and rapid resolution of the neurological symptoms. Our case describes altered mental status, hyperammonemia, deranged LFTs as the presenting signs of DILI distinguishing it from VHE. Early diagnosis and management of DILI is very important as it has high mortality ranging from 11.7% to 17.3% [25]. Due to the poor prognosis of DILI, clinicians must do a thorough work up in the patient taking VPA with altered mental status as it may be a sign of DILI and unrelated to hyperammonemia. In VPA toxicity or any idiosyncratic reactions, evaluation with renal function tests, serum glutamate level, serum carnitine level and screening for urea cycle disorders can be considered especially in VHE. There has been some evidence of potential benefit from carnitine-pantothenic acid in cases with VPA induced DILI [26–28].\n\n4. Conclusion\nAny patient on treatment with valproate, demonstrating features of cognitive impairment, focal neurological deficit, drowsiness, must be assessed for hyperammonemia and liver function tests. Early diagnosis and prompt withdrawal of sodium valproate may lead to clinical improvement in DILI.\n\nDisclosure statement\nNo potential conflict of interest was reported by the authors.\n\nInformed consent\nInformed consent was obtained from the patient.\n==== Refs\nReferences\n[1] Davis R , Peters DH , McTavish D. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy . Drugs . 1994 ;47 (2 ):332 –372 .7512905 \n[2] Wadzinski J. , Franks, R., Roane, D., et al \nValproate-associated hyperammonemic encephalopathy . J Am Board Fam Med . 2007 ;20 (5 ):499 –502 .17823470 \n[3] Nanau RM , Neuman MG \nAdverse drug reactions induced by valproic acid . Clin Biochem . 2013 ;46 (15 ):1323 –1338 .23792104 \n[4] Powell-Jackson P , Tredger J , Williams R \nHepatotoxicity to sodium valproate: a review . Gut . 1984 ;25 (6 ):673 –681 .6428980 \n[5] Tseng Y-L , Huang C-R , Lin C-H , et al \nRisk factors of hyperammonemia in patients with epilepsy under valproic acid therapy . Medicine . 2014 ;93 (11 ):e66.\n[6] Silva MF , Aires CCP , Luis PBM , et al \nValproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review . J Inherit Metab Dis . 2008 ;31 (2 ):205 –216 .18392741 \n[7] Chang TK , Abbott FS \nOxidative stress as a mechanism of valproic acid-associated hepatotoxicity . Drug Metab Rev . 2006 ;38 (4 ):627 –639 .17145692 \n[8] Begriche K , Massart J , Robin M-A , et al \nDrug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver . J Hepatology . 2011 ;54 (4 ):773 –794 .\n[9] Komulainen T , Lodge T , Hinttala R , et al \nSodium valproate induces mitochondrial respiration dysfunction in HepG2 in vitro cell model . Toxicology . 2015 ;331 :47 –56 .25745980 \n[10] Jafarian I , Eskandari MR , Mashayekhi V , et al \nToxicity of valproic acid in isolated rat liver mitochondria . Toxicol Mech Methods . 2013 ;23 (8 ):617 –623 .23819490 \n[11] Pourahmad J , Eskandari MR , Kaghazi A , et al \nA new approach on valproic acid induced hepatotoxicity: involvement of lysosomal membrane leakiness and cellular proteolysis . Toxicol In Vitro . 2012 ;26 (4 ):545 –551 .22342442 \n[12] Tong V , Teng XW , Chang TKH , et al \nValproic acid II: effects on oxidative stress, mitochondrial membrane potential, and cytotoxicity in glutathione-depleted rat hepatocytes . Toxicol Sci . 2005 ;86 (2 ):436 –443 .15858222 \n[13] Aires CCP , Soveral G , Luís PBM , et al \nPyruvate uptake is inhibited by valproic acid and metabolites in mitochondrial membranes . FEBS Lett . 2008 ;582 (23–24 ):3359 –3366 .18775709 \n[14] Li S , Guo J , Ying Z , et al \nValproic acid-induced hepatotoxicity in Alpers syndrome is associated with mitochondrial permeability transition pore opening-dependent apoptotic sensitivity in an induced pluripotent stem cell model . Hepatology . 2015 ;61 (5 ):1730 –1739 .25605636 \n[15] Stewart J.D. , Horvath R, Baruffini E, et al \nPolymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity . Hepatology . 2010 ;52 (5 ):1791 –1796 .21038416 \n[16] Verrotti A , Trotta D , Morgese G , et al \nValproate-induced hyperammonemic encephalopathy . Metab Brain Dis . 2002 ;17 (4 ):367 –373 .12602513 \n[17] Raja M , Azzoni A \nValproate-induced hyperammonaemia . J Clin Psychopharmacol . 2002 ;22 (6 ):631 –633 .12454569 \n[18] Carr RB , Shrewsbury K \nHyperammonemia due to valproic acid in the psychiatric setting . Am J Psychiatry . 2007 ;164 (7 ):1020 –1027 .17606652 \n[19] Takahashi H , Koehler RC , Brusilow SW , et al \nInhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats . Am J Physiology-Heart Circulatory Physiol . 1991 ;261 (3 ):H825 –H829 .\n[20] Patel N , Landry KB, Fargason RE, et al \nReversible encephalopathy due to valproic acid induced hyperammonemia in a patient with bipolar i disorder: a cautionary report . Psychopharmacol Bull . 2017 ;47 (1 ):40–44 .28138203 \n[21] Duarte J , Macias S , Coria F , et al \nValproate-induced coma: case report and literature review . Ann Pharmacother . 1993 ;27 (5 ):582 –583 .8347908 \n[22] Elwadhi D , Prakash R , Gupta M \nThe menacing side of valproate: a case series of valproate-induced hyperammonemia . Indian J Psychol Med . 2017 ;39 (5 ):668 .29200567 \n[23] Naranjo CA , Busto U , Sellers EM , et al \nA method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther . 1981 ;30 (2 ):239 –245 .7249508 \n[24] Andrade R.J. , Robles M, Fernández-Castañer A, et al \nAssessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists . World J Gastroenterol . 2007 ;13 (3 ):329 .17230599 \n[25] Devarbhavi H , Dierkhising R, Kremers WK, et al \nSingle-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality . Am J Gastroenterol. 2010 ;105(11):2396–2404.\n[26] Felker D , Lynn A , Wang S , et al \nEvidence for a potential protective effect of carnitine-pantothenic acid co-treatment on valproic acid-induced hepatotoxicity . Expert Rev Clin Pharmacol . 2014 ;7 (2 ):211 –218 .24450420 \n[27] Maldonado C , Guevara N , Silveira A , et al \nL-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: a case report . J Int Med Res . 2017 ;45 (3 ):1268 –1272 .28425821 \n[28] Raskind JY , El-Chaar GM \nThe role of carnitine supplementation during valproic acid therapy . Ann Pharmacother . 2000 ;34 (5 ):630 –638 .10852092\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2000-9666",
"issue": "8(5)",
"journal": "Journal of community hospital internal medicine perspectives",
"keywords": "Valproic acid; drug-induced liver injury; hepatic encephalopathy; hyperammonemia; liver failure",
"medline_ta": "J Community Hosp Intern Med Perspect",
"mesh_terms": null,
"nlm_unique_id": "101601396",
"other_id": null,
"pages": "311-314",
"pmc": null,
"pmid": "30356994",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "17606652;17145692;22342442;18775709;12602513;18392741;12454569;1679605;17823470;17230599;21145849;25605636;25192484;29200567;28425821;10852092;6428980;7512905;20648003;23792104;7249508;21038416;24450420;25745980;23819490;8347908;15858222;28138203",
"title": "Valproic acid induced acute liver injury resulting in hepatic encephalopathy- a case report and literature review.",
"title_normalized": "valproic acid induced acute liver injury resulting in hepatic encephalopathy a case report and literature review"
} | [
{
"companynumb": "US-CATALENT PHARMA SOLUTIONS-CAT-000065-2018",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BENZTROPINE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nSodium glucose cotransporter 2 (SGLT2) inhibitors are hypoglycemic agents characterized by a weight loss effect. This effect is likely to increase blood levels of other drugs. Reason for the report: SGLT2 inhibitor-induced weight reduction could bring unexpected side effects of other drugs whose blood concentrations are affected by body weight. However, this interaction between SGLT2 inhibitor and other drugs via weight loss effect has not been reported so far.\n\n\nMETHODS\nI describe the case of a 67-year-old male with bipolar I disorder who was treated with valproate. He was diagnosed with type 2 diabetes mellitus, started treatment with empagliflozin, and his body weight decreased gradually. Two months after he started empagliflozin, he developed hand tremor which was one of the symptoms of valproate intoxication, and his tremor was improved by dose reduction of valproate. It seemed that this symptom was brought mainly by weight loss effect of empagliflozin. These observations suggest the existence of a detour where blood concentrations of some drugs are increased by weight loss due to SGLT2 inhibitors. Clinicians need to be aware of the blood levels of drugs in patients with type 2 diabetes mellitus after starting SGLT2 inhibitors. Graphical abstract.",
"affiliations": "KACHI memorial hospital, Toyohashi, Aichi prefecture, Japan. orangetower@gmail.com.",
"authors": "Miyauchi|Tomoya|T|http://orcid.org/0000-0002-0276-6806",
"chemical_list": "D018692:Antimanic Agents; D001559:Benzhydryl Compounds; D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014635:Valproic Acid; C570240:empagliflozin",
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40199-020-00333-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1560-8115",
"issue": "28(1)",
"journal": "Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences",
"keywords": "Interaction; Intoxication; SGLT2 inhibitor; Valproate",
"medline_ta": "Daru",
"mesh_terms": "D000368:Aged; D018692:Antimanic Agents; D001559:Benzhydryl Compounds; D001714:Bipolar Disorder; D003924:Diabetes Mellitus, Type 2; D004347:Drug Interactions; D005960:Glucosides; D006801:Humans; D008297:Male; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014202:Tremor; D014635:Valproic Acid; D015431:Weight Loss",
"nlm_unique_id": "101125969",
"other_id": null,
"pages": "419-421",
"pmc": null,
"pmid": "32103459",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30572757;30285858;31235127;11532648;10594867;24995318;23850055;15013050;24939043;29866460;29328514;29165885;12269862;29185815;11958165;25825021;8010358",
"title": "Valproate intoxication in a patient with bipolar I disorder due to SGLT2 inhibitor-induced weight reduction.",
"title_normalized": "valproate intoxication in a patient with bipolar i disorder due to sglt2 inhibitor induced weight reduction"
} | [
{
"companynumb": "JP-BION-008608",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "1",
"drug... |
{
"abstract": "Tumor lysis syndrome (TLS) is an important oncological emergency that is usually observed with hematological malignancies and rarely with solid tumors. It can be induced either by therapy or spontaneously. Radiotherapy-induced TLS has been rarely reported in the literature. Here we present a patient with a diagnosis of metastatic prostate cancer and chronic lymphocytic leukemia complicated with TLS during palliative radiotherapy.",
"affiliations": "Ankara University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey Phone : +90 312 595 73 21, E-mail : alkanali@yahoo.com.",
"authors": "Alkan|Ali|A|;Kütük|Tuğçe|T|;Karcı|Ebru|E|;Yaşar|Arzu|A|;Hiçsönmez|Ayşe|A|;Utkan|Güngör|G|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/tjh.2015.0259",
"fulltext": "\n==== Front\nTurk J HaematolTurk J HaematolTJHTurkish Journal of Hematology1300-77771308-5263Galenos Publishing 2709389110.4274/tjh.2015.02591767Brief ReportRadiation-Induced Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia Kronik Lenfositik Lösemide Radyasyon İlişkili Tümör Lizis Sendromu Alkan Ali 1*Kütük Tuğçe 2Karcı Ebru 1Yaşar Arzu 1Hiçsönmez Ayşe 2Utkan Güngör 11 \nAnkara University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey\n2 \nAnkara University Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey\n* Address for Correspondence: Ankara University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey Phone: +90 312 595 73 21 E-mail: alkanali@yahoo.com9 2016 19 8 2016 33 3 248 250 2 7 2015 23 3 2016 © Turkish Journal of Hematology, Published by Galenos Publishing.\n\n2016This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Tumor lysis syndrome (TLS) is an important oncological emergency that is usually observed with hematological malignancies and rarely with solid tumors. It can be induced either by therapy or spontaneously. Radiotherapy-induced TLS has been rarely reported in the literature. Here we present a patient with a diagnosis of metastatic prostate cancer and chronic lymphocytic leukemia complicated with TLS during palliative radiotherapy.\n\nTümör lizis sendromu (TLS) sıklıkla hematolojik malignitelerde görülen, nadiren solid tümörlerde karşımıza çıkabilen bir onkolojik acildir. Tedavi ilişkili olabileceği gibi spontan olarak da ortaya çıkabilir. Radyasyon ilişkili TLS literatürde nadiren bildirilmiştir. Burada, kronik lenfositik lösemi ve prostat kanseri tanısıyla izlenen hastada palyatif radyoterapi ile indüklenen TLS olgusu sunulmaktadır.\n\nChronic lymphocytic leukemiaRadiationtumor lysis syndrome\n==== Body\nINTRODUCTION\nTumor lysis syndrome (TLS) is one of the important oncological emergencies in oncology practice, especially in lymphoproliferative malignancies. Aggressive solid tumors with shorter doubling time can be complicated with TLS. Although it is generally triggered by cytotoxic therapy, it can also be observed spontaneously in cases of bulky tumors. Radiation as a cause of TLS has been rarely reported in the literature [1,2,3]. Here we present a patient with 2 primary malignancies experiencing TLS during palliative radiotherapy.\n\nCASE PRESENTATION\nA 69-year-old male patient, without any comorbidities, presented with fullness in the left axilla. The initial examination showed lymphocytosis and lymphadenopathies in the bilateral axillary and inguinal region. There was neither hepatosplenomegaly nor pathological lymph nodes in the abdominal and thoracic cavity. Lymphocytosis and basket cells were seen in the blood smear. Excisional biopsy from the left axilla showed infiltration by CD5-positive cells. Immunohistochemistry was consistent with a diagnosis of chronic lymphocytic leukemia (CLL) infiltration. The bone marrow biopsies supported the diagnosis with hypercellularity and diffuse interstitial infiltration of small atypical lymphoid cells. The patient had been followed with a diagnosis of CLL for 2 years. Due to initial stage 1 disease, the patient had been periodically followed without medical therapy.\n\nIn a routine outpatient visit, the clinically asymptomatic patient was evaluated with lymph node excisional biopsy due to progression of the pathological lymph nodes in order to exclude Richter’s transformation. In addition, bone marrow sampling was performed. Pathology revealed small atypical lymphoid cells consistent with an ongoing lymphoproliferative disease and infiltration of an adenocarcinoma as a second primary malignancy. Further immunohistochemical staining was inconclusive for the origin of the tumor. The age of the patient, osteoblastic metastatic lesions detected in a bone scan, and prostate-specific antigen (PSA) level of 1712 ng/mL led us to order a work-up for prostate cancer. Transrectal prostate biopsy showed prostate adenocarcinoma with a Gleason score of 10. The patient was treated with goserelin (10.8 mg SC, every 12 weeks) and bicalutamide (50 mg daily). The analysis of bone scans before hormonal therapy showed metastatic lesions in the bilateral scapula, thoracic vertebral column, pelvis, bilateral humerus, and femur. For skeletal metastatic disease, zoledronic acid (4 mg intravenous, every 4 weeks) was started and palliative radiotherapy was planned for painful metastatic lesions in the thoracic vertebrae. Radiotherapy to T3-6 and the right scapula with a total of 30 Gy divided into 10 fractions was planned. Pathological lymph nodes associated with CLL, ranging between 1 and 3 cm in diameter in the bilateral inguinal areas, axilla, neck, and hilum, were noted for follow-up. On day 7 of radiotherapy the patient complained about mild nausea, progressive malaise, and perioral numbness. Physical examination was normal except for pathological lymph nodes with minimal regression and paleness. The largest lymph node in the right axilla had regressed from 3 to 2 cm and the other pathological nodes were stable. The hilar fullness in chest X-ray was stable. The only medications used were drugs for prostate cancer (bicalutamide and goserelin), lansoprazole for dyspepsia, and dexamethasone (8 mg), which was planned with the radiotherapy. The laboratory evaluation revealed acute renal failure complicated with TLS (Table 1). The PSA value was stable. The patient was hospitalized and aggressively hydrated with 0.9% NaCl at 500 mL/h in the first 6 h of follow-up with monitorization of hourly urine output. In the initial evaluation, due to hypocalcemia (5.2 mg/dL) with neuromuscular symptoms and prolonged QT interval of 0.50 s, the patient was treated with calcium gluconate replacement under cardiac monitorization. Laboratory results were checked at 4-h intervals. Until we could use rasburicase, allopurinol was the initial specific therapy for TLS. The dosage was titrated according to glomerular filtration rate and a 0.2 mg/kg single dose of rasburicase could be added to therapy on day 3 of hospitalization. The patient’s symptoms and renal dysfunction progressively improved (Table 1). The patient was free of any findings of infection or septicemia. The leukocytosis was linked to the dexamethasone therapy, which was planned during radiotherapy for anti-edema prophylaxis. After stopping the drug, leukocytosis improved. Analysis of the dose-volume histogram showed that during palliative radiotherapy to the thoracal vertebrae, mediastinal, axillary, and supraclavicular lymph nodes were also affected with maximums of 24.8 Gy (mean: 19.8), 34.2 Gy (mean: 20), and 28.1 Gy (mean: 19.1), respectively. A digitally reconstructed radiograph of the scapula field included axillary lymph nodes, supraclavicular lymph nodes, and the upper mediastinal lymph node area (Figure 1). After improvement of TLS, reanalysis of the patient for progression of CLL showed minimal regression of the pathological mediastinal and axillary lymph nodes. There was no progression in other lymph nodes or new organomegaly. With stable clinical findings of CLL and history of lymph node resection three months ago without any aggressive form of lymphoproliferative disease or Richter transformation, rebiopsy was not planned. After six months of follow-up the patient was stable for CLL and the PSA level progressively decreased.\n\nDISCUSSION AND REVIEW OF THE LITERATURE\nTLS is an oncological emergency that results from massive tumor lysis due to therapy or spontaneous bursting of tumor cells. The release of intracellular electrolytes into circulation causes an electrolyte imbalance and, as a result, acute renal failure. Intracellular nucleic acid catabolism and as a result hyperuricemia further contribute to renal dysfunction. The clinical presentation may range from nonspecific malaise and nausea to sudden cardiac death. TLS is diagnosed by both laboratory and clinical findings. Laboratory TLS is defined as the imbalance of two or more electrolytes (hypocalcemia, hyperuricemia, hyperphosphatemia, hyperkalemia), whereas clinical TLS is defined as laboratory TLS plus one clinical finding (increased creatinine, arrhythmia/sudden death, seizure) [4,5,6,7].\n\nIn the literature, radiation has been rarely reported as a cause of TLS. Most reported cases are associated with hematological pathologies and splenic radiation is the most often related scenario [8]. Total body irradiation before allogeneic stem cell transplantation has been related to TLS [9]. TLS as a complication of radiation in solid tumors has been rarely reported. Palliation of bone metastasis from malignant melanoma [10] and prostate carcinoma [3] has been discussed. The outcomes of the patients were good and there were no mortalities as a result of complications.\n\nAfter the diagnosis of a second primary tumor, palliative radiotherapy was indicated due to bone pain refractory to analgesia. The radiotherapy plan for the right scapula and thoracal vertebrae involved the right axilla and mediastinum incidentally, where pathological lymph nodes had been documented. The regression of axillary pathological lymph nodes and stable PSA values after radiotherapy led us to a link between TLS and the radiated pathological lymph nodes. CLL with a leukocyte value of <50,000/µL is accepted as low risk for TLS and there is no recommended precaution except for hydration [11]. Due to the absence of any therapy for CLL, there was no precaution for TLS.\n\nSimilar to the cases in the literature, our patient improved progressively with supportive care. To the best of our knowledge, our experience is the first reported TLS case related to radiation in a CLL patient. While our case gives important clues about a rare complication of radiation, it also reminds us of the importance of radiation planning in a patient with lymphadenopathies.\n\nEthics\nInformed Consent: It was taken.\n\nConcept: Ali Alkan, Tuğçe Kütük, Ebru Karcı, Arzu Yaşar, Ayşe Hiçsönmez, Güngör Utkan; Design: Ali Alkan, Tuğçe Kütük, Ebru Karcı, Arzu Yaşar, Ayşe Hiçsönmez, Güngör Utkan; Data Collection or Processing: Ali Alkan, Tuğçe Kütük, Ebru Karcı, Arzu Yaşar, Ayşe Hiçsönmez, Güngör Utkan; Analysis or Interpretation: Ali Alkan, Tuğçe Kütük, Ebru Karcı, Arzu Yaşar, Ayşe Hiçsönmez, Güngör Utkan; Literature Search: Ali Alkan, Tuğçe Kütük, Ebru Karcı, Arzu Yaşar, Ayşe Hiçsönmez, Güngör Utkan; Writing: Ali Alkan, Tuğçe Kütük, Ebru Karcı, Arzu Yaşar, Ayşe Hiçsönmez, Güngör Utkan.\n\nConflict of Interest: The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.\n\nTable 1 The laboratory parameters before and after radiotherapy and after treatment.\nFigure 1 Digitally reconstructed radiograph of the scapula field including axillary lymph nodes, supraclavicular lymph nodes, and the upper mediastinal lymph node area.\n==== Refs\nReferences\n1 Rostom AY El-Hussainy G Allam A Tumor lysis syndrome following hemi-body irradiation for metastatic breast cancer Ann Oncol 2000 11 1349 1351 11106126 \n2 Noh GY Choe DH Kim CH Lee JC Fatal tumor lysis syndrome during radiotherapy for non-small-cell lung cancer J Clin Oncol 2008 26 6005 6006 19029410 \n3 Kaplan MA Kucukoner M Alpagat G Isikdogan A Tumor lysis syndrome during radiotherapy for prostate cancer with bone and bone marrow metastases without visceral metastasis Ann Saudi Med 2012 32 306 308 22588444 \n4 Mirrakhimov AE Ali AM Khan M Barbaryan A Tumor Lysis Syndrome in Solid Tumors: An up to Date Review of the Literature Rare Tumors 2014 6 5389 25002953 \n5 Cairo MS Bishop M Tumour lysis syndrome: new therapeutic strategies and classification Br J Haematol 2004 127 3 11 15384972 \n6 Howard SC Jones DP Pui CH The tumor lysis syndrome N Engl J Med 2011 364 1844 1854 21561350 \n7 Wilson FP Berns JS Tumor lysis syndrome: new challenges and recent advances Adv Chronic Kidney Dis 2014 21 18 26 24359983 \n8 Chen SW Hwang WS Tsao CJ Liu HS Huang GC Hydroxyurea and splenic irradiation-induced tumourlysis syndrome: a case report and review of the literature J Clin Pharm Ther 2005 30 623 625 16336296 \n9 Fleming DR Henslee-Downey PJ Coffey C Radiation induced acute tumor lysis syndrome in the bone marrow transplant setting Bone Marrow Transplant 1991 8 235 236 1958906 \n10 Dar L Gendelman O Amital H Tumor lysis syndrome presenting in a patient with metastatic melanoma treated with radiation therapy Isr Med Assoc J 2014 16 456 457 25167696 \n11 Cairo MS Coiffier B Reiter A Recommendations for the evaluation of risk and prophylaxis of tumourlysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus Br J Haematol 2010 149 578 586 20331465\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1300-7777",
"issue": "33(3)",
"journal": "Turkish journal of haematology : official journal of Turkish Society of Haematology",
"keywords": null,
"medline_ta": "Turk J Haematol",
"mesh_terms": "D000368:Aged; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D015275:Tumor Lysis Syndrome; D014916:Whole-Body Irradiation",
"nlm_unique_id": "9606065",
"other_id": null,
"pages": "248-50",
"pmc": null,
"pmid": "27093891",
"pubdate": "2016-09-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24359983;22588444;16336296;11106126;25002953;15384972;25167696;21561350;19029410;20331465;1958906",
"title": "Radiation-Induced Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia.",
"title_normalized": "radiation induced tumor lysis syndrome in chronic lymphocytic leukemia"
} | [
{
"companynumb": "TR-BAUSCH-BL-2016-022703",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BICALUTAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment.\n\n\n\nWe used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy.\n\n\n\nDespite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel.\n\n\n\nWe show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.",
"affiliations": "Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester.;Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester.;Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester.;Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester.;The University of Manchester, The Christie NHS Foundation Trust, Manchester.;Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester.;Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester.;Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester.;Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester.;The University of Manchester, The Christie NHS Foundation Trust, Manchester.;Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester NHS Foundation Trust, Manchester, UK.;Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester.;Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester.;Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester.;The University of Manchester, The Christie NHS Foundation Trust, Manchester.;Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester richard.marais@cruk.manchester.ac.uk.",
"authors": "Gremel|G|G|;Lee|R J|RJ|;Girotti|M R|MR|;Mandal|A K|AK|;Valpione|S|S|;Garner|G|G|;Ayub|M|M|;Wood|S|S|;Rothwell|D G|DG|;Fusi|A|A|;Wallace|A|A|;Brady|G|G|;Dive|C|C|;Dhomen|N|N|;Lorigan|P|P|;Marais|R|R|",
"chemical_list": "D054316:Biomarkers, Pharmacological; D000073888:Cell-Free Nucleic Acids; D004273:DNA, Neoplasm; D000068877:Imatinib Mesylate; D016190:Carboplatin; D019009:Proto-Oncogene Proteins c-kit; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdw278",
"fulltext": "\n==== Front\nAnn OncolAnn. OncolannoncannoncAnnals of Oncology0923-75341569-8041Oxford University Press 10.1093/annonc/mdw278mdw278Original ArticlesPrecision MedicineEditor's choiceDistinct subclonal tumour responses to therapy revealed by circulating cell-free DNA Gremel G. 1Lee R. J. 1Girotti M. R. 1Mandal A. K. 1Valpione S. 2Garner G. 1Ayub M. 3Wood S. 13Rothwell D. G. 3Fusi A. 2Wallace A. 4Brady G. 3Dive C. 3Dhomen N. 1Lorigan P. 2Marais R. 1*1 Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester2 The University of Manchester, The Christie NHS Foundation Trust, Manchester3 Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester4 Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester NHS Foundation Trust, Manchester, UK* Correspondence to: Prof. Richard Marais, Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. Tel: +44-161-446-3100; E-mail: richard.marais@cruk.manchester.ac.uk10 2016 08 8 2016 08 8 2016 27 10 1959 1965 5 1 2016 1 5 2016 14 6 2016 12 7 2016 © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.The application of precision medicine requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment. We used next-generation sequencing of cfDNA to monitor therapy responses of a metastatic vaginal mucosal melanoma and show that cfDNA can be used to monitor tumour evolution and subclonal responses to therapy even when biopsies are not available.\n\nBackground\nThe application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment.\n\nPatients and methods\nWe used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy.\n\nResults\nDespite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel.\n\nConclusion\nWe show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.\n\nvaginal mucosal melanomacirculating cell-free DNAnext-generation sequencingclonal response to therapyWellcome Trust100282/Z/12/ZCancer Research UK Manchester InstituteC5759/A12328)\n==== Body\nintroduction\nMucosal melanoma is a rare disease that accounts for ∼1.1% of all melanomas and has an incidence of 2.3 per million person-years [1]. It is characterised by a low mutation burden and a prevalence of chromosomal and copy number aberrations [2, 3]. BRAF mutations are rare, but amplification or mutations in the receptor tyrosine kinase KIT occur in ∼40% of cases [3, 4]. KIT aberrations are also frequent in acral melanomas and cutaneous melanomas arising over chronically sun-damaged skin, prompting clinical trials of KIT inhibitors in KIT-mutant melanoma [4, 5]. A phase II study of 25 patients reported objective responses to the KIT inhibitor imatinib in 54% (7/13) of KIT-mutant patients, versus 0% in patients with KIT amplifications [6]. The most common sites of mucosal melanoma are sinonasal, anorectal and urogenital, and while primary vaginal melanomas are rare, possibly because melanocytes are only found in the vaginal mucosa of ∼3% of women, the outcome for these patients is particularly poor and clinical management guidelines have not yet been agreed [1, 7].\n\nPrecision medicine offers an opportunity to improve patient care, particularly in rare cancers where clinical trials are difficult due to small patient populations. The cornerstone of precision medicine is next-generation sequencing (NGS), which can provide unbiased identification of actionable mutations. These approaches are increasingly used in clinical settings, but require access to high-quality tumour samples and knowledge of the underlying genomic landscape of the tumour to be fully effective. However, due to its rarity and proclivity for metastasising to poorly accessible visceral sites, our knowledge of the genomics of vaginal mucosal melanoma is still limited. A possible way around these limitations is to analyse the DNA released by the tumour into the patient's blood. Critically, circulating cell-free DNA (cfDNA) can accurately reflect the genomic landscapes of solid tumours and has been used to follow patient responses to therapy [8, 9], but to date these studies have largely been limited to analysing mutations identified from previous sequencing campaigns, tumour biopsies, autopsy material or accessible metastatic sites [9–11], none of which are typically available in vaginal mucosal melanoma.\n\nWe describe a patient with KIT-mutant vaginal mucosal melanoma who received sequential targeted, immuno- and chemotherapy. Metastatic lesions were inaccessible for molecular analysis, so we carried out whole-exome sequencing (WES) and targeted longitudinal analysis of cfDNA to monitor the patient's response to therapy. We found that the patient presented two tumour subclones that responded differently to treatment. Moreover, the cfDNA analysis predicted response to therapy and progression several weeks before these were confirmed by radiological scans. Our study shows that the dynamic analysis of cfDNA can reveal tumour heterogeneity, clonal responses to treatment and tumour evolution even when metastatic lesions are inaccessible, illustrating the enormous potential of this approach in supporting precision medicine procedures.\n\npatients and methods\nDNA isolation\nEthical approval was granted by the Manchester Cancer Research Centre (MCRC) Biobank Access Committee (Protocol number 13RIMA01). The patient provided written informed consent. Extraction and quantification of cfDNA was carried out as described previously [12]. Germline DNA was extracted from the remaining whole blood fraction following centrifugation using QIAamp DNA Blood Mini kits (Qiagen, Valencia, CA) by the manufacturer's instructions. DNA from formalin-fixed, paraffin-embedded (FFPE) material was isolated using GeneRead DNA FFPE kits (Qiagen) by the manufacturer's instructions.\n\ntargeted re-sequencing\nA DNA fragment spanning KIT p.L576 (1 ng input cfDNA) or a multiplexed panel of 15 loci (2 ng input cfDNA) were PCR amplified using GeneRead DNAseq Panel PCR Kits V2 (Qiagen). Primer sequences and amplicon characteristics are summarised in supplementary Table S1, available at Annals of Oncology online. The multiplex PCR panel was designed using MPprimer [13], but specific primers could not be generated for UGT2B11 p.D458H. PCR reactions were carried out in a total volume of 40 or 50 μl (for single locus or multiplex amplifications, respectively) and contained 3 or 3.75 U of GeneRead HotStarTaq DNA polymerase (Qiagen) and a final concentration of 0.5 μM of each primer. The PCR programme included 1 cycle at 95°C for 15 min, 35 or 30 cycles of 95°C for 15 s, 55°C for 30 s and 60°C for 30 s and a final elongation step at 72°C for 10 min. PCR products were gel-purified using QIAquick Gel Extraction kits (Qiagen) and 50 or 200 ng used for library preparation. Sequencing libraries were prepared using the NEBNext Ultra DNA Library Prep Kit and NEBNext Multiplex Oligos for Illumina (New England Biolabs, Ipswich, MA) according to the manufacturer's instructions and processed on an Illumina MiSeq (Illumina, San Diego, CA).\n\nRaw reads were first processed using Cutadapt (v. 1.8.3) to clip Illumina adapters and PCR primers. Trimmomatic (v. 0.32) was used to filter out low quality reads. The quality control processed fastq were aligned to the human genome (GRCh37) using BWA (v. 0.7.7) and the GATK (v. 3.3) framework was used for realignment around InDels. Samtools (v. 0.1.19) was used to convert the final BAMs (binary form of alignment output) to pileup format. Variants identified from pileup files using VarScan (v. 2.3.6) were then annotated using Variant Effect Predictor (VEP) (v. 73).\n\nwhole-exome sequencing\nSequencing libraries were generated from 10 or 25 ng cfDNA, or 200 ng sheared germline DNA in Accel-NGS 2S DNA Library Kits for the Illumina Platform (Swift Biosciences, Ann Arbor, MI) by the manufacturer's instructions with the following modifications. Library amplification and indexing was carried out with KAPA HiFi HotStart PCR Kits (Kapa Biosystems, Wilmington, MA) and NEBNext Index Primers for Illumina (New England Biolabs). PCR-amplified libraries were quantified by Qubit 2.0 Fluorometer (Life Technologies, Carlsbad, CA) and 333 ng of each used for whole exome capture on SureSelectXT Reagent Kits (Agilent, Santa Clara, CA) by the manufacturer's instructions. Captured libraries were amplified using KAPA HiFi HotStart PCR Kits and PE1 (5′-AATGATACGGCGACCACCGAGATCT-3′)/PE2 (5′-CAAGCAGAAGACGGCATACGAGAT-3′) primer. Libraries were processed on an Illumina NextSeq (Illumina).\n\nRaw fastq files were processed to remove low-quality reads using Trimmomatic (v. 0.32) and the resultant fastq files aligned to the human genome (GRCh37) using BWA aligner (v. 0.7.7). Picard (v. 1.107) was used to mark PCR duplicates in the BAM files and subsequently, the GATK framework (v. 3.3) and the InDels from 1000 Genome consortia (phase I) and SNPs from dbSNP (release 38) were used to perform realignment and mapping quality score recalibration. Somatic single-nucleotide variations (SNVs) and InDels were identified by comparison to the germline DNA pileup file using VarScan software (v. 2.3.6). Finally, the mutations were annotated for genetic context using VEP (v. 73).\n\ncopy number analysis\nFor WES-based copy number analysis, per base read-depth coverage was generated from final BAM files using bedtools (v. 2.20.1) and ADTEX (v. 2.0) was used to identify regions with copy number alterations by comparing tumor and normal coverage files. Copy number calls were plotted in an exome-wide composite graph using R (v. 3.1.3). For droplet digital PCR, 25 ng DNA isolated from FFPE material or reference germline DNA were subjected to HIndIII/EcoRI (10 U each/reaction) double-restriction enzyme digestion in a total volume of 10 μl for 1 h at 37°C. After adding 90 μl of water, 8.8 μl of the reaction was combined with 11 μl ddPCR Supermix for Probes (No dUTP) (Bio-rad, Hercules, CA), 1.1 μl of KIT (Hs02812715_cn) or NLGN4X (Hs02584007_cn)-specific probe and 1.1 μl of TERT TaqMan Copy Number Reference Assay (all Thermo Fisher Scientific, Waltham, MA). Droplets were generated and analysed using the QX200 AutoDG Droplet Digital PCR system according to the manufacturer's instructions (Bio-rad). For cfDNA analysis, 2 ng cfDNA or reference germline DNA (sheared to ∼150 bp using an S2 series focused-ultrasonicator, Covaris, Woburn, MA) was used directly for analysis. All reactions were carried out in triplicate and repeated at least twice.\n\nthree-dimensional tumour measurements\nThe volumes of all metastatic lesions were estimated based on computed tomography (CT) image measurements using the formula for the volume calculation of ellipsoid shapes V = 4/3 × π(A/2)(B/2)(C/2), where A and B were the perpendicular diameters at maximum area representation on the axial plane and C was calculated from axial slices by multiplying the slice thickness (3 mm) by the number of slices between the cephalic and caudal tip of the metastasis.\n\nresults\nThe patient presented in her mid-40s with a vaginal vestibule mass, which a biopsy revealed to be a 14 mm thick, ulcerated melanoma with 29 mitoses/mm2. CT revealed an advanced tumour invading the rectum, so radical vaginovulvectomy, abdominoperineal resection and abdominal hysterectomy with bilateral salpingo-oophorectomy were carried out. Liver metastases developed 5 months later and following disease progression on dacarbazine (1000 mg/m2, two cycles), given that a KIT p.L576P mutation was present in the primary tumour biopsy, imatinib was administered (400 mg/day). The response to imatinib was mixed, with tumour reduction in an inguinal lymph node, but growth of a liver lesion and a new deposit appearing in the peritoneum, so imatinib was discontinued (Figure 1A–C; supplementary Figure S1, available at Annals of Oncology online).Figure 1. Levels of KIT p.L576P in the circulating cell-free DNA (cfDNA) respond to imatinib. (A) Overview of patient's treatment history, including information on initial diagnosis (35 weeks before follow-up) and surgery. Organ denominations indicate sites of metastatic disease as detected by computed tomography (CT) scans. Red font, progression; green font, response; DTIC, dacarbazine; Ipi., ipilimumab; Pembro., pembrolizumab. (B) Routine CT-generated images of the liver (top panels) and inguinal lymph node (bottom panels) at the indicated times. DTIC, dacarbazine; carbo./pacli., carboplatin/paclitaxel. (C) RECIST 1.1 measurements of a segment II liver metastasis and the inguinal (ing.) lymph node lesion during treatment with dacarbazine (D), imatinib (Im), ipilimumab (Ip), pembrolizumab (Pem) and carboplatin/paclitaxel (C/P) corresponding to (B). (D) Prospective quantification of KIT p.L576P VAF in cfDNA up to week 37. DTIC, dacarbazine.\n\n\n\nDue to disease progression in the liver, the patient received ipilimumab (3 mg/kg), but discontinued after only two cycles because of disease progression and grade 3 toxicity (Figure 1A–C, supplementary Figure S1, available at Annals of Oncology online). The patient also progressed on pembrolizumab (2 mg/kg, five cycles) with widespread intra-abdominal disease, but she responded to paclitaxel (175 mg/m2) and carboplatin (AUC 6), with a 60% reduction in target lesions size (by RECIST 1.1) after two cycles and further reduction in existing lesions and no new lesions on completion of this course of treatment (week 67; Figure 1B and C). The response to paclitaxel/carboplatin was accompanied by a reduction in lactate dehydrogenase from over five times the upper limit of normal to within the normal range. However, a scan at week 80 revealed progression with growth of the tumours in the liver and peritoneum, but not the nodal sites (Figure 1A–C, supplementary Figure S1, available at Annals of Oncology online), so paclitaxel (175 mg/m2) was reinitiated and led to a clear improvement in clinical symptoms.\n\nWe were intrigued by the patient's mixed response to imatinib, particularly because targeted sequencing of the cfDNA revealed complete suppression of KIT p.L576P in the presence of imatinib and then rebounding when imatinib was withdrawn (Figure 1D). Unfortunately, as is common with vaginal mucosal melanoma, the metastatic lesions were inaccessible in this patient and only FFPE samples from the primary tumour were available for analysis, so we carried out WES of cfDNA isolated at week 37 and compared it with DNA isolated from white blood cells. We analysed 10 and 25 ng of cfDNA to provide technical replicates, and this revealed 15 reproducible somatic SNVs (Figure 2A). We developed a custom multiplexed targeted sequencing panel to monitor these SNVs in the patient's cfDNA (supplementary Table S1, available at Annals of Oncology online) and confirmed excellent correlation between the variant allele frequencies (VAF) determined by this panel and WES (R2 = 0.9512, Figure 2B). Note that UGT2B11 p.D458H failed to amplify, so could not be assessed. We also observed excellent correlation between longitudinal KIT p.L576P analyses using the targeted single locus analysis and the multiplex panel (supplementary Figure S2, available at Annals of Oncology online). The results were reproducible in three independent week 37 cfDNA replicates, with a maximum VAF standard deviation of 1.62%, and germline readings not exceeding 0.27%, so a robust detection cut-off of 1% was set for subsequent analyses (supplementary Figure S3, available at Annals of Oncology online).Figure 2. Circulating cell-free DNA (cfDNA) reveals two tumour subclones with distinct responses to therapy. (A) Venn diagram showing single-nucleotide variations identified by whole-exome sequencing (WES) of cfDNA collected at week 37. The diagram shows the mutations detected in the 25 or 10 ng input samples, with common mutations in the intersection. KIT p.L576P is highlighted in red to confirm its identification in both WES runs. (B) Correlation of variant allele frequencies (VAFs) detected by WES or targeted sequencing in the week 37 cfDNA sample. WES-based VAFs represent average values of the two input DNA amounts. (C) VAFs of 14 mutations (see legend within the figure) in cfDNA from samples collected at the indicated times. VAFs of mutations in clusters 1 and 2 are connected by black and blue lines, respectively, and the treatments administered are indicated above the graph. DTIC, dacarbazine; Ipi., ipilimumab. (D) Copy number variation by chromosome (chr.) based on WES from the two different input cfDNA amounts isolated at week 37 of follow-up. Grey and red dots indicate allele loss (both and one, respectively), green dots indicate normal copy number state and blue and light blue dots indicate copy number gains (three and four or more copies, respectively).\n\n\n\nIntriguingly, longitudinal analysis of the patient's cfDNA revealed that the SNVs separated into two clusters with distinct responses to treatment (Figure 2C). Cluster 1 included eight SNVs and emerged during dacarbazine, disappeared under imatinib, returned on ipilimumab and pemprolizumab, and reduced again on carboplatin/paclitaxel (Figure 2C). Note that KIT p.L576P followed the same pattern as cluster 1, but at approximately fivefold higher VAF (Figure 2C). We carried out copy number analysis of the WES data and observed extensive regions of chromosomal loss and gain including focal amplification of KIT (Figure 2D). We confirmed the KIT amplification by droplet digital PCR (supplementary Figure S4, available at Annals of Oncology online) and reasoned that KIT p.L576P belonged to cluster 1, but had increased VAF due to gene amplification. Cluster 2 consisted of six SNVs, including SF3B1 p.R625H and also emerged under dacarbazine, but in contrast to cluster 1, it increased during imatinib (Figure 2C). During ipilimumab cluster 2 decreased, but contrary to cluster 1, it increased on pembrolizumab, before falling away during carboplatin/paclitaxel (Figure 2C). Only cluster 2 SNVs re-emerged after completion of the course of carboplatin/paclitaxel, predicting relapse of this clone 3 weeks before a CT confirmed the growth of tumours in the liver and peritoneum (Figures 1B and C and 2C and supplementary Figure S1, available at Annals of Oncology online). Note also that cluster 2 responded to paclitaxel re-administration and the commensurate improvement in clinical symptoms.\n\nThus, our longitudinal analysis revealed that the patient had two distinct tumour subclones that responded differently to treatment and the patterns of tumour and cfDNA responses suggest that cluster 1 is associated with the nodal disease, whereas cluster 2 is associated with the liver and peritoneal disease. To investigate the source of subclone heterogeneity in this patient, we carried out targeted sequencing of the diagnostic biopsy that was used to identify the KIT p.L576P mutation. We confirmed that all 14 assessable SNVs were present in this primary tumour sample (Figure 3A), but when we examined a second FFPE specimen taken during the patient's subsequent radical surgery, we only observed cluster 2 SNVs (Figure 3A), demonstrating that the second biopsy was dominated by the cluster 2 subclone.Figure 3. Analysis of the primary tumour reveals tumour heterogeneity. (A) Single-nucleotide variations in chromosomal DNA from the diagnostic biopsy of the primary tumour and the radical surgery 2 months after the initial biopsy. n.d., not detected. (B) Copy number determination of KIT and NLGN4X in the diagnostic biopsy and in tissue from the subsequent surgical excision when compared with germline DNA by using droplet digital PCR. ***P < 0.001.\n\n\n\nConsistent with the amplification of mutant KIT in the cluster 1 subclone, targeted sequencing revealed a high KIT p.L576P VAF in the clonally mixed diagnostic biopsy, but not the cluster 2-dominated surgery biopsy (Figure 3A). Unexpectedly, we also observed a high NLGN4X p.T134S VAF in the mixed-clone diagnostic biopsy (Figure 3A), but NLGN4X was not amplified during the cfDNA analysis (Figure 2D and supplementary Figure S4, available at Annals of Oncology online), so we carried out copy number analysis by droplet digital PCR. We confirmed the KIT amplification in the diagnostic biopsy, but not the surgery biopsy (Figure 3B) and while NLGN4X was not amplified in the diagnostic biopsy, we observed copy number loss in the surgery biopsy (Figure 3B). We conclude that the apparent high NLGN4X p.T134S VAF in the clonally mixed diagnostic biopsy is accounted for by the loss of a wild-type NLGN4X allele in the cluster 2 subclone.\n\ndiscussion\nWe report a case of KIT-mutant vaginal mucosal melanoma with a mixed response to imatinib that caused the drug to be withdrawn after only 8 weeks. Longitudinal cfDNA analysis revealed complete loss of KIT p.L576P under imatinib with a rapid return when imatinib was discontinued. Strikingly, this response coincided with shrinkage of a metastatic inguinal nodal lesion under imatinib and progression at this site when imatinib was discontinued, whereas the metastatic liver disease progressed through imatinib. It has been reported that cfDNA can reveal complex responses to therapy, but most previous studies have relied on targeted sequencing panels derived from biopsy or autopsy material, or knowledge of genomic landscapes of the tumours obtained from large sequencing campaigns [8, 9, 11, 14]. However, little is known about the mutational landscape of vaginal melanoma and, as is common in routine management of cancer patients, tumour biopsies from individual metastatic deposits were not available and primary tumour biopsies were preserved as FFPE specimens. Moreover, as the patient is still under treatment, autopsy biopsies were unavailable.\n\nTo overcome these challenges, we used WES of cfDNA to investigate the mechanism underlying the patient's mixed response to therapy and to search for potential therapeutic targets. Our analysis revealed that the patient presented with two tumour subclones that displayed distinct responses to targeted (imatinib) and immuno (pembrolizumab)-therapies. Importantly, targeted sequencing of the diagnostic biopsy did not reveal the presence of two subclones, and sequencing of the surgery biopsy revealed only one of the subclones. This illustrates the limitations in analysing solid tumour biopsies, as single biopsies cannot reveal subclonal mixtures in a tumour unless single-cell analysis is carried out. Moreover, single tumour biopsies may provide incomplete genetic information if there is subclonal dominance within the sampled region and, as in our case, this could result in actionable mutations being missed. Similarly, single cfDNA samples cannot reveal subclonal populations or their responses to therapy. However, the combination of WES and targeted longitudinal monitoring of the cfDNA revealed not only the presence of the individual subclones, but also their genetic constitution and distinct responses to therapy. Critically, we achieved this level of insight even though the patient's metastatic lesions were inaccessible.\n\nOur data are consistent with the mixed response to imatinib and indicate that it was effective, albeit in a single clone. We were not able to determine the relationship between the subclones and it is curious that they appeared not to share any common mutations. One possibility is that they were related through truncal drivers such as copy number gains and losses, fusion genes or epigenetic modifications that are characteristic of mucosal melanoma, but not revealed by longitudinal targeted sequencing. Alternatively, the clones may not have been related, but we confirmed that both were present in at least part of the primary tumour, suggesting that they emerged from the same site. Critically, irrespective of their origins, we identified potential therapeutic targets for both clones in the cfDNA; imatinib was effective against the cluster 1 clone, and a mutation in SF3B1, a component of the spliceosome and a validated drug target [15], was discovered in the cluster 2 clone.\n\nIn conclusion, we show that WES and longitudinal, targeted analysis of cfDNA can overcome the need for biopsies to reveal subclonal responses to treatment. Despite the clinical diagnosis of disease progression, we showed that imatinib controlled one subclone, and its withdrawal allowed this subclone to re-emerge. This suggests that imatinib would be a valid option for combination therapy for this patient, although targeted options for cluster 2 are not yet in the clinic and potential compound toxicity may limit the use of unproven combination therapies in patients. Our analysis also provided an early indication that both subclones responded to chemotherapy and it predicted relapse of one of the subclones before it was revealed by a radiological scan. The key to precision medicine is a better understanding of tumour complexity and the dynamics of response to treatment and we show that this can be provided by the analyses we carried out. Moreover, the approach is convenient for the patient, simple to implement and relatively inexpensive. Although alternative treatment options were not available for our patient, we provide an important proof of principle of how in-depth cfDNA analysis can improve patient care through implementation of personalised medicine.\n\nfunding\nThis work was supported by the Wellcome Trust (100282/Z/12/Z); and the Cancer Research UK Manchester Institute (C5759/A12328). SV was supported by the ESMO Clinical Research Fellowship with the aid of a grant from Novartis. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s) and do not necessarily reflect those of ESMO or Novartis.\n\ndisclosure\nThe authors have declared no conflicts of interest.\n\nSupplementary Material\nSupplementary Data\n acknowledgements\nWe thank the patient and her family. We thank the Molecular Biology Core Facility and Histology Core Facility at the CRUK Manchester Institute for assistance.\n==== Refs\nreferences\n1 Bishop KD , Olszewski AJ \nEpidemiology and survival outcomes of ocular and mucosal melanomas: a population-based analysis . Int J Cancer \n2014 ; 134 : 2961 –2971 .24272143 \n2 Curtin JA , Fridlyand J , Kageshita T et al \nDistinct sets of genetic alterations in melanoma . N Engl J Med \n2005 ; 353 : 2135 –2147 .16291983 \n3 Furney SJ , Turajlic S , Stamp G et al \nGenome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma . J Pathol \n2013 ; 230 : 261 –269 .23620124 \n4 Curtin JA , Busam K , Pinkel D , Bastian BC \nSomatic activation of KIT in distinct subtypes of melanoma . J Clin Oncol \n2006 ; 24 : 4340 –4346 .16908931 \n5 Carvajal RD , Antonescu CR , Wolchok JD et al \nKIT as a therapeutic target in metastatic melanoma . JAMA \n2011 ; 305 : 2327 –2334 .21642685 \n6 Hodi FS , Corless CL , Giobbie-Hurder A et al \nImatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin . J Clin Oncol \n2013 ; 31 : 3182 –3190 .23775962 \n7 Nigogosyan G , Delapava S , Pickren JW \nMelanoblasts in vaginal mucosa. Origin for primary malignant melanoma . Cancer \n1964 ; 17 : 912 –913 .14179553 \n8 Murtaza M , Dawson SJ , Pogrebniak K et al \nMultifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer . Nat Commun \n2015 ; 6 : 8760 .26530965 \n9 Garcia-Murillas I , Schiavon G , Weigelt B et al \nMutation tracking in circulating tumor DNA predicts relapse in early breast cancer . Sci Transl Med \n2015 ; 7 : 302ra133 .\n10 Jamal-Hanjani M , Wilson GA , Horswell S et al \nDetection of ubiquitous and heterogeneous mutations in cell-free DNA from patients with early-stage non-small-cell lung cancer . Ann Oncol \n2016 ; 27 : 862 –867 .26823523 \n11 Siravegna G , Mussolin B , Buscarino M et al \nClonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients . Nat Med \n2015 ; 21 : 827 .26151329 \n12 Girotti MR , Gremel G , Lee R et al \nApplication of sequencing, liquid biopsies, and patient-derived xenografts for personalized medicine in melanoma . Cancer Discov \n2016 ; 6 : 286 –299 .26715644 \n13 Shen Z , Qu W , Wang W et al \nMPprimer: a program for reliable multiplex PCR primer design . BMC Bioinform \n2010 ; 11 : 143 .\n14 Frenel JS , Carreira S , Goodall J et al \nSerial next-generation sequencing of circulating cell-free dna evaluating tumor clone response to molecularly targeted drug administration . Clin Cancer Res \n2015 ; 21 : 4586 –4596 .26085511 \n15 Bonnal S , Vigevani L , Valcarcel J \nThe spliceosome as a target of novel antitumour drugs . Nat Rev Drug Discov \n2012 ; 11 : 847 –859 .23123942\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0923-7534",
"issue": "27(10)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "circulating cell-free DNA; clonal response to therapy; next-generation sequencing; vaginal mucosal melanoma",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D054316:Biomarkers, Pharmacological; D016190:Carboplatin; D000073888:Cell-Free Nucleic Acids; D004273:DNA, Neoplasm; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000068877:Imatinib Mesylate; D008545:Melanoma; D008875:Middle Aged; D009154:Mutation; D017239:Paclitaxel; D057285:Precision Medicine; D019009:Proto-Oncogene Proteins c-kit; D014625:Vaginal Neoplasms; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1959-65",
"pmc": null,
"pmid": "27502704",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23123942;26311728;26530965;21642685;16291983;26151329;14179553;16908931;26823523;23775962;23620124;24272143;20298595;26085511;26715644",
"title": "Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA.",
"title_normalized": "distinct subclonal tumour responses to therapy revealed by circulating cell free dna"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1031755",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nTo analyze the response to dose-dense chemotherapy of weekly paclitaxel and 3-weekly carboplatin in recurrent ovarian cancer, and to report results of literature review.\n\n\nMETHODS\nPatients accepted weekly paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin on day1 at area under curve (AUC) 6 every 21 days were reviewed for the response rate, progression-free survival, overall survival, and toxicity during January 2012 to April 2016 in Chang Gung Memorial Hospital at Linkou, Taiwan.\n\n\nRESULTS\nSixteen patients with recurrent ovarian cancer, including 1 platinum-resistant, 7 partially platinum-sensitive, and 8 platinum-sensitive, accepted a median of 6 cycles of chemotherapy (range 3-10). The overall response rate (ORR) and complete response (CR) rate were 93.8%, and 62.5%, respectively. The median PFS of all patients were 10.9 months (range 4.3-40.5). The median time to response (TTR) was 29.0 days (range 19.6-38.4). The median disease-free survival (DFS) after CR was 5.6 months (range 1.2-34.2). Grade 3 at least toxicity included anemia (6.3%), neutropenia (50%), and thrombocytopenia (18.8%). Twenty-nine articles on phase I, II, III, or retrospective studies of dose-dense chemotherapy with weekly paclitaxel were reviewed.\n\n\nCONCLUSIONS\nThis is the first report using Japanese Gynecologic Oncology Group 3016 protocol, weekly paclitaxel and 3-weely carboplatin, on recurrent ovarian cancer. The current study showed high ORR and CR with tolerable toxicities. Our study suggested dose-dense chemotherapy with paclitaxel, especially combining carboplatin created high efficacy probably by anti-angiogenesis. However, consolidation or maintenance therapy is needed to prolong DFS.",
"affiliations": "Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Taiwan; Chang Gung University, College of Medicine, Taiwan.;Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Taiwan; Chang Gung University, College of Medicine, Taiwan.;Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Taiwan; Chang Gung University, College of Medicine, Taiwan.;Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Taiwan; Chang Gung University, College of Medicine, Taiwan. Electronic address: ma2012@cgmh.org.tw.",
"authors": "Chen|Wei-Chun|WC|;Huang|Huei-Jean|HJ|;Chang|Ting-Chang|TC|;Chou|Hung-Hsueh|HH|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.tjog.2019.10.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-4559",
"issue": "59(1)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "Carboplatin; Dose-dense chemotherapy; Metronomic chemotherapy; Recurrent ovarian cancer; Weekly paclitaxel",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D016190:Carboplatin; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D015996:Survival Rate; D013624:Taiwan; D016896:Treatment Outcome",
"nlm_unique_id": "101213819",
"other_id": null,
"pages": "21-27",
"pmc": null,
"pmid": "32039795",
"pubdate": "2020-01",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin for recurrent ovarian cancer.",
"title_normalized": "dose dense chemotherapy with weekly paclitaxel and 3 weekly carboplatin for recurrent ovarian cancer"
} | [
{
"companynumb": "TW-PFIZER INC-2020000796",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "<p>INTRODUCTION: Many options are available for patients with moderate to severe plaque psoriasis. Patients with moderate disease, however, are often undertreated and do not achieve satisfactory clearance. UNVEIL (NCT02425826) assessed efficacy and safety of apremilast in patients with chronic moderate plaque psoriasis.</p> <p>METHODS: Patients with psoriasis body surface area (BSA) 5% to 10% and static Physician's Global Assessment (sPGA) score of 3 (moderate) without prior exposure to systemics were randomized (2:1) to apremilast 30 mg twice daily or placebo for 16 weeks. The primary efficacy endpoint was mean percentage change in the product of sPGA and BSA scores (PGAxBSA).</p> <p>RESULTS: Of 221 patients (placebo, n=73; apremilast, n=148), >80% had received prior topical therapy. At week 16, apremilast yielded a significantly greater percentage change from baseline in PGAxBSA (-48.1%) vs placebo (-10.2^; P less than 0.0001). Dermatology Life Quality Index scores were significantly improved with apremilast (-4.8) vs placebo (-2.4; P=0.0008). Mean improvements in the Treatment Satisfaction Questionnaire for Medication, version II, were greater with apremilast vs placebo for global satisfaction (63.2 vs 48.7; P less than 0.0001) and treatment effectiveness (57.3 vs 38.8; P less than 0.0001). Most adverse events were mild or moderate; most common were diarrhea, headache, nausea, upper respiratory tract infection, decreased appetite, and vomiting.</p> <p>CONCLUSION: Apremilast was effective and well tolerated, significantly improved quality of life, and was associated with high patient satisfaction in systemic-naive, post-topical patients with moderate plaque psoriasis.</p> <p>ClinicalTrials.gov: NCT02425826</p> <p><em>J Drugs Dermatol. 2017;16(8):801-808.</em></p>.",
"affiliations": null,
"authors": "Strober|Bruce|B|;Bagel|Jerry|J|;Lebwohl|Mark|M|;Stein Gold|Linda|L|;Jackson|J Mark|JM|;Chen|Rongdean|R|;Goncalves|Joana|J|;Levi|Eugenia|E|;Callis Duffin|Kristina|K|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D013792:Thalidomide; C505730:apremilast",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "16(8)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D011788:Quality of Life; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D063189:Symptom Assessment; D013792:Thalidomide; D014481:United States",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "801-808",
"pmc": null,
"pmid": "28809995",
"pubdate": "2017-08-01",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Efficacy and Safety of Apremilast in Patients With Moderate Plaque Psoriasis With Lower BSA: Week 16 Results from the UNVEIL Study.",
"title_normalized": "efficacy and safety of apremilast in patients with moderate plaque psoriasis with lower bsa week 16 results from the unveil study"
} | [
{
"companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2022-05156",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREMILAST"
},
"druga... |
{
"abstract": "Human epidermal growth factor receptor 2 (HER-2) is a checkpoint, controlling cell proliferation and differentiation. Trastuzumab, a humanized monoclonal antibody directed against HER-2, is nowadays standard treatment for breast cancer patients whose tumors express HER-2. It is generally well tolerated, with a small number of patients developing mild adverse reactions. Dermatomyositis is a rare adverse event of trastuzumab therapy not well described in the literature. We herein present a case of a patient treated for hormone-sensitive invasive ductal carcinoma, who presented with symptoms of proximal muscle weakness, arthralgias, skin rash, and generalized fatigue. The symptoms started after the sixth cycle of trastuzumab and progressively deteriorated. The patient's medical and family history was unremarkable. Disease progression as a possible cause of dermatomyositis had been ruled out, and laboratory evaluation revealed moderate elevation of serum muscle proteins and acute-phase reactants. Trastuzumab treatment was discontinued, and 3 months later, the patient was free of symptoms without any further intervention.",
"affiliations": "3rd Department of Internal Medicine, Oncology Unit, Athens School of Medicine, Sotiria General Hospital, Athens, Greece.;3rd Department of Internal Medicine, Oncology Unit, Athens School of Medicine, Sotiria General Hospital, Athens, Greece.;3rd Department of Internal Medicine, Oncology Unit, Athens School of Medicine, Sotiria General Hospital, Athens, Greece.",
"authors": "Trontzas|Ioannis Panagiotis|IP|;Syrigos|Nikolaos Konstantinos|NK|;Kotteas|Elias Alexandros|EA|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jcrt.JCRT_209_19",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "17(4)",
"journal": "Journal of cancer research and therapeutics",
"keywords": "Anti-human epidermal growth factor receptor 2; breast cancer; dermatomyositis; drug-induced myopathies; trastuzumab",
"medline_ta": "J Cancer Res Ther",
"mesh_terms": null,
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "1112-1114",
"pmc": null,
"pmid": "34528573",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of trastuzumab-induced dermatomyositis.",
"title_normalized": "a case of trastuzumab induced dermatomyositis"
} | [
{
"companynumb": "GR-PFIZER INC-202101319882",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "We noted a recent increase in number of immunocompromised children with CMV viremia at our institution. The purpose of this study was to determine the frequency of CMV viremia in this population and evaluate factors associated with drug-resistant mutations. A retrospective review of immunocompromised hosts, 0-21 years of age, who had CMV viremia during 2007-2017. CMV viremia was detected using PCR assays. Genetic mutation assays were performed using PCR sequencing of the phosophotransferase UL 97 gene and the polymerase UL54 gene of CMV using Quest Diagnostics (San Juan Capistrano, CA, USA) or ARUP Labs (Salt Lake City, UT, USA). Thirty-one patients were identified, including 10 (32%) during the last 2 years. Of the 31 patients, 18 had hematopoietic stem cell transplantation (HSCT), 5 had primary immunodeficiency, 4 had malignancies, 3 had heart transplantation and 1 had new Human Immunodeficiency virus (HIV) infection. Antiviral resistance testing was performed on isolates from seven patients: five with persistent viremia (>1 mo), and two prior to starting antiviral therapy. Resistance was identified in three patients' isolates: two with common variable immunodeficiency (CVID) and one with recurrent Hodgkin's lymphoma who had undergone autologous HSCT. The two patients with CVID had chronic diarrhea and malabsorption and had received prolonged oral valganciclovir courses prior to emergence of resistance. The patient with Hodgkin's lymphoma had received a prolonged IV ganciclovir course. All three tested positive for UL97 mutation and two had both UL97 and UL54 gene mutations. Majority of our patients (21/31) with CMV viremia were transplant recipients and ganciclovir resistance developed in 10%. Two had intestinal malabsorption. Treatment with oral valganciclovir should be avoided in patients with poor gut absorption as that may increase the risk of resistance.",
"affiliations": "Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, USA.;Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, USA.;Carman and Ann Adams Department of Pediatrics, Wayne State University, Detroit, Michigan, USA.;Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, USA.",
"authors": "Kim|Edward|E|;Asmar|Basim I|BI|;Thomas|Ronald|R|;Abdel-Haq|Nahed|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2019.1695031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "37(2)",
"journal": "Pediatric hematology and oncology",
"keywords": "CMV; Children; immunocompromised; resistance; viremia",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003587:Cytomegalovirus; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D013997:Time Factors; D014766:Viremia; D055815:Young Adult",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "119-128",
"pmc": null,
"pmid": "31826701",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus viremia and resistance patterns in immunocompromised children: An 11-year experience.",
"title_normalized": "cytomegalovirus viremia and resistance patterns in immunocompromised children an 11 year experience"
} | [
{
"companynumb": "US-SLATE RUN PHARMACEUTICALS-SLTR-AE-19-129",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
... |
{
"abstract": "Red puffy hand syndrome is an uncommon clinical manifestation of intravenous drug abuse, which presents with bilateral, painless and non-pitting erythema and edema of the dorsal hands. The pathophysiology is believed to primarily be the result of lymphatic blockage from either direct toxicity of the injected drug, drainage of impurities, or infection complications. A woman in her 40's with remote intravenous drug use presented with over a decade of fixed, painless erythema and swelling of bilateral dorsal hands. Owing to an elevated rheumatoid factor, which would later be attributed to patient's untreated hepatitis C, these findings were mistaken for rheumatoid arthritis and unnecessarily treated with methotrexate and prednisone. Upon proper recognition of her underlying Red puffy hand syndrome, systemic medications were discontinued and appropriate care was initiated with lymphedema decongestion and occupational therapy. Red puffy hand syndrome, albeit rare, is an important manifestation of intravenous drug abuse; its recognition will spare patients from unnecessary systemic treatments.",
"affiliations": "Oregon Health & Science University, Department of Dermatology, Portland, OR. bartomi@ohsu.edu.",
"authors": "Barton|Michael|M|;Fett|Nicole|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "26(6)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000328:Adult; D001172:Arthritis, Rheumatoid; D003951:Diagnostic Errors; D004487:Edema; D005260:Female; D006225:Hand; D006801:Humans; D015819:Substance Abuse, Intravenous",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32815692",
"pubdate": "2020-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Red puffy hand syndrome mistaken for inflammatory arthritis.",
"title_normalized": "red puffy hand syndrome mistaken for inflammatory arthritis"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-05213",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"d... |
{
"abstract": "BACKGROUND\nTacrolimus is an immunosuppressive drug used to prevent acute rejection following organ transplantation and to treat autoimmune disease. Tacrolimus is usually prescribed in such situation at a dose of 3.0 mg/day. Pneumocystis pneumonia induced by this dose of tacrolimus has been reported in many cases; however, we encountered a rare case of Pneumocystis pneumonia induced by low-dose tacrolimus and methylprednisolone.\n\n\nMETHODS\nWe herein report the case of an 82-year-old Asian Japanese female with rheumatoid arthritis and Pneumocystis pneumonia who was being treated with low-dose tacrolimus and low-dose methylprednisolone therapy. She was diagnosed with rheumatoid arthritis at 52 years of age and was administered oral low-dose methylprednisolone and salazosulfapyridine. Her condition had been stable under this treatment for 30 years. However, her arthralgia worsened three months before admission. The salazosulfapyridine was changed to tacrolimus (0.5 mg/day) by her physician, and her arthralgia almost completely disappeared. She was admitted to our hospital for Pseudomonas pneumonia, and her symptoms improved almost completely with intravenous ceftazidime therapy. However, on the 14th day of admission, she developed acute respiratory failure due to Pneumocystis pneumonia and died on the 17th day of admission in spite of adequate treatment.\n\n\nCONCLUSIONS\nOur report highlights the importance of providing prompt prevention, diagnosis and treatment of Pneumocystis pneumonia in rheumatoid arthritis patients under tacrolimus and low-dose methylprednisolone therapy.",
"affiliations": "Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. mtkatou@juntendo.ac.jp.",
"authors": "Kato|Motoyasu|M|;Tobino|Kazunori|K|;Fujimoto|Yuichi|Y|;Kobayashi|Isao|I|;Sugano|Koji|K|;Tokuda|Hitoshi|H|;Ienaga|Hiroki|H|;Takahashi|Kazuhisa|K|",
"chemical_list": "D016559:Tacrolimus; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1186/1756-0500-6-498",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central 1756-0500-6-4982428928510.1186/1756-0500-6-498Case ReportPneumocystis pneumonia induced by treatment with low-dose tacrolimus and methylprednisolone in a patient with rheumatoid arthritis: a case report Kato Motoyasu 12mtkatou@juntendo.ac.jpTobino Kazunori 12tobino@juntendo.ac.jpFujimoto Yuichi 12yfujimo@juntendo.ac.jpKobayashi Isao 12isao-k@juntendo.ac.jpSugano Koji 12ksugano@juntendo.ac.jpTokuda Hitoshi 3tokuda@shahochu.jpIenaga Hiroki 12h_ienaga@mhp.koshigaya.saitama.jpTakahashi Kazuhisa 1kztakaha@juntendo.ac.jp1 Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan2 Department of Respiratory Medicine, Koshigaya Municipal Hospital, Koshigaya city, Saitama, Japan3 Department of Respiratory Medicine, Social Insurance General Central Hospital, Tokyo, Japan2013 1 12 2013 6 498 498 24 7 2013 27 11 2013 Copyright © 2013 Kato et al.; licensee BioMed Central Ltd.2013Kato 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\nTacrolimus is an immunosuppressive drug used to prevent acute rejection following organ transplantation and to treat autoimmune disease. Tacrolimus is usually prescribed in such situation at a dose of 3.0 mg/day. Pneumocystis pneumonia induced by this dose of tacrolimus has been reported in many cases; however, we encountered a rare case of Pneumocystis pneumonia induced by low-dose tacrolimus and methylprednisolone.\n\nCase presentation\nWe herein report the case of an 82-year-old Asian Japanese female with rheumatoid arthritis and Pneumocystis pneumonia who was being treated with low-dose tacrolimus and low-dose methylprednisolone therapy. She was diagnosed with rheumatoid arthritis at 52 years of age and was administered oral low-dose methylprednisolone and salazosulfapyridine. Her condition had been stable under this treatment for 30 years. However, her arthralgia worsened three months before admission. The salazosulfapyridine was changed to tacrolimus (0.5 mg/day) by her physician, and her arthralgia almost completely disappeared. She was admitted to our hospital for Pseudomonas pneumonia, and her symptoms improved almost completely with intravenous ceftazidime therapy. However, on the 14th day of admission, she developed acute respiratory failure due to Pneumocystis pneumonia and died on the 17th day of admission in spite of adequate treatment.\n\nConclusion\nOur report highlights the importance of providing prompt prevention, diagnosis and treatment of Pneumocystis pneumonia in rheumatoid arthritis patients under tacrolimus and low-dose methylprednisolone therapy.\n\nPneumocystis pneumoniaTacrolimusRheumatoid arthritis\n==== Body\nBackground\nTacrolimus is an immunosuppressive drug often administered to prevent acute rejection following organ transplantation and to treat autoimmune diseases (e.g., rheumatoid arthritis (RA), polymyositis/dermatomyositis and ulcerative colitis (UC)) and atopic dermatitis. Tacrolimus is usually administered at a dose of 3.0 mg/day for these diseases. This dose of tacrolimus can potentially generate an immunocompromised status, leading to opportunistic infections (e.g., fungal infection, Pneumocystis pneumonia (PCP) and cytomegalovirus infection). Our case of PCP was induced by low-dose tacrolimus (0.5 mg/day) and low-dose methylprednisolone (mPSL; 4.0 mg/day) administered in a RA patient. We herein report the first case of PCP caused by low-dose tacrolimus.\n\nCase presentation\nAn 82-year-old Asian Japanese female presented to our hospital with shortness of breath and was admitted for pneumonia. She had felt ill and had a cough for one week before admission. Her dyspnea had worsened and her cough had progressed with the development of hemosputum three days prior to presentation. Her past medical history was significant for RA and five prior admissions for pneumonia and bronchiectasis. She had been diagnosed with RA at 52 years of age and had been administered oral low-dose mPSL and salazosulfapyridine. Her general condition had been stable under this same treatment for 30 years; however, her arthralgia worsened three months before admission. The salazosulfapyridine was changed to low-dose tacrolimus (0.5 mg/day) by her physician, and her arthralgia almost completely disappeared. Her initial vital signs were as follows: body temperature, 38.0°C; blood pressure, 132/74 mmHg; heart rate 96 beats/minute; respiratory rate, 22 breaths/minute; and oxygen saturation (SpO2) on room air, 82%. A physical examination revealed stridor and bilateral basal expiratory wheezes. The laboratory test values were as follows: white blood cells, 8,400/μL with a left shift; lymphocytes, 740/μL; serum lactate dehydrogenase (LDH), 337 IU/L (normal, 130–220 IU/L); and serum C-reactive protein (CRP), 17.58 mg/dL (normal, < 0.3 mg/dL). A chest X-ray film (Figure 1) showed consolidation in the left middle lung field. A sputum Gram stain revealed many Gram-negative organisms, and the sputum culture grew Pseudomonas aeruginosa. Treatment with intravenous ceftazidime (2.0 g/day for nine days) was initiated, and the patient’s symptoms improved almost completely. On the ninth day of admission, the CRP level decreased from 17.58 to 4.00 mg/dL. On the 14th day of admission, the patient presented with severe dyspnea, and a physical examination was remarkable for an SpO2 of 82% on room air. The arterial blood gas values obtained on 5 L/min of oxygen delivered via nasal cannula were as follows: pH: 7.51, PaO2: 52 torr, PaCO2: 46 torr and bicarbonate: 27 mg/dL. A chest X-ray film (Figure 2) showed areas of ground-glass opacity (GGO) bilaterally in almost all lung fields. A chest computed tomography (CT) scan (Figure 3A,B) revealed areas of nonsegmental GGO and subpleural curvilinear shadows with predominance in the upper lobes in both lungs. The laboratory test values on the 14th day of admission were as follows: white blood cells, 5270/μL with a left shift; lymphocytes, 210/μL; serum LDH, 315 IU/L; serum CRP, 25.8 mg/dL; Krebs von den Lungen-6 (KL-6) level, 457 IU/L (normal, < 500 IU/L); surfactant protein-D (SP-D), 358 ng/mL (normal, < 110 ng/mL); plasma (1 → 3) beta-D-glucan level, 716 pg/dL (normal, < 11 pg/mL), which was high compared with the data obtained before this admission (17 pg/mL). Assays for latex-agglutination-Candida antigens and Aspergillus galactomannan antigens in the serum were both negative. The sputum, urine and blood cultures grew no organisms. The patient’s sputum was positive for Pneumocystis jirovecii according to polymerase chain reaction (PCR). She was immediately treated with sulfamethoxazole/trimethoprim (ST) at a dose of 10 mg/kg per day and high-dose mPSL (1 g/day for 3 days) with empirical antibiotic therapy (ciprofloxacin). However, her respiratory status rapidly deteriorated and she died on the 16th day of admission.\n\nFigure 1 Chest X-ray obtained on admission showed consolidation in the left middle and lower lung fields.\n\nFigure 2 Chest X-ray obtained after the diagnosis of pneumocystis pneumonia showed areas of ground-glass opacity bilaterally in almost all lung fields.\n\nFigure 3 A chest computed tomography scan obtained after the diagnosis of pneumocystis pneumonia (upper lung field: 3A, lower lung field: 3B) showed areas of nonsegmental ground-glass opacity and subpleural curvilinear shadows bilaterally in all lobes.\n\nDiscussion\nTo our knowledge, this is the first case report of PCP induced by low-dose tacrolimus and steroid therapy for RA. Tacrolimus is an immunosuppressive drug that was discovered in Japan. Tacrolimus prevents the dephosphorylation of calcineurin and suppresses the production of inflammatory cytokines (i.e., interleukin (IL)-2, IL-3, IL-4, interferon-gamma and tumor necrosis factor (TNF)-alpha from T-cells). It is used to prevent acute rejection following organ transplantation and to treat autoimmune disease. In Japan, approximately 12,000 patients with RA have been treated with tacrolimus since 2005. The efficacy of tacrolimus has been demonstrated by many researchers, and the potential toxicity of this drug has also been reported. The major side effects of tacrolimus include renal dysfunction, interstitial pneumonia, dyspnea, infectious diseases, hyperglycemia, skin rashes and gastric dysfunction (e.g., nausea and abdominal pain). Regarding RA patients with interstitial pneumonitis, tacrolimus has been reported to be associated with either improvement or acute exacerbation of interstitial pneumonia. Ando, et al. reported a case of progressive interstitial pneumonia associated with amyopathic dermatomyositis refractory to cyclosporine that was successfully treated with tacrolimus [1]. Miwa, et al. reported a case of tacrolimus-induced lung injury in an RA patient with interstitial pneumonia [2]. In addition, Koike, et al. reported 27 cases of tacrolimus-induced lung injury [3]. However, to the best of our knowledge, even among these cases, there has so far been no report of lung injury caused by PCP related to low-dose tacrolimus therapy, while there have only been a few reports of PCP in RA patients under tacrolimus and low-dose mPSL therapy. With diseases other than RA, PCP during tacrolimus therapy has been reported in a patient after transplantation, and also two patients with UC [4]. In the setting of organ transplantation, the incidence of PCP is 4.8 cases per 1,000 person-transplant years [5,6]. No significant risk of PCP was reported in patients under tacrolimus therapy. However, combined treatment with tacrolimus and sirolimus carries a significantly higher risk of PCP than other types of combination therapy. Among the UC cases, one patient was medicated with high-dose tacrolimus (0.5 mg/kg/day) and mPSL, while the other was treated with tacrolimus (applied dose: not described) and 6-mercaptopurine. Both patients died from acute respiratory failure. Patients with human immunodeficiency virus (HIV) and autoimmune disease under the administration of high-dose steroids and immunosuppressants are likely to develop PCP. The administration of methotrexate or TNF-alpha inhibitors for autoimmune disease is associated with a higher risk of PCP than other treatments. In normal situations, the dose of tacrolimus is 3.0 mg/day; however, our patient was treated with low-dose tacrolimus and mPSL. To the best of our knowledge, there are no previous reports describing PCP induced by such a low dose of tacrolimus in the literature.\n\nWe diagnosed the patient with PCP due to the high level of beta-D-glucan and positive findings for Pneumocystis jirovecii in the sputum on PCR testing. Tasaka, et al. suggested that a diagnosis of PCP should be made based on a beta-D-glucan level above 31.1 mg/dL and positive findings for Pneumocystis jirovecii in bronchial alveolar lavage fluid (BALF) on PCR testing [7]. However, we were unable to perform bronchoscopy in our case due to the patient’s severe acute progression of respiratory failure. Therefore, we substituted findings of Pneumocystis jirovecii in the sputum on PCR testing for those in BALF. Tokuda, et al. reported that RA-related PCP exhibits both diffuse homogenous GGO with sharp demarcation in the interlobular septa and homogenous or inhomogeneous GGO with sharp demarcation in the intralobular septa on chest CT [8]. The chest CT findings observed in our case revealed non-homogenous GGO without interlobular septal boundaries in accordance with RA-related PCP. We administered steroid pulse therapy with ST because the rapid progression of respiratory failure did not allow us to sufficiently examine and differentiate the etiology of the disease in this case. Our patient was diagnosed with and treated for Pseudomonas pneumonia before diagnose of PCP was made. John, et al. reported that blood CD4+ lymphocyte counts in PCP patients with HIV were lower than 200/μL [9]. Enomoto, et al. reported that average lymphocyte counts in 17 RA patients complicated with PCP were 890/μL at the time of PCP diagnosis [10]. In our case, blood lymphocyte count was 1700/μL at the time of diagnosis of Pseudomonas pneumonia, however, that was 210/μL at the time of PCP diagnosis. The decreased lymphocyte count was considered to be due to the Pseudomonas pneumonia. Therefore, it was considered that some of the changes that occur in the immune response due to the effects of Pseudomonas pneumonia have the potential to trigger PCP. RA-related PCP has a higher mortality rate than HIV-related PCP [11]. It is assumed that providing diagnosis and treatment in the early stage of development of PCP achieves prognostic improvements in RA patients. Our patient rapidly developed respiratory failure following diagnosis and treatment.\n\nConclusions\nIn conclusion, we herein reported the first case of PCP induced by low-dose tacrolimus and steroid treatment for RA. Clinicians should be careful to watch for the development of PCP following the administration of tacrolimus even in small doses in elderly patients and patients with a history of lung disease.\n\nConsent\nWritten informed consent was obtained from the patient’s next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nRA: Rheumatoid arthritis; mPSL: Methylprednisolone; PCP: Pneumocystis pneumonia; SpO2: Oxygen saturation; LDH: Lactate dehydrogenase; CRP: C-reactive protein; CT: Computed tomography; GGO: Ground-glass opacity; KL-6: Krebs von den Lungen-6; SP-D: Surfactant protein-D; PCR: Polymerase chain reaction; ST: Sulfamethoxazole/trimethoprim; IL: Interleukin; TNF: Tumor necrosis factor; UC: Ulcerative colitis; HIV: Human immunodeficiency virus; BALF: Bronchial alveolar lavage fluid.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nMK and KT reviewed the clinical data and were major contributors in writing the manuscript. YF, KS, HI, and KT were involved with patient management. HT performed the radiological examination of the chest x-ray and CT. All authors read and approved the final manuscript.\n==== Refs\nAndo M Miyazaki E Yamasue M Sadamura Y Ishii T Takenaka R Ito T Nureki S Kumamoto T Successful treatment with tacrolimus of progressive interstitial pneumonia associated with amyopathic dermatomyositis refractory to cyclosporine Clin Rheumatol 2010 29 443 445 20130943 \nMiwa Y Isozaki T Wakabayashi K Odai T Matsunawa M Yajima N Negishi M Ide H Kasama T Adachi M Hisayuki T Takemura T Tacrolimus-induced lung injury in a rheumatoid arthritis patient with interstitial pneumonitis Mod Rheumatol 2008 18 208 211 18306979 \nKoike R Tanaka M Komano Y Sakai F Sugiyama H Nanki T Ide H Jodo S Katayama K Matsushima H Miwa Y Morita K Nakashima H Nakamura H Natsumeda M Sato Y Semba S Tateishi M Miyasaka N Harigai M Tacrolimus-induced pulmonary injury in rheumatoid arthritis patients Pulm Pharmacol Ther 2011 24 401 406 21300166 \nEscher M Stange EF Herrlinger KR Two cases of fatal Pneumocystis jirovecii pneumonia as a complication of tacrolimus therapy in ulcerative colitis--a need for prophylaxis J Crohns Colitis 2010 4 606 609 21122569 \nGordon SM LaRosa SP Kalmadi S Arroliga AC Avery RK Truesdell-LaRosa L Longworth DL Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? Clin Infect Dis 1999 28 240 246 10064238 \nNeff RT Jindal RM Yoo DY Hurst FP Agodoa LY Abbott KC Analysis of usrds: incidence and risk factors for pneumocystis jiroveci pneumonia Transplantation 2009 88 135 141 19584693 \nTasaka S Hasegawa N Kobayashi S Yamada W Nishimura T Takeuchi T Ishizaka A Serum indicators for the diagnosis of pneumocystis pneumonia Chest 2007 131 1173 1180 17426225 \nTokuda H Sakai F Yamada H Johkoh T Imamura A Dohi M Hirakata M Yamada T Kamatani N Kikuchi Y Sugii S Takeuchi T Tateda K Goto H Clinical and radiological features of Pneumocystis pneumonia in patients with rheumatoid arthritis, in comparison with methotrexate pneumonitis and Pneumocystis pneumonia in acquired immunodeficiency syndrome: a multicenter study Intern Med 2008 47 915 923 18480575 \nJohn P Alvaro M Roger D Kaslow R Rinaldo C Saah A The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group N Engl J Med 1990 322 161 165 1967190 \nEnomoto T Azuma A Kohno A Kaneko K Saito H Kametaka M Usuki J Gemma A Kudoh S Nakamura S Differences in the clinical characteristics of Pneumocystis jirovecii pneumonia in immunocompromised patients with and without HIV infection Respirology 2010 15 126 131 19947989 \nRoblot F Godet C Le Moal G Garo B Faouzi Souala M Dary M De Gentile L Gandji JA Guimard Y Lacroix C Roblot P Becq-Giraudon B Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients Eur J Clin Microbiol Infect Dis 2002 21 523 531 12172743\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-0500",
"issue": "6()",
"journal": "BMC research notes",
"keywords": null,
"medline_ta": "BMC Res Notes",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008775:Methylprednisolone; D011020:Pneumonia, Pneumocystis; D016559:Tacrolimus",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "498",
"pmc": null,
"pmid": "24289285",
"pubdate": "2013-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18480575;21122569;10064238;18306979;1967190;21300166;20130943;17426225;19584693;19947989;12172743",
"title": "Pneumocystis pneumonia induced by treatment with low-dose tacrolimus and methylprednisolone in a patient with rheumatoid arthritis: a case report.",
"title_normalized": "pneumocystis pneumonia induced by treatment with low dose tacrolimus and methylprednisolone in a patient with rheumatoid arthritis a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2015M1018502",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "This case report describes the progressive wound infection in the left thigh of a 34-year-old man due to an old landmine explosion. The infection developed into rapidly spreading skin and soft tissue necrotising Saksenaea infection, despite antifungal therapy and surgical debridement. The report provides evidence that Saksenaea spp. should be added to the list of mucoralean fungi that can cause severe necrotising infection. It also highlights the need for improved early diagnostic procedures and enhanced understanding of Saksenaea virulence factors that contribute to necrotising infection.",
"affiliations": "Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.;Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Medical Laboratory Science, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.;Health Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.;Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.;Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.;Department of Parasitology and Mycology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.;Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Kachuei|Reza|R|;Badali|Hamid|H|;Vaezi|Afsane|A|;Jafari|Nematollah Jonaidi|NJ|;Ahmadikia|Kazem|K|;Kord|Mohammad|M|;Aala|Farzad|F|;Al-Hatmi|Abdullah Ms|AM|;Khodavaisy|Sadegh|S|",
"chemical_list": "D000935:Antifungal Agents",
"country": "England",
"delete": false,
"doi": "10.12968/jowc.2021.30.6.465",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0969-0700",
"issue": "30(6)",
"journal": "Journal of wound care",
"keywords": "Saksenaea species; cutaneous mucormycosis; infection; mucorales; mucormycosis; necrosis; trauma; wound; wound healing; zygomycosis",
"medline_ta": "J Wound Care",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D003881:Dermatomycoses; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D009090:Mucorales; D009091:Mucormycosis; D009336:Necrosis; D014946:Wound Infection",
"nlm_unique_id": "9417080",
"other_id": null,
"pages": "465-468",
"pmc": null,
"pmid": "34121440",
"pubdate": "2021-06-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal necrotising cutaneous mucormycosis due to novel Saksenaea species: a case study.",
"title_normalized": "fatal necrotising cutaneous mucormycosis due to novel saksenaea species a case study"
} | [
{
"companynumb": "IR-PFIZER INC-202101119348",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": null,
... |
{
"abstract": "Gaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case reports of patients with GD1 receiving lung transplants.\nWe report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation.\nThis is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.",
"affiliations": "Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 2775 Laurel Street, 7th Floor, Vancouver, BC, V5Z 1M9, Canada.;Division of Endocrinology, Department of Medicine, University of British Columbia, 2775 Laurel Street, 4th Floor, Vancouver, BC, V5Z 1M9, Canada.;Lung Transplant Program, Vancouver General Hospital, 2775 Laurel Street, 5th Floor, Vancouver, BC, V5Z 1M9, Canada.;Department of Pathology, University of British Columbia, Room G227 - 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.;Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 2775 Laurel Street, 7th Floor, Vancouver, BC, V5Z 1M9, Canada.;Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 2775 Laurel Street, 7th Floor, Vancouver, BC, V5Z 1M9, Canada.;Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 2775 Laurel Street, 7th Floor, Vancouver, BC, V5Z 1M9, Canada.;Section of Digestive Diseases, Department of Medicine, Yale Liver Center, Yale University, New Haven, CT, USA.;Adult Metabolic Diseases Clinic, Department of Nursing, Vancouver General Hospital, 2775 Laurel Street, 4th Floor, Vancouver, BC, V5Z 1M9, Canada.;Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 2775 Laurel Street, 7th Floor, Vancouver, BC, V5Z 1M9, Canada.",
"authors": "Goobie|Gillian C|GC|;Sirrs|Sandra M|SM|;Yee|John|J|;English|John C|JC|;Bergeron|Celine|C|;Nador|Roland|R|;Swiston|John R|JR|;Mistry|Pramod K|PK|;Paquin|Wendy|W|;Levy|Robert D|RD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2019.100893",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(19)30057-710.1016/j.rmcr.2019.100893100893Case ReportLessons from lung transplantation: Cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease Goobie Gillian C. gcgoobie@alumni.ubc.caa∗Sirrs Sandra M. bYee John deEnglish John C. cBergeron Celine adNador Roland adSwiston John R. adMistry Pramod K. fPaquin Wendy gLevy Robert D. ada Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 2775 Laurel Street, 7th Floor, Vancouver, BC, V5Z 1M9, Canadab Division of Endocrinology, Department of Medicine, University of British Columbia, 2775 Laurel Street, 4th Floor, Vancouver, BC, V5Z 1M9, Canadac Department of Pathology, University of British Columbia, Room G227 – 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canadad Lung Transplant Program, Vancouver General Hospital, 2775 Laurel Street, 5th Floor, Vancouver, BC, V5Z 1M9, Canadae Division of Thoracic Surgery, Department of Surgery, University of British Columbia, 2775 Laurel Street, 11th Floor, Vancouver, BC, V5Z 1M9, Canadaf Section of Digestive Diseases, Department of Medicine, Yale Liver Center, Yale University, New Haven, CT, USAg Adult Metabolic Diseases Clinic, Department of Nursing, Vancouver General Hospital, 2775 Laurel Street, 4th Floor, Vancouver, BC, V5Z 1M9, Canada∗ Corresponding author. gcgoobie@alumni.ubc.ca29 6 2019 2019 29 6 2019 28 10089314 2 2019 27 6 2019 28 6 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nGaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case reports of patients with GD1 receiving lung transplants.\n\nCase presentation\nWe report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation.\n\nConclusions\nThis is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.\n\nKeywords\nLung transplantationPulmonary hypertensionPulmonary arterial hypertensionGaucher diseaseEnzyme replacement therapySplenectomy\n==== Body\nAbbreviations\n(DLCO)Diffusion capacity for carbon monoxide\n\n(ERT)enzyme replacement therapy\n\n(FEV1)forced expiratory volume in 1 second\n\n(FVC)forced vital capacity\n\n(GD1)Gaucher disease type 1\n\n(ILD)interstitial lung disease\n\n(MMF)mycophenolate mofetil\n\n(RVSP)right ventricular systolic pressure\n\n(PAH)pulmonary arterial hypertension\n\n(PH)pulmonary hypertension\n\n(VA-ECMO)venoarterial extracorporeal membrane oxygenation\n\n(VV-ECMO)venovenous extracorporal membrane oxygenation\n\n1 Introduction\nGaucher disease is an autosomal recessive inherited disorder that is the most common lysosomal storage disease, affecting approximately 1/40,000 live births [1]. The three variants of the disease are characterized by deficient activity of the lysosomal enzyme, glucocerebrosidase. This results in the accumulation of its substrate, glucosylceramide, in lysosomes of macrophages, predominately in the bone marrow, liver and spleen [2]. Gaucher disease type 1 (GD1) is the most common variant, especially in patients of Ashkenazi Jewish descent [3].\n\nPulmonary involvement in GD1 can be characterized by interstitial lung disease (ILD) and/or pulmonary hypertension (PH) [1,4]. PH is present in up to 30% of untreated GD1 patients, and 7% of patients receiving enzyme replacement therapy (ERT) [5]. The majority of PH in GD1 patients is seen in splenectomised, female patients, and most cases are responsive to treatment with ERT [5,6]. The patient highlighted in this case was previously included in a series of GD1 patients with PH [5].\n\nTreatment of GD1 with end-stage pulmonary manifestations by lung transplantation has been reported in two previous cases. Ours is the first reported case of lung transplantation in a patient with GD1 for severe PH without pulmonary parenchymal involvement. We also analyze disease-specific concerns for transplant in these patients, including the risk of GD1 pulmonary disease recurrence, immunosuppression in splenectomised patients, and the risk of liver and bone involvement in GD1.\n\n1.1 Case presentation\nOur patient was initially diagnosed with GD1 thirty-six years prior to transplant at age 14 when she presented with splenomegaly and thrombocytopenia. She was treated with a splenectomy, and the diagnosis of GD1 was confirmed with enzymology and genotyping (N370S/F417V). This genotyping also confirmed the absence of any pulmonary arterial hypertension (PAH)-related genes. She was then lost to follow-up, but re-presented in 2000 at age 33 with dyspnea and was found to have severe PH. Treatment with imiglucerase (Cerezyme, Sanofi Genzyme, 45U/kg IV q2weeks), IV epoprostenol (Flolan®, GSK Canada, 92ng/kg/min), and warfarin was initiated. This was followed by addition of bosentan (125 mg PO BID) in 2006, and sildenafil (25 mg PO TID) in 2008. Flolan® was eventually transitioned to a thermostable formulation of IV epoprostenol (Caripul®, Actelion Pharmaceuticals Canada, 88ng/kg/min). She was also managed for her comorbidities of GD1-associated osteopenia and gastroesophageal reflux.\n\nThe patient was referred for evaluation for lung transplantation at age 34 in 2001. She did not require transplantation at that time as she initially had a dramatic clinical response to her PH therapy. After a period with stable cardiopulmonary hemodynamics, her functional status worsened, and she progressed to require 3L of oxygen continuously (Fig. 1). Although her right ventricular systolic pressure (RVSP) from transthoracic echocardiography remained relatively stable, her right ventricular systolic function deteriorated, and she developed paradoxical septal motion with bowing into her left ventricle. As a result of this progression, she was actively listed for lung transplantation in 2016.Fig. 1 Right ventricular systolic pressure according to transthoracic echocardiography (mmHg) and 6-min walk distance (m) prior to lung transplant.\n\nAbbreviations: RVSP, right ventricular systolic pressure; 6-MWD, 6-min walk distance.\n\nFig. 1\n\nThe patient's last pre-transplant forced vital capacity (FVC) was 1.90L (68% predicted), forced expiratory volume in 1 second (FEV1) 1.23L (52% predicted), and diffusion capacity for carbon monoxide (DLCO) 20.50mL/min/mmHg (107% predicted). Imaging demonstrated no evidence of interstitial lung disease. Her last right heart catheterization 3 months prior to transplant demonstrated a mean pulmonary artery pressure of 62 mmHg, a pulmonary vascular resistance of 20.4 Wood units (increased from 11.2 Woods units 41 months previously), and a Fick cardiac output of 2.4L/min (decreased from 5.0L/min 41months previously).\n\nFollowing active listing for transplant, the patient had three admissions for right heart failure and volume overload requiring IV diuresis. Computed tomography pulmonary embolism protocol did not show any evidence of pulmonary embolus but showed new increased interstitial markings in the lung parenchyma consistent with congestive heart failure (Fig. 2). Her condition worsened in 2018 and she was admitted to the critical care unit for vasopressor and inotrope therapy for two weeks until an appropriate donor became available. Her lung allocation score at this time was 45.9. She underwent a bilateral sequential lung transplantation and during the procedure required venoarterial extracorporeal membrane oxygenation (VA-ECMO). There was a size discrepancy with a large donor and a small recipient, so the patient received a left upper lobar transplant and a right lung transplant with a wedge resection of a portion of consolidated donor right lower lobe. The procedure was complicated by significant bleeding requiring massive transfusions and return to the OR for hemostasis.Fig. 2 High resolution computed tomography (HRCT) images pre-transplant. A. gross dilatation of the main pulmonary arteries associated with rapid peripheral tapering, consistent with pulmonary arterial hypertension, and no evident filling defects to indicate venous thromboembolism. B. Cardiomegaly with four chamber enlargement, dilatation of the right ventricle and flattening of the inter-ventricular septum. C. Increased interstitial lung markings consistent with pulmonary edema, but overall preserved pulmonary parenchyma.\n\nFig. 2\n\nThe explanted lungs demonstrated severe pulmonary arterial hypertensive changes, including intimal proliferation, plexiform and angiomatoid lesions (Fig. 3). There was also patchy bronchiolitis and pneumonitis, potentially reflecting microaspiration, mild infection or drug reaction, but there was no evidence of interstitial fibrosis. The lungs did not demonstrate any pathognomonic features of Gaucher disease, such as filling of the alveolar spaces with Gaucher macrophages, accumulation of Gaucher cells in the alveolar septae and capillaries or perilymphatic infiltration of Gaucher cells. There was also no bone marrow emboli in the pulmonary capillaries, a finding that has rarely been described in patients with GD1 and PH [7,8]. The explant pathology in our patient was typical for that seen in patients with WHO PH group 1 PAH.Fig. 3 Pathological specimens from lung explants demonstrating features of pulmonary arterial hypertension. A. Low-power micrograph of a plexiform-dilation lesion. The arrow indicates the classical “glomeruloid-like” plexus of narrow slit-like channels lined by endothelium. The arrowheads indicate the post-stenotic dilation and angiomatoid lesions typifying plexogenic arteriopathy. Original magnification 40X. Movat pentachrome stain. B. Intra-lobular arteriole (arrow) showing severe concentric laminar intimal fibrosis (arrow). Note the tunica media of normal thickness. Movat pentachrome stain; original magnification 100x.\n\nFig. 3\n\nHer post-transplant course was complicated by prolonged support with initially veno-arterial (VA)- then venovenous-ECMO (VV-ECMO). After weaning from VV-ECMO, she required a prolonged period of ventilation, and as a result received a tracheostomy three weeks following her transplant. She was successfully decannulated three weeks later. As a result of hemorrhagic shock, the patient developed acute tubular necrosis, requiring renal replacement therapy.\n\nEight months post-transplant, the patient remains dialysis-dependent with oliguria. Her lung function continues to improve eight months post-transplant with an FVC of 1.80L (63% predicted) and FEV1 of 1.47L (62% predicted). Her restrictive physiology is thought to be related to the donor lung resections and post-transplant hemothoraces resulting in chronic pleural disease. Her follow-up transbronchial biopsies and bronchoalveolar lavage demonstrate no evidence of acute rejection or infection. She is currently being maintained on immunosuppression with MMF, tacrolimus and prednisone, while continuing her ERT with imiglucerase and anticoagulation with warfarin.\n\n2 Discussion\nThere have only been two previous reports of lung transplantation in patients with GD1 [9,10]. The first was in a 10 year old GD1 patient with extensive ILD, previous bronchoalveolar lavage with evidence of Gaucher cells, and pulmonary hypertensive crisis [10]. The second case was in a patient transplanted at age 49 for severe PH and fibrotic ILD [9]. In both cases, the patients were female, had been treated with ERT, and had undergone splenectomy prior to developing end-stage pulmonary disease. Ours is the first case of a lung transplant in a GD1 patient with severe PH, but without significant pulmonary parenchymal disease.\n\nPulmonary vascular disease in GD1 is more common than previously recognized, affecting up to 30% of untreated patients and approximately 7% of patients treated with ERT [5]. The PH seen in GD1 is typically mild-to-moderate in severity, but end-stage PH occurs in approximately 1% of patients with GD1(6). PH in GD1 has been classified into WHO Group 5, for unclear or multifactorial mechanisms [11]. The classic pathophysiologic explanation for PH in GD1 is that Gaucher cells deposit in the pulmonary parenchyma and capillaries, thus obstructing blood flow [8,12]. However, severe PH in GD1 has been described with little-to-no evidence of Gaucher cells within the lungs [2,13]. The impact of long-term ERT on the presence of Gaucher cells in the lungs is unclear, although this treatment may explain the absence of these cells in the explants from our patient. Other proposed mechanisms of PH include plugging of pulmonary capillaries with bone marrow emboli [7,8], post-splenectomy PH [5], and PH via the hepatopulmonary syndrome in patients with GD1-associated liver disease [6]. Analysis of BMPR2 and ALK1 coding regions did not disclose a role for these modifier genes in GD1 [6].\n\nSplenectomy has been shown to be a primary factor in the development of PH in GD1 [5,6]. The proposed mechanism of PH following splenectomy is thought to relate to hypercoagulability from lack of splenic clearance of platelets and megakaryocytes. This results in deposition of megakaryocytes and macrophages within the pulmonary vasculature, leading to development of proximal thrombi (i.e. chronic thromboembolic pulmonary hypertension phenotype) or distal thrombi manifesting as a plexogenic arteriopathy (i.e. pulmonary arterial hypertension phenotype) [5,14].\n\nAsplenia is also an important post-transplant consideration. Asplenic solid organ transplant recipients are more likely to experience bacterial pneumonias post-transplant [15]. However, these patients may be at a lower risk of antibody-mediated rejection (AMR). Splenectomy has previously been used as a salvage treatment for AMR in kidney transplantation [16], and it has also been used to facilitate ABO-incompatible kidney transplants [17]. No studies have evaluated the mortality impact of splenectomy in lung transplant recipients.\n\nAlthough it has previously been mentioned as a theoretical concern [9], the risk of recurrence of PH related to GD1 in transplanted lungs should be extremely low if the patient remains on ERT. Patients treated with ERT have a much lower likelihood of developing PH or other pulmonary manifestations than those without ERT [5]. As evidenced in our patient, long term treatment with imiglucerase may completely eliminate the Gaucher cells in the lungs, although it will not alleviate the thrombogenic risk associated with splenectomy. Ongoing ERT post-transplant and should minimize any risk of post-transplant pulmonary and systemic complications of GD1.\n\n3 Conclusions\nOur case, in conjunction with the two previous cases of lung transplantation in GD1, demonstrates the efficacy of this treatment for patients with end-stage pulmonary disease from this condition, although reported follow-up is limited. Given the success and availability of ERT that has reduced the need for splenectomy, end stage pulmonary disease in GD1 may become less frequent. Nonetheless, 7% of patients with GD1 may develop severe PH despite adequate ERT. This is most common in female, splenectomised patients. As long as ERT is continued in the post-transplant course, there is no reason to anticipate that these patients would have more complications than other lung transplant recipients. Furthermore, the PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 rather than Group 5 PH.\n\nDeclarations of interest\nNone.\n\nConflicts of interest\nThe authors declare that they have no conflicts of interest.\n\nConsent for publication\nConsent for publication of this case report was signed by the patient and submitted with this manuscript.\n\nFunding\nThere was no external funding or study sponsors involved in the collection, interpretation or analysis of data for this manuscript, nor was there any external involvement or funding influencing the production or writing of this manuscript.\n\nAuthors contributions\nG.C.C., S.M.S, J.Y., J.C.E., C.B., R.N., J.R.S, P.K.M, W.P., and R.D.L. all contributed substantially to the acquisition and interpretation of data for this manuscript. The manuscript has been revised by all authors & all have given approval for its publication. All authors are accountable for the accuracy and integrity of information included in this manuscript.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgements\nThe authors would like to acknowledge the efforts of the pre- and post-transplant clinic, the pulmonary hypertension clinic and the adult metabolic diseases clinic at Vancouver General Hospital.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2019.100893.\n==== Refs\nReferences\n1 Grabowski G.A. Lysosomal storage disease 1-phenotype, diagnosis, and treatment of Gaucher's disease Lancet 372 9645 2008 1263 1271 [Internet], [cited 2018 Sep 21], Available from www.thelancet.com 19094956 \n2 den Bakker M.A. Grünberg K. Boonstra A. van Hal P.T.W. Hollak C.E.M. Pulmonary arterial hypertension with plexogenic arteriopathy in enzyme-substituted Gaucher disease Histopathology 61 2 2012 324 326 22690977 \n3 Grabowski G.A. Gaucher disease: gene frequencies and genotype/phenotype correlations Genet. Test 1 1 1997 Jan 5 12 [Internet], [cited 2018 Sep 21], Available from http://www.liebertpub.com/doi/10.1089/gte.1997.1.5 10464619 \n4 Devine M.S. Garcia C.K. Genetic interstitial lung disease Clin. Chest Med. 33 1 2012 95 110 Elsevier Inc 22365249 \n5 Mistry P.K. Sirrs S. Chan A. Pritzker M.R. Duffy T.P. Grace M.E. Pulmonary hypertension in type 1 Gaucher's disease: genetic and epigenetic determinants of phenotype and response to therapy Mol. Genet. Metab 77 1–2 2002 91 98 [Internet], [cited 2018 Sep 21], Available from www.academicpress.com 12359135 \n6 Lo S.M. Liu J. Chen F. Pastores G.M. Knowles J. Boxer M. Pulmonary vascular disease in Gaucher disease: clinical spectrum, determinants of phenotype and long-term outcomes of therapy J. Inherit. Metab. Dis 34 3 2011 643 650 [Internet], [cited 2018 Sep 21], Available from https://link-springer-com.ezproxy.library.ubc.ca/content/pdf/10.1007%2Fs10545-011-9313-9.pdf 21445609 \n7 Smith R.R.L. Hutchins G.M. Sack G.H. Ridolfi R.L. Unusual cardiac, renal and pulmonary involvement in Gaucher's disease. Interstitial glucocerebroside accumulation, pulmonary hypertension and fatal bone marrow embolization Am. J. Med 65 2 1978 352 360 [Internet], [cited 2018 Sep 22], Available from https://ac-els-cdn-com.ezproxy.library.ubc.ca/000293437890832X/1-s2.0-000293437890832X-main.pdf?_tid=d73ccddb-296a-4fe1-a7cc-a524e2468a40&acdnat=1537649891_c0e4311f705945c118a6c2fc36ac4d7e 686020 \n8 Amir G. Ron N. Pulmonary pathology in Gaucher's disease Hum. Pathol 30 6 1999 666 670 [Internet], [cited 2018 Sep 22], Available from https://ac-els-cdn-com.ezproxy.library.ubc.ca/S0046817799900928/1-s2.0-S0046817799900928-main.pdf?_tid=0c5e8ae3-ed96-4b6c-b6f3-61784568102b & acdnat=1537650255_2a267dec1fa6cd03bd20e4a11b4aeda1 10374775 \n9 de Boer G.M. van Dussen L. van den Toorn L.M. den Bakker M.A. Hoek R.A.S. Hesselink D.A. Lung transplantation in gaucher disease a learning lesson in trying to avoid both Scylla and charybdis Chest 149 1 2016 e1 e5 26757299 \n10 Rao A.R. Parakininkas D. Hintermeyer M. Segura A.D. Rice T.B. Bilateral lung transplant in Gauchers type-1 disease Pediatr. Transplant. 9 2 2005 239 243 15787800 \n11 Simonneau G. Gatzoulis M.A. Adatia I. Celermajer D. Denton C. Ghofrani A. Updated clinical classification of pulmonary hypertension J. Am. Coll. Cardiol 62 25 Suppl 2013 D34 D41 [Internet], [cited 2018 Sep 22], Available from 10.1016/j.jacc.2013.10.029 24355639 \n12 Ross D.J. Spira S. Buchbinder N.A. Gaucher cells in pulmonary-capillary blood in association with pulmonary hypertension N. Engl. J. Med 336 1997 379 381 [Internet], [cited 2018 Sep 22], Available from https://www.nejm.org/doi/pdf/10.1056/NEJM199701303360516 \n13 Theise N.D. Ursell P.C. Pulmonary hypertension and Gaucher's disease: logical association or mere coincidence? Am. J. Pediatr. Hematol. Oncol 12 1 1990 74 76 [Internet], [cited 2018 Sep 22], Available from http://www.ncbi.nlm.nih.gov/pubmed/2309982 2309982 \n14 Lahm T. Chakinala M.M. World health organization group 5 pulmonary hypertension Clin. Chest. Med 34 4 2013 753 778 [Internet], [cited 2018 Sep 22], Available from 10.1016/j.ccm.2013.08.005 24267303 \n15 Mermel L.A. Maki D.G. Bacterial pneumonia in solid organ transplantation Semin. Respir. Infect 5 1 1990 10 29 [Internet], Mar [cited 2018 Sep 21], Available from http://www.ncbi.nlm.nih.gov/pubmed/2188317 2188317 \n16 Sadaka B. Alloway R.R. Woodle E.S. Management of antibody-mediated rejection in transplantation Surg. Clin. North Am 93 6 2013 1451 1466 [Internet], [cited 2018 Sep 21], Available from 10.1016/j.suc.2013.08.002 24206861 \n17 Subramanian V. Ramachandran S. Klein C. Wellen J.R. Shenoy S. Chapman W.C. ABO-incompatible organ transplantation Int. J. Immunogenet. 39 4 2012 282 290 22339811\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "28()",
