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"abstract": "Acute myocardial infarction is a common complication of thrombotic thrombocytopenic purpura (TTP), but rarely the presenting manifestation. Anti-thrombotic therapy for myocardial infarction is rarely utilized in the setting of TTP because of elevated bleeding risk. We report a case of TTP presenting with ST-segment elevation myocardial infarction and treated with thrombolytic therapy. The resultant cardiac and neurological complications highlight the challenges of using evidence-based therapy for myocardial infarction in the setting of TTP.",
"affiliations": "Duke University Medical Center, 2301 Erwin Road, DUMC 3845, Durham, NC, 27710, USA, jacob.doll@duke.edu.",
"authors": "Doll|Jacob A|JA|;Kelly|Jacob P|JP|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-013-1018-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "38(1)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": null,
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D006801:Humans; D008297:Male; D009203:Myocardial Infarction; D011697:Purpura, Thrombotic Thrombocytopenic; D015912:Thrombolytic Therapy",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "124-6",
"pmc": null,
"pmid": "24189934",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18028268;16574680;11886570;16672704;10506449;18616514;7031412;10852999;22450533;12192020;20394041",
"title": "ST-segment elevation myocardial infarction treated with thrombolytic therapy in a patient with thrombotic thrombocytopenic purpura.",
"title_normalized": "st segment elevation myocardial infarction treated with thrombolytic therapy in a patient with thrombotic thrombocytopenic purpura"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2014-BI-31180GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TENECTEPLASE"
},
"drugadd... |
{
"abstract": "BACKGROUND\nTranscatheter arterial chemoembolization (TACE) has been used to curtail tumor vasculature and delay tumor progression in hepatocellular carcinoma (HCC). We conducted a phase I trial to evaluate the efficacy and toxicity of thalidomide when combined with TACE in patients with advanced HCC.\n\n\nMETHODS\nBetween June 2000 and November 2003, 56 patients with unresectable HCC and amenable to TACE were enrolled. The starting dose of thalidomide was 200 mg/day and was escalated every 2 weeks as tolerated to a maximum dose of 1,000 mg/day. Dose reductions and discontinuation were determined by toxicity. TACE was performed 4 weeks after initiation of thalidomide therapy and repeated as necessary.\n\n\nRESULTS\nOverall, 47 and 55 patients were evaluable for response and toxicity, respectively; the median dose of thalidomide given was 200 mg/day. Three patients (6.38%) patients achieved complete responses, whereas 10 (21.3%) had partial responses, for an overall response rate of 27.7%, and 27 (57.5%) had stable disease. Median progression-free survival was 7 months (95% confidence interval [CI]: 5-10 months), and median OS was 21 months (95% CI: 16-28 months) (Fig. 1). Fatigue and lethargy (49.1%), constipation (47.3%), and nausea (43.6%) were common. Grade 3-4 toxicities consisted mostly of increased aspartate aminotransferase (43.6%) and elevated alanine aminotransferase (38.2%) (Table 1).\n\n\nCONCLUSIONS\nThalidomide and TACE were commonly associated with nonhematologic side effects, with fatigue and constipation being prominent. With a lack of clear therapeutic benefit, this combination is unlikely to be pursued for HCC.",
"affiliations": "New York University School of Medicine, New York, New York, USA; jennifer.wu@nyumc.org.;Mount Sinai School of Medicine, New York, New York, USA;;Weill Cornell Medical Center, New York, New York, USA;;New York University School of Medicine, New York, New York, USA;;Montefiore Medical Center, New York, New York, USA;;Mount Sinai School of Medicine, New York, New York, USA;;Yale Cancer Center, New Haven, Connecticut, USA.;New York University School of Medicine, New York, New York, USA;",
"authors": "Wu|Jennifer|J|;Ng|Jennifer|J|;Christos|Paul J|PJ|;Goldenberg|Alec S|AS|;Sparano|Joseph|J|;Sung|Max W|MW|;Hochster|Howard S|HS|;Muggia|Franco M|FM|",
"chemical_list": "D013792:Thalidomide",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2014-0283",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "19(12)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D018450:Disease Progression; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D015996:Survival Rate; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1229-30",
"pmc": null,
"pmid": "25361625",
"pubdate": "2014-12",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Chronic thalidomide and chemoembolization for hepatocellular carcinoma.",
"title_normalized": "chronic thalidomide and chemoembolization for hepatocellular carcinoma"
} | [
{
"companynumb": "US-CELGENE-USA-2014113081",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older.\n\n\nMETHODS\nThe present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment.\n\n\nRESULTS\nAmong the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively.\n\n\nCONCLUSIONS\nBoth TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.",
"affiliations": "Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.;Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.",
"authors": "Yamagiwa|Satoshi|S|;Ishikawa|Toru|T|;Waguri|Nobuo|N|;Sugitani|Soichi|S|;Wakabayashi|Hiroto|H|;Ohkoshi|Shogo|S|;Tsukishiro|Takashi|T|;Takahashi|Toru|T|;Watanabe|Toshiaki|T|;Terai|Shuji|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4254/wjh.v9.i5.252",
"fulltext": "\n==== Front\nWorld J HepatolWJHWorld Journal of Hepatology1948-5182Baishideng Publishing Group Inc jWJH.v9.i5.pg25210.4254/wjh.v9.i5.252Retrospective StudyEfficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C Yamagiwa Satoshi Ishikawa Toru Waguri Nobuo Sugitani Soichi Wakabayashi Hiroto Ohkoshi Shogo Tsukishiro Takashi Takahashi Toru Watanabe Toshiaki Terai Shuji Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, JapanToru Ishikawa, Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, JapanNobuo Waguri, Department of Gastroenterology and Hepatology, Niigata City General Hospital, Niigata 950-1197, JapanSoichi Sugitani, Department of Gastroenterology and Hepatology, Tachikawa General Hospital, Nagaoka 940-8621, JapanHiroto Wakabayashi, Department of Gastroenterology and Hepatology, Takeda General Hospital, Aizuwakamatsu 965-8585, JapanShogo Ohkoshi, Department of Internal Medicine, Nippon Dental University Medical Hospital, Niigata 951-8580, JapanTakashi Tsukishiro, Department of Internal Medicine, Itoigawa General Hospital, Itoigawa 941-8502, JapanToru Takahashi, Department of Internal Medicine, Uonuma Hospital, Ojiya 947-0028, JapanToshiaki Watanabe, Watanabe Clinic, Sanjyo 955-0845, JapanAuthor contributions: Yamagiwa S, Ishikawa T, Waguri N and Terai S contributed to study conception and design; Yamagiwa S, Sugitani S, Wakabayashi H, Ohkoshi S, Tsukishiro T, Takahashi T and Watanabe T contributed to data acquisition, data analysis and interpretation; Yamagiwa S and Terai S contributed to drafting the article; all authors contributed to making critical revisions related to important intellectual content of the manuscript; all authors contributed to final approval of the version of the article to be published.\n\nSupported by Grants-in-Aid for Scientific Research (C) (to Yamagiwa S) from Japan Society for the Promotion of Science (JSPS), No. 15K08991.\n\nCorrespondence to: Satoshi Yamagiwa, MD, PhD, Associate Professor, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan. syamagi@med.niigata-u.ac.jp\n\nTelephone: +81-25-2272207 Fax: +81-25-2270776\n\n18 2 2017 18 2 2017 9 5 252 262 22 8 2016 29 12 2016 11 1 2017 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.AIM\nTo evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older.\n\nMETHODS\nThe present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment.\n\nRESULTS\nAmong the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively.\n\nCONCLUSION\nBoth TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.\n\nTelaprevirAged patientsHepatitis C virus genotype 1bInterleukin 28BSimeprevir\n==== Body\nCore tip: We evaluated the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies for elderly patients with chronic hepatitis C, especially patients aged 66 years or older, in a real-world clinical setting. In both the TVR and SMV groups, no significant differences in the SVR and adverse events resulting in treatment discontinuation were found between the younger (aged ≤ 65) and older (aged > 65) patients. Both the TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with chronic hepatitis C virus genotype 1b infection. Genotyping of the interleukin-28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.