"journal": "Respiratory medicine case reports",
"keywords": "Enzyme replacement therapy; Gaucher disease; Lung transplantation; Pulmonary arterial hypertension; Pulmonary hypertension; Splenectomy",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "100893",
"pmc": null,
"pmid": "31334026",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "22365249;24267303;10464619;24355639;2309982;24206861;10374775;21445609;22339811;22690977;2188317;9011805;19094956;12359135;15787800;686020;26757299",
"title": "Lessons from lung transplantation: Cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease.",
"title_normalized": "lessons from lung transplantation cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease"
} | [
{
"companynumb": "CA-VELOXIS PHARMACEUTICALS-2022VELCA-000291",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditio... |
{
"abstract": "Sevoflurane is a volatile anesthetic characterized by low toxicity and is the most used in pediatric age. Unlike other halogenated anesthetic, sevoflurane is not metabolized to reactive intermediates that lead to the formation of hepatotoxic proteins. However, a few cases of hepatotoxicity have been associated with its use. We report a case of an 11-year-old boy who developed acute liver failure after neurosurgical intervention, resection of a posterior fossa mass, under sevoflurane anesthesia and other drugs. Postoperatively, he presented abdominal pain and the laboratory tests showed markedly elevated aminotransferase levels, coagulopathy and thrombocytopenia. He had no fever, hypoglycemia or evidence of encephalopathy. The clinical evolution was favorable and after 7 days, laboratory values were completely normalized. All the possible causes of acute liver failure were evaluated and the differential diagnosis is exposed.",
"affiliations": "Servicio de Cuidados Intensivos Pediátricos, Hospital Clínico Universitario de Valladolid, Valladolid, España. Electronic address: bermudezlorena@hotmail.com.;Servicio de Cuidados Intensivos Pediátricos, Hospital Clínico Universitario de Valladolid, Valladolid, España.;Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, Valladolid, España.;Servicio de Oncohematología Pediátrica, Hospital Clínico Universitario de Valladolid, Valladolid, España.;Servicio de Cuidados Intensivos Pediátricos, Hospital Clínico Universitario de Valladolid, Valladolid, España.",
"authors": "Bermúdez Barrezueta|L|L|;Benito Gutiérrez|M|M|;Martínez Rafael|B|B|;Herraiz Cristóbal|R|R|;Pino Vázquez|A|A|",
"chemical_list": "D018685:Anesthetics, Inhalation; D000077149:Sevoflurane; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.redar.2019.07.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2341-1929",
"issue": "66(9)",
"journal": "Revista espanola de anestesiologia y reanimacion",
"keywords": "Enzimas hepaticas; Fallo hepático; Liver enzymes; Liver failure; Sevoflurane; Sevoflurano; Toxicidad; Toxicity",
"medline_ta": "Rev Esp Anestesiol Reanim (Engl Ed)",
"mesh_terms": "D015746:Abdominal Pain; D000410:Alanine Transaminase; D018685:Anesthetics, Inhalation; D001219:Aspartate Aminotransferases; D002648:Child; D006801:Humans; D007770:L-Lactate Dehydrogenase; D017114:Liver Failure, Acute; D008297:Male; D000077149:Sevoflurane",
"nlm_unique_id": "101778594",
"other_id": null,
"pages": "474-477",
"pmc": null,
"pmid": "31427144",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute liver failure after sevoflurane anesthesia in a pediatric patient.",
"title_normalized": "acute liver failure after sevoflurane anesthesia in a pediatric patient"
} | [
{
"companynumb": "ES-BAXTER-2020BAX017798",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
... |
{
"abstract": "An adnexal mass is a common gynecological finding. Most adnexal masses are benign neoplasms, especially in premenopausal women. Yet, here we report a premenopausal woman with an adnexal mass that turned out to be an ovarian metastasis from colon cancer. This case emphasizes the importance of considering an ovarian metastasis in patients with (partially) solid adnexal masses and low serum CA125 levels. In addition, we identified the same KRAS mutation in the biopsied liver metastasis and resected right ovarian metastasis. This is in accordance with a previous molecular study of matched tumor pairs/trios of colorectal cancer patients with ovarian metastases, suggesting that mutated KRAS is a universal driver of the metastatic disease in women with KRAS-mutated colorectal cancer with ovarian metastases. More than half of all colorectal cancer patients with ovarian metastases harbor KRAS mutations. Future studies may investigate the efficacy of KRAS inhibitors in the treatment of these patients.",
"affiliations": "Department of Gynecology and Obstetrics, Haga Hospital, The Hague, The Netherlands.;Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.;Department of Surgery, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.;Department of Radiology, Haga Hospital, The Hague, The Netherlands.;Department of Internal Medicine, Haga Hospital, The Hague, The Netherlands.;Department of Internal Medicine, Haga Hospital, The Hague, The Netherlands.;Department of Gynecology and Obstetrics, Haga Hospital, The Hague, The Netherlands.",
"authors": "Kemps|Paul Geraeds|PG|;Bol|Mijke|M|;Steller|Ernst Johan Abraham|EJA|;de Pont|Lisa Maria Henrica|LMH|;Holterhues|Cynthia|C|;van Gerven|Leander|L|;Kolkman|Wendela|W|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2021.06.072",
"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433\nElsevier\n\nS1930-0433(21)00449-0\n10.1016/j.radcr.2021.06.072\nCase Report\nColon carcinoma presenting as ovarian metastasis\nKemps Paul Geraeds MD p.g.kemps@lumc.nl\nab⁎\nBol Mijke MD c\nSteller Ernst Johan Abraham MD, PhD d\nde Pont Lisa Maria Henrica MD e\nHolterhues Cynthia MD, PhD f\nvan Gerven Leander MD f\nKolkman Wendela MD, PhD a\na Department of Gynecology and Obstetrics, Haga Hospital, The Hague, The Netherlands\nb Leiden University Medical Center, Leiden, The Netherlands\nc Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands\nd Department of Surgery, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands\ne Department of Radiology, Haga Hospital, The Hague, The Netherlands\nf Department of Internal Medicine, Haga Hospital, The Hague, The Netherlands\n⁎ Corresponding Author. p.g.kemps@lumc.nl\n23 7 2021\n9 2021\n23 7 2021\n16 9 27992803\n17 6 2021\n23 6 2021\n© 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nAn adnexal mass is a common gynecological finding. Most adnexal masses are benign neoplasms, especially in premenopausal women. Yet, here we report a premenopausal woman with an adnexal mass that turned out to be an ovarian metastasis from colon cancer. This case emphasizes the importance of considering an ovarian metastasis in patients with (partially) solid adnexal masses and low serum CA125 levels. In addition, we identified the same KRAS mutation in the biopsied liver metastasis and resected right ovarian metastasis. This is in accordance with a previous molecular study of matched tumor pairs/trios of colorectal cancer patients with ovarian metastases, suggesting that mutated KRAS is a universal driver of the metastatic disease in women with KRAS-mutated colorectal cancer with ovarian metastases. More than half of all colorectal cancer patients with ovarian metastases harbor KRAS mutations. Future studies may investigate the efficacy of KRAS inhibitors in the treatment of these patients.\n\nKeywords\n\nAdnexal mass\nOvarian metastasis\nColorectal cancer\nColon carcinoma\nKrukenberg\nKRAS\n==== Body\nIntroduction\n\nAn adnexal mass is a common gynecological finding, and frequently detected incidentally. Most adnexal masses are benign neoplasms, especially in premenopausal women [1]. Yet, a small proportion represents malignant tumors. These malignant adnexal masses primarily comprise epithelial ovarian cancer, and more rarely ovarian metastases from secondary malignancies or uncommon primary malignancies (e.g., malignant germ cell tumors). Unfortunately, it can be difficult to differentiate between benign and malignant adnexal masses. In general, adnexal masses are not biopsied, to avoid disrupting the ovarian capsule, as this can cause dissemination of malignant cells. Hence, clinicians are reliant on clinical, radiological and laboratory parameters to determine the risk of malignancy and decide whether surgery is indicated or not. One important laboratory parameter is the serum cancer antigen 125 (CA125) level. Since it was first described in 1981, CA125 is well established as a tumor marker for epithelial ovarian cancer. Consequently, it is widely used as a diagnostic tool, supported by its incorporation in various diagnostic prediction models for ovarian malignancy [2]. However, it is crucial to remember that a low serum CA125 level does not rule out ovarian malignancy. Accordingly, here we report a premenopausal woman with a unilateral adnexal mass and low serum CA125 level that turned out to have an ovarian metastasis from colon cancer.\n\nCase report\n\nA 44-year-old woman presented to the gynecology clinic with menorrhagia for six months. Except for the feeling of mild pressure in the lower abdomen, she had no other symptoms. Transvaginal ultrasonography showed no uterine abnormalities (Fig. 1A), but revealed a right adnexal mass of 8×7cm with both solid and cystic components (Fig. 1B). No ascites was observed. The serum CA125 level was measured, and turned out low (18 kU/L). An abdominal computed tomography (CT) scan was requested for within two weeks. Five days later, the woman presented to the gynecologic emergency unit with increased abdominal discomfort. Transvaginal ultrasonography demonstrated significantly increased size of the right adnexal mass, which now measured 12×9cm (Fig. 1C-D). An abdominal CT scan was made the same day, revealing a right ovarian tumor, as well as a mass in the transverse colon and multiple hypodense lesions in both the right and left lobes of the liver (Fig. 2A-B). A diagnosis of metastatic colon cancer was suspected, which was subsequently supported by an increased serum carcinoembryonic antigen (CEA) level of 346 µg/L. Histopathological analysis of a liver biopsy confirmed the diagnosis, revealing classical adenocarcinoma. Immunohistochemical stainings and molecular analysis (using the IdyllaTM KRAS Mutation Assay) demonstrated mismatch repair proficiency and a KRAS p.G12V mutation, respectively. Detailed examination of the patient's family history by a clinical geneticist revealed no relatives with colorectal cancer and/or colonic polyposis. Palliative chemotherapy consisting of Capecitabine, Oxaliplatin and Bevacizumab (CapOx-B) was initiated. Oxaliplatin was discontinued after three courses due to toxicity (acute neuropathy: throat discomfort and muscle cramps). CT scans after three courses of CapOx-B and three subsequent courses of Cap-B showed gradual growth of the right ovarian metastasis (Fig. 2C), whereas the colon tumor and liver metastases had decreased in size after three courses of CapOx-B and stabilized after three courses of Cap-B. Since the abdominal discomfort had also increased, bilateral salpingo-oophorectomy was performed. Notably, Bevacizumab was discontinued several months before surgery and resumed one month after surgery to avoid impaired wound healing. In addition to the right ovarian metastasis (Fig. 2D), histopathological analysis revealed a microscopic focus of metastatic adenocarcinoma in the left ovary. Next-generation sequencing demonstrated the same KRAS p.G12V mutation in the right ovarian metastasis, as well as inactivating mutations in TP53 (p.R282W) and APC (p.K1350fs). Chemotherapy was switched to Folinic acid, Fluorouracil, Irinotecan and Bevacizumab (FOLFIRI-B) five months after surgery due to radiological progression of the colon tumor and liver metastases, as well as increasing serum CEA levels (Fig. 3). After four courses of FOLFIRI-B, partial response was observed on abdominal CT, and serum CEA levels had significantly decreased (Fig. 3). After twelve courses, exploratory laparotomy was performed; however, colectomy and hepatic metastasectomy were not executed because multiple peritoneal metastases were observed. At eighteen months after diagnosis, the patient remains in good clinical condition (WHO performance score 0).Fig 1 Images made during transvaginal ultrasonography at first presentation (A-B), showing a normal uterus without intracavitary abnormalities (A), and a right adnexal mass of 8×7cm (B). Images made during transvaginal ultrasonography at presentation at the gynecologic emergency unit (C-D), showing the enlarged right adnexal mass of 12×9cm with both solid and cystic components (C), and flow on color Doppler imaging (D). Yellow dotted lines indicate measurements.\n\nFig 1\n\nFig. 2 Coronal section of the contrast-enhanced abdominal CT scan performed at diagnosis (A) with graphic correlation (B), showing a 13×8cm large tumor originating from the right ovary with infiltration of surrounding mesenteric fat, as well as a mass in the distal part of the transverse colon with infiltration of mesocolic fat, and a hypodense liver lesion. The coronal section of the contrast-enhanced abdominal CT scan performed after three courses of CapOx-B and three subsequent courses of Cap-B chemotherapy (C) shows decreased size of the hypodense liver lesion (from 39 to 26mm) and increased size of the right ovarian metastasis (from 13 to 18cm). Gross macroscopic image of the resected right ovarian metastasis (D).\n\nFig 2\n\nFig. 3 Timeline depicting the course of serum CEA levels during the period of November 2019 to May 2021. Showed are decreasing serum CEA levels during CapOx-B chemotherapy, followed by gradually increasing serum CEA levels during Cap-B chemotherapy, except for an almost 50% drop after bilateral salpingo-oophorectomy. After switch to FOLFIRI-B chemotherapy in October 2020, serum CEA levels quickly decreased again.\n\nFig 3\n\nDiscussion\n\nAdnexal masses may be found in women of all ages, and can represent a wide variety of lesions of the ovaries, fallopian tubes or surrounding tissues. Although most adnexal masses are benign neoplasms, many women undergo surgery due to the concern that an adnexal mass could be malignant. It is estimated that, at least in the United States, 5%-10% of all women undergo surgery for a suspected ovarian neoplasm during their lifetime [3]. However, benign adnexal masses generally do not require surgery, but can be safely managed with follow-up [4]. Moreover, there are risks associated with any surgery, with a complication rate of false-positive surgery of 3% in a recent randomized controlled trial of ovarian cancer screening in the United Kingdom [5]. Therefore, much research is aimed at discovering clinical, radiological and laboratory parameters that can be used to better determine the risk of malignancy in women presenting with an adnexal mass, so that patients can receive optimal treatment [2]. Radiologically, the proportion of solid tissue is one of the strongest predictors of malignancy [6]. Furthermore, a recent study by Landolfo et al. reported serum CA125 to be the single most dominant protein biomarker for discrimination of benign and malignant ovarian tumors [7]. Yet, it is important to remember that 20% of all patients with epithelial ovarian cancer have normal CA125 levels [8]. Moreover, the study by Landolfo et al. included only seven patients with secondary metastatic tumors, representing just 6% of 126 included patients with malignant adnexal tumors. Thus, their study mainly proved that serum CA125 is the most dominant biomarker for discrimination between benign adnexal tumors and primary ovarian malignancies, but was underpowered to investigate protein biomarkers that can discriminate between benign and secondary metastatic ovarian tumors, as well as between primary ovarian malignancies and ovarian metastases. Previous studies have reported normal serum CA125 levels in approximately 35% of patients with ovarian metastases from non-gynecological cancers [9,10]. Together with our case, these data emphasize the importance of considering an ovarian metastasis in patients with (partially) solid adnexal masses and low serum CA125 levels. In these patients, other serum biomarkers may provide preoperative clues to the metastatic origin of the adnexal mass. For example, elevated serum CEA levels may alert clinicians for the potential presence of ovarian metastases from gastro-intestinal origin [9].\n\nApproximately 5%-15% of all malignant ovarian tumors are ovarian metastases [9]. Ovarian metastases may be the first presenting manifestation of the metastatic disease [11], as illustrated by our case. Moreover, patients can be asymptomatic or only have mild nonspecific symptoms, such as abdominal bloating or abnormal vaginal bleeding [10,11]. The colon is the most common primary malignancy site in patients with ovarian metastases, followed by the endometrium, breast, appendix and stomach [12]. Approximately half of all patients with ovarian metastases have bilateral metastases [12]. Ovarian metastases are often referred to as Krukenberg tumors, although this term is classically restricted to ovarian metastases with signet-ring cell adenocarcinoma morphology. The primary malignancy site of these “classical” Krukenberg tumors is most often the stomach, followed by the colon [12].\n\nOvarian metastases are present in approximately 5%-10% of all women with metastatic colorectal cancer [13]. They disproportionally affect younger women, and are associated with poor survival in comparison with national trends for metastatic colorectal cancer in general [13]. Notably, previous studies have reported frequent disproportionate growth of ovarian metastases under chemotherapy, while other sites of metastasis do respond [13], as seen in our case. Furthermore, resection of ovarian metastases has been demonstrated to be associated with significantly increased survival in patients where all other disease could also be resected [13,14]. In some of these cases, complete surgical cytoreduction may even be curative [13]. However, in patients with unresectable extra-ovarian metastases, such as our case, oophorectomy remains reserved for symptom palliation [13].\n\nIn our case, we identified the same KRAS p.G12V mutation in the biopsied liver metastasis and the resected right ovarian metastasis. Moreover, we identified inactivating mutations in TP53 and APC in the right ovarian metastasis using next-generation sequencing. This is in line with findings of Ganesh et al., who showed that TP53, APC and KRAS were the three most frequently mutated genes in tumors from 38 colorectal cancer patients with ovarian metastases. In addition, they demonstrated that KRAS was mutated in both the primary colorectal tumors, ovarian metastases and/or extraovarian metastases of 14/14 KRAS-mutated patients with available matched tumor pairs/trios [13]. These data suggest that mutated KRAS is a universal driver of the metastatic disease in patients with KRAS-mutated colorectal cancer with ovarian metastases. Interestingly, Ganesh et al. also reported significantly increased frequency of KRAS mutations in tumors of colorectal cancer patients with ovarian metastases, when compared to tumors of 426 colorectal cancer patients without ovarian metastases (66% vs 47%). Accordingly, future studies may investigate the use of KRAS inhibitors for the treatment of KRAS-mutated colorectal cancer patients with ovarian metastases. These novel targeted therapies are currently being tested in multiple phase I/II clinical trials [15], and recent results of the landmark phase I first-in-human trial of the KRAS p.G12C inhibitor Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors, including colorectal cancer [16].\n\nContributions\n\nAll authors were involved in the care of the patient, and contributed to the final version of the manuscript. MB provided the gross macroscopic image of the resected right ovarian metastasis. PK prepared the figures. Written consent for publication was obtained from the patient.\n\nCompeting Interests: None\n\nPatient Consent: Written consent for publication was obtained from the patient.\n==== Refs\nReferences\n\n1 Hermans A. Kluivers K. Janssen L. Siebers A. Wijnen M. Bulten J. Adnexal masses in children, adolescents and women of reproductive age in the Netherlands: A nationwide population-based cohort study Gynecol Oncol 143 1 2016 93 97 27421754\n2 Van Calster B. Valentin L. Froyman W. Landolfo C. Ceusters J. Testa A.C. Validation of models to diagnose ovarian cancer in patients managed surgically or conservatively: multicentre cohort study BMJ 370 2020 m2614 32732303\n3 National institutes of health consensus development conference statement. ovarian cancer: screening, treatment, and follow-up Gynecol Oncol 55 1994 S4 S14 7835809\n4 Froyman W. Landolfo C. De Cock B. Wynants L. Sladkevicius P. Testa A.C. Risk of complications in patients with conservatively managed ovarian tumours (IOTA5): a 2-year interim analysis of a multicentre, prospective, cohort study Lancet Oncol 20 3 2019 448 458 30737137\n5 Jacobs I.J. Menon U. Ryan A. Gentry-Maharaj A. Burnell M. Kalsi J.K. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial Lancet 387 10022 2016 945 956 26707054\n6 Van Calster B. Van Hoorde K. Valentin L. Testa A.C. Fischerova D. Van Holsbeke C. Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study BMJ 349 2014 g5920\n7 Landolfo C. Achten E.T.L. Ceusters J. Baert T. Froyman W. Heremans R. Assessment of protein biomarkers for preoperative differential diagnosis between benign and malignant ovarian tumors Gynecol Oncol 159 3 2020 811 819 32994054\n8 Karam A.K. Karlan B.Y. Ovarian cancer: the duplicity of CA125 measurement Nat Rev Clin Oncol 7 6 2010 335 339 20368726\n9 Stiekema A. Boldingh Q.J.A.J. Korse C.M. van der Noort V. Boot H. van Driel W.J. Serum human epididymal protein 4 (HE4) as biomarker for the differentiation between epithelial ovarian cancer and ovarian metastases of gastrointestinal origin Gynecol Oncol 136 3 2015 562 566 25560808\n10 Zhang J.-J. Cao D.-Y. Yang J.-X. Shen K. Ovarian metastasis from nongynecologic primary sites: a retrospective analysis of 177 cases and 13-year experience J Ovarian Res 13 1 2020 128 33109236\n11 Lewis M.R. Deavers M.T. Silva E.G. Malpica A. Ovarian involvement by metastatic colorectal adenocarcinoma Am J Surg Pathol 30 2 2006 177 184 16434891\n12 Bruls J. Simons M. Overbeek L. Bulten J. Massuger L. Nagtegaal I. A national population-based study provides insight in the origin of malignancies metastatic to the ovary Virchows Arch 467 1 2015\n13 Ganesh K. Shah R.H. Vakiani E. Nash G.M. Skottowe H.P. Yaeger R. Clinical and genetic determinants of ovarian metastases from colorectal cancer Cancer 123 7 2017 1134 1143 27875625\n14 McCormick C.C. Giuntoli R.L. Gardner G.J. Schulick R.D. Judson K. Ronnett B.M. The role of cytoreductive surgery for colon cancer metastatic to the ovary Gynecol Oncol 105 3 2007 791 795 17408727\n15 Moore A.R. Rosenberg S.C. McCormick F. Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov 19 8 2020 533 552 32528145\n16 Hong D.S. Fakih M.G. Strickler J.H. Desai J. Durm G.A. Shapiro G.I. KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors N Engl J Med 383 13 2020 1207 1217 32955176\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1930-0433",
"issue": "16(9)",
"journal": "Radiology case reports",
"keywords": "Adnexal mass; Colon carcinoma; Colorectal cancer; KRAS; Krukenberg; Ovarian metastasis",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101467888",
"other_id": null,
"pages": "2799-2803",
"pmc": null,
"pmid": "34367398",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "30737137;32955176;27421754;32732303;27875625;25894432;33109236;32994054;20368726;7835809;25560808;17408727;25320247;26707054;16434891;32528145",
"title": "Colon carcinoma presenting as ovarian metastasis.",
"title_normalized": "colon carcinoma presenting as ovarian metastasis"
} | [
{
"companynumb": "NL-ACCORD-236040",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Nontuberculous mycobacterial bone infections among human immunodeficiency virus (HIV)-negative patients are rare, although a few studies have described such infections. We retrospectively reviewed the medical and microbiological data of HIV-negative osteomyelitis cases caused by nontuberculous mycobacteria treated in our tertiary-care hospital over 14 years from January 1, 2000, to December 31, 2013. Three HIV-negative patients had contracted bone infections due to nontuberculous mycobacteria. All of the patients had at least 1 predisposing condition that led to the infections: idiopathic CD4-positive lymphocytopenia and/or anti-interferon-γ autoantibody syndrome.",
"affiliations": "AIDS Clinical Center, National Center for Global Health and Medicine.",
"authors": "Kobayashi|Tetsuro|T|;Morino|Eriko|E|;Takasaki|Jin|J|;Nagahara|Yoshinori|Y|;Sugiyama|Haruhito|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.7883/yoken.JJID.2015.100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6304",
"issue": "69(2)",
"journal": "Japanese journal of infectious diseases",
"keywords": null,
"medline_ta": "Jpn J Infect Dis",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D009164:Mycobacterium Infections; D009170:Nontuberculous Mycobacteria; D010019:Osteomyelitis; D012189:Retrospective Studies; D012307:Risk Factors; D062606:Tertiary Care Centers",
"nlm_unique_id": "100893704",
"other_id": null,
"pages": "149-50",
"pmc": null,
"pmid": "26166504",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nontuberculous Mycobacterial Osteomyelitis in Human Immunodeficiency Virus-Negative Patients: A Case Series.",
"title_normalized": "nontuberculous mycobacterial osteomyelitis in human immunodeficiency virus negative patients a case series"
} | [
{
"companynumb": "JP-BAYER-2016-076778",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Infections produced by Mycobacterium abscessus are emerging in immunosuppressed patients, such as solid organ transplant recipients. We report the first case, to our knowledge, of a vertebral osteomyelitis caused by M. abscessus in a heart transplant recipient, and review the risk factors, manifestations, and therapeutic approaches to this uncommon disease.",
"affiliations": "Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\", Universidad Complutense, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\", Universidad Complutense, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\", Universidad Complutense, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\", Universidad Complutense, Madrid, Spain.;Department of Cardiology, Hospital Universitario \"12 de Octubre\", Madrid, Spain.;Department of Cardiology, Hospital Universitario \"12 de Octubre\", Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\", Universidad Complutense, Madrid, Spain.",
"authors": "Silva|J T|JT|;López-Medrano|F|F|;Fernández-Ruiz|M|M|;San-Juan|R|R|;Ruiz-Cano|M J|MJ|;Delgado|J F|JF|;Aguado|J M|JM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017291:Clarithromycin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12381",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Mycobacterium abscessus; orthotopic heart transplantation; vertebral osteomyelitis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D009161:Mycobacterium; D010019:Osteomyelitis; D012141:Respiratory Tract Infections; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "418-23",
"pmc": null,
"pmid": "25816889",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Mycobacterium abscessus pulmonary infection complicated with vertebral osteomyelitis in a heart transplant recipient: case report and literature review.",
"title_normalized": "mycobacterium abscessus pulmonary infection complicated with vertebral osteomyelitis in a heart transplant recipient case report and literature review"
} | [
{
"companynumb": "ES-STRIDES ARCOLAB LIMITED-2016SP000029",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditiona... |
{
"abstract": "Fentanyl transdermal patches have long been used in the palliative care of patients with chronic pain with a favorable safety profile. However, intoxications secondary to intentional and unintentional misuse have been widely reported. In this study, we report an otherwise healthy woman presented to emergency department who used three patches of fentanyl to alleviate her knee pain and with a picture mimicking acute coronary syndrome.",
"affiliations": "Department of Cardiology, Van Education and Research Hospital, Van, Turkey.;Department of Cardiology, Van Army District Hospital, Van, Turkey drugurkucuk@gmail.com.;Department of Cardiology, Van Education and Research Hospital, Van, Turkey.;Department of Cardiology, Gulhane Military Medical Academy Hospital, Ankara, Turkey.;Department of Cardiology, Gulhane Military Medical Academy Hospital, Ankara, Turkey.",
"authors": "Kucuk|H O|HO|;Kucuk|U|U|;Kolcu|Z|Z|;Balta|S|S|;Demirkol|S|S|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1177/0960327115577516",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-3271",
"issue": "35(1)",
"journal": "Human & experimental toxicology",
"keywords": "Fentanyl; acute coronary syndrome; coronary angiography",
"medline_ta": "Hum Exp Toxicol",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000328:Adult; D000701:Analgesics, Opioid; D062787:Drug Overdose; D005260:Female; D005283:Fentanyl; D006801:Humans; D063487:Prescription Drug Misuse; D057968:Transdermal Patch",
"nlm_unique_id": "9004560",
"other_id": null,
"pages": "51-2",
"pmc": null,
"pmid": "25736329",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Misuse of fentanyl transdermal patch mixed with acute coronary syndrome.",
"title_normalized": "misuse of fentanyl transdermal patch mixed with acute coronary syndrome"
} | [
{
"companynumb": "TR-MYLANLABS-2016M1001946",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nNeuroleptic malignant syndrome is rare, but potentially fatal idiosyncratic reaction to antipsychotic medications. It is sometimes difficult to diagnose some clinical cases as neuroleptic malignant syndrome and differentiate it from the acute viral encephalitis.\n\n\nMETHODS\nWe reported a patient diagnosed with acute psychotic reaction which appeared for the first time. The treatment started with typical antipsychotic, which led to febrility. The clinical presentation of the patient was characterised by the signs and symptoms that might have indicated the neuroleptic malignant syndrome as well as central nervous system viral disease. In order to make a detailed diagnosis additional procedures were performed: electroencephalogram, magnetic resonance imaging of the head, lumbar puncture and a serological test of the cerebrospinal fluid. Considering that after the tests viral encephalitis was ruled out and the diagnosis of neuroleptic malignant syndrome made, antipsychotic therapy was immediately stopped. The patient was initially treated with symptomatic therapy and after that with atypical antipsychotic and electroconvulsive therapy, which led to complete recovery.\n\n\nCONCLUSIONS\nWe present the difficulties of early diagnosis at the first episode of acute psychotic disorder associated with acute febrile condition. Concerning the differential diagnosis it is necessary to consider both neuroleptic malignant syndrome and viral encephalitis, i.e. it is necessary to make the neuroradiological diagnosis and conduct cerebrospinal fluid analysis and blood test. In neuroleptic malignant syndrome treatment a combined use of electroconvulsive therapy and low doses of atypical antipsychotic are confirmed to be successful.",
"affiliations": null,
"authors": "Stojanović|Zvezdana|Z|;Spirić|Zeljko|Z|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Serbia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-8450",
"issue": "71(6)",
"journal": "Vojnosanitetski pregled",
"keywords": null,
"medline_ta": "Vojnosanit Pregl",
"mesh_terms": "D000208:Acute Disease; D014150:Antipsychotic Agents; D003937:Diagnosis, Differential; D018792:Encephalitis, Viral; D005334:Fever; D006801:Humans; D008297:Male; D009459:Neuroleptic Malignant Syndrome; D011618:Psychotic Disorders; D055815:Young Adult",
"nlm_unique_id": "21530700R",
"other_id": null,
"pages": "603-7",
"pmc": null,
"pmid": "25039118",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute psychosis followed by fever--malignant neuroleptic syndrome or viral encephalitis?",
"title_normalized": "acute psychosis followed by fever malignant neuroleptic syndrome or viral encephalitis"
} | [
{
"companynumb": "RS-MYLANLABS-2015M1048028",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "Crimean-Congo haemorrhagic fever (CCHF) is a fatal viral infection and an important public health issue in Turkey because of its high case fatality rate. Severity criteria of CCHF were defined previously in adults on the basis of epidemiological, clinical, and laboratory findings,. This study evaluated the course of CCHF in children. Between January, 2009, and November, 2012, 41 patients aged between 1 and 17 years (mean 9.78 ± 4.85) with a diagnosis of CCHF were included in the study. According to results of our study, Turkish pediatric patients had a milder course of CCHF.",
"affiliations": "1 Ankara Hematology Oncology Children's Training and Research Hospital , Ankara, Turkey .",
"authors": "Kızılgun|Murat|M|;Ozkaya-Parlakay|Aslınur|A|;Tezer|Hasan|H|;Gulhan|Belgin|B|;Yuksek|Saliha Kanık|SK|;Celikel|Elif|E|;Tunc|Bahattin|B|",
"chemical_list": "D000914:Antibodies, Viral",
"country": "United States",
"delete": false,
"doi": "10.1089/vbz.2013.1297",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-3667",
"issue": "13(11)",
"journal": "Vector borne and zoonotic diseases (Larchmont, N.Y.)",
"keywords": null,
"medline_ta": "Vector Borne Zoonotic Dis",
"mesh_terms": "D000293:Adolescent; D000914:Antibodies, Viral; D002648:Child; D002675:Child, Preschool; D005260:Female; D003225:Hemorrhagic Fever Virus, Crimean-Congo; D006479:Hemorrhagic Fever, Crimean; D006801:Humans; D007223:Infant; D008297:Male; D014421:Turkey",
"nlm_unique_id": "100965525",
"other_id": null,
"pages": "804-6",
"pmc": null,
"pmid": "24107215",
"pubdate": "2013-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of Crimean-Congo hemorrhagic fever virus infection in children.",
"title_normalized": "evaluation of crimean congo hemorrhagic fever virus infection in children"
} | [
{
"companynumb": "TR-ROCHE-1392215",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Restless legs syndrome (RLS) is a common neurological disorder. Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia after Alzheimer's disease. Both RLS and DLB can be effectively treated by dopaminergic medications, suggesting the role of dopamine dysfunction in the pathogenesis of both diseases. Here, I report on a Japanese woman with probable DLB and RLS who was treated with gabapentin enacarbil, a non-dopaminergic agent. Because a dopamine agonist, a first-line therapy for moderate to severe RLS, caused the occurrence of metamorphopsia, an alternative treatment of gabapentin enacarbil was used; this treatment improved the patient's RLS without worsening her psychiatric symptoms. An alternative treatment is desirable for DLB patients with RLS because they often experience intolerable side-effects with a dopamine agonist, especially visual hallucinations. Administering gabapentin enacarbil also improved the continuous leg pain that occurred in conjunction with the development of RLS. Although the neurobiological mechanism in the development of pain remains unclear, a range of non-dopaminergic structures likely mediated pain processing in DLB in the present case based on neuropharmacological results. This is the first report reporting the effects of gabapentin enacarbil for RLS and leg pain in a DLB patient with psychiatric symptoms.",
"affiliations": "Department of Psychiatry, Nagoya University School of Medicine, Nagoya, Japan.",
"authors": "Fujishiro|Hiroshige|H|",
"chemical_list": "C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D002219:Carbamates; D018491:Dopamine Agonists; D005680:gamma-Aminobutyric Acid",
"country": "England",
"delete": false,
"doi": "10.1111/psyg.12043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-3500",
"issue": "14(2)",
"journal": "Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society",
"keywords": "DLB; Parkinson's disease; dopaminergic agonist; psychiatric symptoms; visual hallucinations",
"medline_ta": "Psychogeriatrics",
"mesh_terms": "D000368:Aged; D002219:Carbamates; D018491:Dopamine Agonists; D005260:Female; D006212:Hallucinations; D006801:Humans; D007564:Japan; D007866:Leg; D020961:Lewy Body Disease; D008279:Magnetic Resonance Imaging; D010146:Pain; D012148:Restless Legs Syndrome; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "101230058",
"other_id": null,
"pages": "132-4",
"pmc": null,
"pmid": "24528871",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effects of gabapentin enacarbil on restless legs syndrome and leg pain in dementia with Lewy bodies.",
"title_normalized": "effects of gabapentin enacarbil on restless legs syndrome and leg pain in dementia with lewy bodies"
} | [
{
"companynumb": "JP-GLENMARK PHARMACEUTICALS INC, USA.-2014GMK011900",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"dru... |
{
"abstract": "OBJECTIVE\nTo observe the efficacy and toxicity of nanoparticle albumin bound paclitaxel (nab-paclitaxel) plus platinum agent (cisplatin or carboplatin) as first line treatment for stage III/IV squamous non-small-cell lung cancer (NSCLC).\n\n\nMETHODS\nForty chemotherapy naive patients with stage III/IV squamous NSCLC received nab-paclitaxel 125 mg/m2 on day 1 and day 8, cisplatin 75 mg/m2 on day 1, carboplatin area under the concentration-time curve of 5 (AUC=5) on day 1. One cycle of treatment was 3 weeks, and at least two were completed in each case.\n\n\nRESULTS\nOf the 40 patients who participated in the study, 25 achieved partial responses (PR), 12 reached a stage of stable disease (SD), and 3 suffered progressive disease (PD). The overall response rate (ORR) was 62.5% and the disease control rate (DCR) was 92.5%. Of the 20 patients without surgery or radiotherapy, 10 achieved PR, 7 reached a stage of SD, and 3 PD. The ORR was 50.0% and the DCR was 85.0%. The median progression-free survival time (PFS) of patients without surgery or radiotherapy was 5.0 months. Of the 20 patients receiving surgery or radiotherapy, 15 had PR and 5 p had SD, with an ORR of 75.0% and a DCR of 85.0%. Specifically, the DDP arm demonstrated a significantly higher ORR than the CBP arm (100%vs 54.5%, P<0.05). Common treatment related adverse events were myelosuppression, gastrointestinal response, baldness and neurotoxicity, most of which were grade 1 to 2.\n\n\nCONCLUSIONS\nNab-paclitaxel plus platinum agent (cisplatin or carboplatin) is effective as a first-line chemotherapy for stage III/IV squamous NSCLC, and its adverse effects are tolerable.",
"affiliations": "Department of Medical Oncology, Jiangsu Tumor Hospital, Nanjing, China E-mail : shimeiqishimeiqi@aliyun.com.",
"authors": "Fang|Ying|Y|;Wang|Li|L|;Xia|Guo-Hao|GH|;Shi|Mei-Qi|MQ|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin",
"country": "Thailand",
"delete": false,
"doi": "10.7314/apjcp.2014.15.17.7453",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1513-7368",
"issue": "15(17)",
"journal": "Asian Pacific journal of cancer prevention : APJCP",
"keywords": null,
"medline_ta": "Asian Pac J Cancer Prev",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D000505:Alopecia; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007970:Leukopenia; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009325:Nausea; D009367:Neoplasm Staging; D020258:Neurotoxicity Syndromes; D017239:Paclitaxel; D011446:Prospective Studies; D013921:Thrombocytopenia; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "101130625",
"other_id": null,
"pages": "7453-7",
"pmc": null,
"pmid": "25227858",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical investigation of efficacy of albumin bound paclitaxel plus platinum compounds as first-line chemotherapy for stage III/IV squamous non-small cell lung cancer.",
"title_normalized": "clinical investigation of efficacy of albumin bound paclitaxel plus platinum compounds as first line chemotherapy for stage iii iv squamous non small cell lung cancer"
} | [
{
"companynumb": "CN-CELGENE-CHN-2014094580",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Although ceftriaxone can be used safely in most instances, it can sometimes induce biliary sludge or stone formation. Most of the patients remain asymptomatic and children are more susceptible to develop this condition, but adults can be affected as well. Because sludge or stones disappear after discontinuing ceftriaxone, this condition is referred to as ceftriaxone-associated pseudolithiasis. A 54-year-old woman was admitted to a local clinic for management of ileus. During admission, she had received ceftriaxone and metronidazole, and had been on nil per os for the past 6 days. She was then referred to our hospital for cholecystectomy due to persistent right upper quadrant pain. Although imaging studies showed gallbladder sludge, pseudolithiasis was suspected because of ceftriaxone administration history and prolonged fasting. After careful watch-and-wait, the condition resolved spontaneously after ceftriaxone discontinuation. Our clear understanding on ceftriaxone-associated gallbladder pseudolithiasis allowed us to avoid an unnecessary cholecystectomy. Herein, we report the case of a 54-year-old woman with ceftriaxone-associated gallbladder pseudolithiasis that was successfully managed by ceftriaxone discontinuation alone.",
"affiliations": "Department of Surgery, Yeungnam University Medical Center, 170 Hyeonchung-ro, Nam-gu, Daegu 705-717, Korea.",
"authors": "Jung|Hwa Kyung|HK|;Lee|Dong-Shik|DS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone",
"country": "Korea (South)",
"delete": false,
"doi": "10.4166/kjg.2014.63.6.378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1598-9992",
"issue": "63(6)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": null,
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D002763:Cholecystectomy; D041761:Cholecystolithiasis; D005260:Female; D005704:Gallbladder; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "378-81",
"pmc": null,
"pmid": "24953617",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clinical review and case report of ceftriaxone-associated gallbladder pseudolithiasis in adult.",
"title_normalized": "clinical review and case report of ceftriaxone associated gallbladder pseudolithiasis in adult"
} | [
{
"companynumb": "KP-LUPIN PHARMACEUTICALS INC.-2016-02995",
"fulfillexpeditecriteria": "2",
"occurcountry": "KP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditiona... |
{
"abstract": "The revised fourth edition of the World Health Organization Classification of Tumors of the Central Nervous System-published in 2016-established 1p19q codeletion as the molecular hallmark for the diagnosis of oligodendrogliomas. Fluorescence in situ hybridization (FISH) is currently the most commonly used modality for 1p19q testing. However, as with most laboratory testing, 1p19q FISH testing has a false-positive rate, potentially resulting in an erroneous diagnosis of oligodendroglioma with significant implications for the choice of therapy and prognosis.\n\n\n\nThe authors describe a case series of 5 patients treated at the Ohio State University James Cancer Center to illustrate the problem of false-positive 1p19q FISH results.\n\n\n\nIn our case series, the authors present a spectrum of possibilities for conflicting 1p19q testing results and the clinical consequences. The authors present 4 cases that, in retrospect, are believed to have had a false 1p19q FISH results. One other case may represent a true transformation of oligodendroglioma to glioblastoma or a second malignancy. Neuro-oncologists should pay attention to additional molecular markers, namely ATRX, TP53, and MGMT methylation status, before discussing the pathology with the patient and formulating a treatment plan.\n\n\n\nPathologists and neuro-oncologists should be aware of false-positive 1p19q FISH results as they can significantly change treatment and prognosis for glioma patients. Moreover, this issue should be taken into account when designing clinical trials specific to this disease cohort.",
"affiliations": "Division of Neuro-Oncology, Department of Neurology, Thomas Jefferson University, Philadelphia, PA.;Department of Neurology, Charleston Area Medical Center, Charleston, WV.;Division of Neuropathology, Department of Pathology.;Division of Neuro-Oncology, Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH.;Division of Neuro-Oncology, Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH.;Division of Neuro-Oncology, Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH.",
"authors": "Alnahhas|Iyad|I|;Rayi|Appaji|A|;Thomas|Diana|D|;Ong|Shirley|S|;Giglio|Pierre|P|;Puduvalli|Vinay|V|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0000000000000755",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "43(11)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000328:Adult; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D003951:Diagnostic Errors; D005189:False Positive Reactions; D005260:Female; D005910:Glioma; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "802-805",
"pmc": null,
"pmid": "32889892",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "False-positive 1p/19q Testing Results in Gliomas: Clinical and Research Consequences.",
"title_normalized": "false positive 1p 19q testing results in gliomas clinical and research consequences"
} | [
{
"companynumb": "US-009507513-2012USA010765",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDrug-induced pneumonia (d-pneumonia) and bacterial pneumonia (b-pneumonia) are often difficult to differentiate; therefore, this study examined the possibility of differentiating them using serum biomarkers.\n\n\nMETHODS\nThe study included 22 and 16 patients diagnosed with b- and d-pneumonia, respectively, at our institution or affiliated institutions. For d-pneumonia, the causative drug was minocycline hydrochloride in four patients, gefitinib in two patients, nivolumab in two patients, pembrolizumab in two patients, sulfasalazine in two patients, loxoprofen in one patient, Bouiougitou in one patient, edoxaban tosilate hydrate in one patient, and abemaciclib in one patient. White blood cell (WBC), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, and SP-A levels were measured in each patient and compared between the groups.\n\n\nRESULTS\nSignificant differences were noted in the WBC and SP-D levels between the two groups (P < 0.05, P < 0.001), but not in the CRP, KL-6, or SP-A levels.\n\n\nCONCLUSIONS\nThe study results suggest that SP-D is a useful marker for differentiating b-pneumonia and d-pneumonia.",
"affiliations": "Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan. yuwaseda@gmail.com.;Department of Respiratory Medicine, National Hospital Organisation Nanao National Hospital, Gifu, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.;Department of Respiratory Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.;Department of Respiratory Medicine, Japan Community Health Care Organisation Kanazawa Hospital, Kanazawa, Japan.;Department of Respiratory Medicine, Kanazawa Municipal Hospital, Kanazawa, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.;Department of Surgery, Houju Memorial Hospital, Nomi, Japan.;Department of Respiratory Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193, Eiheiji, Fukui, Japan.",
"authors": "Waseda|Yuko|Y|http://orcid.org/0000-0002-7120-8517;Yasui|Masahide|M|;Kurokawa|Kousuke|K|;Chikazawa|Ryo|R|;Takeda|Toshihiro|T|;Mitsui|Miho|M|;Sonoda|Tomoaki|T|;Yamaguchi|Makiko|M|;Watanabe|Satoshi|S|;Takato|Hazuki|H|;Ichikawa|Yukari|Y|;Umeda|Yukihiro|Y|;Anzai|Masaki|M|;Ueda|Hiroshi|H|;Kasahara|Kazuo|K|;Ishizuka|Tamotsu|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s41479-021-00087-6",
"fulltext": "\n==== Front\nPneumonia (Nathan)\nPneumonia (Nathan)\nPneumonia\n2200-6133\nBioMed Central London\n\n87\n10.1186/s41479-021-00087-6\nBrief Report\nSurfactant protein D: a useful marker for differentiation of drug-induced pneumonia and bacterial pneumonia\nhttp://orcid.org/0000-0002-7120-8517\nWaseda Yuko yuwaseda@gmail.com\n\n123\nYasui Masahide 4\nKurokawa Kousuke 1\nChikazawa Ryo 1\nTakeda Toshihiro 1\nMitsui Miho 1\nSonoda Tomoaki 1\nYamaguchi Makiko 1\nWatanabe Satoshi 2\nTakato Hazuki 5\nIchikawa Yukari 6\nUmeda Yukihiro 1\nAnzai Masaki 1\nUeda Hiroshi 3\nKasahara Kazuo 2\nIshizuka Tamotsu 1\n1 Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, 910-1193 Eiheiji, Fukui Japan\n2 Department of Respiratory Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan\n3 Department of Surgery, Houju Memorial Hospital, Nomi, Japan\n4 Department of Respiratory Medicine, National Hospital Organisation Nanao National Hospital, Gifu, Japan\n5 Department of Respiratory Medicine, Japan Community Health Care Organisation Kanazawa Hospital, Kanazawa, Japan\n6 Department of Respiratory Medicine, Kanazawa Municipal Hospital, Kanazawa, Japan\n5 6 2021\n5 6 2021\n2021\n13 1126 9 2020\n20 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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/.\nBackground\n\nDrug-induced pneumonia (d-pneumonia) and bacterial pneumonia (b-pneumonia) are often difficult to differentiate; therefore, this study examined the possibility of differentiating them using serum biomarkers.\n\nMethods\n\nThe study included 22 and 16 patients diagnosed with b- and d-pneumonia, respectively, at our institution or affiliated institutions. For d-pneumonia, the causative drug was minocycline hydrochloride in four patients, gefitinib in two patients, nivolumab in two patients, pembrolizumab in two patients, sulfasalazine in two patients, loxoprofen in one patient, Bouiougitou in one patient, edoxaban tosilate hydrate in one patient, and abemaciclib in one patient. White blood cell (WBC), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, and SP-A levels were measured in each patient and compared between the groups.\n\nResults\n\nSignificant differences were noted in the WBC and SP-D levels between the two groups (P < 0.05, P < 0.001), but not in the CRP, KL-6, or SP-A levels.\n\nConclusion\n\nThe study results suggest that SP-D is a useful marker for differentiating b-pneumonia and d-pneumonia.\n\nKeywords\n\nSurfactant protein D\nDrug-induced pneumonia\nBacterial pneumonia\nKrebs von den Lungen-6\nSurfactant protein A\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nDrug-induced pneumonia (d-pneumonia) is an important side-effect that can occur with the use of any drug. The condition can sometimes become severe due to delay in treatment. Therefore, prompt diagnosis and treatment are necessary. Chest computed tomography (CT) characteristics of d-pneumonia are diverse, and this type of pneumonia is often difficult to differentiate from bacterial pneumonia (b-pneumonia). Thus, most cases of d-pneumonia are initially misdiagnosed as b-pneumonia and are treated with antibiotics. In this study, the usefulness of serum biomarkers (Krebs von den Lungen-6 [KL-6], surfactant protein [SP]-D, and SP-A) in the differentiation of d-pneumonia and b-pneumonia, was examined.\n\nMethods\n\nThe subjects were 16 and 23 patients with b- and d-pneumonia, respectively, whose serum KL-6, SP-D, and SP-A levels at the acute stage were examined at our institution or affiliated institutions between April 2003 and December 2020. The subjects did not have any disease that could cause elevated levels of biomarkers and were treated with immunosuppressive agents. KL-6 and SP-D were measured by chemiluminescent enzyme immunoassay (CLEIA), and SP-A was measured using enzyme immunoassay (EIA).\n\nChest CT was performed at the time of diagnosis in all cases, and the diagnosis was confirmed if the image showed consolidation or ground glass attenuation in one or both lungs. The d-pneumonia was established as a pathological condition that (1) targeted the lung tissue, (2) occurred after the use of a certain drug, (3) showed no improvement following the use of antibacterials, (4) improved at least initially with the discontinuation of the drug or with the use of anti-inflammatory drugs such as steroids, (5) showed abnormalities on chest CT images, and (6) was diagnosed following exclusion of infections, pulmonary oedema, and lymphangiosis carcinomatosa, which have clinical manifestations similar to those of d-pneumonia. The b-pneumonia was established as a condition with positive sputum results (including gram stain and culture) that improved with the administration of antibacterial drugs. Moreover, b-pneumonia diagnosis was free of all biases and included all community-acquired pneumonia cases diagnosed over a period of time. The b-pneumonia group did not include hospital-acquired pneumonia and ventilator-associated pneumonia. The β-D glucan and cytomegalovirus antigen were confirmed negative to exclude pneumocystis and cytomegalovirus pneumonia when the shadow had bilateral ground glass attenuation characteristics. Viral PCR was not performed for this study, but other viral pneumonias were excluded based on observation of the clinical course. The following blood tests were performed at the initial examination: WBC, CRP, KL-6, SP-D, and SP-A measurements. Statistical analyses were performed using Student’s unpaired t-test for serum KL-6, SP-D, SP-A, WBC, and CRP levels. The significance level was set at P < 0.05.\n\nThis study was approved by the ethics committee of Kanazawa University Hospital (#1328) and the University of Fukui (#20200151).\n\nResults\n\nPatient characteristics\n\nPatient characteristics are shown in Table 1. The age ranged from 26−83 years for the d-pneumonia group, with a mean age of 65 years. There were nine men and seven women. The causative drug was minocycline hydrochloride in four patients, gefitinib in two patients, nivolumab in two patients, pembrolizumab in two patients, sulfasalazine in two patients, loxoprofen in one patient, the traditional Chinese medicine Bouiougitou in one patient, edoxaban tosilate hydrate in one patient, and abemaciclib in one patient. Table 1 Patient characteristics\n\n\td-pneumonia (n = 16)\tb-pneumonia (n = 22)\t\nage\t65 (26−83)\t67 (28−91)\t\nsex (male / female)\t9 / 7\t15 / 7\t\n\tcausative drug\tminocycline hydrochloride\t4\tcausative bacteria\tKlebsiella pneumoniae\t4\t\n\t\tgefitinib\t2\t\tPSSP\t2\t\n\t\tnivolumab\t2\t\tMSSA\t1\t\n\t\tpembrolizumab\t2\t\tunknown\t16\t\n\t\tsulfasalazine\t2\t\t\t\t\n\t\tloxoprofen\t1\t\t\t\t\n\t\tBOUIOUGITOU\t1\t\t\t\t\n\t\tedoxaban tosilate hydrate\t1\t\t\t\t\n\t\tabemaciclib\t1\t\t\t\t\nWBC (/µL), mean ± SD\t8700 ± 6505\t12468 ± 1739*\t\nCRP (mg/dL), mean ± SD\t11.2 ± 10.4\t13.6 ± 2.9\t\nWBC white blood cells, CRP C-reactive protein, SD standard deviation\n\n*P < 0.05\n\nThe age range was 28−91 years in the b-pneumonia group, and the mean age was 67 years. There were 15 men and seven women. The causative bacteria were Klebsiella pneumoniae in four patients, penicillin-susceptible Streptococcus pneumoniae in two patients, methicillin-sensitive Staphylococcus aureus in one patient, and unknown in 15 patients.\n\nSerum biomarker results\n\nThere was no significant difference in KL-6 levels between the two groups. The KL-6 level was at the cut-off value (500 U/mL) or more in 4 of 16 patients (one patient was not assessed) in the d-pneumonia group and in 1 of 22 patients in the b-pneumonia group (Fig. 1a). Fig. 1 Comparison of serum biomarker and WBC levels between a drug induced group and bacterial pneumonia group. There was no significant correlation between d-pneumonia and b-pneumonia with regard to KL-6 (a) and SP-A (b) levels. However, SP-D (c) and WBC (d) levels showed a significant correlation (P < 0.001, P < 0.05). In the box plots, the boundary of the box closest to zero indicates the 25th percentile, a black line within the box marks the median, and the boundary of the box farthest from zero indicates the 75th percentile. Whiskers above and below the box indicate the 10th and 90th percentiles. Points above and below the whiskers indicate outliers outside the 10th and 90th percentiles. The dotted line indicates the cut off value. KL-6, Krebs von den Lungen-6; SP, Surfactant protein; WBC, White blood cell\n\nThere was no significant difference in the SP-A levels between the two groups. The SP-A level was at the cut-off value (43.8 ng/mL) or greater in 8 of 16 patients (six patients were not assessed) in the d-pneumonitis group and in 15 of 22 patients (one patient was not assessed) in the b-pneumonia group (Fig. 1b).\n\nThe SP-D level in the d-pneumonia group was significantly elevated compared to that in the b-pneumonia group. The SP-D level was at the cut-off value (110.0 ng/mL) or greater in 11 of 16 patients (the drug was not administered in two patients) in the d-pneumonia group and in none of the 22 patients in the b-pneumonia group (Fig. 1c). A significant difference was noted in the WBC levels between the two groups (Fig. 1d), but not in the CRP levels (data not shown).\n\nDiscussion\n\nIn this study, we compared serum KL-6, SP-D, and SP-A levels between patients with d-pneumonia and those with b-pneumonia. SP-D levels were significantly higher in the d-pneumonia group than in the b-pneumonia group. However, there was no difference in KL-6 or SP-A levels between the two groups. When d-pneumonia was determined based on the SP-D cut-off value, both sensitivity and specificity were high.\n\nIn Japan, the following clinical parameters have been used in laboratory tests for interstitial lung diseases (including IIPs): KL-6 [1], SP-A [2], and SP-D [3]. KL-6 is a high-molecular-weight glycoprotein. It is a type of MUC1 mucin recognised by a monoclonal antibody derived from mice immunised with a human lung adenocarcinoma cell line. KL-6 is produced mainly by alveolar type II epithelial cells. SP-A and SP-D are secretory glycoproteins that belong to the lung collecting family. They are similar in their molecular structure but differ in their molecular weight, molecular size, and affinity to phospholipids [4]. SP-A and SP-D are produced mainly by alveolar type II epithelial cells and have regulatory effects on innate immunity [5].\n\nKL-6 and SP-D levels are known to be elevated in d-pneumonia [6–8]. However, one study reported that level was below the cut-off value at onset, increased over time, and then decreased again [9]. Thus, KL-6 levels might differ over time.\n\nThere are several reports regarding the differences between KL-6, SP-A, and SP-D levels. However, there have been no detailed studies. Moreover, SP-A and SP-D are secretory proteins, but KL-6 is a cell membrane protein. This difference may be a factor resulting in differences in serum concentration. Activation of a specific enzyme is necessary to cleave KL-6 from the cell membrane, and it is thought that a more severe injury must occur for the circulating KL-6 level to increase. If there is an elevation of SP-D and no elevation of KL-6, it is likely that only mild injury is present.\n\nBoth SP-A and SP-D are said to have regulatory effects on innate immunity, but there are more reports on the regulatory effects of SP-A compared to those of SP-D. SP-A is known to bind to gram-negative bacilli (such as Escherichia coli, K. pneumoniae, and Haemophilus influenzae) and gram-positive cocci (such as haemolytic streptococcus and pneumococcus). Thus, SP-A levels may be sufficiently elevated in patients with bacterial pneumonia [10, 11].\n\nIn the recent years, various drugs have been used for treating diseases such as cancer and connective tissue disorders, and the incidence of d-pneumonia has increased accordingly. Some cases of d-pneumonia improve rapidly with anti-inflammatory drugs, such as steroids or immunosuppressants, while others associated with cell damage do not improve with these drugs. The patients in this study showed relief after the use of anti-inflammatory drugs at least initially; however, d-pneumonia caused by immune checkpoint inhibitors might be exacerbated once the effect of anti-inflammatory drugs weakens, even if the subjects were relieved initially. The d-pneumonia may require early diagnosis and treatment with adequate anti-inflammatory drugs.\n\nThere have been no reports on the usefulness of SP-D as a biomarker for d-pneumonia. The results of the present study suggest that SP-D can be a useful marker to differentiate between d-pneumonia and b-pneumonia.\n\nThere were some limitations to this study. Since this was a retrospective study, there was some variability in the time until the diagnosis of d-pneumonia. The d-pneumonia caused by molecular-targeted drugs and immune checkpoint inhibitors was diagnosed relatively early; however, that caused by other drugs took longer to diagnose. In the future, blood tests should be performed at the onset of pneumonia, and prospective studies should be conducted.\n\nConclusion\n\nSerum SP-D was useful in differentiating d-pneumonia and b-pneumonia. Our study indicated that d-pneumonia can be treated early by measuring the SP-D level during initial examination.\n\nAbbreviations\n\nb-pneumonia Bacterial pneumonia\n\nCLEIA Chemiluminescent enzymeimmunoassay\n\nCRP C-reactive protein\n\nCT Computed tomography\n\nd-pneumonia Drug-induced pneumonia\n\nEIA Enzyme immunoassay\n\nKL-6 Krebs von den Lungen-6\n\nROC Receiveroperating characteristic\n\nSD Standard deviation\n\nSP Surfactantprotein\n\nWBC White blood cell\n\nAcknowledgements\n\nWe would like to thank Editage (www.editage.jp) for the English language editing.\n\nAuthors’ contributions\n\nYW planned and performed the research and drafted the manuscript. MY proposed and planned the research. KK, RC, TT, MM, TS, MY, SW, HT, YU, MA, and YI helped coordinate the research and assisted with various procedures. KK and TI coordinated the research group. All authors have read and approved the final manuscript.\n\nFunding\n\nThe authors received no funding associated with this study.\n\nAvailability of data and materials\n\nAll data generated or analysed during this study are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study was approved by the ethics committee of Kanazawa University Hospital (#1328) and the University of Fukui (#20200151).\n\nConsent for publication\n\nThis study was a retrospective study and was described at the Kanazawa University and the University of Fukui website homepages so that subjects could withdraw their consent at any time.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Kohno N Kyoizumi S Awaya Y Fukuhara H Yamakido M Akiyama M New serum indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6 Chest 1989 96 1 68 73 2661160\n2. Kuroki Y Tsutahara S Shijubo N Takahashi H Shiratori M Hattori A Honda Y Abe S Akino T Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis Am Rev Respir Dis 1993 147 3 723 9 8442609\n3. Honda Y Kuroki Y Matsuura E Nagae H Takahashi H Akino T Abe S Pulmonary surfactant protein D in sera and bronchoalveolar lavage fluids Am J Respir Crit Care Med 1995 152 6 Pt 1 1860 6 8520747\n4. Tsuzuki A Kuroki Y Akino T Pulmonary surfactant protein A-mediated uptake of phosphatidylcholine by alveolar type II cells Am J Physiol 1993 265 2 Pt 1 L193 9 8368329\n5. Takahashi H Kuroki Y Tanaka H Saito T Kurokawa K Chiba H Sagawa A Nagae H Abe S Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis Am J Respir Crit Care Med 2000 162 1 258 63 10903251\n6. Nakajima M Kawahara Y Yoshida K Miyashita N Niki Y Matsushima T Serum KL-6 as a possible marker for amiodarone-induced pulmonary toxicity Intern Med 2000 39 12 1097 100 11197799\n7. Ohnishi H Yokoyama A Kondo K Hamada H Abe M Nishimura K Hiwada K Kohno N Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases Am J Respir Crit Care Med 2002 165 3 378 81 11818324\n8. Miyata M Sakuma F Fukaya E Kobayashi H Rai T Saito H Kasukawa R Suzuki S Detection and monitoring of methotrexate-associated lung injury using serum markers KL-6 and SP-D in rheumatoid arthritis Intern Med 2002 41 6 467 73 12135181\n9. Nakajima M Manabe T Mitekura H Hashiguchi K Niki Y Matsushima T [Levels of serum KL-6 in a patient with drug-induced pneumonitis] Nihon Kyobu Shikkan Gakkai Zasshi 1997 35 7 813 7 9341289\n10. Lawson PR Reid KB The roles of surfactant proteins A and D in innate immunity Immunol Rev 2000 173 66 78 10719668\n11. Crouch E Hartshorn K Ofek I Collectins and pulmonary innate immunity Immunol Rev 2000 173 52 65 10719667\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2200-6133",
"issue": "13(1)",
"journal": "Pneumonia (Nathan Qld.)",
"keywords": "Bacterial pneumonia; Drug-induced pneumonia; Krebs von den Lungen-6; Surfactant protein A; Surfactant protein D",
"medline_ta": "Pneumonia (Nathan)",
"mesh_terms": null,
"nlm_unique_id": "101663459",
"other_id": null,
"pages": "11",
"pmc": null,
"pmid": "34088359",
"pubdate": "2021-06-05",
"publication_types": "D016428:Journal Article",
"references": "10903251;12135181;8442609;10719668;11818324;8368329;10719667;2661160;11197799;9341289;8520747",
"title": "Surfactant protein D: a useful marker for differentiation of drug-induced pneumonia and bacterial pneumonia.",
"title_normalized": "surfactant protein d a useful marker for differentiation of drug induced pneumonia and bacterial pneumonia"
} | [
{
"companynumb": "JP-DSJP-DSJ-2021-117630",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
"drugadditional": "1",
... |
{
"abstract": "Coagulation abnormalities and thrombosis have been recently identified as sequelae of severe infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report a case of severe coagulopathy manifesting with right upper limb arterial and deep vein thrombosis in an 80-year-old male patient with severe COVID-19 associated pneumonia. He clinically deteriorated and received care in the intensive care unit where he was intubated. At that point, his coagulation laboratory tests were deranged, and he eventually developed dry gangrene in his right thumb and index finger, as well as a deep venous thromboembolism in his right axillary vein. Despite receiving treatment dose anticoagulation and undergoing arterial embolectomy, revascularization was unsuccessful. Amputation of the right arm at the level of the elbow was considered, but the patient died from respiratory failure.",
"affiliations": "First Orthopaedic Department, School of Medicine, Aristotle University of Thessaloniki, George Papanikolaou General Hospital, Thessaloniki 57010, Greece.;School of Basic and Medical Biosciences, King's College London, London SE1 9RT, UK.;First Orthopaedic Department, School of Medicine, Aristotle University of Thessaloniki, George Papanikolaou General Hospital, Thessaloniki 57010, Greece.;Radiology Department, George Papanikolaou General Hospital, Thessaloniki 57010, Greece.;Radiology Department, George Papanikolaou General Hospital, Thessaloniki 57010, Greece.;First Orthopaedic Department, School of Medicine, Aristotle University of Thessaloniki, George Papanikolaou General Hospital, Thessaloniki 57010, Greece.",
"authors": "Galanis|Nikiforos|N|;Stavraka|Chara|C|0000-0001-7623-299X;Agathangelidis|Filon|F|;Petsatodis|Evangelos|E|;Giankoulof|Christos|C|;Givissis|Panagiotis|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jscr/rjaa204",
"fulltext": "\n==== Front\nJ Surg Case Rep\nJ Surg Case Rep\njscr\nJournal of Surgical Case Reports\n2042-8812 Oxford University Press \n\n10.1093/jscr/rjaa204\nrjaa204\nAcademicSubjects/MED00910\njscrep/0180\nCase Report\nCoagulopathy in COVID-19 infection: a case of acute upper limb ischemia\nGalanis Nikiforos 1 http://orcid.org/0000-0001-7623-299XStavraka Chara 2 Agathangelidis Filon 1 Petsatodis Evangelos 3 Giankoulof Christos 3 Givissis Panagiotis 1 1 \nFirst Orthopaedic Department, School of Medicine, Aristotle University of Thessaloniki, George Papanikolaou General Hospital, Thessaloniki 57010, Greece\n2 \nSchool of Basic and Medical Biosciences, King’s College London, London SE1 9RT, UK\n3 \nRadiology Department, George Papanikolaou General Hospital, Thessaloniki 57010, Greece\nCorrespondence address. Guy’s Hospital, Great Maze Pond, SE1 9RT London, UK. Tel:+44 20 7188 7188; E-mail: chara.stavraka@kcl.ac.uk\n6 2020 \n02 7 2020 \n02 7 2020 \n2020 6 rjaa20426 5 2020 1 6 2020 Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2020.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nCoagulation abnormalities and thrombosis have been recently identified as sequelae of severe infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report a case of severe coagulopathy manifesting with right upper limb arterial and deep vein thrombosis in an 80-year-old male patient with severe COVID-19 associated pneumonia. He clinically deteriorated and received care in the intensive care unit where he was intubated. At that point, his coagulation laboratory tests were deranged, and he eventually developed dry gangrene in his right thumb and index finger, as well as a deep venous thromboembolism in his right axillary vein. Despite receiving treatment dose anticoagulation and undergoing arterial embolectomy, revascularization was unsuccessful. Amputation of the right arm at the level of the elbow was considered, but the patient died from respiratory failure.\n\ncoagulopathyarterial thrombosisdeep vein thrombosisnovel coronavirus pneumoniarevascularization\n==== Body\nINTRODUCTION\nSince the beginning of the pandemic, it has become evident that COVID-19 infection does not only affect the respiratory tract but in some patients it seems to evolve to a systemic disease with severe complications such as acute respiratory distress syndrome (ARDS) and multi-organ failure [1]. Approximately 20–55% of patients with COVID-19 infection develop coagulation abnormalities, which correlate with the severity of their infection and are associated with higher mortality [2]. Patients with COVID-19 coagulopathy have a tendency to develop both arterial and venous thromboembolic events than bleeding [3]. There is little knowledge so far as to the optimal management of these patients, as COVID-19-related coagulopathy appears to have distinct clinicopathological features from other systemic coagulopathies associated with severe infection such as disseminated intravascular coagulation (DIC) [4].\n\nWe present a case of an 80-year-old patient with confirmed COVID-19 infection, who developed severe coagulopathy with peripheral arterial infarcts and deep venous thromboembolism. He was admitted to G. Papanikolaou General Hospital in Thessaloniki, a tertiary hospital set as a reference center for COVID-19 patients.\n\nCASE REPORT\nAn 80-year-old man presented to the emergency department with fever, shortness of breath and a dry cough. His past medical history included hypertension, well-controlled non-insulin-dependent diabetes and mild dementia. His regular medications were amlodipine 10 mg once a day and metformin 1000 mg twice daily, and he was not known to have any drug allergies. He was a non-smoker and consumed alcohol socially. Due to the COVID-19 pandemic and according to the guidelines issued by the Greek National Public Health Organization, the patient was admitted under the respiratory medicine department, was isolated as a potential COVID-19 positive case and underwent a nasopharyngeal swab. The diagnosis of COVID-19 infection was confirmed with a reverse transcriptase polymerase chain reaction (RT-PCR) assay.\n\nHe initially received supportive treatment but clinically deteriorated 48 h post admission, developing hypoxemic respiratory failure. His chest X-ray and computed tomography (CT) of the chest at that time revealed multiple ground glass opacities and areas of consolidation (Fig. 1). He was transferred to the intensive care unit (ICU), where he was intubated, and his treatment was escalated to broad-spectrum antibiotics and hydroxychloroquine. He had been on prophylactic enoxaparin (6000 IU/once daily) since the beginning of his hospital admission. Laboratory results upon ICU transfer are summarized in Table 1. In regard to his coagulation parameters, he had a prolonged activated partial thromboplastin time (aPTT), increased D-dimer and fibrinogen. His platelets were within normal range.\n\nFigure 1 CT of the chest showing bilateral multiple ground glass opacities and areas of consolidation consistent with COVID-19 pneumonia.\n\nTable 1 Patient characteristics and laboratory findings\n\nCharacteristic\t\nDemographic characteristics\t\nAge: year\t80\t\nSex\tMale\t\nMedical history\tNon-insulin-dependent diabetes, dementia\t\nLaboratory findings on ICU admission\t\nWhite cell count (per mm3)\t5600\t\nDifferential count (per mm3)\t\t\nNeutrophils\t4900\t\nLymphocytes\t600\t\nMonocytes\t100\t\nPlatelet count (per mm3)\t174 000\t\nHemoglobin (g/L)\t123\t\nAlanine aminotransferase (U/L)\t42\t\nAspartate aminotransferase (U/L)\t43\t\nLactate dehydrogenase (U/L)\t534\t\nAlbumin (g/L)\t27\t\nCreatinine (μmol/L)\t134\t\nProthrombin time (s)\t15.4\t\nActivated partial thromboplastin time (s)\t27.8\t\nInternational normalized ratio\t1:31\t\nFibrinogen (g/L)\t3.6\t\nD-dimer (mg/L)\t13.6\t\nC-reactive protein (mg/L)\t166\t\nFerritin (μg/L)\t721\t\nProcalcitonin (ng/ml)\t0.1\t\nCardiac troponin I (pg/ml)\t342\t\nSeven days later, while his general condition was deteriorating, he developed acute ischemia in his right thumb and index finger (Fig. 2). In the ipsilateral forearm, a radial artery catheter had been inserted for monitoring. An urgent radial artery embolectomy was performed and restored the arterial supply to the right hand. The antithrombotic agent was changed to fondaparinux (7.5 mg/once daily). However, within the next few days, it was clinically evident that the revascularization effort was unsuccessful as the thumb and index finger developed dry gangrene. On examination, there was no palpable radial pulse, the ulnar artery pulse was palpable at the level of the wrist and the capillary refill time was normal at the middle, ring and little fingers. A CT angiography (Figs 3 and 4) was performed, demonstrating complete thrombosis of the radial artery beginning at the level of the elbow as well as a 70% occlusion of the ulnar artery ~15 cm proximal to the wrist. Thrombosis of the right axillary vein was also seen (Fig. 5). Orthopedic review was requested for consideration for finger amputation with a recommendation for arm amputation at the level of the elbow. Unfortunately, the patient died 72 h later from respiratory failure following a 24-day admission in ICU.\n\nFigure 2 Dry gangrene of the right thumb and index fingers.\n\nFigure 3 CT angiography of the right upper limb with volume rendering showing complete radial artery thrombosis beginning at the level of the elbow at the same level that embolectomy was performed. Also, there was significant ulnar artery stenosis near occlusion, ~15 cm proximal to the wrist. The ulnar artery appeared to be normal peripherally to the level of obstruction, with no collaterals being visible.\n\nFigure 4 Multiplanar reformation image shows severe near occlusion 6-mm stenosis of the ulnar artery.\n\nFigure 5 Multiplanar reformation image shows filling defect in the right axillary vein consistent with thrombosis.\n\nDISCUSSION\nThere is a growing amount of evidence associating severe COVID-19 infection with a hypercoagulable state with distinct characteristics from that of other infection-associated coagulopathies [2, 4]. This has been reported to manifest with peripheral arterial infarcts as well as with pulmonary and deep venous thromboembolisms in critically ill patients, even despite anticoagulation [3, 5].\n\nMarked elevation of D-dimers and fibrinogen along with some degree of thrombin (PT) and aPTT prolongation have been frequently reported hemostatic abnormalities in patients with COVID-19 and associated with worse survival outcomes.[6] In some cases, the presence of antiphospholipid antibodies has also been reported [5, 7].\n\nThe exact pathogenetic mechanisms underpinning this hypercoagulable state are yet to be fully elucidated. It remains unclear whether endothelial injury is caused directly by COVID-19 or as consequence of the systemic inflammatory response syndrome or even triggered by the use of intravascular catheters [8]. Results from autopsy studies in patients who died from COVID-19 infection revealed the presence of generalized thrombotic microangiopathy mainly affecting elderly male individuals with obesity and cardiovascular comorbidities.[9] However, arterial events presenting as acute limb ischemia have also been reported in younger patients with no comorbidities and while receiving prophylactic dose low molecular weight heparin [10]. It remains unclear from the existing literature whether amputation has any merit in the management of acute limb ischemia when mechanical and pharmacological attempts for revascularization have failed.\n\nEffective prevention and treatment measures for these thromboembolic events remain a challenge due to the lack of a clear understanding of the exact underlying mechanism, as well as the paucity of high-quality studies. Our case contributes further evidence to the existing literature regarding the systemic thromboembolic complications associated with COVID-19 and highlights their adverse prognostic impact. It is critical to monitor for thromboembolic events particularly in patients with high-risk features. Further evidence is required for the role of amputation surgery and its impact on survival when initial interventions for revascularization fail to restore blood flow.\n\nCONFLICT OF INTEREST\nAll authors declare no conflict of interest.\n\nFunding\nNone.\n==== Refs\nREFERENCES\n1. \nBhatraju PK , Ghassemieh BJ , Nichols M , Kim R , Jerome KR , Nalla AK , et al. \nCovid-19 in critically ill patients in the Seattle region — case series\n. N Engl J Med 2020 ;382 :2012 –2022\n.32227758 \n2. \nLee SG , Fralick M , Sholzberg M \nCoagulopathy associated with COVID-19\n. Can Med Assoc J 2020 ;192:E583 .\n3. \nOxley TJ , Mocco J , Majidi S , Kellner CP , Shoirah H , Singh IP , et al. \nLarge-vessel stroke as a presenting feature of Covid-19 in the young\n. N Engl J Med 2020 ;382 :e60 .32343504 \n4. \nGavriilaki E , Brodsky RA \nSevere COVID-19 infection and thrombotic microangiopathy: success doesn't come easily\n. Br J Haematol 2020 . Online ahead of print. doi: 10.1111/bjh.16783 .\n5. \nZhang Y , Xiao M , Zhang S , Xia P , Cao W , Jiang W , et al. \nCoagulopathy and antiphospholipid antibodies in patients with Covid-19\n. N Engl J Med 2020 ;382 :e38 .32268022 \n6. \nRanucci M , Ballotta A , Di Dedda U , Bayshnikova E , Dei Poli M , Resta M , et al. \nThe procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome\n. J Thromb Haemost 2020 . Epub ahead of print. doi: 10.1111/jth.14854 .\n7. \nBowles L , Platton S , Yartey N , Dave M , Lee K , Hart DP , et al. \nLupus anticoagulant and abnormal coagulation tests in patients with Covid-19\n. N Engl J Med 2020 . Epub ahead of print. doi: 10.1056/NEJMc2013656 .\n8. \nBikdeli B , Madhavan MV , Jimenez D , Chuich T , Dreyfus I , Driggin E , et al. \nCOVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up\n. J Am Coll Cardiol 2020 ;75 :2950 –2973\n.32311448 \n9. \nMenter T , Haslbauer JD , Nienhold R , Savic S , Hopfer H , Deigendesch N , et al. \nPost-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction\n. Histopathology 2020 . Epub ahead of print. doi: 10.1111/his.14134 .\n10. \nBellosta R , Luzzani L , Natalini G , Pegorer MA , Attisani L , Cossu LG , et al. \nAcute limb ischemia in patients with COVID-19 pneumonia\n. J Vasc Surg 2020 . Epub ahead of print. doi: 10.1016/j.jvs.2020.04.483 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2042-8812",
"issue": "2020(6)",
"journal": "Journal of surgical case reports",
"keywords": "arterial thrombosis; coagulopathy; deep vein thrombosis; novel coronavirus pneumonia; revascularization",
"medline_ta": "J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101560169",
"other_id": null,
"pages": "rjaa204",
"pmc": null,
"pmid": "32661487",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "32369610;32302448;32311448;32364264;32268022;32227758;32343504;32360679;32369280;32357997",
"title": "Coagulopathy in COVID-19 infection: a case of acute upper limb ischemia.",
"title_normalized": "coagulopathy in covid 19 infection a case of acute upper limb ischemia"
} | [
{
"companynumb": "GR-MYLANLABS-2021M1022406",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": nu... |
{
"abstract": "Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.",
"affiliations": "Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany.;Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany.;Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany.;Rheumatologische Schwerpunktpraxis Würzburg, Würzburg, Germany.;Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany.;Kinderklinik und Poliklinik, Universität Würzburg, Würzburg, Germany.;Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany.;Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany.",
"authors": "Froehlich|Matthias|M|;Schwaneck|Eva C|EC|;Gernert|Michael|M|;Gadeholt|Ottar|O|;Strunz|Patrick-Pascal|PP|;Morbach|Henner|H|;Tony|Hans-Peter|HP|;Schmalzing|Marc|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2020.01317",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.01317\nImmunology\nCase Report\nAutologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis\nFroehlich Matthias 1* Schwaneck Eva C. 1 Gernert Michael 1 Gadeholt Ottar 2 Strunz Patrick-Pascal 1 Morbach Henner 3 Tony Hans-Peter 1 Schmalzing Marc 1 1Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany\n2Rheumatologische Schwerpunktpraxis Würzburg, Würzburg, Germany\n3Kinderklinik und Poliklinik, Universität Würzburg, Würzburg, Germany\nEdited by: Sudhir Gupta, University of California, Irvine, United States\n\nReviewed by: Neena Kapoor, Children's Hospital of Los Angeles, United States; David Andrew Fulcher, Australian National University, Australia\n\n*Correspondence: Matthias Froehlich froehlich_m@ukw.deThis article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n\n25 6 2020 \n2020 \n11 131702 4 2020 26 5 2020 Copyright © 2020 Froehlich, Schwaneck, Gernert, Gadeholt, Strunz, Morbach, Tony and Schmalzing.2020Froehlich, Schwaneck, Gernert, Gadeholt, Strunz, Morbach, Tony and SchmalzingThis 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.Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.\n\ncommon variable immunodeficiencyprimary immunodeficienciesautoimmunityautologous stem cell transplantationautoimmune encephalitis\n==== Body\nIntroduction\nCommon variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. The primary finding is hypogammaglobulinemia (1). Clinical symptoms are heterogeneous with different levels of immune dysregulation (2). In addition to infectious complications, autoimmune manifestations, including immune cytopenias, pneumonia, inflammatory bowel disease, and granulomatous inflammation, occur in about 20% of cases (3). Central nervous system (CNS) involvement is rare in CVID; most data are found for cerebral granulomatous disease (4), one case reported unilateral optic neuritis (5). Management of CVID includes immunoglobulin replacement (IgRT), immunosuppressive therapy for autoimmune manifestations, and close surveillance for the development of additional comorbidities (2). In this case report, we present a young woman with CVID who developed autoimmune CNS involvement, comprising brain and spinal cord. To our knowledge, this is one of very few cases reporting non-granulomatous CNS involvement. In addition, this is the first case demonstrating the effective and safe performance of autologous HSCT as treatment of a severe, organ-threatening, refractory autoimmune manifestation in CVID.\n\nCase Presentation\nA 35-year-old woman was admitted at our hospital for pleural empyema. Primary antibiotic treatment was followed by surgical removal of the affected lung sub-segment. Histology showed a fibrosing reaction with histological pattern of non-specific interstitial pneumonia (NSIP), as well as typical infectious features. Since adolescence, the patient suffered from recurring respiratory infections. At the age of 15, she developed immune thrombocytopenia, which was successfully treated with several cycles of intravenous immunoglobulins. In her early 30s, she twice suffered from herpes zoster reactivation.\n\nFurther examination revealed splenomegaly, abdominal lymphadenopathy, and decreased serum immunoglobulin levels. According to the guidelines of the European Society for Immunodeficiencies (ESID) (6), diagnosis of CVID could be made. Total immunoglobulin values at diagnosis were IgG 598 mg/dl, IgA < 5 mg/dl, IgM 27 mg/dl. The lymphocyte count was reduced (760/μl) with low levels of CD4+ T-helper cells (234/μl), reduced naïve CD4+ T-helper cells (11,2% of all CD4+ T-cells), but immunophenotyping showed a normal percentage of NK cells, T-cells and B-lymphocytes with disturbed maturation and reduction of switched memory B-cells and an increase in CD21 low B-cells, which according to the classification for immunodeficiencies (EUROclass) corresponds to the following subgroup: smB- TRhigh CD21low (7). Due to the low T-cell count, classification as a combined Immunodeficiency (CID) would also have been possible. Furthermore the patient displayed a decreased frequency of regulatory T cells (Treg) which also indicated a dysfunctional phenotype with low expression of CTLA4 (cytotoxic T-lymphocyte-associated Protein 4) as well as FOXP3 (Supplemental Figure 1). Molecular genetic testing for typical genetic defects in CVID such as LRBA, CD3G, IL2RA, LAT, LCK, PIK3CD, PIK3R1, PTEN, STAT3, ZAP70, or CTLA4 deficiency, yielded no results. Other causes of secondary hypogammaglobulinemia, such as HIV, were excluded. No lymphoma was found by bone marrow trephine biopsy or total body CT scan.\n\nThe patient recovered well under antibiotic therapy. Immunoglobulin replacement therapy (IgRT) with subcutaneous immunoglubulins (0.5 g/kg body weight every 4 weeks combined with hyaluronidase, target trough level of 6 g/l) was initiated. Despite stable clinical representation, a chest CT scan 2 months later showed progressive infiltrates of the lung parenchyma, as well as bronchiectasis. To rule out a new infection, a bronchoscopy was performed, which showed no evidence of bacterial or mycotic infection, including TB. Virus PCR for EBV, CMV, and common respiratory tract infections was negative.\n\nWe therefore considered the infiltrates a manifestation of CVID, most likely as granulomatous-lymphocytic interstitial lung disease (GLILD), and started immunosuppressive therapy with prednisolone (1 mg/kg) and subsequent taper, and azathioprine (2.5 mg/kg/day). A CT scan 6 months later showed a significant improvement of the pulmonary infiltrates, the patient had no relevant infections since starting IgG substitution.\n\n4 months later the patient suffered a generalized epileptic seizure. Cerebral MRI showed several periventricular, subependymal, and leptomeningeal lesions with intensive contrast medium uptake. The criteria for multiple sclerosis were not met on the basis of the distribution pattern and a pattern of different ages of lesions. The largest lesion was located in the left posterior lobe with a diameter of 4.4 cm (Figure 1). CSF analysis showed a mild pleocytosis with a normal protein content. Oligoclonal bands were not detectable. A eubacterial 16S rRNA PCR was negative, as were PCRs for HSV, VZV, EBV, CMV, HHV6, HHV7, HHV8, adenovirus, enterovirus, BK virus, and JC virus.\n\nFigure 1 Hyperintense lesion with perifocal edema left occipital in fluid-suppressed T2 MRI technique (Fluid-attenuated inversion recovery (FLAIR) sequence).\n\nWe proceeded to biopsy the occipital lesion by stereotactic puncture. The histological examination showed an inflammation with predominantly perivascular accumulation of T-lymphocytes and an increase in plasma cells without kappa/lambda light chain restriction. Malignant cells, granulomas, or demyelinating plaques were not detected. Hence, the etiology remained unclear. Another whole-body CT scan as well as a further bone marrow trephine biopsy did not show any pathological findings. Due to the lack of clarity and the therapeutic relevance, a second stereotactic biopsy was performed. This second tissue sample was sent to the German Reference Laboratory for Neuropathology. Again, no signs of malignancy were found, as well as no evidence of infection or demyelination, the pattern of T-cell predominant perivascular lymphocytic infiltration was confirmed. Thus, the histological findings as well as the other previous findings were compatible with an autoimmune encephalitis. Important differential diagnoses like lymphoma or multiple sclerosis were excluded.\n\nIn addition to IgRT, we started a more intensive immunosuppressive therapy with 2 cycles of rituximab 1,000 mg i.v. and high-dose steroids (prednisolone ~1.5 mg/kg/day) with subsequent taper. An MRI control of the CNS a few weeks later showed receding lesions. The patient's condition was stable with additional administration of an anticonvulsant and azathioprine as maintenance therapy. However, under the dose of azathioprine 2.5 mg/kg/day and prednisolone 15 mg/day, another MRI control 2 months later showed a renewed increase in intracerebral inflammatory activity with progressing lesions. Immunosuppressive therapy was escalated using cyclophosphamide (750 mg/m2 iv every 3 weeks), with additional trimethoprim/sulfamethoxazole prophylaxis. Azathioprine was discontinued. A staging MRI 3 cycles of cyclophosphamide showed a mixed response. New lesions were found in the medulla oblongata and in the posterolateral cervical medulla. MRI of the entire spinal cord showed focal lesions in the cervical and thoracic myelon extending to the Th2 segment (Figure 2). The clinical examination was inconspicuous, with no evidence of neurological symptoms.\n\nFigure 2 Hyperintense lesions in medulla oblongata and in cervical and upper thoracic spinal cord in contrast enhanced, fat suppressed T1 MRI technique.\n\nWe initiated therapy with abatacept, a T cell activation modulator 14 mg/kg bw i.v. (week 0, 2, then every 4 weeks), also due to the known Treg CTLA4 deficiency. In addition, a high-dose therapy with steroids (prednisolone 1,000 mg for 3 days) with subsequent dose reduction to 1 mg/kg body weight and then further tapering was performed. Again, MRI control of the CNS and spinal cord after initial improvement showed progression 3 months after starting abatacept.\n\nUp to this point, no treatment regime had led to a sustained improvement in cerebral or spinal inflammation. The diagnosis underwent a critical review, including renewed CT, CSF analysis, and infection screening. No new findings were made. A further biopsy was not performed.\n\nDue to the organ-threatening character of the inflammatory activity, which could not be controlled despite the previous intensive immunosuppression, we saw an autologous stem cell transplantation as the best possibility to intensify the therapy. Other therapy options did not seem promising in this situation. We used a well-established protocol according to the guidelines of European Group for Blood and Marrow Transplantation (EBMT). For mobilization of autologous hematopoietic stem cells, the patient received cyclophosphamide 2 g/m2 together with a daily dose of 105 μg G-CSF, starting on the second day after cyclophosphamide administration. Leukapharesis was performed on day 10. The autologous hematopoietic stem cells underwent CD34+-selection using immunomagnetic separation (CliniMACS CD34 Complete Kit, Miltenyi Biotec, Bergisch Gladbach, Germany). 8 weeks after apheresis, conditioning with cyclophosphamide (4 × 50 mg/kg body weight) and rabbit antithymocyte globulin (rATG) (3 × 5 mg/kg body weight) was administered over 5 days. On day 1 after conditioning, the autologous graft was transplanted (2.6 × 106 CD34+ cells/kg body weight). During the subsequent aplasia phase until engraftment, the patient had several typical adverse events. Due to thrombocytopenia a small, non-significant subdural hematoma occurred. Substitution of 2 platelet concentrates stabilized hemostasis sufficiently. In addition, 2 red cell concentrates were given due to severe anemia. Apart from sinusitis, which was treated with antibiotics, no relevant infectious complications occurred. The patient received oral acyclovir and posaconazole prophylaxis. IgRT was continued unchanged to keep immunoglobulin levels stable within target range (6 g/l). Recovery of neutrophils above 500/μl occurred on day 14 after transplantation. Lymphocyte counts remained low at 700/μl on day 30. However, rather low values had already been measured before transplantation, probably because of the CVID itself, or due to immunosuppressive therapy. As was to be expected, the number of CD4+ T-helper cells was significantly reduced after transplantation (52/μl on day). On the day of discharge a low dose of prednisolone (10 mg/day) was maintained, as well as prophylactic oral therapy with trimethoprim/sulfamethoxazole, oral amphotericin B, and acyclovir. A CNS-MRI 3 weeks after discharge showed a significant decrease in intracerebral and intraspinal inflammation. Further controls after 3, 7, and 12 months showed a complete disappearance of the lesions. The health condition of the patient improved steadily. Regular controls of the immune reconstitution by immunophenotyping showed a gradual increase of T cells and B cells in the following months. After 11 months the CD4+ T helper cells reached 200/μl, so that acyclovir and amphotericin B were discontinued, trimethoprim/sulfamethoxazole was continued. As a sign of increased plasma cell activity during reconstitution there was an increase in polyclonal IgM. We decided to administer rituximab as B cell depleting maintenance therapy (1,000 mg, day 0, 15). The first cycle was given 9 months after transplantation, a second cycle 6 months later, resulting in a complete depletion of B cells and a decrease in IgM. Prednisolone was reduced to a minimal dose of 2.5 mg/day. 18 months after transplantation the patient is in good health without autoimmune symptoms, regular MRI controls show a sustained remission. Under persistent IgRT no severe infection has occurred since transplantation. The patient resumed her daily activities and her former profession.\n\nDiscussion\nWe present a case of a female patient (35) with autoimmune encephalitis as a CNS manifestation of CVID, which was successfully treated by immunoablative conditioning and transplantation of autologous CD34-selected stem cells. CNS involvement in CVID is rare, especially in the form of autoimmune encephalitis (4). It is therefore of utmost importance to distinguish between an autoimmune CVID manifestation of the CNS and differential diagnoses, especially cerebral lymphoma or infectious complications, as far as possible. This was done in our patient by repeated imaging, two biopsies and extensive testing of CSF.\n\nThere is increasing evidence that, in addition to B cell dysfunction, T cell dysfunction plays an important role in autoimmunity in CVID (8). In a large cohort, it was shown that total T cells in CVID patients with autoimmune symptoms were lower than in those without autoimmunity (9). The degree of reduction of CD4+ T cells correlates with the severity of autoimmune symptoms (10, 11). Within the CD4+ T cells, a reduced number of regulatory T cells is associated with autoimmunity in CVID (12). Our patient showed normal total T cells, however, a reduced expression of the T cell surface protein CTLA4 on T reg could be detected as surrogate of disturbed T reg function (13). Mutations of CTLA4 are common in CVID patients and are associated with autoimmunity through the disruption of self-tolerance regulation (11). Based on these findings, our patient was treated with abatacept, a T-cell activation modulator, which has been shown to be effective in the treatment of other syndromes associated with CTLA4 deficiency (14). In this patient, abatacept was ineffective.\n\nThe most intensive form of therapy for primary immunodeficiencies (PID) is allogenic stem cell transplantation. Since most forms of PID are based on monogenetic defects intrinsic to hematopoietic cells (15), the treatment of primary immunodeficiency by replacing the mutated cells with healthy donor hematopoietic stem cells and establishing alloimmunity is a potentially curative approach. Based on proper strategies in selection of a suitable donor (16–19) and GvHD prophylaxis, reduced intensity conditioning regimes (20) and better supportive care overall survival reaches up to 85% today even for patients who undergo transplantation in young adulthood (21).\n\nThe role of allogeneic stem cell transplantation in CVID is controversial. Wehr et al. (22) showed results of a retrospective evaluation of 25 patients who underwent allogeneic stem cell transplantation for CVID. The indication was mainly based on the presence of immune dysregulation and not on infections. However, the mortality rate of CVID patients was 52% after allogeneic HSCT, which is significantly higher than for other PID. The main causes were treatment-resistant graft-vs.-host disease and infectious complications. On the other hand, survivors no longer needed IgRT in 50% of cases, and in 92% of surviving patients, health complaints that were the indication for allogeneic stem cell transplantation were significantly improved.\n\nAutologous stem cell transplantation aims to “reset” the immune system by eradicating the autoreactive immunological memory. In contrast to allogeneic stem cell transplantation, transfusion of the patient's own stem cells does not generate alloimmunity. Immuno-ablative therapy and transfusion of CD34-selected stem cells causes a profound regeneration of the adaptive immune system with lasting changes in T-cell and B-cell subpopulations from memory to naive cell dominance (23, 24). The transplantation leads to a renewal of naive T cells including regulatory T cells via reactivation of the thymus (25). Furthermore, a diversification of the T cell receptor repertoire can be observed (26, 27). This can only be partially seen in our patient so far: While there was a normalization of natural killer cells within 6 months after transplantation, a persistent reduction of T cells was also detectable 18 months after the procedure with low levels of naïve CD4+ T cells. Delayed repopulation of naive CD4+ T lymphocytes was seen in several studies up to 24 months after transplantation (28–30) and correlated with an increase in TCR excision circles (TREC) (31, 32), which serve as a surrogate for increased biosynthesis of the T cell receptor (33, 34).\n\nIn this context it could also be shown that TREC levels were higher in autologous stem cell transplantation when a CD34+ selection of the transplant was performed (25). However, the role of CD34+ selection in SCT of autoimmune diseases is controversially discussed. A retrospective analysis of autoimmune patients in the European Bone Marrow Transplantation Database (EBMT) did not show an improvement of response using CD34+ selected grafts (35). A randomized study on CD34+ selection in autologous stem cell transplantation in patients with rheumatoid arthritis did not show any benefit in the outcome (36), nor did a recent retrospective study evaluating CD34+ selection in systemic sclerosis (37). On the other hand, it is considered that the return of a lymphocyte-depleted transplant results in the most complete eradication of autoreactive T cell clones, which is the basis for a stable, long-lasting remission. This hypothesis is supported by studies in multiple sclerosis patients who received a CD34+ selected autologous stem cell transplant and subsequently had no evidence of new inflammatory activity for up to 13 years after treatment (38). In addition, a prospective evaluation of the EBMT on patients with systemic sclerosis could now demonstrate a benefit of CD34+ selection in autologous stem cell transplantation in terms of outcome, which could possibly be due to the now more homogeneous conditioning regimen (39). A Japanese study recently showed similar results (40).\n\nOne of the main indications for autologous stem cell transplantation in autoimmune diseases today is multiple sclerosis (MS) (35), which is also an autoimmune cerebral inflammation. In contrast to CVID, several studies have already well investigated the effectiveness of autologous stem cell transplantation on MS (41). In a meta-analysis of 280 patients who received autologous stem cell transplantation, the overall survival rate was 93% after 5 years (42). Depending on the different subtypes of the disease, a progression-free survival in terms of a deterioration of the Expanded Disability Status Scale (EDSS) of up to 73% after 5 years was achieved. Similar to the analysis of Wehr et al. on allogeneic transplantation, a higher age, the number of previous therapies and the intensity of the conditioning regimen were predictors of a worse outcome. Despite several pre-treatments, the good response of our patient is thus possibly favored by the young age and the only minor chronic organ damage.\n\nTaken together, good results on the effectiveness in refractory autoimmune diseases, and the excellent control of infectious risk by IgRT in this patient, made us favor autologous against allogeneic SCT as a treatment option.\n\nSo far, there are no guidelines for the therapeutic procedure after successful transplantation of autoimmune diseases, the role of immunosuppressive maintenance therapy was not examined in studies yet and remains controversial. In our patient, IgRT was continued unchanged. Maintenance treatment with rituximab was established due to possibly severe consequences of a relapse and signs of transient excessive B cell activation after SCT.\n\nConclusion\nAutologous hematopoietic stem cell transplantation can be a highly effective therapy for the treatment of severe refractory autoimmune manifestations of CVID. In the present case, it has been shown to induce sustained remission in the rare and life-threatening case of autoimmune encephalitis. Since autoimmunity is also the indication for transplantation in most cases in allogeneic stem cell transplantation in CVID, autologous transplantation could be a viable alternative for the treatment of these patients, considering the high periprocedural morbidity and mortality of allogeneic transplantation in CVID to date. However, the management of the therapy requires a high level of expertise, and studies on larger collectives would therefore be highly desirable.\n\nData Availability Statement\nAll datasets generated for this study are included in the article/Supplementary Material.\n\nEthics Statement\nWritten informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAll authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. MF had full access to all of the data in the Case Report and takes responsibility for the integrity of the data.\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\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.01317/full#supplementary-material\n\nSupplemental Figure 1 Disturbed phenotype of regulatory T cells. Frequency of CD25+CD127-FOXP3 regulatory T cells (Treg) within CD4+ T cells (A), fluorescence intensity (MFI) of FOXP3 expression in CD25+CD127-CD4+ T cells (B), as well as ratio of CTLA4 expression between CD45RO+ Treg and CD45RO-CD25+/-CD127+FOXP3- naïve conventional T cells (Tcon) of healthy control individuals (Co) and the patient (C). The 10th and 90th percentile of each parameter within the group of control indivdiuals is shown as dashed lines. The expression of FOXP3 in CD4+CD25+CD127- T cells of the patient and a healthy control is shown in (D). The expression of CTLA-4 in CD45RO+ Treg and CD45RO- Tcon of the patient and a healthy control is shown in (E).\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Abbott JK Gelfand EW . Common variable immunodeficiency: diagnosis, management, and treatment\n. Immunol Allergy Clin N Am. (2015 ) 35 :637 –58\n. 10.1016/j.iac.2015.07.009 26454311 \n2. Bonilla FA Khan DA Ballas ZK Chinen J Frank MM Hsu JT . Practice parameter for the diagnosis and management of primary immunodeficiency\n. J Allergy Clin Immunol. (2015 ) 136 :1186 –205e1 –78\n. 10.1016/j.jaci.2015.04.049 26371839 \n3. Knight AK Cunningham-Rundles C . Inflammatory and autoimmune complications of common variable immune deficiency\n. Autoimmun Rev. (2006 ) 5 :156 –9\n. 10.1016/j.autrev.2005.10.002 16431351 \n4. Boursiquot JN1 Gérard L Malphettes M Fieschi C Galicier L Boutboul D . Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients\n. J Clin Immunol. (2013 ) 33 :84 –95\n. 10.1007/s10875-012-9778-9 22986767 \n5. Abati E Faravelli I Magri F Govoni A Velardo D Gagliardi D . Central nervous system involvement in common variable immunodeficiency: a case of acute unilateral optic neuritis in a 26-year-old italian patient\n. Front Neurol. (2018 ) 9 :1031 . 10.3389/fneur.2018.01031 30555409 \n6. European Society for Immunodeficiencies \nCommon Variable Immunodeficiency Diagnostic Criteria . Available online at: https://esid.org/Education/Diagnostic-Criteria-PID (accessed January 13, 2020)\n7. Wehr C Kivioja T Schmitt C Ferry B Witte T Eren E . The EUROclass trial: defining subgroups in common variable immunodeficiency\n. Blood. (2008 ) 111 :77 –85\n. 10.1182/blood-2007-06-091744 17898316 \n8. Fischer A Provot J Jais JP Alcais A Mahlaoui N \nmembers of the CEREDIH French PID study group. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies\n. J Allergy Clin Immunol. (2017 ) 140 :1388 –93.e8\n. 10.1016/j.jaci.2016.12.978 28192146 \n9. Azizi G Kiaee F Hedayat E Yazdani R Dolatshahi E Alinia T . Rheumatologic complications in a cohort of 227 patients with common variable immunodeficiency\n. Scand J Immunol. (2018 ) 87 :e12663 . 10.1111/sji.12663 29574865 \n10. Bateman EAL Ayers L Sadler R Lucas M Roberts C Woods A . T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections\n. Clin Exp Immunol. (2012 ) 170 :202 –11\n. 10.1111/j.1365-2249.2012.04643.x 23039891 \n11. Mouillot G Carmagnat M Gérard L Garnier J-L Fieschi C Vince N . B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease\n. J Clin Immunol. (2010 ) 30 :746 –55\n. 10.1007/s10875-010-9424-3 20437084 \n12. Arandi N Mirshafiey A Abolhassani H Jeddi-Tehrani M Edalat R Sadeghi B . Frequency and expression of inhibitory markers of CD4 + CD25 + FOXP3 + regulatory T cells in patients with common variable immunodeficiency\n. Scand J Immunol. (2013 ) 77 :405 –12\n. 10.1111/sji.12040 23432692 \n13. Schubert D Bode C Kenefeck R Hou TZ Wing JB Kennedy A . Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations\n. Nat Med. (2014 ) 20 :1410 –6\n. 10.1038/nm.3746 25329329 \n14. Lo B Zhang K Lu W Zheng L Zhang Q Kanellopoulou C . Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy\n. Science. (2015 ) 349 :436 –40\n. 10.1126/science.aaa1663 26206937 \n15. Castagnoli R Delmonte OM Calzoni E Notarangelo LD . Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives\n. Front Pediatr . (2019 ) 7 :295 . 10.3389/fped.2019.00295 31440487 \n16. Balashov D Shcherbina A Maschan M Trakhtman P Skvortsova Y Shelikhova L . Single-center experience of unrelated and haploidentical stem cell transplantation with TCRαβ and CD19 depletion in children with primary immunodeficiency syndromes\n. Biol Blood Marrow Transplant. (2015 ) 21 :1955 –62\n. 10.1016/j.bbmt.2015.07.008 26187864 \n17. Bertaina A Merli P Rutella S Pagliara D Bernardo ME Masetti R . HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders\n. Blood. (2014 ) 124 :822 –6\n. 10.1182/blood-2014-03-563817 24869942 \n18. Shah RM Elfeky R Nademi Z Qasim W Amrolia P Chiesa R . T-cell receptor αβ+ and CD19+ cell–depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency\n. J Allergy Clin Immunol. (2018 ) 141 :1417 –426.e1\n. 10.1016/j.jaci.2017.07.008 28780238 \n19. Elfeky R Shah RM Unni MNM Ottaviano G Rao K Chiesa R . New graft manipulation strategies improve the outcome of mismatched stem cell transplantation in children with primary immunodeficiencies\n. J Allergy Clin Immunol. (2019 ) 144 :280 –93\n. 10.1016/j.jaci.2019.01.030 30731121 \n20. EBMT/ESID Guidelines for Haematopoietic Stem Cell Transplantation for Primary Immunodeficiencies . Available online at: https://esid.org/layout/set/%20print/Working-Parties/Inborn-Errors-Working-Party-IEWP/Resources/UPDATED!-EBMT-ESID-GUIDELINES-FOR-HAEMATOPOIETICSTEM-CELL-TRANSPLANTATION-FOR-PI (accessed November 25, 2019)\n21. Fox TA Chakraverty R Burns S Carpenter B Thomson K Lowe D . Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency\n. Blood. (2018 ) 131 :917 –31\n. 10.1182/blood-2017-09-807487 29279357 \n22. Wehr C Gennery AR Lindemans C Schulz A Hoenig M Marks R . Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency\n. J Allergy Clin Immunol. (2015 ) 135 :988 –97.e6\n. 10.1016/j.jaci.2014.11.029 25595268 \n23. de Kleer I Vastert B Klein M Teklenburg G Arkesteijn G Yung GP . Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network\n. Blood. (2006 ) 15;107 :1696 –702\n. 10.1182/blood-2005-07-2800 15 \n24. Alexander T Arnold R Hiepe F Radbruch A . Resetting the immune system with immunoablation and autologous haematopoietic stem cell transplantation in autoimmune diseases\n. Clin Exp Rheumatol. (2016 ) 34 :53 –7\n. 27586805 \n25. Douek DC Vescio RA Betts MR Brenchley JM Hill BJ Zhang L . Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution\n. Lancet . (2000 ) 355 :1875 –81\n. 10.1016/S0140-6736(00)02293-5 10866444 \n26. Muraro PA Douek DC Packer A Chung K Guenaga FJ Cassiani-Ingoni R . Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients\n. J Exp Med . (2005 ) 201 :805 –16\n. 10.1084/jem.20041679 15738052 \n27. Delemarre EM van den Broek T Mijnheer G Meerding J Wehrens EJ Olek S . Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells\n. Blood . (2016 ) 127 :91 –101\n. 10.1182/blood-2015-06-649145 26480932 \n28. Cull G Hall D Fabis-Pedrini M Carroll W Forster L Robins F . Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS\n. Mult Scler. (2017 ) 3 :2055217317700167 . 10.1177/2055217317700167 28607754 \n29. Arruda LCM de Azevedo JTC de Oliveira GLV Scortegagna GT Rodrigues ES Palma PVB . Immunological correlates of favorable long-term clin-ical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation\n. Clin Immunol. (2016 ) 169 :47 –57\n. 10.1016/j.clim.2016.06.005 27318116 \n30. Darlington PJ Touil T Doucet JS Gaucher D Zeidan J Gauchat D . Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation\n. Ann Neurol. (2013 ) 73 :341 –54\n. 10.1002/ana.23784 23463494 \n31. Muraro PA Douek DC Packer A Chung K Guenaga FJ Cassiani-Ingoni R . Thymic output generates a new and diverse TCR repertoire after auto-logous stem cell transplantation in multiple sclerosis patients\n. J Exp Med. (2005 ) 201 :805 –16\n. 10.1084/jem.20041679 15738052 \n32. Abrahamsson SV Angelini DF Dubinsky AN Morel E Oh U Jones JL . Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis\n. Brain. (2013 ) 136 (Pt 9 ):2888 –903\n. 10.1093/brain/awt182 23864273 \n33. Mackall CL Fleisher TA Brown MR Andrich MP Chen CC Feuerstein IM . Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy\n. N Engl J Med. (1995 ) 332 :143 –9\n. 10.1056/NEJM199501193320303 7800006 \n34. Sun W Popat U Hutton G Zang YC Krance R Carrum G . Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis\n. Brain. (2004 ) 127 (Pt 5 ):996 –1008\n. 10.1093/brain/awh117 14985264 \n35. Snowden JA Saccardi R Allez M Ardizzone S Arnold R Cervera R . Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the european group for blood and marrow transplantation\n. Bone Marrow Transplant. (2012 ) 47 :770 –90\n. 10.1038/bmt.2011.185 22002489 \n36. Moore J Brooks P Milliken S Biggs J Ma D Handel M . A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe, refractory rheumatoid arthritis\n. Arthritis Rheum. (2002 ) 46 :2301 –9\n. 10.1002/art.10495 12355477 \n37. Oliveira MC Labopin M Henes J Moore J Del Papa N Cras A \nDoes ex vivo CD34+ positive selection influence outcome after autologous hemato-poietic stem cell transplantation in systemic sclerosis patients?\n\nBone Marrow Transplant. (2016 ) 51 :501 –5\n. 10.1038/bmt.2015.299 26642332 \n38. Atkins HL Bowman M Allan D Anstee G Arnold DL Bar-Or A . Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial\n. Lancet. (2016 ) 388 :576 –85\n. 10.1016/S0140-6736(16)30169-6 27291994 \n39. Henes J Oliveira MC Labopin M Badoglio M Scherer HU Del Papa N . Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the european society for blood and marrow transplantation autoimmune disease working party\n. Haematologica . (2020 ). 10.3324/haematol.2019.230128 . [Epub ahead of print].31949011 \n40. Ayano M Tsukamoto H Mitoma H Kimoto Y Akahoshi M Arinobu Y . CD34-selected versus unmanipulated autologous haematopoietic stem cell transplantation in the treatment of severe systemic sclerosis: a post hoc analysis of a phase I/II clinical trial conducted in Japan\n. Arthritis Res Ther. (2019 ) 21 :30 . 10.1186/s13075-019-1823-0 30670057 \n41. Massey JC Sutton IJ Ma DDF Moore JJ . Regenerating immunotolerance in multiplesclerosis with autologous hematopoietic stem cell transplant\n. Front Immunol. (2018 ) 9 :410 . 10.3389/fimmu.2018.00410 29593711 \n42. Muraro PA Pasquini M Atkins HL Bowen JD Farge D Fassas A . Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis\n. JAMA Neurol. (2017 ) 74 :459 –69\n. 10.1001/jamaneurol.2016.5867 28241268\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "11()",
"journal": "Frontiers in immunology",
"keywords": "autoimmune encephalitis; autoimmunity; autologous stem cell transplantation; common variable immunodeficiency; primary immunodeficiencies",
"medline_ta": "Front Immunol",
"mesh_terms": "D000328:Adult; D017074:Common Variable Immunodeficiency; D004660:Encephalitis; D005260:Female; D050031:Hashimoto Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "1317",
"pmc": null,
"pmid": "32670291",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "20437084;22002489;27586805;30670057;30731121;22986767;29593711;7800006;26454311;28241268;26187864;16431351;12355477;29279357;17898316;23864273;25329329;29574865;31440487;26371839;23039891;23432692;16263787;31949011;28192146;26642332;15738052;28607754;14985264;26206937;28780238;24869942;30555409;27291994;27318116;10866444;26480932;23463494;25595268",
"title": "Autologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis.",
"title_normalized": "autologous stem cell transplantation in common variable immunodeficiency a case of successful treatment of severe refractory autoimmune encephalitis"
} | [
{
"companynumb": "DE-PFIZER INC-2020290583",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nWhether a full dosage of afatinib is tolerable and effective for elderly or low performance status (PS) patients with advanced refractory non-small-cell lung cancer (NSCLC) is unclear.\n\n\nMETHODS\nWe retrospectively evaluated the tolerability and efficacy of afatinib in 10 patients (the majority elderly) with a low PS score (2 or 3), who had advanced refractory adenocarcinoma and were carrying active epidermal growth factor receptor mutations. Afatinib was administered at a starting dosage of 20 or 30mg/day, followed by 10mg increases in dose up to a maximum dosage of 40mg/day.\n\n\nRESULTS\nThe median patient age was 76 years and 50% of the patients had a PS of 3. The patients had previously been treated with gefitinib and/or erlotinib, with a median number of three chemotherapy regimens. All the patients received at least 30mg/day of afatinib. Eight patients did not receive the 40mg/day dosage because of patient refusal due to grade 2 diarrhea (n=6) or the judgment of the doctor (n=2). One patient discontinued the treatment because of drug-induced interstitial lung disease. The most frequent adverse event was grade 2 diarrhea. The objective response rate was 11% and the PS score of five cases improved after afatinib therapy. The median progression-free survival and overall survival periods were 3.6 months and 5.8 months, respectively.\n\n\nCONCLUSIONS\nA low starting dosage of afatinib might enable elderly or low PS patients with advanced refractory NSCLC to receive this drug as salvage therapy.",
"affiliations": "Department of Respiratory Medicine, Kumamoto Regional Medical Center, 5-16-10 hon-jo, Kumamoto, 860-0811, Japan. Electronic address: kskkswbr@krmc.or.jp.;Department of Respiratory Medicine, Kumamoto Regional Medical Center, 5-16-10 hon-jo, Kumamoto, 860-0811, Japan.;Department of Respiratory Medicine, Kumamoto Regional Medical Center, 5-16-10 hon-jo, Kumamoto, 860-0811, Japan.;Department of Respiratory Medicine, Kumamoto Regional Medical Center, 5-16-10 hon-jo, Kumamoto, 860-0811, Japan.",
"authors": "Kashiwabara|Kosuke|K|;Semba|Hiroshi|H|;Fujii|Shinji|S|;Tsumura|Shinsuke|S|",
"chemical_list": "D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077716:Afatinib; D066246:ErbB Receptors",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.resinv.2016.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2212-5345",
"issue": "54(6)",
"journal": "Respiratory investigation",
"keywords": "Diarrhea; Elderly; Low performance status; Low starting dosage",
"medline_ta": "Respir Investig",
"mesh_terms": "D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D003967:Diarrhea; D004334:Drug Administration Schedule; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D050152:Intra-Abdominal Fat; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate",
"nlm_unique_id": "101581124",
"other_id": null,
"pages": "468-472",
"pmc": null,
"pmid": "27886859",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tolerability and efficacy of afatinib at a low starting dosage in 10 elderly or low performance status patients with advanced refractory non-small-cell lung cancer.",
"title_normalized": "tolerability and efficacy of afatinib at a low starting dosage in 10 elderly or low performance status patients with advanced refractory non small cell lung cancer"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-57936BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"d... |
{
"abstract": "The SARS-COV-2 virus appears to have originated in Hubei Province in China towards the end of 2019 and has spread worldwide. Currently, there is little literature on COVID-19, and even less on its effect on pregnant mothers and infants. At this time, there are no clear recommendations specific to pregnant women with COVID-19. We report the multidisciplinary team management of a cesarean delivery for a woman infected with SARS-COV-2, including her pre-delivery care, intraoperative considerations, and post-delivery recommendations for the mother and baby. We also discuss the currently available recommendations and guidelines on the management of such cases.",
"affiliations": "Department of Obstetrics and Gynecology, Jordan University of Science and Technology, Irbid, Jordan.;Department of Paediatrics, Division of Neonatology, Sidra Medicine, Doha, Qatar.;American University of Beirut Medical Center, Beirut, Lebanon.;Department of Obstetrics and Gynecology, Jordan University of Science and Technology, Irbid, Jordan.;Department of Obstetrics and Gynecology, Jordan University of Science and Technology, Irbid, Jordan.;Department of Pediatrics and Neonatal Medicine, Jordan University of Science and Technology, Irbid, Jordan.",
"authors": "AlZaghal|Laila A|LA|;AlZaghal|Najwa|N|;Alomari|Safwan O|SO|;Obeidat|Nail|N|;Obeidat|Basil|B|;Hayajneh|Wail A|WA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.crwh.2020.e00212",
"fulltext": "\n==== Front\nCase Rep Womens Health\nCase Rep Womens Health\nCase Reports in Women's Health\n2214-9112\nElsevier\n\nS2214-9112(20)30042-4\n10.1016/j.crwh.2020.e00212\ne00212\nArticle\nMultidisciplinary team management and cesarean delivery for a Jordanian woman infected with SARS-COV-2: A case report\nAlZaghal Laila A. laalzaghal0@just.edu.jo\na⁎\nAlZaghal Najwa b\nAlomari Safwan O. c\nObeidat Nail a\nObeidat Basil a\nHayajneh Wail A. d\na Department of Obstetrics and Gynecology, Jordan University of Science and Technology, Irbid, Jordan\nb Department of Paediatrics, Division of Neonatology, Sidra Medicine, Doha, Qatar\nc American University of Beirut Medical Center, Beirut, Lebanon\nd Department of Pediatrics and Neonatal Medicine, Jordan University of Science and Technology, Irbid, Jordan\n⁎ Corresponding author. laalzaghal0@just.edu.jo\n01 5 2020\n7 2020\n01 5 2020\n27 e0021215 4 2020\n23 4 2020\n24 4 2020\n© 2020 The Authors\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nThe SARS-COV-2 virus appears to have originated in Hubei Province in China towards the end of 2019 and has spread worldwide. Currently, there is little literature on COVID-19, and even less on its effect on pregnant mothers and infants. At this time, there are no clear recommendations specific to pregnant women with COVID-19. We report the multidisciplinary team management of a cesarean delivery for a woman infected with SARS-COV-2, including her pre-delivery care, intraoperative considerations, and post-delivery recommendations for the mother and baby. We also discuss the currently available recommendations and guidelines on the management of such cases.\n\nHighlights\n\n• The literature discussing risks in COVID-19 pregnancy, delivery and the neonatal period is scarce.\n\n• It is essential to prepare the maternity ward with protocols and well-trained personnel to deal with delivery by mothers with COVID-19.\n\n• A mother with COVID-19 should be instructed to follow the appropriate medical recommendations, such as those from the American Academy of Pediatrics.\n\nKeywords\n\nCOVID-19\nJordan\nCesarean delivery\nPregnancy\nHydroxychloroquine\n==== Body\n1 Introduction\n\nThe SARS-COV-2 virus appears to have originated in Wuhan, the capital of Hubei Province in China, towards the end of 2019. The World Health Organization declared the virus outbreak a pandemic on March 11, 2020 [1,2]. The COVID-19 virus is primarily transmitted between people through respiratory droplets and contact routes. However, other routes of transmission, including vertical transmission, are currently being studied [3,4].\n\nThere is little literature on COVID-19, and even less on its effect on pregnant mothers and infants. At this time, there are no clear recommendations specific to pregnant women with COVID-19. To the best of our knowledge, this is the first reported cesarean delivery for a woman infected with SARS-COV-2 in Jordan and the Arab world.\n\n2 Case Presentation\n\nA 30-year-old woman, gravida 4 para 3, was admitted at 36 weeks of gestation in March 2020 after her nasopharyngeal swab tests came back positive for SARS-COV-2 using a rapid PCR technique. She complained of mild dry cough, runny nose, episodes of chills and headache three days prior to admission. She had no shortness of breath, no chest pain, and no muscle ache.\n\nOn admission her vital signs were stable and she had no fever. Oxygen saturation in room air was 98%. Regarding this pregnancy, she mentioned having regular antenatal care.\n\nShe reported that she had attended a social event a few days prior to presentation. Two days later, she started to have symptoms. She initially thought they were not significant but she sought medical advice many days later when a person at the same event had tested positive for SARS-COV-2. Before admission to the hospital she was living with her 2 children and husband.\n\nShe was given hydroxychloroquine 400 mg twice daily for a total of 9 days. Her symptoms were mild. Her blood tests were unremarkable except for mild elevation of D-Dimer 0.65 micrograms/ml (0.1–0.5 micrograms/ml). An ultrasound scan showed appropriate baby growth for age, with average liquor and upper placenta. The mother reported good fetal movement. On the night of her second day of admission, she started to complain of abdominal pain. Upon assessment she was found to be in labor.\n\nHer obstetric history included uncomplicated full-term vaginal delivery of her first daughter. Her second pregnancy was complicated by placental abruption and a cesarean section was done at 35 weeks of gestation. Her third pregnancy ended with a stillborn infant delivered vaginally and was complicated by severe postpartum hemorrhage requiring massive blood transfusion and surgical exploration under general anesthesia. Moreover, multiple cervical and vaginal tears were found and repaired.\n\nThe decision was made to perform a cesarean section on the third day of her admission, based on patient request and maternal indications, given that she already had a cesarean section scar and that her last vaginal delivery was complicated by severe postpartum hemorrhage. Currently, there is no evidence to support one mode of delivery over another in SARS-COV-2-positive mothers.\n\nAn urgent multidisciplinary meeting was held and included obstetric, neonatology, anesthesiology and infection control teams along with a well-qualified midwife and neonatal nurse. The decision was taken to prepare an isolated operating room for her, since the infection control team recommended against using a regular cesarean theatre.\n\nTo reduce the risk of transmission of SARS-COV-2 to the medical team and the baby, certain precautions and recommendations were followed. The procedure was done under regional (spinal) anesthesia, the number of staff in the theatre was minimized and all were wearing appropriate PPE, including a filtering facepiece level 3 (FFP3) mask. An N95 mask was used by the patient throughout the procedure.\n\nA vigorous baby girl was born, weighing 2.5 kg; her APGAR score was 8 at 1 min and 9 at 5 min. No resuscitation was needed at any stage. Immediately after delivery the baby was kept in a separate room and a one-to-one nurse was assigned to bottle-feed and look after her. Nasopharyngeal swabs were taken from the baby on three different occasions (at birth, and after 72 h and 6 days of life) and the rapid PCR was negative on all three occasions. The baby was discharged home 7 days after the mother's admission.\n\nThe mother remained in a stable clinical condition throughout her 11 days of hospital stay and was discharged home after having a nasopharyngeal swab negative after 6 days of treatment. Both the mother and the baby were still doing well at the time of writing. After a breast-milk test was negative for SARS-COV-2, the baby was allowed to breastfeed from the mother.\n\nThe mother and family were instructed to follow the recommendations of the American Academy of Pediatrics' Committee on Fetus and Newborn for the management of infants born to mothers with COVID-19.\n\n3 Discussion\n\nAlthough there are no reports of the SARS-COV-2 virus having been detected in amniotic fluid, placental fluid or cord blood [5,6], emerging evidence suggests that vertical transmission is possible. There are at least two reports of IgM for SARS-COV-2 in neonatal serum at birth. This was attributed to a neonatal immune response to in utero infection, since IgM does not cross the placenta [7,8].\n\nCurrently, no teratogenic effects of the virus have been reported and there is no evidence that COVID-19 infection increases the risk of miscarriage or second-trimester loss. Case reports from early pregnancy studies with SARS and MERS do not convincingy demonstrate a relationship between infection and increased risk of miscarriage or second-trimester loss [9]. However, in other types of coronavirus infection (SARS, MERS), the risks to the pregnant woman appear to increase in particular during the last trimester of pregnancy [10].\n\nThere are a few reports of preterm labor in COVID-19-positive mothers but we are unsure whether these preterm deliveries occurred due to COVID-19-related events or due to obstetric indications [11].\n\nNeonates can acquire SARS-COV-2 from infected mothers after birth and this may raise the concern of severe illnesses that may occur due to their immature immune system. Hence, newborns should be separated from infected mothers when possible. Mothers choosing to room-in with newborns should be informed about the potential risks to the baby and educated about the appropriate precautions [12].\n\nSince there is still no evidence of SARS-COV-2 expression in the breast-milk of mothers with COVID-19, the breast-milk expressed by infected mothers can be given to the baby by a caregiver [12].\n\nUpon discharge, infected mothers need to keep 6 ft away from the baby and use a face mask and hand sanitizers when taking care of the baby [12].\n\n4 Learning Points\n\n• There is literature worldwide on the risk of vertical transmission of COVID-19 during pregnancy, delivery and the neonatal period, and it is absent in the Arab world. More reports and studies are needed to reach conclusions about these aspects of COVID-19.\n\n• It is essential to prepare the maternity ward and the operating rooms with protocols and well-trained personnel to deal with elective and emergency cases of delivery in mothers with COVID-19.\n\n• The mother with COVID-19 should be instructed to follow the appropriate medical recommendations such as those of the American Academy of Pediatrics' Committee on Fetus and Newborn for management of infants born to mothers with COVID-19.\n\n• We encourage all health sectors in the Arab world to report similar cases, in order to help the WHO and other health committees to produce evidence-based protocols for dealing with this major health problem as soon as possible.\n\nContributors\n\nLaila A AlZaghal contributed to the design and drafting of the case report.\n\nNajwa AlZaghal contributed to reviewing the literature and writing the paper.\n\nSafwan O Alomari contributed to reviewing the literature and writing the paper.\n\nNail Obeidat contributed to the design and drafting of the case report.\n\nBasil Obeidat contributed to the design and drafting of the case report.\n\nWail A. Hayajneh contributed to the design and drafting of the case report.\n\nAll authors contributed to revision of the article.\n\nConflict of Interest\n\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n\nFunding\n\nNo funding from an external source supported the publication of this case report.\n\nPatient Consent\n\nObtained.\n\nProvenance and Peer Review\n\nThis case report was peer reviewed.\n==== Refs\nReferences\n\n1 Schwartz D.A. Graham A.L. Potential maternal and infant outcomes from coronavirus 2019-nCoV (SARS-CoV-2) infecting pregnant women: lessons from SARS, MERS, and other human coronavirus infections Viruses 12 2 2020 194\n2 Who.int/health-topics/Coronavirus [serial on Internet] Coronavirus [cited 2020 March 27] Available from http://www.who.int/health-topics/coronavirus 2020\n3 Liu J. Liao X. Qian S. Community transmission of severe acute respiratory syndrome coronavirus 2, Shenzhen, China, 2020 Emerg. Infect. Dis. 2020 10.3201/eid2606.200239\n4 Chan J. Yuan S. Kok K. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Lancet 2020 10.1016/S0140-6736(20)30154-9\n5 Chen Y. Peng H. Wang L. Infants born to mothers with a new coronavirus (COVID-19) Front. Pediatr. 2020 8(104) 10.3389/fped.2020.00104 32083038\n6 Li N. Han L. Peng M. Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study Pre-print 2020 10.1101/2020.03.10.20033605\n7 Dong L. Tian J. He S. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn JAMA 2020 10.1001/jama.2020.4621\n8 Zeng H. Xu C. Fan J. Antibodies in infants born to mothers with COVID-19 pneumonia JAMA 2020 10.1001/jama.2020.4861\n9 Zhang J. Wang Y. Chen L. Clinical analysis of pregnancy in second and third trimesters complicated severe acute respiratory syndrome Zhonghua Fu Chan Ke Za Zhi 38 2003 516 520 14521763\n10 Mullins E. Evans D. Viner R. Coronavirus in pregnancy and delivery: rapid review Ultrasound Obstetrics Gynaecol. 2020 10.1002/uog.22014 (In press)\n11 Chen H. Guo J. Wang C. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Lancet 2020 10.1016/S0140-6736(20)30360-3\n12 INITIAL GUIDANCE Management of Infants Born to Mothers with COVID-19 Date of Document: April 2 2020 Karen M. Puopolo, M.D. Ph.D., Mark L. Hudak, M.D., David W. Kimberlin, M.D., James Cummings, M.D. American Academy of Pediatrics Committee on Fetus and Newborn, Section on Neonatal Perinatal Medicine, and Committee on Infectious Diseases\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-9112",
"issue": "27()",
"journal": "Case reports in women's health",
"keywords": "COVID-19; Cesarean delivery; Hydroxychloroquine; Jordan; Pregnancy",
"medline_ta": "Case Rep Womens Health",
"mesh_terms": null,
"nlm_unique_id": "101682122",
"other_id": null,
"pages": "e00212",
"pmc": null,
"pmid": "32523874",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": "31986261;32050635;32180292;32151335;32215589;32249918;32125269;32266184;32215581;14521763",
"title": "Multidisciplinary team management and cesarean delivery for a Jordanian woman infected with SARS-COV-2: A case report.",
"title_normalized": "multidisciplinary team management and cesarean delivery for a jordanian woman infected with sars cov 2 a case report"
} | [
{
"companynumb": "NVSC2020JO194148",
"fulfillexpeditecriteria": "1",
"occurcountry": "JO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": null,
... |
{
"abstract": "Differentiation Syndrome is a complication of all-trans retinoic acid (ATRA) therapy in patients with acute promyelocytic leukemia (APML). It appears clinically as acute end-organ damage with peripheral edema, hypotension, acute renal failure, and interstitial pulmonary infiltrates. When symptoms develop, physicians are recommended to stop ATRA therapy to minimize complications and reduce mortality immediately. This case report describes a 67-year-old male who was diagnosed with acute promyelocytic leukaemia after he developed episodes of hematuria and easy bruising at home. After beginning a treatment regime of ATRA, steroids, and arsenic, the patient began to have symptoms of differentiation syndrome.",
"affiliations": "Internal Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, USA.;Internal Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.;Anesthesiology, Kansas City University of Medicine and Biosciences, Kansas City, USA.;Critical Care Medicine, AdventHealth Orlando, Orlando, USA.",
"authors": "Reyhanoglu|Gizem|G|;Hughes|Benjamin|B|;King|Katherine E|KE|;Cambridge|Robert|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.12042",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12042\nInternal Medicine\nOncology\nHematology\nDifferentiation Syndrome, a Side Effect From the Therapy of Acute Promyelocytic Leukemia\nMuacevic Alexander Adler John R Reyhanoglu Gizem 1 Hughes Benjamin 2 King Katherine E 3 Cambridge Robert 4 \n1 \nInternal Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, USA \n\n2 \nInternal Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA \n\n3 \nAnesthesiology, Kansas City University of Medicine and Biosciences, Kansas City, USA \n\n4 \nCritical Care Medicine, AdventHealth Orlando, Orlando, USA \n\nGizem Reyhanoglu greyhanogl16074@med.lecom.edu\n12 12 2020 \n12 2020 \n12 12 e1204225 9 2020 12 12 2020 Copyright © 2020, Reyhanoglu et al.2020Reyhanoglu et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/42588-differentiation-syndrome-a-side-effect-from-the-therapy-of-acute-promyelocytic-leukemiaDifferentiation Syndrome is a complication of all-trans retinoic acid (ATRA) therapy in patients with acute promyelocytic leukemia (APML). It appears clinically as acute end-organ damage with peripheral edema, hypotension, acute renal failure, and interstitial pulmonary infiltrates. When symptoms develop, physicians are recommended to stop ATRA therapy to minimize complications and reduce mortality immediately. This case report describes a 67-year-old male who was diagnosed with acute promyelocytic leukaemia after he developed episodes of hematuria and easy bruising at home. After beginning a treatment regime of ATRA, steroids, and arsenic, the patient began to have symptoms of differentiation syndrome.\n\ndifferentiation syndromeall-trans retinoic acidatraacute promyelocytic leukemiaapmlaplarsenicatopml-raraThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nAcute promyelocytic leukemia (APML) is primarily due to the expression of the chimeric gene produced through the translocation that occurs between chromosomes 15 and 17 [1]. Promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) protein results in a blockade in the differentiation of leukemic cells at the promyelocytic stage [1]. Individuals diagnosed with APML are recommended to immediately start all-trans retinoic acid (ATRA), arsenic trioxide, and chemotherapy to prevent the coagulopathy that can be detrimental [2]. Differentiation syndrome (DS), also known as Retinoic Acid Syndrome, is a life-threatening complication that can occur in patients with APML that are undergoing therapy with ATRA or arsenic [3]. This occurs in 2-27% of patients being treated with ATRA or arsenic and usually occurs within a few weeks of initiation of therapy [1]. Although the mechanism of DS is still unclear, it is thought to be due to changes in cytokine secretion and ATRA-induced differentiation of adhesion molecules in APML cells [1]. Diagnostic and peak leukocyte counts, greater than 10 x 10^9/L, as well as abnormal creatinine levels are considered predictive factors for DS [4]. DS is characterized by fever, weight gain of > 5 kg, peripheral edema, hypotension, acute renal failure, and interstitial pulmonary infiltrates [5]. Early recognition of DS, combined with a course of corticosteroid treatment, can significantly decrease morbidity and mortality in these patients [5]. ATRA and arsenic therapy should be stopped immediately when DS is suspected [6].\n\nCase presentation\nHospital Course and Case Presentation\n\nA 67-year-old male with a past medical history of prostate cancer status-post radiation therapy, hypertension, type II diabetes mellitus, and tobacco use disorder had a recent history of hospitalization due to hematuria and difficulty controlling minor bleeding at home. He noted uncontrolled bleeding after flossing his teeth and from shaving his beard. The patient presented to the hospital with the complaint of having found several “red spots” on his body, which were later noted to be diffuse petechiae. He was initially found to have leukopenia and profound thrombocytopenia.\n\nUpon admission, the hematology/oncology team was consulted. Computed tomography of the chest was ordered to rule out metastases because of the patient’s previous history of prostate cancer. It revealed a focal infiltrate in the posterior right upper lobe and ground-glass nodules in the left upper lobe, along with emphysema. Bone marrow pathology revealed acute myeloid leukemia, highly suspicious for the M3 subtype. Acute promyelocytic leukemia with 80% blasts/promyelocytes, was diagnosed with fluorescent in-situ hybridization (FISH) analysis. He began treatment with ATRA), dexamethasone, and arsenic trioxide (ATO) on 08/04/2020 (Table 1).\n\nTable 1 Lab Values Before and After Administration of APML Therapy\nAPML- Acute promyelocytic leukemia; BUN- Blood urea nitrogen; WBC- White Blood Cells\n\nDate\tCreatinine (range: 0.84- 1.2 mg/dL)\tBUN (range: 7 to 20 mg/dL)\tWBC Count (4.5- 11 x 10^9/L)\t\n8/4/20\t1.92\t64\t42.91\t\n8/5/20\t3.19\t103\t28.67\t\n8/6/20\t4.26\t111\t31.53\t\n8/7/20\t5\t117\t10.18\t\n8/8/20\t5.26\t123\t3.56\t\n8/9/20\t5.16\t108\t1.16\t\n8/10/20\t2.73\t70\t1.2\t\n8/11/20\t2.79\t75\t3.18\t\n8/12/20\t3.85\t104\t2.92\t\n8/13/20\t3.8\t98\t3.56\t\n8/14/20\t3.53\t95\t2.59\t\n8/15/20\t2.73\t72\t1.55\t\n8/16/20\t2.44\t64\t2.03\t\nAfter starting ATRA, dexamethasone, and ATO therapy, the patient complained of chest tightness and dyspnea, for which he was given furosemide. The patient’s liver enzymes and white cell count began to elevate rapidly over the next several days (Table 1). He also developed atrial fibrillation with a rapid ventricular response and was placed on metoprolol. Continuing investigation revealed further white cell count elevation, decreased oxygen saturation, acute kidney injury, and a chest x-ray that showed increased infiltrations and worsening pulmonary edema (Figure 1 and 2). The patient was then transferred to the intensive care unit for worsening hypoxemic respiratory failure, hypotension, and acute renal failure (Table 1). He ultimately required intubation, vasopressor support, and initiation of continuous renal replacement therapy (CRRT). ATRA and ATO were held due to concern for worsening symptoms secondary to suspected differentiation syndrome (DS). The patient was then started on one dose of chemotherapy: cytarabine, for debulking and restarted on ATRA two days later, as literature does not recommend holding therapy for APML for too long.\n\nFigure 1 Chest X-Ray 08/05/2020\nFigure 2 Chest X-Ray 08/19/2020\nAfter the initial signs of DS had resolved, the oncology service and critical care service tried to balance the need for ongoing chemotherapy against his current clinical condition. ATO was held until labs revealed improvement of liver enzymes. The patient continued ATRA and dexamethasone and was given a single dose of idarubicin. The patient was finally extubated 11 days after the initial stop of his therapeutic regimen. CRRT was stopped on the same day, but renal function had not significantly improved, so he was converted to conventional hemodialysis. The patient has been stable since the restart of all medications, waiting for a bone marrow transplant in the hospital.\n\nDiscussion\nATRA is associated with cellular migration, endothelial activation, and tissue damage from interleukins, leading to DS [7]. The all-trans retinoic acid and idarubicin (AIDA) regimen is used for patients who are recently diagnosed with APML. Both of these medications had been initiated at different periods in this patient’s course. About one-quarter of patients with APML, who undergo induction therapy with the AIDA regimen, will develop DS [3]. The development of DS often presents with an elevated white blood cell count and occurs between 7 to 12 days following induction therapy [3]. The patient, in this case, presented with a much more rapid onset of DS following induction therapy. The most frequent symptoms associated with DS include dyspnea, pulmonary infiltrates, unexplained fever, pleural effusion, and renal failure; all of which were noted to occur with the patient after induction therapy [3].\n\nManagement for DS has remained more-or-less unchanged throughout the years. Prophylactic corticosteroids are generally used in patients with APML on therapy with ATRA to prevent DS [2]. Although their benefit is not fully understood, it can still be considered. It is supported by the LPA99 trial, which provided candidates with prophylactic prednisone from the initiation of ATRA for 15 days [3]. Corticosteroids, such as prednisone prophylaxis, do not reduce mortality from DS but do reduce the incidence of severe DS. It is recommended that physicians avoid drugs that have been known to cause QT prolongation, as arsenic trioxide can also cause QT prolongation [2]. The patient in this case report had to stop his ATO due to this side effect. There should be temporary discontinuation of ATRA or ATO, as seen in this case report until end-organ damage shows improvement [2]. Abnormal serum creatinine can be considered an independent predictive factor for severe DS [3].\n\nConclusions\nThe patient, in this case, was started on conventional hemodialysis three times a week. His recovery was slow, but he did continue his regimen for APML once he showed signs of stabilization. Other than trending end-organ damage markers to understand the progression of differentiation syndrome, physicians need to look for the symptoms associated with DS before it is too late. Using prophylactic corticosteroids, as seen in this patient, does not pose any harm at this point, but further research into their mechanism of action could be crucial in assisting future APML patients who have an adverse event while on ATRA.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 The \"retinoic acid syndrome\" in acute promyelocytic leukemia Ann Intern Med Frankel SR Eardley A Lauwers G Weiss M Warrell RP Jr 292 296 15 1992 \n2 Acute promyelocytic leukemia (APL): a review of the literature Oncotarget Jimenez JJ Chale RS Abad AC Schally AV 992 1003 17 2020 https://miami.pure.elsevier.com/en/publications/acute-promyelocytic-leukemia-apl-a-review-of-the-literature \n3 Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors Blood Montesinos P Bergua JM Vellenga E 775 783 22 2009 \n4 Rate of differentiation syndrome in patients based on timing of initial all-trans retinoic acid administration Leuk Res Rep Nauffal M Werner L Ni J Stone RM DeAngelo DJ McDonnell AM 100189 12 2019 31867205 \n5 Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet Blood Sanz MA Fenaux P Tallman MS 1630 1643 133 2019 30803991 \n6 Differentiation syndrome in acute promyelocytic leukaemia Br J Haematol Stahl M Tallman MS 157 162 187 2019 31410848 \n7 Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia Sci Rep Yoon JH Kim HJ Min GJ 11935 9 2019 31417123\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(12)",
"journal": "Cureus",
"keywords": "acute promyelocytic leukemia; all-trans retinoic acid; apl; apml; arsenic; ato; atra; differentiation syndrome; pml-rara",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e12042",
"pmc": null,
"pmid": "33447473",
"pubdate": "2020-12-12",
"publication_types": "D002363:Case Reports",
"references": "30803991;31417123;1637024;18945964;31867205;31410848;32215187",
"title": "Differentiation Syndrome, a Side Effect From the Therapy of Acute Promyelocytic Leukemia.",
"title_normalized": "differentiation syndrome a side effect from the therapy of acute promyelocytic leukemia"
} | [
{
"companynumb": "US-NEXUS PHARMA-000029",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Microsurgical clipping is still regarded as the gold-standard treatment for broad-neck intracranial aneurysms. New endovascular techniques like balloon or stent assisted coiling are quickly rising to the challenge and showing promising outcomes. As a result, broad-neck aneurysms are increasingly addressed by these techniques despite they have not been tested against clipping in a randomized controlled trial and long-term complications might be unknown yet. Intraprocedural coil migration has been well documented in the literature, but the same complication in a delayed fashion is scarcely reported. We present a case of delayed coil migration occurring after a balloon-assisted embolization of a wide-necked intracranial aneurysm and we perform a literature review for similar cases. We discuss how, despite seeming an extremely rare complication, with new endovascular techniques increasingly perceived as the safer option in any aneurysm, potential adverse events may become more frequent. Strategies proposed to address this developing scenario are also reviewed.",
"affiliations": "Department of Neurological Surgery, Centro Hospitalar Lisboa Central - Hospital São José, Lisbon, Portugal.;Department of Neurological Surgery, Vall d'Hebron University Hospital, Barcelona, Spain.;Department of Neurological Surgery, Vall d'Hebron University Hospital, Barcelona, Spain. Electronic address: ana.neurosurgery@hotmail.com.;Department of Neurological Surgery, Clinic Hospital, Barcelona, Spain.;Department of Neurological Surgery, Vall d'Hebron University Hospital, Barcelona, Spain.;Department of Neurological Surgery, Vall d'Hebron University Hospital, Barcelona, Spain; Neurotraumatology and Neurosurgery Research Unit (UNINN), Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona (UAB), Spain.;Department of Neurological Surgery, Vall d'Hebron University Hospital, Barcelona, Spain.",
"authors": "Fonseca|Lino|L|;Najarro-Quispe|Rafael|R|;Rodríguez-Hernández|Ana|A|;Torné|Ramon|R|;Gándara-Sabatini|Dario|D|;Arikan|Fuat|F|;Baños-Carrasco|Pilar|P|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.neucir.2018.02.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2529-8496",
"issue": "30(2)",
"journal": "Neurocirugia (English Edition)",
"keywords": "Adverse event; Aneurismas de cuello ancho; Balloon assisted coiling; Broad-neck aneurysm; Coil migration; Embolización asistida por balón; Eventos adversos; Migración de coil; Stent asistido; Stent assisted coiling",
"medline_ta": "Neurocirugia (Astur : Engl Ed)",
"mesh_terms": "D002536:Cerebral Arteries; D004621:Embolization, Therapeutic; D005548:Foreign-Body Migration; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D013997:Time Factors",
"nlm_unique_id": "101778588",
"other_id": null,
"pages": "87-93",
"pmc": null,
"pmid": "29625853",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Symptomatic delayed coil migration after balloon assisted embolization: An underreported adverse event?",
"title_normalized": "symptomatic delayed coil migration after balloon assisted embolization an underreported adverse event"
} | [
{
"companynumb": "ES-BAYER-2019-048376",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPatients with borderline resectable pancreatic cancer are at high risk of incomplete resection with upfront surgery. Currently, no standard induction chemotherapy regimen exists for these patients. Both FOLFIRINOX (5-FU, irinotecan, & oxaliplatin) and gemcitabine plus nab-paclitaxel (GnP) have shown better efficacy than gemcitabine alone in advanced pancreatic cancer. The current study aims to assess outcomes of real-world patients with borderline resectable pancreatic cancer who received induction FOLFIRINOX or GnP.\n\n\nMETHODS\nIn this population-based multicenter retrospective cohort study, patients with biopsy-proven borderline resectable pancreatic cancer diagnosed from 2011 to 2017, in the province of Saskatchewan, Canada, who received FOLFIRINOX or GnP were assessed. Kaplan Meier methods and log rank tests were performed for survival analyses.\n\n\nRESULTS\nOf 161 patients with pancreatic cancer who received FOLFIRINOX or GnP during the study period, 20 eligible patients with borderline resectable pancreatic cancer were identified. Ten patients each received FOLFIRINOX or GnP. Eleven patients had partial response (5, FOLFIRINOX; 6, GnP); 3 progressed during treatment. Five patients (4, FOLFIRINOX; 1, GnP; p = NS) underwent curative surgery. The median progression-free survival was 17 months in FOLFIRINOX (95% CI, 5.3-28.6) vs. 9 months (95% CI, 3.0-15) in GnP groups (p = 0.27). Overall, 80% patients in GnP vs. 40% in FOLFIRINOX died from progressive disease. The median overall survival has not been reached in FOLFIRINOX group versus 16 months (95% CI, 9.3-22.7) in GnP group (p = 0.15).\n\n\nCONCLUSIONS\nThe current study suggests that patients with borderline resectable pancreatic cancer who received FOLFIRINOX tend to have better outcomes. Future studies are warranted to establish a preferred systemic therapy for patients with borderline resectable pancreatic cancer.",
"affiliations": "College of Medicine, University of Saskatchewan, Saskatoon, Canada.;Department of Surgery, University of Saskatchewan, Saskatoon, Canada.;Department of Medical Imaging, University of Saskatchewan, Saskatoon, Canada.;Department of Surgery, University of Saskatchewan, Saskatoon, Canada.;Division of Oncology, University of Saskatchewan, Regina, Canada.;Department of Surgery, University of Saskatchewan, Saskatoon, Canada.;Division of Oncology, University of Saskatchewan, Saskatoon, Canada.;Division of Oncology, University of Saskatchewan, Saskatoon, Canada. shahid.ahmed@saskcancer.ca.",
"authors": "Templeton|Shaina|S|;Moser|Michael|M|;Wall|Chris|C|;Shaw|John|J|;Chalchal|Haji|H|;Luo|Yigan|Y|;Zaidi|Adnan|A|;Ahmed|Shahid|S|http://orcid.org/0000-0002-2099-698X",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; C000627770:folfirinox; D000077150:Oxaliplatin; D000077146:Irinotecan; D017239:Paclitaxel; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1007/s12029-020-00417-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "52(2)",
"journal": "Journal of gastrointestinal cancer",
"keywords": "Borderline resectable pancreatic cancer; Combination chemotherapy; FOLFIRINOX; Gemcitabine plus nab-paclitaxel; Irreversible electroporation; Surgery",
"medline_ta": "J Gastrointest Cancer",
"mesh_terms": "D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D000077150:Oxaliplatin; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D012525:Saskatchewan; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "101479627",
"other_id": null,
"pages": "529-535",
"pmc": null,
"pmid": "32440849",
"pubdate": "2021-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Outcomes of Patients with Borderline Resectable Pancreatic Cancer Treated with Combination Chemotherapy.",
"title_normalized": "outcomes of patients with borderline resectable pancreatic cancer treated with combination chemotherapy"
} | [
{
"companynumb": "CA-BAUSCH-BL-2022-013495",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "Clinical trials of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection reported high response rates in HCV/HIV coinfection, similar to those obtained in HCV monoinfection. We evaluated the safety and efficacy of these regimens in a clinical practice setting.\n\n\n\nIn this prospective observational study, all the HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting from December 2014 to December 2015 were included in the analysis. Sustained virological response 12 weeks after the end of therapy (SVR12) and reported adverse events (AEs) were evaluated. Resistance-associated variants (RAVs) were analysed in a subgroup of patients at baseline and at the time of viral rebound in those with virological failure.\n\n\n\nOne-hundred and nine patients (51 HCV-infected and 58 HCV/HIV-coinfected) were enrolled in the study. Sixty per cent had cirrhosis and 52% were pegylated interferon and ribavirin (pegIFN/RBV)-experienced. Thirty-six per cent received ombitasvir + paritaprevir/ritonavir + dasabuvir, 25% sofosbuvir + daclatasvir, 16% sofosbuvir + simeprevir, 17% sofosbuvir + ribavirin and 6% sofosbuvir + ledipasvir; ribavirin was used in 57% of subjects. The SVR12 rate was 91% and 96% in HIV-infected and uninfected patients, respectively (P = 0.44). The 4-week HCV viral decline was similar in the two groups. RAVs were found at baseline in 23 of 49 patients and did not affect SVR12. No predictors of SVR12 were identified in our cohort.\n\n\n\nTreatment with all-oral DAA combinations of patients infected with HCV and with HCV/HIV under real-life conditions led to high and similar rates of SVR12. Moreover, the historical factors associated with a sustained virological response to pegIFN/RBV were not predictive of the response to all-oral DAAs.",
"affiliations": "Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Clinical Microbiology Virology and Diagnosis of Bioemergency, L. Sacco University Hospital, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy.",
"authors": "Milazzo|L|L|;Lai|A|A|;Calvi|E|E|;Ronzi|P|P|;Micheli|V|V|;Binda|F|F|;Ridolfo|A L|AL|;Gervasoni|C|C|;Galli|M|M|;Antinori|S|S|;Sollima|S|S|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1111/hiv.12429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1464-2662",
"issue": "18(4)",
"journal": "HIV medicine",
"keywords": "direct-acting antivirals; hepatitis C virus kinetics; hepatitis C virus polymorphisms; hepatitis C virus/HIV coinfection",
"medline_ta": "HIV Med",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000998:Antiviral Agents; D060085:Coinfection; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "100897392",
"other_id": null,
"pages": "284-291",
"pmc": null,
"pmid": "27477612",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Direct-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV-coinfected patients: real-life safety and efficacy.",
"title_normalized": "direct acting antivirals in hepatitis c virus hcv infected and hcv hiv coinfected patients real life safety and efficacy"
} | [
{
"companynumb": "IT-ROCHE-1909671",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nMajor depressive disorder (MDD) is a common disease. Despite appropriate antidepressant treatment, approximately one third of patients do not achieve adequate response. In these patients, electroconvulsive therapy (ECT) is a possible option. Nevertheless, some symptoms may persist even after ECT.\n\n\nMETHODS\nThis is a comparative retrospective study assessing the efficacy and safety of pramipexole in the treatment of resistant depression, in combination to ECT or after a partial ECT efficacy.\n\n\nRESULTS\nWe recruited 14 patients with severe MDD. Nine patients received ECT and pramipexole conjointly, the latter being introduced after a mean number of 18 ECT sessions. Five patients received pramipexole after failure of ECT. Montgomery-Asberg Depression Rating Scale and Clinical Global Impression scores all improved significantly after the initiation of pramipexole (jointly with ECT or alone). Moreover, the combination of ECT plus pramipexole was well tolerated. Only 1 patient presented a hypomanic episode, which resolved spontaneously.\n\n\nCONCLUSIONS\nPramipexole is a therapeutic option for MDD resistant to ECT. It could be used jointly to ECT or after a partial remission with ECT. More studies are needed to precisely describe the optimal combination of sequential use of ECT and pramipexole in treatment-resistant MDD.",
"affiliations": "*Department of Psychiatry, Service Hospitalo-Universitaire, Centre Hospitalier Sainte Anne; †Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR S894; ‡INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S894; and §Department of Pharmacy, Centre Hospitalier Sainte Anne, Paris, France.",
"authors": "Gauthier|Claire|C|;Souaiby|Lama|L|;Advenier-Iakovlev|Emmanuelle|E|;Gaillard|Raphaël|R|",
"chemical_list": "D052160:Benzothiazoles; D018491:Dopamine Agonists; D000077487:Pramipexole",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000253",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "40(6)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D052160:Benzothiazoles; D003131:Combined Modality Therapy; D061218:Depressive Disorder, Treatment-Resistant; D018491:Dopamine Agonists; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077487:Pramipexole; D012189:Retrospective Studies",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "264-267",
"pmc": null,
"pmid": "29059135",
"pubdate": "2017",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Pramipexole and Electroconvulsive Therapy in Treatment-Resistant Depression.",
"title_normalized": "pramipexole and electroconvulsive therapy in treatment resistant depression"
} | [
{
"companynumb": "FR-ACCORD-060889",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE DIHYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nVariably considered as a localized subtype of pustular psoriasis, palmoplantar pustulosis (PPP) is commonly treated with topical steroids, acitretin, and local phototherapy with oral or topical psoralen (PUVA). The utility of acitretin for PPP is limited by adverse effects such as myalgias and an extended risk of teratogenicity in female patients. Isotretinoin is a more tolerable retinoid with a shorter teratogenic window, but to date its effectiveness in PPP has not been reported. Herein we present two patients with PPP who responded well to isotretinoin treatment.\n\n\nMETHODS\nTwo patients with PPP refractory to topical therapies were started on acitretin. Both patients developed adverse effects (including headache, myalgias, and mood alterations) leading to acitretin discontinuation. Isotretinoin monotherapy was started in one patient resulting in significant clearing of palmar plaques and scale, and the addition of isotretinoin to UVA therapy resulted in near-complete clearing of recalcitrant plantar plaques in the second patient.\n\n\nCONCLUSIONS\nAcitretin represents an important treatment for PPP, but is limited by adverse effects and extended teratogenicity. Our experience supports the utility of isotretinoin as a potential therapeutic alternative, which may be particularly beneficial in patients who are poor candidates for or unable to tolerate acitretin therapy.",
"affiliations": "University of California Davis Medical Center. emaverakis@ucdavis.edu.",
"authors": "Wilken|Reason|R|;Sharma|Ajay|A|;Patel|Forum|F|;Maverakis|Emanual|E|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D002518:Ceramides; D004338:Drug Combinations; D004643:Emollients; C539259:EpiCeram; D005227:Fatty Acids; C055085:calcipotriene; D002784:Cholesterol; D002990:Clobetasol; D015474:Isotretinoin; D002117:Calcitriol; D017255:Acitretin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "21(8)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D017255:Acitretin; D000893:Anti-Inflammatory Agents; D001706:Biopsy; D002117:Calcitriol; D002518:Ceramides; D002784:Cholesterol; D002990:Clobetasol; D003131:Combined Modality Therapy; D003951:Diagnostic Errors; D004338:Drug Combinations; D057915:Drug Substitution; D004485:Eczema; D004643:Emollients; D005227:Fatty Acids; D005260:Female; D006801:Humans; D015474:Isotretinoin; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D014467:Ultraviolet Therapy",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26437168",
"pubdate": "2015-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of palmoplantar pustulosis with isotretinoin.",
"title_normalized": "successful treatment of palmoplantar pustulosis with isotretinoin"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0055316",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
},
"drugadditional": null,... |
{
"abstract": "Nitrofurantoin is one of the most utilized antibiotics to treat bladder and urinary tract infections (UTIs). Despite the clinical benefits, it requires vigilant monitoring, as it can cause damage to multiple organs, especially the lungs and the liver. This case is an example of clinical vigilance, which provided tremendous benefit for the patient.",
"affiliations": "Internal Medicine, Jersey Shore University Medical Center, Neptune City, USA.;Internal Medicine, Jersey Shore University Medical Center, Neptune City, USA.",
"authors": "Miskoff|Jeffrey A|JA|;Chaudhri|Moiuz|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.3315",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3315Internal MedicinePreventive MedicinePulmonologyNitrofurantoin Toxicity: A Near Case of Mistaken Identity Muacevic Alexander Adler John R Miskoff Jeffrey A 1Chaudhri Moiuz 1\n1 \nInternal Medicine, Jersey Shore University Medical Center, Neptune City, USA \nJeffrey A. Miskoff jamiskoff@yahoo.com17 9 2018 9 2018 10 9 e33158 8 2018 17 9 2018 Copyright © 2018, Miskoff et al.2018Miskoff et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/13992-nitrofurantoin-toxicity-a-near-case-of-mistaken-identityNitrofurantoin is one of the most utilized antibiotics to treat bladder and urinary tract infections (UTIs). Despite the clinical benefits, it requires vigilant monitoring, as it can cause damage to multiple organs, especially the lungs and the liver. This case is an example of clinical vigilance, which provided tremendous benefit for the patient.\n\nnitrofurantoinmistakentoxicitysmall cell lung cancerhyperplasiaThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nNitrofurantoin is an antibacterial agent commonly used in the management of urinary tract infections (UTIs). It is frequently used in the management of acute cystitis and patients with recurrent bladder infections. Nitrofurantoin may cause problems involving different organ systems after short-term or chronic use. Liver and lung toxicity are among the most common organs affected. A majority of the patients presenting with pulmonary manifestations are women ranging in age from 60 to 70 years [1]. A recent study suggested that people 65 or older have a significantly higher rate of suffering from toxicity due to the chronic use of nitrofurantoin (adjusted relative risk of 1.53 with 95% CI of 1.04-2.24). Acute toxicity presents with changes at the molecular level of the lungs along with a different mechanism [2].\n\nCase presentation\nHere, we present a case of a 60-year-old established patient of ours who was initially seen on January 12, 2013, for symptoms related to a paraesophageal hernia. The patient started nitrofurantoin 100 mg daily on October 26, 2013, and it was discontinued on May 1, 2014. Later in the year, the patient developed a productive cough, which did not respond to the outpatient antibiotics. In 2014, the patient presented with a dry cough, a chest x-ray depicting patchy bilateral infiltrates, and a subsequent computed tomography (CT) scan illustrating bilateral opacities described as pneumonia (Figure 1). The patient did not respond to a brief trial of outpatient oral steroidsand antibiotics. A lack of improvement in symptomology led to bronchoscopy, which was unremarkable. Additionally, no densities or masses were identified during the procedure. The patient was also worked up for aspiration by bronchoalveolar lavage (BAL) with cytology brushing and multiple transbronchial biopsies of the right upper lung. Aspiration pneumonia was suspected. Prior to the procedure and the discontinuation of nitrofurantoin, the patients’ aspartate aminotransferase (AST) test was 222 units/liter (reference range 10-42 units/liter) and alanine aminotransferase (ALT) test was 153 units/liter (reference range 10-60 units/liter) along with a low albumin of 3.4 g/dl (reference range 3.5-5.0 g/dl). After the discontinuation of the antibiotic, the patients AST and ALT decreased to 112 and 123 units/liter, respectively.\n\nFigure 1 A computed tomography (CT) scan showing opacities described as pneumonia along with patchy infiltrates (arrow).\nAlthough workup did not reveal the typical presentation of a malignancy or a lung mass, nitrofurantoin was held as a precautionary measure especially since the patient has been using it chronically. A laboratory investigation of the bronchial aspirate suggested moderate growth of normal oropharyngeal flora and scant Candida albicans, the gram stain revealed gram-positive cocci in pairs and rare epithelial cells, and no acid-fast bacilli were recovered. Additionally, lavage was negative for malignant cells but epithelial, squamous and pulmonary macrophages were present. A surgical pathology analysis exhibited atypical pneumonic cystic hyperplasia with a cluster of cells suspicious for neoplasm on initial evaluation by the head of pathology (Figure 2). A preliminary phone call to the pulmonologist was made because of the suspicion of a primary small cell lung carcinoma (SCLC). The pathologist inquired more about the case and more specifically if there was a lung mass on imaging. After further discussion, a final path report excluded carcinoma from the diagnosis even though the initial review of the samples showed cells resembling oat cells.\n\nFigure 2 Epithelial macrophages along with atypical pneumonic cystic hyperplasia suggesting a neoplasm (arrow).\nA peribronchial tissue analysis under the guidance of microscopy showed pseudostratified ciliated columnar epithelium (normal finding), alveoli were lined by enlarged, atypical appearing pneumocytes with a powdery chromatic pattern and small nuclei (Figure 3). The interstitium appeared thickened, with fibrotic and chronic inflammatory cells noted. Also, adjacent peribronchial tissue contained a chronic inflammatory infiltrate, which was mild, and presented with two nests of very atypical cells. The two clusters of cells were within the submucosa without a relationship with the alveolar epithelium (Figure 4). Lastly, the nuclei of the adjacent peribronchial presented with irregularly shaped nuclei, with an irregular distribution of the chromatin pattern and prominent nucleoli. To investigate this step further, two clusters of cells were positive for cytokeratin 7 (CK 7d) and thyroid transcription factor-1 (TTF). However, the sample was negative for cytokeratin 20 (CK20) and a tumor protein 40 (P40). Molecular evidence suggests that the presence of CK20 and CK7 is strongly associated with advanced malignancy and TTF-1 is found in type II pneumocytes and Clara cells, suggesting a better survival rate [3-4]. Lastly, P40 is known to be a highly specific marker of squamous cell carcinoma.\n\nFigure 3 Alveoli surrounded by enlarged atypical pneumocytes with a powdery chromatic pattern and small nuclei (arrow).\nFigure 4 Cluster of cells within the submucosa isolated from the alveolar epithelium (circles).\nDiscussion\nNitrofurantoin is frequently used to treat bladder infections along with providing prophylactic coverage to the patient. Nitrofurantoin can lead to pulmonary conditions presenting in an acute and chronic manner [5-6]. An acute pulmonary reaction presents with interstitial inflammation, focal hemorrhage, and reactive type II pneumocytes. Evidence indicates that the acute onset of symptoms involves hypersensitivity reaction type I or III; the mean onset of hypersensitivity pneumonitis originating from nitrofurantoin is usually seen after 8.7 days [7]. Repeat exposure significantly decreases the time needed for acute symptoms to present [6,8].\n\nChronic reactions can present with significant interstitial pneumonitis, a thickening of the alveolar septa, and, infrequently, vascular sclerosis [9-10]. Less common presentations of chronic reactions can present with chronic eosinophilic pneumonia and desquamative interstitial pneumonia with an abundance of macrophages in the alveoli. The chronic onset of toxicity can be due to cell-mediated or toxin insult [11-12]. Evidence points toward nitrofurantoin metabolites being the culprit by damaging lung microsomes. In addition, it can cause hepatotoxicity, a granulomatous reaction, and autoimmune-mediated hepatitis, which can lead to death [13]. Clinical evidence suggests that nitrofurantoin can lead to sensorimotor polyneuropathy along with other neurotoxic events [14].\n\nNitrofurantoin is one of many medications that can have negative effects on patients. This case is unique in the fact that the preliminary read from the pathologist was concerning for SCLC. Fortunately, the patient did not have a lung mass or other clinical findings to support this diagnosis. Further review of the pathology and the case ultimately led to the correct diagnosis of lung toxicity from chronic nitrofurantoin use. After approximately four to six weeks of 0.5 mg/kg prednisone, the patient clinically improved. Although the patient was lost to follow-up, a recent phone conversation with her confirmed that she does not have any residual pulmonary symptoms or findings to report.\n\nConclusions\nPulmonary drug toxicity may present with different imaging patterns and atypical cells on pathology. Although uncommon, nitrofurantoin, especially when used chronically, may present challenging diagnostic and treatment dilemmas. A careful review of pathology, imaging, and clinical history and presentation were key in order to make the correct diagnosis in this case. \n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Chronic nitrofurantoin-induced lung disease Mayo Clin Proc Mendez J Nadrous H Hartman T Ryu J 1298 1302 80 2005 16212142 \n2 Evaluation of the risk of nitrofurantoin lung injury and its efficacy in diminished kidney function in older adults in a large integrated healthcare system: a matched cohort study J Am Geriatr Soc Santos J Batech M Pelter M Deamer R 798 805 64 2016 27100576 \n3 CK20 and CK7 protein expression in colorectal cancer: demonstration of the utility of a population-based tissue microarray Hum Pathol Hernandez B Frierson H Moskaluk C 275 281 36 2005 15791572 \n4 Value of thyroid transcription factor (TTF)-1 for diagnosis and prognosis of patients with locally advanced or metastatic small cell lung cancer Diagn Pathol Misch D Blum T Boch C 21 10 2015 25889870 \n5 Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials J Antimicrob Chemother Huttner A Verhaegh E Harbarth S Muller A Theuretzbacher U Mouton J 2456 2464 70 2015 26066581 \n6 Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature J Infect Public Health Kabbara W Kordahi M 309 313 8 2015 25747822 \n7 Nitrofurantoin-induced acute, subacute and chronic pulmonary reactions Scand J Respir Dis Sovijarvi A Lemola M Stenius B Idanpaan-Heikkila J 41 50 58 1977 https://www.ncbi.nlm.nih.gov/pubmed/841294 841294 \n8 Nitrofurantoin pulmonary toxicity J Fam Pract Hainer B White A 817 823 13 1981 https://www.ncbi.nlm.nih.gov/pubmed/7031172 7031172 \n9 Nitrofurantoin-associated bronchiolitis obliterans organizing pneumonia: report of a case Can Respir J Fenton M Kanthan R Cockcroft D 311 312 15 2008 18818785 \n10 Nitrofurantoin-induced pulmonary reaction involving respiratory symptoms: case report Can J Hosp Pharm Kanji Z Su V Mainra R 362 365 64 2011 https://pdfs.semanticscholar.org/d5e1/9713305635c6037f4956bbc467b1a776f87c.pdf 22479089 \n11 Severe nitrofurantoin lung disease resolving without the use of steroids J Postgrad Med Bhullar S Lele S Kraman S 111 113 53 2007 http://www.jpgmonline.com/article.asp?issn=0022-3859;year=2007;volume=53;issue=2;spage=111;epage=113;aulast=Bhullar 17495377 \n12 Bronchiolitis obliterans organising pneumonia associated with the use of nitrofurantoin Thorax Cameron R Kolbe J Wilsher M Lambie N 249 251 55 2000 https://thorax.bmj.com/content/thoraxjnl/55/3/249.full.pdf 10679548 \n13 Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication South Med J Sakaan S Twilla J Usery J Winton J Self T 107 113 107 2014 24926677 \n14 Neurotoxic effects associated with antibiotic use: management considerations Br J Clin Pharmacol Grill M Maganti R 381 393 72 2011 21501212\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "10(9)",
"journal": "Cureus",
"keywords": "hyperplasia; mistaken; nitrofurantoin; small cell lung cancer; toxicity",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e3315",
"pmc": null,
"pmid": "30473948",
"pubdate": "2018-09-17",
"publication_types": "D002363:Case Reports",
"references": "16212142;17495377;25747822;26066581;25889870;24926677;15791572;18818785;22479089;27100576;7031172;10679548;21501212;841294",
"title": "Nitrofurantoin Toxicity: A Near Case of Mistaken Identity.",
"title_normalized": "nitrofurantoin toxicity a near case of mistaken identity"
} | [
{
"companynumb": "US-MYLANLABS-2020M1005437",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NITROFURANTOIN"
},
"drugadditional": "1",
... |
{
"abstract": "Primary myelodysplastic syndromes (MDS) occur in the absence of exposure to ionizing radiation, chemotherapeutic agents or myelotoxic drugs, whereas secondary MDS occurs in the presence of such exposure. We encountered 4 patients among 217 patients on hydroxychloroquine for rheumatological conditions in 2005 diagnosed with MDS. Two patients were male and two were female; the median age was 69.75 years, (range 65-76). The dose of hydroxychloroquine for all patients was 400 mg daily with median treatment duration of 10.5 years and a range of 6-16. All patients had bone marrow biopsy confirmation of the diagnosis of MDS. The incidence of MDS in a group older than 70 years ranges from 15 to 50/100,000 persons per year. The diagnosis of 4 cases of MDS among 217 patients in 1 year is approximately 123-137-fold higher than the risk of MDS in the general population aged more than 70 years (P < 0.001) and suggests that long-term treatment with hydroxychloroquine is associated with an increased risk of developing secondary MDS.",
"affiliations": null,
"authors": "Muslimani|Alaa A|AA|;Spiro|Timothy P|TP|;Chaudhry|Asif A|AA|;Daw|Hamed A|HA|",
"chemical_list": "D006886:Hydroxychloroquine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-006-0249-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "86(7)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies; D012216:Rheumatic Diseases",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "531-4",
"pmc": null,
"pmid": "17205285",
"pubdate": "2007-07",
"publication_types": "D016422:Letter",
"references": null,
"title": "Secondary myelodysplastic syndrome after hydroxychloroquine therapy.",
"title_normalized": "secondary myelodysplastic syndrome after hydroxychloroquine therapy"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
},
"drugadditional": "2",
"dru... |
{
"abstract": "The analgesics, codeine, fentanyl, oxycodone and tramadol, frequently occur in postmortem cases and determining their role in the cause of death can be challenging. However, postmortem blood is susceptible to redistribution and may not be available in cases of severe blood loss, putrefaction or burns. Brain tissue may serve as a viable supplement to blood or on its own, as it is resistant to postmortem redistribution and often available as a sample matrix when blood is not available. We present brain and blood concentrations and brain-blood ratios of the four analgesics from 210 autopsy cases. The cases were classified according to the presumed cause of death: A: The compound was believed to have solely caused a fatal intoxication. B: The compound was assumed to have contributed to a fatal outcome in combination with other drugs, alcohol or disease. C: The compound was not regarded as being related to the cause of death. Blood and brain samples were prepared by automatic solid phase extraction and quantified by liquid chromatography-mass spectrometry. The squared correlation coefficients between concentrations in brain tissue and blood ranged 0.45-0.91. The median brain-blood ratios were codeine 1.8 (range 0.47-4.6), fentanyl 2.1 (range 0.29-16), oxycodone 1.8 (range 0.11-6.0) and tramadol 1.8 (range 0.047-6.8). A significantly higher brain-blood ratio of codeine was observed in cases where heroin had been administered, although there was a wide overlap. Intravenous and transdermal fentanyl administration could not be distinguished based on the blood or brain concentration or the brain-blood ratio. The results of this study may benefit the toxicological investigation in postmortem cases where one of the four analgesics are suspected of having contributed to or caused a fatal intoxication.",
"affiliations": "Department of Forensic Medicine, University of Copenhagen, Section of Forensic Chemistry, Frederik V's vej 11, 3. Floor, 2100 Copenhagen, Denmark.;Department of Forensic Medicine, University of Copenhagen, Section of Forensic Chemistry, Frederik V's vej 11, 3. Floor, 2100 Copenhagen, Denmark.;Department of Forensic Medicine, University of Copenhagen, Section of Forensic Chemistry, Frederik V's vej 11, 3. Floor, 2100 Copenhagen, Denmark.",
"authors": "Nedahl|Michael|M|;Johansen|Sys Stybe|SS|;Linnet|Kristian|K|",
"chemical_list": "D000701:Analgesics, Opioid; D014147:Tramadol; D010098:Oxycodone; D005283:Fentanyl; D003061:Codeine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkaa048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "45(1)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000701:Analgesics, Opioid; D001344:Autopsy; D003061:Codeine; D062787:Drug Overdose; D005283:Fentanyl; D053593:Forensic Toxicology; D006801:Humans; D010098:Oxycodone; D015813:Substance Abuse Detection; D014147:Tramadol",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "53-59",
"pmc": null,
"pmid": "32390039",
"pubdate": "2021-02-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postmortem Brain-Blood Ratios of Codeine, Fentanyl, Oxycodone and Tramadol.",
"title_normalized": "postmortem brain blood ratios of codeine fentanyl oxycodone and tramadol"
} | [
{
"companynumb": "DK-ALKEM LABORATORIES LIMITED-DK-ALKEM-2020-02248",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXYCODONE HYDROCHLORIDE"
},
... |
{
"abstract": "Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that is frequently accompanied by systemic complications including peripheral neuropathies. Anti-tumor necrosis factor-alpha agents such as infliximab are an established treatment for immune-mediated diseases. However, they have been associated with adverse effects, including local reactions, infections, congestive heart failure, malignancies, and, rarely, they can cause neurological adverse effects on the central nervous system, as well as peripheral nervous system demyelination. Here, we report the case of an 80-year-old man with CD on infliximab therapy who presented with progressive weakness and numbness. A neurological examination and a nerve conduction study suggested chronic inflammatory demyelinating polyneuropathy (CIDP). The patient was started on oral corticosteroids and experienced transient improvement of his symptoms at the end of this course. Thus, CIDP could be one of the extraintestinal presentations of CD.",
"affiliations": "Department of Medicine, Umm Al-Qura University, Faculty of Medicine, Mecca, SAU.;Department of Medicine, Umm Al-Qura University, Faculty of Medicine, Mecca, SAU.;Neurology Department, King Abdullah Medical City, Mecca, SAU.",
"authors": "Almuntashri|Fahad|F|;Binyaseen|Kenan|K|;Alkhotani|Amal|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.19041",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.19041\nNeurology\nChronic Inflammatory Demyelinating Polyneuropathy in Patients With Crohn’s Disease on Infliximab Therapy\nMuacevic Alexander\nAdler John R\nAlmuntashri Fahad 1\nBinyaseen Kenan 1\nAlkhotani Amal 21\n1 Department of Medicine, Umm Al-Qura University, Faculty of Medicine, Mecca, SAU\n2 Neurology Department, King Abdullah Medical City, Mecca, SAU\nFahad Almuntashri fahadalmuntashri@gmail.com\n25 10 2021\n10 2021\n13 10 e1904124 10 2021\nCopyright © 2021, Almuntashri et al.\n2021\nAlmuntashri et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/69894-chronic-inflammatory-demyelinating-polyneuropathy-in-patients-with-crohns-disease-on-infliximab-therapy\nCrohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that is frequently accompanied by systemic complications including peripheral neuropathies. Anti-tumor necrosis factor-alpha agents such as infliximab are an established treatment for immune-mediated diseases. However, they have been associated with adverse effects, including local reactions, infections, congestive heart failure, malignancies, and, rarely, they can cause neurological adverse effects on the central nervous system, as well as peripheral nervous system demyelination. Here, we report the case of an 80-year-old man with CD on infliximab therapy who presented with progressive weakness and numbness. A neurological examination and a nerve conduction study suggested chronic inflammatory demyelinating polyneuropathy (CIDP). The patient was started on oral corticosteroids and experienced transient improvement of his symptoms at the end of this course. Thus, CIDP could be one of the extraintestinal presentations of CD.\n\nanti-tnf-α treatment\ninfliximab\nneurological complications\ncrohn’s disease\nchronic inflammatory demyelinating polyradiculoneuropathy\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nCrohn’s disease (CD) is a multifactorial, chronic, and progressive inflammatory bowel disease characterized by severe inflammation of the gastrointestinal tract [1]. It is frequently accompanied by extraintestinal manifestations, including uveitis, arthritis, ankylosing spondylitis, primary sclerosing cholangitis, and erythema nodosum, which impact 20-40% of patients [1]. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic autoimmune neuropathy characterized by progressive, symmetric, proximal, and distal muscle weakness, paresthesia, sensory dysfunction, and impaired balance, which evolve gradually over at least two months [2]. CIDP can be one of the extraintestinal presentations of CD [3]. The mechanism of this complication has not been well explained, and it is unclear whether the complication is immune-mediated or secondary to medication use [3]. Although several studies have shown a possible role of anti-tumor necrosis factor-alpha (anti-TNF-α) in the pathogenesis and development of central nervous system (CNS) demyelinating diseases, this relationship is less clear for demyelinating diseases of the peripheral nervous system (PNS) [4]. Here, we report the case of an 80-year-old man with longstanding CD on infliximab therapy who presented with progressive weakness secondary to CIDP.\n\nCase presentation\n\nAn 80-year-old Asian male who had been diagnosed with CD for more than 20 years and bronchial asthma for more than 30 years was referred to our hospital with complaints of upper and lower limb weakness and numbness, which had started eight months prior to presentation.\n\nHis condition had started as gradual and progressive bilateral and symmetrical weakness in the feet, which, along with numbness, had continued to progress in ascending manner up his legs until it reached the upper thighs. Afterward, the upper limbs became involved (numbness and weakness) and progressed distally and proximally until the mid-forearms. The weakness was associated with fatigability, although there was no ocular, bulbar, or respiratory involvement. The patient had no loss of bowel or bladder control, fever history, or symptoms of upper respiratory tract infection. Regarding his CD, initially, he was on azathioprine which was later changed to infliximab after an exacerbation of CD. When he was diagnosed with CIDP, we resumed azathioprine which was effective in controlling his CIDP. He had been stable with no new exacerbation.\n\nUpon presentation, examination revealed a conscious; alert; oriented to time, person, and place; and coherent man with intact memory and fluent speech. Cranial nerve examinations were normal, although the motor examination revealed the symmetrical flaccid weakness of the upper and lower limbs, with 0 power in the distal lower limb and 3/5 power in the proximal lower limb muscles. In the upper limbs, he had 2/5 distal power and 4/5 proximal power with absent reflexes. He had hyperesthesia in the leg up to the knee and from the upper limb up to the mid-forearm. However, his proprioception and vibration senses were intact.\n\nHis workup showed normochromic normocytic anemia with hemoglobin of 9 g/dL. The rest of the parameters were normal. Cerebrospinal fluid examination showed protein of 100 mg/dL with normal cells, white blood cell count of 2 cells/µL, and glucose of 70 mg/dL. A spinal MRI was normal with no nerve roots enlargement, and protein electrophoresis was also normal. Vitamins B1, B6, and B12 were within normal limits. Autoantibodies such as anti-contactin-1 (CNTN1) and anti-nodal neurofascin antibodies (NF) were not tested as they were not available. Additionally, anti-nuclear antibodies (ANA), anti-dsDNA, and anti-neutrophil cytoplasmic antibody (ANCA) were negative. Moreover, hepatitis B and C serology were negative.\n\nA nerve conduction study of the upper and lower limb motor nerves showed prolonged distal onset latency, reduced amplitude, and decreased conduction velocity. The sensory nerve showed prolonged distal peak latency and decreased conduction velocity. The nerve conduction studies (Tables 1, 2), in keeping with severe demyelinating peripheral polyneuropathy, showed significantly reduced conduction velocity with marked temporal dispersion (Figures 1, 2).\n\nTable 1 Summary of the anti-sensory test.\n\nThe sensory nerve showed prolonged distal peak latency and decreased conduction velocity.\n\nSite\tNR\tPeak (ms)\tNormal peak (ms)\tP-T amplitude (μV)\tNormal P-T amplitude (μV)\tSite 1\tSite 2\tDelta-P (ms)\tDistance (cm)\tVelocity (m/s)\tNormal velocity (m/s)\t\nRight ulnar anti-sensory (fifth digit)\t\nWrist\t9.3\t<3.7\t16.4\t>15.0\tWrist\t5th digit\t9.3\t14.0\t15\t>38\t\n\nTable 2 Summary of the motor test.\n\nThe motor study showed prolonged distal onset latency, reduced amplitude, and decreased conduction velocity.\n\nSite\tNR\tOnset (ms)\tNormal (ms)\tO-P amplitude (mV)\tNormal O-P amplitude (mV)\tSite 1\tSite 2\tDelta-0 (ms)\tDistance (cm)\tVelocity (m/s)\tNormal velocity (m/s)\t\nRight median motor (abductor pollicis brevis)\t\nWrist\t7.2\t<4.2\t2.6\t>5\tElbow\tWrist\t10.2\t24.0\t24\t>50\t\nElbow\t17.4\t \t0.9\t \t \t \t \t \t \t \t\nRight ulnar motor (abductor digiti minimi)\t\nWrist\t7.0\t<4.2\t1.6\t>3\tBelow elbow\tWrist\t10.2\t24.0\t24\t>53\t\nElbow\t17.2\t \t0.2\t \t \t \t \t \t \t \t\n\nFigure 1 Right median nerve motor conduction showing reduced amplitude and conduction velocity with marked temporal dispersion.\n\nNCV: nerve conduction velocity\n\nFigure 2 Right ulnar nerve motor conduction showing reduced amplitude and conduction velocity with marked temporal dispersion.\n\nNCV: nerve conduction velocity\n\nThe patient refused treatment with intravenous immunoglobulin or plasma exchange even though they were better options concerning side effects. Instead, he was started on an oral steroid followed by the re-administration of azathioprine with significant improvement in his motor power as his follow-up motor examination revealed -4/5 in the distal lower limb and +4/5 in the proximal lower limb muscles. In the upper limbs, he had +4/5 distal power and 5/5 proximal power with normal reflexes. He became ambulatory with a cane and independent in his daily activities. His CD also remained stable. His treatment with infliximab continued as before after the options were discussed with both the patient and his treating gastroenterologist. Figure 3 summarizes the timeline of the clinical events.\n\nFigure 3 A timeline of the clinical events.\n\nNCS: nerve conduction study; EMG: electromyography\n\nDiscussion\n\nCIDP is the most common immune-mediated chronic polyneuropathy. Although the incidence and prevalence of CIDP differ across studies, a meta-analysis showed a pooled incidence rate of 0.33 per 100,000 person-years and a pooled prevalence rate of 2.81 per 100,000 persons. Additionally, there is a male predominance, and the incidence and prevalence increase with advancing age [5]. Peripheral neuropathy is frequently reported as one of the complications of CD [1,6], but the exact prevalence is controversial [1,6]. Patients with CIDP classically present with symmetrical and progressive proximal and distal weakness [7]. Moreover, the presentation can be focal, multifocal, or sensorial predominantly. The diagnosis of CIDP is multifaceted, involving clinical history, physical examination, laboratory investigation, and electrodiagnostic studies, with the exclusion of other diseases with features similar to CIDP (e.g., hereditary demyelinating neuropathy, multifocal motor neuropathy, or Borrelia burgdorferi infection). Although several criteria have been proposed for CIDP diagnosis, the European Federation Neuropathy Society/Peripheral Neuropathy Society (EFNS/PNS) is the most popular criteria to confirm the diagnosis [5,8]. The EFNS/PNS criteria include clinical and electrodiagnostic criteria, as shown in Tables 3, 4 [9], respectively.\n\nTable 3 Clinical diagnostic criteria.\n\nPOEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; PNS: peripheral nervous system; CIDP: chronic inflammatory demyelinating polyneuropathy\n\nTable adapted from the Joint Task Force of the EFNS and the PNS [9].\n\nInclusion criteria:\t\n(a) Typical CIDP:\t\nChronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least two months; cranial nerves may be affected; and\t\nAbsent or reduced tendon reflexes in all extremities\t\n(b) Atypical CIDP (still considered CIDP but with different features): One of the following, but otherwise as in (a) (tendon reflexes may be normal in unaffected limbs):\t\nPredominantly distal (distal acquired demyelinating symmetric),.or\t\nAsymmetric [multifocal acquired demyelinating sensory and motor neuropathy, Lewis–Sumner syndrome], or\t\nFocal (e.g., involvement of the brachial or lumbosacral plexus or of one or more peripheral nerves in one upper or lower limb),\t\nPure motor, or\t\nPure sensory (including chronic immune sensory polyradiculopathy affecting the central process of the primary sensory neuron)\t\nExclusion criteria:\t\nBorrelia burgdorferi infection (Lyme disease), diphtheria, drug or toxin exposure probably causing the neuropathy\t\nHereditary demyelinating neuropathy\t\nProminent sphincter disturbance\t\nDiagnosis of multifocal motor neuropathy\t\nIgM monoclonal gammopathy with high titer antibodies to myelin-associated glycoprotein\t\nOther causes for demyelinating neuropathy, including POEMS syndrome, osteosclerotic myeloma, and diabetic and non-diabetic lumbosacral radiocomplexes neuropathy. PNS lymphoma and amyloidosis may occasionally have demyelinating features\t\n\nTable 4 Electrodiagnostic criteria.\n\nTo apply these criteria, the median, ulnar (stimulated below the elbow), peroneal (stimulated below the fibular head), and tibial nerves on one side are tested. If the criteria are not fulfilled, the same nerves are tested at the other side, and/or the ulnar and median nerves are stimulated bilaterally at the axilla and the Erb’s point. Motor conduction block is not considered in the ulnar nerve across the elbow and at least 50% amplitude reduction between Erb’s point and the wrist is required for probable conduction block. Temperatures should be maintained to at least 33°C at the palm and 30°C at the external malleolus (good practice points).\n\nCMAP: compound muscle action potential; ULN: upper limit of normal values; LLN: lower limit of normal values; aany nerve meeting any of the criteria (a–g)\n\nTable adapted from the Joint Task Force of the EFNS and the PNS [9].\n\n(1) Definite: at least one of the following:\t\n(a) Motor distal latency prolongation ≥50% above ULN in two nerves (excluding median neuropathy at the wrist from carpal tunnel syndrome), or\t\n(b) Reduction of motor conduction velocity ≥30% below LLN in two nerves, or\t\n(c) Prolongation of F-wave latency ≥30% above ULN in two nerves (≥50% if amplitude of distal negative peak CMAP <80% of LLN values), or\t\n(d) Absence of F-waves in two nerves if these nerves have distal negative peak CMAP amplitudes ≥20% of LLN + ≥1 other demyelinating parameterᵃ in ≥1 other nerve, or\t\n(e) Partial motor conduction block: ≥50% amplitude reduction of the proximal negative peak CMAP relative to distal, if distal negative peak CMAP ≥20% of LLN, in two nerves, or in one nerve + ≥1 other demyelinating parameterᵃ in ≥1 other nerve, or\t\n(f) Abnormal temporal dispersion (>30% duration increase between the proximal and distal negative peak CMAP) in ≥2 nerves, or\t\n(g) Distal CMAP duration (interval between onset of the first negative peak and return to baseline of the last negative peak) increase in ≥1 nerve (median ≥6.6 ms, ulnar ≥6.7 ms, peroneal ≥7.6 ms, tibial ≥8.8 ms) + ≥1 other demyelinating parameterᵃ in ≥1 other nerve\t\n(2) Probable:\t\n(a) ≥30% amplitude reduction of the proximal negative peak CMAP relative to distal, excluding the posterior tibial nerve, if distal negative peak CMAP ≥20% of LLN, in two nerves, or in one nerve + ≥1 other demyelinating parameterin ≥1 other nerve\t\n(3) Possible:\t\n(a) As in (1) but in only one nerve\t\n\nIn rare cases, CIDP can present as an extraintestinal manifestation of CD [10]. Several cases with CD have been reported with CIDP [10]. In some cases, patients developed CIDP between 1 and 30 years after the onset of CD, whereas other cases developed simultaneously, with one acute progressive episode that made the diagnosis difficult and undifferentiated from acute inflammatory demyelinating polyneuropathy [10]. A prospective study evaluated the electrodiagnostic and clinical findings for the presence of polyneuropathy in patients with CD and ulcerative colitis (UC) [11]. Both demyelinating and non-demyelinating neuropathies were observed [11]. Some CD patients presented with demyelinating neuropathy in the form of multifocal motor neuropathy and CIDP, whereas others presented with small to predominantly axonal sensory large fiber [11]. Similarly, UC patients presented with the demyelinating phenotype, whereas individuals with other phenotypes presented with small and large axonal neuropathy [11].\n\nInfliximab is a monoclonal antibody used against TNF-α and has been approved for use in the treatment of several immune-mediated diseases. Infliximab is one of the biological agents that can be used for patients with active CD who failed to respond to immunomodulatory therapy [12-14]. Anti-TNF-α has been reported to be associated with the development of both CNS and PNS demyelination [15]. CIDP has been reported in several cases in association with infliximab use for different rheumatological diseases [16]. One case reported a patient with CD developing CIDP following the use of infliximab therapy [3]. However, the patient did not improve after discontinuation of infliximab and had a recurrence of his symptoms requiring further treatment. This case is similar to our patient as his symptoms developed in a stable CD setting, which makes it likely secondary to anti-TNF-α use.\n\nThe mechanism of developing CIDP with infliximab is not well understood. Several mechanisms are thought to be related to the development of demyelination in a setting of anti-TNF-α that include increased susceptibility to infection, induction of autoimmune process, and an imbalance between TNF-α and their receptors [4]. Our patient developed symptoms 12 months after the start of infliximab therapy in a stable CD setting. His conditions improved with immunotherapy. It is uncertain whether the development of his CIDP is related to infliximab therapy or related to the CD itself. However, the development of CIDP in a setting of stable CD makes it unlikely that it was related to the disease itself.\n\nDifferent cases have reported that discontinuing infliximab may be ineffective in resolving neuropathy [3]. The improvement seen in our patient despite continuing treatment, the findings of nerve conduction studies, and the objective evidence confirming the development of CIDP in patients with CD support the conclusion that CIDP can be one of the extraintestinal manifestations of CD.\n\nThe management of CIDP needs a multidisciplinary approach requiring neurology, physical therapy, and occupational therapy. Pharmacological intervention is the mainstay to target inflammatory demyelination and the functional disability caused by the disease [7]. There are three approved first-line CIDP treatments, namely, corticosteroids, plasma exchange, and intravenous immunoglobulins [7]. Multiple second-line treatments can be used when the first-line treatment cannot be used due to side effects, inconvenience, or cost [7]. The treatment of CD associated with CIDP is similar to the treatment offered to patients with CIDP alone. Patients initially receive immunotherapy via oral or intravenous steroids, intravenous immunoglobulins, or plasma exchange after the exclusion of secondary causes and the diagnosis of peripheral neuropathy with CD [6].\n\nOur patient was treated similar to other cases of CIDP, starting with steroids and then progressing to azathioprine. This yielded a significant improvement of his motor power despite being on infliximab for his CD. In patients with CD who present with progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least two months, a physical examination should be done and electrodiagnostic studies should be obtained to rule out CIDP.\n\nConclusions\n\nFor patients with CD presenting with progressive weakness, an extensive workup is necessary. Moreover, it is important to rule out nutritional causes, medication side effects, and to consider CIDP as a possible etiology. CIDP should be ruled out with electrodiagnostic studies. Once CIDP is diagnosed, treatment should start, and patients should be followed up closely with neurological examinations. The treatment of CIDP in the setting of CD is similar to idiopathic cases.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Chronic inflammatory demyelinating polyradiculoneuropathy in a patient with Crohn's disease Intern Med Ohyagi M Ohkubo T Yagi Y 125 128 52 2013 23291687\n2 Chronic inflammatory demyelinating polyneuropathy Adv Exp Med Biol Kuwabara S Misawa S 333 343 1190 2019 31760654\n3 Chronic inflammatory demyelinating polyneuropathy following anti-TNF-α therapy with infliximab for Crohn's disease ACG Case Rep J Kamel AY Concepcion O Schlachterman A Glover S Forsmark CY 187 189 3 2016 27144200\n4 Infliximab induced chronic inflammatory demyelinating polyneuropathy: a case report Hippokratia Karantali E Katsikaki G Chatzikonstantinou S Papagiannopoulos S 179 180 23 2019 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377590/ 32742170\n5 Incidence and prevalence of chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review and meta-analysis Neuroepidemiology Broers MC Bunschoten C Nieboer D Lingsma HF Jacobs BC 161 172 52 2019 30669140\n6 Peripheral neuropathy: an underreported neurologic manifestation of inflammatory bowel disease Eur J Intern Med García-Cabo C Morís G 468 475 26 2015 26211733\n7 History, diagnosis, and management of chronic inflammatory demyelinating polyradiculoneuropathy Mayo Clin Proc Dyck PJ Tracy JA 777 793 93 2018 29866282\n8 Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews Cochrane Database Syst Rev Oaklander AL Lunn MP Hughes RA van Schaik IN Frost C Chalk CH 0 1 2017\n9 European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society--First Revision J Peripher Nerv Syst 1 9 15 2010\n10 Chronic inflammatory demyelinating polyneuropathy-like neuropathy as an initial presentation of Crohn's disease BMC Neurol Kim S Kang SJ Oh KW 48 15 2015 25886604\n11 Clinical and electrodiagnostic findings in patients with peripheral neuropathy and inflammatory bowel disease Inflamm Bowel Dis Gondim Fde A de Oliveira GR Teles BC 2123 2129 21 2015 25993692\n12 British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults Gut Lamb CA Kennedy NA Raine T 0 68 2019\n13 Crohn's disease: management in adults, children and young people - concise guidance Clin Med (Lond) Tun GS Cripps S Lobo AJ 231 236 18 2018 29858433\n14 Biologic agents for IBD: practical insights Nat Rev Gastroenterol Hepatol Danese S Vuitton L Peyrin-Biroulet L 537 545 12 2015 26284562\n15 Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey Rheumatology (Oxford) Seror R Richez C Sordet C 868 874 52 2013 23287362\n16 Development of chronic inflammatory demyelinating polyneuropathy in a patient receiving infliximab for psoriasis Br J Dermatol Foulkes AC Wheeler L Gosal D Griffiths CE Warren RB 206 209 170 2014 23909440\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(10)",
"journal": "Cureus",
"keywords": "anti-tnf-α treatment; chronic inflammatory demyelinating polyradiculoneuropathy; crohn’s disease; infliximab; neurological complications",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e19041",
"pmc": null,
"pmid": "34858738",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "26284562;27144200;32742170;25886604;31760654;31562236;23291687;30669140;29858433;23287362;25993692;26211733;29866282;20433600;23909440;28084646",
"title": "Chronic Inflammatory Demyelinating Polyneuropathy in Patients With Crohn's Disease on Infliximab Therapy.",
"title_normalized": "chronic inflammatory demyelinating polyneuropathy in patients with crohn s disease on infliximab therapy"
} | [
{
"companynumb": "SA-CELLTRION INC.-2021SA016778",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Although COVID-19 has been reported to be associated with high rates of venous thromboembolism (VTE), the risk of VTE and bleeding after hospitalization for COVID-19 remains unclear, and the optimal hospital VTE prevention strategy is not known. We collected retrospective observational data on thrombosis and bleeding in 303 consecutive adult patients admitted to the hospital for at least 24 hours for COVID-19. Patients presenting with VTE on admission were excluded. Data were collected until 90 days after admission or known death by using medical records and an established national VTE network. Maximal level of care was ward based in 78% of patients, with 22% requiring higher dependency care (12% noninvasive ventilation, 10% invasive ventilation). Almost all patients (97.0%) received standard thromboprophylaxis or were already receiving therapeutic anticoagulation (17.5%). Symptomatic image-confirmed VTE occurred in 5.9% of patients during index hospitalization, and in 7.2% at 90 days after admission (23.9% in patients requiring higher dependency care); half the events were isolated segmental or subsegmental defects on lung imaging. Bleeding occurred in 13 patients (4.3%) during index hospitalization (1.3% had major bleeding). The majority of bleeds occurred in patients on the general ward, and 6 patients were receiving treatment-dose anticoagulation, highlighting the need for caution in intensifying standard thromboprophylaxis strategies. Of 152 patients discharged from the hospital without an indication for anticoagulation, 97% did not receive thromboprophylaxis after discharge, and 3% received 7 days of treatment with low molecular weight heparin after discharge. The rate of symptomatic VTE in this group at 42 days after discharge was 2.6%, highlighting the need for large prospective randomized controlled trials of extended thromboprophylaxis after discharge in COVID-19.",
"affiliations": "Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.;Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.;Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.;Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.;Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.;Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.;Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.;Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.;Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.",
"authors": "Salisbury|Richard|R|;Iotchkova|Valentina|V|;Jaafar|Sarah|S|;Morton|Joshua|J|;Sangha|Gavinda|G|;Shah|Akshay|A|;Untiveros|Paraskevi|P|;Curry|Nicola|N|;Shapiro|Susan|S|",
"chemical_list": "D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2020003349",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "4(24)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001780:Blood Coagulation Tests; D000086382:COVID-19; D003952:Diagnostic Imaging; D019468:Disease Management; D004198:Disease Susceptibility; D004739:England; D005260:Female; D005500:Follow-Up Studies; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D063189:Symptom Assessment; D013997:Time Factors; D054556:Venous Thromboembolism",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "6230-6239",
"pmc": null,
"pmid": "33351117",
"pubdate": "2020-12-22",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "32746455;32853978;31297454;22315261;32320517;32485437;32766883;10477777;32374815;32473124;32502594;32651579;26764429;31034476;32271988;32381264;33091702;32682004;32367170;32402996;32685883;32353746;15289368;32369666;32362349;32554532;32311448;32459046;32330083;28542789;15842354;32492712",
"title": "Incidence of symptomatic, image-confirmed venous thromboembolism following hospitalization for COVID-19 with 90-day follow-up.",
"title_normalized": "incidence of symptomatic image confirmed venous thromboembolism following hospitalization for covid 19 with 90 day follow up"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1882339",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DALTEPARIN"
},
"drugadditional": "3",
... |
{
"abstract": "Coronaviruses can cause multiple systemic infections respiratory complications are the most recognizable symptoms similar to severe acute respiratory syndrome coronavirus (SARS-CoV). Aspiration pneumonia was the most common reason for the Emergency admission of patients with PD.Here we report the case a patient with Parkinson's disease admitted for respiratory insufficiency secondary to Covid-19 and aspiration pneumonia. A 78-years- old male patient, treated for Parkinson's disease, was admitted to the emergency department with symptoms of acute respiratory insufficiency. Four days before his admission, the patient suffered from solid dysphagia. On physical examination, the patient was obnibulated, febrile at 39 °, with clinical signs of respiratory insuffisiency. Computed tomography of the neck and Chest showed patchy areas of subpleural ground glass opacities with vascular dilatation associated with bilateral posterobasal and anterior consolidations with air overlapping imaging characteristics of aspiration and covid 19 pneumonia. The CT scan also showed an oesophageal hypodensity consistant with endoluminal foreign body. Reverse transcription-polymerase chain reaction (RT-PCR) for COVID-19 was positive.The diagnosis of Sars-cov 19 associated with aspiration pneumonia were retained. An esophagoscopy was realized, a foreign body visualized in the upper sphincter of the esophagus and an impacted food bolus was retracted. We would like to emphasize the challenging differential diagnosis of pneumonia caused by aspiration of different materials and Sars-cov 19. Definite discrimination of the two diagnoses might be impossible. Some radiologic features may suggest one diagnos over the other. While lobar or segmental pneumonia, lung abscess, and empyema have been reported as Complications of aspirations pneumonia these outcomes are rarely Considered Complications of COVID-19 pneumonia. Centrilobular nodules and tree-in-bud sign are commonly seen in cases with aspiration. Interestingly, these CT findings are not frequent in COVID-19 pneumonia and have been categorized as \"Atypical\" by the Radiological Society of North America (RSNA), and therefore could be of some Value in proposing a differential diagnosis. Bilateral subpleural patches of ground-glass opacity (GGO), especially in basal distribution, have been described as typical for the diagnosis of COVID-19 pneumonia in suspected Cases. Such a presentation is also fairly common in aspiration Pneumonia.",
"affiliations": "Department of Otorhinolaryngology Head and Neck Surgery, University Hospital of Tangier-Morocco, University of Abdelmalek Essaadi, Tangier, Morocco.;Department of Otorhinolaryngology Head and Neck Surgery, University Hospital of Tangier-Morocco, University of Abdelmalek Essaadi, Tangier, Morocco.;Department of Otorhinolaryngology Head and Neck Surgery, University Hospital of Tangier-Morocco, University of Abdelmalek Essaadi, Tangier, Morocco.",
"authors": "Touihmi|Safaa|S|;El Hassouni|Adam|A|;Rkain|Ilham|I|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.ejro.2021.100379",