\n\nINTRODUCTION\nChronic hepatitis C virus (HCV) infections affect approximately 130-170 million people worldwide and are associated with an increased risk of developing liver cirrhosis and hepatocellular carcinoma (HCC)[1,2]. In Japan, an estimated 1.5-2 million people are infected with HCV[3]. Most of infected patients in Japan are infected with genotype 1 HCV and are older than the infected patients in Europe and the United States[4]. Although older patients with chronic HCV infection have a higher risk of developing HCC than younger patients even at the same liver fibrosis stage[5], older patients have been reported to show poor virological responses to antiviral treatments, especially postmenopausal women[6-8]. Because older patients often have reduced cardiovascular, pulmonary, and renal function and a decreased blood count, they are usually more susceptible to the toxic effects of antiviral treatments, which may lead to a higher rate and severity of adverse events and a poor adherence to the treatment[4]. Therefore, an evaluation of the safety and efficacy of antiviral treatments, especially in elderly patients with chronic HCV infections, is still necessary.\n\nBefore the introduction of direct-acting antiviral agents (DAA), pegylated interferon (PegIFN) α and ribavirin (RBV) were the standard of care for HCV genotype 1 infections. However, with the approval of telaprevir (TVR) that is an HCV non-structural (NS) 3/4A protease inhibitor, the optimum treatment regimen for chronic HCV genotype 1 infections was changed to a triple therapy with a protease inhibitor plus PegIFN α and RBV for 24 wk[9]. The TVR-based triple therapy has achieved an improved sustained virological response (SVR) rate compared to PegIFN monotherapy or PegIFNα plus RBV dual therapy[10,11]. However, the TVR-based triple therapy is associated with an increased rate and severity of adverse events, including pruritus, skin rash, anemia, and anorectal diseases, as well as increased rates of treatment discontinuation compared to patients receiving PegIFNα plus RBV dual therapy[10,11]. Because of the increased risk and severity of adverse events associated with the TVR-based triple therapy, it is difficult to use this therapy in older patients, and, therefore, reports describing the safety and efficacy of TVR-based triple therapy in elderly patients are limited[4].\n\nSimeprevir (SMV) is a second-generation oral HCV NS3/4A protease inhibitor with antiviral activity against HCV genotype 1, 2, 4, 5 and 6 infections[12]. The QUEST 1 and QUEST 2 phase 3 clinical trials demonstrated the SVR rates of 80% and 81%, respectively, in patients treated with SMV-based triple therapy combined with PegIFNα and RBV[13]. In Japan, 4 phase 3 clinical trials (CONCERTO) were conducted, and the SVR rates were 88.6% and 91.7% for treatment-naïve patients; 35.8%, 50.9% and 38.5% for non-responders; and 89.8% and 96.6% for patients that relapsed[14-16]. Although the SMV-based triple therapy shows a favorable efficacy without inducing severe dermatologic and hematologic toxicities, the safety and efficacy of the SMV-based triple therapy for elderly patients has not yet been fully evaluated. Therefore, in the present study, we aimed to assess the efficacy and safety of TVR- and SMV-based triple therapies in elderly patients, specifically patients aged 66 years or older, in a real-world clinical setting.\n\nMATERIALS AND METHODS\nPatients\nThis prospective and multicenter study enrolled 112 and 76 HCV genotype 1b Japanese patients who received 12 wk of TVR-based and SMV-based triple therapies, respectively, followed by a dual therapy that included PegIFNα and RBV for 12 wk. Nine hospitals in Niigata, Japan, including Niigata University Hospital, participated in this study. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with the TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with the SMV-based triple therapy, the older group consists of 39 patients. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. Liver biopsy samples were obtained from 34 (30.6%) and 42 patients (55.2%) in the TVR and SMV groups, respectively. For each sample, the fibrosis stage (F0-4) and activity grade (A0-3) were evaluated according to the Metavir score[17].\n\nAccording to responses to prior treatments, relapse was defied as undetectable HCV during and at the end of treatment with positive HCV RNA detecting later on. Non-responder was defined as detectable HCV RNA for more than 24 wk. Patients with decompensated liver cirrhosis, hepatocellular carcinoma, co-infection with hepatitis B virus or human immunodeficiency virus, autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis, or Wilson’s disease were excluded. Patients with uncontrollable diabetes mellitus, chronic renal failure, depression, and those with a history of alcohol abuse, were also excluded. Information regarding patient profiles was shown in Tables 1 and 2.\n\nTable 1 Patient characteristics by age (telaprevir)\n\nFactors (median, range)\tPatients aged < 66\tPatients aged ≥ 66\tP value\t\nn\t78\t34\t\t\nGender, n (male/female)\t41/37\t20/14\t0.68\t\nAge (yr)\t56 (28-65)\t69 (66-81)\t< 0.001\t\nBody weight (kg)\t61.1 (35.0-97.4)\t57.8 (41.0-74.8)\t0.105\t\nBody mass index (kg/m2)\t22.7 (15.8-32.2)\t22.9 (17.9-28.9)\t0.892\t\nBaseline HCV-RNA (log IU/mL)\t6.7 (3.9-7.7)\t6.7 (3.1-7.8)\t0.766\t\nWhite blood cell (/mm3)\t5000 (1900-8720)\t4500 (2700-7700)\t0.245\t\nHemoglobin (g/dL)\t14.0 (9.1-18.6)\t13.5 (9.5-16.3)\t0.121\t\nPlatelets (× 104/mm3)\t15.8 (6.5-28.7)\t13.4 (8.3-29.0)\t0.068\t\nAlbumin (mg/dL)\t4.1 (2.7-5.9)\t3.9 (2.4-4.4)\t0.007\t\nAST (IU/L)\t40 (17-249)\t45 (20-163)\t0.909\t\nALT (IU/L)\t48 (15-278)\t38 (15-189)\t0.486\t\nγ-GTP (IU/L)\t39 (11-717)\t25 (11-144)\t0.034\t\nSerum creatinine (mg/dL)\t0.7 (0.4-1.2)\t0.8 (0.4-1.0)\t0.036\t\nEstimated GFR (mL/min)\t79.0 (44.0-134.0)\t71.5 (39.0-101.9)\t0.006\t\nPrior treatment response, n (naïve/relapse/non-responder)\t45/26/7\t15/15/4\t0.403\t\nLiver histology (F0-2/3-4/ND)\t21/6/51\t4/3/27\t0.348\t\nIL28B SNP (rs8099917), n (TT/non-TT/ND)\t51/22/5\t28/5/1\t0.235\t\nHCV ISDR, n (0/1-3 /4-/NT)\t32/26/6/14\t15/10/2/7\t0.955\t\nHCV Core 70, n (Wild/Mutant/ND)\t46/18/14\t18/10/6\t0.751\t\nHCV Core 91, n (Wild/Mutant/ND)\t42/22/14\t19/9/6\t1\t\nSerum CXCL10 (pg/mL)\t510 (95-1794)\t543 (118-1218)\t0.445\t\nGFR: Glomerular filtration rate; IL28B SNP: Interleukin-28B single nucleotide polymorphism; ND: Not determined; ISDR: Interferon sensitivity-determining region; HCV Core 70 or 91: At position 70 or 91 of the HCV core protein; CXCL10: Chemokine (C-X-C motif) ligand 10; HCV: Hepatitis C virus; AST: Aspartate transaminase; ALT: Alanine aminotransferase; γ-GTP: γ-glutamyl-transpeptidase.\n\nTable 2 Patient characteristics by age (simeprevir)\n\nFactors (median, range)\tPatients aged < 66\tPatients aged ≥ 66\tP value\t\nn\t37\t39\t-\t\nGender, n (%) (male/female)\t19/18 (48.6)\t14/25 (64.1)\t0.123\t\nAge (yr)\t59 (36-65)\t71 (66-86)\t< 0.001\t\nBody weight (kg)\t62.0 (39.8-94.0)\t56.0 (37.5-76.6)\t0.011\t\nBody mass index (kg/m2)\t22.8 (17.2-30.3)\t22.7 (17.8-32.1)\t0.287\t\nBaseline HCV-RNA (log IU/mL)\t6.7 (5.4-7.8)\t6.6 (4.7-7.6)\t0.631\t\nWhite blood cells (/mm3)\t4620 (2600-7800)\t4300 (2400-8100)\t0.010\t\nHemoglobin (g/dL)\t13.8 (11.0-16.7)\t13.1 (9.8-16.8)\t< 0.001\t\nPlatelets (× 104/mm3)\t16.4 (8.7-28.8)\t16.3 (7.3-31.7)\t0.291\t\nAlbumin (mg/dL)\t4.2 (2.8-4.8)\t4.0 (3.1-4.6)\t0.002\t\nAST (IU/L)\t45 (21-159)\t34 (19-128)\t0.056\t\nALT (IU/L)\t42 (16-316)\t29 (12-112)\t0.006\t\nγ-GTP (IU/L)\t29 (13-260)\t27 (9-171)\t0.388\t\nSerum creatinine (mg/dL)\t0.70 (0.44-1.01)\t0.70 (0.42-1.36)\t0.689\t\nEstimated GFR (mL/min)\t78.7 (50.0-112.6)\t77.4 (41.3-109.0)\t0.221\t\nPrior treatment response, n (naïve/relapse/non-responder)\t20/10/7\t13/16/10\t0.197\t\nLiver histology (F0-2/3-4/ND)\t12/6/19\t19/5/15\t0.483\t\nIL28B SNP (rs8099917), n (TT/non-TT/ND)\t17/19/1\t18/17/4\t1\t\nHCV ISDR, n (0/1-3/4-/ND)\t9/13/5/10\t11/12/2/14\t0.044\t\nHCV Core 70, n (Wild/Mutant/ND)\t17/13/7\t15/8/16\t1\t\nHCV Core 91, n (Wild/Mutant/ND)\t18/12/7\t18/5/16\t0.385\t\nGFR: Glomerular filtration rate; IL28B SNP: Interleukin-28B single nucleotide polymorphism; ND: Not determined; ISDR: Interferon sensitivity-determining region; HCV core 70 or 91: At position 70 or 91 of the HCV core protein; HCV: Hepatitis C virus; AST: Aspartate transaminase; ALT: Alanine aminotransferase; γ-GTP: γ-glutamyl-transpeptidase.\n\nStudy design\nAll patients received a 12-wk triple therapy that included either TVR [1500 or 2250 mg/d; the initial dose of TVR was determined by each attending physician based on each patient’s baseline characteristics such as bodyweight (BW)] (the dose of TVR was also reduced by each attending physician based on each patient’s adverse events such as anemia, malaise, and anorexia) (Telavic; Mitsubishi Tanabe Pharma, Osaka, Japan) or SMV (100 mg/d) (Sovriad; Janssen Pharmaceutical K.K., Tokyo, Japan) combined with PegIFNα2a (180 μg/wk) (Pegasys; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) or PegIFNα2b (1.5 μg/BW kg per week) (Peg-Intron; MSD, Tokyo, Japan) and RBV (600-1000 mg/d according to BW as follows: < 60 kg: 600 mg/d; 60-80 kg: 800 mg/d; > 80 kg: 1000 mg/d; if the patient’s hemoglobin was < 13 g/dL at the start of therapy, RBV was reduced by 200 mg) (Rebetol; MSD or Copegus; Chugai Pharmaceutical Co., Ltd.), followed by dual therapy of PegIFNα2a or PegIFNα2b with RBV for 12 wk.\n\nThis study was conducted in accordance with the Declaration of Helsinki. The study was reviewed and approved by the Niigata University Medical and Dental Hospital Institutional Review Board. Written informed consent was appropriately obtained from all of the individuals who enrolled in the study according to the institutional review board’s approved protocols (approval No. 1474) at the Niigata University Medical and Dental Hospital.\n\nLaboratory and safety assessments\nLaboratory and safety assessments were performed at initiation of treatment; at treatment weeks 2, 4, 8, 12, 16, 20 and 24; at the end of treatment; and at 12 and 24 wk after the end of treatment. Data on adverse events were collected, and physical examinations were performed at each visit, if clinically indicated.\n\nDetection of HCV markers\nThe detection of HCV viremia was performed using a real-time polymerase chain reaction assay (COBAS TaqMan HCV test, Roche Diagnostic, Tokyo, Japan) with a lower limit of quantitation of 15 IU/mL and a linear dynamic range of 1.2-7.8 log IU/mL. The number of amino acid substitutions in the interferon sensitivity-determining region (in the range of 2209-2248 in the HCV NS5A) was determined using a direct sequencing method as reported previously[18]. The core amino acid substitutions at positions 70 and 91 of the HCV genome were determined by direct sequencing as reported previously[19].\n\nTreatment efficacy\nSVR that is defined as undetectable serum HCV RNA at 24 wk after the end of treatment was successful treatment. Early virological responses during the first 12 wk of treatment were defined as rapid virological response (RVR), which was undetectable HCV RNA at week 4, and complete early virological response (cEVR), which was undetectable at week 12. End of treatment response (ETR) was defined as undetectable HCV RNA at the end of treatment. Relapse was defined as an ETR response but non-SVR.\n\nInterleukin 28B single-nucleotide polymorphism\nHuman genomic DNA was extracted from the peripheral blood. Single-nucleotide polymorphism (SNP) genotyping of the interleukin 28B (IL28B) (rs8099917) gene was performed using the TaqMan allelic discrimination demonstration kit (Applied Biosystems, Foster City, CA). The rs8099917 genotype was classified into the following 2 categories: TT (major genotype) and non-TT (minor genotype, TG or GG).\n\nStatistical analysis\nContinuous data from patients are expressed as the median with the interquartile range. The significance of the differences was analyzed statistically by the χ2, Fisher’s exact test, or Mann-Whitney U test, as appropriate, using SPSS software (Ver.18, SPSS Inc., Chicago, IL). To evaluate independent factors for predicting an SVR, variables that reached the P < 0.1 level in the univariate tests were used as candidate factors in a multivariate logistic regression analysis. In all of the cases, the level of significance was set as P value < 0.05.\n\nRESULTS\nPatient characteristics\nThe patient characteristics in the TVR group (n = 112) and SMV group (n = 76) are summarized by age in Tables 1 and 2. The analysis of the pretreatment factors revealed that serum albumin, γ-glutamyl-transpeptidase, and the estimated glomerular filtration rate in the older patients were significantly lower than those of the younger patients in the TVR group (Table 1). Pretreatment serum chemokine C-X-C motif ligand 10 (CXCL10) levels were not significantly different between the younger (543 pg/mL, range: 118-1218 pg/mL) and older (510 pg/mL, range: 95-1794 pg/mL) groups. In the SMV group, BW, white blood cell count, hemoglobin, serum albumin, and serum alanine aminotransferase (ALT) in the older patients were significantly lower than those of the younger patients (Table 2). No significant differences in the prior treatment response, HCV core 70/91 mutations, or IL28B SNPs were found between the younger and older group in both TVR and SMV groups.\n\nVirological response and outcome\nFigure 1 shows the virological responses by age. RVR, cEVR, ETR and SVR did not significantly differ between the younger and older patients in the TVR group (60.2% vs 58.8%, 92.3% vs 94.1%, 87.2% vs 88.2%, and 80.8% vs 88.2%, respectively). Similar to the TVR group, RVR, cEVR, ETR and SVR did not significantly differ between the younger and older patients in the SMV group (81.1% vs 92.3%, 94.6% vs 94.9%, 94.6% vs 100% and 81.1% vs 82.1%, respectively). In the older patients, SVR did not significantly differ between the TVR and SMV groups, although RVR was significantly higher in the SMV group than in the TVR group (92.3% vs 58.5%, P < 0.01).\n\nFigure 1 Rates of virological responses to telaprevir and simeprevir by age. Percentages indicate the proportion of patients with undetectable serum hepatitis C virus (HCV) RNA levels. Patient numbers are shown in parenthesis. TVR: Telaprevir; SMV: Simeprevir; RVR: Rapid virological response; cEVR: Complete early virological response; EOT: End of treatment response; SVR24: Sustained virological response defined as undetectable serum HCV RNA at 24 wk after the end of treatment.\n\nFigure 2 shows the virological responses according to prior treatment responses. In both the TVR and SMV groups, SVR did not significantly differ between the younger and older patients with the same treatment responses. In the older patients in the SMV group, SVR was significantly lower in the prior non-responders than the prior relapsers (60% vs 93.8%, P = 0.033). Figure 3 shows the virological responses according to IL28B (rs8099917) SNP status. In the TVR group, the SVR rate for the older patients with the IL28B TT-genotype was significantly higher than for the older patients with the IL28B TG/GG-genotypes (92.9% and 60%, P = 0.038). In the SMV group, the SVR rate for the older patients with the IL28B TT-genotype was also significantly higher than for the older patients with the IL28B TG/GG-genotypes (100% and 64.7%, P < 0.01).\n\nFigure 2 Rates of sustained virological response to telaprevir and simeprevir by prior treatment responses. Percentages indicate the proportion of patients with undetectable serum hepatitis C virus (HCV) RNA levels at 24 wk after the end of treatment. Patient numbers are shown in parenthesis. aP = 0.033 (compared to relapsers in the older patients). NR: Non-responders; TVR: Telaprevir; SMV: Simeprevir; SVR24: Sustained virological response defined as undetectable serum HCV RNA at 24 wk after the end of treatment.\n\nFigure 3 Rates of sustained virological response to telaprevir and simeprevir by interleukin 28B single-nucleotide polymorphism. Percentages indicate the proportion of patients with undetectable serum hepatitis C virus RNA levels at 24 wk after the end of treatment. Patient numbers are shown in parenthesis. TT, interleukin 28B (IL28B) (rs8099917) TT-genotype; non-TT, IL28B TG/GG-genotypes aP = 0.038 (compared to older patients with the IL28B TT-genotype). bP = 0.005 (compared to older patients with the IL28B TT-genotype). TVR: Telaprevir; SMV: Simeprevir; SVR24: Sustained virological response defined as undetectable serum HCV RNA at 24 wk after the end of treatment.\n\nSafety and tolerability\nTreatment tolerability was summarized in Tables 3 and 4. In the TVR group, adverse events resulted in treatment discontinuation in 16.7% (13/78 cases) and 11.8% (4/34 cases) of patients in the younger and older groups, respectively. Although a greater number of older patients in the TVR group was treated with the lower initial dose of TVR (1500 mg/d) than the younger patients (P < 0.01)[20], 9 patients (26.4%) discontinued TVR because of adverse events (four patients experienced skin rush, four patients experienced anemia, and one patient experienced renal dysfunction). However, the rate of discontinuation of TVR did not significantly differ between the younger and older patients (Table 3). The cumulative exposure to RBV for the whole 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger patients than in the older patients (79.3% ± 26.2% vs 62.7% ± 25.3%, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older patients (88.8% ± 22.8% vs 83.5% ± 25.5%, P = 0.103). Conversely, SMV was not discontinued in either the younger or older patients, although the rate of discontinuation of RBV was significantly higher in the older patients than the younger patients in the SMV group (58.9% vs 29.7%, P = 0.012) because of anemia. Adverse events resulted in treatment discontinuation in 8.1% (3/37 cases) and 7.6% (3/39 cases) of patients in the younger and older groups, respectively.