"fulltext": "\n==== Front\nEur J Radiol Open\nEur J Radiol Open\nEuropean Journal of Radiology Open\n2352-0477\nElsevier\n\nS2352-0477(21)00059-9\n10.1016/j.ejro.2021.100379\n100379\nCase Report\nSars-Cov-19 associated with aspiration pneumonia in a patient with Parkinson disease: A case report\nTouihmi Safaa Safaatouihmi.st@gmail.com\n*\nEl Hassouni Adam\nRkain Ilham\nDepartment of Otorhinolaryngology Head and Neck Surgery, University Hospital of Tangier-Morocco, University of Abdelmalek Essaadi, Tangier, Morocco\n⁎ Corresponding author. Safaatouihmi.st@gmail.com\n02 10 2021\n2021\n02 10 2021\n8 10037920 9 2021\n26 9 2021\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nCoronaviruses can cause multiple systemic infections respiratory complications are the most recognizable symptoms similar to severe acute respiratory syndrome coronavirus (SARS-CoV). Aspiration pneumonia was the most common reason for the Emergency admission of patients with PD.Here we report the case a patient with Parkinson’s disease admitted for respiratory insufficiency secondary to Covid-19 and aspiration pneumonia.\n\nA 78-years- old male patient, treated for Parkinson’s disease, was admitted to the emergency department with symptoms of acute respiratory insufficiency. Four days before his admission, the patient suffered from solid dysphagia. On physical examination, the patient was obnibulated, febrile at 39 °, with clinical signs of respiratory insuffisiency. Computed tomography of the neck and Chest showed patchy areas of subpleural ground glass opacities with vascular dilatation associated with bilateral posterobasal and anterior consolidations with air overlapping imaging characteristics of aspiration and covid 19 pneumonia. The CT scan also showed an oesophageal hypodensity consistant with endoluminal foreign body.\n\nReverse transcription-polymerase chain reaction (RT-PCR) for COVID-19 was positive.The diagnosis of Sars-cov 19 associated with aspiration pneumonia were retained. An esophagoscopy was realized, a foreign body visualized in the upper sphincter of the esophagus and an impacted food bolus was retracted.\n\nWe would like to emphasize the challenging differential diagnosis of pneumonia caused by aspiration of different materials and Sars-cov 19. Definite discrimination of the two diagnoses might be impossible. Some radiologic features may suggest one diagnos over the other. While lobar or segmental pneumonia, lung abscess, and empyema have been reported as Complications of aspirations pneumonia these outcomes are rarely Considered Complications of COVID-19 pneumonia. Centrilobular nodules and tree-in-bud sign are commonly seen in cases with aspiration. Interestingly, these CT findings are not frequent in COVID-19 pneumonia and have been categorized as “Atypical” by the Radiological Society of North America (RSNA), and therefore could be of some Value in proposing a differential diagnosis. Bilateral subpleural patches of ground-glass opacity (GGO), especially in basal distribution, have been described as typical for the diagnosis of COVID-19 pneumonia in suspected Cases. Such a presentation is also fairly common in aspiration Pneumonia.\n\nKeywords\n\nSars-Cov-19\nCoronavirus\nAspiration pneumonia\nDyspnea\nForeign body ingestion\nParkinson's disease\n==== Body\npmc1 Introduction\n\nOn 31 December 2019, a novel coronavirus (COVID-19) was detected in Wuhan City, Hubei Province of China. The symptoms of COVID-19 are dependent on age and the patient’s underlying medical illness and also the condition of the immune system [1]. Coronaviruses can cause multiple systemic infections that respiratory complications are the most recognizable symptoms similar to severe acute respiratory syndrome coronavirus (SARS-CoV). The most prevailing symptoms at the onset of disease, after an incubation period of approximately 5−2 days, are Fever, cough, dyspnea, myalgia, headache, and diarrhea.\n\nParkinson’s disease is a progressive nervous system disorder that affects movement. Symptoms start gradually. Tremors are common, but the disorder also commonly causes stiffness or slowing of movement, loss of automatic movements, impaired posture, and balance. The cause of Parkinson's disease is unknown, but several factors appear to play a role, including genetic and environmental causes. The treatment options vary and include medications and surgery. While Parkinson’s itself is not fatal, disease complications can be serious [2]. Gastrointestinal abnormalities in Parkinson’s disease(PD) have been known since 1817. Aspiration pneumonia was the most common reason for the Emergency admission of patients with PD.\n\nHere we report the case of a patient with Parkinson’s disease admitted for respiratory insufficiency secondary to Covid-19 and aspiration pneumonia, and discuss the diagnosis challenges and the radiological features of each etiology of pneumonia.\n\n2 Case report\n\nA 78-years- old male patient, was admitted to the emergency department with symptoms of acute respiratory insufficiency. Four days before his admission, the patient suffered from solid dysphagia with no other symptom associated, the evolution was towards worsening of the symptomatology, and the development of dyspnea. In the past medical history, the patient is treated for Parkinson’s disease for ten years, with two episodes of aspiration pneumonia in the last two years, the patient is on medical treatment : Levodopa. The patient is also a well-known type 2 diabetes mellitus treated with insulin.\n\nOn physical examination, the patient was obnibulated, febrile at 39 °, with blood pressure :100−85 mm/hg, heart rate :120 beats/minute, respiratory rate 37/minute, and oxygen saturation of 75 % on room air. Given the instability of the patient, no further clinical examination was done.\n\nThe laboratory examination results were as follows: serum glucose 160 mg/dL; blood urea nitrogen : 19 mg/dL ;creatinine 0.13 mg/dL ; alanine aminotransferase 35 IU/L ; aspartate aminotransferase 47 IU/L ; sodium 140 mmol/L ; potassium 3.8 mmol/L, hemoglobin 11.6 g/ dL and white blood cell count 14,700 cells per microliter (neutrophils = 82.7 % ; lymphocytes = 10.4%) ; C-reactive protein :64 mg/l, negative glucose and ketone in complete urinalysis.\n\nComputed tomography of the neck and Chest showed patchy areas of subpleural ground glass opacities with vascular dilatation associated with bilateral posterobasal and anterior consolidations with air bronchogram (Fig. 1), Featuring overlapping imaging characteristics of aspiration and covid 19 pneumonia. The CT scan also showed an oesophageal hypodensity consistant with endoluminal foreign body (Fig. 2).Fig. 1 Computed tomography of the neck and Chest, axial slices: patchy areas of subpleural ground glass opacities with vascular dilatation associated with bilateral anterior and posterobasal, consolidations with air bronchogram, Featuring overlapping imaging characteristics of aspiration and covid 19 pneumonia.\n\nFig. 1\n\nFig. 2 Computed tomography of the neck and Chest: oesophageal endoluminal foreign body.\n\nFig. 2\n\nReverse transcription-polymerase chain reaction (RT-PCR) for COVID-19 was positive.The diagnosis of Sars-cov 19 associated with aspiration pneumonia were retained. The treatment regimen was ventilatory support, high-flow oxygen, the patient was treated with hydroxychloroquine, Lopinavir/Ritonavir (LPV/RTV), and Azythromycin.Under general anesthesia and following the Safety Recommendations for Evaluation and Surgery of the Head and Neck During the COVID-19 pandemic [6], an esophagoscopy was realized, a foreign body visualized in the upper sphincter of the esophagus and an impacted food bolus was retracted (Fig. 3).Fig. 3 Picture of the foreign body retracted from the oesophagus: impacted food bolus.\n\nFig. 3\n\n3 Discussion\n\nAspiration pneumonia is the most common reason for the Emergency admission of patients with PD whose disease the ratio was >5 years [10]. Most of them showed cognitive impairment and a history of psychiatric symptoms. Our protocol at patient admission recommended screening for SARS-Cov2 in patients presenting respiratory symptoms and Epidemiologic risk of contact with the infected or contagious individual, Besides, correct triage of these patients is obligatory to reduce the risk of spread of infection and to protect the medical personnel from inadvertent exposure to The virus. On the other hand, early administration of Antibiotics in the presumed cases of aspiration pneumonia is Urgent to prevent morbidity and mortality [8,3]. In immunocompromised populations, COVID-19 infection should be considered in the presence of an atypical presentation and screening, protocols may be needed to be re-evaluated. Therefore, and since the increase in the number of cases and evidence of asymptomatic transmission among the community, contact with infected individuals was no longer mandatory. The fact that our patient did not have any epidemiologic risk factor for COVID-19 infection, made the diagnosis more likely to be aspiration pneumoniaI [2]. Our patient had Typical symptoms of gastrointestinal complications of Parkinson’s disease that had been begun four days before the appearance of respiratory symptoms even though the patient was under medical treatment. Dopaminergic medication does not necessarily improve swallowing function [5]. PD patients often show an improved swallowing function and reduction in other symptoms after the adjustment of medications. Some Studies have suggested that dysphagia in PD is statistically resistant to dopaminergic stimulation. Another study Suggested that the risk of aspiration may remain unchanged with levodopa. Further studies are nnecessary to confirm the difference in the risk of aspiration between on and off states of levodopa [7,9,10].\n\nWe would like to emphasize the challenging differential diagnosis of pneumonia caused by aspiration of different materials and Sars-cov 19. The Interpretation of chest findings may not be necessarily easy for the Emergency radiologists in the setting of e exact diagnosid. Although the go standard for the diagnosis of COVID Infection is PCR testing, radiologic outcomes together with the clinical data have also been implied at least for initial decision-making. In some cases, definite discrimination of the two diagnoses might be impossible. Some radiologic features may suggest One diagnos over the other. While lobar or segmental pneumonia, lung abscess, and empyema have been reported as Complications of aspirations pneumonia these outcomes are rarely Considered Complications of COVID-19 pneumonia. Centrilobular nodules and tree-in-bud sign are commonly seen in cases [1].\n\nWith aspiration. Interestingly, these CT findings are not frequent in COVID-19 pneumonia and have been categorized as “Atypical” by the Radiological Society of North America (RSNA), and therefore could be of some Value in proposing a differential diagnosis. Bilateral subpleural patches of ground-glass opacity (GGO), especially in basal distribution, have been described as typical for the diagnosis of COVID-19 pneumonia in suspected Cases [4,8]. Such a presentation is also fairly common in aspiration Pneumonia. Although posterodorsal lung Involvement is the most common distribution pattern in both Conditions, anterior lung involvement has rarely been reported in aspiration pneumonia, thus detection of radioLogic findings in anterior parts is more suggestive of COVID Pneumonia rather than aspiration pneumonia.\n\n4 Conclusion\n\nIn summary, this study demonstrates, despite possible radiologic and clinical similarities between aspiration and COVID pneumonia, one Could suggest a correct diagnosis by careful examination of The CT images together with attention to the clinical scenario and judicious utilization of laboratory tests. Timely Diagnosis and treatment positively influence prognosis and Reduce mortality.\n\nEthical statement for solid state ionics\n\n1) This material is the authors' own original work, which has not been previously published elsewhere.\n\n2) The paper is not currently being considered for publication elsewhere.\n\n3) The paper reflects the authors' own research and analysis in a truthful and complete manner.\n\n4) The paper properly credits the meaningful contributions of co-authors and co-researchers.\n\n5) The results are appropriately placed in the context of prior and existing research.\n\n6) All sources used are properly disclosed (correct citation). Literally copying of text must be indicated as such by using quotation marks and giving proper reference.\n\n7) All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content.\n\nFunding statement\n\nNo funding to declare.\n\nDeclaration of Competing Interest\n\nThe authors report no declarations of interest.\n==== Refs\nReferences\n\n1 Monte Francisca Sueli da Silva-Junior Francisco Pereira Mov. Disord. 20 4 2005 457 462 15625689\n2 Guillain Barre syndrome associated with COVID-19 infection: A case Report Zahra Sedaghat a, Narges Karimi Case Reports / Journal of Clinical Neuroscience.\n3 Chaumartin N. Monville M. Lachaux B. Dysphagia or dysphagias during neuroleptic medication? LEncphale 2011 Paris\n4 Forster A. Samaras N. Notaridis G. Morel P. Hua-Stolz J. Samaras D. Assessment and screening of deglutition disorders in geriatric patients NPG Neurol. - Psychiatr. – Geriatr. 2013\n5 Sutton James P. Point of view Dysphagia in Parkinson’s disease is responsive to levodopa Pacific Neuroscience Medical Group, Oxnard, CA 93030, United States Parkinsonism Relat. Disord. 19 2013 282e284 23333537\n6 Givi Babak Safety recommendations for evaluation and surgery of the head and neck during the COVID-19 pandemic JAMA Otolaryngol. Neck Surg. March (31) 2020\n7 Dysphagia in Parkinson’s disease is responsive to levodopa, James P. Sutton, Pacific Neuroscience Medical Group.\n8 Aspiration Pneumonia or COVID-19 Infection: A Diagnostic Challenge, Fariba Zarei, MD, Letter to the Editor.\n9 Oropharyngeal Dysphagia and Aspiration Pneumonia Following Coronavirus Disease 2019: A Case Report, Yoichiro Aoyagi1.\n10 Dysphagia in Parkinson’s DiseaseInga Suttrup 2015 Springer Science+Business Media New York\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-0477",
"issue": "8()",
"journal": "European journal of radiology open",
"keywords": "Aspiration pneumonia; Coronavirus; Dyspnea; Foreign body ingestion; Parkinson's disease; Sars-Cov-19",
"medline_ta": "Eur J Radiol Open",
"mesh_terms": null,
"nlm_unique_id": "101650225",
"other_id": null,
"pages": "100379",
"pmc": null,
"pmid": "34632001",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32381329;23333537;15625689;32232423;22980477;32312628;32533346",
"title": "Sars-Cov-19 associated with aspiration pneumonia in a patient with Parkinson disease: A case report.",
"title_normalized": "sars cov 19 associated with aspiration pneumonia in a patient with parkinson disease a case report"
} | [
{
"companynumb": "MA-LUPIN PHARMACEUTICALS INC.-2022-06238",
"fulfillexpeditecriteria": "2",
"occurcountry": "MA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "The efficacy and safety of atorvastatin in children/adolescents aged 10-17 years with heterozygous familial hypercholesterolemia (HeFH) have been demonstrated in trials of up to 1 year in duration. However, the efficacy/safety of >1 year use of atorvastatin in children/adolescents with HeFH, including children from 6 years of age, has not been assessed.\n\n\n\nTo characterize the efficacy and safety of atorvastatin over 3 years and to assess the impact on growth and development in children aged 6-15 years with HeFH.\n\n\n\nA total of 272 subjects aged 6-15 years with HeFH and low-density lipoprotein cholesterol (LDL-C) ≥4.0 mmol/L (154 mg/dL) were enrolled in a 3-year study (NCT00827606). Subjects were initiated on atorvastatin (5 mg or 10 mg) with doses increased to up to 80 mg based on LDL-C levels.\n\n\n\nMean percentage reductions from baseline in LDL-C at 36 months/early termination were 43.8% for subjects at Tanner stage (TS) 1 and 39.9% for TS ≥2. There was no evidence of variations in the lipid-lowering efficacy of atorvastatin between the TS groups analyzed (1 vs ≥2) or in subjects aged <10 vs ≥10 years, and the treatment had no adverse effect on growth or maturation. Atorvastatin had a favorable safety and tolerability profile, and only 6 (2.2%) subjects discontinued because of adverse events.\n\n\n\nAtorvastatin over 3 years was efficacious, had no impact on growth/maturation, and was well tolerated in children and adolescents with HeFH aged 6-15 years.",
"affiliations": "Department of Endocrinology, Morbid Obesity and Preventive Medicine, Lipid Clinic, Oslo University Hospital, Oslo, Norway. Electronic address: glangsle@ous-hf.no.;Pfizer Inc, New York, NY, USA.;Metabolic Unit, Choremio Goudi Research Institute, 1st Department of Pediatrics, Medical School University of Athens, Aghia Sofia Children's Hospital, Athens, Greece.",
"authors": "Langslet|Gisle|G|;Breazna|Andrei|A|;Drogari|Euridiki|E|",
"chemical_list": "D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D000069059:Atorvastatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4789",
"issue": "10(5)",
"journal": "Journal of clinical lipidology",
"keywords": "Adolescents; Atorvastatin; Children; Heterozygous familial hypercholesterolemia; Low-density lipoprotein cholesterol; Tanner stage",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D000293:Adolescent; D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D000069059:Atorvastatin; D002648:Child; D008078:Cholesterol, LDL; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II; D006965:Hyperplasia; D008297:Male; D011973:Receptors, LDL; D012512:Sarcoma, Ewing; D012727:Sex Characteristics",
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "1153-1162.e3",
"pmc": null,
"pmid": "27678432",
"pubdate": "2016",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia.",
"title_normalized": "a 3 year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia"
} | [
{
"companynumb": "NO-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-282478",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"dr... |
{
"abstract": "Intestinal obstruction is a common complication in patients with advanced abdominal or pelvic cancer. The synthetic somatostatin analogue octreotide can help relieve nausea, vomiting and pain in patients with inoperable obstruction. Here, we report a case of recurrent intestinal obstruction in a patient with adenocarcinoma. Although the obstruction was resolved after 3 days of treatment with octreotide, new episodes of obstruction occurred, resulting in a delay of the chemotherapy treatment. After 3 episodes of obstruction, we initiated treatment with a longer-acting somatostatin analogue, lanreotide Autogel® 120 mg, administered once every 4 weeks. The treatment with lanreotide Autogel is being continued, allowing for continuation of the chemotherapy without further episodes of intestinal subocclusion or obstruction. Until November 2013, the patient received eighteen 4-weekly injections of lanreotide Autogel and did not report side effects. This case report demonstrates the successful treatment of intestinal obstruction with lanreotide Autogel in a patient with adenocarcinoma.",
"affiliations": "AZ Nikolaas, Sint-Niklaas, Belgium.",
"authors": "Lybaert|Willem|W|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000358124",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000358124cro-0007-0043Published online: January, 2014The Use of Lanreotide Autogel® in the Treatment of Intestinal Obstruction in a Patient with Adenocarcinoma Lybaert Willem *AZ Nikolaas, Sint-Niklaas, Belgium*Willem Lybaert, AZ Nikolaas, Lodewijk De Meesterstraat 5, BE-9100 Sint-Niklaas (Belgium), E-Mail willem.lybaert@telenet.beJan-Apr 2014 16 1 2014 16 1 2014 7 1 43 46 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Intestinal obstruction is a common complication in patients with advanced abdominal or pelvic cancer. The synthetic somatostatin analogue octreotide can help relieve nausea, vomiting and pain in patients with inoperable obstruction. Here, we report a case of recurrent intestinal obstruction in a patient with adenocarcinoma. Although the obstruction was resolved after 3 days of treatment with octreotide, new episodes of obstruction occurred, resulting in a delay of the chemotherapy treatment. After 3 episodes of obstruction, we initiated treatment with a longer-acting somatostatin analogue, lanreotide Autogel® 120 mg, administered once every 4 weeks. The treatment with lanreotide Autogel is being continued, allowing for continuation of the chemotherapy without further episodes of intestinal subocclusion or obstruction. Until November 2013, the patient received eighteen 4-weekly injections of lanreotide Autogel and did not report side effects. This case report demonstrates the successful treatment of intestinal obstruction with lanreotide Autogel in a patient with adenocarcinoma.\n\nKey words\nIntestinal obstructionAdenocarcinomaSomatostatin analogueLanreotide Autogel®\n==== Body\nIntroduction\nIntestinal obstruction is a common complication in patients with advanced abdominal or pelvic cancer and has a significant impact on their quality of life. In patients with inoperable malignant bowel obstruction, the synthetic somatostatin analogue octreotide relieves nausea, vomiting and pain, and decreases drainage from a nasogastric tube [1]. Here, we report the use of the long-acting somatostatin analogue lanreotide Autogel® (Somatuline®; Ipsen NV) in the treatment of bowel obstruction in a patient with adenocarcinoma and peritoneal carcinomatosis.\n\nCase Presentation\nIn January 2012, a 60-year-old woman presented with a 3-month history of increasing abdominal pain and a change in the stool pattern with a single episode of anal red blood loss in the past week. She had a medical history of hypercholesterolemia and had previously undergone appendectomy. An ultrasound of the abdomen showed several masses dispersed over the peritoneum, compatible with significant peritoneal metastasis. Diffuse ascites fluid was also noted and could not be tapped. Clinical examination and auscultation showed a slightly enlarged abdomen with good peristalsis of the intestine. No clangor was noted. Colonoscopy revealed a large ulcerating lesion at the level of the sigmoid colon, which was diagnosed as a moderately differentiated adenocarcinoma after biopsy.\n\nNo surgery was performed due to the presence of peritoneal carcinomatosis. Chemotherapy with 18 biweekly cycles (1 cycle every 2 weeks) of FOLFIRI and bevacizumab (Avastin®, Roche) was started. FOLFIRI was administered according to the following schedule: day 1, irinotecan 180 mg/m2; days 1 and 2, leucovorin 100 mg/m2, 5-fluorouracil bolus 400 mg/m2 and 5-fluorouracil infusion 600 mg/m2. Avastin was given at a dose of 5 mg/kg every 2 weeks. If the patient had responded to this treatment, the possibility of performing debulking surgery and hyperthermic intraperitoneal chemotherapy would have been considered. The abdominal pain disappeared after the first month of chemotherapy, while the ascites disappeared after 6 weeks. There was also a slight regression of the peritoneal masses.\n\nDuring the 5th, 6th and 7th cycle of chemotherapy, the patient was hospitalized because of clinical signs of intestinal subocclusion (vomiting, absence of stools and flatus) that evolved into complete obstruction. A CT scan of the abdomen did not reveal the cause of the obstruction or deterioration of the oncological lesions. Based on this observation, a FOLFIRI-induced mucositis, motility disturbances due to peritoneal metastasis or a combination of these two factors were suspected. During hospitalization, fluids, alizapride (Litican®, 300 mg/day; Sanofi-Aventis) and methylprednisolone sodium succinate (Solu-Medrol®, 40 mg/day; Pfizer Inc.) were administered intravenously, paracetamol (1 g/dose) was administered intravenously 4 times a day and octreotide (Sandostatin®, 0.5 mg/dose; Novartis) was administered subcutaneously 3 times a day until the obstruction resolved. Oral consumption of food and fluids was withheld, and a nasogastric tube was placed. At each of the 3 hospitalization episodes, an enema was performed. After the first episode of obstruction, the dose of FOLFIRI was decreased to 75%, while the dose of Avastin was not decreased. All episodes of obstruction resolved after 3 days, and the chemotherapy was reintroduced after 1–2 weeks following resolution of the obstruction. After the third episode of obstruction, we initiated treatment with lanreotide Autogel 120 mg, injected deep subcutaneously once every 4 weeks. The 120-mg dose was chosen based on our experience that the 90-mg dose has a lower efficacy. The treatment with lanreotide Autogel continued during the remaining 11 cycles of chemotherapy, and no further episodes of intestinal subocclusion or obstruction occurred.\n\nBecause tumor response following the 18 cycles of chemotherapy was not sufficient, debulking surgery or hyperthermic intraperitoneal chemotherapy treatment were not recommended. After a 3-month break in the chemotherapy treatment requested by the patient, a second-line chemotherapy course was initiated. Lanreotide Autogel administration was continued during this treatment break. The patient is currently undergoing second-line chemotherapy with FOLFOX4 at 75% of the usual dose, administered once every 2 weeks in 12 cycles according to the following schedule: day 1, oxaliplatin 85 mg/m2 at 75%; days 1 and 2, 75% of leucovorin 100 mg/m2, 5-fluorouracil bolus 400 mg/m2 and 5-fluorouracil infusion 600 mg/m2. The 4-weekly lanreotide Autogel injections have been continued without interruption to support the quality of life of the patient. No new episodes of obstruction occurred until November 2013, and the patient reported no side effects due to lanreotide Autogel.\n\nDiscussion\nIntestinal obstruction is reported in up to 51% of the patients with ovarian cancer and up to 28% of those with gastrointestinal cancer [2] and has an important impact on their quality of life. Due to contraindications such as intra-abdominal carcinomatosis, poor nutritional status or a large volume of ascites, surgery is not an option in a substantial portion of these patients [3, 4]. A nasogastric tube can be placed to drain secretions; however, this often causes a great amount of distress in the patient as well as nasal or pharyngeal irritation, nasal cartilage erosion, occlusion of the tube or spontaneous expulsion [1].\n\nShort-acting somatostatin analogues such as octreotide (Sandostatin) are antisecretory drugs used in the treatment of patients with inoperable bowel obstruction. Somatostatin was initially discovered as an inhibitor of growth hormone release [5], but was later found to play an inhibitory role in the regulation of several organ systems such as the central nervous system, the immune system, vessel walls, the pancreas and the gastrointestinal tract [6]. Somatostatin analogues are valuable in the treatment of patients with malignant bowel obstruction because of their inhibitory effect on gastrointestinal motility and secretions and their ability to increase the absorption of water and electrolytes from the intestinal lumen [1]. The efficacy of short-acting somatostatin analogues in the management of symptoms due to malignant bowel obstruction has been reported in numerous patients, with control of vomiting obtained in more than 60% of the patients (reviewed in [7]). Reversal of malignant bowel obstruction after treatment with short-acting somatostatin analogues has also been reported [8]. The synthetic somatostatin analogue lanreotide has shown efficacy in the symptomatic treatment of inoperable bowel obstruction in patients with peritoneal carcinomatosis when administered in the form of microparticles [9].\n\nHere, we report a case of intestinal obstruction in a patient with adenocarcinoma, which resolved after treatment with octreotide. However, new episodes of obstruction occurred, which each time led to a delay in the administration of chemotherapy. After the third episode, we initiated treatment with lanreotide Autogel. Until November 2013, the patient received eighteen 4-weekly injections of lanreotide Autogel and did not experience any further episodes of obstruction, suggesting that lanreotide prevents recurrence of intestinal obstruction in patients with intestinal cancer. Another advantage is that while short-acting octreotide has to be administered 3 times a day, lanreotide Autogel is administered only once a month, improving a patient's quality of life. Treatment with lanreotide Autogel prevented recurring episodes of obstruction, allowing the patient to continue the chemotherapy course without further delays and to start the second course.\n\nTo our knowledge, this is the first report of a successful use of lanreotide Autogel in the management of malignant bowel obstruction. Our results indicate that lanreotide Autogel could be used as an alternative to a long-acting formulation of octreotide, which has recently shown efficacy in the symptomatic treatment of inoperable malignant bowel obstruction due to peritoneal carcinomatosis [10]. A long-term treatment with lanreotide, as reported herein, is further supported by the results of a study in which 3 patients with malignant bowel obstruction due to ovarian cancer received a monthly-administered long-acting depot form of octreotide (Sandostatin LAR® Depot) for a period of over 9 months, with no significant toxicities reported [11]. The efficacy and safety of lanreotide in the palliative treatment of inoperable malignant intestinal obstruction are currently being investigated in a phase II clinical trial (www.clinicaltrials.gov: NCT01076803).\n\nDisclosure Statement\nDr. Lybaert is a consultant for Ipsen.\n\nAcknowledgements\nWe thank Dr. Vincent de Ruyter (Ipsen) for his support in reviewing this case study report and providing additional information on lanreotide. We also thank Joke Vandewalle (XPE Pharma & Science) who provided medical writing services on behalf of Ipsen. The medical writing services were funded by Ipsen.\n==== Refs\nReferences\n1 Ripamonti C Mercadante S How to use octreotide for malignant bowel obstruction J Support Oncol 2004 2 357 364 \n2 Mercadante S Intestinal dysfunction and obstruction Walsh D: Palliative Medicine 2009 Philadelphia Saunders Elsevier 1267 1275 \n3 Ripamonti C Twycross R Baines M Bozzetti F Capri S De Conno F Gemlo B Hunt TM Krebs HB Mercadante S Schaerer R Wilkinson P Clinical-practice recommendations for the management of bowel obstruction in patients with end-stage cancer Support Care Cancer 2001 9 223 233 \n4 Feuer DJ Broadley KE Shepherd JH Barton DP Systematic review of surgery in malignant bowel obstruction in advanced gynecological and gastrointestinal cancer. The Systematic Review Steering Committee Gynecol Oncol 1999 75 313 322 \n5 Brazeau P Vale W Burgus R Ling N Butcher M Rivier J Guillemin R Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone Science 1973 179 77 79 \n6 Lamberts SW van der Lely AJ Hofland LJ New somatostatin analogs: will they fulfil old promises? Eur J Endocrinol 2002 146 701 705 \n7 Mercadante S Porzio G Octreotide for malignant bowel obstruction: twenty years after Crit Rev Oncol Hematol 2012 83 388 392 \n8 Mercadante S Kargar J Nicolosi G Octreotide may prevent definitive intestinal obstruction J Pain Symptom Manage 1997 13 352 355 \n9 Mariani P Blumberg J Landau A Lebrun-Jezekova D Botton E Beatrix O Mayeur D Herve R Maisonobe P Chauvenet L Symptomatic treatment with lanreotide microparticles in inoperable bowel obstruction resulting from peritoneal carcinomatosis: a randomized, double-blind, placebo-controlled phase III study J Clin Oncol 2012 30 4337 4343 \n10 Laval G Rousselot H Toussaint-Martel S Mayer F Terrebonne E Francois E Brixi H Nguyen T Bourdeix I Bisot-Locard S Zelek L SALTO: a randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction Bull Cancer 2012 99 E1 E9 \n11 Matulonis UA Seiden MV Roche M Krasner C Fuller AF Atkinson T Kornblith A Penson R Long-acting octreotide for the treatment and symptomatic relief of bowel obstruction in advanced ovarian cancer J Pain Symptom Manage 2005 30 563 569\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "7(1)",
"journal": "Case reports in oncology",
"keywords": "Adenocarcinoma; Intestinal obstruction; Lanreotide Autogel®; Somatostatin analogue",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "43-6",
"pmc": null,
"pmid": "24575015",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports",
"references": "11980627;22277783;11430417;9204656;10600282;15357519;4682131;23109694;16376743;22265994",
"title": "The use of lanreotide autogel® in the treatment of intestinal obstruction in a patient with adenocarcinoma.",
"title_normalized": "the use of lanreotide autogel in the treatment of intestinal obstruction in a patient with adenocarcinoma"
} | [
{
"companynumb": "BE-MYLANLABS-2015M1021304",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAcute poisoning is a significant and preventable cause of mortality among children internationally. The aims of this study were to assess the case fatality rate of children admitted to an inner-city hospital for acute poisoning and to compare the demographics and source of poisoning of fatal cases.\n\n\nMETHODS\nThis was a retrospective review of patient data recorded in the Hospital Information System for Loghman Hakim Hospital, that is, the central referral hospital for poisoning in Tehran, Iran. We searched Hospital Information System for all admissions for poisoning in children (age, 0-12 years) over the 10-year period from March 2010 to March 2020, and all cases were included in the analysis. We determined the case fatality rate by dividing the number of fatal cases by the number of included cases.\n\n\nRESULTS\nOf 8158 children admitted for poisoning, 28 cases (0.3%) died, among whom 19 (67.9%) were boys and 9 (32.1%) girls. The median age was 42 months, ranging from 2 to 144 months. Twenty-two cases (78.6%) were 0 to 5 years old. The most common cause of mortality in acute poisoning was methadone (n = 13, 46.4%), followed by raw opium (n = 5, 17.9%), aluminum phosphide, carbon monoxide, and wild mushrooms (n = 2 deaths each, 7.1%). Tramadol, colchicine, and petroleum accounted for 1 death each (3.6%).\n\n\nCONCLUSIONS\nMortality from unintentional poisoning disproportionately affects children younger than 5 years. Opioids (ie, methadone, opium, tramadol) accounted for two thirds of deaths in our sample. Our findings highlight the importance of educating parents that any toxic materials (licit or illicit) must be stored out of reach for children.",
"affiliations": "From the *Department of Pediatrics, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran †King's College London, National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom ‡Kish Institute of Science and Technology §Social Determinants of Health Research Center ∥Department of Clinical Toxicology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Gholami|Narges|N|;McDonald|Rebecca|R|;Farnaghi|Fariba|F|;Hosseini Yazdi|Maryam|M|;Zamani|Nasim|N|;Hassanian-Moghaddam|Hossein|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000002429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": null,
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": null,
"nlm_unique_id": "8507560",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33848098",
"pubdate": "2021-04-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fatal Outcome in Acutely Poisoned Children With Hospitalization: A 10-Year Retrospective Study From Tehran, Iran.",
"title_normalized": "fatal outcome in acutely poisoned children with hospitalization a 10 year retrospective study from tehran iran"
} | [
{
"companynumb": "IR-ALKEM LABORATORIES LIMITED-IR-ALKEM-2022-01284",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "A 69-year-old man with an unremarkable medical history presented with asymptomatic pancytopenia and diagnosed with Bence Jones protein-λ multiple myeloma (MM). Despite treatment with various chemotherapeutic regimens, myelosuppressive neutropenia occurred after each successive course; therefore, the treatment was determined to be ineffective and was discontinued. Consequently, one year after the diagnosis, a daratumumab-based therapy was initiated, and the MM was stabilized without clinical or laboratory evidences of myelosuppression. However, 18 months after the daratumumab induction, the patient developed hematochezia. Following an unremarkable lower gastrointestinal endoscopy, he presented fever and disturbed consciousness. Serum laboratory results showed liver dysfunction, and Listeria monocytogenes meningitis was diagnosed by cerebrospinal fluid examination. Empiric antibacterial treatment was administered for 3 weeks, which resolved the symptoms with no permanent neurological deficit.Daratumumab, a CD38 monoclonal antibodies, binds to expressed CD38 on myeloma cells and has an anti-myeloma cytotoxic effect but also binds to CD38 on activated macrophages. Additionally, activated macrophages play an important role in the immune defense of Listeria monocytogenes. Furthermore, inactivation of macrophages may increase the susceptibility to Listeria infection. Therefore, the possibility of infections such as Listeria meningitis should be considered in patients with MM receiving daratumumab-based therapy.",
"affiliations": "Department of Internal Medicine/General Medicine, Japanese Red Cross Kitami Hospital.;Department of Internal Medicine/General Medicine, Japanese Red Cross Kitami Hospital.;Department of Internal Medicine/General Medicine, Japanese Red Cross Kitami Hospital.",
"authors": "Horikita|Fuka|F|;Hashiguchi|Junichi|J|;Nagashima|Takahiro|T|",
"chemical_list": "D000911:Antibodies, Monoclonal; C556306:daratumumab",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.61.1611",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "61(11)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Daratumumab; Listeria monocytogenes; Meningitis; Multiple myeloma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D006801:Humans; D008297:Male; D008584:Meningitis, Listeria; D009101:Multiple Myeloma",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "1611-1615",
"pmc": null,
"pmid": "33298655",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post colonoscopic Listeria monocytogenes meningitis in a patient with multiple myeloma during daratumumab-based therapy.",
"title_normalized": "post colonoscopic listeria monocytogenes meningitis in a patient with multiple myeloma during daratumumab based therapy"
} | [
{
"companynumb": "JP-JNJFOC-20201246838",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DARATUMUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Extracorporeal photopheresis (ECP) is an effective therapy in children with refractory graft-versus-host disease (GVHD). The two most frequently used instruments are UVAR-XTS® and CELLEX®. We performed a retrospective chart review of ten patients who underwent ECP with both UVAR-XTS® and CELLEX® instruments for steroid-refractory acute or chronic GVHD to compare instrument run times, percentages of cells treated, and complication rates. We found that compared to the UVAR-XTS® instrument, use of the CELLEX® instrument resulted in shorter run times, increased percentage of mononuclear cells treated, reduced incidence of line occlusions requiring TPA treatment, and decreased incidence of patient-related complications.",
"affiliations": "Department of Hematology/Oncology/BMT, Children's National Health System, Washington DC.;Department of Transfusion Medicine, Children's National Health System, Washington DC.;Department of Hematology/Oncology/BMT, Children's National Health System, Washington DC.;Department of Hematology/Oncology/BMT, Children's National Health System, Washington DC.",
"authors": "Kapadia|Ekta|E|;Wong|Edward|E|;Perez-Albuerne|Evelio|E|;Jacobsohn|David|D|",
"chemical_list": "D013256:Steroids",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25487",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "62(8)",
"journal": "Pediatric blood & cancer",
"keywords": "allogeneic transplantation; extracorporeal photopheresis; graft-versus-host-disease",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D017893:Photopheresis; D012189:Retrospective Studies; D013256:Steroids; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1485-8",
"pmc": null,
"pmid": "25881179",
"pubdate": "2015-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Extracorporeal photopheresis performed on the CELLEX® compared with the UVAR-XTS® instrument is more efficient and better tolerated in children with steroid-refractory graft-versus-host disease.",
"title_normalized": "extracorporeal photopheresis performed on the cellex compared with the uvar xts instrument is more efficient and better tolerated in children with steroid refractory graft versus host disease"
} | [
{
"companynumb": "PHHY2015US046810",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"d... |
{
"abstract": "We report on two patients with type 1 diabetes (T1D) after solitary islet transplantation in 2001. They received steroid-sparing immunosuppression (daclizumab, sirolimus, and tacrolimus according to the Edmonton protocol). Both patients became insulin independent for 2 years: Patient A, a 42-year-old female with a 12-year history of T1D, received two islet infusions; patient B, a 53-year-old female with a 40-year T1D history, received one islet infusion. Pretransplant, both had undetectable C-peptide concentrations and frequent and severe hypoglycemia. Pretransplant, hemoglobin A1c (HbA1c) was 7.8% and 8.8% and insulin requirements were 0.47 and 0.33 units/kg/day, respectively. Posttransplant, C-peptide levels remained detectable while immunosuppression was continued, but decreased over time. Insulin was re-started 2 years posttransplant in both patients. Since patient A's glycemia and insulin requirements trended toward pretransplant levels, immunosuppression was discontinued after 13 years. This resulted in a sudden cessation of C-peptide secretion. Patient B continues on immunosuppression, has better HbA1c, and half the insulin requirement compared to pretransplant. Both patients no longer experience severe hypoglycemia. Herein, we document blood glucose concentrations over time (>30 000 measurements per patient) and β cell function based on C-peptide secretion. Despite renewed insulin dependence, both patients express satisfaction with having undergone the procedure.",
"affiliations": "Diabetes, Endocrinology, and Obesity Branch, NIDDK National Institutes of Health, Bethesda, MD.;Diabetes, Endocrinology, and Obesity Branch, NIDDK National Institutes of Health, Bethesda, MD.;Department of Transfusion Medicine, NIH Clinical Center National Institutes of Health, Bethesda, MD.;Diabetes, Endocrinology, and Obesity Branch, NIDDK National Institutes of Health, Bethesda, MD.;Division of Diabetes, Endocrinology, and Nutrition Diabetes Center of Excellence, Department of Internal Medicine, University of Massachusetts Medical School, North Worcester, MA.;Diabetes, Endocrinology, and Obesity Branch, NIDDK National Institutes of Health, Bethesda, MD.",
"authors": "Blau|J E|JE|;Abegg|M R|MR|;Flegel|W A|WA|;Zhao|X|X|;Harlan|D M|DM|;Rother|K I|KI|",
"chemical_list": "D001786:Blood Glucose; D002096:C-Peptide",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.13383",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "15(11)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "Clinical research/practice; immunosuppressant; islet transplantation; monitoring: physiologic; quality of life (QOL)",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D001786:Blood Glucose; D002096:C-Peptide; D003922:Diabetes Mellitus, Type 1; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007165:Immunosuppression Therapy; D016381:Islets of Langerhans Transplantation; D008875:Middle Aged; D008991:Monitoring, Physiologic; D017060:Patient Satisfaction; D011182:Postoperative Care; D011788:Quality of Life; D018570:Risk Assessment; D012494:Sampling Studies; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2995-3001",
"pmc": null,
"pmid": "26184712",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "18360260;23613556;25034311;24305963;11903381;19104418;22080832;19418039;19707375;16426323;24507950;22494609;23398948;23857001;22774994;23804275;19120085;22723582;15983207;24750103;14578266;14633816;18497678;20613523",
"title": "Long-term immunosuppression after solitary islet transplantation is associated with preserved C-peptide secretion for more than a decade.",
"title_normalized": "long term immunosuppression after solitary islet transplantation is associated with preserved c peptide secretion for more than a decade"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2015SP002072",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drug... |
{
"abstract": "Acute thromboembolic disease of the innominate artery (IA) poses a unique set of therapeutic challenges, owing to its contribution to both the cerebral and upper extremity circulation, and risks of distal embolization via the carotid and subclavian arteries, respectively. Herein, we present a 74-year-old female who presents with acute IA thrombus treated successfully with right axillary and common carotid exposure and aspiration catheter-directed mechanical thrombectomy (CDT). Furthermore, an emerging use of CDT and its application in acute thromboembolism are outlined.\nA 74-year-old female with history of right lung transplant for pulmonary fibrosis with severe pulmonary hypertension, and stage IIIA left lung adenocarcinoma status post left lower lobectomy undergoing adjuvant chemotherapy presented with acute IA thrombus and right-sided stroke. She was treated successfully with right axillary and common carotid exposure and aspiration CDT. Computed tomography angiography performed 1 month postoperatively confirmed patent IA with no evidence of residual or recurrent thrombus.\nThere are currently no standard guidelines on the management of acute IA thromboembolism, with mostly individual cases reported in the literature describing this rare entity. Nevertheless, this unique clinical entity mandates expeditious diagnostic and therapeutic approaches in order to avoid permanent neurologic deficits from distal embolization. Our case demonstrates that aspiration CDT may be an effective treatment modality for patients with acute IA thrombus.",
"affiliations": "Division of Vascular and Endovascular Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, New York, NY, USA.;Division of Vascular and Endovascular Surgery, Department of Surgery, New York University Langone Medical Center, New York, NY, USA.;Department of Pathology and Laboratory Medicine, New York University Langone Medical Center, New York, NY, USA.;Department of Pathology and Laboratory Medicine, New York University Langone Medical Center, New York, NY, USA.;Division of Vascular and Endovascular Surgery, Department of Surgery, New York University Langone Medical Center, New York, NY, USA.",
"authors": "Chang|Heepeel|H|https://orcid.org/0000-0001-6709-7423;Rockman|Caron B|CB|;Narula|Navneet|N|;Sabari|Joshua K|JK|;Garg|Karan|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/15266028211054765",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-6028",
"issue": null,
"journal": "Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists",
"keywords": "aspiration catheter-directed mechanical thrombectomy; brachiocephalic artery; innominate artery; stroke; thromboembolism",
"medline_ta": "J Endovasc Ther",
"mesh_terms": null,
"nlm_unique_id": "100896915",
"other_id": null,
"pages": "15266028211054765",
"pmc": null,
"pmid": "34704504",
"pubdate": "2021-10-27",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Presentation, Diagnosis and Management of Innominate Artery Thromboembolism.",
"title_normalized": "presentation diagnosis and management of innominate artery thromboembolism"
} | [
{
"companynumb": "US-FreseniusKabi-FK202209184",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": "3",
... |
{
"abstract": "Rat bite fever is a systemic febrile illness caused by infection with the Gram-negative bacillus Streptobacillus moniliformis following a bite, scratch, or contact with excrement. Only 26 cases of native valve endocarditis have been reported to date. We could find no other reports of severe Streptobacillus endocarditis requiring valve replacement in a young, pregnant patient.\n\n\n\nA pregnant patient sought care for right leg pain, fevers, left upper quadrant pain, generalized weakness, fatigue, and inability to bear weight on her right leg. She had a syncopal episode 9 months earlier, resulting in a mandibular fracture and internal fixation hardware. Her pregnancy was complicated by hyperemesis and weight loss. Her pets included a rescued wild bird, a cat, and four rats. Her parents rescued stray cats, and she recalled multiple cat bites and scratches since childhood. She denied injection drug use. Ultrasound indicated a right popliteal artery thrombus. Transesophageal echocardiogram revealed a 2 cm × 0.7 cm vegetation. Angiography demonstrated multiple splenic infarcts and bilateral renal infarcts. She underwent mitral valve repair. The mitral valve Gram stain demonstrated 2+ Gram-negative rods, rare Gram-positive rods, and moderate white blood cells. Propionibacterium spp. was isolated from the mitral valve tissue on Columbia agar incubated anaerobically. Anaerobic and aerobic cultures of the valve tissue on all other broths and agars remained negative at 14 days. Hematoxylin and eosin stains showed a fibro-inflammatory vegetation. Aggregates of rod-shaped bacteria were identified on Warthin Starry/Steiner stain. Bartonella titers were positive for B. henselae IgG 1:256, IgM < 1:20. Brown-Hopps Gram stain, AFB, and GMS stains for bacterial and fungal microorganisms were negative. Broad range bacterial PCR and sequencing of a segment of 16 s rRNA gene of the valve tissue matched to Streptobacillus sp. (genus level) and most closely related to Streptobacillus moniliformis.\n\n\n\nThis case demonstrates diagnostic and therapeutic challenges associated with a relatively uncommon cause of endocarditis. The diagnosis of rat bite fever was delayed due to symptoms of a concomitant pregnancy. Other confounders included possible alternative sources or co-infections with another zoonosis from multiple pets, and an odontogenic source due to presence of exposed jaw hardware.",
"affiliations": "University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.;Department of Pathology, Rochester Regional Health, Rochester, NY, USA.;Department of Infectious Diseases, Rochester Regional Health, 1425 Portland Ave, Rochester, NY, 14621, USA. carolinelesho@yahoo.com.",
"authors": "Crofton|Kathryn R|KR|;Ye|Jiqing|J|;Lesho|Emil P|EP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D012336:RNA, Ribosomal, 16S",
"country": "England",
"delete": false,
"doi": "10.1186/s13756-020-00789-4",
"fulltext": "\n==== Front\nAntimicrob Resist Infect Control\nAntimicrob Resist Infect Control\nAntimicrobial Resistance and Infection Control\n2047-2994 BioMed Central London \n\n789\n10.1186/s13756-020-00789-4\nCase Report\nSevere recurrent Streptobacillus moniliformis endocarditis in a pregnant woman, and review of the literature\nCrofton Kathryn R. 1 Ye Jiqing 2 Lesho Emil P. carolinelesho@yahoo.com 3 1 grid.412750.50000 0004 1936 9166University of Rochester School of Medicine and Dentistry, Rochester, NY USA \n2 grid.417055.20000 0004 0382 5614Department of Pathology, Rochester Regional Health, Rochester, NY USA \n3 grid.417055.20000 0004 0382 5614Department of Infectious Diseases, Rochester Regional Health, 1425 Portland Ave, Rochester, NY 14621 USA \n29 7 2020 \n29 7 2020 \n2020 \n9 1196 5 2020 23 7 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\nRat bite fever is a systemic febrile illness caused by infection with the Gram-negative bacillus Streptobacillus moniliformis following a bite, scratch, or contact with excrement. Only 26 cases of native valve endocarditis have been reported to date. We could find no other reports of severe Streptobacillus endocarditis requiring valve replacement in a young, pregnant patient.\n\nCase presentation\nA pregnant patient sought care for right leg pain, fevers, left upper quadrant pain, generalized weakness, fatigue, and inability to bear weight on her right leg. She had a syncopal episode 9 months earlier, resulting in a mandibular fracture and internal fixation hardware. Her pregnancy was complicated by hyperemesis and weight loss. Her pets included a rescued wild bird, a cat, and four rats. Her parents rescued stray cats, and she recalled multiple cat bites and scratches since childhood. She denied injection drug use. Ultrasound indicated a right popliteal artery thrombus. Transesophageal echocardiogram revealed a 2 cm × 0.7 cm vegetation. Angiography demonstrated multiple splenic infarcts and bilateral renal infarcts. She underwent mitral valve repair. The mitral valve Gram stain demonstrated 2+ Gram-negative rods, rare Gram-positive rods, and moderate white blood cells. Propionibacterium spp. was isolated from the mitral valve tissue on Columbia agar incubated anaerobically. Anaerobic and aerobic cultures of the valve tissue on all other broths and agars remained negative at 14 days. Hematoxylin and eosin stains showed a fibro-inflammatory vegetation. Aggregates of rod-shaped bacteria were identified on Warthin Starry/Steiner stain. Bartonella titers were positive for B. henselae IgG 1:256, IgM < 1:20. Brown-Hopps Gram stain, AFB, and GMS stains for bacterial and fungal microorganisms were negative. Broad range bacterial PCR and sequencing of a segment of 16 s rRNA gene of the valve tissue matched to Streptobacillus sp. (genus level) and most closely related to Streptobacillus moniliformis.\n\nConclusion\nThis case demonstrates diagnostic and therapeutic challenges associated with a relatively uncommon cause of endocarditis. The diagnosis of rat bite fever was delayed due to symptoms of a concomitant pregnancy. Other confounders included possible alternative sources or co-infections with another zoonosis from multiple pets, and an odontogenic source due to presence of exposed jaw hardware.\n\nKeywords\nPregnancyPregnantRat bite feverEndocarditisStreptobacillus moniliformisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nRat bite fever typically begins with a bite or other exposure, followed by abrupt onset of systemic illness, including intermittent relapsing fever, arthritis, and rash 3 days to 3 weeks later. A maculopapular, petechial, or purpuric rash develops in approximately 75% of those affected in the first symptomatic week [1, 2]. Over half of those affected develop migratory polyarthralgias, with involvement of both large and small joints of the extremities [1]. If untreated, the mortality rate approaches 10% [2]. Endocarditis has been described as a complication, but only 26 cases of native valve endocarditis have been reported to date [3]. We found no reports involving pregnant patients.\n\nWe sought to alert clinicians to the challenges and potential pitfalls in the diagnosis and management of recurrent Streptobacillus endocarditis in a pregnant patient. This case is noteworthy because it demonstrates diagnostic and therapeutic challenges associated with a relatively uncommon cause of endocarditis. For example, the typical symptoms of rat bite fever were masked by the symptoms of a concomitant pregnancy. Other diagnostic confounders included possible alternative sources or co-infections with another zoonosis from multiple exposures, and an odontogenic source due to presence of exposed jaw hardware. It is novel because we could find no other reports of severe Streptobacillus endocarditis requiring valve replacement in a young, pregnant patient.\n\nCase presentation\nA previously healthy 24 year-old female, who was 13 weeks pregnant, sought care for 2 weeks of severe right leg pain and fevers (39.4 degrees C recorded at home), which progressed to bilateral calf and left upper quadrant pain, generalized weakness, fatigue, and inability to bear weight on her right leg. Her past medical history was notable for a syncopal episode 9 months earlier, resulting in a mandibular fracture and internal fixation hardware. Her pregnancy was complicated by hyperemesis and weight loss. Her pets included a rescued wild bird, a cat, and four rats. Her parents rescued stray cats, and she recalled multiple cat bites and scratches since childhood. She also allowed her rats to nibble on her fingers, most recently several weeks prior to admission. The patient also complained of exposed mandibular hardware. She denied injection drug use but used marijuana for nausea. She reported a history of rash when taking penicillin.\n\nShe was pale and had a temperature of 38.4 C, with diminished pedal and tibial pulses on the right. She had a 2/6 high pitched blowing holosystolic murmur, radiating to the axilla. She also had left upper quadrant tenderness and a palpable spleen. There were no rashes or lymphadenopathy. A metal plate was visible below the lower right teeth, with generally good dentition. The right calf was tender to palpation. A healing bite wound on her index finger was clean, without swelling or tenderness. Laboratory evaluation revealed iron deficiency anemia, normal renal function, normal hepatic enzymes, and a normal leukocyte count and differential.\n\nAn ultrasound indicated a right popliteal artery thrombus. Transesophageal echocardiogram revealed a 2 cm × 0.7 cm vegetation on the atrial side of the posterior mitral valve leaflet. Angiography demonstrated multiple splenic infarcts and bilateral renal infarcts.\n\nRight popliteal thrombectomy was performed. Blood and popliteal thrombus cultures remained negative. The patient was treated empirically for Streptobacillus moniliformis given the history of rat bites and Streptococcus viridans/HACEK given history of oral surgery with exposed metal plates. The initial antibiotic regimen was ceftriaxone 2 g q12h and vancomycin 1.5 g q12h. Blood cultures and the popliteal thrombus did not initially grow any organisms, so clindamycin was added for empiric anaerobic coverage, as well as for Streptobacillus moniliformis (given the history of rat bites from her pet rats) and Streptococcus viridans/HACEK (given her history of oral surgery and exposed intra-oral hardware). On hospital day 4, she underwent mitral valve repair using a 27 mm band. The mitral valve Gram stain demonstrated 2+ Gram-negative rods, rare Gram-positive rods, and moderate white blood cells. Propionibacterium spp. was isolated from the mitral valve tissue on Columbia agar incubated anaerobically. Anaerobic and aerobic cultures of the valve tissue on all other broths and agars, including Chocolate, charcoal yeast extract, and serum-supplemented, remained negative at 14 days. Hematoxylin and eosin stains showed a fibroinflammatory vegetation (Fig. 1) and aggregates of rod-shaped bacteria were identified on Warthin Starry/Steiner stain, (Fig. 2). Bartonella titers were strongly positive for B. Henselae IgG 1:256, IgM < 1:20. Brown-Hopps Gram stain, AFB, and GMS stains for bacterial and fungal microorganisms were negative. PCR and 16 s rRNA sequencing of MV tissue identified Streptobacillus spp. DNA, most closely related to S. moniliformis. (The data was analyzed with SmartGene software (Lausanne, Switzerland)).\nFig. 1 Hematoxylin and eosin stain of mitral valve tissue at 20x magnification showing fibroinflammatory vegetation\n\nFig. 2 Warthin Starry stain showing aggregates of rod-shaped bacteria in the vegetation\n\n\n\nThe patient underwent penicillin skin testing, performed by a trained allergy/immunology physician. The skin prick test was administered on the volar forearm with benzylpenicilloyl polylysine (Pre-Pen; ALK) as the major determinant, penicillin G 10,000 U/mL as the minor determinant, histamine 6 mg/mL as the positive control, and sodium chloride 0.9% as the negative control. After a 15-min observation period and with negative skin prick results, intradermal testing was administered using the same materials except with a histamine concentration of 0.02 mg/mL. A positive test result was defined as a wheal ≥3 mm as compared with the negative control.\n\nAfter testing excluded penicillin allergy, penicillin G 24 mU daily (4 mU every 4 h) was started. She completed 6 weeks of that followed by 2 weeks of oral amoxicillin-clavulanate. During that period, she required brief readmissions for heart failure and dysrhythmias but remained afebrile without signs of infection. Two weeks later she was readmitted for heart failure and fever. One of her pet rats had given birth to a large litter and she reported new rat bite exposures. She was found to have a new 8 mm anterior mitral valve vegetation with valve perforation. She underwent elective dilation and evacuation of the pregnancy to allow for definitive bioprosthetic mitral valve replacement. Blood cultures were persistently negative in the post-operative period, and she was treated empirically for Streptobacillus, this time with a six-week course of Penicillin-G and a two-week course of synergistic gentamicin. The repeat mitral valve Gram stain was negative for organisms, and valve fungal, aerobic, and anerobic cultures did not yield any growth.\n\nDiscussion and conclusions\nRat bite fever is a systemic febrile illness caused by infection with the Gram-negative bacillus Streptobacillus moniliformis in North America, or the spirochete Spirillum minus in Asia, following a bite, scratch, or contact with excrement [1, 2]. A third syndrome is Haverhill fever, caused by ingestion of S. moniliformis-contaminated food [1]. Case reports describe exposures among people living in poverty, laboratory technicians, and pet store workers. The affected demographics have broadened, as rats have become more popular pets. S. moniliformis colonizes the nasopharynx of 50–100% of healthy wild, lab, and pet rats, and is also excreted in the urine [2]. It is also found in mice, guinea pigs, gerbils, and squirrels. After a bite or scratch, the wound should be immediately cleaned with soap and warm water, and tetanus prophylaxis administered, if warranted. The efficacy of antibiotic prophylaxis for rat bite is unknown. Some authors suggest administration of amoxicillin/clavulanate at a dosage of 500 mg p.o. every 8 h for 3 days.\n\nS. moniliformis is a pleomorphic (straight, fusiform, or with lateral bulbar swellings), filamentous, Gram-negative, nonmotile, and non-acid-fast rod [1]. However, on Gram stains it can appear as either Gram-negative or Gram-positive rods.\n\nRat bite fever typically begins with a bite or other exposure, followed by abrupt onset of systemic illness, including intermittent relapsing fever, arthritis, and rash 3 days to 3 weeks later. A maculopapular, petechial, or purpuric rash develops in approximately 75% of those affected in the first symptomatic week [1, 2]. Over half of those affected develop migratory polyarthralgias, with involvement of both large and small joints of the extremities [1]. If untreated, the mortality rate approaches 10% [2]. Endocarditis is a well-described complication, but only 26 cases of native valve endocarditis have been reported to date [3]. We found no reports involving pregnant patients.\n\nOur patient’s presentation was notably atypical in multiple respects. First, the hyperemesis she experienced was likely wrongly attributed to pregnancy and contributed to delayed diagnosis. Second, she denied a history of rash or arthralgias. Third, eroded intra-oral hardware made fastidious Streptococcal spp. or other oral flora equally likely pathogens. Fourth, the diagnosis of the primary infectious agent in this case was further complicated by the positive Bartonella IgG titers. Bartonella IgG titers between 1:64 and 1:256 represent possible active or recent Bartonella infection; our patient’s IgG titers were 1:256. IgM titers > 1:20 strongly suggest current infection; our patients IgM titers were negative. Furthermore, she had no characteristic cutaneous lesions or lymphadenopathy, and there was no Bartonella signal detected on the PCR. Taken together, the above essentially rule out Bartonella endocarditis. Another confounder was the identification of Propionibacterium spp. on the mitral valve specimen. Propionibacterium spp. are a very rare cause of infectious endocarditis, and almost always cause prosthetic valve endocarditis. Here, they were most likely a contaminant. Finally, she suffered septic emboli to the right popliteal artery, spleen, and kidneys - a rare complication of rat bite fever endocarditis [4].\n\nDiagnosis of S. moniliformis is difficult, requiring a high index of suspicion. It is fastidious, requiring microaerophilic conditions (5–10% CO2 or anaerobic conditions supplemented with 20% normal rabbit serum) [2]. Furthermore, growth is inhibited by 0.05% sodium polyanethol sulfonate (an anticoagulant routinely added to most aerobic blood culture bottles) [1]. When blood cultures remain negative after prolonged incubation, PCR can be used diagnostically. 16sRNA gene sequencing has been used successfully on heart valves, bone, and synovial fluid, but this method is specific only to the Streptobacillus genus and not the species [5]. PCR is effective even after antibiotic treatment has been initiated, even if the blood culture is sterile, as the DNA remains detectable in the infected valve.\n\nIn this case, blood and valve cultures were persistently negative, despite repeated anaerobic and aerobic sub culturing on various agars and broths including Chocolate, Charcoal Yeast Extract, Columbia, and serum supplemented media. The initial mitral valve specimen was collected surgically 4 days after initiation of empiric antibiotic therapy, likely contributing to the difficulty in culturing the specimen. Broad range bacterial PCR and sequencing of a segment of 16 s rRNA gene matched to Streptobacillus sp. (genus level) and most closely related to Streptobacillus moniliformis (species level). Speciation of 16 s rRNA gene sometimes can be difficult and erroneous. The patient was counseled about the risks associated with rats especially pertaining to bites.\n\nRecommended treatment of S. moniliformis endocarditis is dual therapy with high-dose penicillin G for 4 weeks in combination with streptomycin or gentamicin for 2 weeks [1, 2]. Ceftriaxone (2gIV daily for 6 weeks) has also been effective [3]. In this case, treatment was limited by the patient’s pregnancy until she underwent dilation and evacuation. Aminoglycosides are pregnancy class D, given several reports of congenital deafness; they are known to cross the placenta.\n\nA literature review was performed by a professional medical librarian using the search strategy presented in the supplemental file. This revealed only two cases, but neither involved endocarditis [6, 7]. One involved a 22 year old woman who developed Streptobacillus moniliformis amnionitis [6], and the other involved polymicrobial chorioamnionitis with Aerococcus christensenii, Gemella spp., Snethia spp., Parvimonas micra, and Streptobacillus moniliformis in a pregnant woman [7].\n\nOur report is limited by the usual features of a single case report, and that more and different samples were not available for duplicate and triplicate laboratory testing. Despite these limitations, it includes the key laboratory and management detail useful for providers who may encounter this in the future, and it appears to be a first reported case based on a thorough literature review described in the supplemental material.\n\nThis case highlights the diagnostic and management challenges of an infrequent cause culture negative endocarditis that was further complicated by pregnancy, thromboembolic phenomenon, and a patient’s undaunted love of her pets.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nAll authors contributed equally in the writing and revision of the manuscript. The author(s) read and approved the final manuscript.\n\nFunding\nThere was no funding source.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nConsent for publication was obtained.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Elliott SP Rat bite fever and Streptobacillus moniliformis Clin Microbiol Rev 2007 20 13 22 10.1128/CMR.00016-06 17223620 \n2. Vyas JM Rakel D Kellerman RD Rat Bite Fever Conn’s current therapy 2019 2019 1 Philadelphia Elsevier Saunders \n3. Torres-Miranda D Moshgriz M Siegel M Streptobacillus moniliformis mitral valve endocarditis and septic arthritis: the challenges of diagnosing rat-bite fever endocarditis Infect Dis Rep 2018 10 7731 10.4081/idr.2018.7731 30344968 \n4. Fenn DW, Ramoutar A, Jacob G, Xiao HB. An unusual tale of rat-bite fever endocarditis. BMJ Case Rep. 2014. 10.1136/bcr-2014-204989.\n5. Eisenberg T Ewers C Rau J Akimkin V Nicklas W Approved and novel strategies in diagnostics of rat bite fever and other Streptobacillus infections in humans and animals Virulence. 2016 7 630 648 10.1080/21505594.2016.1177694 27088660 \n6. Faro S Walker C Pierson RL (1980). Amnionitis with intact amniotic membranes involving Streptobacillus moniliformis Obstet Gynecol 1980 55 9S 11S 10.1097/00006250-198003001-00003 7360458 \n7. Carlstein C Søes LM Christensen JJ (2016). Aerococcus christensenii as part of severe polymicrobial chorioamnionitis in a pregnant woman Open Microbiol J 2016 10 27 31 10.2174/1874285801610010027 27014376\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2047-2994",
"issue": "9(1)",
"journal": "Antimicrobial resistance and infection control",
"keywords": "Endocarditis; Pregnancy; Pregnant; Rat bite fever; Streptobacillus moniliformis",
"medline_ta": "Antimicrob Resist Infect Control",
"mesh_terms": "D000818:Animals; D000900:Anti-Bacterial Agents; D001733:Bites and Stings; D002415:Cats; D005260:Female; D006801:Humans; D057805:Pets; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012336:RNA, Ribosomal, 16S; D011906:Rat-Bite Fever; D051381:Rats; D012008:Recurrence; D013288:Streptobacillus; D055815:Young Adult; D015047:Zoonoses",
"nlm_unique_id": "101585411",
"other_id": null,
"pages": "119",
"pmc": null,
"pmid": "32727581",
"pubdate": "2020-07-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "7360458;25414213;30344968;27014376;17223620;27088660",
"title": "Severe recurrent Streptobacillus moniliformis endocarditis in a pregnant woman, and review of the literature.",
"title_normalized": "severe recurrent streptobacillus moniliformis endocarditis in a pregnant woman and review of the literature"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP011075",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BENZYLPENICILLOYL POLYLYSINE"
},
... |
{
"abstract": "Valproic acid (VPA) is a broad-spectrum antiseizure drug used for a variety of clinical conditions, such as epilepsy and mood disorders. Drug-induced hypersensitivity syndrome (DRESS) accompanied by hyponatremia, thrombocytopenia, hypoalbuminemia and elevated aminotransferase has never been reported as an adverse effect of VPA monotherapy during titration for epilepsy in Asian population. Hereby, we present the case of a 73-year-old Chinese male who suffered from DRESS and other complications two weeks after initiating VPA treatment for epilepsy. Understanding the risk associated with VPA-induced DRESS, and taking effective measures to avoid the severe side effects are necessary.",
"affiliations": "Department of Neurology, West China Hospital, Sichuan University, China.;Department of Neurology, West China Hospital, Sichuan University, China.;Department of Neurology, West China Hospital, Sichuan University, China.;Department of Neurology, West China Hospital, Sichuan University, China.;Department of Neurology - Biomagnetism, University Hospital Erlangen, Germany.",
"authors": "Wu|X T|XT|;Hong|P W|PW|;Suolang|D J|DJ|;Zhou|D|D|;Stefan|H|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ebcr.2017.06.003",
"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(17)30052-X10.1016/j.ebcr.2017.06.003ArticleDrug-induced hypersensitivity syndrome caused by valproic acid as a monotherapy for epilepsy: First case report in Asian population Wu X.T. aHong P.W. aSuolang D.J. aZhou D. aStefan H. althea_tong00@hotmail.comb⁎a Department of Neurology, West China Hospital, Sichuan University, Chinab Department of Neurology – Biomagnetism, University Hospital Erlangen, Germany⁎ Corresponding author at: Department of Neurology – Biomagnetism, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.Department of Neurology – BiomagnetismUniversity Hospital ErlangenSchwabachanlage 6Erlangen91054Germany althea_tong00@hotmail.com20 6 2017 2017 20 6 2017 8 108 110 4 4 2017 23 5 2017 7 6 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Valproic acid (VPA) is a broad-spectrum antiseizure drug used for a variety of clinical conditions, such as epilepsy and mood disorders. Drug-induced hypersensitivity syndrome (DRESS) accompanied by hyponatremia, thrombocytopenia, hypoalbuminemia and elevated aminotransferase has never been reported as an adverse effect of VPA monotherapy during titration for epilepsy in Asian population. Hereby, we present the case of a 73-year-old Chinese male who suffered from DRESS and other complications two weeks after initiating VPA treatment for epilepsy. Understanding the risk associated with VPA-induced DRESS, and taking effective measures to avoid the severe side effects are necessary.\n\nAbbreviations\nVPA, valproic acidDRESS, drug-induced hypersensitivity syndromeASDs, antiseizure drugsSCARs, severe cutaneous adverse drug reactionsPHT, phenytoinCBZ, carbamazepineLTG, lamotrigineVGB, vigabatrineLEV, levetiracetamECG, electrocardiogramAHS, acute hypersensitivity syndromeMDH, multiple drug hypersensitivityHLA, human leukocyte antigenSJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysisKeywords\nValproate acidDrug-induced hypersensitivity syndrome (DRESS)Cutaneous adverse drug reactionsAntiseizure drugsSkin rash\n==== Body\n1 Introduction\nValproate acid (VPA), one of first-line traditional antiseizure drugs (ASDs), effectively controls many types of seizure. As reported, VPA-induced hyponatremia could happen in patients with epilepsy, especially in elderly people [1]. VPA-induced drug-induced hypersensitivity syndrome (DRESS) is rare in patients with epilepsy-related seizures. DRESS is a type of severe cutaneous adverse drug reactions (SCARs), characterized by generalized acute maculopapular eruptions, accompanying high fever and internal organ involvement. It is a rare, but potentially fatal adverse event with a mortality range from 10%–40% [2]. It's most often caused by first-line aromatic ASDs. The risk is highest for phenytoin (PHT) of 5%–7%, carbamazepine (CBZ) of 5%–17%, and lamotrigine (LTG) of 5%–10%. SCARs with internal organ dysfunction such as DRESS are approximated between 1/1000 and 1/ 10,000 exposures [3]. It seldom happens with patients taking non-aromatic antiseizure drugs such as valproic acid (VPA), vigabatrin (VGB), levetiracetam (LEV), and benzodiazepines. Moreover, SCARs accompanying with hyponatremia, thrombocytopenia, hypoalbuminemia and high aminotransferase are rare in patient under VPA treatment. Given the rarity of this severe case, it is important to recognize the possibility of SCARs associated with VPA.\n\n2 Case report\nA 73-year-old male taking VPA monotherapy for epilepsy, was admitted to the dermatology department of West China Hospital of Sichuan University, because of generalized ruptured skin erythema followed by high fever, hyponatremia, thrombocytopenia and high aminotransferase for 2 weeks.\n\nThe patient had seizures and diagnosed with epilepsy in a local hospital 8 months ago without treatment. Almost 1 month ago, he was prescribed VPA (500 mg/d, increased to 1000 mg/d one week later) for epilepsy in the local hospital because of his recurrent seizures. Two weeks after VPA exposure, he suffered from erythematous maculopapular eruptions without mucous membrane involving a large area of his face, back, bilateral shoulders and both lower limbs (Fig. 1). He didn't have feelings of pain, itch, or burning, etc. His symptoms worsened gradually by the disease processing, presenting with a fever of 39.5 °C, fused maculopapular rash, oval erythema and ruptured blisters over his whole body, with face and lower limbs edema (+/4, ++/4 separately). This patient's other vital signs were stable.Fig. 1 a— Maculopapular eruptions on his back; b— oval erythema on his abdomen; c— oval erythema and blisters; d— ruptured blister with desquamation.\n\nFig. 1\n\nThis patient suffered from and had atrial fibrillation beginning one year ago. He persistently took warfarin as anticoagulation treatment afterwards without routine monitoring. He used to smoke for more than 40 years and quitted for one year. He had no history of drug allergies previously.\n\nAfter the hospitalization, laboratory tests showed normocytic and normochromic anemia (HGB 119 g/L), hyponatremia (Na +: 127.1 mmol/L), thrombocytopenia (PLT: 79 ∗ 109/L), hypoalbuminemia (TP: 51.3 g/L, ALB 29.4 g/L), elevated levels of hypersensitive C reactive protein (HsCRP: 6.81 mg/L), transaminases (ALT: 219 IU/L, AST: 128 IU/L), and gamma-glutamyl transpeptidase (GGT: 243 IU/L). A HLA-B*1502 test was negative. Serology for human immunodeficiency virus, syphilis test and hepatitis B were negative. Chest radiography revealed chronic inflammatory changes in bilateral lungs without acute infections, while abdominal ultrasound showed no significant changes. Electrocardiogram (ECG) confirmed the atrial fibrillation. Echocardiography showed enlarged atrias with normal left ventricular systolic function. Head CT demonstrated an old infarction in right temporal lobe.\n\nInfusion of methylprednisolone for 5 days (40 mg/d) followed by prednisone tablets (40 mg/d), human serum albumin, gamma globulin, intravenous calcium gluconate, cyclosporine (100 mg/d) and other symptomatic treatments were used to treat this patient, besides replacing VPA with LEV for epilepsy. Two months after admission and several treatment cycles, this patient became better was discharged from the hospital.\n\n3 Discussion\nDrug-induced hypersensitivity syndrome (DRESS) is a rare but a potentially fatal reaction to ASDs. Several researches reported the incidence and manifestations of ASDs-induced DRESS. It is well known that aromatic ASDs, including PB, PHT, CBZ, LTG and OXC are common causative drugs, however, typically does not include non-aromatic ASDs such as VPA, TPM, LEV, GBP, VGB and benzodiazepines.\n\nIn our case, the patient had DRESS and hyponatremia, thrombocytopenia, hypoalbuminemia and high aminotransferase two weeks after VPA for his epilepsy. The exact mechanism is still not known yet. As previous studies note, human leukocyte antigen (HLA) alleles are the genetic factors involved in DRESS [1], [2] which was confirmed by several studies that HLA-B*1502 has the strong association with CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [3]. These linkages can be explained by an off-target activity of a particular drug to a certain HLA protein [4]. Although, no specific HLA allele is identified as a biomarker of VPA-related DRESS so far, a genetic predisposition and related immunologic reactions could be the potential explanation.\n\nFurthermore, our patient increased the dosage of VPA from 500 mg/d to 1000 mg/d in one week. The titration of VPA was fast. Previous studies found that age ≤ 13 years, female, higher starting dose, rapid titration, and concomitant use of VPA are risk factors for patients suffering from LTG-induced SCARs, but not the VPA-monotherapy-induced DRESS [5], [6]. Although slower titration rate is commonly recommended to reduce the risk of severe rash, ASDs-induced SCARs are generally considered idiosyncratic, unpredictable and non-dose dependent [7]. More studies focusing on this point should be done in the future.\n\nThere are a few reports concerning VPA in combination with LTG causing acute hypersensitivity syndrome (AHS) with multiple organ dysfunction [8], [9], [10], [11], but all these patients had a concomitant use of LTG and VPA, not VPA alone. That's why LTG rather than VPA is probably the causal drug, or VPA enhanced the adverse reaction. Moreover, Arevalo-Lorido et al. described a 36-year-old man with AHS caused by VPA two weeks after initial CBZ, which was discontinued because of severe skin rash [12]. Bota et al. discussed the case of a 25-year-old woman with bipolar disorder who experienced DRESS caused by valproic acid one month after withdrawal of LTG because of a nonspecific skin rash [13]. Replacement treatment of VPA with other aromatic ASDs may cause DRESS. It might be former aromatic ASDs activated the immunologic mechanism, which would be considered as multiple drug hypersensitivity (MDH), a novel syndrome re-proposed by Pichler WJ and his colleagues recently [14]. The T-cell activations in MDH are not due to cross-reactivity [14]. Prior drug exposure initiates severe T-cell reactions, which appear to have a long-lasting effect on the patient's immune system. VAP as the second drug stimulates the activated immune system, and then causes DRESS.\n\nThere are also some reports of VPA combination with other drugs besides for ASDs. A 19-year-old female patient diagnosed as DRESS with positive Brucella Coombs test and Rose Bengal test undergoing VPA for his chorea as well as streptomycin and tetradox capsules as polytherapy for the brucellosis [15]. In this case, whether the brucellosis might be the dominant cause for DRESS was unknown. One case presented a 26-year-old man with DRESS and acute liver failure after an intracerebral bleed for 5 months and epileptic seizure for 1.5 months, taking VPA, baclofen, clemastine and acetaminophen daily [16]. One case reported a 60-year-old Iranian man who had been treated with oral VPA (1000 mg/d) to prevent seizures after subarachnoid hemorrhage and developed DRESS. This patient had insulin at the same time for his diabetes [17]. Another case reported a 20-year-old Brazilian female with DRESS after a treatment with VAP and haloperidol [18]. Our patient took warfarin for his previous ischemic stroke and atrial fibrillation for a long time, while he took VPA for epilepsy. So, many patients suffered from DRESS when they had at least two kinds of drugs because of comorbidities. Therefore, a question is proposed for further studies: which drug or which type of drug combinations or potential risk from comorbidities could be a possible cause of DRESS?\n\nWhat's more, Yang et al. concluded that most of the patients tolerated nonaromatic ASDs, especially VPA, after their SCARs episodes caused by aromatic ASDs [19]. Considering VPA has a potential risk of DRESS which could be accompanied by certain complications, especially, the patients with previous drug-allergic symptoms, when using VPA as a replacement therapy, doctors should be aware of possible MDH, meanwhile, closely monitoring the clinical features and laboratory results with is quite important and necessary.\n\n4 Conclusion\nThis is the first case report of VPA monotherapy in epilepsy accompanied by hyponatremia, thrombocytopenia, hypoalbuminemia and high aminotransferase in the Asian population. Understanding the potential risk associated with VPA-induced DRESS and taking effective measures to avoid the severe side effects are necessary. When skin rash occurs in a patient taking VPA, the possibility of an adverse effect to this drug should be considered, and switching the patient to a different drug may be a good option. Moreover, laboratory tests should be done for detecting other side effects, such as hyponatremia, thrombocytopenia, hypoalbuminemia and high aminotransferase, in order to intervene before the patient suffers severe adverse effects. Furthermore, when using VPA as a replacement therapy, doctors should be aware of possible MDH. Finally, if VPA is considered for patients, especially those with co-morbidity or under polytherapy for other diseases, the clinical and laboratory observations of these patients should be closely monitored. Additional studies should be done in order to find out the potential mechanisms of VPA-induced DRESS in the future.\n\nEthical statement\nInformed consent was obtained from the patient.\n\nConflict of interest\nThe authors have no conflicts of interest to report.\n\nFund support\nThis research work is supported by National Natural Science Foundation of China (No. 81301186).\n\nDeclaration\nWe confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\n==== Refs\nReferences\n1 Zhou P. Zhang S. Wang Y. Yang C. Huang J. Structural modeling of HLA-B*1502/peptide/carbamazepine/T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis J Biomol Struct Dyn 34 8 Aug 2016 1806 1817 26488421 \n2 Illing P.T. Vivian J.P. Dudek N.L. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire Nature 486 7404 Jun 28 2012 554 558 22722860 \n3 Wu X.T. Hu F.Y. An D.M. Association between carbamazepine-induced cutaneous adverse drug reactions and the HLA-B*1502 allele among patients in central China Epilepsy Behav 19 3 Nov 2010 405 408 20833111 \n4 Adam J. Wuillemin N. Watkins S. Abacavir induced T cell reactivity from drug naive individuals shares features of allo-immune responses PLoS One 9 4 2014 e95339 \n5 Hirsch L.J. Weintraub D.B. Buchsbaum R. Predictors of lamotrigine-associated rash Epilepsia 47 2 Feb 2006 318 322 16499755 \n6 Messenheimer J.A. Rash in adult and pediatric patients treated with lamotrigine Can J Neurol Sci 25 4 Nov 1998 S14 S18 9827240 \n7 Toledano R. Gil-Nagel A. Adverse effects of antiepileptic drugs Semin Neurol 28 3 Jul 2008 317 327 18777478 \n8 Guberman A.H. Besag F.M. Brodie M.J. Lamotrigine-associated rash: risk/benefit considerations in adults and children Epilepsia 40 7 Jul 1999 985 991 10403224 \n9 Bin-Nakhi H.A. Sadeq S. Pinto R.G. Habeeb Y. Anticonvulsant hypersensitivity syndrome: report of 2 cases from Kuwait Med Princ Pract 12 3 Jul–Sep 2003 197 199 12766341 \n10 Dreesman A. Hoorens A. Hachimi-Idrissi S. Multiple organ dysfunction syndrome: infection or hypersensitivity reaction? Eur J Emerg Med 17 4 Aug 2010 228 229 19820401 \n11 Yapici A.K. Fidanci M.K. Kilic S. Stevens-Johnson syndrome triggered by a combination of clobazam, lamotrigine and valproic acid in a 7-year-old child Ann Burns Fire Disasters 27 3 Sep 30 2014 121 125 26170788 \n12 Arevalo-Lorido J.C. Carretero-Gomez J. Bureo-Dacal J.C. Montero-Leal C. Bureo-Dacal P. Antiepileptic drug hypersensitivity syndrome in a patient treated with valproate Br J Clin Pharmacol 55 4 Apr 2003 415 416 12680893 \n13 Bota R.G. Ligasan A.P. Najdowski T.G. Novac A. Acute hypersensitivity syndrome caused by valproic acid: a review of the literature and a case report Perm J 15 2 Spring 2011 80 84 21841930 \n14 Pichler W.J. Srinoulprasert Y. Yun J. Hausmann O. Multiple drug hypersensitivity Int Arch Allergy Immunol 172 3 Mar 18 2017 129 138 28315874 \n15 Albayrak F. Cerrah S. Albayrak A. Dursun H. Yildirim R. Uyanik A. DRESS syndrome with fatal results induced by sodium valproate in a patient with brucellosis and a positive cytoplasmic antineutrophilic cytoplasmic antibody test result Rheumatol Int 32 7 Jul 2012 2181 2184 20354855 \n16 van Zoelen M.A. de Graaf M. van Dijk M.R. Valproic acid-induced DRESS syndrome with acute liver failure Neth J Med 70 3 Apr 2012 155 22516584 \n17 Darban M. Bagheri B. Drug reaction with eosinophilia and systemic symptoms induced by valproic acid: a case report Iran Red Crescent Med J 18 9 Sep 2016 e36825 \n18 Silva S.A. Figueiredo M.M. Carneiro L.N. Reiss D.B. Damasio M.A. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) Rev Assoc Med Bras 62 3 May–Jun 2016 227 230 (1992) 27310545 \n19 Yang C.Y. Dao R.L. Lee T.J. Severe cutaneous adverse reactions to antiepileptic drugs in Asians Neurology 77 23 Dec 06 2011 2025 2033 22116946\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-3232",
"issue": "8()",
"journal": "Epilepsy & behavior case reports",
"keywords": "AHS, acute hypersensitivity syndrome; ASDs, antiseizure drugs; Antiseizure drugs; CBZ, carbamazepine; Cutaneous adverse drug reactions; DRESS, drug-induced hypersensitivity syndrome; Drug-induced hypersensitivity syndrome (DRESS); ECG, electrocardiogram; HLA, human leukocyte antigen; LEV, levetiracetam; LTG, lamotrigine; MDH, multiple drug hypersensitivity; PHT, phenytoin; SCARs, severe cutaneous adverse drug reactions; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; Skin rash; VGB, vigabatrine; VPA, valproic acid; Valproate acid",
"medline_ta": "Epilepsy Behav Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101614202",
"other_id": null,
"pages": "108-110",
"pmc": null,
"pmid": "29204346",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "22116946;27310545;18777478;22722860;26170788;12766341;19820401;20833111;28315874;20354855;16499755;12680893;9827240;28144463;10403224;21841930;24751900;22516584;26488421",
"title": "Drug-induced hypersensitivity syndrome caused by valproic acid as a monotherapy for epilepsy: First case report in Asian population.",
"title_normalized": "drug induced hypersensitivity syndrome caused by valproic acid as a monotherapy for epilepsy first case report in asian population"
} | [
{
"companynumb": "ES-BION-006831",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
"dru... |
{
"abstract": "Neuronal ceroid lipofuscinoses (CLN) are neurodegenerative disorders among the most frequent, inherited as an autosomal recessive trait. Affected patients can present with progressive decline in cognitive and motor functions, seizures, a shortened life span and visual deficiency. CLN2 is one of the rare CLN that benefits from treatment by cerliponase alpha an enzyme replacement therapy. Preliminary results on treated animal models have shown delayed neurological signs and prolonged life span. However, cerliponase alpha did not prevent vision loss or retinal degeneration in those animal models. Cerliponase alpha has currently been delivered to a few CLN2-affected patients. We report the case of one patient suffering from CLN2 treated with intracerebroventricular infusions of cerliponase alpha 300 mg every two weeks. Evolution of his retinal function was assessed by three successive flash-ERG and flash-VEP recordings throughout his treatment over a 4-year period.\n\n\n\nBefore treatment at the age of 4 years 5 months, patient's retinas were normal (normal fundi and normal flash-ERG). After 29 infusions at the age of 6 years 10 months, a-wave combined response was absent, while cone and flicker responses were normal. After 80 infusions at the age of 8 years 9 months, a-wave cone response was absent with b-wave peak time increased, and no combined response.\n\n\n\nDespite treatment, our patient's retinas showed a progressive abnormal and inhomogeneous function. Rods function was altered first, then the scotopic system and afterward, the cones. This result differs from those recorded in animal models. The relative preservation of cone functioning for a while could not be unequivocally attributed to enzyme replacement therapy as we lack comparison with the evolution of flash-ERGs recorded in untreated subjects.",
"affiliations": "Service de Physiologie Clinique. Explorations Fonctionnelles, Hôpital Lariboisière, AP-HP, Paris, France. rigaudiereflo@aol.com.;Service des Explorations Fonctionnelles, Hôpital Robert Debré, AP-HP, Paris, France.;Neurologie Pédiatrique, Hôpital Robert Debré, AP-HP, Paris, France.;Service d'Ophtalmologie Pédiatrique, Hôpital Robert Debré, AP-HP, Paris, France.;Service des Explorations Fonctionnelles, Hôpital Robert Debré, AP-HP, Paris, France.;Service de Physiologie Clinique. Explorations Fonctionnelles, Hôpital Lariboisière, AP-HP, Paris, France.;Faculté de Médecine Paris-Diderot, Université de Paris, Paris, France.;Service des Explorations Fonctionnelles, Hôpital Robert Debré, AP-HP, Paris, France.",
"authors": "Rigaudière|Florence|F|0000-0002-7369-7887;Nasser|Hala|H|;Pichard-Oumlil|Samia|S|;Delouvrier|Eliane|E|;Lopez-Hernandez|Elisa|E|;Milani|Paolo|P|;Auvin|Stéphane|S|;Delanoë|Catherine|C|",
"chemical_list": "C072312:ERG protein, human; D000071230:Transcriptional Regulator ERG; D000091346:Tripeptidyl-Peptidase 1; C000717267:TPP1 protein, human",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10633-021-09825-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-4486",
"issue": "143(1)",
"journal": "Documenta ophthalmologica. Advances in ophthalmology",
"keywords": "Cerliponase alpha; Evolution of retinopathy in CLN2; Flash-ERG and flash-VEP in CLN2; Human tripeptidyl peptidase-1 (TPP1); Neuronal ceroid lipofuscinosis CLN2",
"medline_ta": "Doc Ophthalmol",
"mesh_terms": "D000818:Animals; D002648:Child; D002675:Child, Preschool; D004596:Electroretinography; D056947:Enzyme Replacement Therapy; D006801:Humans; D009472:Neuronal Ceroid-Lipofuscinoses; D012160:Retina; D012162:Retinal Degeneration; D000071230:Transcriptional Regulator ERG; D000091346:Tripeptidyl-Peptidase 1",
"nlm_unique_id": "0370667",
"other_id": null,
"pages": "99-106",
"pmc": null,
"pmid": "33956290",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27491216;2081856;19112529",
"title": "Evolution of the retinal function by flash-ERG in one child suffering from neuronal ceroid lipofuscinosis CLN2 treated with cerliponase alpha: case report.",
"title_normalized": "evolution of the retinal function by flash erg in one child suffering from neuronal ceroid lipofuscinosis cln2 treated with cerliponase alpha case report"
} | [
{
"companynumb": "FR-BIOMARINAP-FR-2021-136599",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CERLIPONASE ALFA"
},
"drugadditional": "3"... |
{
"abstract": "To report on an early adopter series of collagenase Clostridium histolyticum (CCh) for Peyronie's disease (PD). Postapproval studies of CCh have been anticipated after recent Food and Drug Administration authorization of its use for men with PD as definitive and durable nonsurgical interventions have been long desired.\n\n\n\nFrom May 2014 to October 2015, a database consisting of PD patients with >30° of penile curvature received CCh from a single provider at a single institution. Objective penile curvature measurements and deformity directions were assessed pre- and posttreatment. Using the validated Peyronie's Disease Questionnaire (PDQ), changes in subjective symptoms of intercourse ability, penile pain, and bother were also noted.\n\n\n\nWe followed 49 unique PD patients treated with CCh. Mean follow-up was 183 days with a median of 6 injections over 3 cycles performed per patient. The mean pretreatment penile curvature was 49.3 degrees. Curvature was reduced by 15.4 degrees (32.4%, P < .01) after therapy. There were 10 out of 22 patients who regained ability to perform vaginal intercourse. Subjectively, there was an improvement in the ability to perform intercourse (29.1% improvement, P < .01) and bother symptoms (mean decrease 43.2%, P < .01), but no significant changes in penile pain (P = .89). Five notable bleeding events (10.2%) were noted, including 1 penile fracture requiring operative exploration.\n\n\n\nCCh use for PD yielded improvements in penile curvature, subjective intercourse, and bother symptoms. Further postanalysis studies of greater follow-up are needed to assess long-term durability, efficacy, and safety.",
"affiliations": "Institute of Urology, Lahey Hospital & Medical Center, Burlington, MA. Electronic address: kevinyg@gmail.com.;Institute of Urology, Lahey Hospital & Medical Center, Burlington, MA.",
"authors": "Yang|Kevin K|KK|;Bennett|Nelson|N|",
"chemical_list": "D003012:Microbial Collagenase",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "94()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059026:Diagnostic Self Evaluation; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D003012:Microbial Collagenase; D008875:Middle Aged; D010411:Penile Induration; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "143-7",
"pmc": null,
"pmid": "27211926",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Peyronie's Disease and Injectable Collagenase Clostridium histolyticum: Safety, Efficacy, and Improvements in Subjective Symptoms.",
"title_normalized": "peyronie s disease and injectable collagenase clostridium histolyticum safety efficacy and improvements in subjective symptoms"
} | [
{
"companynumb": "US-ENDO PHARMACEUTICALS INC-2016-003579",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COLLAGENASE CLOSTRIDIUM HISTOLYTICUM"
},
... |
{
"abstract": "A 59-year-old woman presented to the emergency department with shortness of breath. She had significant oropharyngeal swelling obstructing her upper respiratory tract. A diagnosis of laryngeal myxoedema was made, which was attributed to severe hypothyroidism. She required invasive ventilation and subsequently a tracheostomy. She was treated with levothyroxine and hydrocortisone. She completely recovered with this therapy. In this review, we will discuss similar cases and different therapeutic options. This case also highlights the fact that establishing a diagnosis of laryngeal myxoedema, a condition that can potentially have lethal outcomes and can be challenging.",
"affiliations": "Michigan State University, East Lansing, Michigan, USA.;Michigan State University College of Human Medicine, East Lansing, Michigan, USA Iraziq.fazal462@gmail.com.;University of Connecticut, Storrs, Connecticut, USA.;St Francis Hospital, Hartford, Connecticut, USA.",
"authors": "Iftikhar|Mian Harris|MH|;Raziq|Fazal I|FI|;Coll|Patrick|P|;Dar|Aneeqa Yousaf|AY|",
"chemical_list": "D013974:Thyroxine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-241313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(4)",
"journal": "BMJ case reports",
"keywords": "drugs and medicines; ear; endocrine system; general practice / family medicine; nose and throat/otolaryngology; thyroid disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D005260:Female; D006801:Humans; D007037:Hypothyroidism; D007830:Larynx; D008875:Middle Aged; D009230:Myxedema; D013974:Thyroxine; D014139:Tracheostomy",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33795283",
"pubdate": "2021-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Laryngeal myxoedema: a literature review of an uncommon complication of hypothyroidism.",
"title_normalized": "laryngeal myxoedema a literature review of an uncommon complication of hypothyroidism"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP025423",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditio... |
{
"abstract": "Hydroxyzine is an antihistaminic with sedative properties used in the control of anxiety and emesis. Peripheral blood hydroxyzine concentrations are compared to central blood and liver concentrations in 10 medical examiner cases. Specimens were initially screened for alcohol and simple volatiles by GC-FID headspace analysis, ELISA for drugs of abuse, and alkaline drugs by GC/MS. Hydroxyzine, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a specific GC-NPD procedure. Data suggest that postmortem peripheral blood hydroxyzine concentrations may be considered therapeutic to at least 0.24 mg/L and corresponding liver concentrations to at least 4.9 mg/kg. Hydroxyzine concentrations ranged 0.07-3.0mg/L in peripheral blood, 0.04-3.8 mg/L in central blood, and 0.88-55 mg/kg in liver. Hydroxyzine central blood to peripheral blood ratios averaged 0.92±0.25 (±standard deviation; N=6). Liver to peripheral blood ratios, on the other hand, were higher and averaged 13.8±6.2 (±standard deviation; N=10). Given that a liver to peripheral blood ratio less than 5 is consistent with little to no postmortem redistribution while exceeding 20-30 is indicative of propensity for significant postmortem redistribution, these data suggest that hydroxyzine is prone to a moderate degree of postmortem redistribution.",
"affiliations": "Forensic Toxicology Division, County of San Diego Medical Examiner's Office, 5570 Overland Avenue, Suite 101, San Diego, CA 92123, USA. Iain.McIntyre@sdcounty.ca.gov",
"authors": "McIntyre|Iain M|IM|;Mallett|Phyllis|P|;Trochta|Amber|A|;Morhaime|Jacquelyn|J|",
"chemical_list": "D006634:Histamine H1 Antagonists; D006919:Hydroxyzine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "231(1-3)",
"journal": "Forensic science international",
"keywords": "Central blood; Hydroxyzine; Liver; Peripheral blood; Postmortem redistribution",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D005260:Female; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D005766:Gastrointestinal Contents; D006634:Histamine H1 Antagonists; D006801:Humans; D006919:Hydroxyzine; D008099:Liver; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "28-33",
"pmc": null,
"pmid": "23890613",
"pubdate": "2013-09-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hydroxyzine distribution in postmortem cases and potential for redistribution.",
"title_normalized": "hydroxyzine distribution in postmortem cases and potential for redistribution"
} | [
{
"companynumb": "2015HINLIT0126",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROXYZINE\\HYDROXYZINE HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "Rivaroxaban (Xarelto; Johnson & Johnson Services, Inc) is a direct oral anticoagulant (DOAC) that works by directly inhibiting the active site of factor Xa (FXa). Rivaroxaban is metabolized and cleared via the kidney and liver. The results of various studies have shown that patients with severe renal impairment should receive reduced dosages of rivaroxaban or another anticoagulant due to impaired clearance. Although it is not required, monitoring rivaroxaban is useful in some conditions; however, the assays required for such monitoring are not readily available. Herein, we present a case of a 68-year-old Caucasian male patient who was receiving rivaroxaban (20 mg/day) for atrial flutter and had mild renal impairment. The patient was found to have increased effect of rivaroxaban due to further impairment of renal clearance caused by several renally cleared medications. This case highlights the importance of closely examining the renal function of and medication list for a patient before starting DOACs such as rivaroxaban.",
"affiliations": "Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.;Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.;Department of Hematology and Oncology, University of Rochester Medical Center, Rochester, New York.;Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.;Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.",
"authors": "Milito|Chelsea|C|;McRae|Hannah|H|;Victor|Adrienne|A|;Refaai|Majed A|MA|;Schmidt|Amy E|AE|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
"country": "England",
"delete": false,
"doi": "10.1093/labmed/lmz044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-5027",
"issue": "51(2)",
"journal": "Laboratory medicine",
"keywords": "DOAC; anticoagulation; bleeding; prolonged PT; renal impairment; rivaroxaban",
"medline_ta": "Lab Med",
"mesh_terms": "D000368:Aged; D001282:Atrial Flutter; D065427:Factor Xa Inhibitors; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D011517:Prothrombin Time; D051437:Renal Insufficiency; D000069552:Rivaroxaban",
"nlm_unique_id": "0250641",
"other_id": null,
"pages": "211-216",
"pmc": null,
"pmid": "31340380",
"pubdate": "2020-03-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent Rivaroxaban Effect Due to Impaired Renal Clearance and Medication Effects.",
"title_normalized": "persistent rivaroxaban effect due to impaired renal clearance and medication effects"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2020GMK047615",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nWe evaluate the early toxicity of concurrent use of radiotherapy, pertuzumab and trastuzumab in patients with HER2-positive metastatic or locally recurrent unresectable breast cancer.\n\n\nMETHODS\nA retrospective study was performed in a population of 23 consecutive patients between 2013 and 2015. Radiotherapy was performed on the chest area or metastatic sites during maintenance with pertuzumab and trastuzumab after six cycles of pertuzumab, trastuzumab and docetaxel. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria version 4.\n\n\nRESULTS\nIrradiation volumes were whole breast (8 patients) and chest wall (9 patients) at 50Gy in 25 fractions, the supraclavicular nodes (16 patients), the axillary area (nine patients) and the internal mammary nodes (9 patients) at 46Gy in 23 fractions. For five patients, radiotherapy was palliative: bone irradiation (4 patients), whole brain radiotherapy (one patient). Median follow-up was 12.6 months (range: 6.1-21.6 months) since the start of pertuzumab and trastuzumab. One patient presented an asymptomatic decrease of left ventricular ejection fraction below 50%. No symptomatic cardiac events were reported. Two patients presented asymptomatic grade I radiation pneumonitis. Acute skin toxicity was grade III (one patient), grade II (6 patients), and grade I (5 patients). There were two grade II esophagitis.\n\n\nCONCLUSIONS\nCombination of pertuzumab, trastuzumab and radiotherapy was well tolerated, which should be confirmed by the results of larger studies.",
"affiliations": "Department of radiation oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: zahra.ajgal@gmail.com.;Department of radiation oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France.;Department of medical oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France.;Department of medical oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France.;Department of radiation oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France.;Department of radiation oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France.;Department of radiation oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France.",
"authors": "Ajgal|Z|Z|;de Percin|S|S|;Diéras|V|V|;Pierga|J Y|JY|;Campana|F|F|;Fourquet|A|A|;Kirova|Y M|YM|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Receptor, ErbB-2; C485206:pertuzumab; D000068878:Trastuzumab",
"country": "France",
"delete": false,
"doi": "10.1016/j.canrad.2016.10.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1278-3218",
"issue": "21(2)",
"journal": "Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique",
"keywords": "Breast cancer; Cancer du sein; HER2; Pertuzumab; Radiotherapy; Radiothérapie; Toxicity; Toxicité; Trastuzumab",
"medline_ta": "Cancer Radiother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011878:Radiotherapy; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D000068878:Trastuzumab",
"nlm_unique_id": "9711272",
"other_id": null,
"pages": "114-118",
"pmc": null,
"pmid": "28347625",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combination of radiotherapy and double blockade HER2 with pertuzumab and trastuzumab for HER2-positive metastatic or locally recurrent unresectable and/or metastatic breast cancer: Assessment of early toxicity.",
"title_normalized": "combination of radiotherapy and double blockade her2 with pertuzumab and trastuzumab for her2 positive metastatic or locally recurrent unresectable and or metastatic breast cancer assessment of early toxicity"
} | [
{
"companynumb": "FR-ROCHE-1734572",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "An 83-year-old man with multiple medical problems, including gout, pseudogout, and renal insufficiency, presented with more than a year of proximal weakness. He had an extensive previous medical workup, including a normal creatinine kinase. His weakness persisted despite endurance and strength training. Electrodiagnostic findings were consistent with a myopathy, although without abnormal spontaneous activity and a length-dependent neuropathy. On the basis of these findings, colchicine was discontinued. The patient experienced marked symptomatic improvement within a week. Myopathies with neuropathies may be found with the use of colchicine. This case was unusual because of the absence of abnormal spontaneous activity and increased creatinine kinase, as typically reported with colchicine myopathy.\n\n\n\nV.",
"affiliations": "Departments of Physical Medicine and Rehabilitation and Neurology, Northwestern University; and Rehabilitation Institute of Chicago, Room 1154, 345 E. Superior, Chicago, IL 60611.;Department of Physical Medicine and Rehabilitation, Harvard Medical School, and Spaulding Rehabilitation Hospital, Boston, MA.;Midwest Orthopedics at Rush University Medical Center, Chicago, IL.;North Shore Pediatrics, Evanston, IL.;Departments of Physical Medicine and Rehabilitation and Neurology, Chicago, IL.",
"authors": "Marciniak|Christina|C|;Babu|Ashwin|A|;Ghannad|Leda|L|;Burnstine|Richard|R|;Keeshin|Susan|S|",
"chemical_list": "D003078:Colchicine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.pmrj.2016.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1934-1482",
"issue": "8(10)",
"journal": "PM & R : the journal of injury, function, and rehabilitation",
"keywords": null,
"medline_ta": "PM R",
"mesh_terms": "D000369:Aged, 80 and over; D003078:Colchicine; D006073:Gout; D006801:Humans; D008297:Male; D009468:Neuromuscular Diseases",
"nlm_unique_id": "101491319",
"other_id": null,
"pages": "1016-1019",
"pmc": null,
"pmid": "26972360",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unusual Electromyographic Findings Associated With Colchicine Neuromyopathy: A Case Report.",
"title_normalized": "unusual electromyographic findings associated with colchicine neuromyopathy a case report"
} | [
{
"companynumb": "US-INGENUS PHARMACEUTICALS NJ, LLC-ING201611-000113",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"d... |
{
"abstract": "BACKGROUND\nThere is a need for further evaluation of hyaluronic acid fillers for aesthetic use in Asia, where treatment goals may differ from western countries.\n\n\nOBJECTIVE\nTo evaluate 24-month safety and effectiveness of two hyaluronic acid fillers with lidocaine when used for full-face aesthetic treatment in Asian patients.\n\n\nMETHODS\nThis was a 24-month, evaluator-blinded, non-comparative, multi-center study. Female subjects were injected with 3-5 mL Restylane® Lidocaine and/or Restylane Lyft Lidocaine, manufactured using the NASHA™ technology, in 2–4 pre-defined areas; upper cheeks, nasolabial folds, temples, nose, and chin. A second treatment was performed after 12 months. Assessments included aesthetic improvement, subject satisfaction, assessment scales for upper cheeks and nasolabial folds, and safety (adverse events and subject diaries).\n\n\nRESULTS\nOne hundred subjects were included; total mean volumes were 4.7 mL and 3.1 mL at first and second treatment, respectively. At least 82% of subjects were rated as aesthetically improved over 24 months by subjects themselves and by investigators. Most subjects (73-90%) were satisfied with the treatment throughout the study. Upper cheek improvement 12 months after treatment was significantly higher after second treatment (≥69% of subjects) than after first treatment (≥38%), P<0.0001, Fisher’s exact test. A total of 29 treatment related adverse events were reported by 16% of subjects, all were mild (79%) or moderate (21%) in intensity. Most commonly reported were pain and bruising. Tenderness was the most common diary record in all treatment areas.\n\n\nCONCLUSIONS\nFull-face treatments with the study products resulted in long-term aesthetic improvement, perceived by both subjects and investigators. Subject satisfaction was high and maintained over 24 months with one re-treatment. Repeated treatment of several facial indications showed a satisfactory safety profile. J Drugs Dermatol. 2020;19(9):836-842. doi:10.36849/JDD.2020.5374.",
"affiliations": null,
"authors": "Huang|She-Hung|SH|;Tsai|Tsen-Fang|TF|",
"chemical_list": "D000067548:Dermal Fillers; D004338:Drug Combinations; C502935:Perlane; D006820:Hyaluronic Acid; D008012:Lidocaine; C445361:Restylane",
"country": "United States",
"delete": false,
"doi": "10.36849/JDD.2020.10.36849/JDD.2020.5374",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "19(9)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000328:Adult; D044466:Asians; D000067548:Dermal Fillers; D004338:Drug Combinations; D004954:Esthetics; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid; D007279:Injections, Subcutaneous; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D010146:Pain; D010147:Pain Measurement; D015361:Rhytidoplasty; D015595:Skin Aging; D013624:Taiwan; D016896:Treatment Outcome",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "836-842",
"pmc": null,
"pmid": "33026748",
"pubdate": "2020-09-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Safety and Effectiveness of Hyaluronic Acid Fillers With Lidocaine for Full-Face Treatment in Asian Patients.",
"title_normalized": "safety and effectiveness of hyaluronic acid fillers with lidocaine for full face treatment in asian patients"
} | [
{
"companynumb": "US-DENTSPLY PHARMACEUTICAL-2020SCDP000357",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nVagus nerve stimulation system (VNS) has been employed worldwide as adjunctive therapy in drug-resistant epileptic patients. Only nine previous pregnancies with six-positive outcomes have been reported in women with epilepsy treated with VNS since 1998.\n\n\nOBJECTIVE\nTo communicate the experience of pregnancies in women treated with VNS in our country.\n\n\nMETHODS\nClinical data of four female patients treated with VNS during pregnancy and delivery in five gestations is described.\n\n\nRESULTS\nFour pregnancy outcomes were positive and one ended in spontaneous abortion, probably more related to the use antiepileptic drugs than VNS itself. Two births were vaginal and the other two with cesarean section. None of the complications during delivery were attributed to VNS. No teratogenicity was documented.\n\n\nCONCLUSIONS\nBased on our experience VNS constitutes a safe therapy for the treatment of drug-resistant epilepsy in women of childbearing potential and during pregnancy and delivery. Larger series will be useful to confirm this finding.",
"affiliations": "Neurology Department, Complexo Hospitalario Universitario, Santiago de Compostela, Spain.;Neurology Department, Complexo Hospitalario Universitario, Santiago de Compostela, Spain.;Neurology Department, Hospital Universitario Cruces, Barakaldo, Spain.;Neurosurgery Department, Hospital Clinic, Barcelona, Spain.;Neurology Department, Hospital Universitario Cruces, Barakaldo, Spain.;Neurosurgery Department, Complexo Hospitalario Universitario, Santiago de Compostela, Spain.;Neurology Department, Hospital Clinic, Barcelona, Spain.",
"authors": "Rodríguez-Osorio|X|X|http://orcid.org/0000-0003-1211-5107;López-González|F J|FJ|;Garamendi|Í|Í|;Rumià|J|J|;Matute|A|A|;Prieto-González|Á|Á|;Carreño|M|M|",
"chemical_list": "D000927:Anticonvulsants",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ane.12780",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6314",
"issue": "136(4)",
"journal": "Acta neurologica Scandinavica",
"keywords": "delivery; pharmaco-resistant epilepsy; pregnancy; teratogenicity; vagus nerve stimulation",
"medline_ta": "Acta Neurol Scand",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D003131:Combined Modality Therapy; D004827:Epilepsy; D005260:Female; D006801:Humans; D011247:Pregnancy; D016896:Treatment Outcome; D055536:Vagus Nerve Stimulation",
"nlm_unique_id": "0370336",
"other_id": null,
"pages": "372-374",
"pmc": null,
"pmid": "28560798",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "VNS and pregnancy: A multicentric experience of four cases.",
"title_normalized": "vns and pregnancy a multicentric experience of four cases"
} | [
{
"companynumb": "ES-AUROBINDO-AUR-APL-2018-030034",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "4... |
{
"abstract": "BACKGROUND\nBronchial dehiscence is a life-threatening complication after lung transplant. If it is not treated by placement of stent or reanastomosis, the chance of survival will depend on the availability of a new graft. However, retransplant is not a practical management option in Japan, where waiting time for lung transplant is extensive. We described a case of refractory bilateral bronchial dehiscence managed by veno-venous extracorporeal oxygenation membrane (VV ECMO) while allowing the dehiscence to heal.\n\n\nMETHODS\nA 25-year-old man with idiopathic pulmonary arterial hypertension underwent a bilateral lung transplant. The patient developed bilateral bronchial dehiscence. Open reanastomosis was not successful, and air leakage recurred under low positive pressure ventilation. VV ECMO was established to maintain oxygenation with spontaneous breathing until both dehiscence were closed by adhesions.\n\n\nCONCLUSIONS\nIn a patient with refractory bilateral bronchial dehiscence, VV ECMO may provide bronchial rest and serve as a bridge therapy to recovery.",
"affiliations": "Department of Anesthesiology and Resuscitology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. tani-m1@cc.okayama-u.ac.jp.",
"authors": "Tani|Makiko|M|http://orcid.org/0000-0003-0265-8247",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s40981-021-00480-6",
"fulltext": "\n==== Front\nJA Clin Rep\nJA Clin Rep\nJA Clinical Reports\n2363-9024\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n480\n10.1186/s40981-021-00480-6\nCase Report\nVeno-venous extracorporeal membrane oxygenation in the management of refractory bilateral bronchial dehiscence after lung transplant: a case report\nhttp://orcid.org/0000-0003-0265-8247\nTani Makiko tani-m1@cc.okayama-u.ac.jp\n\ngrid.261356.5 0000 0001 1302 4472 Department of Anesthesiology and Resuscitology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558 Japan\n16 10 2021\n16 10 2021\n12 2021\n7 7721 8 2021\n10 9 2021\n8 10 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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/.\nBackground\n\nBronchial dehiscence is a life-threatening complication after lung transplant. If it is not treated by placement of stent or reanastomosis, the chance of survival will depend on the availability of a new graft. However, retransplant is not a practical management option in Japan, where waiting time for lung transplant is extensive. We described a case of refractory bilateral bronchial dehiscence managed by veno-venous extracorporeal oxygenation membrane (VV ECMO) while allowing the dehiscence to heal.\n\nCase presentation\n\nA 25-year-old man with idiopathic pulmonary arterial hypertension underwent a bilateral lung transplant. The patient developed bilateral bronchial dehiscence. Open reanastomosis was not successful, and air leakage recurred under low positive pressure ventilation. VV ECMO was established to maintain oxygenation with spontaneous breathing until both dehiscence were closed by adhesions.\n\nConclusion\n\nIn a patient with refractory bilateral bronchial dehiscence, VV ECMO may provide bronchial rest and serve as a bridge therapy to recovery.\n\nKeywords\n\nBronchial dehiscence\nExtracorporeal membrane oxygenation\nLung transplant\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nBronchial dehiscence is one possible anastomotic airway complication after lung transplant. Bronchial dehiscence has been reported in 1–10% of lung transplant recipients [1], but it is associated with high mortality [2]. Treatment options for bronchial dehiscence are placement of stents, surgical suture, pneumonectomy, and retransplant [3]. Indication of the options should be considered based on estimated effectiveness, operability, and availability for new lung graft.\n\nPulmonary infections after lung transplant predispose patients to bronchial dehiscence [3]. Impaired tissue oxygenation and carbon dioxide elimination because of pneumonia necessitate mechanical ventilation, which increases the risk of bronchial dehiscence.\n\nHere, we report a case of bilateral bronchial dehiscence with pneumonia, in which none of the management options for bronchial dehiscence described above was effective or applicable. We utilized veno-venous extracorporeal membrane oxygenation (VV ECMO) until the dehiscence closed in order to prevent air leak and maintain oxygenation and ventilation.\n\nCase presentation\n\nWe obtained a written informed consent from the patient for the publication of this case report.\n\nA 25-year-old male with idiopathic pulmonary arterial hypertension underwent double lung transplant. He was extubated on postoperative day (POD) 4 uneventfully other than 2 days being febrile. However, CT scan on POD 6 revealed filtration in both lungs. We diagnosed the filtration as pneumonia due to Pseudomonas aerginosa, Enterobacter, and methicillin-resistant Staphylococcus aureus, and administered antibiotics specific to the bacteria. On POD 17, a chest X-ray revealed right-sided pneumothorax, and a chest tube was inserted into the right chest cavity. A subsequent CT scan revealed bilateral bronchial dehiscence (Fig. 1) and adhesion of pulmonary arteries (PAs) into the bronchus.Fig. 1 A, B Images of computed tomography scan performed 15 days after the transplantation showing bronchial dehiscence (red arrows), pneumothorax (black arrows), and associated pneumonia (blue arrow)\n\nThe patient was transferred to the operating room for emergency surgical inspection. With ECMO on standby, general anesthesia was induced. The trachea was intubated with a double lumen tube. Bronchoscopy was performed before surgery which revealed dehiscence of bilateral bronchial anastomosis.\n\nSurgical inspection revealed both-sided bronchial dehiscence and adhesion of the left PA to the left bronchus. Due to a risk of PA penetration into the bronchus, the dehiscence could not be sutured circumferentially. Then, the dehiscence was repaired with partial suture combined with omentoplasty and thymus wrapping under mechanical ventilation. We did not establish ECMO or cardiopulmonary bypass due to concerns that bleeding from the PA could become uncontrollable due to anticoagulation. A tracheostomy was also performed at the end of the surgery. There was no pneumothorax or air leakage from the bilateral chest tubes.\n\nAfter the surgery, we attempted to wean the patient from ventilator support to minimize positive pressure on the repair site. However, respiratory suppression by high dose sedatives (propofol 250 mg/h, morphine 6 mg/h, and dexmedetomidine 0.5 mcg/kg/h) to prevent coughing and impaired oxygenation due to pneumonia necessitated positive airway ventilation (positive end-expiratory pressure 3–5 cmH2O, pressure control 5–8 cmH2O) with inhaled nitric oxide. The patient spent 3 days with no air leakage. On POD 21, massive air leakage appeared from both chest tubes under peak inspiratory pressure (PIP) 13 cmH2O. Ineffective ventilation due to air leakage as well as pneumonia deteriorated the gas exchange to PaO2 70 mmHg, PaCO2 100 mmHg (FIO2 1.0, positive end-expiratory pressure 8 cmH2O, PIP 15 cmH2O). Hypercarbia necessitated emergent installation of VV ECMO through both femoral veins, and positive airway ventilation was discontinued. The patient was assisted with VV ECMO while breathing spontaneously through the tracheostomy, resulting in improved gas exchange and cessation of air leakage.\n\nPlacement of stents and re-opening for exploration were management options for the dehiscence; however, we decided neither was indicated for the patient because of PA adhesion and concern of subsequent PA perforation into the bronchus. Retransplant for this patient was theoretically a treatment option; however, retransplant was not practical because of the paucity of lung donors in Japan.\n\nDuring ECMO support, we tolerated partial flow (60–70% of total flow and 4L/min sweep gas) as to not administer excess volume and to keep the lungs dry. We also used high flow oxygen therapy (FIO2 1.0 and oxygen flow rate 20 L/minute) for spontaneous breathing support and preventing lung collapse, and PaO2 80s mmHg and PaCO2 40s mmHg were maintained. In addition, activated clotting time (ACT) was controlled at approximately 150 seconds to prevent bleeding particularly from the anastomosis site and tracheostomy.\n\nUnder VV ECMO support, we provided conservative therapy for the patient. Intravenous morphine was continued for suppressing cough and avoiding high pressure on the repair lesions. Instead, sputum was removed with bronchoscopy every four hours. We awakened the patient in the daytime and encouraged physical therapy to prevent muscle atrophy and improve pulmonary function. Antibiotics were continued for pneumonia.\n\nOn POD 29, improvement of bronchial dehiscence was confirmed by bronchoscopy and CT scan (Fig. 2A, B); however, bilateral pneumonia remained. After the pneumonia improved, the patient was successfully weaned from ECMO on POD 32, the twelfth day after ECMO installation. The patient could maintain oxygenation (PaO2 81mmHg) and carbon dioxide removal (PaCO2 38mmHg) by high-flow oxygen therapy (FIO2 0.9 and oxygen flow 20L/minute). ECMO circuit exchange was necessary twice due to blood clots within the artificial lung during the 12 days. However, the patient had neither embolic nor hemorrhagic complications. He was discharged from the intensive care unit after 1 month.Fig. 2 A, B The follow-up CT scan 12 days after the surgical repair revealing good healing of the bilateral dehiscence (red arrows)\n\nDiscussion\n\nThis is a case of bilateral bronchial dehiscence with respiratory failure which resolved after 12 days of VV ECMO support, despite the fact that the sites of dehiscence were not completely repaired surgically.\n\nManagement of patients with repaired bronchial dehiscence and respiratory failure is challenging because there is a management dilemma. Airway pressure should be minimized to protect repaired anastomosis, whereas adequate respiratory support is required to maintain oxygenation and ventilation. Implementing VV ECMO for patients with bronchial dehiscence has two benefits: (1) Influence on the surgical repair of the bronchial dehiscence by inspiratory positive airway pressure can be reduced. Positive airway pressure decreases pulmonary blood flow and worsens bronchial ischemia [4]. In addition, reduction of pulmonary shear stress has a protective effect on bronchial healing [5]. (2) Reduced oxygenation and carbon dioxide elimination induced by respiratory failure were substituted.\n\nThere is no clear consensus on treatment for bronchial dehiscence, and management practice depends on the severity of the dehiscence and associated complications [6]. For cases with large dehiscence or cases of failed stent placement, surgical repair is considered. However, surgical repair in such cases is difficult due to the presence of infection and ischemia, resulting in high failure rate and poor outcome [6, 7]. If the management mentioned above is not successful, allograft resection or re-transplant could be therapeutic options. In this case, these strategies were considered when air leakage recurred after surgical repair; however, neither strategy was adopted. The bronchial dehiscence was both-sided, and both grafts were affected by an infection. A one-sided allograft resection would not have been tolerable. Furthermore, the waiting time for a lung transplant did not depend on the allocation score in Japan, as the average waiting time was about 900 days in Japan. Thus, emergency re-transplant was not a viable option.\n\nFor reviving the impaired allografts, management strategy during ECMO support was critical. First, we set the lower ACT goal of heparinization for ECMO than the popular ACT range of 180-200 seconds with the aim of preventing hemorrhage [8]. Hemorrhage from anastomosis and tracheostomy could be life-threatening in this case. Second, we started physical therapy while the patient was on ECMO support to improve respiratory function. There are some complications from physical therapy combined with ECMO, such as a decrease in peripheral oxygen saturation, cannula fracture, and obstructive thrombus in return cannula [9]; however, physical therapy together with ECMO is relatively safe and effective for secretion clearance and pulmonary recovery [10, 11].\n\nWe did not implement VV ECMO during the surgical repair considering the risk of bleeding from the PA which was firmly adhered to the bronchus. We should have used VV ECMO right after the surgical repair was completed, an action that could have prevented recurrent air leakage which was induced by inspiratory airway pressure affecting the reanastomosis.\n\nConclusion\n\nBronchial dehiscence after lung transplant is life-threatening. In our case, VV ECMO provided bronchial rest and served as a bridge therapy to recovery.\n\nAbbreviations\n\nVV ECMO Veno-venous extracorporeal oxygenation membrane\n\nPOD Postoperative day\n\nPA Pulmonary artery\n\nPIP Peak inspiratory pressure\n\nPaO2 Arterial partial pressure of oxygen\n\nPaCO2 Arterial partial pressure of carbon dioxide\n\nFIO2 Fraction of inspiratory oxygen\n\nACT Activated clotting time\n\nAcknowledgements\n\nThe author acknowledges Dr. Motomu Kobayashi, in the Department of Anesthesiology and Resuscitology in Okayama University Hospital, for his critical revision. In addition, the author would like to thank Ms. Rebecca Lahniche for English language editing.\n\nAuthor’s contributions\n\nMT reviewed the literature and elaborated on the manuscript. The author(s) read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nNot applicable due to patient privacy concerns.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable\n\nConsent for publication\n\nThe patient has provided written consent to publish this case.\n\nCompeting interests\n\nThe author declares that she has no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Usuda KGT, Pandya C, Mahta AC. Bronchial Dehiscence. J Bronchol. 2005;12:164–5.\n2. Kshettry VR Kroshus TJ Hertz MI Hunter DW Shumway SJ Bolman RM Early and late airway complications after lung transplantation: incidence and management Ann Thorac Surg. 1997 63 1576 1583 10.1016/S0003-4975(97)83852-0 9205151\n3. Mahajan AK Folch E Khandhar SJ Channick CL Santacruz JF Mehta AC Nathan SD The diagnosis and management of airway complications following lung transplantation Chest. 2017 152 627 638 10.1016/j.chest.2017.02.021 28274791\n4. Yokomise H Cardoso PF Kato H Keshavjee SH Wada H Slutsky AS Patterson GA The effect of pulmonary arterial flow and positive end-expiratory pressure on retrograde bronchial mucosal blood flow J Thorac Cardiovasc Surg. 1991 101 201 208 10.1016/S0022-5223(19)36753-4 1825125\n5. Iglesias M Jungebluth P Petit C Matute MP Rovira I Martinez E Catalan M Ramirez J Macchiarini P Extracorporeal lung membrane provides better lung protection than conventional treatment for severe postpneumonectomy noncardiogenic acute respiratory distress syndrome J Thorac Cardiovasc Surg. 2008 135 1362 1371 10.1016/j.jtcvs.2007.08.074 18544387\n6. Crespo MM McCarthy DP Hopkins PM Clark SC Budev M Bermudez CA Benden C Eghtesady P Lease ED Leard L D'Cunha J Wigfield CH Cypel M Diamond JM Yun JJ Yarmus L Machuzak M Klepetko W Verleden G Hoetzenecker K Dellgren G Mulligan M ISHLT Consensus Statement on adult and pediatric airway complications after lung transplantation: Definitions, grading system, and therapeutics J Heart Lung Transplant. 2018 37 548 563 10.1016/j.healun.2018.01.1309 29550149\n7. Alvarez A Algar J Santos F Lama R Aranda JL Baamonde C Lopez-Pujol J Salvatierra A Airway complications after lung transplantation: a review of 151 anastomoses Eur J Cardiothorac Surg. 2001 19 381 387 10.1016/S1010-7940(01)00619-4 11306300\n8. Lafc G Budak AB Yener AU Cicek OF Use of extracorporeal membrane oxygenation in adults Heart Lung Circ. 2014 23 10 23 10.1016/j.hlc.2013.08.009 24144910\n9. Ferreira DDC Marcolino MAZ Macagnan FE Plentz RDM Kessler A Safety and potential benefits of physical therapy in adult patients on extracorporeal membrane oxygenation support: a systematic review Rev Bras Ter Intensiva. 2019 31 227 239 10.5935/0103-507X.20190017 31090853\n10. Cork G Barrett N Ntoumenopoulos G Justification for chest physiotherapy during ultra-protective lung ventilation and extra-corporeal membrane oxygenation: a case study Physiother Res Int. 2014 19 126 128 10.1002/pri.1563 23955843\n11. Kikukawa T Ogura T Harasawa T Suzuki H Nakano M H1N1 influenza-associated pneumonia with severe obesity: successful management with awake veno-venous extracorporeal membrane oxygenation and early respiratory physical therapy Acute Med Surg. 2016 3 186 189 10.1002/ams2.165 29123779\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2363-9024",
"issue": "7(1)",
"journal": "JA clinical reports",
"keywords": "Bronchial dehiscence; Extracorporeal membrane oxygenation; Lung transplant",
"medline_ta": "JA Clin Rep",
"mesh_terms": null,
"nlm_unique_id": "101682121",
"other_id": null,
"pages": "77",
"pmc": null,
"pmid": "34654984",
"pubdate": "2021-10-16",
"publication_types": "D016428:Journal Article",
"references": "9205151;11306300;31090853;29123779;29550149;28274791;18544387;24144910;23955843;1825125",
"title": "Veno-venous extracorporeal membrane oxygenation in the management of refractory bilateral bronchial dehiscence after lung transplant: a case report.",
"title_normalized": "veno venous extracorporeal membrane oxygenation in the management of refractory bilateral bronchial dehiscence after lung transplant a case report"
} | [
{
"companynumb": "JP-MALLINCKRODT-T202105250",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NITRIC OXIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Omalizumab, a monoclonal anti-immunoglobulin E antibody, has been used as an effective treatment for severe asthma associated with atopy over the past decade. Sarcoidosis is an idiopathic granulomatous disorder in which first-line treatment is usually glucocorticoids. To the authors' knowledge, the present report describes the first case of an association between omalizumab therapy and revelation of cutaneous sarcoidosis with the withdrawal of systemic glucocorticoids. A 56-year-old woman with severe allergic asthma dependent on oral prednisone initiated omalizumab treatment. As her symptoms of asthma improved over the course of a year, her prednisone was gradually tapered. After being off glucocorticoids, she developed skin nodules that had biopsy characteristics of sarcoidosis. The present case illustrates the need to monitor closely for potential unmasking of glucocorticoid-responsive conditions when transitioning from systemic glucocorticoids to omalizumab therapy.",
"affiliations": null,
"authors": "Yung|Samuel|S|;Han|Duhyun|D|;Lee|Jason K|JK|",
"chemical_list": "D018927:Anti-Asthmatic Agents; D005938:Glucocorticoids; D000069444:Omalizumab",
"country": "Egypt",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-2241",
"issue": "22(6)",
"journal": "Canadian respiratory journal",
"keywords": null,
"medline_ta": "Can Respir J",
"mesh_terms": "D018927:Anti-Asthmatic Agents; D001249:Asthma; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008875:Middle Aged; D000069444:Omalizumab; D012507:Sarcoidosis; D012871:Skin Diseases",
"nlm_unique_id": "9433332",
"other_id": null,
"pages": "315-6",
"pmc": null,
"pmid": "26401982",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11496232;11529281;16790701;16946094;18206510;19411292;19839977;21266686;21410369",
"title": "Cutaneous sarcoidosis in a patient with severe asthma treated with omalizumab.",
"title_normalized": "cutaneous sarcoidosis in a patient with severe asthma treated with omalizumab"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-108632",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "OBJECTIVE\nTo assess the prevalence of delirium and coma in mechanically ventilated patients sedated with dexmedetomidine or propofol alone; to evaluate the hospital length of stay for both treatment groups; and to evaluate the level of sedation, adverse effects, and hospital outcomes.\n\n\nMETHODS\nMedical records were reviewed retrospectively for patients who were admitted to the medical or surgical intensive care units (ICUs) in a 591-bed teaching hospital and who received either dexmedetomidine or propofol alone for 24 hours or more for sedation.\n\n\nRESULTS\nA total of 111 patients were included in the study, with 56 patients in the dexmedetomidine group and 55 patients in the propofol group. Results of the analysis showed that the propofol group had a higher prevalence of coma (43.6% versus 12.5%; P < 0.001). Dexmedetomidine patients had a longer median hospital length of stay of 23.5 days (interquartile range [IQR], 11.5-39.5 days) versus 15.0 days (IQR, 7.0-24.0 days; P = 0.01). The rates of delirium were similar in both groups, with 16% in dexmedetomidine-treated patients versus 20% in propofol-treated patients (P = 0.63).\n\n\nCONCLUSIONS\nNo difference in the prevalence of delirium was found when comparing the dexmedetomidine- and propofol-treated groups. Propofol was associated with more coma and oversedation; dexmedetomidine was associated with longer time to extubation, longer length of stay in the ICU, and longer hospital length of stay.",
"affiliations": null,
"authors": "Jiang|Yi Kai Johnny|YK|;Wang|Shan|S|;Lam|Timothy S|TS|;Hanna|Adel|A|;DeMuro|Jonas P|JP|;Calixte|Rose|R|;Brathwaite|Collin E M|CE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-1372",
"issue": "41(7)",
"journal": "P & T : a peer-reviewed journal for formulary management",
"keywords": "coma; delirium; dexmedetomidine; intensive care; mechanical ventilation; propofol; sedation",
"medline_ta": "P T",
"mesh_terms": null,
"nlm_unique_id": "9015516",
"other_id": null,
"pages": "442-5",
"pmc": null,
"pmid": "27408521",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": "23269131;18073360;15082703;23592359;24092976;19188334;15071384;18795253",
"title": "Prevalence of Delirium and Coma In Mechanically Ventilated Patients Sedated With Dexmedetomidine or Propofol.",
"title_normalized": "prevalence of delirium and coma in mechanically ventilated patients sedated with dexmedetomidine or propofol"
} | [
{
"companynumb": "US-PAR PHARMACEUTICAL COMPANIES-2016SCPR015757",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nHypertriglyceridemia induced acute pancreatitis is associated with more severe clinical course than acute pancreatitis caused by other etiologies. Therapeutic plasma exchange (TPE) is a potential treatment for patients with severe hypertriglyceridemia induced acute pancreatitis due to its rapid effect in lowering triglycerides (TG) levels and reducing inflammatory cytokines. However, clinical data regarding the effectiveness and safety of TPE is limited.\n\n\nMETHODS\nWe retrospectively reviewed eight cases of hypertriglyceridemia induced acute pancreatitis and treated with TPE. Patients' demographic data, personal history, clinical course, laboratory results, apheresis data and clinical outcome were collected and analyzed.\n\n\nRESULTS\nAt initial presentation, the average TG levels for the eight patients was 3381.6 mg/dl (SD: 1491.6 mg/dl). Twelve procedures were performed on the eight patients in the study, and TG levels decreased by an average of 2673.2 mg/dl (SD: 2306.3 mg/dl) with a corresponding average reduction rate of 60.3 % (SD:21.1 %), ranging from 14.6%-84.9%. A 60 % or greater reduction was achieved in 66.7 % of all the procedures; however, the degree of reduction for each procedure was not predictable, even among repeat procedures on the same patient.\n\n\nCONCLUSIONS\nOur study indicates that TPE is an effective and safe treatment option for patients with hypertriglyceridemia induced acute pancreatitis. However, due to the unpredictability of TG removal, repeat procedures may be necessary for some patients.",
"affiliations": "Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States.;Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States.;Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States. Electronic address: lawrencewilliams@uabmc.edu.",
"authors": "Fei|Fei|F|;Boshell|Nick|N|;Williams|Lance A|LA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.transci.2019.102699",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-0502",
"issue": "59(2)",
"journal": "Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis",
"keywords": "Hypertriglyceridemia induced acute pancreatitis; Therapeutic plasma exchange (TPE); Triglycerides (TG)",
"medline_ta": "Transfus Apher Sci",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D010951:Plasma Exchange; D012189:Retrospective Studies",
"nlm_unique_id": "101095653",
"other_id": null,
"pages": "102699",
"pmc": null,
"pmid": "32085931",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Predictability and efficacy of therapeutic plasma exchange for hypertriglyceridemia induced acute pancreatitis.",
"title_normalized": "predictability and efficacy of therapeutic plasma exchange for hypertriglyceridemia induced acute pancreatitis"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP000945",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OMEGA-3-ACID ETHYL ESTERS"
},
... |
{
"abstract": "A 61-year-old man underwent CapeOX plus bevacizumab chemotherapyafter right hemicolectomyfor metastatic ascending colon cancer. On the 7th dayafter the first administration, he had sudden abdominal pain and nausea. Contrast-enhanced computed tomographyrevealed aortic thrombosis and a superior mesenteric artery(SMA)embolism that was considered to be associated with bevacizumab. Bevacizumab was discontinued and anticoagulation therapyusing heparin and urokinase was performed. Brain infarction of the left middle cerebral arteryoccurred on the 15th dayafter the first administration and thrombectomywas performed. Anticoagulation therapyusing heparin, bayaspirin, and edoxaban tosilate hydrate was performed. The aortic thrombosis and SMA embolism resolved with treatment, but the patient died following an increase in peritoneal dissemination. It should be noted that unexpectedlysevere aortic thrombosis occurred during the first administration of CapeOX plus bevacizumab for metastatic colon cancer.",
"affiliations": "Dept. of Surgery, National Hospital Organization, Oita Medical Center.",
"authors": "Korehisa|Shotaro|S|;Kabashima|Akira|A|;Nambara|Sho|S|;Watanabe|Kiminori|K|;Umeda|Kenji|K|;Koso|Hidenori|H|;Tahara|Kouichiro|K|;Nakamura|Yusuke|Y|;Anai|Hideaki|H|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000069287:Capecitabine; D003110:Colonic Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013927:Thrombosis",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "989-992",
"pmc": null,
"pmid": "32541181",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Severe Aortic Thrombosis during the First Chemotherapy Regimen of CapeOX plus Bevacizumab for Metastatic Colon Cancer.",
"title_normalized": "a case of severe aortic thrombosis during the first chemotherapy regimen of capeox plus bevacizumab for metastatic colon cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2020327458",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nIntravenous recombinant tissue plasminogen activator (tPA) at a dose of 0.9 mg/kg body weight is associated with a high hemorrhagic transformation (HT) rate. Low-dose tPA (0.6 mg/kg) may have a lower hemorrhage rate but the mortality and disability rates at 90 days cannot be confirmed as non-inferior to standard-dose tPA. Whether the doses 0.7 and 0.8 mg/kg have better efficacy and safety needs further investigation. Therefore, this study is to compare the efficacy and safety of each dose of tPA (0.6, 0.7, 0.8, and 0.9 mg/kg body weight) and to investigate the factors affecting early neurological improvement (ENI) and early neurological deterioration (END).\n\n\nMETHODS\nFor this observational study, data were obtained from 274 patients who received tPA thrombolytic therapy in Chia-Yi Christian Hospital stroke unit. The tPA dose was given at the discretion of each physician. The definition of ENI was a >8 point improvement (compared with baseline) at 24 h following thrombolytic therapy or an improvement in the National Institutes of Health Stroke Score (NIHSS) to 0 or 1 toward the end of tPA infusion. The definition of END was a >4 point increase in NIHSS (compared with baseline) within 24 h of tPA infusion. The primary objective was to investigate whether 0.7 and 0.8 mg/kg of tPA have higher ENI rate, lower END rate, and better outcome at 6 months. Poor outcome was defined as having a modified Rankin Scale of 3 to 6 (range, 0 [no symptoms] to 6 [death]). The secondary objective was to investigate whether low-dose tPA has a lower risk of intracerebral HT than that with standard-dose tPA. We also investigated the factors affecting ENI, END, HT, and 6-month outcome.\n\n\nRESULTS\nA total of 274 patients were included during the study period, of whom 260 were followed up for >6 months. There was a trend for the HT rate to increase as the dose increased (P=0.02). The symptomatic HT rate was not significantly different among the low-dose and standard-dose groups. The ENI and END (P=0.52) were not significantly different among the four dosage groups. The clinical functional outcome at 6 months after stroke onset was poorer in the standard-dose group (P=0.02). Stroke severity (P<0.01), stroke type (P=0.03), and diabetes mellitus (P=0.04) affected the functional outcome at 6 months.\n\n\nCONCLUSIONS\nAmong the 274 patients receiving tPA thrombolytic therapy, the HT rate increased as dose increased. The symptomatic HT, ENI and END rates were not significantly different among the low-dose (0.6, 0.7, and 0.8 mg/kg) and standard-dose groups. Stroke severity (NIHSS >12), stroke type (cardioembolism and large artery atherosclerosis) and diabetes mellitus were associated with poor outcome at 6 months.",
"affiliations": "Department of Neurology, Chia-Yi Christian Hospital.;Department of Family Medicine, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.;Department of Neurology, Chia-Yi Christian Hospital.;Department of Neurology, Chia-Yi Christian Hospital.",
"authors": "Ong|Cheung-Ter|CT|;Wong|Yi-Sin|YS|;Wu|Chi-Shun|CS|;Su|Yu-Hsiang|YH|",
"chemical_list": "D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/DDDT.S133759",
"fulltext": "\n==== Front\nDrug Des Devel TherDrug Des Devel TherDrug Design, Development and TherapyDrug Design, Development and Therapy1177-8881Dove Medical Press 10.2147/DDDT.S133759dddt-11-1559Original ResearchOutcome of stroke patients receiving different doses of recombinant tissue plasminogen activator Ong Cheung-Ter 12Wong Yi-Sin 3Wu Chi-Shun 1Su Yu-Hsiang 11 Department of Neurology, Chia-Yi Christian Hospital2 Department of Nursing, Chung Jen Junior College of Nursing, Health Science and Management3 Department of Family Medicine, Chia-Yi Christian Hospital, Chia-Yi, TaiwanCorrespondence: Cheung-Ter Ong, Department of Neurology, Chia-Yi Christian Hospital, 539 Chung-Shao Road, Chia-Yi, Taiwan, Tel +886 5276 5041, Email ctong98@yahoo.com.tw2017 18 5 2017 11 1559 1566 © 2017 Ong et al. This work is published and licensed by Dove Medical Press Limited2017The 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.Background and purpose\nIntravenous recombinant tissue plasminogen activator (tPA) at a dose of 0.9 mg/kg body weight is associated with a high hemorrhagic transformation (HT) rate. Low-dose tPA (0.6 mg/kg) may have a lower hemorrhage rate but the mortality and disability rates at 90 days cannot be confirmed as non-inferior to standard-dose tPA. Whether the doses 0.7 and 0.8 mg/kg have better efficacy and safety needs further investigation. Therefore, this study is to compare the efficacy and safety of each dose of tPA (0.6, 0.7, 0.8, and 0.9 mg/kg body weight) and to investigate the factors affecting early neurological improvement (ENI) and early neurological deterioration (END).\n\nMethods\nFor this observational study, data were obtained from 274 patients who received tPA thrombolytic therapy in Chia-Yi Christian Hospital stroke unit. The tPA dose was given at the discretion of each physician. The definition of ENI was a >8 point improvement (compared with baseline) at 24 h following thrombolytic therapy or an improvement in the National Institutes of Health Stroke Score (NIHSS) to 0 or 1 toward the end of tPA infusion. The definition of END was a >4 point increase in NIHSS (compared with baseline) within 24 h of tPA infusion. The primary objective was to investigate whether 0.7 and 0.8 mg/kg of tPA have higher ENI rate, lower END rate, and better outcome at 6 months. Poor outcome was defined as having a modified Rankin Scale of 3 to 6 (range, 0 [no symptoms] to 6 [death]). The secondary objective was to investigate whether low-dose tPA has a lower risk of intracerebral HT than that with standard-dose tPA. We also investigated the factors affecting ENI, END, HT, and 6-month outcome.\n\nResults\nA total of 274 patients were included during the study period, of whom 260 were followed up for >6 months. There was a trend for the HT rate to increase as the dose increased (P=0.02). The symptomatic HT rate was not significantly different among the low-dose and standard-dose groups. The ENI and END (P=0.52) were not significantly different among the four dosage groups. The clinical functional outcome at 6 months after stroke onset was poorer in the standard-dose group (P=0.02). Stroke severity (P<0.01), stroke type (P=0.03), and diabetes mellitus (P=0.04) affected the functional outcome at 6 months.\n\nConclusion\nAmong the 274 patients receiving tPA thrombolytic therapy, the HT rate increased as dose increased. The symptomatic HT, ENI and END rates were not significantly different among the low-dose (0.6, 0.7, and 0.8 mg/kg) and standard-dose groups. Stroke severity (NIHSS >12), stroke type (cardioembolism and large artery atherosclerosis) and diabetes mellitus were associated with poor outcome at 6 months.\n\nKeywords\nstrokethrombolytic therapyoutcomeneurological deteriorationtissue plasminogen activatorthrombolysis\n==== Body\nIntroduction\nIntravenous tissue plasminogen activator (tPA) was approved for the treatment of patients with acute ischemic stroke within 3 h of onset by the US Food and Drug Administration in 1996 and is still a standard treatment for patients with ischemic stroke.1–3 Recently, the extended time window of thrombolysis to 4.5 h has been widely accepted in clinical practice.4,5 Because of a higher symptomatic hemorrhagic transformation (sHT) rate in patients who received thrombolytic therapy,1,6,7 a lower dose of tPA for ischemic stroke patients was suggested.8 Based on the J-ACT study that reported that IV low-dose recombinant tPA (0.6 mg/kg) could offer both clinical efficacy and safety as a standard dose,9 the Japanese drug safety authority has approved the use of tPA 0.6 mg/kg for patients with ischemic stroke. Some studies have investigated the use of low dose (IV recombinant tPA 0.6 mg/kg) for patients with ischemic stroke within 4.5 h of stroke onset and found the low dose to be as effective as the standard dose.10 Other studies found the standard dose to be better than the low dose in terms of functional outcome, and there was no difference in the hemorrhage rate.3,11 A study in Taiwan found that in comparison with the standard dose, patients who were treated with a low dose (0.55–0.84 mg/kg) had a lower hemorrhagic rate, lower mortality, and better functional outcome, especially in patients older than 70 years.7 In contrast to the study by Chao et al, a study in China found that in comparison with different low-dose tPA regimens, the standard dose had a better functional outcome, and the hemorrhagic rate was not different.3 An international study (the ENCHANTED study) showed that the sHT rate was significantly lower in patients treated with low-dose tPA, and both the mortality rate and functional outcome at 90 days were not significantly different between the low-dose and standard-dose groups.12 Because the results regarding the efficacy and safety of low-dose tPA are inconsistent, a well-controlled study about the efficacy and dose of tPA is necessary. The early neurological improvement (ENI) rate is believed to be related to the restoration of blood flow in the occluded artery.13,14 As the thrombolytic effect of tPA lasts for only 3.5 h,15 the response to thrombolysis is best evaluated after the first 24 h. Whether the doses 0.7 and 0.8 mg/kg have better efficacy and safety needs further investigation. Therefore, we performed a single-center study in the Chia-Yi Christian Hospital stroke unit. The primary objective was to investigate ENI, early neurological deterioration (END), and clinical outcome at both discharge and 6 months in patients administered each dose of tPA. The secondary objective was to investigate the relationship between the risk of intracerebral hemorrhagic transformation (HT) and dose of tPA infusion. We also investigated the factors affecting ENI, END, HT, and 6-month outcome.\n\nMethods\nIn this retrospective observational study, all data were drawn from the stroke registry database of a teaching hospital in central Taiwan. We have been regularly using tPA for patients with acute stroke who are eligible for thrombolytic therapy since January 2007. According to the stroke management guidelines in Taiwan, tPA ≤0.9 mg/kg appears to be appropriate for ischemic stroke patients, and patients aged >80 years should not be given thrombolytic therapy.16 A neurologist was consulted when patients presented to the emergency department with acute ischemic stroke within 3 h of stroke onset without contraindications to thrombolytic therapy. On the basis of the aforementioned guidelines, all the patients in whom thrombolytic therapy was feasible were allocated to receive one of the doses (0.6 to 0.9 mg/kg) at the discretion of each physician. Factors that may influence both tPA dose and treatment regimen were as follows: 1) Doctor experience: if the doctor had repeated experiences of patients having (sHT) or dying after being given standard-dose tPA, the physician may decide to use low dose. 2) Patient’s condition: if a doctor thinks that the patient had a higher risk of HT, the physician may choose low-dose tPA. In patients aged >80 years without other contraindications who arrived within 3 h of stroke onset and requested thrombolytic treatment, tPA was given as well. Data from all the patients with stroke who received IV tPA treatment between January 2007 and December 2015 were included in the study. When the dosage of tPA was determined, IV 10% of the total dose was administered as a bolus, and the remainder as a continuous IV infusion for >1 h. Brain computed tomography (CT) was performed for every patient before IV tPA. Patients were followed up with CT or magnetic resonance imaging (MRI) for 24 h following tPA infusion. The National Institutes of Health Stroke Score (NIHSS) was used to assess stroke severity. An NIHSS-certified stroke team member at our facility performed the scoring and evaluation after every 6 h for the first 24 h and at discharge. No response was defined as an increase in NIHSS ≤4 or a decrease in NIHSS ≤8. An ENI was defined as an >8-point improvement (compared with baseline) after 24 h following thrombolytic therapy or an improvement in NIHSS to 0 or 1 toward the end of tPA infusion. Neurological improvement (NI) was defined as an >8-point improvement (compared with baseline) or an improvement in NIHSS to 0 or 1 at discharge. Neurological deterioration (ND) was defined as a >4-point increase in NIHSS (compared with baseline) at discharge. END was defined as a >4-point increase in NIHSS (compared with baseline) within 24 h of tPA infusion. All brain CT and MRI scans were evaluated by an independent radiologist who was blind to the dose of tPA. HT was defined as any sign of hemorrhage on the follow-up CT or MRI scans. The subtype of HT were HI1 (small petechiae), HI2 (more confluent petechiae), PH1 (≤30% of the infarcted area with mild space-occupying effect), PH2 (>30% of the infarcted area with significant space-occupying effect) (Figure 1).17 sHT was defined as blood clots in the brain observed during follow-up CT or MRI, with an increase in NIHSS by ≥4 points.18 The modified Rankin Scale (mRS) was used to evaluate stroke severity and functional outcomes. Good and poor outcomes were defined as mRS ≤2 and mRS >2, respectively. This study was approved by the Ethics Committee of the Chia-Yi Christian Hospital (CYCH-IRB: 096022) and written informed consent was obtained from each patient or the legal representative.\n\nStatistical analysis\nStatistical significance of the differences between age groups was analyzed using the chi-square or Fisher’s exact test for categorical variables and analysis of variance for continuous variables including blood pressure, and time from stroke onset to tPA infusion (tPA time); and Kruskal–Wallis test for NIHSS. Multiple logistic regression analysis was used to identify risk factors for HT, ENI, and clinical outcome. A P-value <0.05 was considered to indicate statistical significance. The analyses were performed using SPSS software, version 21.0 of the SPSS system for Windows (Version 21.0; IBM Corporation, Somers, NY, USA).\n\nResults\nFrom January 2007 to December 2015, a total of 274 patients received IV tPA for acute ischemic stroke within 3 h of stroke onset in our hospital. Being a single-center study with a relatively small number of patients receiving thrombolysis, the dose of tPA was given at the discretion of the attending physician. Of the 274 patients included in the current study, there were 71 patients in the 0.6 mg/kg group, 59 in the 0.7 mg/kg group, 88 in the 0.8 mg/kg group, and 56 in the 0.9 mg/kg group. A bolus of 10% of the total tPA dose was given for 1–2 min, and the remaining dose was given within 60 min. The baseline characteristics of the patients, including sex, hypertension, atrial fibrillation, heart disease, smoking, lipidemia, stroke severity, time of tPA infusion, blood pressure, and stroke subtype, were not significantly different among the four groups except for age (Table 1). Age was slightly higher in patients who received 0.6 mg/kg. Of the 274 patients, 260 were followed up for more than 6 months, and 14 lost to follow-up. There were 63 patients in the 0.6 mg/kg group, 57 in the 0.7 mg/kg group, 85 in the 0.8 mg/kg group, and 55 in the 0.9 mg/kg group. In the 24 h after thrombolytic therapy, ENI was found in 31% (22/71) of patients who received 0.6 mg/kg, 35.6% (21/59) in the 0.7 mg/kg group, 36.4% (32/88) in the 0.8 mg/kg group, and 25.0% (14/56) in the 0.9 mg/kg group. No response rates were 64.8% (46/71) in the 0.6 mg/kg group, 55.9% (33/59) in the 0.7 mg/kg group, 56.8% (50/88) in the 0.8 mg/kg group, and 62.5% (35/56) in the 0.9 mg/kg group. The END rates were 4.2% (3/71) in the 0.6 mg/kg group, 8.5% (5/59) in the 0.7 mg/kg group, 6.8% (6/88) in the 0.8 mg/kg group, and 12.5% (7/56) in the 0.9 mg/kg group. In the 24 h after thrombolysis, both the ENI and ND rates were not significantly different between the groups (P=0.52). The HT rate was highest in the 0.9 mg/kg group at 21.4% (12/56) followed by 5.6% (4/71) in the 0.6 mg/kg group, 8.5% (5/59) in the 0.7 mg/kg group and 9.1% (8/88) in the 0.8 mg/kg group (Table 2). In comparison with the 0.6 mg/kg group, the odds ratios of HT were 1.55 in the 0.7 mg/kg group, 1.67 in 0.8 mg/kg group, and 3.59 in 0.9 mg/kg group (P=0.02). There was a tendency for the HT rate to increase as the dose increased (trend for the hemorrhage rate <0.01) (Figure 2). The tendency of HT also increased as stroke severity increased. In comparison with the NIHSS 6–12 group, the odds ratios of hemorrhage were 1.90 in the NIHSS 13–20 group and 4.39 in the NIHSS 21–26 group (P<0.01). The factors associated with HT were stroke severity and tPA dose (0.9 mg/kg) (Table 3). The HT rates were 22.0% (18/82) in cardioembolism, 5.0% (4/80) in large artery atherosclerosis, 0 in small vessel occlusion, and 9.8% (8/82) in patients with an undetermined cause. The subtypes of HT were HI1 in six, HI2 in eight, PH1 in nine and PH2 in six patients. In patients without HT, the ENI and END rates were not significantly different among the four groups. During patient discharge following stroke treatment, functional outcome was not significantly different among the four groups. There were 33.8% (24/71) of patients in the 0.6 mg/kg group, 40.7% (24/59), in the 0.7 mg/kg group, 48.9% (43/88) in the 0.8 mg/kg group, and 30.3% (17/56) in the 0.9 mg/kg group (P=0.08) with good functional outcome (Figure 3). At 6 months after stroke onset, diabetes mellitus, stroke severity (NIHSS >12), and stroke type (cardioembolism and large artery atherosclerosis) were associated with poor outcome. Functional outcome was poorer in patients receiving the standard dose (0.9 mg/kg). In comparison with the 0.6 mg/kg group, the odds ratios of poor outcome were 1.67 in the 0.7 mg/kg group, 2.07 in the 0.8 mg/kg group, and 2.97 in the 0.9 mg/kg group (P=0.02) (Table 4). Good functional outcome was observed in 50.8% (32/63) of the patients in the 0.6 mg/kg group, 56.1% (32/57) in the 0.7 mg/kg group, 64.7% (55/85) in the 0.8 mg/kg group, and 38.2% (21/55) in the 0.9 mg/kg group (Figure 4). In comparison with the patients in the NIHSS 6–12 group, the odds ratios of poor outcome at 6 months were 3.7 (P<0.01) in the NIHSS 13–20 group and 7.8 (P<0.01) in the NIHSS 20–26 group.\n\nDiscussion\nOur study has three important findings regarding the dosage of tPA infusion. First, the ENI and END rates were not significantly different among the four groups. Second, the HT rate increased as the tPA dose increased. Third, the functional outcome at 6 months after stroke onset was associated with stroke severity, stroke type, and diabetes mellitus. In the current study, the total HT rate was 10.6% (29/274), which is compatible with those of previous studies6,19 that reported HT rates were between 9.1% and 10.6%. However, in our patients who received 0.9 mg/kg tPA, the HT rate was 21.4% (12/56), which is twice that of previous studies. In our study, the HT rate in patients in the lower-dose group was between 5.6% and 9.1%. Although this HT rate is lower than the rate reported in Japan, it is similar to the studies performed in Western countries with IV tPA 0.9 mg/kg in patients with ischemic stroke.20 Their HT rate was between 23.2% and 25.7%.8,10 Our study confirmed the findings of Mehta et al, who found that in comparison with Caucasian patients, the HT rate was higher in African-American and Asian patients.19 Our results show that the HT rate increased rapidly in patients who received 0.9 mg/kg IV tPA (Figure 2). Whether these results imply that 0.9 mg/kg is not the best choice of tPA for Taiwanese people is an unresolved issue that requires further investigation. This result is compatible with those of previous studies.3,21 Our results are also compatible with the results of the ENCHANTED study with respect to both HT rate and long-term outcome. The ENCHANTED study showed that the fatality rate and disability rate at 90 days was not significantly different between the low-dose and the standard-dose groups. That study also showed the sHT rate was significantly lower in the low-dose group than in the standard-dose group.12 Our result showed the sHT rate was not different between the low-dose and standard-dose groups and the clinical outcome at 6 months was poorer in the 0.9 mg/kg group. This difference may be related to the international level enrollment of the ENCHANTED study, which included 63% of Asians and 37% of non-Asians, whereas our study had a relatively small patient number. However, the results of our study showed a trend toward increase in the hemorrhage risk as the dose increased. The ENI rate is considered to be related to re-canalization of the occluded artery.13,14 The ENI rates were 32.5% (89/274) of the total 274 patients, 31.0% in the 0.6 mg/kg group, 35.6% in the 0.7 mg/kg group, 36.4% in the 0.8 mg/kg group, and 25% (14/56) in patients who received 0.9 mg/kg tPA. Our study showed a higher ENI rate than that reported by Felberg et al (22%).14 However, this difference may be because Felberg et al study included only patients with middle cerebral artery occlusion. In our study, the ENI rate was not significantly different among the four groups. Even if we exclude the impact of HT, the ENI rate was slightly lower in the 0.9 mg/kg group. The cause of the lower ENI rate in the standard-dose group may be related to lower rates of large artery occlusion and lower cardioembolic stroke in the lower-dose group, which lead to a lower blood clot burden in the lower-dose group. In this study, the rates of large artery occlusion and cardioembolic stroke were 52.1% (37/71) in the 0.6 mg/kg group, 61% (36/59) in the 0.7 mg/kg group, 51.1% (45/88) in the 0.8 mg/kg group, and 78.6% (44/56) in the 0.9 mg/kg groups. These results show that the ENI rate may be affected by multiple factors, and increasing the tPA dose does not increase the ENI rate. The study by Restrepo et al, found that hypercholesterolemia decreases the likelihood of NI in patients after intra-arterial fibrinolysis and percutaneous mechanical embolectomy.22 Their study also found that statin therapy could improve outcome. This result highlights the importance of the treatment of hyperlipidemia. Some studies found low total cholesterol and low-density lipoprotein cholesterol levels to be associated with high sHT rates.23 Our results did not find an association of hyperlipidemia with either ENI or HT rate. This difference may be related to the types of patients evaluated in the study of Restrepo et al, that included only patients who received intra-arterial fibrinolysis and percutaneous mechanical embolectomy. It is reasonable to expect that a higher bolus dose may increase the ENI rate. In the ENCHANTED study, the patients received 10% of total dose (tPA) in the 0.9 mg/kg group and 15% of total dose in the 0.6 mg/kg group as a bolus dose.13 In contrast to the ENCHANTED study, we used 10% of the total dose as the bolus dose. Our results showed that the ENI rate was not significantly different among the four dose groups. Functional outcome was not significantly different at discharge, but functional outcome at 6 months after stroke onset was poorer in the 0.9 mg/kg group than in the 0.6 mg/kg group. After multiple variable analyses, diabetes mellitus, stroke severity (NIHSS >12), and stroke type (cardioembolism and large artery atherosclerosis) were associated with poor 6-month outcome. Our results echo the findings of Chao et al, who reported that lower doses of tPA had lower HT rates and better outcome.7 Previous studies that compared the functional outcome between the low dose and standard dose showed the standard dose to be better than the low dose or found no difference between the low and standard doses.10,12,21 In the present study, the ENI rate and NI rate increased as the dose increased from 0.6 to 0.8 mg/kg and declined at 0.9 mg/kg. The HT, END, and ND rates mildly increased at doses from 0.6 to 0.8 mg/kg and sharply increased at dose 0.9 mg/kg. These results suggest that 0.8 mg/kg is the optimal dose for Taiwanese patients. However, this hypothesis needs to be confirmed by further large-scale investigations. Our study has several limitations. First, the study was not a randomized study; the selection of tPA dose was decided by a neurologist, and the selection of a dose by a physician may be affected by the patient’s condition. The patients who may be considered at higher risk of HT may be given a lower dose. This may lead to an underestimation of the benefits of a lower dose. However, the condition of the patients in each of our groups did not significantly differ. Second, most of our patients who were older than 80 years received 0.6 mg/kg tPA. Third, this was a single-center study involving a relatively small number of patients; therefore, the present study could not offer definitive evidence of the usefulness of this thrombolytic therapy. Fourth, the bolus dose was different in each group, which may affect both the ENI and the HT rates.\n\nConclusion\nThe HT rate increased as the dose increased. The sHT, ENI and the END rates were not significantly different among the lower-dose and standard-dose groups. Diabetes mellitus, stroke severity (NIHSS >12) and stroke type (cardioembolism and large artery atherosclerosis) were associated with poor outcome at 6 months.\n\nAcknowledgments\nWe thank Enago for their contribution to English editing.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Subtype of hemorrhagic transformation HI1 (top left), HI2 (top right), PH1: (bottom left), PH2: (bottom right).\n\nAbbreviations: HI1, small petechiae subtype; HI2, more confluent petechiae subtype; PH1, ≤30% of the infarcted area with mild space-occupying effect; PH2, >30% of the infarcted area with significant space-occupying effect.\n\nFigure 2 Hemorrhagic transformation rate at each dosage of tPA (P=0.02).\n\nNote: tPA dose indicates the intravenous dose the patient received at mg/kg of body weight.\n\nAbbreviations: CI, confidence interval; OR, odds ratio; tPA, tissue plasminogen activator.\n\nFigure 3 Functional outcomes at discharge according to mRS score.\n\nNotes: The figure shows the distribution of scores on the mRS at discharge. Scores on the mRS range from 0 to 6, with 0 indicating no symptoms, 1 – without clinical disability, 2 – mild disability, 3 – moderate disability, 4 – moderately severe disability, 5 – severe disability, and 6 – death.\n\nAbbreviation: mRS, modified Rankin Scale.\n\nFigure 4 Functional outcomes 6 months after stroke, according to modified Rankin Scale score.\n\nNotes: The figure shows the distribution of scores on the modified Rankin Scale at 6 months after stroke. Scores on the modified Rankin Scale range from 0 to 6, with 0 indicating no symptoms, 1 – without clinical disability, 2 – mild disability, 3 – moderate disability, 4 – moderately severe disability, 5 – severe disability, and 6 – death.\n\nAbbreviation: mRS, modified Rankin Scale.\n\nTable 1 Characteristics of patients at baseline\n\nVariables\ttPA\n\tP-value\t\n0.6 mg (N=71)\t0.7 mg (N=59)\t0.8 mg (N=88)\t0.9 mg (N=56)\t\nSex (M), n\t31\t38\t55\t34\t0.05a\t\nAge (years), mean ± SD\t71.8±10.6\t65.3±13.5\t62.2±12.9\t66.5±11.6\t0.01b\t\nHTN, n\t57\t43\t67\t43\t0.70a\t\nDM, n\t30\t18\t21\t24\t0.57a\t\nAF, n\t27\t17\t25\t22\t0.92a\t\nHeart disease, n\t38\t21\t38\t28\t0.88a\t\nSmoking, n\t24\t29\t41\t24\t0.29a\t\nLipidemia, n\t42\t29\t51\t30\t0.77a\t\nNIHSS, mean ± SD\t14.9±7.2\t13.8±5.7\t13.1±5.9\t14.9±6.3\t0.24c\t\ntPA time (min), mean ± SD\t111.7±37.0\t120.1±36.7\t113.6±44.2\t122.1±45.5\t0.41b\t\nBlood pressure\t\nSystolic mmHg, mean ± SD\t159.9±28.8\t160.7±28.9\t154.3±29.5\t155.8±27.8\t0.46b\t\nDiastolic mmHg, mean ± SD\t90.1±17.6\t90.5±17.4\t90.4±17.8\t92.9±16.3\t0.80b\t\nStroke type\t\nLarge artery, n (%)\t20 (28.2)\t18 (30.5)\t21 (23.9)\t21 (37.5)\t0.03a\t\nSmall vessel < n (%)\t5 (7.0)\t7 (11.9)\t15 (17.0)\t3 (5.4)\t\t\nCardioembolism, n (%)\t17 (23.9)\t18 (30.5)\t24 (27.3)\t23 (41.0)\t\t\nUndetermined, n (%)\t29 (40.9)\t16 (27.1)\t28 (31.8)\t9 (16.1)\t\t\nLOS (days), mean ± SD (95% CI)\t10.4±8.8 (9.5–13)\t9.3±7.3 (6.8–10.5)\t10.2±8.4 (8.3–11.9)\t13.5±10.9 (10.6–11.6)\t0.06c\t\nNotes:\n\na Chi-square test;\n\nb ANOVA test;\n\nc Kruskal–Wallis test.\n\nAbbreviations: AF, atrial fibrillation; ANOVA, analysis of variance; CI, confidence interval; DM, diabetes mellitus; HTN, hypertension; LOS, length of stay; NIHSS, National Institutes of Health Stroke Score; SD, standard deviation; tPA, tissue plasminogen activator.\n\nTable 2 Primary and secondary outcomes at 24 h and discharge\n\nVariables\ttPA\n\tP-value (χ2)\t\n0.6 mg/kg (N=71)\t0.7 mg/kg (N=59)\t0.8 mg/kg (N=88)\t0.9 mg/kg (N=56)\t\nResponse at 24 h\t\nNo\t46 (64.8)\t33 (55.9)\t50 (56.8)\t35 (62.5)\t0.52\t\nENI\t22 (31.0)\t21 (35.6)\t32 (36.4)\t14 (25)\t\t\nEND\t3 (4.2)\t5 (8.5)\t6 (6.8)\t7 (12.5)\t\t\nResponse at discharge\t\nNo\t30 (42.3)\t26 (44.1)\t31 (35.1)\t23 (41.1)\t0.51\t\nNI\t34 (47.9)\t26 (44.1)\t49 (55.7)\t23 (41.1)\t\t\nND\t7 (9.9)\t7 (11.8)\t8 (9.1)\t10 (17.8)\t\t\nHemorrhagic\t4 (5.6)\t5 (8.5)\t8 (9.1)\t12 (21.4)\t0.02 (trend <0.01)\t\nSICH\t1 (1.4)\t5 (8.5)\t1 (1.1)\t3 (5.4)\t0.07\t\nGood outcome\t24 (33.8)\t24 (40.7)\t43 (48.9)\t17 (30.3)\t0.08\t\n6 m good outcome#\t32/63 (50.8)\t32/57 (56.1)\t55/85 (64.7)\t21/55 (38.2)\t0.02\t\nNotes: Data shown as n (%).\n\n# Modified ranking scale ≤2 at 6 months.\n\nAbbreviations: END, early neurological deterioration; ENI, early neurological improvement; ND, neurological deterioration; NI, neurological improvement; No, no neurological improvement and no neurological deterioration; SICH, symptomatic hemorrhagic transformation.\n\nTable 3 Factors affect hemorrhagic transformation\n\nVariables\tPatients (N=274)\tOR (95% CI)a\tP-valuea\tOR (95% CI)b\tP-valueb\t\nSex (F)\t15/116 (9.3%)\t1.41 (0.66–3.02)\t0.37\t1.38 (0.43–4.44)\t0.58\t\nDose\t\n0.6 mg/kg\t5/71 (7.0%)\t1\t\t1\t\t\n0.7 mg/kg\t5/59 (8.5%)\t2.73 (0.96–9.00)\t0.06\t2.65 (0.90–7.78)\t0.07\t\n0.8 mg/kg\t8/88 (9.1%)\t2.95 (1.04–7.18)\t0.04\t3.21 (0.94–10.9)\t0.06\t\n0.9 mg/kg\t12/56 (21.4%)\t3.60 (1.19–10.9)\t0.02\t3.78 (1.12–12.7)\t0.03\t\nAtrial fibrillation\t14/91 (15.4%)\t1.90 (0.88–4.08)\t0.10\t3.58 (0.09–1.04)\t0.05\t\nDiabetes mellitus\t8/93 (8.6%)\t0.68 (0.29–1.59)\t0.38\t0.90 (0.33–2.40)\t0.83\t\nHypertension\t25/210 (11.9%)\t1.60 (0.58–4.35)\t0.36\t1.36 (0.43–4.28)\t0.59\t\nStroke severity\t\nNIHSS 6–12\t8/130 (6.2%)\t1\t\t1\t\t\nNIHSS 13–20\t12/94 (12.8%)\t1.71 (0.68–4.29)\t0.25\t1.77 (0.60–5.15)\t0.29\t\nNIHSS 21–26\t10/50 (20.0%)\t3.81 (1.41–10.3)\t0.008\t2.64 (0.84–8.21)\t0.09\t\nSmoking\t11/118 (9.3%)\t0.93 (0.57–1.52)\t0.77\t1.01 (0.30–3.38)\t0.98\t\nAlcohol\t1/28 (3.6%)\t0.78 (0.35–1.76)\t0.55\t0.40 (0.04–3.63)\t0.41\t\nHyperlipidemia\t13/152 (8.6%)\t1.24 (0.76–2.03)\t0.3\t0.58 (0.24–1.37)\t0.21\t\nStroke type\t\nCardioembolism\t18/82 (22.0%)\t1\t\t1\t\t\nLAA\t4/80 (5.0%)\t0.38 (0.16–0.94)\t0.04\t0.25 (0.07–0.92)\t0.04\t\nSMO\t0/30\tNA\tNA\t\tNA\t\nUN\t8/82 (9.8%)\t2.05 (0.59–7.11)\t0.25\t2.75 (0.73–10.39)\t0.13\t\nAge (years)\t\n≤50\t1/32\t1\t\t1\t\t\n51–70\t13/119\t1.22 (0.56–2.66)\t0.62\t0.85 (0.34–2.12)\t0.72\t\n>70\t16/123\t4.64 (0.59–36.4)\t0.14\t2.18 (0.24–198)\t0.48\t\nNotes:\n\na Multiple logistic regression (univariate analysis);\n\nb multiple logistic regression adjusted for age, sex, dose, atrial fibrillation, diabetes mellitus, hypertension, stroke severity, smoking, alcohol, hyperlipidemia, and stroke type.\n\nAbbreviations: CI, confidence interval; LAA, large artery atherosclerosis; NA, not available; NIHSS, National Institutes of Health Stroke Score; OR, odds ratio; SMO, small vessel occlusion; UN, undetermined.\n\nTable 4 Prognostic factors for unfavorable outcome at 6 months\n\nVariables\tPatients (N=260)\tOR (95% CI)a\tP-valuea\tOR (95% CI)b\tP-valueb\t\nSex (F)\t56/110 (50.9%)\t1.39 (0.85–2.29)\t0.19\t1.80 (0.78–3.83)\t0.18\t\nDose\t\n0.6 mg/kg\t31/63 (49.2%)\t1\t\t1\t\t\n0.7 mg/kg\t25/57 (43.9%)\t1.67 (0.80–3.49)\t0.17\t1.50 (0.72–4.18)\t0.22\t\n0.8 mg/kg\t30/85 (35.3%)\t2.07 (0.97–4.41)\t0.58\t1.68 (0.74–4.39)\t0.19\t\n0.9 mg/kg\t34/55 (61.8%)\t2.97 (1.47–5.99)\t0.02\t3.55 (0.97–5.15)\t0.06\t\nAtrial fibrillation\t43/86 (50.0%)\t1.26 (0.75–2.11)\t0.38\t0.77 (0.28–1.61)\t0.38\t\nDiabetes mellitus\t49/86 (57.0)\t1.92 (1.14–3.24)\t0.14\t1.97 (1.02–3.80)\t0.04\t\nHypertension\t103/201 (51.2%)\t2.60 (1.37–4.86)\t0.003\t2.14 (0.98–4.67)\t0.06\t\nStroke severity\t\nNIHSS 6–12\t34/125 (27.2%)\t1\t\t1\t\t\nNIHSS 13–20\t51/88 (58.0)\t2.12 (0.97–4.62)\t0.06\t1.49 (0.72–4.14)\t0.22\t\nNIHSS 21–26\t35/47 (74.5%)\t7.81 (3.63–16.8)\t<0.01\t18.9 (2.96–17.50)\t<0.01\t\nSmoking\t51/113 (45.1%)\t\t\t0.12 (0.53–2.47)\t0.72\t\nAlcohol\t11/27 (40.7%)\t0.78 (0.35–1.79)\t0.552\t0.50 (0.50–4.32)\t0.47\t\nHyperlipidemia\t69/142 (48.6%)\t1.24 (0.76–2.03)\t0.39\t0.38 (0.66–2.18)\t0.53\t\nStroke type\t\nCardioembolism\t40/79 (50.6%)\t1\t\t1\t\t\nLAA\t45/73 (61.6%)\t0.68 (0.36–1.28)\t0.2\t0. 78 (0.30–1.97)\t0.60\t\nSMO\t3/30 (10%)\t0.43 (0.23–0.83)\t0.01\t0.42 (0.19–0.91)\t0.03\t\nUN\t32/78 (41.0%)\t6.26 (1.75–22.4)\t0.005\t3.16 (0.79–12.5)\t0.10\t\nAge (years)\t\n≤50\t7/30 (23.3%)\t1\t\t1\t\t\n51–70\t50/114 (43.9%)\t1.52 (0.91–2.56)\t0.11\t0.97 (0.72–2.63)\t0.32\t\n>70\t63/116 (54.3%)\t3.91 (1.55–9.82)\t0.004\t3.06 (0.88–8.68)\t0.08\t\nNotes:\n\na Multiple logistic regression (univariate analysis);\n\nb multiple logistic regression adjusted for age, sex, dose, atrial fibrillation, diabetes mellitus, hypertension, stroke severity, smoking, alcohol, hyperlipidemia, and stroke type.\n\nAbbreviations: CI, confidence interval; LAA, large artery atherosclerosis; NA, not available; NIHSS, National Institutes of Health Stroke Score; OR, odds ratio; SMO, small vessel occlusion; UN, undetermined.\n==== Refs\nReferences\n1 Mazya MV Lees KR Collas D IV thrombolysis in very severe and severe ischemic stroke: results from the SITS-ISTR Registry Neurology 2015 85 24 2098 2106 26546630 \n2 Ong CT Sung SF Wu CS Early neurological improvement after intravenous tissue plasminogen activator infusion in patients with ischemic stroke aged 80 years or older J Chin Med Assoc 2014 77 4 179 183 24657175 \n3 Liao X Wang Y Pan Y Standard-dose intravenous tissue-type plasminogen activator for stroke is better than low doses Stroke 2014 45 8 2354 2358 25013020 \n4 Hacke W Kaste M Bluhmki E ECASS Investigators Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke N Engl J Med 2008 359 13 1317 1329 18815396 \n5 Asplund K Glader EL Norrving B Eriksson M Riks-Stroke Collaboration Effects of extending the time window of thrombolysis to 4.5 hours observations in the Swedish stroke register (riks-stroke) Stroke 2011 42 9 2492 2497 21799155 \n6 Rao NM Levine SR Gornbein JA Saver JL Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: analysis of the National Institute of Neurological Disorders and Stroke tissue-type plasminogen activator trials Stroke 2014 45 9 2728 2733 25096731 \n7 Chao AC Hsu HY Chung CP Outcomes of thrombolytic therapy for acute ischemic stroke in Chinese patients: the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) Study Stroke 2010 41 5 885 890 20224056 \n8 Miyagi T Koga M Shiokawa Y Intravenous alteplase at 0.6 mg/kg for acute stroke patients with basilar artery occlusion: the stroke acute management with urgent risk factor assessment and improvement (SAMURAI) Recombinant tissue plasminogen activator registry J Stroke and Cerebrovasc Dis 2013 22 7 1098 1106 23063059 \n9 Yamaguchi T Mori E Minematsu K Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT) Stroke 2006 37 7 1810 1815 16763187 \n10 Takayanagi S Ochi T Hanakita S Suzuki Y Maeda K The safety and effectiveness of low-dose recombinant tissue plasminogen activator (0.6 mg/kg) therapy for elderly acute ischemic stroke patients (≥80 years old) in the pre-endovascular era Neurol Med Chir (Tokyo) 2014 54 6 435 440 24670312 \n11 Dharmasaroja PA Pattaraarchachai J Low versus standard dose of recombinant tissue plasminogen activator in treating East Asian patients with acute ischemic stroke Neurol India 2011 59 2 180 184 21483113 \n12 Anderson CS Robinson T Lindley RI ENCHANTED Investigators and Coordinators Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke N Engl J Med 2016 374 24 2313 2323 27161018 \n13 Alexandrov AV Demchuk AM Felberg RA High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2-MHz transcranial doppler monitoring Stroke 2000 31 3 610 614 10700493 \n14 Felberg RA Okon NJ El-Mitwalli A Burgin WS Grotta JC Alexandrov AV Early dramatic recovery during intravenous tissue plasminogen activator infusion: clinical pattern and outcome in acute middle cerebral artery stroke Stroke 2002 33 5 1301 3107 11988607 \n15 Merino JG Latour LL An L Hsia AW Kang DW Warach S Reperfusion half-life: a novel pharmacodynamic measure of thrombolytic activity Stroke 2008 39 7 2148 2150 18451344 \n16 Chang YJ Ryu SJ Chen JR Hu HH Yip PK Chiu TF Consensus Group of Taiwan Stroke Society Guidelines for the general management of patients with acute ischemic stroke Acta Neurol Taiwan 2008 17 4 275 294 Chinese 19280874 \n17 Fiorelli M Bastianello S von Kummer R Hemorrhagic transformation within 36 hours of cerebral infarct Relationship with early clinical deterioration and 3-month outcome in the European cooperative acute stroke study I (ECASS I) cohort Stroke 1999 30 11 2280 2284 10548658 \n18 Hacke W Kaste M Fieschi C Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators Lancet 1998 352 9136 1245 1251 9788453 \n19 Mehta RH Cox M Smith EE Get With The Guidelines-Stroke Program Race/Ethnic differences in the risk of hemorrhagic complications among patients with ischemic stroke receiving thrombolytic therapy Stroke 2014 45 8 2263 2269 25070958 \n20 Demchuk AM Morgenstern LB Krieger DW Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke Stroke 1999 30 34 39 9880385 \n21 Kim BJ Han MK Park TH Low-versus standard-dose alteplase for ischemic strokes within 4.5 hours: a comparative effectiveness and safety study Stroke 2015 46 9 2541 2548 26243232 \n22 Restrepo L Bang OY Ovbiagele B Impact of hyperlipidemia and statins on ischemic stroke outcomes after intra-arterial fibrinolysis and percutaneous mechanical embolectomy Cerebrovasc Dis 2009 28 4 384 390 19713698 \n23 Bang OY Saver JL Liebeskind DS Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis Neurology 2007 68 10 737 742 17182976\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-8881",
"issue": "11()",
"journal": "Drug design, development and therapy",
"keywords": "neurological deterioration; outcome; stroke; thrombolysis; thrombolytic therapy; tissue plasminogen activator",
"medline_ta": "Drug Des Devel Ther",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015897:Comorbidity; D003920:Diabetes Mellitus; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D020300:Intracranial Hemorrhages; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D020127:Recovery of Function; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D020521:Stroke; D013624:Taiwan; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101475745",
"other_id": null,
"pages": "1559-1566",
"pmc": null,
"pmid": "28572721",
"pubdate": "2017",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": "24657175;17182976;18451344;9788453;25070958;26546630;25013020;19713698;18815396;26243232;21799155;27161018;19280874;23063059;9880385;16763187;10548658;21483113;20224056;24670312;25096731;10700493;11988607",
"title": "Outcome of stroke patients receiving different doses of recombinant tissue plasminogen activator.",
"title_normalized": "outcome of stroke patients receiving different doses of recombinant tissue plasminogen activator"
} | [
{
"companynumb": "TW-ROCHE-1955437",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nIfosfamide (IFX), an alkylating agent and isomer of cyclophosphamide, is used as a single agent or a component of multi-agent chemotherapy in the treatment of ovarian, testicular, head and neck cancers, sarcomas and lymphomas. Encephalopathy is manifested by cerebellar ataxia, confusional state, complex visual hallucinations, extrapyramidal signs, seizures, and mutism.\n\n\nMETHODS\nWe report two patients with non-Hodgkin's lymphoma presenting with mutism and confusional state after IFX infusion. Nonconvulsive status epilepticus (NCSE) as the cause of confusion was diagnosed on the basis of EEG pattern and the apparent improvement following intravenous administration of diazepam.\n\n\nCONCLUSIONS\nElectroencephalogram abnormalities during IFX treatment have been described but recordings are only available in six cases. In three of them, paroxysmal alterations warranted the diagnosis of NCSE; however, most cases of IFX encephalopathy might have associated NCSE.",
"affiliations": "Department of Neurological Sciences and Vision, University of Genova, Italy.",
"authors": "Primavera|Alberto|A|;Audenino|Daniela|D|;Cocito|Leonardo|L|",
"chemical_list": "D000927:Anticonvulsants; D018906:Antineoplastic Agents, Alkylating; D003975:Diazepam; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0317-1671",
"issue": "29(2)",
"journal": "The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques",
"keywords": null,
"medline_ta": "Can J Neurol Sci",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D018906:Antineoplastic Agents, Alkylating; D003975:Diazepam; D004569:Electroencephalography; D004829:Epilepsy, Generalized; D005260:Female; D006801:Humans; D007069:Ifosfamide; D008228:Lymphoma, Non-Hodgkin; D008875:Middle Aged; D020258:Neurotoxicity Syndromes",
"nlm_unique_id": "0415227",
"other_id": null,
"pages": "180-3",
"pmc": null,
"pmid": "12035842",
"pubdate": "2002-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ifosfamide encephalopathy and nonconvulsive status epilepticus.",
"title_normalized": "ifosfamide encephalopathy and nonconvulsive status epilepticus"
} | [
{
"companynumb": "IT-PFIZER INC-2020308342",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nNivolumab is an immune checkpoint inhibitor specific for the programmed death 1 (PD-1) receptor that has led to clinical responses in many cancer types. Identifying biomarkers predictive of response to PD-1 blockade is an area of active investigation.\n\n\nMETHODS\nWe present a patient with recurrent, metastatic, PD-L1-negative small cell neuroendocrine carcinoma of the cervix (SCNEC) who experienced a complete response to nivolumab. Though nivolumab was discontinued over 4 months ago due to treatment-related adverse events, she continues to have no evidence of disease.\n\n\nCONCLUSIONS\nImmune checkpoint inhibitors may be active in neuroendocrine cervical cancer, with potential for dramatic responses in a modest subset of patients.",
"affiliations": "Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California Irvine Medical Center, 33 City Blvd. West #1400, Orange, CA 92868 USA.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California Irvine Medical Center, 33 City Blvd. West #1400, Orange, CA 92868 USA.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California Irvine Medical Center, 33 City Blvd. West #1400, Orange, CA 92868 USA.",
"authors": "Paraghamian|Sarah E|SE|;Longoria|Teresa C|TC|;Eskander|Ramez N|RN|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40661-017-0038-9",
"fulltext": "\n==== Front\nGynecol Oncol Res PractGynecol Oncol Res PractGynecologic Oncology Research and Practice2053-6844BioMed Central London 3810.1186/s40661-017-0038-9Case ReportMetastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report Paraghamian Sarah E. paraghas@uci.edu Longoria Teresa C. longoria@uci.edu Eskander Ramez N. eskander@uci.edu 0000 0004 0434 883Xgrid.417319.9Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California Irvine Medical Center, 33 City Blvd. West #1400, Orange, CA 92868 USA 2 2 2017 2 2 2017 2017 4 331 12 2016 21 1 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNivolumab is an immune checkpoint inhibitor specific for the programmed death 1 (PD-1) receptor that has led to clinical responses in many cancer types. Identifying biomarkers predictive of response to PD-1 blockade is an area of active investigation.\n\nCase presentation\nWe present a patient with recurrent, metastatic, PD-L1-negative small cell neuroendocrine carcinoma of the cervix (SCNEC) who experienced a complete response to nivolumab. Though nivolumab was discontinued over 4 months ago due to treatment-related adverse events, she continues to have no evidence of disease.\n\nConclusions\nImmune checkpoint inhibitors may be active in neuroendocrine cervical cancer, with potential for dramatic responses in a modest subset of patients.\n\nKeywords\nSmall cell neuroendocrine carcinomaCervical cancerPD-1 inhibitorNivolumabImmunotherapyT32CA06039611issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nSmall cell neuroendocrine carcinoma of the cervix (SCNEC) is a rare and aggressive histology. It accounts for less than 2% of cervical cancers [1]. Unlike squamous cell and adenocarcinoma, SCNEC is more likely to have lymphovascular space invasion and lymph node involvement at the time of diagnosis [1, 2]. Patients frequently present with locally advanced tumors or distant metastases, resulting in poor oncologic outcomes with a 5-year survival rate estimated at 36.8% for early stage disease and less than 10% for advanced disease [1, 2]. Given these poor outcomes, as well as a lack of prospective data to guide treatment decisions, patients with SCNEC pose a therapeutic challenge.\n\nSCNEC is morphologically similar to small cell lung cancer (SCLC) and treatment considerations draw on studies conducted in small cell lung cancer cohorts. For early stage disease, multimodal therapy with surgery followed by adjuvant cisplatin/etoposide with or without pelvic radiation is favored [1, 2]. More recently, results from the SCLC cohort of CheckMate 032 were published, describing durable responses in a pretreated patient population with single agent nivolumab or combination nivolumab and ipilimumab (Antonia, 2016 #2913) To date, there are no studies informing treatment of progressive or recurrent SCNEC after failure of platinum-based therapy [2]. There is an urgent, unmet clinical need to develop effective treatments.\n\nNivolumab is an immune checkpoint inhibitor that is specific for the programmed death 1 (PD-1) receptor. PD-1 can be expressed transiently or chronically on T cells depending on the duration of antigen exposure. The interaction of PD-1 with its ligand, PD-L1 or PD-L2, results in downstream signaling that inhibits T cell cytotoxicity and cytokine release. The rationale behind blockade of the PD-1 pathway is to abrogate an immunosuppressive mechanism present in the tumor microenvironment (TME). In this report, we present the clinical experience of a woman with recurrent, metastatic, SCNEC who had a complete response to treatment with nivolumab.\n\nCase presentation\nA 38-year-old nulligravida with no history of abnormal pap smears presented to her primary gynecologist with complaint of malodorous brown vaginal discharge. A pap smear was performed, which returned positive for adenocarcinoma and high-risk human papillomavirus (HPV). She was subsequently referred to gynecologic oncology and diagnosed with a Federation of Gynecology and Obstetrics (FIGO) stage IB2 cervical cancer. Biopsies revealed a high-grade small cell neuroendocrine carcinoma, and positron emission tomography–computed tomography (PET/CT) showed no evidence of metastatic disease. Plan was made for radical surgical excision followed by adjuvant chemotherapy and radiation.\n\nThe patient underwent radical abdominal hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Pathology was negative for involvement of the surgical margins, parametria or pelvic lymph nodes. The primary tumor was 4.5 by 3.3 cm in size and involved half of the cervical stroma, with lymphovascular space involvement. Her postoperative course was complicated by a pelvic abscess requiring re-exploration and washout. Following recovery, she was treated with 6 cycles of cisplatin 80 mg/m2 intravenously (IV) on day 1 and etoposide 100 mg/m2 IV on day 1, 2 and 3. Chemotherapy was well tolerated with only grade 1 nausea and fatigue.\n\nOne month after completion of chemotherapy, surveillance pelvic exam was significant for a 1.5-cm, firm, smooth anterior vaginal wall mass. PET/CT demonstrated interval development of multiple hypermetabolic mesenteric deposits, largest measuring 21 mm with a standard uptake value (SUV) of 10.6. Shortly thereafter, she was admitted for small bowel obstruction, with imaging revealing multifocal progression of the pelvic lesions (Fig. 1). Given disease distribution, systemic chemotherapy was favored over local radiotherapy, and she received 2 cycles of paclitaxel 135 mg/m2 IV on day 1 and topotecan 0.75 mg/m2 IV on day 1, 2 and 3. Following cycle 2 of therapy, the patient was admitted for progressive pelvic pain due disease progression resulting in obstructive uropathy (Fig. 1). While hospitalized, a right percutaneous nephrostomy tube was placed, and palliative pelvic radiation therapy was initiated. The patient ultimately received a total of 37.5 Gy in 15 fractions directed towards the obstructive lesion along the right pelvic side wall. The original tumor was sent for molecular testing to help inform future therapy and approval for the off-label use of nivolumab was requested from her insurance provider.Fig. 1 Progressive recurrent pelvic disease resulting in hydronephrosis\n\n\n\n\nNivolumab was initiated at a dose of 3 mg/kg IV every 2 weeks prior to molecular characterization of her tumor, which showed absent PD-L1 expression. After 2 doses, radiographic imaging demonstrated a decreased in size of all target lesions (Fig. 2). Concurrently, all cell counts began to decrease. After 4 doses, the patient reported vision changes and light sensitivity. She was evaluated by ophthalmology and diagnosed with severe dry eyes and pre-glaucoma. Despite standard topical therapies, her symptoms progressed and the decision was made to discontinue treatment for persistent grade 3 ocular toxicity after the 6th dose. PET/CT obtained 3 weeks after the final dose demonstrated complete resolution of all target and non-target lesions (Fig. 3). Cell counts nadired (grade 2 lymphocytopenia and thrombocytopenia, grade 3 anemia) 5 weeks after cessation of therapy and began to show significant recovery by week 7. Hematologic evaluation, inclusive of bone marrow biopsy, failed to identify an alternate source of her pancytopenia, which was attributed to nivolumab.Fig. 2 Reduction in lesion size after starting nivolumab\n\n\nFig. 3 Complete resolution of all lesions after 6th dose of nivolumab\n\n\n\n\nDiscussion\nWe present a patient with recurrent, metastatic, PD-L1-negative SCNEC who experienced a complete response to nivolumab therapy. Though nivolumab was discontinued over 4 months ago due to treatment-related adverse events, she continues to have no evidence of disease.\n\nFrom a therapeutics standpoint, orphan diseases such as SCNEC are traditionally unable to keep pace with more common malignancies. The low likelihood of achieving sufficient patient numbers for efficacy trials discourages scientific initiatives specifically designed for rare tumor types. The typical solution to this problem has been to extrapolate treatment strategies from more frequently encountered cancers of the same cell type, such as SCLC in the case of SCNEC. This practice assumes that cell origin or morphology is the key feature to predict response to treatment. The National Cancer Institute – Molecular Analysis for Therapy Choice (NCI-MATCH) trial is evidence that this thought process is changing. In this trial, treatment with various targeted therapies is directed by genetic testing. Patients with solid tumors or lymphomas that have progressed following at least one line of standard treatment (or for which no agreed upon treatment approach exists) are assigned to a treatment arm based on the DNA sequencing results of their tumor. This strategy recognizes the heterogeneity that exists not only between different types of cancer but also between cancers of the same type.\n\nIn the search for predictive biomarkers to immune checkpoint inhibitors, the prevalence of somatic mutations has been the most promising. From the outset, mutagen-induced malignancies, namely melanoma and lung cancer, have had the greatest success in clinical trials. These cancers approach or exceed 10 somatic mutations per megabase, constituting the highest mutation frequencies of all cancers [3]. It is hypothesized that the greater the number of somatic mutations, the greater the number of neoantigens and the more immunogenic the tumor. This principle was assessed by Le and colleagues in a phase II trial designed to evaluate the clinical activity of pembrolizumab in patients with progressive metastatic carcinoma with or without mismatch-repair deficiency, which is associated with a difference of 10–100 times the number of somatic mutations [4]. They found an immune-related objective response rate of 40% and immune-related, 20-week progression-free survival rate of 78% in patients with mismatch repair–deficient colorectal cancers, compared to 0 and 11%, respectively, in patients with mismatch repair–proficient colorectal cancers. Patients with mismatch repair–deficient non-colorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer.\n\nThe number of somatic mutations is unlikely to be the only determinant of tumor immunogenicity. Topalian and colleagues hypothesize that integrated oncogenic viruses are uniquely equipped to generate neoantigens that engage the immune system [5]. While point mutations or rearrangements of the tumor genome typically generate a single or limited number of T cell epitopes, the products of viral oncogenes are completely non-self and are likely to contain many more potential antigenic peptides for T cell recognition. Moreover, as drivers of tumorigenesis, products of viral oncogenes are less likely to be silenced or deleted as a mechanism of immune evasion. This theory has found support in a phase II trial of pembrolizumab in advanced Merkle-cell carcinoma [6]. Merkle-cell carcinoma, a rare but aggressive skin cancer, has been linked to 2 major causative factors, ultraviolet (UV) light and Merkle-cell polyomavirus (MCPyV), whose large T antigen is expressed in tumor cells and inactivates p53 and Rb. MCPyV-negative, UV-induced Merkel-cell carcinomas have a median of 1121 mutations per exome, which exceeds the mutational burden reported for cancers that have been most responsive to PD-1 blockade (i.e. melanoma, lung cancers, GU cancers). In contrast, MCPyV-positive Merkel-cell carcinomas, with a median of 12.5 mutations per exome, carry a mutational burden that is below cancers that have demonstrated a poor response to PD-1 blockade (i.e. prostate and pancreatic cancers). Among 25 patients assigned to pembrolizumab 2 mg per kg every 3 weeks, 44% (4 of 9 patients) of those with MCPyV-negative tumors and 62% (10 of 16 patients) of those with MCPyV-positive tumors had an objective response. In this trial, neither PD-L1 expression on tumor cells nor infiltrating immune cells was associated with clinical response to pembrolizumab.\n\nThe best correlate to Merkle-cell carcinoma in an HPV-associated cancer is head and neck squamous cell carcinoma (HNSCC). Just as in Merkle-cell carcinoma, HNSCC may be mutagen-driven (tobacco) or virus-driven, with the greater mutational burden found in the virus-negative tumors. In KEYNOTE-012, a phase Ib trial of pembrolizumab 10 mg per kg every 2 weeks in patients with PD-L1-positive recurrent or metastatic HNSCC, overall response rate (ORR) in all patients was 18% (8 of 45 patients), which consisted of 4 of 29 (14%) patients with HPV-negative tumors and 4 of 16 (25%) patients with HPV-positive tumors [7]. Similar results were found in an expansion cohort of PD-L1 positive or negative patients that received a fixed dose of pembrolizumab at a less frequent dosing schedule (200 mg IV every 3 weeks) [8]. Compared to 14% (15 of 104 patients) of patients with HPV-negative tumors, 32% (9 of 28 patients) of those with HPV-positive tumors had an objective response. Nivolumab has also performed well in recurrent or metastatic HNSCC. In CheckMate-141, a phase III trial, median overall survival (OS) was 7.5 months among patients who received nivolumab 3 mg per kg every 2 weeks compared to 5.1 months among patients who received single-agent systemic therapy [9]. There was a median OS difference of 4.7 months among patients with HPV-positive tumors (9.1 months in nivolumab group vs 4.4 months in standard-therapy group; hazard ratio for death, 0.56; 95% CI, 0.32–0.99) and a difference of 1.7 months among patients with HPV-negative tumors (7.5 months in nivolumab group versus 5.8 months in standard-therapy group; hazard ratio, 0.73; 95% CI, 0.42–1.25).\n\nIt remains to be seen whether integrated oncogenic viruses may ultimately be validated as a predictive biomarker for immune checkpoint inhibitors. While we await the results of additional trials examining checkpoint inhibition in subjects with virus-positive and virus-negative cervical cancer (NCT02488759, NCT02257528), it is important to note that complete responses and sustained responses remain rare. Of 177 patients in KEYNOTE-012 who were evaluated by central review, only 5 patients (2.8%), 4 of which where HPV-positive, demonstrated a complete response to therapy. In our patient, we hypothesize that radiotherapy may have served to sensitize or prime the immune system. Tumor-directed radiotherapy has been shown to stimulate the immune system by increasing antigen presentation and promoting a proinflammatory tumor microenvironment (TME), with well-documented changes in the cytokine milieu and expression of cell surface molecules [10]. These anti-tumor-specific immune responses may extend to distant, non-irradiated tumor sites, a phenomenon termed the abscopal effect. Using various mouse models, the combination of radiotherapy and immune checkpoint inhibitors has not only been shown to have synergistic effects on the TME [11] but also to extend survival [12, 13]. Dramatic responses to this combination have been reported in humans [14] and are being evaluated in the clinical trial setting (NCT02383212).\n\nConclusions\nUnlike the more common histological types of cervical cancer, SCNEC is rarely cured, even when diagnosed at an early stage. Its resistance to traditional therapies, reflected in the heterogeneity of treatment sequence described in the literature, encourages oncologists to look to novel therapies. Immunotherapy has the capacity to turn the causative agent, high-risk HPV, into a feature that may be exploited for clinical benefit. Among recurrent, chemotherapy-resistant, metastatic cervical cancer patients treated with adoptive T-cell therapy (ACT) involving a single infusion of ex vivo–expanded tumor-infiltrating T cells, HPV reactivity of the infusion product positively correlated with clinical response [15]. More research is needed to evaluate whether HPV infection is a predictive biomarker for immune checkpoint inhibitors, which have the potential for dramatic responses in a modest subset of patients.\n\nAbbreviations\nFIGOFederation of Gynecology and Obstetrics\n\nHPVHuman papillomavirus\n\nHSNCCHead and neck squamous cell carcinoma\n\nIVIntravenously\n\nMCPyVMerkle-cell polyomavirus\n\nORROverall response rate\n\nOSOverall survival\n\nPD-1Programmed death 1\n\nPET/CTPositron emission tomography-computed tomography\n\nSCLCSmall cell lung cancer\n\nSCNECSmall cell neuroendocrine carcinoma of the cervix\n\nSUVStandard uptake value\n\nTMETumor microenvironment\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis study was supported by the Ruth L Kirschstein NRSA Institutional Training Research Grant, 2T32 CA06039611.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nAll authors contributed to the design, data acquisition, data analysis and interpretation and manuscript preparation (writing and assembly). All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Gardner GJ Reidy-Lagunes D Gehrig PA Neuroendocrine tumors of the gynecologic tract: a society of gynecologic oncology (SGO) clinical document Gynecol Oncol 2011 122 190 8 10.1016/j.ygyno.2011.04.011 21621706 \n2. Satoh T Takei Y Treilleux I Devouassoux-Shisheboran M Ledermann J Viswanathan AN Mahner S Provencher DM Mileshkin L Avall-Lundqvist E Pautier P Reed NS Fujiwara K Gynecologic Cancer InterGroup (GCIG) consensus review for small cell carcinoma of the cervix Int J Gynecol Cancer 2014 24 S102 8 10.1097/IGC.0000000000000262 25341572 \n3. Alexandrov LB Nik-Zainal S Wedge DC Aparicio SA Behjati S Biankin AV Bignell GR Bolli N Borg A Borresen-Dale AL Boyault S Burkhardt B Butler AP Caldas C Davies HR Desmedt C Eils R Eyfjord JE Foekens JA Greaves M Hosoda F Hutter B Ilicic T Imbeaud S Imielinski M Jager N Jones DT Jones D Knappskog S Kool M Lakhani SR Lopez-Otin C Martin S Munshi NC Nakamura H Northcott PA Pajic M Papaemmanuil E Paradiso A Pearson JV Puente XS Raine K Ramakrishna M Richardson AL Richter J Rosenstiel P Schlesner M Schumacher TN Span PN Teague JW Totoki Y Tutt AN Valdes-Mas R van Buuren MM van Veer TL Vincent-Salomon A Waddell N Yates LR Zucman-Rossi J Futreal PA McDermott U Lichter P Meyerson M Grimmond SM Siebert R Campo E Shibata T Pfister SM Campbell PJ Stratton MR Signatures of mutational processes in human cancer Nature 2013 500 415 21 10.1038/nature12477 23945592 \n4. Le DT Uram JN Wang H Bartlett BR Kemberling H Eyring AD Skora AD Luber BS Azad NS Laheru D Biedrzycki B Donehower RC Zaheer A Fisher GA Crocenzi TS Lee JJ Duffy SM Goldberg RM de la Chapelle A Koshiji M Bhaijee F Huebner T Hruban RH Wood LD Cuka N Pardoll DM Papadopoulos N Kinzler KW Zhou S Cornish TC Taube JM Anders RA Eshleman JR Vogelstein B Diaz LA Jr PD-1 blockade in tumors with mismatch-repair deficiency N Engl J Med 2015 372 2509 20 10.1056/NEJMoa1500596 26028255 \n5. Topalian SL Taube JM Anders RA Pardoll DM Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy Nat Rev Cancer 2016 16 275 87 10.1038/nrc.2016.36 27079802 \n6. Nghiem PT Bhatia S Lipson EJ Kudchadkar RR Miller NJ Annamalai L Berry S Chartash EK Daud A Fling SP Friedlander PA Kluger HM Kohrt HE Lundgren L Margolin K Mitchell A Olencki T Pardoll DM Reddy SA Shantha EM Sharfman WH Sharon E Shemanski LR Shinohara MM Sunshine JC Taube JM Thompson JA Townson SM Yearley JH Topalian SL Cheever MA PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma N Engl J Med 2016 374 2542 52 10.1056/NEJMoa1603702 27093365 \n7. Seiwert TY Burtness B Mehra R Weiss J Berger R Eder JP Heath K McClanahan T Lunceford J Gause C Cheng JD Chow LQ Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial Lancet Oncol 2016 17 956 65 10.1016/S1470-2045(16)30066-3 27247226 \n8. Chow LQ Haddad R Gupta S Mahipal A Mehra R Tahara M Berger R Eder JP Burtness B Lee SH Keam B Kang H Muro K Weiss J Geva R Lin CC Chung HC Meister A Dolled-Filhart M Pathiraja K Cheng JD Seiwert TY Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort J Clin Oncol 2016 34 3838 45 \n9. Ferris RL Blumenschein G Jr Fayette J Guigay J Colevas AD Licitra L Harrington K Kasper S Vokes EE Even C Worden F Saba NF Iglesias Docampo LC Haddad R Rordorf T Kiyota N Tahara M Monga M Lynch M Geese WJ Kopit J Shaw JW Gillison ML Nivolumab for recurrent squamous-cell carcinoma of the head and neck N Engl J Med 2016 375 1856 1867 10.1056/NEJMoa1602252 27718784 \n10. Salama AK Postow MA Salama JK Irradiation and immunotherapy: from concept to the clinic Cancer 2016 122 1659 71 10.1002/cncr.29889 26914620 \n11. Deng L Liang H Burnette B Beckett M Darga T Weichselbaum RR Fu YX Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice J Clin Invest 2014 124 687 95 10.1172/JCI67313 24382348 \n12. Demaria S Kawashima N Yang AM Devitt ML Babb JS Allison JP Formenti SC Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer Clin Cancer Res 2005 11 728 34 15701862 \n13. Zeng J See AP Phallen J Jackson CM Belcaid Z Ruzevick J Durham N Meyer C Harris TJ Albesiano E Pradilla G Ford E Wong J Hammers HJ Mathios D Tyler B Brem H Tran PT Pardoll D Drake CG Lim M Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas Int J Radiat Oncol Biol Phys 2013 86 343 9 10.1016/j.ijrobp.2012.12.025 23462419 \n14. Reynders K Illidge T Siva S Chang JY De Ruysscher D The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant Cancer Treat Rev 2015 41 503 10 10.1016/j.ctrv.2015.03.011 25872878 \n15. Stevanovic S Draper LM Langhan MM Campbell TE Kwong ML Wunderlich JR Dudley ME Yang JC Sherry RM Kammula US Restifo NP Rosenberg SA Hinrichs CS Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells J Clin Oncol 2015 33 1543 50 10.1200/JCO.2014.58.9093 25823737\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2053-6844",
"issue": "4()",
"journal": "Gynecologic oncology research and practice",
"keywords": "Cervical cancer; Immunotherapy; Nivolumab; PD-1 inhibitor; Small cell neuroendocrine carcinoma",
"medline_ta": "Gynecol Oncol Res Pract",
"mesh_terms": null,
"nlm_unique_id": "101676223",
"other_id": null,
"pages": "3",
"pmc": null,
"pmid": "28174665",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "27079802;15701862;27093365;25872878;27646946;24382348;26914620;25823737;25341572;27247226;23945592;27718784;21621706;26028255;23462419",
"title": "Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report.",
"title_normalized": "metastatic small cell neuroendocrine carcinoma of the cervix treated with the pd 1 inhibitor nivolumab a case report"
} | [
{
"companynumb": "US-MYLANLABS-2017M1039949",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Arsenic trioxide (ATO) is the backbone of acute promyelocytic leukemia (APL) treatment and is dosed based on weight with no upper limit, therefore obese patients receive large doses and may be vulnerable to adverse effects and dose holdings. Twenty-seven patients receiving ATO during induction were categorized as obese (N = 16) or non-obese (N = 11) based on body mass index (BMI) ≥30 kg/m2 in this retrospective study. Doses were held or modified due to composite adverse effects in 9 (56%) obese patients and 7 (64%) non-obese patients (p = 1.00). There were higher rates of dose holdings (13% versus 0%; p = .5) and dose modifications (13% versus 0%; p = .5) due to hepatotoxicity in obese versus non-obese patients. There were no differences in efficacy parameters. These data suggest that obese patients have similar overall incidence of adverse effects to ATO as non-obese patients; any difference in risk of hepatotoxicity will require clarification in a larger study.",
"affiliations": "Department of Pharmacy, Long Island Jewish Medical Center, New Hyde Park, NY, USA.;Department of Pharmacy, North Shore University Hospital, Manhasset, NY, USA.;Department of Pharmacy, North Shore University Hospital, Manhasset, NY, USA.;Department of Hematology/Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.",
"authors": "Barsoum|Barbara|B|;Henneman|Amrita|A|;Ahmad|Samrah|S|;Ghiuzeli|Cristina|C|",
"chemical_list": "D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2020.1837797",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "62(3)",
"journal": "Leukemia & lymphoma",
"keywords": "Arsenic trioxide; acute promyelocytic leukemia; obese",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000077237:Arsenic Trioxide; D001152:Arsenicals; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D009765:Obesity; D010087:Oxides; D012189:Retrospective Studies; D014212:Tretinoin",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "703-708",
"pmc": null,
"pmid": "33107373",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of the efficacy and safety of arsenic trioxide dosing in obese patients with acute promyelocytic leukemia.",
"title_normalized": "evaluation of the efficacy and safety of arsenic trioxide dosing in obese patients with acute promyelocytic leukemia"
} | [
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-064974",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ARSENIC TRIOXIDE"
},
"drug... |
{
"abstract": "Burn patients are often plagued by fever due to the inflammatory nature of their injuries as well as the normal postoperative systemic inflammatory response syndrome. One etiology for fever, often not initially considered, is drug-induced fever. A rare cause of drug-induced fever is heparin with only one documented case reported in the literature. We present a case of heparin-induced fever in a patient who experienced a 32% total BSA friction burn after a motorcycle crash.",
"affiliations": "Department of Plastic Surgery, University of South Florida Morsani College of Medicine, Tampa.;Department of Emergency Medicine, Florida Hospital Orlando.;Tampa General Hospital Regional Burn Center, Florida.;Department of Plastic Surgery, University of South Florida Morsani College of Medicine, Tampa.",
"authors": "Laun|Jake|J|;Laun|Katie|K|;Farooqi|Adeel|A|;Smith|David J|DJ|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "England",
"delete": false,
"doi": "10.1093/jbcr/irz064",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1559-047X",
"issue": "40(5)",
"journal": "Journal of burn care & research : official publication of the American Burn Association",
"keywords": null,
"medline_ta": "J Burn Care Res",
"mesh_terms": "D000925:Anticoagulants; D002056:Burns; D005260:Female; D005334:Fever; D006493:Heparin; D006801:Humans; D055815:Young Adult",
"nlm_unique_id": "101262774",
"other_id": null,
"pages": "723-724",
"pmc": null,
"pmid": "30977800",
"pubdate": "2019-08-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Heparin-Induced Fever: A Case Report and Literature Review.",
"title_normalized": "heparin induced fever a case report and literature review"
} | [
{
"companynumb": "US-PFIZER INC-2019202683",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Montelukast, a selective leukotriene receptor antagonist, is recommended in guidelines for the treatment of asthma in both children and adults. However, its effectiveness is debated, and recent studies have reported several adverse events such as neuropsychiatric disorders and allergic granulomatous angiitis. This study aims to obtain more insight into the safety profile of montelukast and to provide prescribing physicians with an overview of relevant adverse drug reactions in both children and adults. We retrospectively studied all adverse drug reactions on montelukast in children and adults reported to the Netherlands Pharmacovigilance Center Lareb and the WHO Global database, VigiBase® until 2016. Depression was reported most frequently in the whole population to the global database VigiBase® (reporting odds ratio (ROR) 6.93; 95% CI: 6.5-7.4). In the VigiBase® , aggression was reported the most in children (ROR, 29.77; 95% CI: 27.5-32.2). Headaches were reported the most frequently to the Dutch database (ROR, 2.26; 95% CI: 1.61-3.19). Furthermore, nightmares are often reported for both children and adults to the Dutch and the global database. Eight patients with allergic granulomatous angiitis were reported to the Dutch database and 563 patients in the VigiBase® . These data demonstrate that montelukast is associated with neuropsychiatric adverse drug reactions such as depression and aggression. Especially in children nightmares are reported frequently. Allergic granulomatous angiitis is also reported, a causal relationship has not been established.",
"affiliations": "Department of Pediatric Cardiology, Center for Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen, The Netherlands.;Netherlands Pharmacovigilance Center Lareb, Den Bosch, The Netherlands.;Department of Pediatrics, Medical Center Leeuwarden, Leeuwarden, The Netherlands.",
"authors": "Haarman|Meindina G|MG|0000-0002-1223-6067;van Hunsel|Florence|F|;de Vries|Tjalling W|TW|",
"chemical_list": "D000085:Acetates; D003521:Cyclopropanes; D011804:Quinolines; D013440:Sulfides; C093875:montelukast",
"country": "United States",
"delete": false,
"doi": "10.1002/prp2.341",