\n\nTable 3 Treatment tolerability (telaprevir)\n\n\tPatients aged < 66\tPatients aged ≥ 66\tP value\t\nInitial doses (median, range)\t\t\t\t\nPEG-IFN/BW (μg/kg per week)\t1.48 (0.98-2.00)\t1.49 (1.15-1.87)\t0.859\t\nTVR/BW (mg/kg per day)\t33.0 (19.2-64.3)\t29.2 (7.5-54.2)\t0.044\t\nTVR (2250 mg/1500 mg/others), n\t55/23/0\t11/21/2\t< 0.001\t\nRBV/BW (mg/kg per day)\t11.4 (6.8-20.0)\t11.4 (5.7-28.0)\t0.103\t\nDose reduction, n (%)\t\t\t\t\nPEG-IFN\t7 (8.9)\t6 (17.6)\t0.209\t\nTVR\t19 (24.3)\t12 (35.3)\t0.256\t\nRBV\t40 (51.2)\t27 (79.4)\t0.006\t\nDiscontinuation, n (%)\t\t\t\t\nPEG-IFN\t13 (16.7)\t4 (11.8)\t0.580\t\nTVR\t12 (15.4)\t9 (26.5)\t0.192\t\nRBV\t12 (15.4)\t7 (20.6)\t0.585\t\nAdherence, mean ± SD (%)\t\t\t\t\nPEG-IFN\t88.2 ± 25.7\t90.1 ± 19.8\t0.606\t\nTVR\t88.8 ± 22.8\t83.5 ± 25.5\t0.103\t\nRBV\t79.3 ± 26.2\t62.7 ± 25.3\t< 0.001\t\nPEG-IFN: Pegylated interferon; BW: Bodyweight; TVR: Telaprevir; RBV: Ribavirin.\n\nTable 4 Treatment tolerability (simeprevir)\n\n\tPatients aged < 66\tPatients aged ≥ 66\tP value\t\nInitial doses (median, range)\t\t\t\t\nPEG-IFNα2a (180/90) (μg/wk)\t19/0\t10/1\t0.366\t\nPEG-IFNα2b (120/100/80/others) (μg/wk)\t2/16/5/1\t0/25/5/1\t0.422\t\nSMV/BW (mg/kg per day)\t1.6 (1.1-2.5)\t1.8 (1.3-2.7)\t0.011\t\nRBV/BW (mg/kg per day)\t11.6 (6.8-17.1)\t12.3 (6.0-20.6)\t0.166\t\nDose reduction, n (%)\t\t\t\t\nPEG-IFN\t5 (13.5)\t6 (15.3)\t1\t\nSMV\t0\t0\t1\t\nRBV\t3 (8.1)\t6 (15.3)\t0.481\t\nDiscontinuation, n (%)\t\t\t\t\nPEG-IFN\t5 (13.5)\t5 (12.8)\t1\t\nSMV\t2 (5.4)\t2 (5.1)\t1\t\nRBV\t11 (29.7)\t23 (58.9)\t0.012\t\nAdherence, mean ± SD (%)\t\t\t\t\nPEG-IFN\t93.6 ± 16.8\t92.3 ± 19.5\t0.592\t\nSMV\t98.1 ± 7.2\t93.9 ± 18.1\t0.079\t\nRBV\t91.0 ± 16.1\t86.8 ± 20.2\t0.126\t\nPEG-IFN: Pegylated interferon; SMV: Simeprevir; BW: Bodyweight; RBV: Ribavirin.\n\nPredictive factors correlated with SVR24\nTo identify pretreatment and treatment factors that contribute to SVR, univariate and multivariate analyses were performed in the TVR and SMV groups including the following variables: Gender, age, body mass index, baseline HCV viral load, serum ALT, hemoglobin, platelet counts, IL28B SNP, initial dose of TVR, TVR/BW (mg/kg per day), SMV/BW (mg/kg per day), dose reduction of treatments, and RVR (Tables 5 and 6). In the TVR group, the IL28B SNP significantly correlated with SVR according to the univariate analysis. A multivariate logistic regression analysis identified the IL28B TT-genotype (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR (Table 5). In the SMV group, the IL28B SNP and the absence of a dose reduction in PegIFN significantly correlated with SVR according to the univariate analysis. In the multivariate logistic regression analysis, the independent factors associated with the SVR were IL28B TT-genotype (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040) and the absence of a dose reduction in PegIFN (OR = 6.557; 95%CI: 1.328-32.377, P = 0.021) (Table 6).\n\nTable 5 Univariate and multivariate analysis of factors contributing to SVR24 (telaprevir)\n\nFactors\tUnivariate analysis\tMultivariate analysis\t\nOdds ratio (95%CI)\tP value\tOdds ratio (95%CI)\tP value\t\nAge\t1.012 (0.955-1.072)\t0.689\t\t\t\nGender (female)\t0.784 (0.262-2.342)\t0.663\t\t\t\nBody mass index (kg/m2)\t1.074 (0.875-1.318)\t0.495\t\t\t\nPrior treatment response (non-NR)\t3.850 (0.830-17.861)\t0.085\t\t\t\nBaseline HCV-RNA (log IU/mL)\t1.264 (0.457-3.495)\t0.652\t\t\t\nBaseline ALT (IU/mL)\t1.008 (0.998-1.017)\t0.105\t\t\t\nBaseline platelets (× 104/mm3)\t1.017 (0.906-1.142)\t0.775\t\t\t\nBaseline hemoglobin (g/dL)\t1.038 (0.736-1.464)\t0.830\t\t\t\nIL28B SNP (TT)\t6.700 (1.826-24.584)\t0.004\t8.160 (1.593-41.804)\t0.012\t\nInitial dose of TVR (2250 mg/d)\t2.069 (0.670-6.553)\t0.204\t\t\t\nTVR/BW (mg/kg per day)\t0.938 (0.870-1.011)\t0.093\t\t\t\nRBV/BW (mg/kg per day)\t0.811 (0.617-1.066)\t0.133\t\t\t\nPEG-IFN dose reduction (none)\t2.134 (0.253-17.988)\t0.486\t\t\t\nTVR dose reduction (none)\t1.020 (0.281-3.703)\t0.976\t\t\t\nRBV dose reduction (none)\t1.548 (0.433-5.525)\t0.501\t\t\t\nAdherence of RBV (> 60%)\t6.873 (1.784-26.474)\t0.005\t11.052 (1.160-105.273)\t0.037\t\nRVR (none)\t0.88 (0.123-1.216)\t0.104\t\t\t\nHCV: Hepatitis C virus; ALT: Alanine aminotransferase; NR: Non-responder; IL28B SNP: Interleukin-28B single nucleotide polymorphism; TVR: Telaprevir; RVR: Rapid virological response; PEG-IFN: Pegylated interferon; BW: Bodyweight; RBV: Ribavirin.\n\nTable 6 Univariate and multivariate analysis of factors contributing to SVR24 (simeprevir)\n\nFactors\tUnivariate analysis\tMultivariate analysis\t\nOdds ratio (95%CI)\tP value\tOdds ratio (95%CI)\tP value\t\nAge\t0.998 (0.942-1.058)\t0.953\t\t\t\nGender (female)\t0.330 (0.083-1.314)\t0.116\t\t\t\nBody mass index (kg/m2)\t1.164 (0.934-1.450)\t0.175\t\t\t\nPrior treatment response (non-NR)\t2.955 (0.811-10.764)\t0.101\t\t\t\nBaseline HCV-RNA (log IU/mL)\t0.767 (0.328-1.791)\t0.540\t\t\t\nBaseline ALT (IU/mL)\t0.998 (0.985-1.012)\t0.785\t\t\t\nBaseline platelets (× 104/mm3)\t1.082 (0.953-1.228)\t0.224\t\t\t\nBaseline hemoglobin (g/dL)\t1.257 (0.827-1.910)\t0.285\t\t\t\nIL28B SNP (TT)\t12.593 (1.516-104.576)\t0.019\t9.677 (1.114-84.087)\t0.040\t\nSMV/BW (mg/kg per day)\t0.306 (0.054-1.742)\t0.182\t\t\t\nRBV/BW (mg/kg per day)\t1.085 (1.138-3.913)\t0.501\t\t\t\nPEG-IFN dose reduction (none)\t7.250 (1.712-30.700)\t0.007\t6.557 (1.328-32.377)\t0.021\t\nRBV dose reduction (none)\t1.556 (0.470-5.160)\t0.470\t\t\t\nRVR (none)\t0.351 (0.075-1.637)\t0.183\t\t\t\nHCV: Hepatitis C virus; ALT: Alanine aminotransferase; NR: Non-responder; IL28B SNP: Interleukin-28B single nucleotide polymorphism; SMV: Simeprevir; BW: Bodyweight; PEG-IFN: Pegylated interferon; RBV: Ribavirin; RVR: Rapid virological response.\n\nDISCUSSION\nIn this study, we evaluated and compared the efficacy and safety of TVR- and SMV-based triple therapies in combination with PegIFN and RBV in elderly Japanese patients with chronic hepatitis C (CHC), specifically patients aged 66 years or older. The rate of SVR did not differ significantly between younger and older patients in either the TVR or the SMV groups. Among the older patients who were more difficult to treat, more patients carrying the IL28B TG/GG genotypes and prior non-responders were enrolled in the SMV group than the TVR group. However, the rate of SVR did not differ significantly between the TVR and SMV group, although the rates of RVR and relapse were significantly higher in the SMV group than the TVR group. When we performed univariate analyses of factors associated with SVR in all the enrolled patients, we did not find any significance in the type of treatment (TVR vs SMV) (OR = 1.115, 95%CI: 0.415-3.192, P = 0.787). Ogawa et al[21] reported that the rates of SVR were similar for patients with HCV genotype 1b who were treated with TVR- and SMV-based triple therapies, although patients treated with TVR-based triple therapy had more frequent severe adverse events than those treated with SMV-based triple therapy. In this study, the rate of adverse events that resulted in treatment discontinuation did not differ between the younger and older patients in either the TVR or the SMV group, although a higher frequency and severity of adverse events have been reported in patients treated with TVR-based triple therapy compared to patients treated with PegIFN and RBV dual therapy[10,11]. We found that both TVR- and SMV-based triple therapy were effective and tolerable among older patients aged 66 years or older.