"fulltext": "\n==== Front\nPharmacol Res PerspectPharmacol Res Perspect10.1002/(ISSN)2052-1707PRP2Pharmacology Research & Perspectives2052-1707John Wiley and Sons Inc. Hoboken 10.1002/prp2.341PRP2341Original ArticleOriginal ArticlesAdverse drug reactions of montelukast in children and adults M.G. Haarman et al.Haarman Meindina G. http://orcid.org/0000-0002-1223-6067m.g.haarman@umcg.nl \n1\nvan Hunsel Florence \n2\nde Vries Tjalling W. \n3\n\n1 \nDepartment of Pediatric Cardiology\nCenter for Congenital Heart Diseases\nBeatrix Children's Hospital\nUniversity Medical Center Groningen\nThe Netherlands\n\n2 \nNetherlands Pharmacovigilance Center Lareb\nDen Bosch\nThe Netherlands\n\n3 \nDepartment of Pediatrics\nMedical Center Leeuwarden\nLeeuwarden\nThe Netherlands\n* Correspondence\n\nMeindina G Haarman, Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Hanzeplein 1, PO‐box 30.001, 9700RB Groningen, The Netherlands.\n\nTel: +31503613363; Fax: +31503614235;\n\nE‐mail: m.g.haarman@umcg.nl\n20 9 2017 10 2017 5 5 10.1002/prp2.2017.5.issue-5e0034129 6 2017 02 7 2017 © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nMontelukast, a selective leukotriene receptor antagonist, is recommended in guidelines for the treatment of asthma in both children and adults. However, its effectiveness is debated, and recent studies have reported several adverse events such as neuropsychiatric disorders and allergic granulomatous angiitis. This study aims to obtain more insight into the safety profile of montelukast and to provide prescribing physicians with an overview of relevant adverse drug reactions in both children and adults. We retrospectively studied all adverse drug reactions on montelukast in children and adults reported to the Netherlands Pharmacovigilance Center Lareb and the WHO Global database, VigiBase® until 2016. Depression was reported most frequently in the whole population to the global database VigiBase® (reporting odds ratio (ROR) 6.93; 95% CI: 6.5–7.4). In the VigiBase®, aggression was reported the most in children (ROR, 29.77; 95% CI: 27.5–32.2). Headaches were reported the most frequently to the Dutch database (ROR, 2.26; 95% CI: 1.61–3.19). Furthermore, nightmares are often reported for both children and adults to the Dutch and the global database. Eight patients with allergic granulomatous angiitis were reported to the Dutch database and 563 patients in the VigiBase®. These data demonstrate that montelukast is associated with neuropsychiatric adverse drug reactions such as depression and aggression. Especially in children nightmares are reported frequently. Allergic granulomatous angiitis is also reported, a causal relationship has not been established.\n\nAsthmadrug safetytherapeutic drug monitoring source-schema-version-number2.0component-idprp2341cover-dateOctober 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:24.10.2017\n\n\nM. G. \nHaarman \n, \nF. \nvan Hunsel \n, \nT. W \nde Vries \n. Adverse drug reactions of montelukast in children and adults , Pharma Res Per , 5 (5 ), 2017 , e00341, https://doi.org/10.1002/prp2.341\n\n\n\nPrincipal Investigator: Tjalling W de Vries MD PhD\n==== Body\nAbbreviations\nADRadverse drug reaction\n\nATCanatomical and therapeutic chemical classification\n\nICSRindividual case safety report\n\nLTRAleukotriene receptor antagonist\n\nMedDRAMedical Dictionary for Regulatory Activities\n\nRORreporting odds ratio\n\nSmPCsummary of product characteristics\n\nUMCUppsala Monitoring Center\n\nWHOWorld Health Organization\n\nIntroduction\nMontelukast is a selective leukotriene receptor antagonist (LTRA) and is prescribed in both children and adults for, that is, the maintenance treatment of asthma and allergic rhinitis. Although the effectiveness is debated, (Hon et al. 2014; Brodlie et al. 2015, 2016) guidelines recommend montelukast for treatment of asthma (British Thoracic Society; Scottish Intercollegiate Guidelines Network, 2014). The most common adverse events in adults according to the summary of product characteristics (SmPC) are upper airway infections (in >10% of all users) fever, rash, nausea, vomiting, diarrhea, and elevated levels of liver enzymes (Dutch Farmacotherapeutic Compass, 2016). Most common adverse events in children (1–10% of all users) according to the SmPC are headaches, abdominal pain, rash, thirst, hyperkinesia, asthma, and eczema (Dutch Children's Formulary, 2016). Recent studies have also reported adverse events such as sleeping disorders and psychiatric disorders (Calapai et al. 2014). In addition, allergic granulomatous angiitis (Churg‐Strauss syndrome) may also be associated with the use of montelukast (Calapai et al. 2014).\n\nThe aim of this study is to obtain more insight into the safety profile of montelukast in daily practice to provide prescribing physicians with an overview of relevant adverse drug reactions (ADRs) in children and adults. We therefore studied the reports of ADRs associated with montelukast in the Dutch spontaneous reporting database of the Netherlands Pharmacovigilance Center Lareb and the WHO Global Individual Case Safety Report (ICSR) database VigiBase®, maintained by the Uppsala Monitoring Center (UMC) in Sweden.\n\nMaterials and methods\nWe retrospectively examined all ADRs on montelukast (Anatomical and Therapeutic Chemical classification (ATC) code R03DC03) in children aged 0–18 years and adults aged 19 years and older reported to the Netherlands Pharmacovigilance Center Lareb and the WHO Global ICSR database, VigiBase® until 2016.\n\nThe reports in the Dutch spontaneous database (until 13‐07‐2016) were coded with the Medical Dictionary for Regulatory Activities (MedDRA®) and individually assessed for causality by trained assessors.\n\nFor the Netherlands Pharmacovigilance Center Lareb, data, including suspect drug, co‐medication, age and sex of the patient, and the suspected ADR, were extracted from the database. Reported ADRs were classified into the categories “non‐serious” and “serious” based on international criteria. The latter included fatal outcome, life‐threatening, requiring (prolongation of) hospitalisation, resulting in significant disability/incapacity, and other medically important conditions. All other ADRs were classified as nonserious (European Medicines Agency, 2009).\n\nWe report the serious and most often reported ADRs. In selected cases, we reassessed the causality of the reported drug reactions based on the Naranjo score. Moreover, the reporting odds ratio (ROR) was calculated for selected associations.\n\nThe Naranjo score is a quantitative method for determining the likelihood that an ADR is due to the drug (Naranjo et al. 1981). The ROR compares the rate of reporting a specific adverse effect in a drug with the rate of reporting the same adverse effect in all other drugs. The ROR is calculated by the following division: the numerator is the number of cases in which montelukast was used and a specific ADR was reported divided by the number of cases using montelukast in which this ADR was not reported; the denominator is the number of pediatric and adult cases using other suspected drugs, reporting a specific ADR divided by the number of cases using other suspected drugs without reporting that specific ADR. It is expressed as a point estimate with corresponding 95% confidence intervals (95% CIs). Furthermore, at least three reports have to be present in the database to compute a reliable ROR (Rothman et al. 2004). We calculated RORs for ADRs associated with montelukast based on the whole database and a separate ROR restricted to children <19 years of age. The ROR offers insight into disproportionality of an association, not into causality.\n\nFor the global database VigiBase®, we obtained numbers of reports and disproportionality (ROR) per reported association, both in adults and children through VigiLyze®, which is a search and analysis tool (available to member countries of the WHO Program for International Drug Monitoring).\n\nBecause no patients were involved, we did not ask the Institutional Review Board for approval.\n\nResults\nNetherlands pharmacovigilance center Lareb\nIn the Dutch spontaneous reporting database, 331 reports on ADRs after montelukast were present of which 124 (37.5%) were reported in men and 203 (61.3%) in women. In 4 cases (1.2%), the gender was unknown. In almost a third (107; 32.3%), the reports concerned individuals aged between 0 and 18 years and in 214 cases (64.7%), adults aged 19 years and older. In 10 cases of ADRs (3%) age was not reported. Of all reports, 45 (13.6%) were reported as serious (Table 1). There were two deaths: a 20‐year‐old woman with pulmonary embolism with a doubtful relation between the use of montelukast and the reaction, and a woman of unknown age with renal failure with a possible relation between the use of montelukast and the reaction. In 26 cases, the ADR led to hospitalisation; 10 patients recovered completely, seven patients have not yet recovered, three patients did not recover, and the recovery status of six patients was not known; none of them died. Reasons for hospitalisation were epilepsy, chest pain, insomnia, movement disorder, toxic skin eruption, neurological disorder, vasculitis, anesthesia, urticaria, gastrointestinal tract bleeding, abnormal liver function test, angioedema, general health deterioration, membranous lipodystrophy, eosinophilia, coughing, and anaphylactic reaction. In 16 patients, the adverse event was called serious because of angioedema, hypersensitivity, fatigue, epilepsy, aggression, pain in extremity, immune system disorder, confusional state, hemorrhage, abnormal dreams, excoriation, eosinophil count increased, and abdominal pain. In one patient, the adverse event was called serious but the report was on an accidental overdose.\n\nTable 1 Adverse drug reactions (ADRs) after montelukast reported to the Netherlands Pharmacovigilance Center Lareb and deemed serious, for example, leading to death, hospitalisation, or life threatening condition\n\nAdverse drug reaction\tComments\tRelation with montelukast according to the Naranjo score (Naranjo et al. 1981)\t\nDeath\t\n20‐year‐old woman with pulmonary embolism\n\nWoman of unknown age with renal failure.\n\t\t\nAllergic granulomatous angiitis\t\nAngioedema\t4‐year‐old girl with concomitant use of pulmicort and foradil. Patient was treated with tavergil and prednisone. Montelukast was discontinued. Angioedema disappeared.\tPossible\t\nMalaise\t45‐year‐old woman with concomitant use of 8 other medicines. Montelukast was discontinued and she recovered.\tPossible\t\nEpilepsy\t9‐year‐old boy with no concomitant use of other medicines. Montelukast was discontinued and he recovered.\tPossible\t\nChest pain\tMan of unknown age with concomitant use of seretide. Montelukast was discontinued and he recovered.\tPossible\t\nHallucination\t13‐year‐old boy with no concomitant use of medicines. Montelukast was discontinued and he recovered.\tPossible\t\nMyalgia\t47‐year‐old man with concomitant use of 5 other medicines. Montelukast was discontinued and he recovered.\tPossible\t\nEosinophilia\t66‐year‐old woman with concomitant use of seretide. Montelukast was discontinued and she recovered slowly.\tProbable\t\nNightmare/somnambulism\t72‐year‐old woman with concomitant use of 9 other medicines. Montelukast was discontinued and she recovered.\tProbable\t\nChest discomfort\t\nWoman of unknown age with concomitant use of 5 other medicines. Further information unknown\n\nWoman of unknown age with concomitant use of 3 other medicines. Further information unknown.\n\t\nPossible\n\nPossible\n\t\nAnaphylactic reaction\t13‐year‐old boy with concomitant use of 4 other medicines. Montelukast was discontinued and he recovered.\tProbable\t\nJohn Wiley & Sons, LtdOf the 45 patients with serious adverse events, eight patients had allergic granulomatous angiitis of which six patients were hospitalised; all patients survived. Their characteristics are presented in Table 2.\n\nTable 2 Characteristics of six patients hospitalised with allergic granulomatous angiitis reported to the Netherlands Pharmacovigilance Center Lareb\n\nDescription\tLatency\tConcomitant medicine use\tAction and outcome\tRelation with Montelukast\t\n33‐year‐old woman with a history of asthma\t6 months\tDoxycycline, prednisone, flixonase\tPatient was treated with high dose oral prednisone; not yet recovered at the time of reporting.\tPossible\t\n53‐year‐old man with an unknown history\t5 years\tFlixonase, seretide\tMontelukast has been Withdrawn; patient has not recovered at the time of reporting.\tDoubtful\t\n55‐year‐old woman with a history of asthma\t8 months\tCetirizine, seretide, flixonase\tMontelukast has been withdrawn; patient recovered after treatment with prednisone.\tPossible\t\n75‐year‐old woman with a history of asthma\t7 days\tPhenprocoumon, furosemide, digoxine, isosorbide mononitrate, carvedilol, ramipril, omeprazole, tiotropium\tMontelukast has been withdrawn; patient was treated with prednisone and is recovering.\tPossible\t\n59‐year‐old woman with a history of asthma, rhinitis, and bronchiectasis\t3 months\tMometasone, tiotropium, ciclesonide, beclometasone/formoterol\tMontelukast has been withdrawn, and the patient is treated with prednisone. She is recovering.\tProbable\t\n75‐year‐old woman with a history of asthma\tUnknown\tPhenprocoumon, omeprazole, calcium carbonate, digoxine, furosemide, ramipril, isosorbide mononitrate, beclometasone/formoterol, tiotropium, cardvedilol\tMontelukast has been withdrawn; patient recovered.\tPossible\t\nDisclaimer: This publication contains information obtained from UMC through https://vigilyze.who-umc.org (restricted access), accessed at 03‐11‐2016. The information derives from a variety of sources, and the likelihood that the suspected adverse reaction is drug‐related is not the same in all cases. The information provided in this article does not represent the opinion of the World Health Organization. For more information, see http://www.who-umc.org/graphics/25300.pdf\n\n\nJohn Wiley & Sons, LtdWHO global ICSR database, VigiBase®\n\nIn the global spontaneous reporting database, 17,723 reports on ADRs after montelukast were present of which 6960 (39.3%) were reported in men and 9732 (54.9%) in women. In 1031 cases (5.8%), the gender was unknown. Approximately a third (5743; 32.4%) of the reports concerned individuals aged 0–18 years old. Additionally, age was not reported in 3,665 cases of ADRs (20.7%).\n\nMost common adverse events Netherlands Pharmacovigilance Center Lareb and WHO global ICSR database, VigiBase®\n\nTable 3 depicts the most frequent ADRs with RORs for all cases and for individuals under <19 years of age reported to both the Netherlands Pharmacovigilance Center Lareb and the WHO Global ICSR database, VigiBase®.\n\nTable 3 Most common adverse drug reactions (ADRs) after montelukast reported to the Netherlands Pharmacovigilance Centre Lareb and the WHO Global ICSR database VigiBase®\n\n\nAdverse drug reaction\tTotal number of reports at VigiBase®\n\tRORa VigiBase® (95% CI)\tNumber of reports in children <19 year at VigiBase®\n\tRORa VigiBase® in children <19y (95% CI)\tTotal number of reports at Lareb\tRORa Lareb (95% CI)\tNumber of reports in children <19 year at Lareb\tRORa Lareb in children <19 year (95% CI)\t\nDepression\t1188\t6.93 (6.54–7.36)\t493\t20.52 (18.65–22.58)\t5\t1.91 (0.79–4.62)\t–\t–\t\nHeadache\t1128\t1.85 (1.75–1.97)\t371\t1.91 (1.72–2.12)\t37\t2.26 (1.61–3.19)\t17\t3.18 (2.66–3.70)\t\nAggression\t1101\t24.99 (23.49–26.59)\t808\t29.77 (27.54–32.18)\t11\t9.27 (5.06–16.99)\t7\t12.02 (11.24–12.80)\t\nSuicidal ideation\t1047\t20.43 (19.18–21.76)\t495\t38.27 (34.68–42.22)\t1\t–\t–\t–\t\nInsomnia\t1020\t5.08 (4.77–5.41)\t417\t11.15 (10.07–12.35)\t15\t3.45 (2.05–5.81)\t7\t4.60 (3.83–5.38)\t\nAnxiety\t948\t5.11 (4.79–5.46)\t468\t16.99 (15.41–18.72)\t6\t2.79 (1.24–6.26)\t2\t–\t\nAbnormal behavior\t892\t34.05 (31.79–36.46)\t643\t17.64 (15.99–19.46)\t7\t12.02 (5.64–25.61)\t7\t8.56 (7.79–9.34)\t\nNightmares\t749\t22.48 (20.87–24.21)\t448\t78.04 (69.95–87.07)\t25\t19.29 (12.75–29.17)\t13\t56.72 (56.09–57.35)\t\nDyspnea\t649\t1.30 (1.20–1.41)\t120\t1.14 (0.95–1.36)\t13\t1.47 (0.84–2.56)\t–\t—\t\nRash\t540\t0.65 (0.59–0.71)\t161\t0.31 (0.26–0.36)\t17\t1.77 (1.09–2.89)\t7\t1.28 (0.51–2.05)\t\nAbdominal pain\t511\t1.81 (1.66–1.98)\t222\t2.24 (1.95–2.56)\t15\t2.24 (1.33–3.77)\t8\t3.67 (2.95–4.40)\t\nDizziness\t541\t0.89 (0.82–0.97)\t97\t0.72 (0.59–0.88)\t12\t0.94 (0.53–1.68)\t–\t–\t\nMyalgia\t352\t1.66 (1.49–1.84)\t58\t1.57 (1.21–2.03)\t12\t1.26 (0.71–2.25)\t–\t–\t\nMuscle spasms\t291\t2.44 (2.17–2.74)\t57\t3.98 (3.06–5.17)\t10\t2.87 (1.53–5.40)\t–\t–\t\nNausea\t557\t0.61 (0.56–0.66)\t104\t0.56 (0.46–0.68)\t10\t0.65 (0.35–1.23)\t4\t1.17 (0.16–2.17)\t\nDisclaimer: This publication contains information obtained from UMC through https://vigilyze.who-umc.org (restricted access), accessed at 03‐11‐2016. The information comes from a variety of sources, and the likelihood that the suspected adverse reaction is drug‐related is not the same in all cases, The information shown in this article does not represent the opinion of the World Health Organization. For more information see http://www.who-umc.org/graphics/25300.pdf\n\n\na ROR computed when more than two cases. The numerator is the number of cases in which montelukast was used and a specific ADR was reported divided by the number of cases using montelukast in which this ADR was not reported. The denominator is the number of pediatric cases using other suspected drugs reporting a specific ADR divided by the number of pediatric cases using other suspected drugs without reporting that specific ADR. The ROR was calculated for the entire group as well as for children.\n\nJohn Wiley & Sons, LtdAs can be observed, depression was reported most frequently in the whole population to the global database, VigiBase®. The ROR is 6.93 (95% CI: 6.5–7.4). In the VigiBase®, aggression was reported the most in children <19 years of age. The ROR in children is 29.77 (95% CI: 27.5–32.2).\n\nThe highest RORs were found for aggression (24.99; 95% CI: 23.5–26.6), suicidal ideation (20.4; 95% CI: 19–22), abnormal behavior (34.05; 95% CI: 31.8–36.5), and nightmares (22.46; 95% CI: 20.9–24.2).\n\nOther common ADRs in the whole population were headaches (ROR 1.85; 95% CI: 1.75–1.970), insomnia (5.08; 95% CI 4.8–5.4), anxiety (5.11; 95% CI: 4.8–5.5), dyspnea (1.30; 95% CI: 1.20–1.41), dizziness (0.89; 95% CI: 0.82–0.97), myalgia (1.66; 95% CI: 1.49–1.84), and muscle spasms (2.44; 95% CI: 2.17–2.74).\n\nHeadaches were most frequently reported to the Dutch database for both the whole population and children. The RORs were 2.26 (95% CI: 1.61–3.19) and 3.18 (95% CI: 2.66–3.70), respectively. Other common ADRs in the whole population were aggression, insomnia, anxiety, abnormal behavior, dyspnea, rash, abdominal pain, and muscle spasms. The RORs and 95% CIs for these ADRs can be found in Table 3.\n\nTo the Dutch and the global database, nightmares were reported frequently for both children and adults aged 19 years and older. For VigiBase®, the RORs were 22.48 (95% CI: 20.8–24.2) and 78.04 (95% CI: 70.0–87.1) for the whole population and children aged <19 years, respectively. For Lareb, the RORs were 19.29 (95% CI: 12.8–29.2) for all cases and 56.72 (95% CI: 56.1–57.4) for individuals under 19 years of age.\n\nIn the VigiBase®, allergic granulomatous angiitis was reported in 563 patients.\n\nDiscussion\nIn this study, we found several reported adverse drug events that were deemed serious, and we saw a high number of patients with allergic granulomatous angiitis in both the Dutch and the global database. Most of all, we found a high number of patients with neuropsychiatric adverse effects.\n\nA fatal outcome was reported in two reported adverse drug events in the Netherlands Pharmacovigilance Center database. One patient, a 20‐year‐old woman, died after pulmonary embolism, and another woman of unknown age died due to renal failure. The relation between montelukast and the adverse event in the first patient was considered doubtful, and in the second patient, the relation between the use of montelukast and the reaction was possible. However, due to the limited information in both reported cases, we cannot confirm that these adverse events are caused by the use of montelukast. As far as we could establish, there are no other known cases reported in the literature nor were pulmonary embolism and renal failure found in the VigiBase®. Furthermore, we could not detect a specific pattern in the other reports of serious ADRs.\n\nAllergic granulomatous angiitis was reported in eight patients in the Netherlands Pharmacovigilance Center Lareb and in 563 patients in the WHO Global ICSR database, VigiBase®. Allergic granulomatous angiitis is a rare disease, and it is stated that allergic granulomatous angiitis will occur in <0.01% of patients treated with montelukast (Dutch Farmacotherapeutic Compass, 2016; Dutch Children's Formulary, 2016). Former studies have revealed that the association between montelukast and allergic granulomatous angiitis is somewhat doubtful. To illustrate, Calapai et al. (2014) argued that most of the patients treated with montelukast who developed symptoms of allergic granulomatous angiitis were also receiving other medications such as corticosteroids or salbutamol, making the relationship with montelukast uncertain. Moreover, all patients with allergic granulomatous angiitis only exhibited symptoms after montelukast had been administered, yet some patients had a decrease in the intake of oral corticosteroids concomitantly. This means that the disease could be masked by the use of corticosteroids and the patient already had angiitis. However, it has been reported that the symptoms of allergic granulomatous angiitis disappeared in some patients after withdrawing montelukast. This can be seen regarded as an argument for a causal relationship.\n\nIn an earlier study, it was found that patients treated with montelukast had a 4.5‐fold higher risk of allergic granulomatous angiitis onset within 3 months. Nonetheless, the authors questioned a causal relationship because there could be confounding by a general escalation of asthma therapy before allergic granulomatous angiitis onset (Hauser et al. 2008). We could not find animal studies in which a relation between allergic granulomatous angiitis was established. Further prospective studies in larger patient populations are needed to discern the exact relation between montelukast and the occurrence of allergic granulomatous angiitis. Until then, patients treated with montelukast should be followed to detect signs and symptoms of allergic granulomatous angiitis.\n\nFormer studies have provided contradictory reports on neuropsychiatric adverse events in montelukast users. In 2009, the US Food and Drug Administration mandated a label change for montelukast and other leukotriene receptor antagonists to include neuropsychiatric adverse events (e.g., depression and suicidality) as a precaution (FDA, 2017). Nonetheless, Ali could not establish a significant association between montelukast and neuropsychiatric events in children with asthma (Ali et al. 2015).\n\nOur data indicate that neuropsychiatric symptoms, such as depression, aggression, suicidal ideation, abnormal behavior, and nightmares, were significantly frequently reported in children and in adults in both the Dutch and the global database. The RORs found in these adverse events were high, pointing to a strong relationship. In addition, although Aldea Perona et al. have argued that more neuropsychiatric symptoms were reported more frequently in children compared to adults (Aldea Perona et al. 2016), we cannot confirm this.\n\nIn a recent Spanish study, 24 patients (17 children and seven adults) reported nightmares after montelukast. In 18 patients, the nightmares appeared within the first week of treatment. In 21 cases, the nightmares rapidly resolved after montelukast had been discontinued (Cereza et al. 2012). The relatively high ROR indicates a strong statistical relation between montelukast and nightmares. This was true for both the Dutch and worldwide population. Although nightmares are often transient in children, they can be frightening for both child and parents and can influence school performance. In adults, sleep disorders can lead to potential dangerous situations in traffic or working with machines (Levin and Nielsen 2007; Simor et al. 2012). This means that the clinician must discuss the possibility of these adverse events with the patient and parents.\n\nAs a probable mechanism for the development of neuropsychiatric symptoms, it has been postulated that montelukast causes a higher blood‐brain permeability and inhibits the production of neurotransmitters such as serotonin and noradrenalin. Yet, human studies have revealed that the brain does not express leukotriene receptors (Singh et al. 2013) and that montelukast may even cause an inhibition of the blood‐brain barrier permeability (Biber et al. 2009). A reason for the higher incidence of agitation in children can be that children have more energy because their symptoms of asthma and/or allergic rhinitis are being tempered by montelukast and parents may interpret this as abnormal behavior or aggression (de Vries and van Hunsel 2016). As of yet, no pathophysiologic explanation is found.\n\nIt has been established that asthma symptoms are associated with depression and a lower quality of life (Goldney et al. 2003). This means that in some cases, the adverse effect is not a result of the drug but merely a result of unresolved asthma. Further research is required to reveal the mechanism for the higher incidence of neuropsychiatric symptoms in patients using montelukast in comparison with other medications.\n\nThe strength of this study is that the study material consisted of all pediatric and adult ADRs reports on montelukast located in both the database of the Netherlands Pharmacovigilance Center Lareb and the WHO Global ICSR database, VigiBase®. As far as we are aware, this is the first study that reports both ADRs in children and adults extracted from two large databases.\n\nHowever, underreporting is a limitation of using a system of voluntary spontaneous reporting. This entails that the true occurrence of ADRs associated with montelukast cannot be extrapolated from these data. On the other hand, because reporting is voluntary, it will only occur when patients, parents, or professionals suspect a correlation. Moreover, a voluntary reporting system provides early warnings of drug‐related harm. Another limitation of voluntary reporting data is that the causality of the reported ADRs is not always certain.\n\nConclusion\nThis article offers a comprehensive overview of the safety of montelukast in clinical practice. Serious ADRs include allergic reactions and chest pain. Although the relation between allergic granulomatous angiitis and montelukast is not elucidated, the prescribing physicians should be alert for signs and symptoms of this rare disease. Severe neuropsychiatric symptoms can occur after montelukast in both adults and children for whom montelukast was prescribed; especially nightmares may occur soon after starting montelukast.\n\nAuthor's Contributions\nStudy conception and design: MH, FH, TV; Data acquisition: FH; Data analysis: MH, FH, TV; Data interpretation: MH, FH, TV; Manuscript drafting and revising: MH, FH, TV.\n\nDisclosure\nThe authors report no conflicts of interest related to the manuscript.\n==== Refs\nReferences\n\n\nAldea Perona \nA \n, \nGarcia‐Saiz \nM \n, \nSanz Alvarez \nE \n. (2016 ). Psychiatric disorders and montelukast in children: a disproportionality analysis of the VigiBase((R)) . Drug Saf \n39 :69 –78 .26620206 \n\n\nAli \nMM \n, \nO'Brien \nCE \n, \nCleves \nMA \n, \nMartin \nBC \n (2015 ). Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case‐control study . Pharmacoepidemiol Drug Saf \n24 : 435 –445 .25683909 \n\n\nBiber \nN \n, \nToklu \nHZ \n, \nSolakoglu \nS \n, \nGultomruk \nM \n, \nHakan \nT \n, \nBerkman \nZ \n, et al. (2009 ). Cysteinyl‐leukotriene receptor antagonist montelukast decreases blood‐brain barrier permeability but does not prevent oedema formation in traumatic brain injury . Brain Inj \n23 : 577 –584 .19484631 \n\nBritish Thoracic Society; Scottish Intercollegiate Guidelines Network \n(2014 ). British guideline on the management of asthma . Thorax \n69 (Suppl 1 ): 1 –192 .\n\n\nBrodlie \nM \n, \nGupta \nA \n, \nRodriguez‐Martinez \nCE \n, \nCastro‐Rodriguez \nJA \n, \nDucharme \nFM \n, \nMcKean \nMC \n. (2015 ). Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children . Cochrane Database Syst Rev \nCD008202 .26482324 \n\n\nBrodlie \nM \n, \nGupta \nA \n, \nRodriguez‐Martinez \nCE \n, \nCastro‐Rodriguez \nJA \n, \nDucharme \nFM \n, \nMcKean \nMC \n (2016 ). Leukotriene receptor antagonists as maintenance or intermittent treatment in pre‐school children with episodic viral wheeze . Paediatr Respir Rev \n17 : 57 –59 .26628194 \n\n\nCalapai \nG \n, \nCasciaro \nM \n, \nMiroddi \nM \n, \nCalapai \nF \n, \nNavarra \nM \n, \nGangemi \nS \n (2014 ). Montelukast‐induced adverse drug reactions: a review of case reports in the literature . Pharmacology \n94 (1–2 ): 60 –70 .25196099 \n\n\nCereza \nG \n, \nGarcia Dolade \nN \n, \nLaporte \nJR \n (2012 ). Nightmares induced by montelukast in children and adults . Eur Respir J \n40 : 1574 –1575 .23204025 \n\nDutch Children's Formulary \n. (2016 ). Avaliable at: https://www.kinderformularium.nl (accessed 6 December 2016).\n\nDutch Farmacotherapeutic Compass \n. (2016 ). Avaliable at: https://www.farmacotherapeutischkompas.nl (accessed 6 December 2016).\n\nEuropean Medicines Agency \n(2009 ). Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002749.pdf\n\n\nFDA \n(2017 ). Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR). Available at: http://www.fda.gov/Drugs/DrugSafetyPostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm165489.htm (accessed on 1 March 2017)\n\n\nGoldney \nRD \n, \nRuffin \nR \n, \nFisher \nLJ \n, \nWilson \nDH \n (2003 ). Asthma symptoms associated with depression and lower quality of life: a population survey . Med J Aust \n178 : 437 –441 .12720509 \n\n\nHauser \nT \n, \nMahr \nA \n, \nMetzler \nC \n, \nCoste \nJ \n, \nSommerstein \nR \n, \nGross \nWL \n, et al. (2008 ). The leucotriene receptor antagonist montelukast and the risk of churg‐strauss syndrome: a case‐crossover study . Thorax \n63 : 677 –682 .18276721 \n\n\nHon \nKL \n, \nLeung \nTF \n, \nLeung \nAK \n. (2014 ). Clinical effectiveness and safety of montelukast in asthma. What are the conclusions from clinical trials and meta‐analyses? \nDrug Des Devel Ther \n8 :839 –850 .\n\n\nLevin \nR \n, \nNielsen \nTA \n (2007 ). Disturbed dreaming, posttraumatic stress disorder, and affect distress: a review and neurocognitive model . Psychol Bull \n133 : 482 –528 .17469988 \n\n\nNaranjo \nCA \n, \nBusto \nU \n, \nSellers \nEM \n, \nSandor \nP \n, \nRuiz \nI \n, \nRoberts \nEA \n, et al. (1981 ). A method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther \n30 : 239 –245 .7249508 \n\n\nRothman \nKJ \n, \nLanes \nS \n, \nSacks \nST \n (2004 ). The reporting odds ratio and its advantages over the proportional reporting ratio . Pharmacoepidemiol Drug Saf \n13 : 519 –523 .15317031 \n\n\nSimor \nP \n, \nHorvath \nK \n, \nGombos \nF \n, \nTakacs \nKP \n, \nBodizs \nR \n (2012 ). Disturbed dreaming and sleep quality: altered sleep architecture in subjects with frequent nightmares . Eur Arch Psychiatry Clin Neurosci \n262 : 687 –696 .22526731 \n\n\nSingh \nRK \n, \nTandon \nR \n, \nDastidar \nSG \n, \nRay \nA \n (2013 ). A review on leukotrienes and their receptors with reference to asthma . J Asthma \n50 : 922 –931 .23859232 \n\n\nde Vries \nTW \n, \nvan Hunsel \nF \n (2016 ). Adverse drug reactions of systemic antihistamines in children in the Netherlands . Arch Dis Child \n101 : 968 –970 .27091848\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2052-1707",
"issue": "5(5)",
"journal": "Pharmacology research & perspectives",
"keywords": "Asthma; drug safety; therapeutic drug monitoring",
"medline_ta": "Pharmacol Res Perspect",
"mesh_terms": "D000085:Acetates; D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015267:Churg-Strauss Syndrome; D003521:Cyclopropanes; D016208:Databases, Factual; D003863:Depression; D004325:Dreams; D005260:Female; D006261:Headache; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D060735:Pharmacovigilance; D011804:Quinolines; D012189:Retrospective Studies; D013440:Sulfides; D055815:Young Adult",
"nlm_unique_id": "101626369",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28971612",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": "27091848;7249508;23859232;25196099;28971612;23204025;25061277;17469988;12720509;22526731;15317031;19484631;26482324;26628194;26620206;25323740;18276721;25683909",
"title": "Adverse drug reactions of montelukast in children and adults.",
"title_normalized": "adverse drug reactions of montelukast in children and adults"
} | [
{
"companynumb": "PHHY2018NL024043",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUTICASONE PROPIONATE\\SALMETEROL XINAFOATE"
},
"drug... |
{
"abstract": "Pregnancy is rare in women on hemodialysis. Recommendations for the treatment of secondary hyperparathyroidism (sHPT) and preservation of bone health in pregnant dialysis patients are lacking.\n\n\n\nWe present the case of a young woman with end-stage kidney disease (ESKD) due to lupus nephritis, who developed multiple brown tumors while on hemodialysis during her second pregnancy. During her first pregnancy sHPT was well controlled and no skeletal complications occurred. Before the second pregnancy she developed severe sHPT. During pregnancy, dialysis time was increased to 24 h per week, the patient was given oral calcitriol, and the dialysate calcium concentration was set at 1.5 mmol/l. In week 20 the patient complained about bone pain in her left hip. Magnetic resonance imaging revealed a cystic lesion compatible with a brown tumor. The baby was delivered in the 36th week by cesarean section. Further assessment identified multiple brown tumors of her skeleton, including the acetabulum, tibia, ribs, skull, thoracic spine and thumb. She required multiple orthopedic surgeries. Three months after pregnancy, etelcalcetide was started, which brought about a gradual improvement in her sHPT.\n\n\n\nThis case demonstrates that the combination of pregnancy and severe sHPT in dialysis patients can have deleterious consequences for bone health.",
"affiliations": "Department of Internal Medicine III, Academic Teaching Hospital Feldkirch, Carinagasse 47, Feldkirch, Austria.;Department of Internal Medicine III, Academic Teaching Hospital Feldkirch, Carinagasse 47, Feldkirch, Austria.;Department of Internal Medicine IV, Medical University of Innsbruck, Innsbruck, Austria.;Institute for Diagnostic and Interventional Radiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.;Department of Internal Medicine III, Academic Teaching Hospital Feldkirch, Carinagasse 47, Feldkirch, Austria. karl.lhotta@lkhf.at.",
"authors": "Sprenger-Mähr|Hannelore|H|;Zitt|Emanuel|E|;Kronbichler|Andreas|A|;Cejna|Manfred|M|;Lhotta|Karl|K|0000-0002-8156-7775",
"chemical_list": "D010281:Parathyroid Hormone; D010455:Peptides; C583569:etelcalcetide hydrochloride; D002118:Calcium",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-019-1603-8",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 160310.1186/s12882-019-1603-8Case ReportA hemodialysis patient with bone disease after pregnancy: a case report Sprenger-Mähr Hannelore 1Zitt Emanuel 1Kronbichler Andreas 2Cejna Manfred 3http://orcid.org/0000-0002-8156-7775Lhotta Karl +43 5522 303 2700karl.lhotta@lkhf.at 11 0000 0000 9585 4754grid.413250.1Department of Internal Medicine III, Academic Teaching Hospital Feldkirch, Carinagasse 47, Feldkirch, Austria 2 0000 0000 8853 2677grid.5361.1Department of Internal Medicine IV, Medical University of Innsbruck, Innsbruck, Austria 3 0000 0000 9585 4754grid.413250.1Institute for Diagnostic and Interventional Radiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria 21 11 2019 21 11 2019 2019 20 4251 8 2019 28 10 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPregnancy is rare in women on hemodialysis. Recommendations for the treatment of secondary hyperparathyroidism (sHPT) and preservation of bone health in pregnant dialysis patients are lacking.\n\nCase presentation\nWe present the case of a young woman with end-stage kidney disease (ESKD) due to lupus nephritis, who developed multiple brown tumors while on hemodialysis during her second pregnancy. During her first pregnancy sHPT was well controlled and no skeletal complications occurred. Before the second pregnancy she developed severe sHPT. During pregnancy, dialysis time was increased to 24 h per week, the patient was given oral calcitriol, and the dialysate calcium concentration was set at 1.5 mmol/l. In week 20 the patient complained about bone pain in her left hip. Magnetic resonance imaging revealed a cystic lesion compatible with a brown tumor. The baby was delivered in the 36th week by cesarean section. Further assessment identified multiple brown tumors of her skeleton, including the acetabulum, tibia, ribs, skull, thoracic spine and thumb. She required multiple orthopedic surgeries. Three months after pregnancy, etelcalcetide was started, which brought about a gradual improvement in her sHPT.\n\nConclusions\nThis case demonstrates that the combination of pregnancy and severe sHPT in dialysis patients can have deleterious consequences for bone health.\n\nKeywords\nHemodialysisSecondary hyperparathyroidismOsteitis fibrosa cysticaPregnancyEtelcalcetideissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nPractically all dialysis patients have chronic kidney disease-associated mineral and bone disorder (CKD-MBD), with secondary hyperparathyroidism (sHPT) being most frequent. The most severe form of hyperparathyroid bone disease is osteitis fibrosa cystica (OFC) caused by massive bone resorption mediated by parathyroid hormone (PTH). The clinical presentation is characterized by bone pain and swelling, skeletal deformities and fractures. Imaging studies show osteolytic bone lesions [1]. Histologically, multinucleated osteoclasts (giant cells) with tunneling bone resorption, peritrabecular fibrosis and woven bone are pathognomonic findings. Hemosiderin deposition causes the macroscopic appearance of a brown tumor (BT). Current treatment options for sHPT such as phosphate binders, calcitriol and its analogs, calcimimetics, and finally parathyroidectomy, have made OFC a rare finding in dialysis patients [2, 3]. OFC occasionally develops in patients with primary hyperparathyroidism (pHPT). Pregnant women with pHPT seem to be predisposed to OFC, as illustrated by numerous case reports, suggesting that in pregnancy bone is particularly vulnerable to the effect of PTH [4–7]. The combination of severe sHPT in a dialysis patient and pregnancy may therefore be the worst-case scenario for bone health. As pregnancy is still very rare in women of childbearing age on dialysis, data on bone disease in that clinical situation are practically absent and guidance for sHPT treatment and the preservation of bone health in pregnant dialysis patients is lacking. We here report the case of a young woman on hemodialysis, who had two successful pregnancies. After the second one, which she entered with severe sHPT, she developed devastating and refractory OFC.\n\nCase report\nThe 26-year-old Caucasian woman had developed end-stage kidney disease (ESKD) at the age of 21 due to lupus nephritis. She was treated with conventional maintenance hemodialysis therapy three times a week. At age 22 she became pregnant for the first time. Pregnancy was first recognized at 23 weeks of gestation. The dialysis schedule was intensified to 24 h per week. The patient was treated with sevelamer. She received no vitamin D or calcium and the dialysis bath calcium concentration was kept at 1.25 mmol/l. During pregnancy CKD-MBD was well controlled with calcium and phosphate levels in the normal range and PTH levels around 150 pg/ml. The baby was delivered in week 32 by cesarean section. The premature child was small for gestational age with a birth weight of 1735 g, and a length of 43 cm. Apgar score was 7/8/9. The mother breastfed the newborn for only a few weeks.\n\nDuring the following three years the patient developed severe sHPT with gradually increasing PTH levels to around 1500 pg/ml, primarily because she refused to take any oral medication such as phosphate binders, calcitriol or cinacalcet.\n\nAt age 25 she became pregnant again. Her dialysis schedule was increased to 24 h per week (6 × 4 h), according to the current recommendations [8]. Dry weight was adjusted weekly, erythropoetin and iron supplementation were adapted as required. Oral calcitriol 0.25 μg after each dialysis session and cholecalciferol 6000 IU per week were administered and the dialysate calcium concentration was increased to 1.5 mmol/l. The patient was normophosphatemic, serum calcium was at the lower limits of normal and PTH decreased from about 1600 pg/ml to around 500 to 800 pg/ml (time-course of calcium and PTH is shown in Figs. 1 and 2). Table 1 depicts levels of serum phosphate, alkaline phosphatase and 25OH-vitamin D3 before, during and after her second pregnancy.\nFig. 1 Monthly serum calcium levels starting with the seond pregnancy pregnancy. Calcium was normal during pregnancy. Under treatment with etelcalcetide mild hypocalcemia was present\n\n\nFig. 2 Monthly PTH levels starting with the second of pregnancy. PTH declined during pregnancy and especially with etelcalcetide. Two rebounds of PTH were caused by a *two-week and a **three-week treatment period in another unit, where etelcalcetide was not available. PTH was measured with a third generation 1–84 intact PTH assay (Elecsys PTH (1–84) assay, Roche)\n\n\nTable 1 Other relevant laboratory parameters before, during and after the second pregnancy\n\nparameter (normal range)\t3 month before second pregnancy\t1. trimenon\t2. trimenon\t3. trimenon\t3 months after pregnancy\t\nphosphate (0.81–1.45 mmol/l)\t2.33\t1,08\t0,94\t1,24\t1.71\t\nalkaline phosphatase (35–105 U/l)\t306\t327\t261\t366\t235\t\n25OH-vitamin D3 (20–100 μg/l)\t14\t13\t11\t19\t11\t\n\n\nAt 20 weeks of gestation the patient began to complain about pain in her right hip. Magnetic imaging revealed a cystic lesion in the right acetabulum, femoral neck and trochanter majus, highly suggestive of a BT.\n\nAfter 36 weeks of gestation the patient gave birth to a female baby by cesarean section. Apgar score was 8/10/10, birth weight was 2755 g, and body length 47 cm. Except for a complete atrioventricular septum defect, which had already been diagnosed prenatally, the baby was healthy. The patient breastfed the neonate for five weeks.\n\nAfter pregnancy, hemodialysis frequency was reduced to a conventional schedule of four hours three times weekly. PTH levels started to increase rapidly again, reaching up to 2000 pg/ml (Fig. 2). Treatment with cinacalcet with rapid dose increase from 30 to 90 mg was started, and calcitriol was continued at 0.5 μg. Both cinacalcet and calcitriol were given three times per week after the dialysis session, because the patient refused to take these medications on dialysis-free days. Further computed tomography, magnetic resonance and x-ray imaging identified multiple additional BTs of her skeleton, including the right acetabulum, the right trochanter majus, os pubis (Fig. 3a), the right tibia (Fig. 3b), several ribs, the skull and the left thumb (Fig. 3c). The patient had to be partially immobilized because of the high fracture risk. The BT in the right acetabulum and right tibia were enucleated, and the cavities were filled with autologous and homologous bone graft and an osteosynthesis of the tibia had to be performed for stabilization. Histopathology of the enucleated material confirmed the diagnosis of BTs, showing cell-rich tumor tissue with osteoclastic giant cells, multiple sideromacrophages and hemosiderin deposition (Fig. 4).\nFig. 3 Imaging studies of selected osteolytic lesions. a. CT scan of the right hip. Osteolytic lesions are present in the acetabulum, femoral neck and trochanter majus (arrows). b. MRI scan showing a large brown tumor in the head of the right tibia (*). c. x-ray of the left thumb reveals osteolytic destruction of the end phalanx (arrow)\n\n\nFig. 4 Histopathology of the brown tumor removed from the right tibia. Hematoxylin-eosin staining (400× magnification). Proliferation of mesenchymal cells with oval nuclei and eosinophilic cytoplasm. Scattered throughout the stroma are numerous osteoclast-like multinucleated giant cells containing varying numbers of vesicular nuclei (arrows)\n\n\n\nDespite treatment with cinacalcet, PTH concentration remained at around 1500 pg/ml. At that time, etelcalcetide was approved by the European Medicines Agency. Three months after delivery treatment with etelcalcetide was initiated. The initial dose of 2.5 mg after hemodialysis had to be gradually increased to 10 mg per dialysis session. Although PTH decreased to around 500 pg/ml and further on to 200 pg/ml when undergoing treatment with etelcalcetide (Fig. 2), OFC lesions did not show any sign of regression. Second enucleations of the BT in the right acetabulum and in the right tibia became necessary eight and 12 months after starting with etelcalcetide, because the bone grafts had been absorbed. In spite of sHPT being well-controlled with etelcalcetide, calcium and calcitriol supplementation, a new BT developed in the thoracic spine two years after starting etelcalcetide. A costotransversectomy on the right side of the fifth thoracic vertebral body, filling of the cavity with homologous bone graft and spondylodesis TH 4 to TH 6 was performed. Table 2 summarizes all surgical procedures performed during the course of the disease. After all these interventions the patient was fully mobile and without pain. Bone mineral density assessed by dual-energy x-ray absorptiometry in the second year after pregnancy revealed low bone mass (osteopenia) both in the lumbar spine (0.970 g/cm2, T-score − 1.8) and femoral necks (0.760 g/cm2, T-score − 2.0).\nTable 2 Surgical procedures related to brown tumors performed during the course of the disease\n\nTime after delivery\tProcedure\t\n3 months\tenucleation of BT in the right tibia and acetabulum bone graft filling osteosynthesis\t\n12 months\tenucleation of BT right acetabulum bone graft filling\t\n16 months\tenucleation of relapsing BT right tibia and acetabulum bone graft filling osteosynthesis\t\n19 months\tenucleation of BT in the left thumb\t\n28 months\tcostotransversectomy thoracic vertebra 5 osteosynthesis thoracic vertebra 4 to 6, bone graft filling\t\n\n\nDiscussion and conclusions\nThis case illustrates that uncontrolled sHPT during pregnancy in a dialysis patient can have deleterious effects for the maternal skeleton.\n\nPregnancy, particularly multiparity, is still rare in dialysis patients. A systematic review demonstrated an increasing number of reported pregnancies from 90 cases in the period from 2000 to 2008 to 574 pregnancies in 543 women from 2000 to 2014 [9]. Increased dialysis dose goes along with higher fertility and intensified dialysis schedules, especially daily hemodialysis, quotidian long-hour dialysis or nocturnal hemodialysis, result in better maternal and fetal outcomes [10, 11].\n\nOFC is a rare manifestation of severe pHPT and sHPT, especially in developed countries. Osteoclastic bone resorption with destruction of trabeculae is accompanied by cellular repair mechanisms that result in the accumulation of fibrous stroma and connective tissue cells along with multinucleated giant cells. The name “brown tumor” derives from the color, which is caused by hypervascularity, hemorrhage and deposits of hemosiderin. The lesions are localized in areas of intense bone resorption, preferentially in the facial skeleton but also in the clavicle, ribs and pelvic bones [4]. On imaging, they appear as lytic lesions with regular borders and thinned cortical bone, not accompanied by periosteal reaction or inflammation.\n\nIn general, BTs are three times more common in women than in men, possibly related to the large amounts of calcium and vitamin D required during pregnancy and lactation [4].\n\nIn pregnancy adaptive mechanisms are needed to cope with the calcium requirements of the developing fetus. The human fetus accretes about 30 g of calcium by term, mostly in the third trimester [12]. To meet this increased demand maternal intestinal calcium absorption more than doubles beginning in the 12th week of pregnancy, driven in part by an increase in serum calcitriol [13]. PTH is suppressed and therefore not the cause of increased calcitriol levels. Evidence from animal models suggests that prolactin or placental lactogen, and also PTH-related peptide (PTHrP) may stimulate the renal 1α-hydroxylase to produce calcitriol [12]. Although the placenta also expresses the key enzyme 1α-hydroxylase, it seems that the maternal kidneys account for most of the circulating calcitriol during pregnancy, as illustrated by an anephric woman on hemodialysis who had low calcitriol before and during her pregnancy [12].\n\nDuring lactation, maternal calcium and bone metabolism must adapt to the extra demand for calcium (300–400 mg/days). The major source providing calcium during breastfeeding is bone [14]. Maternal bone mass declines during lactation by about 10% over the first six months, the losses being greatest in the trabecular skeleton [14]. The lactating breast secretes PTHrP into the systemic circulation and milk. PTHrP mobilizes skeletal calcium stores. Concomitant estrogen deficiency secondary to hypogonadotropic hypogonadism may increase bone loss [4]. Randomized clinical trials and observational studies have found that higher calcium supplementation does not reduce lactational bone density decline [15]. In the postweaning phase the skeleton is restored to its previous strength and mineral content [13].\n\nIn a pregnant dialysis patient the kidneys obviously cannot increase calcitriol synthesis. Therefore, if calcitriol and calcium are not supplemented, calcium will probably be mobilized from maternal bone. This may be aggravated by preexisting uncontrolled sHPT. In pregnancy, bone is probably particularly vulnerable to the effects of PTH, as exemplified by cases of OFC in pregnant women with pHPT. In addition, the physiologic repair mechanisms of bone in the postweaning phase may not be as effective in an ESKD patient with sHPT. Therefore, our patient may have entered the second pregnancy with an already pre-damaged and vulnerable skeleton.\n\nWhat implications can be derived from normal physiology during pregnancy and from the bone and mineral derangements in CKD-MBD for the management of a pregnant dialysis patient?\n\nFirst of all, pregnancy in a dialysis patient needs to be carefully planned with the medical team, not only considering blood pressure, volume or anemia management, but also avoidance or therapy of severe sHPT before entering pregnancy. On both occasions our patient did not inform the medical team about her plan to become pregnant. Pregnancy in a patient with uncontrolled sHPT should not be pursued. The first pregnancy with well controlled sHPT did not cause obvious or clinically significant damage to the maternal skeleton, whereas during the second pregnancy severe sHPT led to generalized OFC.\n\nSecond, the special fetal demands for calcium need consideration. The World Health Organization (WHO) recommends daily supplementation of 1.5 to 2 g of calcium for pregnant women after the 20th week of pregnancy, especially in those at risk for preeclampsia and in regions with low dietary calcium intake [16]. Dialysis patients are at risk for preeclampsia, and their calcium intake from milk products is usually low, because the intake of dairy products is discouraged due to their phosphate content. Therefore, oral calcium supplementation should be considered in a pregnant dialysis patient.\n\nThe WHO guidelines for antenatal care advise against routine vitamin D supplementation in pregnancy [17]. In a dialysis patient in whom renal calcitriol synthesis is absent, calcitriol supplementation - and not native vitamin D supplementation - is probably necessary to facilitate intestinal calcium absorption.\n\nAnother means of calcium supplementation in a dialysis patient is to increase the calcium dialysate concentration. Whereas a four hour bicarbonate dialysis with a dialysate calcium of 1.25 mmol /l results in a neutral calcium balance, increasing the dialysate calcium to 1.5 mmol/l provides a positive calcium balance of around 300 mg per session [18]. Whether this amount is sufficient to cover the needs of pregnancy and lactation or whether additional oral supplementation is necessary is unknown. In any case, our patient refused to take oral calcium supplements and increasing calcium in the dialysate bath seemed a plausible alternative.\n\nAll these measures, namely intensive dialysis with normalization of serum phosphate levels, calcium and calcitriol supplementation or increasing the dialysis calcium bath, will lead to a reduction in PTH levels, as observed in our patient’s second pregnancy.\n\nCinacalcet and etelcalcetide are calcimimetic agents, which effectively reduce PTH, calcium and phosphorous in dialysis patients [19–21]. With regard to bone turnover and histology, cinacalcet has been shown to decrease histomorphometric markers of bone turnover after six to twelve months of treatment in dialysis patients with biopsy-proven high bone turnover [3]. The package insert for cinacalcet states that cinacalcet should be used during pregnancy only if the benefits outweigh potential harms. Experimental animal studies showed cinacalcet to have no teratogenicity. Only a few case reports describe treatment with cinacalcet during pregnancy, mainly in pHPT patients to control hypercalcemia, and only for a few weeks during the third trimester [5, 22].\n\nCKD-MBD guidelines suggest parathyroidectomy for those patients with severe hyperparathyroidism who fail to respond to pharmacological therapy [23]. Parathyroidectomy during pregnancy has to our knowledge been performed only in pHPT, but not in sHPT [24]. The current recommendation is to perform parathyroidectomy during the second trimester of pregnancy due to incomplete organogenesis in the first trimester and the risk of preterm labor in the third trimester [25]. During pregnancy PTH levels were not in the range above 800 pg/ml, where surgery is recommended and serum calcium and phosphorus were normal. For this reason, we did not consider parathyroidectomy during the second pregnancy. In the postpartal period with normalization of the dialysis schedule PTH increased rapidly despite cinacalcet (Fig. 2), and parathyroidectomy was strongly considered. We were, however, reluctant to take this step because of the fear of consequent adynamic bone disease precluding the healing of osteolytic lesions, and severe and sustaining hypocalcemia in a patient with known poor adherence in the long term.\n\nEtelcalcetide is a novel second-generation calcimimetic given intravenously after each hemodialysis session [20]. When this new drug became available, we quickly administered it in our patient. Indeed, our patient was the first to be treated with this new second-generation calcimimetic in Europe outside clinical trials. Serum PTH levels declined with increasing doses, but rose episodically whenever the patient was treated for a short period of time in other dialysis units where etelcalcetide was not available at that time. When pharmacological treatment of sHPT to cure OFC is pursued, the precise target level of PTH, which ensures optimal bone turnover for healing, is currently unknown. During the first two years on etelcalcetide PTH levels undulated around 500 pg/ml. As shown in our patient, this level of PTH is obviously too high to allow regression of BTs. Therefore, we targeted a lower level between 100 and 200 pg/ml. Whether this PTH range allows regression of the lesions remains to be seen.\n\nLooking at this case in retrospect, would there have been opportunities to improve patient management and outcome? Using a dialysate calcium concentration of 1.5 mmol/l in the period between the two pregnancies might have counteracted the development of severe sHPT. Secondly, parathyroidectomy before the second pregnancy would have been an option bearing in mind the possibility of postsurgical hypoparathyroidism and the development of adynamic bone disease in a young patient (potentially aggravated by her non-adherence). Thirdly, increasing the dose of calcitriol and oral calcium supplementation during pregnancy avoiding overt hypercalcemia may have been considered. Finally, a more liberal up-titration of etelcalcetide to reduce PTH accepting some degree of hypocalcemia could have been helpful.\n\nShould breastfeeding be recommend in a dialysis patient? We are aware of only one case report on this topic [26]. Breast milk composition varies between pre- and post-dialysis samples, and post-dialysis milk is preferable for breastfeeding [26]. Under normal physiologic conditions breastfeeding puts greater stress on the skeleton than does pregnancy itself. Therefore, we suggest that in a patient with sHPT and bone disease breastfeeding should be discouraged to prevent further aggravation of bone resorption.\n\nThis case highlights the clinical problems that may arise when a dialysis patient enters pregnancy with severe sHPT. The combined effects of sHPT and pregnancy can cause OFC, requiring multiple surgical interventions. Clinical experience with usual therapeutic interventions to control PTH such as calcimimetic drugs or parathyroidectomy is practically absent. Therefore a woman on hemodialyis should be advised to get pregnant only after PTH and mineral metabolism are well controlled.\n\nAbbreviations\nBT Brown tumor\n\nCKD-MBDChronic kidney disease-associated mineral and bone disorder\n\nESKDEnd-stage kidney disease\n\nOFCOsteitis fibrosa cystica\n\npHPT Primary hyperparathyroidism\n\nPTH Parathyroid hormone\n\nPTHrP PTH-related peptide\n\nsHPTSecondary hyperparathyroidism\n\nWHO World Health Organization\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank Amgen Austria for providing etelcalcetide for immediate treatment of our patient.\n\nAuthors’ contributions\nHSM, EZ, AK and KL are reponsible for the clinical management of the patient, MC for the interpretation of imaging studies. All authors have read and approved the manuscript.\n\nAuthors’ information\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nData sharing is not applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was optained from the patient for publication of the case report including images.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Bandeira F Cassibba S Hyperparathyroidism and bone health Curr Rheumatol Rep 2015 17 7 48 10.1007/s11926-015-0523-2 26105042 \n2. Malluche HH Mawad HW Monier-Faugere MC Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients J Bone Miner Res 2011 26 6 1368 1376 10.1002/jbmr.309 21611975 \n3. Behets GJ Spasovski G Sterling LR Goodman WG Spiegel DM De Broe ME D'Haese PC Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism Kidney Int 2015 87 4 846 856 10.1038/ki.2014.349 25337774 \n4. Casteras A, Darder L, Zafon C, Hueto JA, Alberola M, Caubet E, Mesa J. Brown tumor of the jaw after pregnancy and lactation in a MEN1 patient. Endocrinol Diabetes Metab Case Rep. 2016;2016.\n5. Gonzalo Garcia I Robles Fradejas M Martin Macias MLA Biain Ciganda A Bustinza Beaskoetxea Z Ruiz Perez E Fernandez Matia G Martinez Guisasola J Primary hyperparathyroidism in pregnancy treated with cinacalcet: a case report J Obstet Gynaecol 2018 38 1 132 134 10.1080/01443615.2017.1325862 28760052 \n6. Lehnerdt G Metz KA Kruger C Dost P A bone-destroying tumor of the maxilla. Reparative giant cell granuloma or brown tumor? HNO 2003 51 3 239 244 10.1007/s00106-002-0690-0 \n7. Zou H Song L Jia M Wang L Sun Y Brown tumor of multiple facial bones associated with primary hyperparathyroidism: a clinical case report Medicine (Baltimore) 2018 97 33 e11877 10.1097/MD.0000000000011877 30113484 \n8. Cabiddu G Castellino S Gernone G Santoro D Giacchino F Credendino O Daidone G Gregorini G Moroni G Attini R Best practices on pregnancy on dialysis: the Italian study group on kidney and pregnancy J Nephrol 2015 28 3 279 288 10.1007/s40620-015-0191-3 25966799 \n9. Piccoli GB Minelli F Versino E Cabiddu G Attini R Vigotti FN Rolfo A Giuffrida D Colombi N Pani A Pregnancy in dialysis patients in the new millennium: a systematic review and meta-regression analysis correlating dialysis schedules and pregnancy outcomes Nephrol Dial Transplant 2016 31 11 1915 1934 10.1093/ndt/gfv395 26614270 \n10. Hladunewich MA Hou S Odutayo A Cornelis T Pierratos A Goldstein M Tennankore K Keunen J Hui D Chan CT Intensive hemodialysis associates with improved pregnancy outcomes: a Canadian and United States cohort comparison J Am Soc Nephrol 2014 25 5 1103 1109 10.1681/ASN.2013080825 24525032 \n11. Barua M Hladunewich M Keunen J Pierratos A McFarlane P Sood M Chan CT Successful pregnancies on nocturnal home hemodialysis Clin J Am Soc Nephrol 2008 3 2 392 396 10.2215/CJN.04110907 18308997 \n12. Kovacs CS Calcium and bone metabolism disorders during pregnancy and lactation Endocrinol Metab Clin N Am 2011 40 4 795 826 10.1016/j.ecl.2011.08.002 \n13. Kirby BJ Ma Y Martin HM Buckle Favaro KL Karaplis AC Kovacs CS Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone J Bone Miner Res 2013 28 9 1987 2000 10.1002/jbmr.1925 23505097 \n14. Wysolmerski JJ Interactions between breast, bone, and brain regulate mineral and skeletal metabolism during lactation Ann N Y Acad Sci 2010 1192 161 169 10.1111/j.1749-6632.2009.05249.x 20392232 \n15. Kalkwarf HJ Specker BL Bianchi DC Ranz J Ho M The effect of calcium supplementation on bone density during lactation and after weaning N Engl J Med 1997 337 8 523 528 10.1056/NEJM199708213370803 9262495 \n16. . In: Guideline: Calcium Supplementation in Pregnant Women. edn. Geneva; 2013.\n17. Roth DE Leung M Mesfin E Qamar H Watterworth J Papp E Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials BMJ 2017 359 j5237 10.1136/bmj.j5237 29187358 \n18. Basile C Libutti P Di Turo AL Vernaglione L Casucci F Losurdo N Teutonico A Lomonte C Effect of dialysate calcium concentrations on parathyroid hormone and calcium balance during a single dialysis session using bicarbonate hemodialysis: a crossover clinical trial Am J Kidney Dis 2012 59 1 92 101 10.1053/j.ajkd.2011.08.033 22000728 \n19. Urena P Jacobson SH Zitt E Vervloet M Malberti F Ashman N Leavey S Rix M Os I Saha H Cinacalcet and achievement of the NKF/K-DOQI recommended target values for bone and mineral metabolism in real-world clinical practice--the ECHO observational study Nephrol Dial Transplant 2009 24 9 2852 2859 10.1093/ndt/gfp144 19369690 \n20. Friedl C Zitt E Role of etelcalcetide in the management of secondary hyperparathyroidism in hemodialysis patients: a review on current data and place in therapy Drug Des Devel Ther 2018 12 1589 1598 10.2147/DDDT.S134103 \n21. Pereira L Meng C Marques D Frazao JM Old and new calcimimetics for treatment of secondary hyperparathyroidism: impact on biochemical and relevant clinical outcomes Clin Kidney J 2018 11 1 80 88 10.1093/ckj/sfx125 29423207 \n22. Rey E Jacob CE Koolian M Morin F Hypercalcemia in pregnancy - a multifaceted challenge: case reports and literature review Clin Case Rep 2016 4 10 1001 1008 10.1002/ccr3.646 27761256 \n23. Kidney Disease: Improving Global Outcomes CKDMBDUWG: KDIGO 2017 Clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011) 2017, 7(1):1–59.\n24. Dochez V Ducarme G Primary hyperparathyroidism during pregnancy Arch Gynecol Obstet 2015 291 2 259 263 10.1007/s00404-014-3526-8 25367603 \n25. Kamenicky P Lecoq AL Chanson P Primary hyperparathyroidism in pregnancy Ann Endocrinol (Paris) 2016 77 2 169 171 10.1016/j.ando.2016.04.010 27157105 \n26. Balzer MS Gross MM Lichtinghagen R Haller H Schmitt R Got Milk? Breastfeeding and Milk analysis of a mother on chronic hemodialysis PLoS One 2015 10 11 e0143340 10.1371/journal.pone.0143340 26571490\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "20(1)",
"journal": "BMC nephrology",
"keywords": "Etelcalcetide; Hemodialysis; Osteitis fibrosa cystica; Pregnancy; Secondary hyperparathyroidism",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000328:Adult; D002118:Calcium; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D007676:Kidney Failure, Chronic; D008181:Lupus Nephritis; D010002:Osteitis Fibrosa Cystica; D010281:Parathyroid Hormone; D010455:Peptides; D011247:Pregnancy; D011248:Pregnancy Complications; D006435:Renal Dialysis",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "425",
"pmc": null,
"pmid": "31752733",
"pubdate": "2019-11-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12627253;25367603;26614270;30113484;29423207;9262495;26105042;29187358;21611975;20392232;22000728;29910605;27761256;27933172;26571490;27157105;25337774;18308997;22108281;25966799;24525032;28760052;19369690;23505097",
"title": "A hemodialysis patient with bone disease after pregnancy: a case report.",
"title_normalized": "a hemodialysis patient with bone disease after pregnancy a case report"
} | [
{
"companynumb": "AT-VALIDUS PHARMACEUTICALS LLC-AT-2019VAL000865",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCITRIOL"
},
"drugadd... |
{
"abstract": "The association between guttate psoriasis and infection with group A Streptococcus (GAS) has been well established in the medical literature. However, responses to treatments aimed at GAS eradication such as systemic antibiotics or tonsillectomy are inconsistent. Further complicating treatment recommendations for a disease with a suspected microbial trigger, the standard therapy for severe psoriasis is with systemic immunosuppressant medications. This case report illustrates the role of GAS as a trigger for acute onset severe psoriasis in a child whose skin disease initially worsened with a trial of methotrexate. An immune evaluation confirmed a co-existing selective antibody deficiency. Subsequent treatment with intravenous immune globulin dramatically improved his underlying immune function and decreased GAS infections. This improvement in overall immune function and decrease in GAS infections cleared his skin disease. An interval change in formulation to subcutaneous immune globulin was not as effective.",
"affiliations": "Department of Dermatology, University of California, Davis, Sacramento, CA USA, Department of Biological Sciences, California State Univeristy, Sacramento, CA USA. raja.sivamani.md@gmail.com.",
"authors": "Clark|Ashley K|AK|;Shi|Vivian Y|VY|;Sivamani|Raja K|RK|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "23(8)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008911:Minocycline; D014581:Urticaria",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29469742",
"pubdate": "2017-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unique urticarial presentation of minocycline-induced lupus erythematosus.",
"title_normalized": "unique urticarial presentation of minocycline induced lupus erythematosus"
} | [
{
"companynumb": "US-TEVA-815599USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": "3",
"d... |
{
"abstract": "We here report on a 74-year-old man diagnosed with a pT3cN0 BRAF-mutated and mismatch repair-deficient adenocarcinoma in the colon ascendens and 3 liver metastases. After hemicolectomy, the patient received treatment with the PD-1 inhibitor pembrolizumab. Three weeks later (on day 22), laboratory tests showed leukocytosis and an increase in transaminases; immune checkpoint inhibitor (ICI)-induced hepatitis was suspected and prednisolone therapy was initiated. On day 29, the patient was acutely hospitalized due to dyspnea, somnolence and walking difficulties. Dysarthria, hoarseness, muscle pain and weakness had developed and the dose of prednisolone was increased. Serum levels of lactate dehydrogenase, creatine kinase and myoglobin were increased and ICI-induced myositis was suspected. Antibodies against acetylcholine receptor and titin were present, indicating myasthenia gravis. Eventually, bulbar myopathy developed, including dysarthria and dysphagia, and the patient could no longer attain saturation without oxygen. The patient was transferred to the intensive care unit, intubated and given methylprednisolone, intravenous immunoglobulins and infliximab. The patient developed carbon dioxide retention and died on day 39. Microscopical examination of the intercostal musculature, diaphragm, cervical musculature and tongue showed inflammatory infiltration and fibrosis consistent with a pronounced myositis. In the liver, microscopical examination did not show metastases from colorectal cancer but instead a hepatocellular cancer. The cause of death was determined as respiratory insufficiency due to polymyositis. In conclusion, ICIs may induce myositis combined with neurological immune-related adverse events. In patients developing muscle weakness and pain under ICI therapy, myositis should be suspected.",
"affiliations": "Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.;Department of Medicine, Halland Hospital Varberg, Varberg, Sweden.;Department of Pathology, Halland Hospital Halmstad, Halmstad, Sweden.;Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.",
"authors": "Giglio|Daniel|D|;Berntsson|Henrik|H|;Fred|Åsa|Å|;Ny|Lars|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000510740",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000510740\ncro-0013-1252\nCase Report\nImmune Checkpoint Inhibitor-Induced Polymyositis and Myasthenia Gravis with Fatal Outcome\nGiglio Daniel a* Berntsson Henrik b Fred Åsa c Ny Lars ad aDepartment of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden\nbDepartment of Medicine, Halland Hospital Varberg, Varberg, Sweden\ncDepartment of Pathology, Halland Hospital Halmstad, Halmstad, Sweden\ndDepartment of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden\n*Daniel Giglio, Department of Oncology, Sahlgrenska University Hospital, Blå Stråket 2, SE–41345 Gothenburg (Sweden), daniel.giglio@pharm.gu.se\nSep-Dec 2020 \n14 10 2020 \n14 10 2020 \n13 3 1252 1257\n25 7 2020 3 8 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We here report on a 74-year-old man diagnosed with a pT3cN0 BRAF-mutated and mismatch repair-deficient adenocarcinoma in the colon ascendens and 3 liver metastases. After hemicolectomy, the patient received treatment with the PD-1 inhibitor pembrolizumab. Three weeks later (on day 22), laboratory tests showed leukocytosis and an increase in transaminases; immune checkpoint inhibitor (ICI)-induced hepatitis was suspected and prednisolone therapy was initiated. On day 29, the patient was acutely hospitalized due to dyspnea, somnolence and walking difficulties. Dysarthria, hoarseness, muscle pain and weakness had developed and the dose of prednisolone was increased. Serum levels of lactate dehydrogenase, creatine kinase and myoglobin were increased and ICI-induced myositis was suspected. Antibodies against acetylcholine receptor and titin were present, indicating myasthenia gravis. Eventually, bulbar myopathy developed, including dysarthria and dysphagia, and the patient could no longer attain saturation without oxygen. The patient was transferred to the intensive care unit, intubated and given methylprednisolone, intravenous immunoglobulins and infliximab. The patient developed carbon dioxide retention and died on day 39. Microscopical examination of the intercostal musculature, diaphragm, cervical musculature and tongue showed inflammatory infiltration and fibrosis consistent with a pronounced myositis. In the liver, microscopical examination did not show metastases from colorectal cancer but instead a hepatocellular cancer. The cause of death was determined as respiratory insufficiency due to polymyositis. In conclusion, ICIs may induce myositis combined with neurological immune-related adverse events. In patients developing muscle weakness and pain under ICI therapy, myositis should be suspected.\n\nKeywords\nColorectal adenocarcinomaHepatocellular carcinomaMicrosatellite-instable tumorPembrolizumabMyositisMyasthenia gravis\n==== Body\nIntroduction\nThe interaction between programmed cell death ligand 1 (PD-L1) on tumor cells and programmed cell death 1 (PD-1) expressed by cytotoxic T lymphocytes leads to T-cell exhaustion and tumor immune escape [1]. The use of immune checkpoint inhibitors (ICIs) targeting the interaction between PD-1 and PD-L1 has led to a paradigm shift in the prognosis of stage IV melanoma. The use of ICIs has been expanded to many other solid tumor forms including renal cancer, urinary bladder cancer, lung cancer and colorectal cancer. Pembrolizumab is a humanized antibody targeting PD-1 approved for the treatment of melanoma and many solid tumors including certain tumors of the gastrointestinal tract. PD-L1 is, however, not only expressed on tumor cells but also on cells in different tissues of the body. Patients treated with ICIs may therefore experience immune-related adverse events (irAEs) of variable severity. The most common immune-related side effects occur in the endocrine system, skin, and pulmonary and gastrointestinal tract. irAEs affecting the nervous system are rare and comprise conditions such as Guillain-Barré syndrome, myasthenia gravis (MG), aseptic meningitis, transverse myelitis and immune encephalitis [2]. Myositis may also occur and may be accompanied by MG [3].\n\nHere, we report on a patient experiencing a combination of ICI-induced myositis and neurological irAEs, having subtle initial symptoms but a dramatic and fatal course.\n\nCase Report\nA 74-year-old man with hypertension and insulin-dependent diabetes mellitus type 2 including diabetic retinopathy was referred to the surgery department due to an 8-kg weight loss and iron deficiency anemia. Computed tomography and magnetic resonance imaging displayed a tumor in the colon ascendens and 3 liver metastases (15, 20 and 65 mm in dimension). The patient underwent right hemicolectomy. The pathology report showed a 60 × 70 × 50 mm low-grade pT3cN0 adenocarcinoma, absence of metastases in 24 excised lymph nodes and presence of lymphovascular growth but no vascular or perineural growth. The tumor had an activated BRAF mutation in exon 15 (V600E) and loss of expression of MLH1 and PMS2 and was defined as a mismatch repair-deficient (MMR-D)/microsatellite-instable (MSI) tumor. Since the patient had a nonfavorable prognostic profile for response to chemotherapy but fulfilled tumor criteria for a high chance of response to immunotherapy, the patient initiated therapy with the PD-1 inhibitor pembrolizumab (Keytruda®; 200-mg intravenous flat dose) in order to potentially be eligible for liver metastasectomy.\n\nOn day 7 after the first infusion of pembrolizumab, the patient reported having symptoms of a cold but was otherwise asymptomatic. A laboratory test showed leukocytosis (white blood cell count 13.49 × 109/L) and a slight increase in C-reactive protein (24 mg/L; Fig. 1a). The cold was still present on day 22, when he was planned for the second cycle of pembrolizumab. The patient now reported dry coughing, had no fever and was otherwise asymptomatic. A laboratory test showed an increase in AST and ALT (>3× ULN; Fig. 1b) and was judged to have ICI-induced hepatitis grade 2, and the patient therefore initiated prednisolone therapy (50 mg once daily), which resulted in a decrease in C-reactive protein and AST, but white blood cells and neutrophils were increased (Fig. 1b). The second dose of pembrolizumab (on day 22) was not given. On day 29, the patient was acutely hospitalized due to dyspnea. Initially, myocardial infarction was suspected due to an elevation of troponin T (482 ng/L); echocardiography showed septal hypokinesia, but troponin T did not show any dynamic change over time. The patient developed somnolence and had difficulty walking. On day 30, a clinical examination revealed that the patient had developed dysarthria and hoarseness. The patient complained about pain in his neck and right leg and had difficulty raising his right leg. The dose of prednisolone was increased to 80 mg once daily. Computed tomography did not show signs of stroke. Creatine kinase (CK) and myoglobin levels (1,276 μg/L) were increased, and ICI-induced myositis was therefore suspected. In addition, a gradual decrease in creatinine levels was observed (Fig. 1c). Antibodies against acetylcholine receptor (2.6 nmol/L) and titin were present, indicating MG. In addition, albumin (516 mg/L) was present in the cerebrospinal fluid. On day 34, the patient was unable to sit up, had pain in his neck and shoulders, had developed severe dysarthria and dysphagia, and could not attain saturation without oxygen. The patient had absent reflexes in the biceps, brachioradialis, triceps, and patellar and Achilles tendons. The same day, he was transferred to the intensive care unit; he was intubated the following day due to suspected immunological involvement of the intercostal musculature. The patient was given methylprednisolone (1 g/kg) during 3 days and intravenous immunoglobulins. On day 37, he was given infliximab (5 mg/kg). On day 38, the patient felt better and had better muscle strength in his hands. On day 39, the patient developed carbon dioxide retention and needed noninvasive ventilation, and he developed sinus bradycardia. He eventually died on day 39.\n\nAutopsy showed a significant stenosis of the right coronary artery but no fibrosis or signs of recent myocardial infarction. The tongue was softened. No surgical complication after hemicolectomy was observed. A 50 × 60 mm metastasis and 3–4 up to 5-mm metastases were observed in the right liver lobe. Microscopical examination of the intercostal musculature, diaphragm, cervical musculature and tongue showed pronounced inflammatory infiltration of lymphocytes, occasional plasma cells and granulocytes, and fibrosis, consistent with a pronounced myositis (Fig. 2). Biopsies from the heart showed fibrosis in one area, consistent with myocardial infarction. In a small area of the heart, an inflammatory infiltrate was observed, with similarities to the inflammatory infiltrates in the skeletal musculature. In the liver, microscopical examination did not show metastases from colorectal cancer but instead a hepatocellular cancer (HCC) positive for hepatocytes and negative for glypican, CDX2, CK20 and CK7. In addition, fibrosis stage 2–3 according to Batts and Ludwig in the porta field was observed. The cause of death was determined as respiratory insufficiency due to polymyositis.\n\nDiscussion\nDespite the fact that our patient was given high doses of corticosteroids, intravenous immunoglobulins, infliximab and intensive care (according to clinical practice), the patient succumbed to irAEs. Autopsy displayed ICI-induced autoimmune involvement of both skeletal muscles and cardiac muscles. Haddox et al. [4] reported a case of autopsy-verified pembrolizumab-induced bulbar myopathy, myocarditis, T-cell infiltration of the diaphragm and respiratory insufficiency. Not only did our patient show signs of myositis including muscular pain and weakness, but laboratory testing also indicated myositis with increased levels of CK and myoglobin. We initially suspected hepatitis due to an elevation of AST and ALT. However, there are many extrahepatic sources of AST and ALT − for example, skeletal and cardiac muscles [5].\n\nShi et al. [6] reported that neurological irAEs occurred in 2.6% of patients under PD-1 targeted therapy. In that study, almost half of the cases had encephalitis and less than 0.5% neuropathy. Suzuki et al. [7] showed that 0.12% of nivolumab-treated patients developed MG. In our case, antibodies against acetylcholine receptor and titin were observed, showing that the patient also had developed MG [8]. Antibodies against acetylcholine receptor are common in ICI-induced MG [9]. In patients developing neurological irAEs, it is common with overlap syndromes, that is, with combined syndromes of myositis, MG and neuropathy [10]. It is also common with concomitant myositis and myocarditis and high levels of serum CK along with ICI-induced MG [3, 7]. Positivity for anti-titin has previously been reported for pembrolizumab-induced MG combined with necrotizing myositis [11]. Clinical signs of MG were difficult to identify in the predominant clinical picture of polymyositis in our patient. In addition, albumin was present in the cerebrospinal fluid, which could be consistent with the Guillain-Barré syndrome [12]. As mentioned, in the predominant clinical picture of polymyositis, absence of reflexes was difficult to separate from a general detriment to muscle force. We were not able to perform neurography as well.\n\nTo our surprise, autopsy revealed no presence of colorectal metastases but instead the presence of HCC. The HCC seemed to have responded partly to pembrolizumab therapy. Pembrolizumab has shown efficacy against HCC, and it was approved in 2017 for solid tumors with MMR-D/MSI-H including HCC and in 2018 for advanced HCC [13]. ICIs have been suggested to be used against PD-1/PD-L1-expressing HCC [14]. Our patient had two primary cancers, of which the colorectal tumor was MMR-D. Lynch syndrome is a condition due to germline mutations in MMR genes. We do not know whether our patient had Lynch syndrome; however, patients with Lynch syndrome are not only at risk of developing colorectal cancer and endometrial cancer, but also at an increased risk of developing other primary cancers including tumors in the hepatobiliary tract [15].\n\nIn conclusion, ICI-induced myositis may be accompanied by neurological irAEs which may have a subtle course initially but may take a dramatic and fatal course eventually. In patients experiencing muscle pain and weakness after receiving immunotherapy, myositis should be suspected.\n\nStatement of Ethics\nThis case report was accomplished in accordance with the Declaration of Helsinki. The patient's wife has given informed consent to publish this case report.\n\nConflict of Interest Statement\nThe authors declare no conflict of interest.\n\nFunding Sources\nNo funding was received for this case report.\n\nAuthor Contributions\nD.G. and L.N. were responsible for the design of the case report, for acquisition and interpretation of the data, and for drafting of the manuscript. D.G. was responsible for the oncological care of the patient, H.B. for the neurological care of the patient, and Å.F. for immunohistochemistry, autopsy and the pathology report. All authors contributed to and approved the final draft of the manuscript.\n\nFig. 1 Changes in plasma levels of C-reactive protein (CRP), white blood cell count (WBC) and absolute neutrophil count (ANC) (a), of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) (b), and of creatinine and creatine kinase (CK) (c) during the clinical course.\n\nFig. 2 Biopsies taken at autopsy from the intercostal musculature (×200) and diaphragm (×50) showing a pronounced inflammatory infiltrate of the skeletal muscle.\n==== Refs\nReferences\n1 Boussiotis VA Chatterjee P Li L Biochemical signaling of PD-1 on T cells and its functional implications Cancer J 2014 Jul-Aug 20 (4) 265 71 25098287 \n2 Hottinger AF Neurologic complications of immune checkpoint inhibitors Curr Opin Neurol 2016 12 29 (6) 806 12 27653290 \n3 Vermeulen L Depuydt CE Weckx P Bechter O Van Damme P Thal DR Myositis as a neuromuscular complication of immune checkpoint inhibitors Acta Neurol Belg 2020 4 120 (2) 355 64 31993961 \n4 Haddox CL Shenoy N Shah KK Kao JC Jain S Halfdanarson TR Pembrolizumab induced bulbar myopathy and respiratory failure with necrotizing myositis of the diaphragm Ann Oncol 2017 Mar 1 28 (3) 673 5 27993808 \n5 Wroblewski F The clinical significance of alterations in transaminase activities of serum and other body fluids Adv Clin Chem 1958 1 (2) 313 51 13571034 \n6 Shi S Jaoube JA Kanwar R Jin MC Amorin A Varanasi V Neurological adverse effects due to programmed death 1 (PD-1) inhibitors J Neurooncol 2020 6 148 (2) 291 7 32350779 \n7 Suzuki S Ishikawa N Konoeda F Seki N Fukushima S Takahashi K Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan Neurology 2017 Sep 12 89 (11) 1127 34 28821685 \n8 Lazaridis K Tzartos SJ Autoantibody specificities in myasthenia gravis; implications for improved diagnostics and therapeutics Front Immunol 2020 11 212 32117321 \n9 Becquart O Lacotte J Malissart P Nadal J Lesage C Guillot B Myasthenia gravis induced by immune checkpoint inhibitors J Immunother 2019 10 42 (8) 309 12 31246640 \n10 Möhn N Beutel G Gutzmer R Ivanyi P Satzger I Skripuletz T Neurological immune related adverse events associated with nivolumab, ipilimumab, and pembrolizumab therapy − review of the literature and future outlook J Clin Med 2019 10 8 (11) 1777 \n11 Onda A Miyagawa S Takahashi N Gochi M Takagi M Nishino I Pembrolizumab-induced ocular myasthenia gravis with anti-titin antibody and necrotizing myopathy Intern Med 2019 6 58 (11) 1635 8 30713313 \n12 Ropper AH The Guillain-Barré syndrome N Engl J Med 1992 4 326 (17) 1130 6 1552914 \n13 Zhu AX Finn RS Edeline J Cattan S Ogasawara S Palmer D Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial Lancet Oncol 2018 7 19 (7) 940 52 29875066 \n14 Moris D Rahnemai-Azar AA Zhang X Ntanasis-Stathopoulos I Tsilimigras DI Chakedis J Program death-1 immune checkpoint and tumor microenvironment in malignant liver tumors Surg Oncol 2017 12 26 (4) 423 30 29113661 \n15 Win AK Lindor NM Young JP Macrae FA Young GP Williamson E Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome J Natl Cancer Inst 2012 Sep 19 104 (18) 1363 72 22933731\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(3)",
"journal": "Case reports in oncology",
"keywords": "Colorectal adenocarcinoma; Hepatocellular carcinoma; Microsatellite-instable tumor; Myasthenia gravis; Myositis; Pembrolizumab",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1252-1257",
"pmc": null,
"pmid": "33250739",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "31246640;29875066;32117321;27993808;28821685;31653079;32350779;22933731;29113661;1552914;25098287;13571034;31993961;27653290;30713313",
"title": "Immune Checkpoint Inhibitor-Induced Polymyositis and Myasthenia Gravis with Fatal Outcome.",
"title_normalized": "immune checkpoint inhibitor induced polymyositis and myasthenia gravis with fatal outcome"
} | [
{
"companynumb": "SE-CELLTRION INC.-2020SE033560",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional":... |
{
"abstract": "We present a case of simultaneous cardiotoxicity and stroke-like neurotoxicity in a patient treated with FOLFOX, a 5-Fluorouracil (5-FU)-containing chemotherapy regimen. Within hours of FOLFOX infusion, the patient began to exhibit signs and symptoms of myocardial ischemia and stroke mimic. Coronary vasoconstriction and vasospasm is a known mechanism of 5-FU-induced cardiotoxicity. 5-FU-induced neurotoxicity commonly presents as encephalopathy and is likely attributable to the accumulation of ammonia, a product of 5-FU metabolism. However, our patient presented with focal neurological signs and normal levels of ammonia. This suggests that 5-FU-induced vasospasm in the coronary arteries and cerebral vasculature is a likely cause of the simultaneous cardiac and neurological events we report here which have not been reported previously. Recognition of these toxicities as complications of 5-FU chemotherapy is crucial for the proper diagnosis and treatment of patients.",
"affiliations": "Department of Medicine, SUNY-Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.;Department of Medicine, SUNY-Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.;Department of Medicine, SUNY-Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.;Department of Medicine, SUNY-Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.;Department of Medicine, SUNY-Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.;Department of Medicine, SUNY-Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.;Department of Medicine, SUNY-Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.",
"authors": "Ray|Justina|J|;Mahmood|Abdullah|A|;Dogar|Muhammad|M|;Guo|Junjing|J|;Nwamaghinna|Felix|F|;Salciccioli|Louis|L|;McFarlane|Samy I|SI|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-2151",
"issue": "8(3)",
"journal": "American journal of medical case reports",
"keywords": "5-FU; 5-fluorouracil; FOLFOX; cardiotoxicity; chemotherapy; neurotoxicity",
"medline_ta": "Am J Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730497",
"other_id": null,
"pages": "73-75",
"pmc": null,
"pmid": "32149185",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "2083185;20622967;9748055;16529545;25186061;2466960;16567310;23582737;15033676;16436463;23019400;14749623;21273620;10327032;15899622;8391384;17826933;28711275;10895000;17343330;28283339;19415535",
"title": "Simultaneous Cardiotoxicity and Neurotoxicity Associated with 5-fluorouracil Containing Chemotherapy: A Case Report and Literature Review.",
"title_normalized": "simultaneous cardiotoxicity and neurotoxicity associated with 5 fluorouracil containing chemotherapy a case report and literature review"
} | [
{
"companynumb": "US-ACCORD-176970",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "1",
"dru... |
{
"abstract": "A 78-year-old man had received interferon therapy and achieved sustained virologic response for chronic hepatitis C 10 years before. He came to our hospital due to liver damage. Abdominal ultrasonography showed a 90-mm mass lesion in the liver. The echoic level was high in the central part and low in the edge of the tumor. Moreover, there was an accumulation of low echoic irregular mass lesions around the hepatic portal region. Cervical ultrasonography also revealed several 15-mm mass lesions on the left clavicle, the imaging character of which was similar to the liver tumor. The liver tumor seemed to be hypovascular on dynamic computed tomography, but contrast-enhanced ultrasonography showed hyperenhancement at the early vascular phase and at maximum intensity projection showed a treelike branch vascular structure that derived from the central part to the margin of the mass. A needle biopsy of the liver tumor and a cervical lymph node resection were performed, which led to the definitive diagnosis of undifferentiated carcinoma of the liver with multiple lymph node metastasis, upon histological analysis. Undifferentiated carcinoma of the liver is extremely rare and contrast-enhanced ultrasonography was the most useful device for evaluating vascular characteristics in this case.",
"affiliations": "Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan. sa3110@f2.dion.ne.jp.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Pathology, Toranomon Hospital, Tokyo, Japan.;Department of Oncology, Toranomon Hospital, Tokyo, Japan.;Clinical Laboratory, Toranomon Hospital, Tokyo, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.;Department of Oncology, Toranomon Hospital, Tokyo, Japan.;Department of Oncology, Toranomon Hospital, Tokyo, Japan.;Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.",
"authors": "Ogasawara|Nobuhiko|N|;Saitoh|Satoshi|S|;Suzuki|Fumitaka|F|;Kinowaki|Keiichi|K|;Masuda|Jun|J|;Denpou|Hideyuki|H|;Akuta|Norio|N|;Fujiyama|Shunichiro|S|;Kawamura|Yusuke|Y|;Sezaki|Hitomi|H|;Hosaka|Tetsuya|T|;Kobayashi|Masahiro|M|;Suzuki|Yoshiyuki|Y|;Arase|Yasuji|Y|;Ikeda|Kenji|K|;Miura|Yuji|Y|;Takano|Toshimi|T|;Kumada|Hiromitsu|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-020-01180-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(6)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Carcinoma; Hepatitis C; Ultrasonography; Undifferentiated",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000368:Aged; D002277:Carcinoma; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1225-1232",
"pmc": null,
"pmid": "32651870",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Undifferentiated carcinoma of the liver demonstrated by contrast-enhanced ultrasonography.",
"title_normalized": "undifferentiated carcinoma of the liver demonstrated by contrast enhanced ultrasonography"
} | [
{
"companynumb": "JP-PFIZER INC-2021487637",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Pembrolizumab is a selective anti-PD-L1 humanised monoclonal antibody approved by the Food and Drug Administration for treating multiple cancers, including cervical cancer, non-small cell lung cancer (NSCLC), renal cell carcinoma, bladder cancer, and squamous head and neck cancer. Pneumonitis is a rare but known complication of pembrolizumab treatment for NSCLC. The median time frame of its appearance is 2.8 months. However, we present a case of pneumonitis appearing within 48 hours. The patient presented with rapidly progressive respiratory failure, and imaging demonstrated diffuse bilateral patchy involvement of the upper lung lobe and pre-hilar regions, which likely indicate pneumonitis. Because of likely grade 3 pneumonitis, he was treated with steroids and showed immediate improvement of symptoms. Repeated CT imaging showed resolution of bilateral patchy infiltrates. He was discharged to the rehabilitation unit. Rapid recognition of pneumonitis as a side effect of pembrolizumab is important because early treatment can help prevent respiratory failure and possible death.",
"affiliations": "Internal Medicine, McLaren Regional Medical Center, Flint, Michigan, USA joshua.christy@mclaren.org.;Internal Medicine, McLaren Regional Medical Center, Flint, Michigan, USA.;Internal Medicine, McLaren Regional Medical Center, Flint, Michigan, USA.;Internal Medicine, McLaren Regional Medical Center, Flint, Michigan, USA.",
"authors": "Christy|Joshua|J|;Rafae|Abdul|A|http://orcid.org/0000-0003-4113-3304;Kandah|Emad|E|;Kunadi|Arvind|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242493",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "chemotherapy; immunology; lung cancer (oncology); pharmacology and therapeutics; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D002289:Carcinoma, Non-Small-Cell Lung; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D011014:Pneumonia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34266820",
"pubdate": "2021-07-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early presentation of pembrolizumab-associated pneumonitis.",
"title_normalized": "early presentation of pembrolizumab associated pneumonitis"
} | [
{
"companynumb": "US-009507513-2107USA007987",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThere is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics-related cardiac dysfunction (CTRCD).\n\n\nOBJECTIVE\nWe aimed to discover new biomarkers associated with doxorubicin- and trastuzumab-induced CTRCD using high-throughput proteomic profiling.\n\n\nRESULTS\nPlasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from 3 cases with CTRCD and 4 age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography-mass spectrometry. From these analyses, 862 proteins were identified from case/control pairs 1 and 2 and 1360 proteins from case/control pair 3. Proteins with a >1.5-fold change in cases compared with controls with a P<0.05 either at the time of CTRCD diagnosis or across all time points were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E, with higher levels detected at baseline and across all time points in controls without CTRCD as compared with matched CTRCD cases (P<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline immunoglobulin E levels were associated with a significantly lower risk of CTRCD (P=0.018).\n\n\nCONCLUSIONS\nIn patients receiving doxorubicin and trastuzumab, high baseline immunoglobulin E levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin- and trastuzumab-induced cardiac dysfunction.",
"affiliations": "From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.;From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.;From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.;From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.;From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.;From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.;From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. bonnie.ky@uphs.upenn.edu.",
"authors": "Beer|Lynn A|LA|;Kossenkov|Andrew V|AV|;Liu|Qin|Q|;Luning Prak|Eline|E|;Domchek|Susan|S|;Speicher|David W|DW|;Ky|Bonnie|B|",
"chemical_list": "D000970:Antineoplastic Agents; D015415:Biomarkers; D007074:Immunoglobulin G; D007073:Immunoglobulin E; D004317:Doxorubicin; D003520:Cyclophosphamide; D000068878:Trastuzumab; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCRESAHA.116.309004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-7330",
"issue": "119(10)",
"journal": "Circulation research",
"keywords": "CTRCD; cardiomyopathy; immune mediators; label-free quantitation; plasma biomarkers; proteomics",
"medline_ta": "Circ Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D001943:Breast Neoplasms; D009202:Cardiomyopathies; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure; D006801:Humans; D007073:Immunoglobulin E; D007074:Immunoglobulin G; D008875:Middle Aged; D017239:Paclitaxel; D040901:Proteomics; D013318:Stroke Volume; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left; D055815:Young Adult",
"nlm_unique_id": "0047103",
"other_id": null,
"pages": "1135-1144",
"pmc": null,
"pmid": "27582370",
"pubdate": "2016-10-28",
"publication_types": "D016428:Journal Article",
"references": "22663150;12767102;22223209;24942700;23203882;17687157;21142075;15833839;16258083;15254680;17646669;19029910;10669540;12456484;11862579;24467266;9012621;19298913;17595802;27098623;11248153;19254676;19647861;25559473;18606918;15925558;20596087",
"title": "Baseline Immunoglobulin E Levels as a Marker of Doxorubicin- and Trastuzumab-Associated Cardiac Dysfunction.",
"title_normalized": "baseline immunoglobulin e levels as a marker of doxorubicin and trastuzumab associated cardiac dysfunction"
} | [
{
"companynumb": "US-ROCHE-1838207",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 71-year-old man operated for a sigmoid tumour remained in the surveillance after adjuvant chemotherapy. After 3 years, a left axillary lymph node was visible on CT scan. The biopsy revealed a necrotising and abscessed granulomatous lymphadenitis, suggestive of cat scratch disease. The patient confirmed having been scratched by a cat and the serology for Bartonella henselae was IgM+/IgG-. Direct and culture examinations for tuberculosis were negative. The patient was treated for cat scratch disease. One year later, the CT scan showed increased left axillary lymph nodes and a left pleural effusion. Direct and cultural examinations to exclude tuberculosis were again negative. Interferon-γ release assay testing for tuberculosis was undetermined and then positive. Lymph node and pleural tuberculosis were diagnosed and treated with a good radiological response. This article has provides evidence of the importance of continued search for the right diagnosis and that two diagnoses can happen in the same patient.",
"affiliations": "Oncology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisboa, Portugal.",
"authors": "Matias|M|M|;Marques|T|T|;Ferreira|M A|MA|;Ribeiro|L|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D018416:Bartonella henselae; D002372:Cat-Scratch Disease; D006801:Humans; D061705:Image-Guided Biopsy; D008297:Male; D049268:Positron-Emission Tomography; D011183:Postoperative Complications; D012811:Sigmoid Neoplasms; D014057:Tomography, X-Ray Computed; D014388:Tuberculosis, Lymph Node; D014396:Tuberculosis, Pleural",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24334464",
"pubdate": "2013-12-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2118407;9655532;17073081;4061408;9230358;11095849;2196725",
"title": "Cat scratch disease and lymph node tuberculosis in a colon patient with cancer.",
"title_normalized": "cat scratch disease and lymph node tuberculosis in a colon patient with cancer"
} | [
{
"companynumb": "PT-TEVA-551303ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"d... |
{
"abstract": "Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40 years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.",
"affiliations": "Department of Human Genetics, McGill University, Montreal, QC, Canada.;College of Medicine at Peoria, University of Illinois, Peoria, IL, USA.;College of Medicine at Peoria, University of Illinois, Peoria, IL, USA.;Illinois Cancer Care, Peoria, IL, USA.;Department of Pathology, McGill University, Montreal, QC, Canada.;Duke University Medical Center, Durham, NC, USA.;Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.;Institute of Neuropathology, University Hospital Münster, Münster, Germany.;Department of Human Genetics, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.",
"authors": "Witkowski|Leora|L|;Donini|Nancy|N|;Byler-Dann|Rebecca|R|;Knost|James A|JA|;Albrecht|Steffen|S|;Berchuck|Andrew|A|;McCluggage|W Glenn|WG|;Hasselblatt|Martin|M|;Foulkes|William D|WD|",
"chemical_list": "D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10689-016-9957-6",
"fulltext": "\n==== Front\nFam CancerFam. CancerFamilial Cancer1389-96001573-7292Springer Netherlands Dordrecht 27866340995710.1007/s10689-016-9957-6Short CommunicationThe hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases Witkowski Leora 12Donini Nancy 3Byler-Dann Rebecca 3Knost James A. 4Albrecht Steffen 5Berchuck Andrew 6McCluggage W. Glenn 7Hasselblatt Martin 8Foulkes William D. william.foulkes@mcgill.ca 1291 0000 0004 1936 8649grid.14709.3bDepartment of Human Genetics, McGill University, Montreal, QC Canada 2 0000 0000 9401 2774grid.414980.0Lady Davis Institute and Segal Cancer Center, Jewish General Hospital, 3755 Cote Ste Catherine Road, Montreal, QC H3T 1E2 Canada 3 0000 0001 0741 4132grid.430852.8College of Medicine at Peoria, University of Illinois, Peoria, IL USA 4 Illinois Cancer Care, Peoria, IL USA 5 0000 0004 1936 8649grid.14709.3bDepartment of Pathology, McGill University, Montreal, QC Canada 6 0000000100241216grid.189509.cDuke University Medical Center, Durham, NC USA 7 0000 0000 9565 2378grid.412915.aDepartment of Pathology, Belfast Health and Social Care Trust, Belfast, UK 8 0000 0004 0551 4246grid.16149.3bInstitute of Neuropathology, University Hospital Münster, Münster, Germany 9 0000 0000 9064 4811grid.63984.30Department of Medical Genetics and Cancer Research Program, Research Institute, McGill University Health Centre, Montreal, QC Canada 19 11 2016 19 11 2016 2017 16 3 395 399 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40 years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.\n\nKeywords\nOvarian cancerHereditarySCCOHTSMARCA4RhabdoidMutationhttp://dx.doi.org/10.13039/501100000015Canadian Cancer Society Research InstituteINNOV14-2Foulkes William D. Small Cell Ovarian Cancer Foundationhttp://dx.doi.org/10.13039/501100000156Fonds de Recherche du Québec - Santéissue-copyright-statement© Springer Science+Business Media B.V. 2017\n==== Body\nIntroduction\nSmall cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated form of ovarian cancer in women below age 40. It is an aggressive cancer with 5-year survival rates of 53.8% in stage I disease [1]. SCCOHT is a monogenic and at times hereditary disease, characterized by germline and somatic mutations in the chromatin remodelling gene, SMARCA4, a member of the SWI/SNF complex [1]. Further analyses have revealed that these tumours are very similar to rhabdoid tumours (RTs) on clinical, morphological, and genetic levels. As such, we have proposed that SCCOHT should be regarded as an RT of the ovary [2]. RTs are pediatric soft tissue tumours that usually arise in the kidney but can arise elsewhere, and along with the intracranial variant, called atypical teratoid/rhabdoid tumours (ATRTs), they are usually characterized by mutations in SMARCB1, another gene in the SWI/SNF complex. In rare instances, however, RTs are caused by mutations in SMARCA4 [3]. These mutations almost always lead to loss of their encoded protein (SMARCA4 or SMARCB1) by immunohistochemistry, making this an important diagnostic marker for these tumours [1].\n\nIn rare instances, RTs and SCCOHTs have been found to arise in familial settings due to germline mutations in either SMARCA4 or SMARCB1 [1]. Up to 35% of RTs are caused by germline SMARCB1 mutations [4], and up to 43% of SCCOHTs by germline SMARCA4 mutations [1]; this has implications for management of the diseases in the affected families. Germline SMARCB1 or SMARCA4 mutations define rhabdoid tumour predisposition syndrome type 1 (RTPS1; OMIM #609322) or type 2 (RTPS2, OMIM #613325), respectively. Although the ovarian type of RT (SCCOHT) is almost always caused by mutations in SMARCA4, and extra-ovarian RT by mutations in SMARCB1, it is possible for multiple tumour types within the rhabdoid tumour spectrum to be caused by the same mutation [3–5].\n\nHere we describe two previously unpublished families, both consisting of two females with SCCOHT. The affected women were diagnosed between the ages of 23 and 36, and three of the four eventually succumbed to their disease. We discuss the implications of familial occurrence of SCCOHT and propose necessary steps for diagnosis and management of the disease in a genetic context.\n\nMaterials and methods\nSamples\nDNA was extracted from patients’ blood and FFPE tumour tissue as previously described. RNA was extracted from patients’ blood as previously described [6].\n\nSanger sequencing and immunohistochemistry were performed as previously described [5].\n\nResults\nFamily 1\nFamily 1 consists of a proband who was diagnosed with SCCOHT at age 23 years (Fig. 1a, patient III:1) and her paternal half-sister (Fig. 1a, patient III:3), who was diagnosed with SCCOHT at age 30. Patient III:1 was diagnosed with FIGO stage IC SCCOHT of the right ovary. Bilateral salpingo-oophorectomy and omentectomy, followed by cisplatin and etoposide with adjuvant pelvic radiation achieved a complete response. However, she relapsed in a periaortic lymph node eighteen months after diagnosis and received further cisplatin and etoposide as well as adjuvant radiotherapy to the periaortic nodal recurrence. She underwent subsequent exploratory laparotomy and resection of the right periaortic mass. She is currently recovering from surgery.Fig. 1 Family 1. a Pedigree of family 1. b Mutations found by Sanger sequencing in affected patients. Top: Germline mutation found in both patients; middle: representative chromatogram from patient III:1 showing somatic LOH found in tumours of both patients; bottom: cDNA sequencing across mutation, showing that splice mutation leads to skipping of exon 19. Loss of expression was seen in both SCCOHT tumors and representative SMARCA4 immunohistochemistry is shown in two tumors—c in the SCCOHT from patient III:3, with complete loss of SMARCA4 staining and positive internal controls and d: in the lung tumor from patient II:4. In d immunohistochemistry for SMARCA4 shows loss of nuclear SMARCA4 staining in pleomorphic tumor cells, but retained staining in small round lymphocytic nuclei (internal positive control). Original magnification 600×. TAH/BSO, total abdominal hysterectomy/bilateral salpingo-oophorectomy\n\n\n\n\nPatient III:3, the half-sister of patient III:1, was diagnosed with FIGO stage IIIB SCCOHT of the left ovary. She underwent a left salpingo-oophorectomy, right oophorectomy, omentectomy, and peritoneal biopsies. Her omentum and peritoneal biopsies showed involvement by tumour. She received cisplatin plus etoposide for one cycle with no response. Six weeks after diagnosis she received palliative radiation for three weeks and died 2 weeks later, three months after the original diagnosis.\n\nThe patients’ family history is remarkable in that their father (Fig. 1a, patient II:2), a smoker, had died from metastatic lung carcinoma at age 53 with underlying chronic obstructive pulmonary disease. Histologically, his lung tumor was a mucinous adenocarcinoma without any rhabdoid features. All three patients were found to carry a germline splice mutation in the SMARCA4: c.2859+1G>C, which led to an in-frame deletion of exon 19 (Fig. 1b). Both women showed loss of heterozygosity (LOH) of the mutation in their SCCOHT (Fig. 1b). The SMARCA4 protein was immunohistochemically lost in both SCCOHTs (Fig. 1c) and the lung carcinoma (Fig. 1d). The second half-sister of the proband (Fig. 1a, patient III:4) as well as the daughter of patient III:2 (Fig. 1a, patient IV:1) were both found to carry the familial germline mutation. Patient III:4 underwent a prophylactic oophorectomy, while patient IV:1 is being followed with biannual pelvic ultrasonography. It should be noted that this screening has not been proven to be effective and should not replace oophorectomy as a management strategy, particularly for those women who have completed child-bearing.\n\nFamily 2\nFamily 2 consists of a proband who was diagnosed with SCCOHT at age 23 (Fig. 2, patient III:2) and her mother (Fig. 2, patient II:3), who had been diagnosed with an ovarian “rhabdoid tumour”, consistent with a diagnosis of SCCOHT 19 years earlier, at age 36 (see below). Patient III:2 (Fig. 2) was diagnosed with FIGO stage IIIB SCCOHT of the right ovary. She underwent a right salpingo-oophorectomy, an omentectomy, and resection of right periaortic and pelvic lymph nodes. There was tumour involvement of the abdominal peritoneum and metastases to her pelvic and periaortic lymph nodes. She received 6 cycles of chemotherapy, consisting of cisplatin and etoposide. She then received radiotherapy and single agent taxol for 4 cycles but rapidly progressed and died 14 months post diagnosis.Fig. 2 Family 2. a Pedigree of family 2. b Mutations found by Sanger sequencing in affected patients. Top germline mutation found in both patients; middle LOH seen in tumour from patient II:3; bottom somatic LOH found in tumours of both patients. c Representative SMARCA4 immunohistochemistry in tumour of patient III:2. Loss of expression was seen in both patients. Pr Ca, Prostate cancer\n\n\n\n\nPatient II:3 was the mother of Patient III:2. At age 36, she was diagnosed with a “poorly differentiated adenocarcinoma with extensive rhabdoid features” of her right ovary. We now know that this description is compatible with a diagnosis of SCCOHT, but when she was diagnosed, SCCOHT was a relatively newly described entity (first described in 1979 [7]). The patient underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and tumour debulking. Due to her unstable condition post-operatively no chemotherapy was given. The patient died three weeks after her original diagnosis.\n\nAside from the two affected women, the family history was unremarkable (Fig. 2a). The SMARCA4 gene was sequenced in germline and tumour DNA of both patients and a germline nonsense mutation was found: c.175C>T; p.Asn59* (Fig. 2b). The tumour of patient III:2 harboured a second somatic mutation: c.2375T > C; p.Leu792Pro. The tumours of both patients displayed loss of the SMARCA4 protein by immunohistochemistry (Fig. 2C). The sister of the proband did not carry the familial germline mutation.\n\nDiscussion\nHere we report two new familial occurrences of SCCOHT. Previously, only four familial cases of SCCOHT were sequenced, and all affected patients were found to carry SMARCA4 mutations with second somatic mutations in their tumours (Table 1) [1]. While the incidence of SCCOHT occurring in families is low, the incidence of germline mutations in SCCOHT patients is relatively high (43%) [1]. This is likely due to the fact that this tumour characteristically occurs in young females (and at a younger age in those with germline mutations than those with only somatic mutations [1]). Most carriers are diagnosed prior to having children and either die of their disease, or survive infertile due to therapy. Furthermore, half of patients with germline mutations have been found to inherit the mutation from their father [1]. Only one case of RT of the ovary has been reported to be due to a de novo germline mutation, and the daughter of the patient developed an ATRT [5].\n\nThe unknown penetrance of these mutations remains a challenge when counselling patients and their families. Only one female SMARCA4 carrier has been reported to remain healthy past her sixth decade; this was the grandmother of an ATRT patient [3]. Further testing of affected and unaffected family members will hopefully elucidate the true penetrance and allow carriers to be more informed when making potentially life-altering decisions, such as prophylactic oophorectomies [8].\n\nDue to the high incidence of germline mutations in SCCOHT, it is recommended that all patients with the disease undergo genetic testing. Although it has not been shown to alter the treatment or outcome of patients, it can benefit relatives who may carry the mutation. Female carriers of truncating mutations are at risk for SCCOHT, and infant carriers of both genders may be at risk for RTs. SMARCA4-mutated RTs have not been seen in patients older than 46 months [3], so the development of these tumours in older carriers is unlikely. However, the oldest woman to date diagnosed definitively with SCCOHT (showing loss of SMARCA4 staining in her tumour) was 56 years old at diagnosis. As SMARCA4 mutations overlap between SCCOHT and RTs, it is still unknown why patients develop one tumour over the other. While the lung tumour of the father in Family 1 showed loss of expression of SMARCA4, it is unclear whether the cancer was related to the SMARCA4 germline mutation; the patient was a smoker and many lung tumours display loss of SMARCA4 expression [9].\n\nThe types of SMARCA4 mutations seen in SCCOHT vary, yet all but two have led to loss of expression of the protein, with the remaining two being a missense and an in-frame deletion [1]. Germline mutations in SMARCA4, SMARCB1, and other SWI/SNF components also cause Coffin-Siris syndrome (CSS) [10, 11], a developmental disorder primarily characterized by developmental delay and intellectual and physical disabilities. Interestingly, germline SMARCA4 and SMARCB1 mutations causing CSS have mostly been missense and de novo, whereas those causing RTs or SCCOHT have mostly been truncating and inherited, with only one reported RT caused by a de novo SMARCA4 mutation [5]. Unlike in SCCOHT and RTs, no overlap of mutations has been reported between CSS and either SCCOHT or RT. Furthermore, no patients with SMARCA4-deficient cancers have been reported to show a CSS phenotype, and no CSS patients have been found to develop RTs. However, one patient with a SMARCB1 mutation and CSS has been reported to develop schwannomatosis, another type of tumour caused by germline SMARCB1 mutations [12]. The mutations leading to schwannomatosis are most often missense variants, but may be loss of function as well. Interestingly, in some patients with loss of function mutations, the SMARCB1 mRNA has been found to escape degradation by reinitiating translation at the AUG codon encoding methionine at position 27 of the SMARCB1 protein [13]. While it is still not entirely clear why some mutations in the SWI/SNF complex predispose to cancer, while others lead to intellectual disability, but it has been postulated that the mutations in any of the SWI/SNF complex members that lead to developmental disorders exert either dominant-negative or gain-of-function effects, while those leading to SCCOHT are loss-of-function mutations [10]. Similarly, both loss of function and missense mutations in SMARCB1 can lead to schwannomatosis [14], and it still remains unclear why some carriers develop schwannomas, while other develop RTs.\n\nAlthough the familial incidence of SCCOHT is low, it is important to note the high fraction caused by germline SMARCA4 mutations and to recognize that even without a family history, it may be hereditary, for example if the patient has inherited a germline mutation from her father or acquired one de novo. Furthermore, the similarity between SCCOHT and RTs is striking and, in addition to SCCOHT, infant SMARCA4 mutation carriers may be at risk for these tumours.\n\n\nAcknowledgements\nWe would like to thank the Small Cell Ovarian Cancer foundation, the Canadian Cancer Society Research Institute, and the Fonds de Recherche du Québec—Santé for funding this study.\n\nCompliance with ethical standards\nConflict of interest\nNo authors declare any conflict of interest.\n==== Refs\nReferences\n1. Witkowski L Goudie C Ramos P The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type Gynecol Oncol 2016 26975901 \n2. Fahiminiya S Witkowski L Nadaf J Molecular analyses reveal close similarities between small cell carcinoma of the ovary, hypercalcemic type and atypical teratoid/rhabdoid tumor Oncotarget 2015 7 2 1732 1740 \n3. Hasselblatt M Nagel I Oyen F SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis Acta Neuropathol 2014 128 3 453 456 10.1007/s00401-014-1323-x 25060813 \n4. Eaton KW Tooke LS Wainwright LM Judkins AR Biegel JA Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors Pediatr Blood Cancer 2011 56 1 7 15 10.1002/pbc.22831 21108436 \n5. Witkowski L Lalonde E Zhang J Familial rhabdoid tumour ‘avant la lettre’—from pathology review to exome sequencing and back again J Pathol 2013 231 1 35 43 10.1002/path.4225 23775540 \n6. Thiffault I Hamel N Pal T Germline truncating mutations in both MSH2 and BRCA2 in a single kindred Br J Cancer 2004 90 2 483 491 10.1038/sj.bjc.6601424 14735197 \n7. Scully RE Hartmann WH Cowan WR Tumors of the ovary and maldeveloped gonads Atlas of tumor pathology second series 1979 16 Washington Armed Forces Institute of Pathology \n8. Berchuck A Witkowski L Hasselblatt M Foulkes WD Prophylactic oophorectomy for hereditary small cell carcinoma of the ovary, hypercalcemic type Gynecol Oncol Rep 2015 12 20 22 10.1016/j.gore.2015.02.002 26076152 \n9. Imielinski M Berger Alice H Hammerman Peter S Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing Cell 2012 150 6 1107 1120 10.1016/j.cell.2012.08.029 22980975 \n10. Kosho T Miyake N Carey JC Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing Am J Med Genet 2014 166 3 241 251 10.1002/ajmg.c.31415 \n11. Tsurusaki Y Okamoto N Ohashi H Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome Nat Genet 2012 44 4 376 378 10.1038/ng.2219 22426308 \n12. Gossai N Biegel JA Messiaen L Berry SA Moertel CL Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis Am J Med Genet A 2015 167 12 3186 3191 10.1002/ajmg.a.37356 \n13. Hulsebos TJM Kenter S Verhagen WIM Premature termination of SMARCB1 translation may be followed by reinitiation in schwannomatosis-associated schwannomas, but results in absence of SMARCB1 expression in rhabdoid tumors Acta Neuropathol 2014 128 3 439 448 10.1007/s00401-014-1281-3 24740647 \n14. Hadfield KD Newman WG Bowers NL Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis J Med Genet 2008 45 6 332 339 10.1136/jmg.2007.056499 18285426\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1389-9600",