\n\nIn Japan, an estimated 1.5-2 million people are infected with HCV, and these patients are older than those infected in Europe and the United States[3,22]. However, previous studies describing the safety and efficacy of TVR- and SMV-based triple therapies, especially in elderly patients with CHC, are limited. One of the reasons may be that the inclusion criteria for clinical trials were usually set to a maximum age of 65 years[11,23]. Furusyo et al[4] reported that there were no differences in the efficacy, frequency and severity of adverse events between patients aged > 60 years and those aged ≤ 60 years who were treated with TVR-based triple therapy. Consistent with our study, they reported that a multivariate analysis revealed that the IL28B TT-genotype and the achievement of RVR were independent factors associated with SVR. Although the decrease in hemoglobin was significantly higher in patients aged > 60 years compared to younger patients aged ≤ 60 years, the rate of adverse events that resulted in treatment discontinuation was similar between the two groups[4]. Abe et al[23] also reported that in patients treated with TVR-based triple therapy, the SVR rate in patients aged > 65 years was similar to that of patients aged ≤ 65 years and that there was no notable increase of the rate of treatment discontinuation. In our study, the rate of adverse events that resulted in treatment discontinuation in the older patients was lower in the SMV group than in the TVR group, but the difference was not statistically significant. However, considering the risk of higher frequency and severity of adverse events associated with TVR-based triple therapy, we recommend the use of SMV rather than TVR.\n\nThe IL28B SNP genotype had a limited impact on the SVR rate with triple therapy in treatment-experienced patients[24], and the strength of the association between the IL28B genotype and the treatment outcome was attenuated in the triple therapy compared to the dual therapy[23,25]. In the present study, the IL28B SNP genotype displayed a striking influence on the outcome of both TVR- and SMV-based triple therapy, especially in older patients. In the older patients carrying the IL28B TT-genotype, the rates of SVR were 92.9% and 100% in the TVR and SMV groups, respectively. In contrast, in the older patients carrying the IL28B TG or GG-genotype, the rates of SVR were significantly decreased to 60% and 64.7% in the TVR and SMV groups (P = 0.038 and P < 0.01), respectively. Although the substitutions in the core aa70 of the HCV genotype 1b were reported to be important predictors of the efficacy of dual therapy and triple therapy[26,27], our study revealed that the substitutions in the HCV core aa70 were not associated with the achievement of SVR (data not shown). This discrepancy may be explained by the differences in the study population, as our study consisted of a relatively higher number of aged patients. We also measured serum CXCL10 in patients treated with TVR-based triple therapy because previous studies have reported that pretreatment serum CXCL10 concentrations were associated with early virological response and treatment efficacy in patients treated with this therapy[28,29]. However, we did not confirm the utility of pretreatment CXCL10 concentrations as a predictor of virological response in patients treated with TVR-based triple therapy.\n\nThe present study has a number of limitations. First, the sample size might have provided inadequate statistical power to detect definitive differences between the SVR and no-SVR data in both the older and younger patients. However, the best of our knowledge, this is the first study to compare the efficacy and safety of TVR- and SMV-based triple therapies for elderly patients aged 66 years or older. Second, we only investigated Japanese patients with the HCV genotype 1b. Among the Japanese population, the favorable IL28B SNP is found in the majority of the population (approximately 75%)[4]. Therefore, our results may not be generalizable to other racial cohorts. Third, the older patients who enrolled in the study did not have any severe baseline complications, such as renal and hematological diseases. Therefore, the conclusions drawn regarding the safety of triple therapies may be limited. However, we believe that our selection of older patients for the triple therapies was appropriate and acceptable. Therefore, our findings regarding the absence of severe adverse events, even in the older patients, are important.\n\nTreatment for CHC has been changing worldwide[30,31], and IFN-free DAA combination therapies are now available in Japan. Although the majority of CHC patients are usually treated with IFN-free DAA combination therapies, PegIFN and RBV-based therapy may still have utility in a small number of patients who do not show a favorable effect after the treatment with IFN-free DAA therapies. Moreover, considering the effect of preventing HCC by an eradication of HCV, long-term prevention of HCC has been shown only through the use of IFN-based therapies thus far[32,33]. Therefore, we believe that the present study will provide useful information regarding antiviral treatment for older patients with CHC.\n\nIn conclusion, we found that both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b CHC. The IL28B genotype indicates a potential to achieve SVR in these difficult-to-treat older patients.\n\nCOMMENTS\nBackground\nIn Japan, an estimated 1.5-2 million people are infected with hepatitis C virus (HCV), and these patients are older than those infected in Europe and the United States. However, previous studies describing the safety and efficacy of telaprevir (TVR)- and simeprevir (SMV)-based triple therapies, especially in elderly patients with chronic HCV infections, are limited.\n\nResearch frontiers\nThe patients were categorized into two groups according to age as follows: a younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. The rate of sustained virological response (SVR) did not significantly differ between the younger and older patients in both the TVR and SMV groups. The rate of SVR did not significantly differ between the TVR and SMV group, although the rate of rapid virological response was significantly higher in the SMV group than the TVR group. The rate of adverse events resulted in treatment discontinuation did not differ between the younger and older patients in both TVR and SMV group, although a higher frequency and severity of adverse events has been reported in patients treated with TVR-based triple therapy compared to patients treated with pegylated interferon (PegIFN) and ribavirin (RBV) dual therapy.\n\nInnovations and breakthroughs\nIn this study, the authors found that both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C (CHC). The interleukin 28B genotype indicates a potential to achieve SVR in these difficult-to-treat elderly patients.\n\nApplications\nTreatment for CHC has been changing worldwide, and interferon (IFN)-free direct-acting antiviral agents (DAA) combination therapies are now available in. Although the majority of CHC patients are usually treated with IFN-free DAA combination therapies, PegIFNα and RBV-based therapy may still have utility in a small number of patients who do not show a favorable effect after the treatment with IFN-free DAA therapies. Importantly, HCV mutants that are resistant to multiple IFN-free DAA therapies have been shown to be sensitive to IFN-based therapies. Moreover, considering the effect of preventing HCC by an eradication of HCV, long-term prevention of HCC has been shown only through the use of IFN-based therapies thus far. Therefore, they believe that the present study will still provide useful information regarding antiviral treatment for older patients with CHC.\n\nTerminology\nTVR: An HCV non-structural 3/4A (NS3/4A) protease inhibitor; SMV: A second-generation oral HCV NS3/4A protease inhibitor with antiviral activity against HCV genotype 1, 2, 4, 5, and 6 infections.\n\nPeer-review\nThe manuscript is well written and it is clear.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: Japan\n\nPeer-review report classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C, C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInstitutional review board statement: The study was reviewed and approved by Niigata University Medical and Dental Hospital Institutional Review Board.\n\nInformed consent statement: Written informed consent under institutional review board-approved protocols (approval no. 1474) at Niigata University Medical and Dental Hospital was appropriately obtained from all the individuals enrolled in the study.\n\nConflict-of-interest statement: We have no financial relationships to disclose.\n\nData sharing statement: No additional data are available.