"issue": "16(3)",
"journal": "Familial cancer",
"keywords": "Hereditary; Mutation; Ovarian cancer; Rhabdoid; SCCOHT; SMARCA4",
"medline_ta": "Fam Cancer",
"mesh_terms": "D000328:Adult; D018288:Carcinoma, Small Cell; D004265:DNA Helicases; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006934:Hypercalcemia; D009154:Mutation; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms; D010375:Pedigree; D014157:Transcription Factors; D055815:Young Adult",
"nlm_unique_id": "100898211",
"other_id": null,
"pages": "395-399",
"pmc": null,
"pmid": "27866340",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22980975;26076152;18285426;25169878;22426308;21108436;26646792;24740647;14735197;26975901;26364901;25060813;23775540",
"title": "The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases.",
"title_normalized": "the hereditary nature of small cell carcinoma of the ovary hypercalcemic type two new familial cases"
} | [
{
"companynumb": "CA-ACCORD-056163",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nTNF blockers have been recently evaluated for treating refractory sarcoidosis and could be efficient. However, several cases of sarcoidosis have been diagnosed during anti-TNF therapy. Here, we report the largest series of sarcoid-like granulomatosis following TNF blocker treatment.\n\n\nMETHODS\nA call for observations of sarcoid-like granulomatosis following TNF blocker treatment was sent to the members of the French 'Club Rhumatismes et Inflammation'. Histological evidence of granulomatosis was required.\n\n\nRESULTS\nObservations of 10 patients [seven females; median age 50.5 (range 27-72) years] with sarcoid-like granulomatosis while on anti-TNF treatment were collected: five were treated with etanercept and five with monoclonal antibodies; four patients received TNF blockers for RA and six for SpA. The median delay between anti-TNF agent introduction and granulomatosis diagnosis was 18 (range 1-51) months. Clinical symptoms were mainly pulmonary and cutaneous. Angiotensin-converting enzyme activity was increased in six cases. Lymph-node and/or lung involvement were observed by CT scan of the chest for eight patients. The median delay between drug discontinuation and remission was 6 (range 1-11) months for clinical signs and 6 (range 2-12) months for biological and radiographic findings. Improvement was observed in all patients after drug discontinuation with or without steroids.\n\n\nCONCLUSIONS\nSarcoid-like granulomatosis is rare but not exceptional in patients treated with TNF blockers (approximately 1/2800) and does not seem to be related to gender, rheumatic disease or in our series the type of anti-TNF drug used (monoclonal antibodies or soluble receptor). Discontinuation of anti-TNF usually leads to recovery.",
"affiliations": "CHU Lapeyronie, Service d'Immuno-Rhumatologie, Montpellier, France.",
"authors": "Daïen|Claire Immediato|CI|;Monnier|Agnes|A|;Claudepierre|Pascal|P|;Constantin|Arnaud|A|;Eschard|Jean-Paul|JP|;Houvenagel|Eric|E|;Samimi|Mahtab|M|;Pavy|Stephan|S|;Pertuiset|Edouard|E|;Toussirot|Eric|E|;Combe|Bernard|B|;Morel|Jacques|J|;|||",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/kep046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "48(8)",
"journal": "Rheumatology (Oxford, England)",
"keywords": null,
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D000068800:Etanercept; D005260:Female; D006099:Granuloma; D006801:Humans; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor; D012216:Rheumatic Diseases; D012507:Sarcoidosis; D017565:Sarcoidosis, Pulmonary; D012871:Skin Diseases",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "883-6",
"pmc": null,
"pmid": "19423648",
"pubdate": "2009-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases.",
"title_normalized": "sarcoid like granulomatosis in patients treated with tumor necrosis factor blockers 10 cases"
} | [
{
"companynumb": "FR-CELLTRION INC.-2017FR002501",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Massive metformin overdose can cause metabolic acidosis with hyperlactatemia. A 55-year-old woman presented 5 h after multidrug overdose, including 132 g extended-release metformin. Continuous venovenous haemodiafiltration (CVVHDF) and noradrenaline were commenced due to metabolic acidosis (pH 7.0, lactate 17 mmol l-1 ) and shock. Despite 3 h of CVVHDF, her acidosis worsened (pH 6.83, lactate 24 mmol l-1 ). Intermittent haemodialysis (IHD) improved acidosis (pH 7.13, lactate 26 mmol l-1 ) but again worsened (pH 6.91, lactate 30 mmol l-1 ) with CVVHDF recommencement. IHD (12 h), CVVHDF (26 h) and vasopressor support for 7 days resulted in survival. Measured metformin concentrations were extremely high with a peak of 292 μg ml-1 at 8 h postingestion. IHD, but not CVVHDF in this case, was associated with improvement in metabolic acidosis and hyperlactataemia. Pharmacokinetic analysis of metformin concentrations found a reduced apparent oral clearance of 8.2 l h-1 and a half-life of approximately 30 h. During IHD, the apparent oral clearance increased to 22.2 l h-1 with an approximate half-life of 10 h. The impact of prolonged oral absorption from a pharmacobezoar and redistribution of metformin from peripheral sites (including erythrocytes) on the pharmacokinetic profile cannot be determined from the data available.",
"affiliations": "New South Wales Poisons Information Centre, Children's Hospital at Westmead, Westmead, New South Wales, Australia.;School of Pharmacy, University of Otago, Dunedin, New Zealand.;Intensive Care Unit, Western Health, Melbourne, Victoria, Australia.;New South Wales Poisons Information Centre, Children's Hospital at Westmead, Westmead, New South Wales, Australia.;School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.;Emergency Department and Victorian Poisons Information Centre, The Austin Hospital, Melbourne, Victoria, Australia.;School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.;New South Wales Poisons Information Centre, Children's Hospital at Westmead, Westmead, New South Wales, Australia.",
"authors": "Chiew|Angela L|AL|0000-0002-0079-5056;Wright|Daniel F B|DFB|0000-0001-9313-9252;Dobos|Nicola M|NM|;McArdle|Kylie|K|;Mostafa|Ahmed A|AA|;Newth|Annemarie|A|;Roberts|Michael S|MS|;Isbister|Geoffrey K|GK|0000-0003-1519-7419",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13582",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "84(12)",
"journal": "British journal of clinical pharmacology",
"keywords": "extracorporeal elimination; metabolic acidosis; metformin; overdose",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000138:Acidosis; D062787:Drug Overdose; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D008875:Middle Aged; D006435:Renal Dialysis; D014018:Tissue Distribution",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "2923-2927",
"pmc": null,
"pmid": "29534338",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23475568;2500402;12225607;29534338;20335644;27751611;22117616;8989177;29055035;21241070;19556031;29149325;25659252;25155462;25860205;29318220",
"title": "'Massive' metformin overdose.",
"title_normalized": "massive metformin overdose"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2018-01714",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PERINDOPRIL"
},
"drug... |
{
"abstract": "We report a case of a middle-aged woman who initially presented with a painful solitary destructive lesion at fifth lumbar vertebra. The initial diagnosis of plasma cell neoplasm was made based on limited histological information obtained from fragmented tissue sample. Clinicopathological findings were consistent with a solitary plasmacytoma, and she was treated with definitive radiotherapy. A month after completing radiotherapy, she was found to have multiple liver lesions. Subsequent liver biopsy confirmed plasmablastic lymphoma (PBL). She was treated with multiple lines of chemo/immunotherapy regimens with limited or no response. She died of progression of liver lesions causing hepatic failure 16 months post diagnosis. Because of its rarity and heterogeneous presentations, PBL could easily be overlooked clinically and pathologically in immunocompetent patients. Diagnosis of PBL should be considered when there is coexpression of myeloma and lymphoma immune markers.",
"affiliations": "Radiation Oncology, Northern NSW Local Health District, Lismore, New South Wales, Australia.;Radiation Oncology, Northern NSW Cancer Institute, Lismore, New South Wales, Australia.;Lismore Cancer Care and Haematology Unit, Northern NSW Local Health District, Lismore, New South Wales, Australia.",
"authors": "Diaz|Rodrigo|R|http://orcid.org/0000-0003-3358-5458;Amalaseelan|Julan|J|;Imlay-Gillespie|Louise|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225374",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2018-22537410.1136/bcr-2018-225374Rare Disease15061523Case ReportPlasmablastic lymphoma masquerading solitary plasmacytoma in an immunocompetent patient http://orcid.org/0000-0003-3358-5458Diaz Rodrigo 12Amalaseelan Julan 2Imlay-Gillespie Louise 31 Radiation Oncology, Northern NSW Local Health District, Lismore, New South Wales, Australia2 Radiation Oncology, Northern NSW Cancer Institute, Lismore, New South Wales, Australia3 Lismore Cancer Care and Haematology Unit, Northern NSW Local Health District, Lismore, New South Wales, AustraliaCorrespondence to Dr Rodrigo Diaz, drrdiaz@gmail.com2018 21 10 2018 21 10 2018 2018 bcr201822537425 9 2018 © BMJ Publishing Group Limited 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2018This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/We report a case of a middle-aged woman who initially presented with a painful solitary destructive lesion at fifth lumbar vertebra. The initial diagnosis of plasma cell neoplasm was made based on limited histological information obtained from fragmented tissue sample. Clinicopathological findings were consistent with a solitary plasmacytoma, and she was treated with definitive radiotherapy. A month after completing radiotherapy, she was found to have multiple liver lesions. Subsequent liver biopsy confirmed plasmablastic lymphoma (PBL). She was treated with multiple lines of chemo/immunotherapy regimens with limited or no response. She died of progression of liver lesions causing hepatic failure 16 months post diagnosis. Because of its rarity and heterogeneous presentations, PBL could easily be overlooked clinically and pathologically in immunocompetent patients. Diagnosis of PBL should be considered when there is coexpression of myeloma and lymphoma immune markers.\n\nmalignant and benign haematologyradiotherapychemotherapyspecial-featureunlocked\n==== Body\nBackground\nPlasmablastic lymphoma (PBL) is distinct type of diffuse large B cell lymphoma (DLBCL) predominantly seen in HIV-positive patients.1 The diagnosis of PBL could be a challenge due to its overlapping characterises with those of myeloma and lymphoma. Because of its rarity, no standard management strategy has been established. A review by Morscio et al showed a median overall survival (OS) of 8 months. It also revealed HIV-negative patients have slightly better OS (11 months) compared with HIV-positive patients (10 months).2\n\nHIV-negative PBL has been shown to affect relatively higher proportion of female patients in contrast to HIV-positive patients. The median age of HIV-negative PBL patients was 55 years.3 PBL in immunocompetent patients appeared to be more heterogeneous in terms of sites of involvement.3\n\nWe describe a HIV-negative case of PBL who initially appeared to have solitary plasmacytoma. Three months later, she was found to have stage IV PBL. She was treated with different chemotherapy and immunotherapy combinations and survived for 16 months.\n\nCase presentation\nA middle-aged previously healthy woman initially presented with 2 months history of left-sided sciatica-like pain. The pain then progressed to involve lower back. She did not have any B symptoms. The initial CT of lumbar spine showed a pathological fracture in L5. Subsequent MRI of lumbosacral spine demonstrated posterior extradural mass at L5 level with compression of L5 nerve root (figure 1). She proceeded to have laminectomy and surgical decompression. Intraoperatively fibrous organising lesion intimately associated with theca at S1 level was identified. The culture from surgical material grew Staphylococcus epidermidis, probably from contamination. Nevertheless, she was treated with antibiotic therapy for extended period.\n\nFigure 1 Sagittal section of T1 MRI with Gd contrast (A) reveals an enhancing extradural soft tissue mass at the level of L5. The axial view (B) revealed compression of the left L5 nerve root.\n\nThe histopathological examination of surgical specimen revealed poorly differentiated malignancy, likely haematological origin (figure 2). Immunophenotyping showed positive staining for CD45, CD138 and vimentin and negative staining for CD20, cytokeratin and thyroid transcription factor 1 (TTF-1). The ki67 index was high (70%). No fluorescence in situ hybridization (FISH) panel was performed and the specimen was negative for Epstein-Barr virus assessed by the Epstein-Barr virus encoded RNAs (EBER) in situ hybridisation. The myeloid markers were negative and a diagnosis of plasma cell neoplasm was made. Subsequent (positron emission tomography) PET did not show any other fluorodeoxyglucose (FDG) avid areas apart from L5 lesion with a maximum standardised uptake value (SUVmax) of 11.5. Bone marrow aspirate showed no increased plasma cells, no clonality and normal cytogenetics. Capillary serum electrophoresis and serum-free light chains did not demonstrate a paraprotein or light chain excess. Full blood count (FBC), liver function including lactate dehydrogenase (LDH) level were within normal range.\n\nFigure 2 Histological study of the lumbar lesion. A high-power view of the sample showing a poorly differentiated tumour composed of medium to large cells.\n\nShe received 45Gy in 25 fractions of radical radiotherapy to the L5 region. Her back pain and sciatica completely resolved after the radiotherapy.\n\nSix weeks after completing radiotherapy (4 months since initial diagnosis), she developed upper abdominal pain and non-specific flu-like symptoms. A restaging PET demonstrated complete metabolic response on the L5 region. However, multiple new liver lesions (figure 3) were identified. In addition, a new FDG avid left internal mammary node and a bony lesion at the right scapula were noted. Her LDH level was elevated to 868 U/L (normal: 120–250). Alanine transaminase (ALT), aspartate transaminase (AST) and gamma glutamyl transferase (GGT) levels were slightly elevated. FBC was normal.\n\nFigure 3 CT/positron emission tomography demonstrates multiple FDG avid liver lesions. FDG, fluorodeoxyglucose.\n\nA biopsy from the liver lesion was suggestive of high-grade non-Hodgkin’s lymphoma (figure 4). The following markers showed positive immunostaining: CD45, MUM1, c-Myc, CD138, Bcl2 and Bcl6 (weak). Negative staining was noted for CD79a CD20, ALK, CD43, CD56, CD15, CD34 and chromogranin. Approximately 90% of tumour cells showed ki67 nuclear staining. Bcl2 gene rearrangement was not detected on FISH but did show loss of 3’ end of the MYC locus. This was considered as an abnormality of uncertain significance. Expert anatomical pathology opinion was that the features were consistent with a CD20 negative, aggressive B-cell lymphoma, most likely PBL. The morphological and immunological features of original biopsy taken from L5 were found to be consistent with that of the liver biopsy. The International Prognostic Index (IPI) score was 3 (increased LDH, more than one extranodal site and stage IV).\n\nFigure 4 Histological and immunohistochemical study of the liver lesion. (A) Histology showed high-grade malignant tumour cells. The tumour consists of enlarged cells with hyperchromatic angulate nuclei and modest volumes of eosinophilic cytoplasm. (B) The tumour cells express positive staining for c-Myc (>80% cells).\n\nShe was started on chemotherapy regimen comprised of dose‐adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (DA-EPOCH). She also received bortezomib infusion and intrathecal cytarabine. A restaging PET performed after four cycles of chemotherapy showed progression of liver disease and SUVmax of 14.6. Subsequently, she proceeded to ifosfamide, carboplatin and etoposide (ICE) combination with bortezomib as salvage. A PET performed after two cycles of ICE showed a partial response particularly in the liver, and she proceeded to the third cycle.\n\nAfter the third cycle, she presented with acute abdominal pain, fever and rapidly increasing LDH level (>5 X upper limit of normal value). She was started on steroids in view of rapid clinical progression. Subsequent PET showed some persistent disease in the liver with no definite disease progression; however, its interpretation was problematic due to 5 days of steroid therapy.\n\nSalvage was commenced with gemcitabine and vinorelbine and a period of clinical stability was achieved. As symptoms of disease progression returned, a PET performed after five cycles confirmed progression of disease. Gemcitabine-based chemotherapy was ceased and she started on lenalidomide and dexamethasone. Unfortunately, she could not tolerate lenalidomide due to rapid deterioration of liver function associated with upper abdominal pain that likely reflected further disease progression. She received a course of palliative radiotherapy to liver to control the abdominal pain.\n\nInvestigations\nSee above\n\nDifferential diagnosis\nDifferential diagnosis consideration for PBL include a wide range of other lymphoid tumours1 4 with immunoblastic, plasmablastic or plasmacytic or immunoblastic appearances, such as DLBCL with plasmacytic differentiation, plasmablastic myeloma and solitary plasmacytoma (table 1). A comparison of clinical features, morphology and immunophenotype is listed on the following table.\n\nTable 1 Differential diagnosis of plasmablastic lymphoma (PBL)\n\n\tPBL\tDLBCL\tPlasmablastic myeloma/plasmacytoma\t\nClinical features\tAggressive with poor prognosis (median survival 6–12 months)\n\nUsually oral cavity location\n\nFrequent association with immunodeficiency (HIV infection, transplantation)\n\nEBV (+) 50%–60%\n\n\tWide variety of presentation\n\nVariable association with HIV\n\nEBV rare\n\n\tMostly immunocompetent\n\nUsually EBV (–)\n\nEnd-organ impairment\n\n\t\nMorphology\tAggressive with poor prognosis (median survival 6–12 months)\n\nProliferation of large plasmablastic/immunoblastic cells\n\nDiffuse sheets of monomorphic cells\n\nExtraoral and immunocompetent cases have plasmacytic differentiation\n\n\tVariable but characterised by diffuse architecture dominated by centroblasts on a centrocytic background\n\nFrequent mitotic figures and apoptosis\n\n\tLarge plasma cells containing enlarged, hyperchromatic nucleus with prominent nucleoli\n\nPlasmablastic subtype virtually identical to PBL\n\n\t\nImmunophenotype\tPositive for: CD138, CD38, CD79a, CD56\n\nNegative for CD20\n\n\tPositive for: CD20, CD79a\n\nNegative for CD138\n\n\tPlasma cell phenotype: positive CD138, CD38\n\nNegative for CD20\n\n\t\nDLBCL, diffuse large B cell lymphoma.\n\nDLBCL include a wide of clinical and morphological presentations. These tumours can be differentiated from PBL on the basis of positive immunoreactivity for B cell markers, such as CD20 and CD79a. However, both PBL and plasmablastic plasma cells neoplasms share virtually identical morphological and immunophenotype features. Hence, the distinction between these two entities must be based on clinical differences: EBV positivity is usually associated with PBL, while end-organ damage presentation (ie, renal failure, anaemia, hypercalcaemia, renal impairment) favours a diagnosis of multiple myeloma.\n\nTreatment\nSee above\n\nOutcome and follow-up\nAs the last resort, she was commenced on nivolumab. Following the first cycle, she rapidly progressed to develop hepatic failure due to continuing progression of her disease and passed away around 16 months after the initial diagnosis.\n\nDiscussion\nPBL is a rare type of high-grade lymphoma frequently involving extranodal sites. HIV-negative PBL patients are known to present with relatively advanced clinical stage with B symptoms, and less common bone marrow involvement than in HIV- positive patients.3\n\nOur patient initially presented like a typical solitary plasmacytoma. The fragmented histology sample taken from laminectomy procedure favoured plasma cell neoplasm. However, extensive crush artefacts and necrosis made it difficult to recognise lymphoma-related histological features. Therefore, we should highlight the importance to obtain adequate tissue samples to facilitate accurate diagnosis. After the confirmation of PBL on liver biopsy, the original sample taken from L5 lesion was compared with the liver cores. Both specimens showed identical histological and immunological features, which confirmed same pathological process.\n\nOne of the important differential diagnoses for PBL is plasmablastic myeloma. Absence of bone marrow involvement or hypercalcaemia/renal dysfunction in our patient makes plasmablastic myeloma an unlikely diagnosis.\n\nTo our knowledge, this is a first published report on HIV-negative PBL mimicking solitary plasmacytoma. In 2010, Castillo et al5 conducted a systematic review of 76 cases of HIV-negative PBL with predominately extraoral locations and reported a median survival time of 9 months and 2-year overall survival of only 10%. Liu et al6 reviewed eight cases of HIV-negative patients with PBL who underwent chemotherapy and reported complete response in seven cases.\n\nUnfortunately, her disease rapidly progressed to involve multiple sites, predominantly liver.\n\nThere is no well-established treatment regimen for PBL due to its rarity. Cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (CHOP) is considered as a suboptimal treatment option and the National Comprehensive Cancer Network (NCCN) guideline recommends more aggressive therapy.7 One of the treatment options for patients with HIV-associated PBL is bortezomib alone or in combination with CHOP.8 9 Another alternative is DA-EPOCH.10 Our patient was initially treated with DA-EDOCH with intrathecal cytarabine. The role of intrathecal chemotherapy as central nervous system (CNS) prophylaxis was not well studied. In view of frequent extranodal site involvement and aggressive natural history of disease, CNS prophylaxis was justified by some authors.3\n\nGiven the unfavourable outcome of PBL and expression of myeloma markers, clinicians frequently try agents that are not standard component of lymphoma management but are routinely used in the treatment of multiple myeloma. Proteasome inhibitors have been used in PBL with variable response.11–13 Unfortunately, our patient did not respond well to bortezomib/chemotherapy combination.\n\nOur patient failed to respond with the second and third lines of treatment (ICE and gemcitabine and vinorelbine, respectively). She could not tolerate lenalidomide. Lenalidomide based-chemotherapy has been shown to achieve good response in PBL.14–16 However, lenalidomide alone was seldom used in PBL. Interestingly, there are few case reports that has described dramatic response to single-agent lenalidomide in PBL.17 18 Nivolumab is a programmed cell death protein 1 (PD-1) inhibitor that has shown anticancer activity in relapsed haematological malignancies.19 Our patient’s disease rapidly progressed after first cycle of nivolumab and she died of hepatic failure 3 weeks later.\n\nLearning points\nThis is a first reported case of plasmablastic lymphoma (PBL) mimicking solitary plasmacytoma.\n\nThe case once again emphasises the need for obtaining adequate tissue sample to facilitate accurate diagnosis on the first instance.\n\nCoexpression of myeloma and lymphoma markers should raise the suspicion of PBL in any patient.\n\nContributors: RD conceived the work and wrote the article. He assisted with the literature research, image formatting for presentation in the journal, final editing and submission of the paper. LI-G was involved in the care of the patient and assisted writing the report. JA also oversaw the creation of the report and assisted in the clinical assessment of the patient. He helped in the production of the paper, literature review and final editing. JA is also responsible for the overall content as guarantor and approved the final draft.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent: Not required.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Swerdlow SH \nWHO classification of tumours of haematopoietic and lymphoid tissues . 4th ed \nLyon : IARC , 2017 .\n2 Morscio J , Dierickx D , Nijs J , et al \nClinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: single-center series of 25 cases and meta-analysis of 277 reported cases . Am J Surg Pathol \n2014 ;38 :875 –86 . 10.1097/PAS.0000000000000234 24832164 \n3 Castillo JJ , Bibas M , Miranda RN \nThe biology and treatment of plasmablastic lymphoma . Blood \n2015 ;125 :2323 –30 . 10.1182/blood-2014-10-567479 25636338 \n4 Harmon CM , Smith LB \nPlasmablastic lymphoma: a review of clinicopathologic features and differential diagnosis . Arch Pathol Lab Med \n2016 ;140 :1074 –8 . 10.5858/arpa.2016-0232-RA 27684979 \n5 Castillo JJ , Winer ES , Stachurski D , et al \nHIV-negative plasmablastic lymphoma: not in the mouth . Clin Lymphoma Myeloma Leuk \n2011 ;11 :185 –9 . 10.1016/j.clml.2011.03.008 21575922 \n6 Liu JJ , Zhang L , Ayala E , et al \nHuman immunodeficiency virus (HIV)-negative plasmablastic lymphoma: a single institutional experience and literature review . Leuk Res \n2011 ;35 :1571 –7 . 10.1016/j.leukres.2011.06.023 21752466 \n7 Guidelines Version NCCN , 2014 \nAIDS-Related B-Cell lymphomas \nhttp://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf (accessed 18 Sep 2014 ).\n8 Bibas M , Grisetti S , Alba L , et al \nPatient with HIV-associated plasmablastic lymphoma responding to bortezomib alone and in combination with dexamethasone, gemcitabine, oxaliplatin, cytarabine, and pegfilgrastim chemotherapy and lenalidomide alone . J Clin Oncol \n2010 ;28 :e704 –8 . 10.1200/JCO.2010.30.0038 20823416 \n9 Fernandez-Alvarez R , Gonzalez-Rodriguez AP , Rubio-Castro A , et al \nBortezomib plus CHOP for the treatment of HIV-associated plasmablastic lymphoma: clinical experience in three patients . Leuk Lymphoma \n2016 ;57 :463 –6 . 10.3109/10428194.2015.1050666 25976108 \n10 Noy A , Lensing SY , Moore PC , et al \nPlasmablastic lymphoma is treatable in the HAART era. A 10 year retrospective by the AIDS Malignancy Consortium . Leuk Lymphoma \n1731 ;2016 :57 .\n11 Bibas M , Grisetti S , Alba L , et al \nPatient with HIV-associated plasmablastic lymphoma responding to bortezomib alone and in combination with dexamethasone, gemcitabine, oxaliplatin, cytarabine, and pegfilgrastim chemotherapy and lenalidomide alone . J Clin Oncol \n2010 ;28 :e704 –e708 . 10.1200/JCO.2010.30.0038 20823416 \n12 Cao C , Liu T , Zhu H , et al \nBortezomib-contained chemotherapy and thalidomide combined with CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) play promising roles in plasmablastic lymphoma: a case report and literature review . Clin Lymphoma Myeloma Leuk \n2014 ;14 :e145 –e150 . 10.1016/j.clml.2014.03.002 25225082 \n13 Castillo JJ , Reagan JL , Sikov WM , et al \nBortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma . Br J Haematol \n2015 ;169 :352 –5 . 10.1111/bjh.13300 25612847 \n14 Schmit JM , DeLaune J , Norkin M , et al \nA case of plasmablastic lymphoma achieving complete response and durable remission after lenalidomide-based therapy . Oncol Res Treat \n2017 ;40 :46 –8 . 10.1159/000455146 28095384 \n15 Yanamandra U , Sahu KK , Jain N , et al \nPlasmablastic lymphoma: successful management with CHOP and lenalidomide in resource constraint settings . Ann Hematol \n2016 ;95 :1715 –7 . 10.1007/s00277-016-2732-9 27324386 \n16 Pretscher D , Kalisch A , Wilhelm M , et al \nRefractory plasmablastic lymphoma-a review of treatment options beyond standard therapy . Ann Hematol \n2017 ;96 :967 –70 . 10.1007/s00277-016-2904-7 28011983 \n17 Carras S , Regny C , Peoc’h M , et al \nDramatic efficacy of low dose lenalidomide as single agent in a patient with refractory gastric non-human immunodeficiency virus-associated plasmablastic lymphoma . Leuk Lymphoma \n2015 ;56 :2986 –8 . 10.3109/10428194.2015.1016931 25676034 \n18 Sher T , Miller KC , Lee K , et al \nRemission induction with lenalidomide alone in a patient with previously untreated plasmablastic myeloma: a case report . Clin Lymphoma Myeloma \n2009 ;9 :328 –30 . 10.3816/CLM.2009.n.065 19717386 \n19 Lesokhin AM , Ansell SM , Armand P , et al \nNivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study . J Clin Oncol \n2016 ;34 :2698 –704 . 10.1200/JCO.2015.65.9789 27269947\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "chemotherapy; malignant and benign haematology; radiotherapy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001859:Bone Neoplasms; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007121:Immunocompetence; D008113:Liver Neoplasms; D008159:Lumbar Vertebrae; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D000069293:Plasmablastic Lymphoma; D010954:Plasmacytoma; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30344143",
"pubdate": "2018-10-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25676034;21575922;27269947;25612847;25636338;19717386;27684979;21752466;28011983;24832164;20823416;28095384;26674561;25976108;25225082;27324386",
"title": "Plasmablastic lymphoma masquerading solitary plasmacytoma in an immunocompetent patient.",
"title_normalized": "plasmablastic lymphoma masquerading solitary plasmacytoma in an immunocompetent patient"
} | [
{
"companynumb": "PHHY2018AU157712",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nThe use of ursodeoxycholic acid (UDCA) to prevent gallstone formation after gastric bypass (RYGB) is still debated. Furthermore, only 1 study has assessed the effectiveness of UDCA after sleeve gastrectomy (SG) with mitigated results.\n\n\nOBJECTIVE\nTo compare the incidence of cholelithiasis (CL) between patients treated or not treated with UDCA after RYGB and SG.\n\n\nMETHODS\nUniversity hospital, France.\n\n\nMETHODS\nSince January 2008, a postoperative ultrasound monitoring was scheduled for all patients without previous cholecystectomy who underwent bariatric surgery in our institution. Patients who underwent at least 1 ultrasound in the first postoperative year (±6 months) were included. We started to systematically prescribe UDCA (500 mg/d) for 6 months postoperatively, in February 2012 for RYGB (once or twice daily) and in October 2013 for SG (once daily).\n\n\nRESULTS\nMean follow-up was 13.0±3.4 months. The incidence of CL was 32.5% in the 117 nontreated RYGB and 25.5% in the 51 nontreated SG. It was reduced to 2.4% in the 42 SG treated once daily (P = .005), to 5.7% in the 87 RYGB with 250 mg twice daily (P<.001), but only to 18.6% in the 102 RYGB with 500 mg once daily (P = .03).\n\n\nCONCLUSIONS\nUDCA 500 mg once daily for 6 months is efficient to prevent CL 1 year after SG, but the twice-daily doses seem to be more effective after RYGB. The effectiveness of UDCA once daily after SG and the superiority of the twice-daily doses after RYGB should be confirmed with more patients and longer follow-up.",
"affiliations": "Service des Explorations Fonctionnelles, Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), Hôpital Louis Mourier (AP-HP), Université Paris Diderot, Sorbonne Paris Cité, France. Electronic address: muriel.coupaye@aphp.fr.;Service de Chirurgie, Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), Hôpital Louis Mourier (AP-HP), Université Paris Diderot, Sorbonne Paris Cité, France.;Service des Explorations Fonctionnelles, Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), Hôpital Louis Mourier (AP-HP), Université Paris Diderot, Sorbonne Paris Cité, France.;Service de Chirurgie, Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), Hôpital Louis Mourier (AP-HP), Université Paris Diderot, Sorbonne Paris Cité, France.;Service des Explorations Fonctionnelles, Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), Hôpital Louis Mourier (AP-HP), Université Paris Diderot, Sorbonne Paris Cité, France.",
"authors": "Coupaye|Muriel|M|;Calabrese|Daniela|D|;Sami|Ouidad|O|;Msika|Simon|S|;Ledoux|Séverine|S|",
"chemical_list": "D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.soard.2016.11.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-7289",
"issue": "13(4)",
"journal": "Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery",
"keywords": "Bariatric surgery; Cholelithiasis; Gallstones; Gastric bypass; Sleeve gastrectomy; Ursodeoycholic acid",
"medline_ta": "Surg Obes Relat Dis",
"mesh_terms": "D000328:Adult; D050110:Bariatric Surgery; D015992:Body Mass Index; D002756:Cholagogues and Choleretics; D002769:Cholelithiasis; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D015994:Incidence; D008297:Male; D011183:Postoperative Complications; D012189:Retrospective Studies; D014580:Ursodeoxycholic Acid; D015431:Weight Loss",
"nlm_unique_id": "101233161",
"other_id": null,
"pages": "681-685",
"pmc": null,
"pmid": "28089591",
"pubdate": "2017-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Evaluation of incidence of cholelithiasis after bariatric surgery in subjects treated or not treated with ursodeoxycholic acid.",
"title_normalized": "evaluation of incidence of cholelithiasis after bariatric surgery in subjects treated or not treated with ursodeoxycholic acid"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1002022",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
... |
{
"abstract": "Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an immune-mediated disorder of the central nervous system characterized by an inflammatory response to amyloid-beta (Aβ) deposition within cerebral blood vessel walls. Immunosuppressive therapy is the mainstay of treatment. We present a case of CAA-ri in a subject already on immunosuppressive therapy after orthotopic heart transplantation (OHT). A 57-year-old man 8 months post-OHT for sarcoid cardiomyopathy developed headaches and staring spells while hospitalized for disseminated mycobacterial infection. His brain MRI revealed bi-hemispheric T2-weighted fluid-attenuated inversion recovery white matter hyperintensities and widespread microhemorrhages. Two weeks later, he developed gait ataxia and alterations in mental status, and repeat brain MRI showed more extensive confluent white matter hyperintensities. Leptomeningeal and cortex biopsy revealed changes consistent with amyloid angiitis, with perivascular and intramural histiocyte and lymphocyte collections. Mass spectroscopy confirmed Aβ deposition. Notably, the patient was on immunosuppression with daily 5 mg oral prednisone and tacrolimus before biopsy. After high-dose intravenous followed by oral corticosteroids, he demonstrated significant clinical and radiographic improvement. No relapse was noted despite the relatively rapid tapering of the prednisone therapy over 3 months, as mandated by his systemic infection. Despite the lack of a standard treatment protocol for CAA-ri, case series have reinforced the benefit of prolonged courses of glucocorticoids as single agent or in combination with other immunomodulatory agents. Hence, management of CAA-ri in patients with disseminated mycobacterial infections or OHT is challenging. Our case is unique, as review of existing literature has not revealed any similar cases of patients on chronic immunosuppression at the time of CAA-ri diagnosis, which one would expect to protect against this disorder. In addition, CAA-ri in association with cardiopulmonary sarcoidosis was not previously reported; however, a common immunopathogenic mechanism may exist.",
"affiliations": "Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.;Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.;Division of Neuropathology, Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.;Division of Heart Transplantation, Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.;Division of Heart Transplantation, Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.;Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.",
"authors": "Nelson|Thomas|T|;Leung|Bo|B|;Bannykh|Serguei|S|;Shah|Kevin S|KS|;Patel|Jignesh|J|;Dumitrascu|Oana M|OM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2019.01283",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2019.01283NeurologyCase ReportCerebral Amyloid Angiopathy-Related Inflammation in the Immunosuppressed: A Case Report Nelson Thomas 1Leung Bo 1Bannykh Serguei 2Shah Kevin S. 3Patel Jignesh 3Dumitrascu Oana M. 1*1Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States2Division of Neuropathology, Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, United States3Division of Heart Transplantation, Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesEdited by: Sally Ann Frautschy, University of California, Los Angeles, United States\n\nReviewed by: Xavier Ayrignac, Université de Montpellier, France; Jacopo C. DiFrancesco, University of Milano Bicocca, Italy; Harry Vinters, UCLA Neuropathology Consultation Service, United States\n\n*Correspondence: Oana M. Dumitrascu oana.dumitrascu@cshs.orgThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n06 12 2019 2019 10 128325 9 2019 19 11 2019 Copyright © 2019 Nelson, Leung, Bannykh, Shah, Patel and Dumitrascu.2019Nelson, Leung, Bannykh, Shah, Patel and DumitrascuThis 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.Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an immune-mediated disorder of the central nervous system characterized by an inflammatory response to amyloid-beta (Aβ) deposition within cerebral blood vessel walls. Immunosuppressive therapy is the mainstay of treatment. We present a case of CAA-ri in a subject already on immunosuppressive therapy after orthotopic heart transplantation (OHT). A 57-year-old man 8 months post-OHT for sarcoid cardiomyopathy developed headaches and staring spells while hospitalized for disseminated mycobacterial infection. His brain MRI revealed bi-hemispheric T2-weighted fluid-attenuated inversion recovery white matter hyperintensities and widespread microhemorrhages. Two weeks later, he developed gait ataxia and alterations in mental status, and repeat brain MRI showed more extensive confluent white matter hyperintensities. Leptomeningeal and cortex biopsy revealed changes consistent with amyloid angiitis, with perivascular and intramural histiocyte and lymphocyte collections. Mass spectroscopy confirmed Aβ deposition. Notably, the patient was on immunosuppression with daily 5 mg oral prednisone and tacrolimus before biopsy. After high-dose intravenous followed by oral corticosteroids, he demonstrated significant clinical and radiographic improvement. No relapse was noted despite the relatively rapid tapering of the prednisone therapy over 3 months, as mandated by his systemic infection. Despite the lack of a standard treatment protocol for CAA-ri, case series have reinforced the benefit of prolonged courses of glucocorticoids as single agent or in combination with other immunomodulatory agents. Hence, management of CAA-ri in patients with disseminated mycobacterial infections or OHT is challenging. Our case is unique, as review of existing literature has not revealed any similar cases of patients on chronic immunosuppression at the time of CAA-ri diagnosis, which one would expect to protect against this disorder. In addition, CAA-ri in association with cardiopulmonary sarcoidosis was not previously reported; however, a common immunopathogenic mechanism may exist.\n\ncerebral amyloid angiopathy-related inflammationmycobacteriaimmunosuppressionsarcoidosistransplantation\n==== Body\nBackground\nCerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare disorder of the central nervous system (CNS) that arises from development of autoantibodies to amyloid-beta protein (Aβ) within the walls of the leptomeningeal and cortical blood vessels (1–5). It affects immunocompetent individuals who present with non-specific symptoms or focal neurological deficits, which typically elicits a broad etiological investigation until the condition is recognized (6–8). The presumptive diagnosis is based on clinical and neuroimaging data, whereas the definitive diagnosis is histological (9). The mainstay of CAA-ri management is with prolonged courses of immunosuppression, although no standard treatment protocol has been established to date. We present the case of a patient who developed CAA-ri despite chronic immunosuppression for sarcoidosis and orthotopic heart transplantation (OHT).\n\nCase Presentation\nA 57-year-old male geologist with history of cardiopulmonary sarcoidosis complicated by dilated cardiomyopathy presented approximately 8 months after OHT, with a 6-weeks history of diffuse painful, raised skin lesions and open sores of the hands. His immunosuppressive regimen consisted of a combination of methotrexate, leflunomide, tacrolimus, and 5 mg prednisone daily. Blood and skin cultures isolated Mycobacterium hemophilum. The patient was treated with intravenous antibiotics for 11 days when he developed complex partial seizures, headaches, blurry vision, and mood changes. Brain MRI with contrast demonstrated abnormal T2-weighted fluid-attenuated inversion recovery signal hyperintensity in the cortical and subcortical right temporal, parietal, and occipital lobes without contrast enhancement (Figure 1). Susceptibility-weighted imaging sequences revealed innumerable chronic microhemorrhages in the bilateral infra- and supratentorial cerebral hemispheres. Early considerations included neurosarcoidosis, CNS infection, and lymphoma. However, cerebrospinal fluid studies were non-specific with two white blood cells, two red blood cells, glucose of 70, and mildly elevated protein of 47. Angiotensin-converting enzyme, meningoencephalitis PCR panel (including Escherichia coli K1, Haemophilus influenza, Listeria monocytogenes, Neisseria meningitidis, Enterovirus, Herpes simplex virus 1 and 2, human herpesvirus 6, varicella zoster virus, parechovirus, and Cryptococcus neoformans/Cryptococcus gatii), Coccidioides and Cryptococcus antibodies, mycobacteria, viral and fungal cultures, flow cytometry, and cytology testing of the cerebrospinal fluid were unrevealing. Owing to disseminated mycobacterial infection, his immunosuppressive regimen was narrowed to tacrolimus (at goal level, 4–8 ng/ml) and prednisone 5 mg daily. Two weeks after discharge, the patient returned with progressively worsening gait ataxia. Repeat neuroimaging was significant for more extensive, confluent, non-enhancing right hemispheric white matter hyperintensities; and stable diffuse microhemorrhages (Figure 2). Spinal MR imaging was unremarkable. Right parietal leptomeningeal and cortex biopsy revealed changes consistent with CAA-ri. The vasculature showed presence of congophilic polarizable birefringent deposits, which stained strongly with anti-Aβ 6F/3D monoclonal antibody, and intramural and perivascular collections of histiocytes and lymphocytes (Figure 3). Tissue acid-fast and Gram stains were negative. Liquid chromatography–mass spectroscopy confirmed the presence of Aβ/A4 peptide deposition. Despite systemic mycobacterial infection, the pathological diagnosis of CAA-ri prompted immediate treatment with intravenous methylprednisolone 1 g daily for 5 days followed by 60 mg oral prednisone. Steady clinical improvement followed shortly, and significant radiographic improvement was noted on repeat neuroimaging a month later (Figure 4). Subsequently, the decision was made to taper oral prednisone over 3 months, as mandated by the underlying systemic infection. No neurological recurrence was noted to date, at 6-months follow-up.\n\nFigure 1 Initial MRI brain without and with gadolinium. Axial fluid-attenuated inversion recovery (FLAIR) sequences (A,B) illustrate scattered T2 FLAIR hyperintensities in the right temporal and parietal lobes involving the cortex and subcortical white matter. The lesions did not demonstrate contrast enhancement, and no leptomeningeal enhancement was noted either (C). Susceptibility-weighted imaging (SWI) sequence shows numerous bihemispheric microhemorrhages, in the cortical and subcortical white matter (D).\n\nFigure 2 MRI brain without and with contrast approximately 3 weeks after the initial scan. Axial FLAIR sequence demonstrates significant progression of the hyperintense lesions in the right temporal, occipital, and fronto-parietal areas, with mild mass effect on the right lateral ventricle and midline shift (A,B). No contrast enhancement is appreciated (C). SWI sequence shows stable, diffuse, bihemispheric microhemorrhages (D).\n\nFigure 3 Brain biopsy stained with hematoxylin and eosin discloses thickened microvasculature with amorphous hyaline-like material replacing the media and associated with mononuclear as well as granulomatous infiltrates (arrows on A). Congo Red stain without (B) and with polarization (C) highlights congophilic (B) bi-refringent (C) amyloid deposits, immunoreactive with antibody to Aβ (D). Immunophenotyping of the inflammatory cells shows staining for macrophage marker CD163 (E–G), T lymphocyte marker CD8 (H), and cytotoxic granule marker T-cell intracellular antigen (TIA) (I). Bars: 100 μ.\n\nFigure 4 MRI brain without and with contrast 1 month after the brain biopsy and treatment with high-dose corticosteroids. The right cerebral T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) hyperintensities have decreased in size, and the midline shift has resolved (A,B). No contrast enhancement is noted (C).\n\nDiscussion\nOur case is unique in presenting the development of pathologically proven CAA-ri in a patient with sarcoidosis and on chronic immunosuppression in a post-cardiac transplantation setting.\n\nCerebral amyloid angiopathy (CAA) is localized amyloidosis affecting cerebral blood vessels through Aβ deposition. A small subset of CAA patients develops a secondary vasculitis due to autoantibody formation to Aβ, leading to a syndrome known as CAA-ri (1, 3, 4). Although histology provides a definitive diagnosis, large case series have posited that clinical features and typical MRI findings may obviate the need for invasive testing and can stratify patients into probable or possible CAA-ri (7, 9). Our patient's clinicoradiographical presentation was non-specific, with potential for complications due to his chronic immunosuppression (such as CNS infection, malignancy, posterior reversible encephalopathy syndrome), or post-OHT status (cerebral microhemorrhages). Hence, given rapid progression of the white matter lesions and clinical deterioration, a histological diagnosis was obtained. The complex presentation not only delayed the diagnosis but also posed a therapeutic challenge. No standard treatment regimens have been established to date for CAA-ri, but prolonged courses of glucocorticoids as single-agent therapy or in conjunction with other immunosuppressants have been proposed (2, 6, 7, 10). There is clinical equipoise about the selection of an appropriate agent, dose, and duration of treatment. However, CAA-ri tends to require longer courses of immunosuppression—usually 6 months—with rare recurrence. Given our patient's systemic mycobacterial infection, the decision was made for a relatively shortened, 3-months course of oral prednisone taper. The robust and sustained clinicoradiographic response observed despite relatively fast corticosteroid tapering may suggest that this approach could be considered in other similar, complex patients.\n\nTo our knowledge, there are no other similar reports of patients on chronic immunosuppression at the time of diagnosis of CAA-ri, which one would expect to protect against this disorder. There is no evidence that our patient was on suboptimal immunosuppression considering his opportunistic disseminated mycobacterial infection and absence of cardiac allograft rejection.\n\nIn addition, review of existing literature did not reveal any prior cases of patients with both sarcoidosis and CAA-ri. However, there is evidence of comorbid autoimmune disease with sarcoidosis and possible potentiation of inflammatory responses seen with CAA-ri. Specifically, prior series have associated sarcoidosis with autoimmune thyroid disease, Sjogren disease, ankylosing spondylitis, systemic sclerosis, giant cell arteritis, and inflammatory myopathy, among other disorders (11–14). A large case series reported CAA-ri patients with comorbid Grave disease, pernicious anemia, rheumatoid arthritis, and autoimmune hepatitis (7). It is unclear whether there is a direct or indirect interaction between these conditions, but it is likely that a genetic predisposition for a robust and disproportionate inflammatory response may precipitate this autoimmune damage. Such a genetic predisposition has been proposed between APOE ε4/ε4 genotype and increased Aβ fibril deposition, particularly perivascularly, that may potentiate the inflammatory response seen in CAA-ri (2, 13, 15, 16). Moreover, there appears to be a contribution of amyloid, specifically serum amyloid A, to granuloma formation in sarcoidosis (17). Serum amyloid A may act to trap the etiologic antigen, leading to chronic sarcoidosis, and highlights a possible pathogenic similarity in both sarcoidosis and CAA-ri development (17, 18).\n\nConclusion\nOur report illustrates that CAA-ri may occur despite seemingly adequate immunosuppression in patients with an underlying predisposition for autoimmune disease. Faster corticosteroid tapering may be considered in complex CAA-ri patients with systemic infections, with close clinical and radiological surveillance.\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nTN, BL, and OD contributed conception and design of the study. BL and SB organized the figures. TN wrote the first draft of the manuscript. TN, BL, SB, KS, JP, and OD wrote sections of the manuscript. OD critically revised the final manuscript draft. All authors contributed to manuscript revision, read and approved the submitted version.\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==== Refs\nReferences\n1. DiFrancesco JC Brioschi M Brighina L Ruffmann C Saracchi E Costantino G . Anti-Aβ autoantibodies in the CSF of a patient with CAA-related inflammation: a case report . Neurology . (2011 ) 76 :842 –4 . 10.1212/WNL.0b013e31820e773c 21357837 \n2. Eng JA Frosch MP Choi K William Rebeck G Greenberg SM . Clinical manifestations of cerebral amyloid angiopathy-related inflammation . Ann Neurol . (2004 ) 55 :250 –6 . 10.1002/ana.10810 14755729 \n3. Piazza F Greenberg SM Savoiardo M Gardinetti M Chiapparini L Raicher I . Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies . Ann Neurol . (2013 ) 73 :449 –58 . 10.1002/ana.23857 23625526 \n4. Savoiardo M Erbetta A Di Francesco JC Brioschi M Silani V Falini A . Cerebral amyloid angiopathy-related inflammation: an emerging disease . Neuroradiol J . (2011 ) 24 :253 –7 . 10.1177/197140091102400214 24059616 \n5. Vinters H Tung S \nCerebral amyloid angiopathy: clinicopathologic features and pathogenesis . In: Blood-Brain Barrier in Health and Disease, Vol 2 . Boca Raton, FL : CRC Press (2015 ). p. 299 –327 . 10.1201/b19299-15 \n6. Scolding NJ . A -related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy . Brain . (2005 ) 128 :500 –15 . 10.1093/brain/awh379 15659428 \n7. Danve A Grafe M Deodhar A . Amyloid beta-related angiitis—a case report and comprehensive review of literature of 94 cases . Sem Arthr Rheum . (2014 ) 44 :86 –92 . 10.1016/j.semarthrit.2014.02.001 24636849 \n8. Ng DW Magaki S Terashima KH Keener AM Salamon N Karnezis S . Amyloid-β-related angiitis: a report of 2 cases with unusual presentations . Hum Pathol. ( 2017) 64 :191 –7 . 10.1016/j.humpath.2017.01.008 28161339 \n9. Auriel E Charidimou A Gurol ME Ni J Van Etten ES Martinez-Ramirez S . Validation of clinicoradiological criteria for the diagnosis of cerebral amyloid angiopathy–related inflammation . JAMA Neurol. (2016 ) 73 :197 –202 . 10.1001/jamaneurol.2015.4078 26720093 \n10. Chung KK Anderson NE Hutchinson D Synek B Barber PA . Cerebral amyloid angiopathy related inflammation: three case reports and a review . J Neurol Neurosurg Psychiatr . (2011 ) 82 :20 –6 . 10.1136/jnnp.2009.204180 20935328 \n11. Carmi O Berla M Edelstein E Levy Y . Coexisting systemic sclerosis-polymyositis and sarcoidosis . JCR . (2018 ) 24 :238 –40 . 10.1097/RHU.0000000000000699 29461345 \n12. Wu C-H Chung P-I Wu C-Y Chen Y-T Chiu Y-W Chang Y-T . Comorbid autoimmune diseases in patients with sarcoidosis: a nationwide case-control study in Taiwan . J Dermatol . (2017 ) 44 :423 –30 . 10.1111/1346-8138.13654 27786368 \n13. Anders KH Wang ZZ Kornfeld M Gray F Soontornniyomkij V Reed LA . Giant cell arteritis in association with cerebral amyloid angiopathy: immunohistochemical and molecular studies . Hum Pathol . (1997 ) 28 :1237 –46 . 10.1016/S0046-8177(97)90196-9 9385928 \n14. Yu M Sandhu VK Lezcano SD Maken K Kirk S Torralba KD . Sarcoidosis and systemic sclerosis: strange bedfellows . Case Rep Rheum . (2017 ) 2017 :1 –4 . 10.1155/2017/7851652 29312791 \n15. Greenberg SM William Rebeck G Vonsattel JPG Gomez-Isla T Hyman BT . Apolipoprotein E ϵ4 and cerebral hemorrhage associated with amyloid angiopathy . Ann Neurol . (1995 ) 38 :254 –9 . 10.1002/ana.410380219 7654074 \n16. Schmechel DE Saunders AM Strittmatter WJ Crain BJ Hulette CM Joo SH . Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease . Proc Natl Acad Sci USA . (1993 ) 90 :9649 –53 . 10.1073/pnas.90.20.9649 8415756 \n17. Chen ES Song Z Willett MH Heine S Yung RC Liu MC . Serum amyloid A regulates granulomatous inflammation in sarcoidosis through toll-like receptor-2 . Am J Resp Crit Care Med . (2010 ) 181 :360 –73 . 10.1164/rccm.200905-0696OC 19910611 \n18. Müller-Quernheim J Prasse A Zissel G . Pathogenesis of sarcoidosis . Presse Med . (2012 ) 41 :e275 –87 . 10.1016/j.lpm.2012.03.018 22595775\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "10()",
"journal": "Frontiers in neurology",
"keywords": "cerebral amyloid angiopathy-related inflammation; immunosuppression; mycobacteria; sarcoidosis; transplantation",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "1283",
"pmc": null,
"pmid": "31866934",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "14755729;23625526;19910611;9385928;26720093;7654074;20935328;24636849;29461345;27786368;8415756;15659428;22595775;28161339;24059616;29312791;21357837",
"title": "Cerebral Amyloid Angiopathy-Related Inflammation in the Immunosuppressed: A Case Report.",
"title_normalized": "cerebral amyloid angiopathy related inflammation in the immunosuppressed a case report"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/20/0119009",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin's Lymphomas (NHL) is well established. Antiviral therapy (AVT) is the first-line treatment for HCV-related indolent NHL whereas diffuse large B-cell lymphoma (DLBCL) requires immediate start of chemoimmunotherapy (CIT), usually deferring AVT. However, an early HCV elimination may reduce the risk of CIT-induced liver toxicity and consequent CIT interruption or withdrawal. To date few data are available on safety and efficacy of concomitant administration of direct-acting antivirals (DAA) and CIT in HCV-associated DLBCL.\n\n\n\n7 consecutive patients (5 males, median age 65 years) with HCV infection (four genotype 2a/2c, two genotype 1b, one genotype 4; one patient with compensated cirrhosis) and DLBCL received different DAA regimens concurrently with CIT.\n\n\n\nAll patients completed the scheduled AVT and CIT with neither interruption nor withdrawal of the latter. One case of neutropenia was observed during concomitant therapy, no liver toxicity occurred. All patients achieved sustained virological response and complete DLBCL response (median follow-up of 12 months).\n\n\n\nConcomitant administration of DAA and CIT for HCV-associated DLBCL is safe and may prevent CIT-induced liver toxicity. Large, prospective studies are needed to confirm these preliminary data and to assess prognostic implications.",
"affiliations": "Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy. Electronic address: vincenzocchipinti@gmail.com.;Hematological Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy.;Hematological Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy.;Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy.;Hematological Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy.",
"authors": "Occhipinti|Vincenzo|V|;Farina|Lucia|L|;Viganò|Mauro|M|;Capecchi|Marco|M|;Labanca|Sara|S|;Fanetti|Ilaria|I|;Corradini|Paolo|P|;Rumi|Mariagrazia|M|",
"chemical_list": "D000998:Antiviral Agents; D000069283:Rituximab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2018.10.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "51(5)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Chemoimmunotherapy; Diffuse large B-cell lymphoma; Direct-acting antivirals; Hepatitis C virus; Rituximab; Safety",
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000998:Antiviral Agents; D018572:Disease-Free Survival; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D000069283:Rituximab; D012720:Severity of Illness Index; D000072230:Sustained Virologic Response",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "719-723",
"pmc": null,
"pmid": "30502232",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Concomitant therapy with direct-acting antivirals and chemoimmunotherapy in HCV-associated diffuse large B-cell lymphoma.",
"title_normalized": "concomitant therapy with direct acting antivirals and chemoimmunotherapy in hcv associated diffuse large b cell lymphoma"
} | [
{
"companynumb": "IT-PFIZER INC-2019009299",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "The recent literature on intrahepatic cholestasis of pregnancy raises questions on the best management of such a disease. Improved evidence might be achieved by meta-analyses.\nProviding data for allowing individual patients meta-analyses and aggregate data meta-analyses.\nData were collected retrospectively at the Fabia Mater Hospital of Rome (Italy), between 2013 and 2018. Several variables were collected and analyzed according to low-level bile acid (less than 40 μmol/L) and high-level bile acid (at least 40 μmol/L). Eighty-three cases of pregnancy cholestasis, diagnosed according to itching symptoms and excluding bile diseases, were collected and analyzed, both descriptively and inferentially.\nThe analyzed data do not provide significant evidence supporting the use of ursodeoxycholic acid to prevent composite adverse fetal outcomes but they can be included in further meta-analyses.",
"affiliations": "Maternal and Fetal Department, Complex Operative Unit of Obstetrics and Gynecology, \"Alto Tevere\" Hospital of Città di Castello, ASL I Umbria, Città di Castello, Italy.;Department of Surgical and Medical Sciences and Translational Medicine, \"Sapienza\" University, Rome, Italy.;Department of Surgical and Medical Sciences and Translational Medicine, \"Sapienza\" University, Rome, Italy.;Division of Obstetric and Gynecology, San Pietro Hospital, Rome, Italy.;Division of Obstetric and Gynecology, Fabia Mater Hospital, Rome, Italy.;Department of Surgical and Medical Sciences and Translational Medicine, \"Sapienza\" University, Rome, Italy.",
"authors": "Indraccolo|Ugo|U|https://orcid.org/0000-0002-7660-6864;Corleto|Chiara Carol|CC|;Milazzo|Giusi Natalia|GN|;Bonito|Marco|M|;De Angelis|Carlo|C|;Di Iorio|Romolo|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/14767058.2021.1940128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": null,
"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": "Intrahepatic cholestasis; data set; meta-analysis; outcome; pregnancy; therapy",
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": null,
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "34134582",
"pubdate": "2021-06-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ursodeoxycholic acid in the treatment of pregnancy cholestasis: a data-set available for Meta-analyses.",
"title_normalized": "ursodeoxycholic acid in the treatment of pregnancy cholestasis a data set available for meta analyses"
} | [
{
"companynumb": "IT-CHEPLA-2021000035",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nSaprochaete capitata (formerly known as Geotrichum capitatum and Blastoschizomyces capitatus) is a ubiquitous fungus found in soil, water, air, plants and dairy products. It colonizes the skin, and bronchial and intestinal tract of healthy people producing serious opportunistic infections in patients with haematological malignancies, especially in those with acute leukaemia. Since 1960s its presence is being increasingly recognized in this group of patients. The clinical spectrum of S. capitata disseminated infections is very similar to that produced by Candida, being easily misinterpreted. The associated high mortality and low susceptibility to fluconazole and echinocandins of S. capitata require the acknowledgement of this emergent infection so that it can be properly treated.\n\n\nMETHODS\nWe report 5 new cases of S. capitata disseminated infection in patients with advanced haematological malignancies observed in the haematology unit between the years 2004 and 2010, and review the state-of-the-art for diagnosis and treatment of this infection.\n\n\nCONCLUSIONS\nBased on our experience, the prophylactic use of or the empirical antifungal treatment with fluconazole and/or echinocandins would not be adequate for oncohaematological patients in those hospitals where S. capitata infection may be highly prevalent.",
"affiliations": "Servicio de Hematología y Hemoterapia, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain.",
"authors": "García-Ruiz|Juan Carlos|JC|;López-Soria|Leyre|L|;Olazábal|Iñigo|I|;Amutio|Elena|E|;Arrieta-Aguirre|Inés|I|;Velasco-Benito|Verónica|V|;Pontón|Jose|J|;Moragues|Maria-Dolores|MD|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-1406",
"issue": "30(4)",
"journal": "Revista iberoamericana de micologia",
"keywords": "Antifungals; Antimicóticos; Blastoschizomyces capitatus; Cáncer hematológico; Diagnóstico molecular; Geotrichum capitatum; Haematological malignancies; Molecular diagnostics; Saprochaete capitata",
"medline_ta": "Rev Iberoam Micol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002051:Burkitt Lymphoma; D055499:Catheter-Related Infections; D003428:Cross Infection; D055157:Dipodascus; D025141:Drug Resistance, Fungal; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D064147:Febrile Neutropenia; D005260:Female; D016469:Fungemia; D006801:Humans; D016867:Immunocompromised Host; D007938:Leukemia; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections",
"nlm_unique_id": "9425531",
"other_id": null,
"pages": "248-55",
"pmc": null,
"pmid": "23583265",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Invasive infections caused by Saprochaete capitata in patients with haematological malignancies: report of five cases and review of the antifungal therapy.",
"title_normalized": "invasive infections caused by saprochaete capitata in patients with haematological malignancies report of five cases and review of the antifungal therapy"
} | [
{
"companynumb": "PHHY2014ES125695",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMSACRINE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Allogeneic hematopoietic stem cell transplantation (HSCT) can retard the progression of early infantile Krabbe disease (EIKD). Superior outcomes are achieved if HSCT is performed before the onset of symptoms; however, little information is available about the long-term outcomes in surviving patients. We now describe functional outcomes in presymptomatic infants who underwent HSCT for EIKD at ≤ 2 months of age. Records of the 19 patients who underwent HSCT for EIKD at ≤ 2 months of age from 1996 to 2010 were reviewed. Long-term functional outcomes were compared between those transplanted at < 30 days and ≥ 30 days of life. Median age at transplant was 27 days (range, 19 to 61). Median follow-up of the cohort was 12.6 years. Overall survival at 5 and 10 years post-transplant was 84.2% (95% confidence interval, 58.7% to 94.6%) and 78.6% (95% confidence interval, 52.5% to 91.4%), respectively. More favorable outcomes were seen in patients who underwent HSCT at < 30 days of age, particularly in domains of mobility (P = .01), communication (P = .02), and feeding (P = .008). Improved functional outcomes were observed when HSCT was performed in the first month of life, defining a critical period for intervention. These results support the implementation of newborn screening to enable rapid diagnosis and early treatment of infants with EIKD.",
"affiliations": "Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina. Electronic address: heather.allewelt@gmail.com.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.",
"authors": "Allewelt|Heather|H|;Taskindoust|Mahsa|M|;Troy|Jesse|J|;Page|Kristin|K|;Wood|Susan|S|;Parikh|Suhag|S|;Prasad|Vinod K|VK|;Kurtzberg|Joanne|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.06.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "24(11)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Krabbe disease; Umbilical cord blood transplantation",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D036101:Cord Blood Stem Cell Transplantation; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007231:Infant, Newborn; D007965:Leukodystrophy, Globoid Cell; D008297:Male; D016019:Survival Analysis; D019172:Transplantation Conditioning; D016896:Treatment Outcome",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "2233-2238",
"pmc": null,
"pmid": "29933067",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-Term Functional Outcomes after Hematopoietic Stem Cell Transplant for Early Infantile Krabbe Disease.",
"title_normalized": "long term functional outcomes after hematopoietic stem cell transplant for early infantile krabbe disease"
} | [
{
"companynumb": "US-OTSUKA-2019_006270",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Hypercalcemia in HIV patients has been previously reported, but 1,25-(OH)2 vitamin D-mediated hypercalcemia, due to increased activity of extrarenal 1-alpha hydroxylase, is rarely described with HIV-related infections or malignancies. We describe a case of 1,25-(OH)2 vitamin D-mediated hypercalcemia in a patient presenting with progressive cognitive decline and weakness. Initial evaluation revealed a new diagnosis of HIV, for which he was started on antiretroviral therapy (ART). He was also noted to have mild asymptomatic hypocalcemia, likely from his acute illness and malnutrition, which was not further investigated at the time. While the patient's mental status initially improved with ART, he became progressively delirious and was found to be hypercalcemic approximately 4 weeks after the initiation of ART. Possible etiologies for hypercalcemia were vigorously evaluated, including granulomatous disease, infection, and malignancy, in the setting of suspected immune reconstitution inflammatory syndrome (IRIS), due to recent initiation of ART. Infectious workup was unrevealing, but computed tomography (CT) of the chest, abdomen, and pelvis revealed new extensive diffuse lymphadenopathy and hepatomegaly, not present on admission studies. Cytology and flow cytometry of a liver biopsy specimen revealed CD10 positive high-grade B-cell lymphoma. Chemotherapy was not pursued due to poor performance status. Over the next week, spontaneous tumor lysis developed, and the patient expired. Postmortem, his 1,25-(OH)2 vitamin D level returned as markedly elevated. Immunohistochemical staining of his liver biopsy tissue showed strong expression of CYP27B1. 1,25-(OH)2 vitamin D-mediated hypercalcemia is uncommon in a patient with newly diagnosed HIV and, in this case, was likely due to IRIS unmasking an underlying high-grade lymphoma and restoration of immune function (including T-cells and cytokine production). This case emphasizes the importance of including aggressive lymphomas, capable of progressing over days to weeks, in the evaluation of hypercalcemia in HIV patients at risk for developing IRIS and the rapid dynamic changes in mineral homeostasis that can occur with such an aggressive tumor in an immunocompromised host.",
"affiliations": "Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, United States of America.;Division of Infectious Disease, Department of Medicine, University of California, San Francisco, United States of America.;Endocrine Research Unit, Department of Medicine, San Francisco Veterans Affairs Health Care System, United States of America.;Endocrine Research Unit, Department of Medicine, San Francisco Veterans Affairs Health Care System, United States of America.;Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, United States of America.;Division of Endocrinology and Metabolism, Department of Medicine, Zuckerberg San Francisco General Hospital, United States of America.",
"authors": "Kim|Stephanie J|SJ|;Peluso|Michael J|MJ|;Wang|Yongmei|Y|;Bikle|Daniel|D|;Shoback|Dolores|D|;Kim|Sarah|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bonr.2018.100194",
"fulltext": "\n==== Front\nBone RepBone RepBone Reports2352-1872Elsevier S2352-1872(18)30064-010.1016/j.bonr.2018.100194100194ArticleRapid onset of hypercalcemia from high-grade lymphoma in the setting of HIV-related immune reconstitution inflammatory syndrome Kim Stephanie J. stephanie.kim@ucsf.edua⁎Peluso Michael J. bcWang Yongmei dBikle Daniel dShoback Dolores adKim Sarah ea Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, United States of Americab Division of Infectious Disease, Department of Medicine, University of California, San Francisco, United States of Americac Division of HIV, Infectious Disease, and Global Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital, United States of Americad Endocrine Research Unit, Department of Medicine, San Francisco Veterans Affairs Health Care System, United States of Americae Division of Endocrinology and Metabolism, Department of Medicine, Zuckerberg San Francisco General Hospital, United States of America⁎ Corresponding author at: 400 Parnassus Avenue A559, Box 1222, San Francisco, CA 94117, United States of America. stephanie.kim@ucsf.edu28 12 2018 6 2019 28 12 2018 10 10019419 9 2018 21 11 2018 27 12 2018 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Hypercalcemia in HIV patients has been previously reported, but 1,25-(OH)2 vitamin D-mediated hypercalcemia, due to increased activity of extrarenal 1-alpha hydroxylase, is rarely described with HIV-related infections or malignancies. We describe a case of 1,25-(OH)2 vitamin D-mediated hypercalcemia in a patient presenting with progressive cognitive decline and weakness. Initial evaluation revealed a new diagnosis of HIV, for which he was started on antiretroviral therapy (ART). He was also noted to have mild asymptomatic hypocalcemia, likely from his acute illness and malnutrition, which was not further investigated at the time. While the patient's mental status initially improved with ART, he became progressively delirious and was found to be hypercalcemic approximately 4 weeks after the initiation of ART. Possible etiologies for hypercalcemia were vigorously evaluated, including granulomatous disease, infection, and malignancy, in the setting of suspected immune reconstitution inflammatory syndrome (IRIS), due to recent initiation of ART. Infectious workup was unrevealing, but computed tomography (CT) of the chest, abdomen, and pelvis revealed new extensive diffuse lymphadenopathy and hepatomegaly, not present on admission studies. Cytology and flow cytometry of a liver biopsy specimen revealed CD10 positive high-grade B-cell lymphoma. Chemotherapy was not pursued due to poor performance status. Over the next week, spontaneous tumor lysis developed, and the patient expired. Postmortem, his 1,25-(OH)2 vitamin D level returned as markedly elevated. Immunohistochemical staining of his liver biopsy tissue showed strong expression of CYP27B1.\n\n1,25-(OH)2 vitamin D-mediated hypercalcemia is uncommon in a patient with newly diagnosed HIV and, in this case, was likely due to IRIS unmasking an underlying high-grade lymphoma and restoration of immune function (including T-cells and cytokine production). This case emphasizes the importance of including aggressive lymphomas, capable of progressing over days to weeks, in the evaluation of hypercalcemia in HIV patients at risk for developing IRIS and the rapid dynamic changes in mineral homeostasis that can occur with such an aggressive tumor in an immunocompromised host.\n\nHighlights\n• 1,25‑(OH)2 vitamin D-mediated hypercalcemia is uncommon in patients with HIV.\n\n• Lymphomas are associated with immune reconstitution inflammatory syndrome (IRIS).\n\n• Consider lymphoma in the evaluation of hypercalcemia in HIV patients at risk for IRIS.\n\n\n\nKeywords\nHypercalcemia1,25-(OH)2 vitamin DLymphomaHIVImmune reconstitution inflammatory syndrome\n==== Body\n1 Introduction\nHypercalcemia is uncommon, occurring in 0.2 to 4% of the general population, and is most often due to hypercalcemia of malignancy or primary hyperparathyroidism (Tebben et al., 2016). Hypercalcemia in HIV-infected patients has been previously described, although 1,25-(OH)2 vitamin D-mediated hypercalcemia, due to HIV-related infections or malignancies, is distinctly unusual. HIV-infected patients may present with 1,25-(OH)2 vitamin D-mediated hypercalcemia in association with immune reconstitution inflammatory syndrome (IRIS) (Murdoch et al., 2007). IRIS is defined as the paradoxical clinical worsening of a preexisting condition or the unmasking of a new condition, after the initiation of antiretroviral therapy (ART), and is attributed to the recovery of the immune system, with both positive and negative outcomes for the host (French, 2009). Prior case reports describe 1,25-(OH)2 vitamin D-mediated hypercalcemia in IRIS-associated infections caused by Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) (Tsao et al., 2009; Tsao et al., 2012). Hypercalcemia from IRIS-related non-infectious conditions such as lymphoma, however, have not, to our knowledge, been reported.\n\nRecent studies suggest that patients with HIV have an increased incidence of presenting with non-Hodgkin or Hodgkin lymphoma during the first 3 to 6 months following the initiation of ART (Lanoy et al., 2011; Jaffe et al., 2011; Yanik et al., 2013). In fact, 12% of patients studied in a large HIV-associated lymphoma cohort had presentations compatible with lymphoma in the setting of unmasking lymphoma IRIS, defined as lymphoma diagnosed within 6 months after ART initiation with a ≥0.5 log reduction in HIV RNA (Gopal et al., 2014). We describe a case of 1,25-(OH)2 vitamin D-mediated hypercalcemia due to rapidly progressive lymphoma within 4 weeks of ART initiation in a patient with newly diagnosed HIV, whose viral load demonstrated a 3-log reduction during that time period. Furthermore, this patient's presentation was remarkable in that the rapid onset of spontaneous tumor lysis, due to the high-grade lymphoma, negated the initially symptomatic moderate hypercalcemia.\n\n2 Materials and methods\nFor immunohistochemistry, sections were deparaffinized and rehydrated. Endogenous peroxidase was blocked with 3% hydrogen peroxide. Goat CYP27B1 antibody (1:50) or rabbit PTHrP antibody (1:100) was applied to paraffin-embedded liver sections (1:50, overnight, 4C) and was detected with biotinylated anti-goat secondary antibody, followed by ABD peroxidase reagent (all antibodies were from Santa Cruz Biotechnology, Inc., Santa Cruz, CA). 1-alpha hydroxylase expression was visualized by diaminobenzidine substrate and hematoxylin counterstaining. Skin sections were used as positive (goat CYP27B1 antibody, 1:50) and negative (normal goat serum) controls, respectively. Deidentified normal liver biopsy sections were obtained as controls for these studies from the University of California, San Francisco (UCSF) Department of Gastroenterology through a protocol approved by the UCSF Institutional Review Board. Normal skin biopsy sections were obtained from the Department of Pathology and Laboratory Medicine at the San Francisco Veterans Affairs Health Care System.\n\n3 Case report\nA 64-year-old man with a history of schizophrenia presented to a local free clinic shortly after relocating from Turkmenistan to San Francisco. His daughter reported that he had developed a productive cough, slowed speech, mild confusion, generalized weakness, anorexia and a 45-pound weight loss over the prior 5 months. While he was previously employed as a healthcare worker and independent in his activities of daily living (ADLs), he had become gradually dependent on others for assistance with ADLs and was now wheelchair-bound. A few months prior to presentation, he was evaluated by a physician in Turkmenistan to rule out a cerebrovascular accident and was diagnosed with prior hepatitis B infection by core antibody positivity, as well as a “nonspecific encephalopathy”. In the clinic, the patient was found to be hypotensive (systolic blood pressure 70 mmHg) and tachycardic [pulse 110 beats per minute (bpm)], and he was sent to the Zuckerberg San Francisco General Hospital Emergency Department for further evaluation of progressive cognitive and physical decline.\n\nIn the Emergency Department, the patient's vital signs included temperature 36.7 °C, blood pressure 88/56 mmHg, heart rate 112 bpm, respirations 20/min, and oxygen saturation 98% without supplemental oxygen. On physical examination, he was ill-appearing and cachectic with temporal wasting and was oriented only to self. He exhibited generalized weakness and was unable to sit up or stand without assistance. Cardiopulmonary exam revealed rales at the left lung base. He had no scleral icterus or oral thrush, and the remainder of his examination revealed normal heart, abdomen, skin, and joints.\n\nInitial laboratory evaluation revealed that the patient was HIV antibody positive. HIV parameters at admission included a CD4 cell count of 46 cells/uL (ref 420–1250), CD4 percentage of 3% (ref 28–59) and HIV viral load >4 million copies/mL. Complete blood count showed white blood cell count 4.6 k/uL (ref 3.9–11.7), hemoglobin 8.9 g/dL (ref (13.3–17.7), hematocrit 27.2% (ref 39.8–52.2), platelets 113 k/uL (ref 150–400). Chemistry panel was notable for total serum albumin corrected calcium of 7.9 mg/dL (ref 8.6–10.5), with the remainder of the chemistry panel normal, including a serum phosphate of 3.2 mg/dL (ref 2.5–4.5) and serum creatinine of 1.0 mg/dL (ref 0.7–1.3) (Fig. 1). Liver function tests were normal. The patient's initial hypocalcemia was not further evaluated at this time.Fig. 1 Serum total calcium (mg/dL), phosphorus (mg/dL), uric acid (mg/dL), and creatinine (mg/dL) (upper panel) and CD4 cell count (cells/mL), CD4 percentage, and viral load (copies/mL) (lower panel) during the patient's 38 days of hospitalization.\n\nFor reference, CD4 cell counts were 46 cells/ml and 43 cells/ml on days 2 and 33, respectively (ref 420–1250). CD4% were 3% and 7% on days 2 and 33, respectively (ref 28–59). Viral loads were 4,002,666 copies/mL, 24,132 copies/mL, and 1317 copies/mL on days 3, 15, and 33, respectively.\n\nAbbreviations: ART, antiretroviral therapy; PTH, parathyroid hormone; PTHrP, PTH-related protein; AMS, altered mental status; TLS, tumor lysis syndrome; VL, viral load.\n\nFig. 1\n\nAdmission imaging included a chest X-ray and CT for evaluation of productive cough, which showed mild bibasilar consolidation. The patient underwent diagnostic evaluation for tuberculosis, which was negative by serial sputum AFB smears, cultures, and Gene Xpert® testing. Broncho-alveolar lavage cultures grew Pseudomonas aeruginosa, and he was treated with a 7-day course of levofloxacin.\n\nHead CT was performed to evaluate declining mental status and was negative for acute abnormalities. A subsequent brain magnetic resonance imaging (MRI) revealed patchy areas of T2/FLAIR hyperintensity in the periventricular and right frontal subcortical white matter, as well as confluent white matter hyperintensity in the bilateral occipital lobes, without associated enhancement or diffusion abnormalities. Cerebrospinal fluid (CSF) examination was negative for opportunistic pathogens, including negative cryptococcal antigen testing and John Christopher [JC] virus polymerase chain reaction (PCR). Altered mental status was attributed to HIV encephalopathy. Additional workup for opportunistic pathogens included negative acid-fast bacilli-specific blood cultures and negative fungal markers. ART with standard therapy doses of tenofovir alafenamide, emtricitabine, and dolutegravir was started on hospital day 6, after CNS opportunistic infections had been excluded. Appropriate prophylaxis for opportunistic infections, including daily fluconazole for Cryptococcus prophylaxis, was also initiated. Abdominal CT angiography was performed to assess for cirrhosis and showed normal liver size and contour, without evidence of cirrhosis, but revealed 2 subcentimeter lesions, thought to be benign (LI-RADS classification 2). A psychiatric consultant diagnosed bipolar disorder, rather than schizophrenia, and he was treated with olanzapine. With these interventions, the patient's mental status markedly improved by hospital day 9. He became more oriented, conversant with his family, and cooperative with providers. His albumin-corrected serum total calcium also improved on ART to 9.7 mg/dL (Fig. 1).\n\nThe patient remained hospitalized, awaiting discharge to a rehabilitation facility. By hospital day 15, his HIV viral load had decreased to 24,132 copies/mL. On hospital day 28, his mental status worsened, and he became progressively more impulsive, agitated, and delirious. Laboratory testing now demonstrated an elevated albumin-corrected serum total calcium of 13.0 mg/dL, confirmed by elevated ionized calcium of 1.59 mM (ref 1.12–1.32). Lactate dehydrogenase (LDH) level was high at 850 U/L (ref 110–210), and serum creatinine rose to 1.53 mg/dL (ref 0.7–1.3)] (Fig. 1). Plasma intact parathyroid hormone (PTH) was undetectable [<6.3 pg/mL (ref 14–72)], serum PTH-related protein (PTHrP) was 2.4 pmol/L (ref 0–2.3), serum 25-OH vitamin D was low at 8 ng/mL (ref 30–80), and the serum 1,25-(OH)2 vitamin D level not available at this time later returned as markedly elevated to 138 pg/mL (ref 19.9–79.3) (Fig. 1). Additionally, liver function tests were newly elevated [aspartate aminotransferase (AST) 168 U/L (ref 10–48), alanine aminotransferase (ALT) 171 U/L (ref 10-40), alkaline phosphatase 1093 U/L (ref 56–119), total bilirubin 5.3 mg/dL (ref 0.1–1.1), and direct bilirubin 4.0 mg/dL (ref 0.1–0.3)]. Due to increasing serum creatinine, the patient's hypercalcemia was initially treated with intramuscular calcitonin injections (administered at a dose of 4 units/kg) on hospital days 36 and 37. Possible etiologies of hypercalcemia, including granulomatous disease, infection, and malignancy, were evaluated in the setting of presumed IRIS due to recent initiation of ART. The entire serologic workup for opportunistic infections was repeated and remained negative. HIV parameters were rechecked and showed a CD4 T lymphocyte count of 43 cells/uL, CD4 percentage of 7%, and HIV viral load of 1317 copies/mL.\n\nRenal ultrasound was performed to assess etiologies for acute kidney injury and incidentally revealed 2 large, complex hepatic lesions. CT of the abdomen and pelvis now showed new bilateral pleural effusions and extensive diffuse lymphadenopathy, including a large area of hypoattenuation in the liver, suggestive of an infiltrative process (Fig. 2). Cytology and flow cytometry of a liver biopsy specimen revealed CD10 positive lymphocytes, compatible with a high-grade B-cell lymphoma. Based upon these findings, an unmasking lymphoma IRIS was diagnosed, and the patient was evaluated by oncology consultants. The consensus was that his performance status was too poor to undergo chemotherapy, and his family decided to focus his care on comfort measures only.Fig. 2 Abdominal imaging during the patient's hospitalization.\n\nA: CT angiography of the abdomen on admission showed two subcentimeter, low density lesions with no lymphadenopathy.\n\nB: CT of the abdomen and pelvis after 27 days of ART showed new extensive diffuse lymphadenopathy (arrows), including a large area of hypoattenuation in the liver (circled).\n\nFig. 2\n\nDuring the next week, the patient developed spontaneous tumor lysis syndrome, and corrected serum calcium fell from 13 to 11 mg/dL without any treatment. Serum phosphate rose to 4.3 from 2.6 mg/dL, and serum uric acid and LDH became elevated to 12 mg/dL (ref 3.5–8.5) and 987 U/L (ref 110–210), respectively, and the patient expired shortly thereafter.\n\nTo investigate the source of the markedly elevated serum 1,25-(OH)2 vitamin D level, immunostaining of liver tumor sections and other control tissues was performed using a CYP27B1, 1-alpha hydroxylase, antibody, as previously described (Bikle et al., 2018). Positive control was a normal skin biopsy, and negative controls were sections from normal liver biopsies from HIV positive and HIV negative, normocalcemic subjects as described in Materials and Methods. Strong expression of 1-alpha hydroxylase was evident in the lymphocytes of the liver tumor compared to absent staining in normal control liver biopsy (Fig. 3). Additionally, the lymphocytes did not stain for PTHrP. Strongly positive staining of the skin biopsy for 1-alpha hydroxylase was also noted, confirming the specificity of the immunostaining procedures, since this protein is known to be strongly expressed there.Fig. 3 Immunostaining of sections from the liver tumor biopsy from the patient and from normal liver and skin biopsies from control subjects for detection of Cyp27B1 or 1-alpha hydroxylase were completed as described in Materials and Methods. Bars = 50 μm.\n\nA and B: Sections of the patient's liver tumor showed strong and diffuse staining for 1-alpha hydroxylase (brown) in the lymphocytes (solid arrow), but not in normal hepatocytes (dashed arrow). Magnification is 20×.\n\nC and D: Skin section from a healthy control subject in which the 1-alpha hydroxylase antibody was omitted from the incubation (negative control); skin section from a healthy control subject showing positive (brown) immunostaining for 1-alpha hydroxylase in the epidermis. Magnification is 10×.\n\nE: Section from liver biopsy from a HIV negative, normocalcemic control subject showed absent staining for 1-alpha hydroxylase. Magnification is 10×.\n\nF: Section from liver biopsy from an HIV positive, normocalcemic patient showed absent staining for 1-alpha hydroxylase. Magnification is 10×. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 3\n\n4 Discussion\nHypercalcemia in HIV-infected patients is uncommon, with one study of 66 patients reporting an incidence of only 2.9% (Peter, 1992) with the most common etiologies identified as granulomatous diseases and malignancies. Hypercalcemia associated with high 1,25-(OH)2 vitamin D levels is typically due to the increased and unregulated activity of extrarenal 1-alpha hydroxylases in ectopic sites, resulting in overproduction of 1,25-(OH)2 vitamin D from 25-(OH) vitamin D.\n\nRisk factors for IRIS in this case included nadir CD4 T lymphocyte count <100 cells/uL and a plasma HIV viral load decrease of 2.5 logs at the time of IRIS, compared with levels before ART initiation (Manabe et al., 2007). A recent study suggested higher odds for developing IRIS with the initiation of contemporary more potent HIV regimens versus older treatments (Perez-Rueda et al., 2017). Conditions associated with IRIS after the initiation of ART can lead to 1,25-(OH)2 vitamin D-mediated hypercalcemia and, in most cases, are attributable to opportunistic infections. Case reports have described 1,25-(OH)2 vitamin D-mediated hypercalcemia, associated with mycobacterial infections in HIV-infected patients, (Tsao et al., 2009; Tsao et al., 2012) and noninfectious inflammatory conditions, such as sarcoidosis (Gomez et al., 2000) and autoimmune thyroiditis and Graves disease (Jubault et al., 2000), as well as the presentation of new malignancies.\n\nLymphomas are known to cause hypercalcemia, occurring in about 13% of non-Hodgkin lymphomas and 5% of Hodgkin lymphomas, due to increased 1,25-(OH)2 vitamin D production in essentially all cases of Hodgkin lymphoma and ~30–40% in non-Hodgkin lymphoma (Tebben et al., 2016). In the remaining 60-70% of cases of non-Hodgkin lymphoma, hypercalcemia is mediated by PTHrP. In an older case series of 15 patients with lymphoma and hypercalcemia, seven of these patients presented with elevated 1,25-(OH)2 vitamin D levels (Adams et al., 1989). The types of lymphoma varied (B-cell, small noncleaved and immunoblastic sarcoma 40%, follicular center cell 27%, Hodgkin 20%, T-cell 13%). This study also included 4 patients with AIDS-associated lymphoma. That series was reported in 1989, a time when highly effective ART was not available and included one patient with HIV-related lymphoma with a high 1,25-(OH)2 vitamin D level (Adams et al., 1989). Further laboratory studies using lymphoma cells cultured from the HIV-infected host showed that these cells had the capacity to metabolize 25-(OH) vitamin D into a compound similar to 1,25-(OH)2 vitamin D by chromatography. Another case report described two patients with Burkitt lymphoma who presented with hypercalcemia and suppressed PTH, although 1,25-(OH)2 vitamin D levels were not reported (Spiegel et al., 1978). Recent studies have shown that patients with HIV infection have an increased incidence of non-Hodgkin and Hodgkin lymphoma during the first 3 to 6 months of ART (Lanoy et al., 2011; Jaffe et al., 2011; Yanik et al., 2013), the time-frame in which our patient presented with his aggressive lymphoma and high tumor burden. In a cohort of 482 patients with HIV-associated lymphoma, approximately 12% of patients studied were found to have a course compatible with IRIS unmasking the presence of a lymphoma, with 9% of those patients (n = 5) having Burkitt lymphoma (Gopal et al., 2014).\n\nThis patient initially presented with hypocalcemia, thought to be due to acute illness, malnutrition and possibly vitamin D deficiency; further evaluation was not pursued. He quickly developed hypercalcemia following the initiation of ART, along with rapid interval presentation of high-grade B-cell lymphoma. Initial imaging studies of the brain, chest, abdomen, and pelvis showed no sign of underlying malignancy prior to ART initiation. Thus, lymphoma was thought to be an unmasking phenomenon associated with immune reconstitution in the setting of highly potent ART. We demonstrated strong immunostaining in the lymphocytes of his tumor for 1-alpha hydroxylase, ectopically overexpressed by this B cell lymphoma, whereas staining for PTHrP was absent in these cells. It has been reported that cytokines may stimulate 1,25-(OH)2 vitamin D in B- and T-lymphocytes, with CYP27B1 expression increased when these cells are activated (Bikle et al., 2018). Other studies have shown that macrophages, after activation by cytokines such as interferon-ɣ (IFN-ɣ), stimulate 1-alpha hydroxylase activity in granulomatous diseases (Seymour and Gagel, 1993). B-cell lymphomas have been shown to overexpress 1-alpha hydroxylase and be associated with hypercalcemia. Activated macrophages within the tumor itself are also thought to be involved in the pathogenesis of lymphoma-associated hypercalcemia (Luceri and Haenel, 2013). However, to date, none of these tumors was reported to be associated with HIV-related IRIS. Multiple cytokines, including IFN-ɣ, interleukin-18 (IL-18), and interferon-inducible protein 10 (IP-10 or CXCL-10), have been found to be helpful as biomarkers for IRIS (Sereti et al., 2010), although the time course of cytokine production as reflected in serum levels after the initiation of ART has not been firmly established. Therefore, we postulate that T-cell derived cytokines may also play a role in activating lymphoma cells and macrophages leading to 1,25-(OH)2 vitamin D-mediated hypercalcemia in patients with lymphoma in the setting of IRIS. We also note that the patient received fluconazole daily starting on hospital day 3 for Cryptococcus prophylaxis. Fluconazole is an inhibitor of 1-alpha-hydroxyalase and has been shown to reduce levels 1,25-(OH)2 vitamin D (Sayers et al., 2015), so it is possible that the elevation in the patient's 1,25-(OH)2 vitamin D level may have been even more pronounced had he not been treated with fluconazole.\n\nWe report this case because it dramatically unfolded over just 38 days. The patient initially presented with advanced AIDS along with hypocalcemia, likely from severe malnutrition and illness. With the initiation of ART inducing IRIS, his serum calcium normalized as he rapidly developed marked tumor burden from a high-grade lymphoma producing 1,25-(OH)2 vitamin D, leading to hypercalcemia. This is just one form of hypercalcemia due to malignancy. He had no bone metastases, and PTHrP and PTH levels were not elevated. Spontaneous tumor lysis then ensued, common in rapidly growing lymphomas like his, and serum calcium levels spontaneously decreased. This fall in serum calcium (counteracting the high 1,25-(OH)2 vitamin D levels) was likely driven by rising serum phosphorus levels characteristic of the tumor lysis syndrome. Unfortunately, due to a tenuous functional status, chemotherapy was not initiated because it was felt that he could not tolerate it.\n\nIn conclusion, 1,25-(OH)2 vitamin D-mediated hypercalcemia, driven by an increase in extrarenal 1-alpha hydroxylase expression, is uncommon in patients with newly diagnosed advanced HIV. In our patient, 1,25-(OH)2 vitamin D overproduction and hypercalcemia emerged, likely due to the development of IRIS. IRIS, we speculate, unmasked an underlying high-grade lymphoma as immune function (T-cells and cytokine production) was restored. This case emphasizes the importance of considering IRIS in a patient who has recently initiated ART, because granulomatous infections and lymphomas are capable of causing hypercalcemia, and aggressive lymphomas in the setting of IRIS may progress rapidly (in just days) with ART initiation. This sequence can result in marked effects on serum calcium homeostasis with clinical consequences.\n\nTransparency document\nTransparency document.\n\nImage 1 \n\nAcknowledgements\nWe would like to thank Jennifer C. Price, MD from the University of California, San Francisco Department of Gastroenterology for allowing us to use tissue samples from her laboratory for this report and James P. Grenert, MD, PhD from the Zuckerberg San Francisco General Hospital Department of Pathology and Laboratory Medicine for reviewing pathology results with us.\n\nThe Transparency document associated with this article can be found, in online version.\n==== Refs\nReferences\nAdams J.S. Fernandez M. Gacad M.A. Vitamin D metabolite-mediated hypercalcemia and hypercalciuria patients with AIDS- and non-AIDS-associated lymphoma Blood 73 1989 235 239 2910361 \nBikle D.D. Patzek S. Wang Y. Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review Bone Rep. 8 2018 255 267 29963603 \nFrench M.A. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal Clin. Infect. Dis. 48 2009 101 107 19025493 \nGomez V. Smith P.R. Burack J. Daley R. Rosa U. Sarcoidosis after antiretroviral therapy in a patient with acquired immunodeficiency syndrome Clin. Infect. Dis. 31 2000 1278 1280 11073764 \nGopal S. Patel M.R. Achenbach C.J. Lymphoma immune reconstitution inflammatory syndrome in the center for AIDS research network of integrated clinical systems cohort Clin. Infect. Dis. 59 2014 279 286 24755860 \nJaffe H.W. De Stavola B.L. Carpenter L.M. Porter K. Cox D.R. Immune reconstitution and risk of Kaposi sarcoma and non-Hodgkin lymphoma in HIV-infected adults AIDS (London, England) 25 2011 1395 1403 \nJubault V. Penfornis A. Schillo F. Sequential occurrence of thyroid autoantibodies and Graves' disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients J. Clin. Endocrinol. Metab. 85 2000 4254 4257 11095463 \nLanoy E. Rosenberg P.S. Fily F. HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy Blood 118 2011 44 49 21551234 \nLuceri P.M. Haenel LCt A challenging case of hypercalcemia J. Am. Osteopath. Assoc. 113 2013 490 493 23739761 \nManabe Y.C. Campbell J.D. Sydnor E. Moore R.D. Immune reconstitution inflammatory syndrome: risk factors and treatment implications J. Acquir. Immune Defic. Syndr. 46 2007 456 462 (1999) 18077835 \nMurdoch D.M. Venter W.D. Van Rie A. Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options AIDS Res. Ther. 4 2007 9 17488505 \nPerez-Rueda M. Hernandez-Cabrera M. Frances-Urmeneta A. Immune reconstitution inflammatory syndrome in HIV-infected immigrants Am. J. Trop. Med. Hyg. 97 2017 1072 1077 28820685 \nPeter S.A. Disorders of serum calcium in acquired immunodeficiency syndrome J. Natl. Med. Assoc. 84 1992 626 628 1629927 \nSayers J. Hynes A.M. Srivastava S. Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole Clin. Kidney J. 8 2015 453 455 26251716 \nSereti I. Rodger A.J. French M.A. Biomarkers in immune reconstitution inflammatory syndrome: signals from pathogenesis Curr. Opin. HIV AIDS 5 2010 504 510 20966640 \nSeymour J.F. Gagel R.F. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas Blood 82 1993 1383 1394 8364192 \nSpiegel A. Greene M. Magrath I. Balow J. Marx S. Aurbach G.D. Hypercalcemia with suppressed parathyroid hormone in Burkitt's lymphoma Am. J. Med. 64 1978 691 695 206138 \nTebben P.J. Singh R.J. Kumar R. Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment Endocr. Rev. 37 2016 521 547 27588937 \nTsao Y.T. Wu Y.C. Yang C.S. Lin Y.T. Immune reconstitution associated hypercalcemia Am. J. Emerg. Med. 27 2009 (629.e1-3) \nTsao Y.T. Lee S.W. Hsu J.C. Ho F.M. Wang W.J. Surviving a crisis of HIV-associated immune reconstitution syndrome Am. J. Emerg. Med. 30 2012 (1661.e5-7) \nYanik E.L. Napravnik S. Cole S.R. Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy Clin. Infect. Dis. 57 2013 756 764 23735330\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-1872",
"issue": "10()",
"journal": "Bone reports",
"keywords": "1,25-(OH)2 vitamin D; HIV; Hypercalcemia; Immune reconstitution inflammatory syndrome; Lymphoma",
"medline_ta": "Bone Rep",
"mesh_terms": null,
"nlm_unique_id": "101646176",
"other_id": null,
"pages": "100194",
"pmc": null,
"pmid": "30627599",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "11073764;11095463;1629927;17488505;18077835;19025493;19497480;206138;20966640;21551234;21572307;22033392;23735330;23739761;24755860;26251716;27588937;28820685;2910361;29963603;8364192",
"title": "Rapid onset of hypercalcemia from high-grade lymphoma in the setting of HIV-related immune reconstitution inflammatory syndrome.",
"title_normalized": "rapid onset of hypercalcemia from high grade lymphoma in the setting of hiv related immune reconstitution inflammatory syndrome"
} | [
{
"companynumb": "US-VIIV HEALTHCARE LIMITED-US2019GSK037430",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditio... |
{
"abstract": "Central Nervous System (CNS) lymphoma is a rare presentation of post-transplantation lymphoproliferative disorder (PTLD).\nThis single center retrospective study reviewed presentations, management and outcomes of CNS lymphomas in kidney transplant patients transplanted 1968 to 2015, and reviews relevant current literature.\nWe identified 5773 adult kidney transplant recipients of who 90 had a PTLD diagnosis confirmed. CNS disease was diagnosed in 6/90 (7%). Median age at presentation was 60 years and time from transplant 4.5 years. Immunosuppression at diagnosis included mycophenolate mofetil and prednisolone without calcineurin inhibitor in 5/6 patients. Histological analysis diagnosed monomorphic disease in 5/6, and one polymorphic case with tissue positive for Epstein-barr virus (EBV) in 5/6 cases. Despite this 2/4 EBV positive cases had no detectable EBV in peripheral blood or CSF at diagnosis. Treatment strategies included reduction in immunosuppression in all, chemotherapy (n=5), radiotherapy (n=3), Cytotoxic T-Lymphocytes and Craniotomy (n=2). Patient survival was 40% at 1 year with CTL treated patients surviving beyond three years from diagnosis.\nThis study supports observational data suggesting MMF treated patients without CNI may have increased risk of disease. Peripheral blood screening for EBV DNAemia does not seem helpful in early identification of those at risk.",
"affiliations": "Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.;Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.;Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.;Department of Radiology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.;Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.;Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.;Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.",
"authors": "Velvet|Anju John John|AJJ|;Bhutani|Shiv|S|;Papachristos|Stavros|S|;Dwivedi|Reena|R|;Picton|Michael|M|;Augustine|Titus|T|;Morton|Muir|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.26522",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 2652210.18632/oncotarget.26522Research PaperA single-center experience of post-transplant lymphomas involving the central nervous system with a review of current literature Velvet Anju John John 2Bhutani Shiv 1Papachristos Stavros 2Dwivedi Reena 4Picton Michael 1Augustine Titus 23Morton Muir 11 Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK2 Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK3 Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK4 Department of Radiology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UKCorrespondence to:Anju John John Velvet,anjujohn198924@gmail.com11 1 2019 11 1 2019 10 4 437 448 14 5 2018 13 12 2018 Copyright: © 2019 Velvet et al.2019This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.Background\nCentral Nervous System (CNS) lymphoma is a rare presentation of post-transplantation lymphoproliferative disorder (PTLD).\n\nMethods\nThis single center retrospective study reviewed presentations, management and outcomes of CNS lymphomas in kidney transplant patients transplanted 1968 to 2015, and reviews relevant current literature.\n\nResults\nWe identified 5773 adult kidney transplant recipients of who 90 had a PTLD diagnosis confirmed. CNS disease was diagnosed in 6/90 (7%). Median age at presentation was 60 years and time from transplant 4.5 years. Immunosuppression at diagnosis included mycophenolate mofetil and prednisolone without calcineurin inhibitor in 5/6 patients. Histological analysis diagnosed monomorphic disease in 5/6, and one polymorphic case with tissue positive for Epstein-barr virus (EBV) in 5/6 cases. Despite this 2/4 EBV positive cases had no detectable EBV in peripheral blood or CSF at diagnosis. Treatment strategies included reduction in immunosuppression in all, chemotherapy (n=5), radiotherapy (n=3), Cytotoxic T-Lymphocytes and Craniotomy (n=2). Patient survival was 40% at 1 year with CTL treated patients surviving beyond three years from diagnosis.\n\nConclusion\nThis study supports observational data suggesting MMF treated patients without CNI may have increased risk of disease. Peripheral blood screening for EBV DNAemia does not seem helpful in early identification of those at risk.\n\nCNS-PTLDEBVmycophenolatetransplantationimmunosuppression\n==== Body\nINTRODUCTION\nLymphomas in the central nervous system are a rare presentation of PTLD. Outcomes are often poor and diagnosis made late. CNS PTLD is frequently monomorphic, B-cell in origin [1] and positive for EBV infection in up to 70% cases [2, 3, 7]. Among CNS disorders presenting after transplantation, PTLD follows cerebrovascular disease and infection in frequency and post-transplant autopsy series have found CNS PTLD in 2-7% of brains examined [4, 5]. Retrospective analyses of primary CNS PTLD presenting in SOT recipients found the greatest incidence in kidney allograft recipients (79%), followed by liver, heart, lung and pancreas [6].\n\nRetrospective studies have suggested an increase in the incidence of Primary CNS PTLD since the introduction of new immunosuppression regimes. Crane et al investigated the association of immunosuppression in a total of 174 patients including 29 with primary CNS PTLD. The study suggested that the use of CNI may be protective and that the increasing use of MMF may be associated with an increasing incidence of EBV positive primary CNS PTLD [7]. Anecdotal review of cases presenting to our unit in recent times suggested that patients presenting with CNS PTLD were typically on MMF and prednisolone without CNI.\n\nGuidelines recommend the monitoring of EBV DNA in peripheral blood in the first post-transplant year in high risk EBV seronegative recipients. However, there is no specific guidance on screening for EBV DNAemia in the late post-transplant period. Case reports have suggested individuals presenting with EBV positive CNS lymphoma may have no detectable EBV viremia at time of diagnosis in peripheral blood or cerebrospinal fluid [33].\n\nA diagnosis of PTLD is generally associated with a poor prognosis due to either graft failure from reduction of immunosuppression (RI), disease progression or toxicity from therapy [8]. Registry series have published overall response rates of 60% and survival rates of 54% at 3 years and 45% survival at 10 years with treatment related mortality causing 13% [9, 6].\n\nAims\nTo perform a single center review of presentation, management and outcomes of CNS lymphomas in kidney transplant patients transplanted from 1968 to 2015 along with a systematic review of relevant literature.\n\nRESULTS\nWe identified CNS PTLD in 6/90 (7%) patients, of which 4 patients presented with primary CNS PTLD and 2 patients presented with systemic PTLD with CNS involvement. Patients included 3 male and 3 female with a median age of 48.5 years at transplant and 59.5 year at diagnosis 59.5 years. Median time from transplant to diagnosis was 4.5 years, with 2 presenting early within 1 year of transplant and 4 late.\n\nPrimary disease, comorbidities and family history are presented in Table 1. Two patients had some previous form of low grade cancer which included Bowen's disease and anal intraepithelial neoplasia. Two had positive family history for cancer, one patient with a family history of colorectal cancer and the other recipient's first degree relative was diagnosed with Hodgkin's lymphoma.\n\nTable 1 Demographics and background history\nPatient\tGender\tAge (at diagnosis)\tTime from transplant (Years)\tPrimary Disease\tComorbidities\tFamily History\t\n1\tM\t62\t1\tSLE\tDVT, HTN, Osteoporosis\t\t\n2\tF\t66\t20\tGN\tBowen's disease, Atrial Flutter, HTN\t\t\n3\tF\t57\t13\tHTN\tTB, Bronchiectasis, MGUS\tFirst degree relative with Hodgkin's lymphoma\t\n4\tM\t69\t3\tGN\tHTN, Hyperlipidaemia\t\t\n5\tM\t55\t6\tPKD\tAIN, psoriasis, HTN, stroke, cmv colitis, hypercholesterolaemia\tColorectal cancer\t\n6\tF\t35\t2\tBergers nephropathy\tHTN, retinopathy\t\t\nAbbreviations: SLE; systemic lupus erythematosus, HTN; hypertension, GN; glomerulonephritis, PKD; polycystic kidney disease, DVT; deep vein thrombosis, TB; tuberculosis, MGUS; monoclonal gammopathy of undetermined significance, AIN; acute interstitial nephritis, CMV; cytomegalo virus.\n\nTable 2 describes the initial presentation and prognostic indicators at the time of diagnosis. Patient 1 who was 62 years old presented initially, 3 months after transplantation, with B symptoms and lymphadenopathy. He received Basiliximab as an induction agent with no episodes of rejection requiring therapy and immunosuppression at presentation included Tacrolimus, MMF and prednisolone. The patient was EBV seronegative at transplant, and at presentation had EBV DNA detected by PCR at 13428 copies/ml (log = 4.13) consistent with primary infection. CT demonstrated nodal disease in the mediastinum, neck, right and inguinal regions. Histology showed an EBV positive diffuse large B-cell lymphoma (DLBCL), with a raised LDH of 800. PET identified metabolically active disease above and below the diaphragm. Chemotherapy was commenced with a regimen of RCHOP which led to complete remission at the sites identified on PET scanning, however 6 months after chemotherapy, PET showed a new metabolically active area in the cerebellum (Figure 2). He therefore went on to have an MRI scan with gadolinium enhancement (Figure 1). This revealed multifocal white matter lesions including the cerebellum. Neuro-radiological consensus was of PTLD. EBV DNA in both blood and CSF were not detected during the time when CNS PTLD was diagnosed. The patient received CNS radiotherapy and 4 cycles of EBV specific CTL infusion. Initial repeat MRI scan at 1 month of treatment showed improvement in infratentorial lesions (Figure 3), improvement or static change in many supratentorial lesions but development of one lesion within the right middle frontal gyrus. MRI scan 1 year later showed no further significant changes in the previously identified intracranial lesions. of the brain showed a mixed picture of ongoing CNS lesions. Clinically the patient has remained stable over 3 years with no new focal neurological symptoms, headaches or B symptoms. Further MR imaging and clinical review is awaited.\n\nTable 2 The year of diagnosis and clinical, radiological and biochemistry at the time of diagnosis\nPatient No\tClinical presentation\tYear at Diagnosis\tRadiological Findings\tAlbumin at diagnosis (g/L)\tLDH (U/L)\tLymphocytes at diagnosis (X10^9/L)\tPlatelet at diagnosis (X10^9/L)\t\n1\tCervical, Superior mediastinal, inguinal lymphadenopathy, fever, collapse and weight loss.\t2015\tMulti-focal white matter lesions in the frontal and cerebellar lobes.\t38\t734\t0.44\t314\t\n2\tRight maxillary swelling.\t2011\tFocal abnormality in the right temporal region.\t36\t739\t7.3\t223\t\n3\tPeriods of depressed mood, tearfulness, memory impairment and prosopagnosia. Confusion, memory loss, headache and tingling in fingers and shoulders.\t2014\t12*9 mm ring enhancing lesion within left frontal lobe, white matter edema in frontal, parietal and temporal lobes.\t28\t\t0.52\t147\t\n4\tTruncal ataxia, dysphasia, incontinence and collapse.\t2008\tMultiple intrinsic enhancing brain lesions in the left cerebellum, right occipital, frontal and parietal lobes.\t39\t421\t1.75\t252\t\n5\tSpasms, twitches, abnormal gait, global weakness, memory impairment, expressive dysphasia, confusion, anorexia, weight loss and drenching night sweats.\t2007\tMultiple cerebral lesions in left fronto-parietal lesion, high parietal region and right parafalcine area.\t35\t\t0.52\t210\t\n6\tVertigo, double vision, right side hearing loss and cerebellar symptoms.\t2004\t4 lesions with involvement of the right cerebellum, the left posterior frontal area and the right posterior parietal region.\t47\t\t2.12\t284\t\nFigure 1 MRI brain of patient 1 before treatment showing a lesion in the cerebellum\nFigure 2 PET CT of patient 1 before treatment showing increased uptake in the cerebellum\nFigure 3 MRI brain of patient 1 shows resolution of lesion post treatment\nThe second patient was 66 years old at the time of diagnosis, was initially on Tacrolimus monotherapy as maintenance immunosuppression which was then substituted with MMF and prednisolone due to deteriorating graft function and had a biopsy showing CNI induced toxicity in the graft. Tacrolimus was withdrawn approximately 11 months prior to PTLD presentation. The patient then presented with a non-healing ulcer in the oral cavity with biopsy showing a high grade oral lymphoma and a subsequent focal abnormality in the right temporal region, about 20 years after transplantation. EBV DNA was detected in whole blood by PCR at 1085 copies/ml. Brain biopsy was not performed and CNS PTLD was diagnosed on the basis of the radiological findings with the oral cavity biopsy.\n\nPatient 6 presented 6 weeks post-transplant with decline in kidney function and a kidney biopsy showing micro thrombi within arterioles attributed to Ciclosporin. She was treated with high dose IV methyl prednisolone, cyclosporine was stopped and MMF was introduced. She subsequently remained on MMF and prednisolone for approximately 16 months when she presented with CNS symptoms and MRI brain showing multiple lesions and biopsy consistent with diffuse large B-cell lymphoma.\n\nTwo out of these six patients had characteristic ring enhancing lesions on cross-sectional imaging. Brain biopsy was performed in 4 patients of which 3 showed DLBCL (2 EBV positive, 1 unknown), while one patient was diagnosed with EBV positive polymorphic PTLD. Patient 1 and 2 had no brain biopsy and the basis for their CNS lymphoma diagnoses described above but had EBV tissue positive PTLD. All cases in this series were identified after 2004. As per the WHO classification of PTLD, 5 patients in our cohort presented with diffuse large B-cell Lymphoma, out of which one patient had tissue diagnosis from his inguinal lymph node and no brain biopsy. Case 4 was given an initial diagnosis of Diffuse-large B cell lymphoma but subsequent review by the Hematological malignancy diagnostic service (HMDS) concluded an EBV positive polymorphic PTLD. Case 3 also had review by the HMDS and case 6 a second opinion from a specialist haemato-oncology pathologist. Cases 1 and 2 did not have brain biopsy performed. Case 1 had PTLD diagnosed on the basis of his inguinal lymph node biopsy and subsequent radiological and clinical findings in relation to his brain. Case 2 had cerebral PTLD diagnosed on basis of biopsy of maxilla showing PTLD and radiological findings consistent. PTLD diagnoses in these last 2 cases were based on HMDS review. Despite EBV positive tissue (n=5 tested), EBV DNA was only mildly positive (1000 copies/ml) in blood (PCR) at the time of diagnosis in 2 out of 5 and negative in 3 patients. EBV was not detected in the CSF of any patients who had lumbar puncture performed (n=3) although 2 had EBV viremia at the time and all had EBV positive PTLD.\n\nTreatment\nAll cases presented were diagnosed after 2004 and all cases except 1 fit the classification of diffuse large B cell lymphoma in the current WHO classification. The authors acknowledge that treatment strategies continue to develop and can only report the strategies used for the patients who are presented. Treatment of lymphoma included reduction in immunosuppression in all patients, chemotherapy (n=5), radiotherapy (n=3), and Craniotomy (n=2). N=2 received EBV specific CTLs with good resolution of lesions in the MRI scans post treatment. Table 3 shows the treatment received, outcome and the cause of death.\n\nTable 3 Treatment received\n\tTreatment\tOutcome - Patient Survival\tCause of Death\t\n1.\tRIS, Chemotherapy, Radiotherapy, 4 cycles of CTLs\tMixed response, has a new CNS lesion with resolution of previous lesions, probable ongoing disease and alive 3 years post diagnosis.\tAlive\t\n2.\tRIS, systemic and intrathecal chemotherapy\tDied. 25 days\tChest Sepsis\t\n3.\tRIS,\tDied. 2 months\tAdvanced Lymphoma\t\n4.\tRIS, craniotomy, radiotherapy, rituximab.\tDied 5 months\nGraft failure requiring hemodialysis,\tAcute Left ventricular Failure\t\n5.\tRIS, radiotherapy, chemotherapy.\tDied 3 years\tunknown\t\n6.\tRIS, 8 cycles of CTLs\tDied 9 years\tPulmonary Embolism\t\nAbbreviations: RIS; reduction in immunosuppression, CNS; central nervous system, CTLs; cytotoxic T lymphocytes.\n\nOutcomes\nPatient survival at 6 months from diagnosis was 66.6%, 1 year 40% and 5 years 20% with median of 5 months duration from diagnosis to death in 5/6 patients. Death censored graft loss occurred in 1 patient who returned to dialysis. The two patients who presented within 1 year of transplantation showed a better response to treatment and had a better survival. The above two patients also received CTLs showing a better response to treatment with one of them still alive at 3 years post diagnosis and the other patient passed away 9 years after the diagnosis, with cause of death being recorded as due to pulmonary embolism.\n\nDISCUSSION\nMalignancy is the result of a multifactorial process with complex interlinking, predisposing and modulating mechanisms. There is an increased 2-3 fold cancer risk after solid organ transplantation when compared to the general population [10]. The innate protective mechanisms and barriers of a competent immune system through the action of CTLs, macrophages and natural killer cells are silenced by immunosuppression required to prevent rejection of the transplanted organ. This disruption of the immune system promotes mitotic transformation of cells and allows them to escape immune recognition. [11]\n\nPTLD has a bimodal presentation with a high risk period identified during the first year in seronegative recipients but the period of greatest incidence is in the late post-transplant period for CNS PTLD [12]. Report of a large nationwide French registry showed early onset(<12 months) in 14% this included systemic and CNS PTLD [9]. CNS PTLD in the large case series published to date suggest the period of greatest incidence is at approximately 5 years post-transplant where among 84 PCNS PTLD median time from transplant to PTLD diagnosis was 54 months [6].\n\nA pathological diagnosis is based on the WHO classification which has four major categories-early lesions, polymorphic PTLD, monomorphic PTLD which includes the DLBCL and classical Hodgkin lymphoma type PTLD [13]. However, in clinical practice it usually broadly varies between early lesions, polymorphic and monomorphic PTLD [13]. The use of increased immunosuppression at the first year of transplant or immediately after organ rejection increases the risk of developing “early PTLD” [14]. With a preservation of the tissue architecture there are two “Early” histological patterns that are identified-plasmacytic hyperplasia and Infectious Mononucleosis like lesion, showing EBER positivity on immuno-phenotype and oligo clonal or polyclonal EBV genome on molecular analysis [13]. Our study identified two patients who presented “early” with CNS lymphoma within the first year of transplantation, with the other patients presenting “late” from 3 years to about 20.35 years after transplantation. Early PTLD is usually EBV positive, involves the allograft in 57% and may respond well to RI. Late PTLD is usually monomorphic, more often EBV negative, less frequently involves the allograft and may respond less to RI.\n\nAs per the WHO classification of PTLD, 5 patients in our cohort were given a pathological diagnosis of monomorphic diffuse large B-cell Lymphoma, out of which one patient had tissue diagnosis from his inguinal lymph node and no brain biopsy. Another patient had a diagnosis of polymorphic PTLD which was confirmed by HMDS review.\n\nDLBCL is one of the most common lymphoproliferative disorders that occurs in an immunocompromised setting and one third of these cases are related to EBV infection. DLBCL is usually rapidly growing and its symptoms are most likely related to secondary mass effect [15].\n\nClinical presentations corresponded to the area of the brain involved along with general symptoms like fever, weight loss, night sweats, mood disturbances, tearfulness, memory disturbances and confusion. MRI and a positive histopathological diagnosis of PTLD is the gold standard in the diagnosis of PTLD [2] with diffusion-weighted imaging MRI playing an important role for evaluating treatment response [16].\n\nThe presence of EBV infected tumor cells in a high proportion of the PTLD population highlights the important role that EBV has to play in the development of post-transplant lymphomas [17]. In our study, 4 patients were found to have positive EBV LMP and EBER-ISH in the diseased tissue obtained from brain biopsy; one patient had no examination of the tissue for EBV and a further patient with EBV positive PTLD in a inguinal lymph node biopsy. The incompetence of the immune system in controlling latent EBV infection is the original cause of EBV-positive PTLD [18]. Transplant patients receiving high amounts of immunosuppression causing severe T cell immunosuppression allows EBV infected B cells to be transformed and immortalized, and multiply causing malignant lymphoproliferation [19]. A prospective study in heart and lung transplant patients looking at the correlation of EBV levels and clinical events shows that during the first 9 months post-transplant is the period when no CTL activity was detected in any patients due to high immunosuppressive therapy to prevent any acute rejection and this is when the detection of peripheral blood EBV levels are very high at about 80% and the incidence of early PTLD is very high [20]. EBV was detected in 85% of throat washings (TW) of patients in 3-6 months which then decreased to 71% in 6-12 months and 65% in 12-24 months [20]. A paper by Morton et al showed that of well adult kidney transplant patients screened for EBV viremia in the late post-transplant period (beyond 1 year) had detectable viremia including persistent viremia but no PTLD [21]. Also 2/6(33%) PTLD cases occurred in seronegative recipients and a patient with tissue negative for EBV had persistent EBV DNAemia during the sampling period, however during the time of PTLD diagnosis it was found to be negative in blood [21]. In addition the study demonstrates an association of detectable EBV levels and the use of MMF, this is suggested to be due to the reduction of EBV carrying B cell population [21]. The study advises that high risk seronegative recipients should receive equal attention on screening for symptoms and clinical examination along with monitoring EBV DNA levels as 50% of late PTLDs have a EBV negative diagnosis in adult renal transplant patients [21]. CNS PTLD is associated with >90% EBV positivity by EBER in situ hybridization which is more than the association of EBV with systemic PTLD [22]. However, only 27% were positive for detectable levels of EBV DNA in peripheral blood at the time of diagnosis. This obvious discrepancy between undetectable EBV DNA levels in blood and EBER positivity in tissue is mostly put down to the disease being more localized to the CNS with minimal systemic involvement causing low peripheral EBV DNA levels [22]. An extensive analysis evaluating the differences in the association of EBV with CNS and systemic PTLD by studying the expression of latent and lytic EBV transcripts and viral and cellular micro RNA in 9 EBV positive CNS PTLD and 16 EBV positive systemic PTLD identified 28 different microRNAs between systemic and CNS PTLD [23]. The activation of lytic replication or reactivation of the latent phase is what causes the EBV infected B cells to activate their growth program and differentiate and then the infected B cells are released into the blood stream, making it possible to detect levels of virus in the blood stream. An analysis of latent and lytic intra-tumoral EBV infection in a 35 patient series showed a low correlation between PCR in blood and replication in the involved organs [17].\n\nPatients in our study who had EBV detected in the biopsy samples still did not show positivity in the CSF samples or blood samples at the time of PTLD diagnosis. This indicates that only monitoring EBV PCR levels in the blood might not be helpful in diagnosing suspected CNS disease. Table 4 describes the histology, EBV status pre transplant and at the time of diagnosis. A study conducted by the Helsinki University Central Hospital, looked into the EBV DNA in CSF and EBV positivity was found to be the lowest in CNS lymphoproliferative disorder along with meningitis when compared to other CNS disorders like encephalitis and brain abscess which showed increased EBV DNA positivity in CSF [24]. The specificity and positive predictive value of EBV PCR in detecting CNS-PTLD is low and monitoring viral load alone would not help in the early diagnosis of CNS-PTLD [2]. EBV naïve individuals receiving an EBV positive organ and younger groups are at particular risk for PTLD [10].\n\nTable 4 Histology and EBV status at the time of diagnosis\n\tHistology\tEBV status Pre-Transplant (Recipient)\tEBV status in Tissue\tEBV status in Blood\tEBV status in CSF\t\n1.\tDiffuse large B cell Lymphoma\tNegative\tNo CNS biopsy (Positive Inguinal LN biopsy)\tPositive\tNegative\t\n2.\tDiffuse Large B-Cell Lymphoma\tPositive\tNo CNS biopsy (Positive maxillary biopsy)\tLow level Positive\tNegative\t\n3.\tDiffuse Large B-Cell Lymphoma\tUnknown\tPositive\tNegative\tNegative\t\n4.\tPolymorphic\tUnknown\tPositive\tLow level Positive\tNot done\t\n5.\tDiffuse Large B-Cell Lymphoma\tPositive\tUnknown\tNegative\tNot done\t\n6.\tDiffuse Large B-Cell Lymphoma\tUnknown\tPositive\tNegative\tNot done\t\nAbbreviations: CNS; central nervous system, LN; lymph node.\n\nFrench registry data analyzing 500 adult kidney transplant patients with PTLD between 1998-2007 developed prognostic factors for PTLD using Kaplan–Meier and Cox analyses. CNS localization was one of the independent prognostic indicators of poor survival, with an adjusted hazard ratio of 2.65 on multivariable analysis along with age >55 years at diagnosis, late onset PTLD, high LDH and creatinine levels, widespread PTLD, T cell lymphoma and monomorphic histology associated with a poor prognosis [9].\n\nIn our study, it is interesting that at the time of the diagnosis 5/6 patients were on only MMF as a mono-therapeutic agent of immunosuppression. Table 5 describes the immunosuppression regimes our patients received at induction and as maintenance. These patients previously were exposed to tacrolimus or cyclosporine but were changed or maintained on MMF due to reasons such as chronically disordered graft function, CNI toxicity or a rise in creatinine. MMF is a selective inhibitor of inosine monophosphate dehydrogenase, which is the rate limiting enzyme important for leukocyte production. Therefore, it inhibits the proliferation of T and B lymphocytes. EBV positive DLBCL involving the CNS has been reported in the use of MMF for autoimmune disorders like systemic lupus erythematosus [11]. There are few case reports which describe the development of CNS PTLD in four patients where MMF was used for other conditions other than transplant [25]. In a retrospective study that looked at patients developing late CNS PTLD, 6/10 patients had a change in their immunosuppression regimen from azathioprine to MMF just before PTLD presentation [26]. In a retrospective review of all PTLDs diagnosed at the John Hopkins Hospital, it was found that patients with CNS PTLD were more likely to have been taking MMF (15/16) when compared to non-CNS PTLD (37/102) in the year prior to or at the time of diagnosis [7]. In addition, a larger dataset from the UNOS-OPTN showed that 66.7% of the PCNS PTLD cases were in patients with MMF with no CNIs and 1.7% in those with a CNI and no MMF. This increases the odds for patients on MMF without CNIs to develop PCNS by about 118 folds compared to non-CNS PTLD, than patients on CNIs alone (95%CI, 8.7–1597; p < 0.001) [7]. Analysis of the UNOS-OPTN dataset using Firth's penalized regression method showed that the odds of PCNS PTLD were significantly increased when taking MMF as compared to not taking MMF (odds 2.9; 95% CI, 1.7–5.1; p < 0.002). CNIs significantly reduced the odds of PCNS disease compared to not taking CNIs (odds 0.34; 95% CI, 0.20–0.58; p < 0.001) [7]. These findings suggest that CNS may have an inherent susceptibility to lymphoproliferative disease in the context of immunosuppression, and the specific immunosuppressive regimen affects the likelihood of PCNS disease. CNIs, when given alone or in combination with MMF, appear to protect against the development of PCNS PTLD. Thus, our observed rise in the incidence of PCNS PTLD is likely not only due to immunosuppression with MMF but also due to a decline in the usage of the protective CNIs [27, 26]. This shows the importance of immunosuppression regimes having a role to play in the development of CNS PTLD.\n\nTable 5 Immunosuppression received and its duration\n\tInduction\tPrimary immunosuppression\tImmunosuppression at Diagnosis\tMMF dose (mg)\tPeriod of CNI exposure\tDuration on MMF\t\n1.\tBasiliximab\tTacrolimus, MMF and prednisolone\tMMF, Tacrolimus and Prednisolone\t720\t3 months\t3 months\t\n2.\tNil\tTacrolimus monotherapy\tMMF and prednisolone\t1500\t9 years\t1 year, 11 months\t\n3.\tNil\tCiclosporin\tMMF and Prednisolone\t1000\t6 years\t6 years\t\n4.\tBasiliximab\tTacrolimus\tMMF and Prednisolone\t250\tunknown\tunknown\t\n5.\tNil\tCiclosporin\tMMF and Prednisolone\t1000\tunknown\tunknown\t\n6.\tNil\tCiclosporin and prednisolone\tMMF and prednisolone\t1500\t4 months\t16 months\t\nAbbreviations: MMF; mycophenolate mofetil.\n\nThe challenge in treating PTLD of the CNS is that most of the chemotherapeutic agents do not cross the blood brain barrier. High dose methotrexate has been found to be useful in treating CNS PTLD [28]. Isolated CNS PTLD could be treated with radiation therapy alone, which has been effective in 85% of cases but with a median survival of just 26-36 months [27] and a five year survival of <5%2. Adult patients with recurrent disease after chemotherapy have used whole brain radiation therapy as a salvage treatment [2].\n\nIn a prospective study of 43 patients where rituximab was used to treat B-cell systemic PTLD with an exclusion of CNS involvement, showed an overall response rate of 40% with a one year survival rate of 67% [29]. An international multi-center open-label phase 2 trial which included 70 patients with systemic PTLD supports the sequential treatment using rituximab followed by CHOP as a first-line to all patients who do not respond to a reduction in immunosuppression [30]. Rituximab being a 145-kDa molecule cannot readily cross the blood brain barrier, with a CSF concentration of only 0.1% of the systemic level [2] and might not be effective in the treatment of CNS-PTLD. In the face of this disadvantage Bonney et al successfully treated two children with isolated CNS PTLD with intrathecal rituximab [27, 2]. In a study that looked at the efficacy of intrathecal rituximab in 8 children with CNS-EBV-PTLD showed that 7/8 patients responded well with just 2 patients showing persistent changes on their MRI brain scan [31]. However, this needs further large trials to confirm the efficacy of using intrathecal rituximab in the treatment of CNS PTLD.\n\nA reduction in immunosuppression in established systemic PTLD aims at restoring an immune response to EBV and this could induce a tumor regression in 50 % cases without any additional therapies, especially in polymorphic forms of PTLD [32]. However in case of a late onset monomorphic PTLD which is usually EBV negative, a RI seems to be ineffective [33]. When it comes specifically to CNS PTLD patients receive aggressive treatment modalities therefore management with just a reduction of immunosuppression has not been evaluated extensively. In a case series of 34 patients, 2 patients received only a reduction in immunosuppression. One of whom remained alive at 89 months with a complete response in a follow up MRI and the other to 7.4 months [32].\n\nAll of our patients were treated with a RI. RI comes with an increased risk of rejection, HLA sensitization and the need for transplant nephrectomy [10]. Indicators of poor response to RI are bulky disease, LDH >2.5 times the upper limit of normal, organ dysfunction and the involvement of multiple sites. There is always a risk of graft rejection in up to 39% of solid organ transplants with the RI [34]. 1/6 of our patients developed biopsy proven graft rejection requiring dialysis. A study has shown that holding immunosuppression while the patient is on chemotherapy and restarting RI was found to be safe in terms of graft outcomes [15].\n\n2/6 patients who presented with early CNS PTLD in our study received EBV specific CTLs which showed a good resolution of the lesions in the MRI scan done post treatment. EBV specific CTL therapy has been found to be useful in EBV positive PTLD even when they are resistant to rituximab. However, the facilities and experience in using it is not widely available [15, 22] and there is always a risk of graft versus host disease with allogenic T cells [15].\n\nMATERIALS AND METHODS\nNinety adult patients with a diagnosis of PTLD were identified in a single center. Retrospective case based review was performed of identified cases. Diagnosis was established from the clinical presentation, radiological and pathological findings. We analyzed patient demographics, primary disease, immunosuppression at the time of transplantation and diagnosis, clinical presentation, time of clinical presentation after kidney transplantation, timing of diagnosis after kidney transplantation, treatment received and both graft and patient survival. In addition detection of EBV in histological specimens, peripheral blood and CSF was analyzed in patients with disease. The histological specimens for 3/6 patients had a subsequent review by the Hematological malignancy diagnostic services (HMDS) in Leeds. We also looked at the duration of CNI exposure and MMF monotherapy where known, LDH, Albumin, Lymphocyte, platelet levels pre diagnosis to identify any prognostic factors. Informed consent was obtained from living patient and patient identifiable information not included in the manuscript.\n\nCONCLUSIONS\nIn our series CNS PTLD is uncommon involving only 7% cases, and presents late (median 4.5 years). Histology is typically DLBCL and EBV positive yet blood and CSF samples may have undetectable or low level EBV viral loads at diagnosis. Further studies on targeting EBV associated pathways in the pathogenesis needs to be encouraged which would introduce different treatment options in the future. We observed a high prevalence of patients on MMF at diagnosis with prior CNI withdrawn. Further research is needed to look into the mechanism of action of immunosuppressive regimes that might make patients susceptible to developing a CNS-PTLD.\n\nAuthor contributions\n\nMuir Morton: Co-author, study design and data collection. Titus Augustine: Created the opportunity to perform the study. Anju John John Velvet: Co-author, participated in study design, data collection and writing the paper.\n\nShiv Bhutani, Stavros Papachristos, Michael Picton, Titus Augustine, Muir Morton: Editing. Reena Dwivedi: Provided the required images.\n\nCONFLICTS OF INTEREST\n\nThe authors of this manuscript have no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1 Evens AM Roy R Sterrenberg D Moll MZ Chadburn A Gordon LI Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy Curr Oncol Rep 2010 12 383 94 10.1007/s11912-10-0132-1 20963522 \n2 Twombley K Pokala H Ardura MI Harker-Murray P Johnson-Welch SF Weinberg A Seikaly M Intraventricular rituximab and systemic chemotherapy for treatment of central nervous system post-transplant lymphoproliferative disorder after kidney transplantation Pediatr Transplant 2012 16 E201 09 10.1111/j.1399-3046.2012.01699.x 22646132 \n3 Suzuki M Kosugi I Terada T Shirakawa K Suzuki H Kono S Miyajima H A case of Epstein-Barr virus associated post-transplant lymphoproliferative disorder with CNS involvement: pathological findings at both biopsy and autopsy Neuropathology 2011 31 440 45 10.1111/j.1440-1789.2010.01177.x 21134001 \n4 Gallardo D Ferrà C Berlanga JJ Banda ED Ponce C Salar A Alonso E Espanñol I Riu C Grañena A Neurologic complications after allogeneic bone marrow transplantation Bone Marrow Transplant 1996 18 1135 39 8971384 \n5 Martínez AJ The neuropathology of organ transplantation: comparison and contrast in 500 patients Pathol Res Pract 1998 194 473 86 10.1016/S0344-0338(98)80116-7 9728364 \n6 Evens AM Choquet S Kroll-Desrosiers AR Jagadeesh D Smith SM Morschhauser F Leblond V Roy R Barton B Gordon LI Gandhi MK Dierickx D Schiff D Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era Am J Transplant 2013 13 1512 22 10.1111/ajt.12211 23721553 \n7 Crane GM Powell H Kostadinov R Rocafort PT Rifkin DE Burger PC Ambinder RF Swinnen LJ Borowitz MJ Duffield AS Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage Oncotarget 2015 6 33849 66 10.18632/oncotarget.5292 26460822 \n8 Green M Michaels MG Webber SA Rowe D Reyes J The management of Epstein-Barr virus associated posttransplant lymphoproliferative disorders in pediatric solidorgan transplant recipients Pediatr Transplant 1999 3 271 81 10.1034/j.1399-3046.1999.00066.x 10562971 \n9 Caillard S Porcher R Provot F Dantal J Choquet S Durrbach A Morelon E Moal V Janbon B Alamartine E Pouteil Noble C Morel D Kamar N Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score J Clin Oncol 2013 31 1302 9 10.1200/JCO.2012.43.2344 23423742 \n10 AlBugami M Kiberd B Malignancies: pre and post transplantation strategies Transplant Rev (Orlando) 2014 28 76 83 10.1016/j.trre.2013.12.002 24439783 \n11 Bagg A Dunphy CH Immunosuppressive and immunomodulatory therapy-associated lymphoproliferative disorders Semin Diagn Pathol 2013 30 102 12 10.1053/j.semdp.2012.08.005 23541274 \n12 Morton M Coupes B Roberts SA Klapper PE Byers RJ Vallely PJ Ryan K Picton ML Epidemiology of posttransplantation lymphoproliferative disorder in adult renal transplant recipients Transplantation 2013 95 470 78 10.1097/TP.0b013e318276a237 23222821 \n13 Parker A Bowles K Bradley JA Emery V Featherstone C Gupte G Marcus R Parameshwar J Ramsay A Newstead C Haemato-oncology Task Force of the British Committee for Standards in Haematology and British Transplantation Society Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS Guidelines Br J Haematol 2010 149 675 92 10.1111/j.1365-2141.2010.08161.x 20408847 \n14 Sola-Valls N Rodríguez CNY Arcal C Duran C Oppenheimer F Ribalta T Lopez-Guillermo A Campistol JM Graus F Diekmann F Primary brain lymphomas after kidney transplantation: an under-recognized problem? J Nephrol 2014 27 95 102 10.1007/s40620-013-0026-z 24469958 \n15 Le J Durand CM Agha I Brennan DC Epstein-Barr virus and renal transplantation Transplant Rev (Orlando) 2017 31 55 60 10.1016/j.trre.2016.12.001 28089555 \n16 Ginat DT Purakal A Pytel P Susceptibility-weighted imaging and diffusion-weighted imaging findings in central nervous system monomorphic B cell post-transplant lymphoproliferative disorder before and after treatment and comparison with primary B cell central nervous system lymphoma J Neurooncol 2015 125 297 305 10.1007/s11060-015-1903-1 26341369 \n17 Gonzalez-Farre B Rovira J Martinez D Valera A Garcia-Herrera A Marcos MA Sole C Roue G Colomer D Gonzalvo E Ribera-Cortada I Araya M Lloreta J In vivo intratumoral Epstein-Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications Mod Pathol 2014 27 1599 611 10.1038/modpathol.2014.68 24762547 \n18 Rasche L Kapp M Einsele H Mielke S EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT Bone Marrow Transplant 2014 49 163 67 10.1038/bmt.2013.96 23832092 \n19 Pope JH Horne MK Scott W Transformation of foetal human keukocytes in vitro by filtrates of a human leukaemic cell line containing herpes-like virus Int J Cancer 1968 3 857 66 10.1002/ijc.2910030619 4894385 \n20 Haque T Thomas JA Parratt R Hunt BJ Yacoub MH Crawford DH A prospective study in heart and lung transplant recipients correlating persistent Epstein-Barr virus infection with clinical events Transplantation 1997 64 1028 34 9381525 \n21 Morton M Coupes B Roberts SA Johnson SL Klapper PE Vallely PJ Picton ML Epstein-Barr virus infection in adult renal transplant recipients Am J Transplant 2014 14 1619 29 10.1111/ajt.12703 24815922 \n22 Sundin A Grzywacz BJ Yohe S Linden MA Courville EL B-cell posttransplant lymphoproliferative disorder isolated to the central nervous system is Epstein-Barr virus positive and lacks p53 and Myc expression by immunohistochemistry Hum Pathol 2017 61 140 47 10.1016/j.humpath.2016.12.007 27993575 \n23 Fink SE Gandhi MK Nourse JP Keane C Jones K Crooks P Jöhrens K Korfel A Schmidt H Neumann S Tiede A Jäger U Dührsen U A comprehensive analysis of the cellular and EBV-specific microRNAome in primary CNS PTLD identifies different patterns among EBV-associated tumors Am J Transplant 2014 14 2577 87 10.1111/ajt.12858 25130212 \n24 Martelius T Lappalainen M Palomäki M Anttila VJ Clinical characteristics of patients with Epstein Barr virus in cerebrospinal fluid BMC Infect Dis 2011 11 281 10.1186/1471-2334-11-281 22018204 \n25 O'Neill BP Vernino S Dogan A Giannini C EBV-associated lymphoproliferative disorder of CNS associated with the use of mycophenolate mofetil Neuro Oncol 2007 9 364 69 10.1215/15228517-2007-004 17522336 \n26 Boersma MN van der Zanden A Laverman GD Sanders JS de Vries PA Epstein-Barr virus-positive post-transplant lymphoproliferative disorder of the central nervous system, after renal transplantation with a discrepancy in viral load between peripheral blood and cerebrospinal fluid Transpl Int 2012 25 e113 16 10.1111/j.1432-2277.2012.01552.x 22909403 \n27 Yaginuma T Yamamoto H Mitome J Tanno Y Yamamoto I Kobayashi A Mafune A Hayakawa H Yokoyama K Mori R Ohashi H Kaito N Joki T Successful treatment of monomorphic primary central nervous system post-transplantation lymphoproliferative disorder 5 years after kidney transplantation Transpl Infect Dis 2012 14 E102 06 10.1111/j.1399-3062.2012.00781.x 22931101 \n28 Hatton O Martinez OM Esquivel CO Emerging therapeutic strategies for Epstein-Barr virus+ post-transplant lymphoproliferative disorder Pediatr Transplant 2012 16 220 29 10.1111/j.1399-3046.2012.01656.x 22353174 \n29 Choquet S Leblond V Herbrecht R Socié G Stoppa AM Vandenberghe P Fischer A Morschhauser F Salles G Feremans W Vilmer E Peraldi MN Lang P Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study Blood 2006 107 3053 57 10.1182/blood-2005-01-0377 16254143 \n30 Trappe R Oertel S Leblond V Mollee P Sender M Reinke P Neuhaus R Lehmkuhl H Horst HA Salles G Morschhauser F Jaccard A Lamy T German PTLD Study Group European PTLD Network Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial Lancet Oncol 2012 13 196 206 10.1016/S1470-2045(11)70300-X 22173060 \n31 Czyzewski K Styczynski J Krenska A Debski R Zajac-Spychala O Wachowiak J Wysocki M Intrathecal therapy with rituximab in central nervous system involvement of post-transplant lymphoproliferative disorder Leuk Lymphoma 2013 54 503 06 10.3109/10428194.2012.718342 22873830 \n32 Cavaliere R Petroni G Lopes MB Schiff D International Primary Central Nervous System Lymphoma Collaborative Group Primary central nervous system post-transplantation lymphoproliferative disorder: an International Primary Central Nervous System Lymphoma Collaborative Group Report Cancer 2010 116 863 70 10.1002/cncr.24834 20052713 \n33 Lim WH Russ GR Coates PT Review of Epstein-Barr virus and post-transplant lymphoproliferative disorder post-solid organ transplantation Nephrology (Carlton) 2006 11 355 66 10.1111/j.1440-1797.2006.00596.x 16889577 \n34 Le J Oncogenic γ Herpesviruses EBV and HHV8 in Kidney Transplantation Semin Nephrol 2016 36 362 71 10.1016/j.semnephrol.2016.05.013 27772621\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "10(4)",
"journal": "Oncotarget",
"keywords": "CNS-PTLD; EBV; immunosuppression; mycophenolate; transplantation",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "437-448",
"pmc": null,
"pmid": "30728897",
"pubdate": "2019-01-11",
"publication_types": "D016428:Journal Article",
"references": "10562971;16254143;16889577;17522336;20052713;20408847;20963522;21134001;22018204;22173060;22353174;22646132;22873830;22909403;22931101;23222821;23423742;23541274;23721553;23832092;24439783;24469958;24762547;24815922;25130212;26341369;26460822;27772621;27993575;28089555;4894385;8971384;9381525;9728364",
"title": "A single-center experience of post-transplant lymphomas involving the central nervous system with a review of current literature.",
"title_normalized": "a single center experience of post transplant lymphomas involving the central nervous system with a review of current literature"
} | [
{
"companynumb": "PHHY2019GB027733",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nBefore the era of intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment, only prevention for visual loss might have been achieved in a limited number of neovascular age-related macular generation (nAMD) patients with different treatment options.\n\n\nOBJECTIVE\nTo compare the efficacy of intravitreal bevacizumab (IVB) for the treatment of nAMD between phakic and pseudophakic eyes.\n\n\nMETHODS\nThe newly diagnosed nAMD patients were included in this retrospective study. The patients were divided into the phakic and pseudophakic groups. Initially, the patients received three consecutive, monthly, IVB injections, and then the treatment was continued on an as-needed regimen. The patients were examined monthly, and the data at the baseline, at 3, 6, 9, and 12 months and at the last follow-up were evaluated. The changes in the visual acuity (VA), central retinal thickness (CRT) and the number of injections were compared between the two groups.\n\n\nRESULTS\nThe study included 62 eyes of 62 patients (39 phakic, and 23 pseudophakic patients). The mean follow-up time was 19.7 and 17.2 months in the phakic and pseudophakic groups, respectively (p=0.06). The mean Log MAR VA at the baseline, 12 months and the last follow-up was 0.82, 0.72 and 0.75 in the phakic group and 0.77, 0.67, and 0.68 in the pseudophakic group, respectively. The change in the mean BCVA from the baseline to 12 months and at the last follow-up was not statistically different between the two groups (p=0.9 and p=0.7, respectively). The mean injection number at 12 months was 4.5 and 4.9 in the phakic and pseudophakic group, respectively (p=0.2).\n\n\nCONCLUSIONS\nThe beneficial effect of IVB is equal in both the phakic and pseudophakic group of nAMD patients. The functional and anatomical outcomes of the treatment and the number of injections were similar in the two groups.",
"affiliations": "Department of Ophthalmology, Beyoglu Eye Training and Research Hospital, and Medeniyet University, Istanbul, Turkey.",
"authors": "Ozkaya|Abdullah|A|;Alkin|Zeynep|Z|;Perente|Irfan|I|;Yuksel|Kemal|K|;Baz|Okkes|O|;Alagoz|Cengiz|C|;Yazici|Ahmet Taylan|AT|;Demirok|Ahmet|A|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "Nepal",
"delete": false,
"doi": "10.3126/nepjoph.v6i2.11706",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2072-6805",
"issue": "6(2)",
"journal": "Nepalese journal of ophthalmology : a biannual peer-reviewed academic journal of the Nepal Ophthalmic Society : NEPJOPH",
"keywords": null,
"medline_ta": "Nepal J Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration; D008297:Male; D008875:Middle Aged; D015861:Retinal Neovascularization; D012189:Retrospective Studies; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "101505288",
"other_id": null,
"pages": "145-52",
"pmc": null,
"pmid": "25680245",
"pubdate": "2014",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparison of intravitreal bevacizumab treatment between phakic and pseudophakic neovascular age-related macular degeneration.",
"title_normalized": "comparison of intravitreal bevacizumab treatment between phakic and pseudophakic neovascular age related macular degeneration"
} | [
{
"companynumb": "TR-ROCHE-1641969",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nTo describe a case of a male adolescent with symptomatic idiopathic intracranial hypertension (IIH) associated with obesity treated with bariatric surgery.\n\n\nMETHODS\nA 16-year-and-6-month-old severely obese boy [weight: 133.6 kg; height: 1.74 m (Z score: +0.14); BMI: 44.1 kg/m2 (Z score: +4.4)], Tanner pubertal stage 5, presented biparietal, high-intensity, and pulsatile headaches, about five times per week, associated with nocturnal awakenings, and partial improvement with common analgesics, for three months. Ophthalmologic evaluation evidenced bilateral papilledema. Cranial computed tomography revealed no mass or anatomic abnormalities. Lumbar puncture showed increased intracranial pressure of 40 cmH2O (reference value: <28 cmH2O) with a normal content. After being diagnosed with IIH, the patient was started on acetazolamide. However, after three months, he was still symptomatic. He was diagnosed with obesity due to excess energy intake and, as he had failed to lose weight after a conventional clinical treatment, bariatric surgery was indicated. The patient (at 16 years and nine months) underwent an uncomplicated laparoscopic sleeve gastrectomy. Ophthalmologic evaluation, performed five months after surgery, revealed normal visual acuity in both eyes and improvement of bilateral papilledema. Follow-up at 18 months showed a 67.5% loss of excess weight (weight: 94.5 kg and BMI: 31.2 kg/m2) and complete resolution of IIH symptoms.\n\n\nCONCLUSIONS\nIIH is characterized by increased intracranial pressure with no evidence of deformity or obstruction of the ventricular system on neuroimaging. It has been associated with obesity. Bariatric surgery may be a valid alternative approach for morbidly obese adolescent patients with refractory symptoms.",
"affiliations": "Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.",
"authors": "Ybarra|Marina|M|http://orcid.org/0000-0001-7697-2218;Santos|Tiago Jeronimo Dos|TJD|http://orcid.org/0000-0001-9682-0289;Queiroz|Edjane Santos|ES|http://orcid.org/0000-0002-8672-1751;Rachid|Ludmilla|L|http://orcid.org/0000-0001-5843-5646;Franco|Ruth Rocha|RR|http://orcid.org/0000-0001-5811-7656;Cominato|Louise|L|http://orcid.org/0000-0001-9752-1117;Moura|Frederico Castelo|FC|http://orcid.org/0000-0002-7949-6832;Velhote|Manoel Carlos|MC|http://orcid.org/0000-0001-9018-1164;Damiani|Durval|D|http://orcid.org/0000-0002-2748-4442",
"chemical_list": "D004232:Diuretics; D000086:Acetazolamide",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1984-0462/2020/38/2018239",
"fulltext": "\n==== Front\nRev Paul PediatrRev Paul PediatrrppRevista Paulista de Pediatria0103-05821984-0462Sociedade de Pediatria de São Paulo 10.1590/1984-0462/2020/38/201823900605Case ReportBARIATRIC SURGERY AS A TREATMENT FOR IDIOPATHIC INTRACRANIAL HYPERTENSION IN A MALE ADOLESCENT: CASE REPORT CIRURGIA BARIÁTRICA COMO TRATAMENTO DE PSEUDOTUMOR CEREBRAL PRIMÁRIO EM ADOLESCENTE DO SEXO MASCULINO: RELATO DE CASO http://orcid.org/0000-0001-7697-2218Ybarra Marina \na\n*http://orcid.org/0000-0001-9682-0289dos Santos Tiago Jeronimo \na\nhttp://orcid.org/0000-0002-8672-1751Queiroz Edjane Santos \na\nhttp://orcid.org/0000-0001-5843-5646Rachid Ludmilla \na\nhttp://orcid.org/0000-0001-5811-7656Franco Ruth Rocha \na\nhttp://orcid.org/0000-0001-9752-1117Cominato Louise \na\nhttp://orcid.org/0000-0002-7949-6832Moura Frederico Castelo \na\nhttp://orcid.org/0000-0001-9018-1164Velhote Manoel Carlos \na\nhttp://orcid.org/0000-0002-2748-4442Damiani Durval \na\n\na Universidade de São Paulo, São Paulo, SP, Brazil.* Corresponding author. E-mail: marinaybarra@gmail.com (M. Ybarra).The authors declare no conflict of interests.\n\n13 1 2020 2020 38 e201823919 7 2018 26 9 2018 20 12 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution LicenseABSTRACT\nObjective:\nTo describe a case of a male adolescent with symptomatic idiopathic intracranial hypertension (IIH) associated with obesity treated with bariatric surgery.\n\nCase description:\nA 16-year-and-6-month-old severely obese boy [weight: 133.6 kg; height: 1.74 m (Z score: +0.14); BMI: 44.1 kg/m2 (Z score: +4.4)], Tanner pubertal stage 5, presented biparietal, high-intensity, and pulsatile headaches, about five times per week, associated with nocturnal awakenings, and partial improvement with common analgesics, for three months. Ophthalmologic evaluation evidenced bilateral papilledema. Cranial computed tomography revealed no mass or anatomic abnormalities. Lumbar puncture showed increased intracranial pressure of 40 cmH2O (reference value: <28 cmH2O) with a normal content. After being diagnosed with IIH, the patient was started on acetazolamide. However, after three months, he was still symptomatic. He was diagnosed with obesity due to excess energy intake and, as he had failed to lose weight after a conventional clinical treatment, bariatric surgery was indicated. The patient (at 16 years and nine months) underwent an uncomplicated laparoscopic sleeve gastrectomy. Ophthalmologic evaluation, performed five months after surgery, revealed normal visual acuity in both eyes and improvement of bilateral papilledema. Follow-up at 18 months showed a 67.5% loss of excess weight (weight: 94.5 kg and BMI: 31.2 kg/m2) and complete resolution of IIH symptoms.\n\nComments:\nIIH is characterized by increased intracranial pressure with no evidence of deformity or obstruction of the ventricular system on neuroimaging. It has been associated with obesity. Bariatric surgery may be a valid alternative approach for morbidly obese adolescent patients with refractory symptoms.\n\nRESUMO\nObjetivo:\nDescrever um caso de cirurgia bariátrica como tratamento de pseudotumor cerebral primário (PTCP) em adolescente do sexo masculino com obesidade.\n\nDescrição do caso:\nAdolescente, sexo masculino, 16 anos e 6 meses, com obesidade exógena [peso:133,6 kg; estatura:1,74 m (escore z: +0,14); IMC: 44,1 kg/m2 (escore z: +4,4)], estadiamento puberal de Tanner 5, apresentando cefaleia bi-parietal, pulsátil e de alta-intensidade, cerca de cinco vezes por semana, associada a despertares noturnos, e com melhora parcial com analgésicos comuns, há três meses. A avaliação oftalmológica evidenciou papiledema bilateral e a tomografia computadorizada de crânio não revelou massas ou alterações anatômicas. A punção lombar mostrou pressão intracraniana elevada de 40 cmH2O (Referência: <28 cmH2O) com conteúdo normal. Feito o diagnóstico, o paciente foi iniciou uso de acetazolamida. No entanto, após 3 meses, o paciente mantinha-se sintomático. Ele foi diagnosticado com obesidade devido ao consumo calórico excessivo e, como não havia obtido sucesso na perda de peso com tratamento clínico convencional, a cirurgia bariátrica foi indicada. Aos 16 anos e 9 meses, o paciente foi submetido a gastrectomia vertical laparoscópica sem complicações. A avaliação oftalmológica, cinco meses após a cirurgia, revelou melhora do papiledema bilateral com acuidade visual normal em ambos os olhos. Apresentou perda de excesso de peso de 67,5% (peso: 94,5 kg e IMC:31,2 kg/m2) e resolução completa dos sintomas de PPTC 18 meses após a cirurgia.\n\nComentários:\nO PTCP é caracterizado pelo aumento da pressão intracraniana, sem evidência de deformidade ou obstrução do sistema ventricular na neuroimagem. Está associado à obesidade. A cirurgia bariátrica pode ser uma alternativa terapêutica válida para pacientes adolescentes obesos graves com sintomas refratários.\n\nKeywords:\nPseudotumor cerebriObesityBariatric surgeryAdolescentPalavras-chave:\nPseudotumor cerebralObesidadeCirurgia bariátricaAdolescente\n==== Body\nINTRODUCTION\nIdiopathic intracranial hypertension (IIH), also known as primary pseudotumor cerebri, is clinically characterized by increased intracranial pressure in an alert and oriented patient, with no evidence of deformity or obstruction of the ventricular system on neuroimaging.1 Cerebrospinal fluid (CSF) analysis is normal except for an increased intracranial pressure at the lumbar puncture,1 greater than the 90th percentile (28 cmH2O) in the pediatric population.2 Papilledema may or may not be present.3\n\n\nHeadache is the most common symptom of IIH (84%) and is often described as daily, bilateral, frontal, or retro-ocular. Visual loss is the main morbidity of IIH, and transient visual disturbances can occur in up to 68% of patients.4,5\n\n\nObesity is a consistent risk factor for the development of IIH. Body mass index (BMI) has been associated with risk of IIH.2 IIH in adolescents appears to have similar characteristics to those in adults, including the association with obesity.3 Early diagnosis and treatment of IIH are imperative to prevent permanent vision loss.5 Our objective was to describe a case of a male adolescent with symptomatic IIH associated with obesity and treated with bariatric surgery.\n\nCASE DESCRIPTION\nA 16-year-and-6-month-old severely obese boy [weight: 133.6 kg; height: 1.74 m (+0.14 standard deviation — SD); BMI: 44.1 kg/m2 (+4.4 SD)], Tanner pubertal stage 5, followed for obesity due to excess energy intake in our Pediatric Endocrinology Clinic since he was eight years old, and with a history of severe obstructive sleep apnea, gastrointestinal reflux disease, depression, insulin resistance (HOMA-IR 9.8), moderate hepatic steatosis [based on ultrasound findings and ALT: 41 U/L (reference value: <40 U/L)], and systemic arterial hypertension with cardiac left ventricular hypertrophy, presented biparietal, high-intensity, and pulsatile headaches.\n\nThe headaches had progressively worsened over the prior three months. They occurred five times per week and were associated with nocturnal awakenings. There was partial improvement with common analgesics. He was not able to stand still or walk straight without falling during the headache episodes. Ophthalmologic evaluation confirmed bilateral papilledema (Figure 1A), normal visual acuity, and absence of abducens nerve palsy. Cranial computed tomography revealed no mass or anatomic abnormalities. Lumbar puncture showed increased intracranial pressure of 40 cmH2O (reference value: <28 cmH2O) with a normal content. Optical coherence tomography (OCT) was not performed.6 IIH was diagnosed. The patient was started on acetazolamide q12h with partial improvement of his symptoms. However, after three months, he was still symptomatic.\n\nAs he had already failed to lose weight after being enrolled in a medically supervised weight-loss program (composed of a multidisciplinary team including a nutritionist, physical therapist, psychologist, and pediatric surgeon specialized in bariatric surgery), and exhibited a bone age of a 17-year-old, we indicated bariatric surgery. During this period, he and his family were encouraged to make lifestyle changes (healthy diet and physical activity). They were also followed monthly by a psychologist. The patient was treated with sibutramine, fluoxetine, and metformin, but showed no response. Our decision was taken after considering the criteria established by the Brazilian Federal Council of Medicine guidelines to undergo bariatric surgery in adolescence,7 which the patient fulfilled. The family formally consented, and the patient assented to the procedure.\n\nAt the age of 16 years and nine months, the patient underwent an uncomplicated laparoscopic sleeve gastrectomy. Ophthalmologic evaluation, performed five months after surgery, revealed normal visual acuity in both eyes and improvement of bilateral papilledema (Figure 1B). Follow-up at 18 months showed a 67.5% loss of excess weight (weight: 94.5 kg and BMI: 31.2 kg/m2) and complete resolution of IIH symptoms. Insulin resistance (HOMA-IR: 2.4) and hepatic steatosis normalized, and antihypertensive drugs were no longer needed.\n\nDISCUSSION\nWe present a case of a severely obese male adolescent with IIH who had complete symptom resolution with bariatric surgery after a failed clinical treatment.\n\nFigure 1 Eye fundus photography before (A) and after (B) laparoscopic sleeve gastrectomy. Note the improvement of bilateral papilledema.\nAlthough there is no current consensus on the best management strategy for IIH, the goals should be to preserve visual function and reduce long-term headache disability.8 In adults with obesity-related IIH, weight reduction — either by diet or bariatric surgery — improved vision, with papilledema and IIH resolution.9,10 Surgical interventions were associated with 100% of postoperative IIH resolution against 66.7% in the non-surgical group (95%CI 45.6–87.8; p<0.005).11 Some authors even consider bariatric surgery as the procedure of choice for severely obese patients with IIH.11 A prospective randomized trial in adults is currently evaluating its effectiveness.12\n\n\nThere is a paucity of evidence-based recommendations for the treatment of IIH in children or adolescents.1 According to the International and the Brazilian Guidelines, adolescents with a BMI greater than 35 kg/m2, associated with severe comorbidities and complete growth plate (epiphyseal cartilage) closure, may clinically benefit from surgical weight loss.7,13 Chandra et al. published a case report which demonstrated complete resolution of IIH symptoms after a gastric bypass in an adolescent girl.14 Other reports also showed the safety of the bariatric surgery as a treatment for IIH.15-17 Laparoscopic sleeve gastrectomy could be an alternative surgery since it has already proven to be safe and effective in the treatment of morbidly obese adolescents.18 Mortality rates after bariatric surgery are low.19 A wide range of surgical complications may occur after bariatric surgery. Pulmonary and venous thromboembolism occur in <0.5% of bariatric surgery patients, usually within the first postoperative month.20 Other complications are procedure-specific and may include anastomotic leak, anastomotic stricture, bowel perforation, hemorrhage, incisional hernia, and marginal ulcer.21 Common gastrointestinal side effects after bariatric surgery include: vomiting, diarrhea, dumping syndrome, hypoglycemic syndrome, and cholelithiasis.22 Micronutrient deficiencies may also occur after bariatric surgery.22\n\n\nOur case shows that bariatric surgery may be a valid alternative approach for morbidly obese adolescent patients with refractory symptoms. Our patient presented complete resolution of IIH signs and symptoms and experienced a 67.5% loss of excess weight after surgery.\n\nACKNOWLEDGMENTS\nThe authors would like to thank the patient who consented to and authorized the elaboration of this manuscript, Mariza Kazue for helping with the bibliographic research; Luiz Fernando Ybarra, MD, Ph.D., MBA, for reviewing the manuscript, and Tania Giannone, MD, Prince Kevin Danieles, and Nora Young for proofreading the manuscript.\n\nFunding\nThis study did not receive funding.\n==== Refs\nREFERENCES\n1 Matthews YY Dean F Lim MJ McLachlan K Rigby AS Solanki GA Pseudotumor cerebri syndrome in childhood: incidence, clinical profile and risk factors in a national prospective population-based cohort study Arch Dis Child 2017 102 715 721 10.1136/archdischild-2016-312238 28356250 \n2 Avery RA Shah SS Licht DJ Seiden JA Huh JW Boswinkel J Reference range for cerebrospinal fluid opening pressure in children N Engl J Med 2010 363 891 893 10.1056/NEJMc1004957 20818852 \n3 Friedman DI Liu GT Digre KB Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children Neurology 2013 81 1159 1165 10.1212/WNL.0b013e3182a55f17 23966248 \n4 Wall M Kupersmith MJ Kieburtz KD Corbett JJ Feldon SE Friedman DI The idiopathic intracranial hypertension treatment trial: clinical profile at baseline JAMA Neurol 2014 71 693 701 10.1001/jamaneurol.2014.133 24756302 \n5 Mollan SP Ali F Hassan-Smith G Botfield H Friedman DI Sinclair AJ Evolving evidence in adult idiopathic intracranial hypertension: pathophysiology and management J Neurol Neurosurg Psychiatry 2016 87 982 992 10.1136/jnnp-2015-311302 26888960 \n6 Chatziralli I Theodossiadis P Theodossiadis G Asproudis I Perspectives on diagnosis and management of adult idiopathic intracranial hypertension Graefes Arch Clin Exp Ophthalmol 2018 256 1217 1224 10.1007/s00417-018-3970-4 29619550 \n7 Conselho Federal de Medicina Resolução CFM n° 2.131/2015, que altera o anexo da Resolução CFM n° 1.942/10, publicada no D.O.U. de 12 de fevereiro de 2010, Seção I 72 Brasília (DF) Diário Oficial da União 2015 \n8 Piper RJ Kalyvas AV Young AM Hughes MA Jamjoom AA Fouyas IP Interventions for idiopathic intracranial hypertension Cochrane Database Syst Rev 2015 CD003434 10.1002/14651858.CD003434.pub3 26250102 \n9 Banik R Obesity and the role of nonsurgical and surgical weight reduction in idiopathic intracranial hypertension Int Ophthalmol Clin 2014 54 27 41 10.1097/IIO.0b013e3182aabf2e 24296369 \n10 Moss HE Bariatric surgery and the neuro-ophthalmologist J Neuroophthalmol 2016 36 78 84 10.1097/WNO.0000000000000332 26764529 \n11 Manfield JH Yu KK Efthimiou E Darzi A Athanasiou T Ashrafian H Bariatric surgery or non-surgical weight loss for idiopathic intracranial hypertension? a systematic review and comparison of meta-analyses Obes Surg 2017 27 513 521 10.1007/s11695-016-2467-7 27981458 \n12 Ottridge R Mollan SP Botfield H Frew E Ives NJ Matthews T Randomised controlled trial of bariatric surgery versus a community weight loss programme for the sustained treatment of idiopathic intracranial hypertension: the Idiopathic Intracranial Hypertension Weight Trial (IIH:WT) protocol BMJ Open 2017 7 e017426 10.1136/bmjopen-2017-017426 \n13 Styne DM Arslanian SA Connor EL Farooqi IS Murad MH Silverstein JH Pediatric obesity-assessment, treatment, and prevention: an endocrine society clinical practice guideline J Clin Endocrinol Metab 2017 102 709 757 10.1210/jc.2016-2573 28359099 \n14 Chandra V Dutta S Albanese CT Shepard E Farrales-Nguyen S Morton J Clinical resolution of severely symptomatic pseudotumor cerebri after gastric bypass in an adolescent Surg Obes Relat Dis 2007 3 198 200 10.1016/j.soard.2006.11.015 17324634 \n15 Mancera N Murr MM Drucker M Bariatric surgery and its impact on pseudotumor cerebri: A case report Am J Ophthalmol Case Rep 2018 10 68 70 10.1016/j.ajoc.2018.01.047 29780918 \n16 Hoang KB Hooten KG Muh CR Shunt freedom and clinical resolution of idiopathic intracranial hypertension after bariatric surgery in the pediatric population: report of 3 cases J Neurosurg Pediatr 2017 20 511 516 10.3171/2017.6.PEDS17145 28960170 \n17 Cazzo E Gestic MA Utrini MP Chaim FD Chaim FH Candido EC Bariatric surgery as a treatment for pseudotumor cerebri: case study and narrative review of the literature Sao Paulo Med J 2018 136 182 187 10.1590/1516-3180.2016.0305060117 28562736 \n18 Franco RR Ybarra M Cominato L Mattar L Steinmetz L Damiani D Laparoscopic sleeve gastrectomy in severely obese adolescents: effects on metabolic profile Arch Endocrinol Metab 2017 61 608 613 10.1590/2359-3997000000310 29412386 \n19 Shi X Karmali S Sharma AM Birch DW A review of laparoscopic sleeve gastrectomy for morbid obesity Obes Surg 2010 20 1171 1177 10.1007/s11695-010-0145-8 20379795 \n20 Winegar DA Sherif B Pate V DeMaria EJ Venous thromboembolism after bariatric surgery performed by Bariatric Surgery Center of Excellence Participants: analysis of the Bariatric Outcomes Longitudinal Database Surg Obes Relat Dis 2011 7 181 188 10.1016/j.soard.2010.12.008 21421182 \n21 Nguyen NT Rivers R Wolfe BM Factors associated with operative outcomes in laparoscopic gastric bypass J Am Coll Surg 2003 197 548 555 10.1016/S1072-7515(03)00648-3 14522321 \n22 Mechanick JI Youdim A Jones DB Garvey WT Hurley DL McMahon MM Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery Surg Obes Relat Dis 2013 9 159 191 10.1016/j.soard.2012.12.010 23537696\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0103-0582",
"issue": "38()",
"journal": "Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo",
"keywords": null,
"medline_ta": "Rev Paul Pediatr",
"mesh_terms": "D000086:Acetazolamide; D000293:Adolescent; D000359:Aftercare; D050110:Bariatric Surgery; D004232:Diuretics; D005654:Fundus Oculi; D006261:Headache; D006801:Humans; D008297:Male; D009767:Obesity, Morbid; D010211:Papilledema; D011559:Pseudotumor Cerebri; D013129:Spinal Puncture; D016896:Treatment Outcome; D015431:Weight Loss",
"nlm_unique_id": "9109353",
"other_id": null,
"pages": "e2018239",
"pmc": null,
"pmid": "31939513",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "28356250;23966248;20379795;21421182;26888960;29412386;29619550;28963303;26764529;23537696;20818852;28562736;17324634;24756302;27981458;29780918;28960170;26250102;24296369;14522321;28359099",
"title": "BARIATRIC SURGERY AS A TREATMENT FOR IDIOPATHIC INTRACRANIAL HYPERTENSION IN A MALE ADOLESCENT: CASE REPORT.",
"title_normalized": "bariatric surgery as a treatment for idiopathic intracranial hypertension in a male adolescent case report"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-253865",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIBUTRAMINE"
},
"dru... |
{
"abstract": "A 75-year-old man with rectal cancer had consumed an average of6 6 g of alcohol per day for 47 years. However, his liver function was within normal limits and his Child-Pugh classification was A before initiation of therapy. He underwent neoadjuvant chemoradiation and a low anterior resection. The patient then received CapeOX as an adjuvant therapy. During the fourth cycle of CapeOX, computed tomography(CT)showed massive ascites. The chemotherapy was discontinued and treatment including a diuretic agent was initiated. The ascites gradually decreased and 8 months after the discontinuation of CapeOX, CT showed neither the presence ofascites nor recurrence ofthe cancer or metastasis. When a patient has a history ofexcessive alcohol intake, even iftest results for liver function are within normal limits, we should be aware ofthe hepatic toxicity ofCapeOX.",
"affiliations": "Dept. of Surgery, Nagahama City Hospital.",
"authors": "Yonenaga|Yoshikuni|Y|;Nio|Marika|M|;Yata|Yoshihiro|Y|;Higashide|Shunichi|S|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000069287:Capecitabine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(9)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001201:Ascites; D000069287:Capecitabine; D059248:Chemoradiotherapy; D006801:Humans; D008108:Liver Diseases, Alcoholic; D008297:Male; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012004:Rectal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "801-803",
"pmc": null,
"pmid": "28912413",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Alcoholic Liver Disease Presenting as Prominent Accumulation of Ascites Associated with Liver Damage Due to CapeOX.",
"title_normalized": "a case of alcoholic liver disease presenting as prominent accumulation of ascites associated with liver damage due to capeox"
} | [
{
"companynumb": "PHHY2018JP042522",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "1",
"drug... |
{
"abstract": "We herein report a 64-year-old man who was treated with pembrolizumab for relapsed Hodgkin lymphoma. After the third administration of pembrolizumab, he showed acute anemia with a positive direct anti-globulin test. Because of the markedly erythroid hypoplasia, he was diagnosed with pure red cell aplasia (PRCA) caused by pembrolizumab. He was initially treated with prednisolone, but the reticulocytes decreased after tapering prednisolone. He then received high-dose intravenous immunoglobulin (IVIG) with prednisolone, and PRCA was successfully treated. Although the pathogenesis of PRCA caused by immune checkpoint inhibitors (CPIs) remains unclear, IVIG treatment may be effective for some steroid-refractory CPI-induced PRCA cases.",
"affiliations": "Department of Hematology, National Hospital Organization Shibukawa Medical Center, Japan.;Department of Hematology, National Hospital Organization Shibukawa Medical Center, Japan.;Department of Hematology, National Hospital Organization Shibukawa Medical Center, Japan.;Department of Hematology, National Hospital Organization Shibukawa Medical Center, Japan.;Department of Hematology, National Hospital Organization Shibukawa Medical Center, Japan.;Department of Hematology, National Hospital Organization Shibukawa Medical Center, Japan.;Department of Hematology, National Hospital Organization Shibukawa Medical Center, Japan.",
"authors": "Isoda|Atsushi|A|;Miyazawa|Yuri|Y|;Tahara|Kenichi|K|;Mihara|Masahiro|M|;Saito|Akio|A|;Matsumoto|Morio|M|;Sawamura|Morio|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D016756:Immunoglobulins, Intravenous; D011239:Prednisolone; C582435:pembrolizumab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.4467-20",
"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32389947\n10.2169/internalmedicine.4467-20\nCase Report\nPembrolizumab-induced Pure Red Cell Aplasia Successfully Treated with Intravenous Immunoglobulin\nIsoda Atsushi 12 Miyazawa Yuri 1 Tahara Kenichi 1 Mihara Masahiro 1 Saito Akio 1 Matsumoto Morio 1 Sawamura Morio 1 \n1 Department of Hematology, National Hospital Organization Shibukawa Medical Center, Japan\n\n2 Department of Hematology, Hoshi Clinic, Japan\nCorrespondence to Dr. Atsushi Isoda, hoshiclinic01@gmail.com\n\n\n8 5 2020 \n15 8 2020 \n59 16 2041 2045\n11 1 2020 16 3 2020 Copyright © 2020 by The Japanese Society of Internal MedicineThe 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/).We herein report a 64-year-old man who was treated with pembrolizumab for relapsed Hodgkin lymphoma. After the third administration of pembrolizumab, he showed acute anemia with a positive direct anti-globulin test. Because of the markedly erythroid hypoplasia, he was diagnosed with pure red cell aplasia (PRCA) caused by pembrolizumab. He was initially treated with prednisolone, but the reticulocytes decreased after tapering prednisolone. He then received high-dose intravenous immunoglobulin (IVIG) with prednisolone, and PRCA was successfully treated. Although the pathogenesis of PRCA caused by immune checkpoint inhibitors (CPIs) remains unclear, IVIG treatment may be effective for some steroid-refractory CPI-induced PRCA cases. \n\npure red cell aplasiapembrolizumabprogramed cell death 1immune-related adverse eventsdirect anti-globulin testintravenous immunoglobulin\n==== Body\nIntroduction\nPure red cell aplasia (PRCA) is a hematological syndrome characterized by a normocytic normochromic anemia with severe reticulocytopenia and marked reduction in or absence of erythroid precursors from the bone marrow (1). With the increasing use of immune checkpoint inhibitors (CPIs) targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and the programed cell death 1 (PD-1) pathway in a variety of malignancies, there is a growing number of reports of hematologic toxicities as immune-related adverse events (irAEs) (2, 3). However, PRCA as irAEs caused by CPIs has been rarely documented, and its management guidelines remain unclear.\n\nWe herein report a case of PRCA followed by the PD-1 antagonist pembrolizumab for refractory Hodgkin lymphoma, which was successfully treated with high-dose intravenous immunoglobulin (IVIG).\n\nCase Report\nA 64-year-old Japanese man was originally diagnosed with stage IIB classical Hodgkin lymphoma (mixed cellular type) and underwent chemotherapy with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) for 6 cycles. His disease relapsed two year later, but he refused to receive salvage chemotherapies or brentuximab vedotin because of the peripheral neuropathy. He was therefore started on immunotherapy using the PD-1 antagonist pembrolizumab (200 mg/m2, every 3 weeks).\n\nShortly after the third administration of pembrolizumab, he developed acute normocytic normochromic anemia (hemoglobin 7.0 g/dL) with normal white blood cells and platelet counts. Although a direct anti-globulin test (DAT) converted to positive, his absolute reticulocyte counts were decreased (0.5×104/μL), and other laboratory data showed no apparent hemolysis (Table 1). A bone marrow examination revealed marked erythroid hypoplasia with no obvious morphological abnormalities, which was consistent with PRCA (Table 2, Fig. 1).\n\nTable 1. Laboratory Findings.\n\n\tBefore pembrolizumab \ntreatment\tAfter 3rd pembrolizumab \nadministration\t\nWBC (/μL)\t10,400\t3,100\t\nNeutrophil (%)\t82.5\t59.0\t\nLymphocyte (%)\t5.5\t36.0\t\nMonocyte (%)\t10.0\t3.5\t\nEosinophil (%)\t1.5\t0.5\t\nBasophil (%)\t0.5\t1.0\t\nRBC (×106/μL)\t3.89\t2.45\t\nHemoglobin (g/dL)\t11.5\t7.0\t\nHematocrit (%)\t34.5\t20.5\t\nPlatelets (×104/μL)\t26.1\t31.4\t\nReticulocytes (×104/μL)\t7.0\t0.5\t\n \t\t\t\nTP (g/dL)\t6.6\t7.0\t\nT-Bil (mg/dL)\t0.55\t0.88\t\nAST (IU/L)\t19\t18\t\nALT (U/L)\t14\t18\t\nLDH (U/L)\t271\t162\t\nALP (U/L)\t287\t259\t\nBUN (mg/dL)\t14.0\t14.9\t\nCRE (mg/dL)\t0.95\t0.93\t\nNa (mEq/L)\t138\t137\t\nK (mEq/L)\t3.9\t4.2\t\nCl (mEq/L)\t103\t105\t\nCRP (mg/dL)\t4.21\t0.47\t\nDAT\tnegative\tpositive\t\nErythropoietin (mIU/mL)\t30.0\t65.9\t\nSIL-2R (U/mL)\t1,460\t1,200\t\nWBC: white blood cell, RBC: red blood cell, TP: total protein, T-Bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRE: creatinine, CRP: C-reactive protein, DAT: direct anti-globulin test, SIL-2R: soluble interleukin-2 receptor\n\nTable 2. Bone Marrow Examination.\n\n\tBefore pembrolizumab \ntreatment\tAfter 3rd pembrolizumab \nadministration\t\nBlast (%)\t0.0\t0.8\t\nPromyelocyte (%)\t3.6\t1.8\t\nMyelocyte (%)\t24.6\t11.6\t\nMetamyelocyte (%)\t13.2\t9.4\t\nBanded neutrophil (%)\t16.0\t7.0\t\nSegmented neutrophil (%)\t20.8\t31.4\t\nProEBL (%)\t0.0\t0.2\t\nBasoEBL (%)\t0.2\t0.4\t\nPolyEBL (%)\t14.6\t1.6\t\nOrthoEBL (%)\t0.0\t0.0\t\nLymphocyte (%)\t3.2\t24.8\t\nMonocyte (%)\t0.4\t6.4\t\nEosinophil (%)\t2.4\t3.6\t\nBasophil (%)\t0.0\t0.4\t\nmyelocyte/erythrocyte ratio\t5.45\t29.64\t\nEBL: erythroblast\n\nFigure 1. Bone marrow pictures obtained at the diagnosis of PRCA. A Wright-Giemsa-stained slide of a bone marrow smear (A, 400×). A glycophorin A-stained slide of a bone marrow aspirate section (B, 100×). A bone marrow examination showed marked hypoplasia of erythroid cells.\n\nComputed tomography (CT) showed partial remission of Hodgkin lymphoma and no evidence of thymoma. Serological tests for parvovirus B19 and Epstein-Barr virus were negative, and parvovirus B19 DNA was not detected by polymerase chain reaction. No increase in large granular lymphocytes was found in the peripheral blood. Based on these findings, he was diagnosed with PRCA as irAEs due to pembrolizumab. He also exhibited severe blistering and ulceration on the oral and pharynx mucosa, which was diagnosed as an autoimmune bullous disease by dermatologists. The pembrolizumab treatment was therefore interrupted, and oral prednisone 60 mg daily was started (Fig. 2).\n\nFigure 2. The clinical course of the patient. IVIG: intravenous immunoglobulin, RBC-LR: red blood cells-leukocytes reduced, DAT: direct anti-globulin test, Hb: hemoglobin, Ret: reticulocytes\n\nFour weeks later, his reticulocyte counts increased, and the oral mucosal lesions were transiently improved. However, after tapering prednisolone dosing to 35 mg daily, his reticulocytes decreased again, and the mucosal lesions worsened. Prednisone dosing was therefore returned to 60 mg daily, and 1 course of IVIG (400 mg/kg for 5 days) was added as second-line therapy for steroid-refractory autoimmune bullous disease.\n\nOne week after IVIG treatment, his reticulocyte counts promptly recovered, and the mucosal lesions disappeared again. Six weeks later, the DAT converted to negative, and his hemoglobin level reached the normal range despite tapering of prednisolone. Follow-up positron emission tomography (PET)/CT at 18 months after the last pembrolizumab infusion showed no recurrence of Hodgkin lymphoma, although no treatment for lymphoma was given during this period. PRCA and oral mucosal lesions have not recurred.\n\nDiscussion\nMost acquired PRCA is considered to be caused by an immune mechanism that interrupts erythroid cell differentiation (1). In some primary and secondary PRCA associated with large granular lymphocytic leukemia or thymoma, cellular immunity has been regarded to be involved in the pathogenesis through the direct or indirect injury of erythroblasts by T-cells or natural killer cells (4-6). Therefore, immunosuppressants such as cyclosporine with or without concurrent corticosteroids are generally used as initial therapy for acquired PRCA (1). In contrast, a few case reports have shown that IVIG was effective for PRCA in patients with chronic lymphocytic leukemia (7) or persistent parvovirus B19 infection (8, 9).\n\nIn the present case, IVIG treatment was effective for pembrolizumab-induced PRCA that was refractory to corticosteroid therapy. Although PRCA as an irAE secondary to CPI is a rare finding, Gordon et al. reported a case of PRCA in a patient with metastatic melanoma receiving the anti-CTLA-4 antagonist ipilimumab (10). More recently, Nair et al. also described a case of PRCA following pembrolizumab therapy for relapsed malignant melanoma (11). Notably, these two previously reported CPI-induced PRCA cases were accompanied by DAT positivity and successfully treated with IVIG, as in our present case. The coexistence of PRCA and DAT positivity have been occasionally documented, especially in patients with lymphoid malignancies (12, 13) or autoimmune diseases (14, 15). Although the significance of DAT positivity in such cases is poorly understood, humoral mechanisms, including the production of autoantibodies against both erythrocytes and erythroid precursors, are suspected.\n\nThe mechanism of action of IVIG in most autoimmune diseases remains unclear; however, various mechanisms have been proposed, such as blockade of Fc receptors on macrophages and effector cells, neutralization of circulating autoantibodies, selective downregulation of autoreactive B-cells, regulation of the production of helper-T-cell cytokines, and decreased immune-complex-mediated inflammation (16). In pemphigus vulgaris, a type of autoimmune bullous disease, IVIG has been suggested to reduce the serum levels of pemphigus antibodies by increasing catabolism or manipulating the idiotype network (17). In contrast, the blockade of Fc receptors on macrophages, the immunomodulating effect on B-cell activation, and complement neutralization are thought to underlie the mechanisms of IVIG in idiopathic thrombocytopenic purpura and other autoantibody-mediated cytopenias (18). The pathogenesis of PRCA induced by PD-1 antagonists has not been elucidated. PD-1 is expressed not only on CD8+ T-cells but also on CD4+ T-cells and activated B-cells, and the modulation of B-cells through both T-cell-dependent and T-cell-independent mechanisms has been shown in PD-1 pre-clinical models (19, 20). In addition, some clinical studies have shown that PD-1 antagonists can contribute to the production of pathogenic autoantibodies against thyroid (21) and muscle tissues (22). Furthermore, several case reports described cases in which rituximab, a humanized anti-CD20 monoclonal antibody, was effective for treating some irAEs caused by PD-1 antagonists, such as myasthenia gravis (23), cold agglutinin syndrome (24), autoimmune hemolytic anemia (25), and acquired hemophilia A (26). These observations suggest that humoral immunity may also play an important role in the etiology of various types of irAEs, including hematological toxicities.\n\nIn conclusion, we experienced a rare case of PRCA following pembrolizumab treatment in a patient with refractory Hodgkin lymphoma. Similar to the two previously reported CPI-induced PRCA cases (10, 11), our present case also had DAT positivity and was successfully treated with IVIG. Further studies are needed in order to clarify the specific mechanism underlying CPI-induced PRCA and its appropriate management.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nMeans RT Jr \nPure red cell aplasia\n. Blood \n128 : 2504 -2509\n, 2016 .27881371 \n2. \nDavis EJ , Salem JE , Young A , et al \nHematologic complications of immune checkpoint inhibitors\n. Oncologist \n24 : 584 -588\n, 2019 .30819785 \n3. \nDelanoy N , Michot JM , Comont T , et al \nHaematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study\n. Lancet Haematol \n6 : e48 -e57\n, 2019 .30528137 \n4. \nMizobuchi S , Yamashiro T , Nonami Y , et al \nPure red cell aplasia and myasthenia gravis with thymoma: a case report and review of the literature\n. Jpn J Clin Oncol \n28 : 696 -701\n, 1998 .9861237 \n5. \nHandgretinger R , Geiselhart A , Moris A , et al \nPure red-cell aplasia associated with clonal expansion of granular lymphocytes expressing killer-cell inhibitory receptors\n. N Engl J Med \n340 : 278 -284\n, 1999 .9920952 \n6. \nMasuda M , Saitoh H , Mizoguchi H \nClonality of acquired primary pure red cell aplasia\n. Am J Hematol \n62 : 193 -195\n, 1999 .10539887 \n7. \nClauvel JP , Vainchenker W , Herrera A , et al \nTreatment of pure red cell aplasia by high dose intravenous immunoglobulins\n. Br J Haematol \n55 : 380 -382\n, 1983 .6615731 \n8. \nKoduri PR , Kumapley R , Valladares J , Teter C \nChronic pure red cell aplasia caused by parvovirus B19 in AIDS: use of intravenous immunoglobulin-a report of eight patients\n. Am J Hematol \n61 : 16 -20\n, 1999 .10331506 \n9. \nSong KW , Mollee P , Patterson B , Brien W , Crump M \nPure red cell aplasia due to parvovirus following treatment with CHOP and rituximab for B-cell lymphoma\n. Br J Haematol \n119 : 125 -127\n, 2002 .12358915 \n10. \nGordon IO , Wade T , Chin K , Dickstein J , Gajewski TF \nImmune-mediated red cell aplasia after anti-CTLA-4 immunotherapy for metastatic melanoma\n. Cancer Immunol Immunother \n58 : 1351 -1353\n, 2009 .19052742 \n11. \nNair R , Gheith S , Nair SG \nImmunotherapy-associated hemolytic anemia with pure red-cell aplasia\n. N Engl J Med \n374 : 1096 -1097\n, 2016 .26981948 \n12. \nSuzuki A , Takahashi T , Taniguchi A , et al \nPure red cell aplasia associated with non-Hodgkin's lymphoma and hemolytic anemia\n. Jpn J Clin Oncol \n21 : 384 -387\n, 1991 .1753420 \n13. \nKatayama H , Takeuchi M , Yoshino T , et al \nEpstein-Barr virus associated diffuse large B-cell lymphoma complicated by autoimmune hemolytic anemia and pure red cell aplasia\n. Leuk Lymphoma \n42 : 539 -542\n, 2001 .11699422 \n14. \nAssimakopoulos SF , Michalopoulou S , Melachrinou M , et al \nPrimary Sjögren syndrome complicated by autoimmune hemolytic anemia and pure red cell aplasia\n. Am J Med Sci \n334 : 493 -496\n, 2007 .18091373 \n15. \nHara A , Wada T , Kitajima S , et al \nCombined pure red cell aplasia and autoimmune hemolytic anemia in systemic lupus erythematosus with anti-erythropoietin autoantibodies\n. Am J Hematol \n83 : 750 -752\n, 2008 .18626921 \n16. \nKazatchkine MD , Kaveri SV \nImmunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin\n. N Engl J Med \n345 : 747 -755\n, 2001 .11547745 \n17. \nBystryn JC , Rudolph JL \nIVIg treatment of pemphigus: how it works and how to use it\n. J Invest Dermatol \n125 : 1093 -1098\n, 2005 .16354177 \n18. \nBjörkholm M \nIntravenous immunoglobulin treatment in cytopenic haematological disorders\n. J Intern Med \n234 : 119 -126\n, 1993 .8340734 \n19. \nSage PT , Francisco LM , Carman CV , Sharpe AH \nThe receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood\n. Nat Immunol \n14 : 152 -161\n, 2013 .23242415 \n20. \nThibult ML , Mamessier E , Gertner-Dardenne J , et al \nPD-1 is a novel regulator of human B-cell activation\n. Int Immunol \n25 : 129 -137\n, 2013 .23087177 \n21. \nOsorio JC , Ni A , Chaft JE , et al \nAntibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer\n. Ann Oncol \n28 : 583 -589\n, 2017 .27998967 \n22. \nSeki M , Uruha A , Ohnuki Y , et al \nInflammatory myopathy associated with PD-1 inhibitors\n. J Autoimmun \n100 : 105 -113\n, 2019 .30862448 \n23. \nCrusz SM , Radunovic A , Shepherd S , et al \nRituximab in the treatment of pembrolizumab-induced myasthenia gravis\n. Eur J Cancer \n102 : 49 -51\n, 2018 .30138772 \n24. \nHasanov M , Konoplev SN , Hernandez CMR \nNivolumab-induced cold agglutinin syndrome successfully treated with rituximab\n. Blood Adv \n2 : 1865 -1868\n, 2018 .30072374 \n25. \nKhan U , Ali F , Khurram MS , Zaka A , Hadid T \nImmunotherapy-associated autoimmune hemolytic anemia\n. J Immunother Cancer . Forthcoming.\n26. \nGokozan HN , Friedman JD , Schmaier AH , et al \nAcquired hemophilia A after nivolumab therapy in a patient with metastatic squamous cell carcinoma of the lung successfully managed with rituximab\n. Clin Lung Cancer \n20 : e560 -e563\n, 2019 .31311716\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(16)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "direct anti-globulin test; immune-related adverse events; intravenous immunoglobulin; pembrolizumab; programed cell death 1; pure red cell aplasia",
"medline_ta": "Intern Med",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D006689:Hodgkin Disease; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D012010:Red-Cell Aplasia, Pure",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2041-2045",
"pmc": null,
"pmid": "32389947",
"pubdate": "2020-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30819785;12358915;19052742;27881371;30862448;10539887;26981948;6615731;8340734;10331506;30138772;9861237;18091373;18626921;30072374;31311716;23087177;9920952;27998967;23242415;28239468;11699422;30528137;16354177;11547745;1753420",
"title": "Pembrolizumab-induced Pure Red Cell Aplasia Successfully Treated with Intravenous Immunoglobulin.",
"title_normalized": "pembrolizumab induced pure red cell aplasia successfully treated with intravenous immunoglobulin"
} | [
{
"companynumb": "JP-009507513-1807JPN002918J",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "This two-patient case series describes a rare sequela of postoperative empty sella syndrome (ESS) following transsphenoidal resection of pituitary macroadenomas. This is characterized by progressive hormone dysfunction, diabetes insipidus (DI), and associated MRI evidence of pituitary stalk disruption.\nThis phenomenon was retrospectively evaluated in a review of 2000 pituitary tumor resections performed by a single neurosurgeon (KOL). Chart review was retrospectively conducted to gather data on demographics, pituitary hormone status, tumor characteristics, and management. We identified 2 (0.1%) cases of progressive pituitary endocrine dysfunction occurring in the postoperative period associated with MRI evidence of pituitary stalk disruption within 6 weeks of discharge from the hospital. This was felt to be caused by the rapid descent of the residual normal pituitary gland down to the floor of the postoperative empty sella, causing relatively swift stalk stretching. Both patients developed DI, and one patient demonstrated increased pituitary hormone dysfunction.\nThis phenomenon is a rare manifestation of postoperative ESS, secondary to surgical resection of a pituitary macroadenoma. We discuss the associated potential risk factors and strategies for avoidance in these two cases. Routine instillation of intrasellar fat in patients at risk is felt to be protective.",
"affiliations": "Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, United States.;Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, United States.;Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, United States.",
"authors": "Winograd|Evan|E|;Kortz|Michael W|MW|;Lillehei|Kevin O|KO|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.25259/SNI_530_2021",
"fulltext": "\n==== Front\nSurg Neurol Int\nSurg Neurol Int\nSurgical Neurology International\n2229-5097\n2152-7806\nScientific Scholar USA\n\n10.25259/SNI_530_2021\n10.25259/SNI_530_2021\nCase Report\nRadiographic pituitary stalk disruption: A rare sequela of secondary empty sella syndrome\nWinograd Evan evanwinograd@gmail.com\n\nKortz Michael W. michael.kortz@ucdenver.edu\n\nLillehei Kevin O. kevin.lillehei@cuanschutz.edu\n\nDepartment of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, United States.\n* Corresponding author: Michael W. Kortz, Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, United States. michael.kortz@ucdenver.edu\n2021\n03 8 2021\n12 38528 5 2021\n12 7 2021\nCopyright: © 2021 Surgical Neurology International\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.\nBackground:\n\nThis two-patient case series describes a rare sequela of postoperative empty sella syndrome (ESS) following transsphenoidal resection of pituitary macroadenomas. This is characterized by progressive hormone dysfunction, diabetes insipidus (DI), and associated MRI evidence of pituitary stalk disruption.\n\nCase Description:\n\nThis phenomenon was retrospectively evaluated in a review of 2000 pituitary tumor resections performed by a single neurosurgeon (KOL). Chart review was retrospectively conducted to gather data on demographics, pituitary hormone status, tumor characteristics, and management. We identified 2 (0.1%) cases of progressive pituitary endocrine dysfunction occurring in the postoperative period associated with MRI evidence of pituitary stalk disruption within 6 weeks of discharge from the hospital. This was felt to be caused by the rapid descent of the residual normal pituitary gland down to the floor of the postoperative empty sella, causing relatively swift stalk stretching. Both patients developed DI, and one patient demonstrated increased pituitary hormone dysfunction.\n\nConclusion:\n\nThis phenomenon is a rare manifestation of postoperative ESS, secondary to surgical resection of a pituitary macroadenoma. We discuss the associated potential risk factors and strategies for avoidance in these two cases. Routine instillation of intrasellar fat in patients at risk is felt to be protective.\n\nEmpty sella syndrome\nEndocrine dysfunction\nPituitary adenoma\nPituitary stalk disruption\nTranssphenoidal resection\n==== Body\npmc\n\nINTRODUCTION\n\nEmpty sella syndrome (ESS) is a condition in which the sella turcica is partially or filled with cerebrospinal fluid (CSF) resulting in downward displacement of the normal pituitary gland.[13] ESS can be primary, due to an inherent weakness of the diaphragma sellae and downward herniation of arachnoid into the sella, or secondary, following surgical or medical management of a pituitary macroadenoma. The incidence of ESS is thought to be more common than is reported in the literature, given that most cases are asymptomatic.[8,14] A well-described complication of secondary ESS is the downward migration of the optic chiasm, resulting in progressive visual acuity and visual field deterioration.[2,4] Although downward displacement of the residual normal pituitary gland is often seen on postoperative imaging, corresponding hormone dysfunction is rarely noted.[13]\n\nWe describe two cases of secondary ESS associated with downward displacement of the residual normal pituitary gland, with MRI evidence of pituitary stalk disruption. Both cases were without optic chiasm involvement. In the postoperative period, these two patients exhibited progressive endocrine dysfunction along with the delayed onset of diabetes insipidus (DI). The finding of progressing endocrine dysfunction in the weeks following surgery, with MRI evidence of pituitary stalk disruption is rare, seen in two cases to date at our institution in review of 2000 transsphenoidal tumor resections.\n\nMATERIALS AND METHODS\n\nStudy design and eligibility criteria\n\nPatients aged 18 years or older who underwent transsphenoidal surgery (TSS) for a pituitary tumor at our institution from July 2000 to January 2020 were retrospectively identified. In our review, 2000 patients underwent TSS at our institution in the study period. Of this cohort, only 2 (0.10%) demonstrated rapid short-term pituitary endocrinopathy and DI with MRI evidence of pituitary stalk disruption. Case presentations are described below. Data were then retrospectively gathered through electronic health record review, including demographics, laboratory values, radiographs, and operative management. Per independent Colorado Multiple Institutional Review Board guidelines, this study was determined to be exempt.\n\nPituitary adenoma clinical protocol\n\nAt our institution, surgical management for patients with pituitary adenomas is recommended for those presenting with symptoms of mass effect (headache, visual compromise, or endocrinopathy), growth hormone, adrenocorticotropic hormone, or thyroid-stimulating hormone (TSH) hypersecretion, or hyperprolactinemia refractory to medical management. The choice of microscopic or endoscopic TSS depends on surgeon preference, patient anatomy, and tumor characteristics (i.e. cavernous sinus involvement or suprasellar extension). Hormone dysfunction in the postoperative period is managed with the corresponding agent until there is evidence of resolution. Routine follow-up consists of an MRI of the pituitary 3 months postoperatively and then at various intervals thereafter depending on resection rate and the patient’s symptoms.\n\nCASE DESCRIPTION\n\nCase 1\n\nA 54-year-old male presented to his primary care physician 5 years before neurosurgical evaluation with progressive fatigue. Laboratory testing was significant for a low free testosterone of 6.4 ng/mL (normal: 247–827 ng/mL), an luteinizing hormone (LH) of <0.2 mIU/mL (normal: 1.24–7.8 mIU/mL), follicular-stimulating hormone (FSH) <0.7 mIU/mL (normal: 1–18 mIU/mL), and a borderline high prolactin of 15.6 ng/mL (normal: 3–13 ng/mL). Laboratories 1 month later were remarkable for an elevated alpha subunit of 1.4 c (normal: <0.05 μg/L), low free T3 of 3.3 ng/dL (normal: 80–180 ng/dL), and an elevated prolactin of 28.38 ng/mL (normal: 3–13 ng/mL) [Table 1]. The patient was initially managed conservatively with monthly intramuscular testosterone injections. However, his serum testosterone remained subtherapeutic and his fatigue continued to progress. An MRI of the pituitary was subsequently performed and showed a large sellar and suprasellar mass displacing the optic chiasm upwards, consistent with a pituitary macroadenoma [Figure 1]. The normal pituitary gland was seen to be draped centrally over the superior aspect of the mass. Subsequent ophthalmologic evaluation revealed evidence of a bitemporal hemianopsia.\n\nFigure 1: Case 1 preoperative contrast-enhanced T1-weighted MRI scan: (a) sagittal; (b) coronal. Arrows delineate the thin rim of normal pituitary gland draped superiorly over the tumor.\n\nTable 1: Case 1 laboratory testing.\n\nOne month later, he underwent TSS. The surgery was uneventful and achieved gross total resection of the tumor and good visualization of the diaphragma sellae. The diaphragma was noted to descend into the sella turcica at the time of surgery, partially obliterating the resection cavity. The normal gland was observed layered over the diaphragma superiorly and the resection was felt to be atraumatic to the gland. There was no intraoperative evidence of a CSF leak, and no packing was placed into the sella. The sellar floor was reconstructed using a layer of Gelfoam and a horizontal bone strut harvested from the anterior sphenoid during the initial exposure. Over the first 24 h, the patient had 15 L of urine output, with an upward trending sodium from 131 mEq/L to 141 mEq/L (normal: 135–145 mEq/L). The urine output subsequently stabilized with the serum sodium remaining in the ~140 mEq/L range after serial testing. Specific gravity was 1.002 and the patient was tolerating output by matching with oral fluid intake. His urine output subsequently diminished, and he was discharged home on the 3rd postoperative day with an as-needed prescription for desmopressin (DDAVP) if increased urine output recurred. Final surgical pathology was consistent with a chromophobic pituitary adenoma.\n\nFollow-up with his endocrinologist 2 weeks postoperatively revealed serologic evidence of panhypopituitarism, including new hypoadrenalism [Table 1]. He was then started on adrenal supplementation, with thyroid replacement and testosterone initiated 2 weeks later. At this time, his initial postoperative symptoms of DI appeared to be reemerging and he was placed on daily DDAVP. His postoperative MRI taken 1 month following surgery revealed a marked descent of the residual pituitary gland to the floor of the sella, with either severe stretching or complete disruption of the pituitary stalk [Figure 2]. Overtime, the patient’s DI resolved but he continues to suffer from panhypopituitarism.\n\nFigure 2: Case 1 2-month postoperative contrast-enhanced T1-weighted MRI scan: (a) sagittal; (b) coronal. Arrows delineate the proximal and distal aspect of the pituitary stalk.\n\nCase 2\n\nA 58-year-old male presented to the neurosurgery clinic with a 2-year history of progressive vision loss. Initial ophthalmologic evaluation revealed bilateral cataracts, for which he underwent surgery. While he initially noted improvement, he subsequently developed unexplained right-sided vision loss. Visual field testing revealed evidence of a right-sided temporal field loss. A pituitary MRI revealed a 2.2 cm × 2.4 cm × 4.0 cm cystic sellar mass, with suprasellar extension [Figure 3]. On review of systems, the patient noted decreased energy and symptoms suggestive of sleep apnea (without a formal diagnosis). Endocrine laboratory studies revealed an FSH of 4 mIU/mL (normal: 1–18 mIU/mL), LH of 1.6 mIU/mL (normal: 1.24–7.8 mIU/mL), random AM cortisol of 3.0 mg/dL (normal: 4–22 μg/L), free T3 of 64 ng/ dL (normal: 80–180 ng/dL), TSH of 5.71 mIU/L (normal: 0.34–5.6 mIU/L), free T4 of 0.36 ng/dL (normal: 0.89– 1.76 ng/dL), free testosterone of 181 ng/dL (normal: 241– 827 ng/dL), and prolactin of 510.2 ng/mL (normal: 3–13 ng/ mL) [Table 2].\n\nTable 2: Case 2 laboratory testing.\n\nFigure 3: Case 2 pituitary MRI scan: (a) preoperative sagittal noncontrast-enhanced T1-weighted image, (b) preoperative sagittal contrast-enhanced T1-weighted image, (c) preoperative coronal noncontrast-enhanced T2-weighted image pituitary. Note the fluid-fluid level within the sella in each, consistent with subacute hemorrhage.\n\nThe MRI revealed a substantial cyst within the sella and suprasellar region with a fluid-fluid level consistent with subacute hemorrhage. The patient was diagnosed with a probable hemorrhagic macroprolactinoma with associated panhypopituitarism. There was no evidence of DI. Due to the sizable subacute hematoma and vision changes, TSS was recommended. Surgery was uneventful with evacuation of the hematoma and removal of a significant amount of soft tumor tissue lining the cavity. The diaphragma was noted to descend downward into the sella at the time of surgery, covered by a layer of normal appearing pituitary gland. Gross total tumor resection was felt to have been obtained with no evidence of a CSF leak. Postoperatively, he initially did well, and his vision improved, leading to discharge on postoperative day 3. The patient was discharged home on both thyroid and adrenal hormone replacement, based on his preoperative hormone levels.\n\nAt discharge, he had no evidence of polyuria with a stable serum sodium level. He subsequently returned several days later to the emergency department with weakness, myalgia, and nausea. Laboratory testing revealed hyponatremia with a serum sodium level of 118 mEq/L (normal: 135–145 mEq/L). He was admitted to the hospital with the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. This resolved over several days and he was discharged home on his previous adrenal and thyroid replacement. Over the next 4 weeks, he gradually developed symptoms consistent with DI and was started on DDAVP 5 weeks postoperatively. An MRI obtained at that time, due to the new symptoms, revealed a marked descent of the residual pituitary gland and diaphragma sellae down to the floor of the sella, with severe thinning and apparent discontinuity of the pituitary stalk [Figure 4]. A postoperative ophthalmologic examination revealed improvement in his right visual field deficit, with the left visual field remaining normal. His 1- and 2-year postoperative endocrine evaluations showed that he continues to suffer from panhypopituitarism, with resolution of his DI. He is on no treatment for his prolactinoma with the most recent prolactin level being 16.5, which has remained stable over serial evaluation [Table 2].\n\nFigure 4: Case 2 postoperative pituitary MRI scan. (a) Contrast-enhanced T1-weighted sagittal image, (b) contrast-enhanced T1-weighted coronal image, (c) coronal noncontrast-enhanced T2-weighted image. Arrows delineate the proximal pituitary stalk, with no distal stalk remnant seen.\n\nDISCUSSION\n\nESS was first described in 1951 after 788 human cadavers with no history of pituitary disease were examined.[8] They noted a finding of an incomplete diaphragma sellae with flattening of the normal pituitary gland at the bottom of the sella turcica in 40 (5.1%) of the 788 cases.[8] Although the phenomenon is rare and is generally asymptomatic, both primary and secondary causes of ESS are well described. Primary ESS on neuroimaging is found incidentally in approximately 12% of cases, with a 5:1 female-to-male predominance.[5,8] Symptoms associated with primary ESS include headache, menstrual irregularities, galactorrhea, hirsutism, and sterility. Being overweight and frank obesity are seen in 73% and 14% of patients, respectively.[10] Endocrine abnormalities can be variable, with growth hormone deficiency and prolactin elevation being common. Secondary ESS is most seen following surgical removal of a pituitary macroadenoma, radiation therapy, or medical treatment of a macroprolactinoma with dopaminergic agonist therapy. The most common complication described in secondary ESS is the onset of gradual visual disturbance secondary to egress of the optic chiasm into the sella.[6,7] Welch and Stears, in 1971, reported the first surgical treatment of this condition with a transcranial chiasmapexy.[15] The first chiasmapexy performed through the transsphenoidal route was reported by Olson et al. in 1972.[12]\n\nTo the best of our knowledge, the phenomenon of rapid postoperative descent of the residual pituitary gland and diaphragma into the sella with MRI evidence of pituitary stalk disruption has not been previously described. Historically, sustained postoperative pituitary endocrine dysfunction has been noted to occur in <2% of patients.[1,3,4,11] Postoperative DI can occur transiently in about 12% of patients, based on one review, with Black et al. noting an incidence of near 1% for microadenomas and up to 9.5% for macroadenomas.[3] Ciric et al. described an overall rate of prolonged DI of 3.4%, with Barker et al. noting a range from 8.7% to 12.6% in their series.[4]\n\nIn the two cases described in this report, the rapid descent of the residual pituitary gland into the sella turcica was felt to contribute to severe stretching of the pituitary stalk. This led to an associated increase in pituitary hormone dysfunction with the need for additional adrenal hormone replacement in one patient and the onset of delayed DI in both cases. On review of the patients’ preoperative imaging, factors that may have predisposed our two cases to this phenomenon are large tumor volume, a deep sella extending into the inferior sphenoid region and a residual normal pituitary gland centered superiorly along the diaphragma. This, therefore, allowed the descent of the entire residual pituitary gland down to the floor of the sella turcica, bringing the diaphragma and pituitary stalk down with it. A protective variable may be a gland offset to the lateral side of the sella, allowing adherence of the gland laterally and theoretically preventing this degree of descent.\n\nAs a result of this experience, we have changed the operative technique at our institution. In our current practice, we do not routinely place fat into the sella turcica during routine macroadenoma resection, unless there is evidence of an intraoperative CSF leak. However, based on these two cases and recognition of the risk factors mentioned above, we now place intrasellar fat after tumor resection to bolster the gland superiorly in those patients felt at risk. Overtime, as the fat is reabsorbed, this may promote a gentler and more gradual descent of the residual gland, allowing the pituitary stalk to elongate slowly overtime, without disruption.[9]\n\nAlthough a rare occurrence, since adopting this practice, we have seen no further instances of this phenomenon of “pituitary ptosis,” a syndrome of postoperative ESS with MRI evidence of pituitary stalk disruption, increasing pituitary hormone dysfunction, and delayed-onset DI.\n\nLimitations\n\nThis study is limited by its design (retrospective two-patient case series), which hinders our ability to predict the risk or severity of this phenomenon. Similarly, because routine postoperative care at our institution involves routine MRI at 3 months after surgery, we cannot comment on the exact rate of diaphragmatic descent before that time. No other cases of pituitary stalk disruption at 3 months postoperatively have been observed at our institution, but our investigation is thus at risk of bias and results may thus not be generalizable to the greater population.\n\nFuture directions\n\nThis phenomenon of postsurgical pituitary stalk disruption is important for neurosurgeons and endocrinologists to be aware of, given the potential ability to prevent subsequent postoperative pituitary endocrinopathy, a significant source of quality-of-life morbidity for pituitary adenoma patients. The rarity of symptomatic secondary ESS represents an opportunity to conduct a larger investigation to query the true prevalence of this disorder. It may be that other variables, such as obesity, may independently predict a patient’s risk. In addition, serial radiographic and laboratory examinations could better characterize the rate and degree of diaphragma descent and stalk disruption, in correspondence with panhypopituitarism. Finally, our technique of preemptive sellar packing warrants further investigation as it relates to the risk of this phenomenon.\n\nCONCLUSION\n\nWe describe two cases of “pituitary ptosis” endocrinopathy at our institution, demonstrated by MRI evidence of pituitary stalk elongation and disruption after TSS. This is a rare syndrome of panhypopituitarism associated with DI, manifesting as progressive endocrine dysfunction in the perioperative period following macroadenoma resection. In patients at risk of this complication, placement of intrasellar fat can potentially prevent rapid descent of the gland into the sella turcica and is a rational preventative measure.\n\nDeclaration of patient consent\n\nPatient’s consent not required as patients identity is not disclosed or compromised.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\nHow to cite this article: Winograd E, Kortz MW, Lillehei KO. Radiographic pituitary stalk disruption: A rare sequela of secondary empty sella syndrome. Surg Neurol Int 2021;12:385.\n==== Refs\nREFERENCES\n\n1 Barker FG 2nd Klibanski A Swearingen B Transsphenoidal surgery for pituitary tumors in the United States, 1996-2000: Mortality, morbidity, and the effects of hospital and surgeon volume J Clin Endocrinol Metab 2003 88 4709 19 14557445\n2 Barzaghi LR Donofrio CA Panni P Losa M Mortini P Treatment of empty sella associated with visual impairment: A systematic review of chiasmapexy techniques Pituitary 2018 21 98 106 29027644\n3 Black PM Zervas NT Candia GL Incidence and management of complications of transsphenoidal operation for pituitary adenomas Neurosurgery 1987 20 920 4 3614573\n4 Ciric I Ragin A Baumgartner C Pierce D Complications of transsphenoidal surgery: Results of a national survey, review of the literature, and personal experience Neurosurgery 1997 40 225 36 discussion 236-7 9007854\n5 de Marinis L Bonadonna S Bianchi A Maira G Giustina A Primary empty sella J Clin Endocrinol Metab 2005 90 5471 7 15972577\n6 Fouad W Review of empty sella syndrome and its surgical management Alexandria J Med 2011 47 139 47\n7 Graillon T Passeri T Boucekine M Meyer M Abritti R Bernat AL Chiasmapexy for secondary empty sella syndrome: Diagnostic and therapeutic considerations Pituitary 2021 24 292 301 33136230\n8 Kaufman B The “empty” sella turcica-a manifestation of the intrasellar subarachnoid space Radiology 1968 90 931 41 5300448\n9 Laws ER Jr Autograft fat in neurological surgery World Neurosurg 2013 80 489 90 23153866\n10 Maira G Anile C Mangiola A Primary empty sella syndrome in a series of 142 patients J Neurosurg 2005 103 831 6 16304986\n11 Olson BR Gumowski J Rubino D Oldfield EH Pathophysiology of hyponatremia after transsphenoidal pituitary surgery J Neurosurg 1997 87 499 507 9322839\n12 Olson DR Guiot G Derome P The symptomatic empty sella prevention and correction via the transsphenoidal approach J Neurosurg 1972 37 533 7 5076370\n13 Ucciferro P Anastasopoulou C Empty sella Stat Pearls. US National Library of Medicine 2021 Treasure Island, FL Stat Pearls Publishing\n14 Vance ML Perioperative management of patients undergoing pituitary surgery Endocrinol Metab Clin North Am 2003 32 355 65 12800536\n15 Welch K Stears JC Chiasmapexy for the correction of the traction on the optic nerves and chiasm associated with their descent into an empty sella turcica J Neurosurg 1971 35 760 4 5117229\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "12()",
"journal": "Surgical neurology international",
"keywords": "Empty sella syndrome; Endocrine dysfunction; Pituitary adenoma; Pituitary stalk disruption; Transsphenoidal resection",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "385",
"pmc": null,
"pmid": "34513152",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "33136230;15972577;3614573;29027644;5117229;14557445;9007854;5300448;23153866;12800536;5076370;16304986;9322839",
"title": "Radiographic pituitary stalk disruption: A rare sequela of secondary empty sella syndrome.",
"title_normalized": "radiographic pituitary stalk disruption a rare sequela of secondary empty sella syndrome"
} | [
{
"companynumb": "US-CIPLA LTD.-2021US08090",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TESTOSTERONE"
},
"drugadditional": "3",
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.