\n\nPeer-review started: August 24, 2016\n\nFirst decision: September 27, 2016\n\nArticle in press: January 14, 2017\n\nP- Reviewer: Conti B, Kawakami Y, Larrubia JR, Liang XS S- Editor: Kong JX L- Editor: A E- Editor: Li D\n==== Refs\n1 Seeff LB Buskell-Bales Z Wright EC Durako SJ Alter HJ Iber FL Hollinger FB Gitnick G Knodell RG Perrillo RP Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group N Engl J Med 1992 327 1906 1911 1454085 \n2 Mohd Hanafiah K Groeger J Flaxman AD Wiersma ST Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence Hepatology 2013 57 1333 1342 23172780 \n3 Namiki I Nishiguchi S Hino K Suzuki F Kumada H Itoh Y Asahina Y Tamori A Hiramatsu N Hayashi N Management of hepatitis C; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009) Hepatol Res 2010 40 347 368 20394674 \n4 Furusyo N Ogawa E Nakamuta M Kajiwara E Nomura H Dohmen K Takahashi K Satoh T Azuma K Kawano A Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C J Hepatol 2013 59 205 212 23542346 \n5 Asahina Y Tsuchiya K Tamaki N Hirayama I Tanaka T Sato M Yasui Y Hosokawa T Ueda K Kuzuya T Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection Hepatology 2010 52 518 527 20683951 \n6 Zeuzem S Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med 2004 140 370 381 14996679 \n7 Honda T Katano Y Shimizu J Ishizu Y Doizaki M Hayashi K Ishigami M Itoh A Hirooka Y Nakano I Efficacy of peginterferon-alpha-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C Liver Int 2010 30 527 537 19523048 \n8 Furusyo N Ogawa E Sudoh M Murata M Ihara T Hayashi T Ikezaki H Hiramine S Mukae H Toyoda K Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: a randomized trial J Hepatol 2012 57 1186 1192 22889955 \n9 Reddy KR Zeuzem S Zoulim F Weiland O Horban A Stanciu C Villamil FG Andreone P George J Dammers E Simeprevir versus telaprevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): a randomised, double-blind, non-inferiority phase 3 trial Lancet Infect Dis 2015 15 27 35 25482330 \n10 Jacobson IM McHutchison JG Dusheiko G Di Bisceglie AM Reddy KR Bzowej NH Marcellin P Muir AJ Ferenci P Flisiak R Telaprevir for previously untreated chronic hepatitis C virus infection N Engl J Med 2011 364 2405 2416 21696307 \n11 Zeuzem S Andreone P Pol S Lawitz E Diago M Roberts S Focaccia R Younossi Z Foster GR Horban A Telaprevir for retreatment of HCV infection N Engl J Med 2011 364 2417 2428 21696308 \n12 Fried MW Buti M Dore GJ Flisiak R Ferenci P Jacobson I Marcellin P Manns M Nikitin I Poordad F Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study Hepatology 2013 58 1918 1929 23907700 \n13 Jacobson IM Dore GJ Foster GR Fried MW Radu M Rafalsky VV Moroz L Craxi A Peeters M Lenz O Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial Lancet 2014 384 403 413 24907225 \n14 Hayashi N Izumi N Kumada H Okanoue T Tsubouchi H Yatsuhashi H Kato M Ki R Komada Y Seto C Simeprevir with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial J Hepatol 2014 61 219 227 24727123 \n15 Izumi N Hayashi N Kumada H Okanoue T Tsubouchi H Yatsuhashi H Kato M Ki R Komada Y Seto C Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies J Gastroenterol 2014 49 941 953 24626851 \n16 Kumada H Hayashi N Izumi N Okanoue T Tsubouchi H Yatsuhashi H Kato M Rito K Komada Y Seto C Simeprevir (TMC435) once daily with peginterferon-α-2b and ribavirin in patients with genotype 1 hepatitis C virus infection: The CONCERTO-4 study Hepatol Res 2015 45 501 513 24961662 \n17 Bedossa P Poynard T An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group Hepatology 1996 24 289 293 8690394 \n18 Enomoto N Sakuma I Asahina Y Kurosaki M Murakami T Yamamoto C Ogura Y Izumi N Marumo F Sato C Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection N Engl J Med 1996 334 77 81 8531962 \n19 Akuta N Suzuki F Sezaki H Suzuki Y Hosaka T Someya T Kobayashi M Saitoh S Watahiki S Sato J Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy Intervirology 2005 48 372 380 16024941 \n20 Hara T Akuta N Suzuki F Sezaki H Suzuki Y Hosaka T Kobayashi M Kobayashi M Saitoh S Kumada H A pilot study of triple therapy with telaprevir, peginterferon and ribavirin for elderly patients with genotype 1 chronic hepatitis C J Med Virol 2013 85 1746 1753 23861088 \n21 Ogawa E Furusyo N Kajiwara E Nomura H Kawano A Takahashi K Dohmen K Satoh T Azuma K Nakamuta M Comparative effectiveness and safety study of triple therapy with simeprevir or telaprevir for non-cirrhotic patients with chronic hepatitis C virus genotype 1b infection J Gastroenterol Hepatol 2015 30 1759 1767 26095167 \n22 Yoshizawa H Tanaka J Miyakawa Y National prevention of hepatocellular carcinoma in Japan based on epidemiology of hepatitis C virus infection in the general population Intervirology 2006 49 7 17 16166783 \n23 Abe H Tsubota A Shimada N Atsukawa M Kato K Takaguchi K Asano T Chuganji Y Sakamoto C Toyoda H Predictors of response to 24-week telaprevir-based triple therapy for treatment-naïve genotype 1b chronic hepatitis C patients Gastroenterol Res Pract 2014 2014 549709 25197269 \n24 Pol S Aerssens J Zeuzem S Andreone P Lawitz EJ Roberts S Younossi Z Foster GR Focaccia R Horban A Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure J Hepatol 2013 58 883 889 23321318 \n25 Holmes JA Desmond PV Thompson AJ Does IL28B genotyping still have a role in the era of direct-acting antiviral therapy for chronic hepatitis C infection? J Viral Hepat 2012 19 677 684 22967098 \n26 Akuta N Suzuki F Hirakawa M Kawamura Y Sezaki H Suzuki Y Hosaka T Kobayashi M Kobayashi M Saitoh S Amino acid substitution in HCV core/NS5A region and genetic variation near IL28B gene affect treatment efficacy to interferon plus ribavirin combination therapy Intervirology 2012 55 231 241 21734353 \n27 Akuta N Suzuki F Hirakawa M Kawamura Y Yatsuji H Sezaki H Suzuki Y Hosaka T Kobayashi M Kobayashi M Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin Hepatology 2010 52 421 429 20648473 \n28 Matsuura K Watanabe T Iijima S Murakami S Fujiwara K Orito E Iio E Endo M Kusakabe A Shinkai N Serum interferon-gamma-inducible protein-10 concentrations and IL28B genotype associated with responses to pegylated interferon plus ribavirin with and without telaprevir for chronic hepatitis C Hepatol Res 2014 44 1208 1216 24372894 \n29 Nishikawa H Enomoto H Nasu A Aizawa N Saito M Tamori A Kawada N Kimura T Osaki Y Nishiguchi S Clinical significance of pretreatment serum interferon-gamma-inducible protein 10 concentrations in chronic hepatitis C patients treated with telaprevir-based triple therapy Hepatol Res 2014 44 E397 E407 24628684 \n30 Webster DP Klenerman P Dusheiko GM Hepatitis C Lancet 2015 385 1124 1135 25687730 \n31 Fujii H Nishimura T Umemura A Nishikawa T Yamaguchi K Moriguchi M Sumida Y Mitsuyoshi H Yokomizo C Tanaka S Comparison of peg-interferon, ribavirin plus telaprevir vs simeprevir by propensity score matching World J Hepatol 2015 7 2841 2848 26668696 \n32 Cardoso AC Moucari R Figueiredo-Mendes C Ripault MP Giuily N Castelnau C Boyer N Asselah T Martinot-Peignoux M Maylin S Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis J Hepatol 2010 52 652 657 20346533 \n33 Ikeda K Saitoh S Arase Y Chayama K Suzuki Y Kobayashi M Tsubota A Nakamura I Murashima N Kumada H Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: A long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis Hepatology 1999 29 1124 1130 10094956\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": null,
"issue": "9(5)",
"journal": "World journal of hepatology",
"keywords": "Aged patients; Hepatitis C virus genotype 1b; Interleukin 28B; Simeprevir; Telaprevir",
"medline_ta": "World J Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101532469",
"other_id": null,
"pages": "252-262",
"pmc": null,
"pmid": "28261382",
"pubdate": "2017-02-18",
"publication_types": "D016428:Journal Article",
"references": "24626851;20394674;8531962;26095167;16166783;24907225;22889955;23907700;10094956;26668696;20683951;24727123;20648473;1454085;25687730;19523048;22967098;14996679;21734353;20346533;8690394;23321318;23542346;21696308;24628684;21696307;16024941;24961662;23861088;25197269;24372894;25482330;23172780",
"title": "Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C.",
"title_normalized": "efficacy and safety of telaprevir and simeprevir based triple therapies for older patients with chronic hepatitis c"
} | [
{
"companynumb": "JP-JNJFOC-20170317369",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
},
"drugadditional": null,
... |
{
"abstract": "A 37-year-old woman was diagnosed with chronic phase chronic myeloid leukemia. Nilotinib treatment was initiated; however, it had to be discontinued due to an allergic reaction one month later, and dasatinib treatment was provided. Although favorable response was obtained, she started complaining of shortness of breath 7 months after initiating dasatinib treatment. Chest X-ray and echocardiography indicated pulmonary congestion and hypertension. Further, she was diagnosed with mixed connective tissue disease (MCTD) based on Raynaud phenomenon, swollen fingers, sclerodactyly, pancytopenia, hypocomplementemia, and positive anti-U1-RNP antibody. Consequently, dasatinib treatment was discontinued, and she was administered prednisolone (1 mg/kg/day), which was effective and successfully tapered with concomitant administration of cyclophosphamide. This is the first case of MCTD that developed during dasatinib treatment. However, because the present case was a young woman, the development of MCTD could probably be attributed to autoimmune diatheses or it may be a coincidence. However, the possibility of patients receiving dasatinib treatment developing autoimmune diseases needs to be assessed.",
"affiliations": "Division of Hematology, Department of Medicine, Keio University School of Medicine.;Division of Hematology, Department of Medicine, Keio University School of Medicine.;Division of Hematology, Department of Medicine, Keio University School of Medicine.;Division of Hematology, Department of Medicine, Keio University School of Medicine.;Division of Hematology, Department of Medicine, Keio University School of Medicine.;Division of Hematology, Department of Medicine, Keio University School of Medicine.;Division of Hematology, Department of Medicine, Keio University School of Medicine.;Division of Rheumatology, Department of Medicine, Keio University School of Medicine.;Division of Rheumatology, Department of Medicine, Keio University School of Medicine.;Division of Rheumatology, Department of Medicine, Keio University School of Medicine.;Division of Cardiology, Department of Medicine, Keio University School of Medicine.;Division of Hematology, Department of Medicine, Keio University School of Medicine.;Division of Hematology, Department of Medicine, Keio University School of Medicine.",
"authors": "Watanuki|Shintaro|S|;Kikuchi|Taku|T|;Toyama|Takaaki|T|;Abe|Ryohei|R|;Nakayama|Hitomi|H|;Karigane|Daiki|D|;Shimizu|Takayuki|T|;Kikuchi|Jun|J|;Matsumoto|Kotaro|K|;Yasuoka|Hidetaka|H|;Kataoka|Masaharu|M|;Okamoto|Shinichiro|S|;Mori|Takehiko|T|",
"chemical_list": "D000069439:Dasatinib",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.59.174",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "59(2)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Chronic myeloid leukemia; Dasatinib; Mixed connective tissue disease; Pulmonary hypertension",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069439:Dasatinib; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008947:Mixed Connective Tissue Disease; D016896:Treatment Outcome",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "174-177",
"pmc": null,
"pmid": "29515069",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mixed connective tissue disease with pulmonary hypertension developing in a chronic myeloid leukemia patient on dasatinib treatment.",
"title_normalized": "mixed connective tissue disease with pulmonary hypertension developing in a chronic myeloid leukemia patient on dasatinib treatment"
} | [
{
"companynumb": "PHJP2017JP032653",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NILOTINIB"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "BACKGROUND\nDupuytren, Ledderhose, and Peyronie diseases are chronic fibrotic conditions related to progressive fibrosis of the palmar fascia, plantar fascia, and tunica albuginea, respectively. These conditions have been associated with antiepileptic drug use, mainly phenobarbital and primidone.\n\n\nMETHODS\nA 71-year-old man developed simultaneous Dupuytren, Ledderhose, and Peyronie diseases after primidone use for essential tremor.\n\n\nCONCLUSIONS\nThere are a few reports associating barbiturate use to connective tissue disorders, and some suggest that drug withdrawal may result in a better prognosis. Therefore, physicians must be aware of such adverse events when caring for patients on long-term barbiturate use.",
"affiliations": "Department of Neurology, Federal Hospital of Servidores do Estado, Rio de Janeiro-RJ, Brazil.",
"authors": "Vasconcellos|Luiz Felipe R|LFR|;Nassif|Daniel|D|;Spitz|Mariana|M|",
"chemical_list": "D000927:Anticonvulsants; D011324:Primidone",
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "24(5)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D004387:Dupuytren Contracture; D020329:Essential Tremor; D000071380:Fibromatosis, Plantar; D006801:Humans; D008297:Male; D010411:Penile Induration; D011324:Primidone",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "150-151",
"pmc": null,
"pmid": "31478998",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dupuytren, Ledderhose, and Peyronie Diseases After Primidone Use For Essential Tremor.",
"title_normalized": "dupuytren ledderhose and peyronie diseases after primidone use for essential tremor"
} | [
{
"companynumb": "BR-AMNEAL PHARMACEUTICALS-2019-AMRX-01938",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRIMIDONE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nAbiraterone acetate is an inhibitor of androgens biosynthesis, approved as first-line treatment in castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. Abiraterone has been rarely associated with severe rhabdomyolysis, but the mechanism of muscle toxicity is unknown.\n\n\nMETHODS\nWe hereby present a case of severe rhabdomyolysis resulting in acute on chronic kidney injury following abiraterone initiation in a patient previously under rosuvastatin.\nRhabdomyolysis was resolutive after rosuvastatin and abiraterone discontinuation, and kidney function recovered. There was no recurrence of muscle toxicity after re-initiation of abiraterone alone.\n\n\nCONCLUSIONS\nAbiraterone selectively inhibits CYP17 as well as the hepatic transporter OATP1B1. OATP1B1 is an efflux transporter, whose function is to extract several drugs from the portal blood, allowing them to undergo hepatic metabolism. We hypothesize that abiraterone-induced inhibition of plasmatic uptake of rosuvastatin by OATP1B1 increased plasmatic concentration of rosuvastatin, leading to toxicity on muscle cells. We therefore suggest that the association between rosuvastatin and abiraterone should be avoided.",
"affiliations": "Department of Intensive Care, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Department of Clinical Pharmacy, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Department of Oncology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Department of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Department of Intensive Care, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Department of Intensive Care, Cliniques Universitaires Saint-Luc, Brussels, Belgium.",
"authors": "Ould-Nana|Ismail|I|;Cillis|Marine|M|;Gizzi|Marco|M|;Gillion|Valentine|V|;Hantson|Philippe|P|;Gérard|Ludovic|L|https://orcid.org/0000-0002-8842-6270",
"chemical_list": "D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; D000068718:Rosuvastatin Calcium; D000069501:Abiraterone Acetate",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220923001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(1)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Abiraterone; OATP1B1; acute kidney injury; rhabdomyolysis; rosuvastatin; uptake transporter",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000069501:Abiraterone Acetate; D058186:Acute Kidney Injury; D000368:Aged; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D012206:Rhabdomyolysis; D000068718:Rosuvastatin Calcium",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "216-219",
"pmc": null,
"pmid": "32397905",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rhabdomyolysis and acute kidney injury induced by the association of rosuvastatin and abiraterone: A case report and review of the literature.",
"title_normalized": "rhabdomyolysis and acute kidney injury induced by the association of rosuvastatin and abiraterone a case report and review of the literature"
} | [
{
"companynumb": "BE-JNJFOC-20200601890",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"d... |
{
"abstract": "Clozapine may be associated with cardiovascular adverse effects including QTc prolongation and, more rarely, with myocarditis and pericarditis. Although rare, these latter cardiovascular adverse effects may be life-threatening and must be immediately recognized and treated. Several cases of clozapine related-pericarditis have been described and often it has a subtle and insidious onset with symptoms that may be often misdiagnosed with psychiatric manifestations (e.g. anxiety, panic or somatization) leading to a delayed correct diagnosis with potential fatal consequences. In the present report we describe the case of a 27-year-old girl with schizoaffective disorder taking long acting aripiprazole and valproate who developed a sudden onset clozapine-related pericarditis during titration phase that resolved with immediate clozapine discontinuation and indomethacin administration. We underline the importance of an early diagnosis of clozapine-related pericarditis and the need to have monitoring protocols to prevent this potentially fatal adverse effect especially when polypharmacy is administered to patients taking clozapine.",
"affiliations": "National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital \"G. Mazzini\", Teramo, Italy.;Polyedra Research Group, Teramo, Italy.;Polyedra Research Group, Teramo, Italy.;National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital \"G. Mazzini\", Teramo, Italy.;National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital \"G. Mazzini\", Teramo, Italy.;National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital \"G. Mazzini\", Teramo, Italy.;National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital \"G. Mazzini\", Teramo, Italy.;Department of Cardiovascular, Hospital \"G. Mazzini\", Teramo, Italy.;National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital \"G. Mazzini\", Teramo, Italy.;Department of Neurosciences and Imaging, University \"G. d'Annunzio\", Chieti, Italy.",
"authors": "De Berardis|Domenico|D|;Fornaro|Michele|M|;Orsolini|Laura|L|;Olivieri|Luigi|L|;Nappi|Francesco|F|;Rapini|Gabriella|G|;Vellante|Federica|F|;Napoletano|Cosimo|C|;Serroni|Nicola|N|;Giannantonio|Massimo Di|MD|",
"chemical_list": null,
"country": "Korea (South)",
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"doi": "10.9758/cpn.2018.16.4.505",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 10.9758/cpn.2018.16.4.505cpn-16-505Case ReportClozapine-related Sudden Pericarditis in a Patient Taking Long Acting Aripiprazole and Valproate: A Case Report De Berardis Domenico 12Fornaro Michele 34Orsolini Laura 356Olivieri Luigi 1Nappi Francesco 1Rapini Gabriella 1Vellante Federica 12Napoletano Cosimo 7Serroni Nicola 1Di Giannantonio Massimo 2\n1 National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, Teramo, \nItaly\n2 Department of Neurosciences and Imaging, University “G. d’Annunzio”, Chieti, \nItaly\n3 Polyedra Research Group, Teramo, \nItaly\n4 New York Psychiatric Institute, Columbia University, New York, NY, \nUSA\n5 School of Life and Medical Sciences, University of Hertfordshire, Hatfield, \nUK\n6 Department of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, \nThe Netherlands\n7 Department of Cardiovascular, Hospital “G. Mazzini”, Teramo, \nItalyAddress for correspondence: Domenico De Berardis, MD, PhD, National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, Piazza Italia 1, 64100 Teramo, Italy, Tel: +39-0861429708, Fax: +39-0861429709, E-mail: domenico.deberardis@aslteramo.it, ORCID: https://orcid.org/0000-0003-4415-505811 2018 30 11 2018 16 4 505 507 27 3 2017 02 5 2017 03 5 2017 Copyright © 2018, Korean College of Neuropsychopharmacology2018This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Clozapine may be associated with cardiovascular adverse effects including QTc prolongation and, more rarely, with myocarditis and pericarditis. Although rare, these latter cardiovascular adverse effects may be life-threatening and must be immediately recognized and treated. Several cases of clozapine related-pericarditis have been described and often it has a subtle and insidious onset with symptoms that may be often misdiagnosed with psychiatric manifestations (e.g. anxiety, panic or somatization) leading to a delayed correct diagnosis with potential fatal consequences. In the present report we describe the case of a 27-year-old girl with schizoaffective disorder taking long acting aripiprazole and valproate who developed a sudden onset clozapine-related pericarditis during titration phase that resolved with immediate clozapine discontinuation and indomethacin administration. We underline the importance of an early diagnosis of clozapine-related pericarditis and the need to have monitoring protocols to prevent this potentially fatal adverse effect especially when polypharmacy is administered to patients taking clozapine.\n\nClozapinePericarditisValproic acidPolypharmacyDrug monitoring\n==== Body\nINTRODUCTION\nEven if clozapine represents the “gold standard” antipsychotic for treatment-resistant schizophrenia and other psychotic disorders, it may be associated with cardiovascular adverse effects1) including QTc prolongation and, more rarely, with myocarditis and pericarditis.2) Although rare, these latter cardiovascular adverse effects may be life-threatening and must be immediately recognized and treated.3) Clozapine related-pericarditis may have a subtle and insidious onset and symptoms may include shortness of breath, heart palpitations, fatigue and chest pain.4) These symptoms may be often misdiagnosed with psychiatric manifestations (e.g., anxiety, panic or somatization) leading to a delayed correct diagnosis with potential fatal consequences.5)\n\nIn the present case report we describe the case of a sudden onset clozapine-related pericarditis during titration phase in a patient taking long acting aripiprazole and valproate.\n\nCASE\nA 27-year-old girl was diagnosed with schizoaffective disorder at age of 19 years and previously treated with haloperidol and, after, risperidone and valproate with small clinical improvement and development of adverse side effect (i.e., parkinsonism). Risperidone was gradually tapered off and long-acting aripiprazole 400 mg once monthly (OM) was added to her regimen with mild improvement and disappearance of parkinsonism.\n\nHowever, she was voluntarily admitted in half October 2016 in psychiatric ward of Teramo (Italy) due to a clinical picture characterized by persistence of affective flattening, reduced ability to plan or carry out activities, mild agitation and moderate elevated/irritable mood in conjunction with persecutory and grandiosity delusions and moderate disorganization. She was taking long acting aripiprazole 400 mg/day OM (last injection at the end of September), lorazepam 1 mg once daily (OD) and valproate 500 mg twice daily (BID).\n\nWe decided to add a low dose of clozapine (100 mg BID) jointly with other ongoing treatments. Before starting clozapine analysis of white blood cell count (WBC) and absolute neutrophil count (ANC) was evaluated and was within normal limits. Other routine blood analyses were normal (including B-type natriuretic peptide [BNP], troponin and C-reactive protein [CRP]) as well as electroencephalogram, electrocardiogram and echocardiography. Clozapine was initiated following drug data sheet and slowly titrated after six days up to 100 mg/day, without significant side effects. At the eight day, following a routine monitoring based on a protocol developed by us from Ronaldson et al.6) for clozapine-related myocarditis, we found an increase of CRP (30.03 mg/L, range 0–5 mg/L), troponin (30.03 pg/ml, range 0–14 pg/ml) and creatinkinase (CPK, 455 U/L, range 20–170 455 U/L). BNP was normal (5.0 pg/ml, cutoff <14) as well as blood cell count. Electrocardiogram showed only a sinus tachycardia (121 bpm). However, the patient was almost asymptomatic and complained (only from the night before blood samples) of mild shortness of breath (that patient attributed to “anxiety”) and mild elevation in body temperature (37°C). No other symptoms were reported. We immediately executed an echocardiography (Fig. 1) that documented an hyperkinetic cardiac activity with a preserved ventricular kinetic without dilatation. However, in the right ventricle, mild pericardial effusion was documented without cardiac tamponade or myocardial dysfunction, a clinical picture leading to the hypothesis of clozapine-related pericarditis.\n\nClozapine was immediately discontinued and, following cardiologist recommendation, she was initiated with indomethacin 50 mg per oral BID, maintaining valproate 500 mg BID. After five days a new blood routine showed a normalization of CRP, CPK and troponin. As well, a new echocardiography documented the reversal of pericarditis. The patient was after discharged with the addiction of quetiapine 50 mg.\n\nThe last observation was made in March 2017; the patient was taking long acting aripiprazole 400 mg/day OM (last injection at the end of February), lorazepam 1 mg OD, quetiapine 50 mg/day and valproate 500 mg BID without adverse effects and good improvement. WBC and ANC were within normal limits as well as electrocardiogram, CRP, CPK and troponin.\n\nThe patient provided informed consent to present this report.\n\nDISCUSSION\nTo date, this was the first reported case of a clozapine-related pericarditis in a patient who was taking both long acting aripiprazole and valproate. In this case, the patient developed a sudden clozapine-related pericarditis which is mostly asymptomatic with mild pericardial effusion, at the end of 100 mg/day titration phase, although a prompt diagnosis of mild pericardial effusion avoided cardiac tamponade complication. The clozapine-related pericarditis is a relatively uncommon adverse effect of this drug. We conducted a Medline search of publications from 1989 to 2017 and, using the keywords pericarditis and clozapine, we found 25 papers, mostly case reports, on this topic. There are several clinical presentations from mild-to-moderate shortness of breath and postural pleuritic-like chest pain to cardiac tamponade.7–9) In the majority of reviewed cases, clozapine treatment was immediately discontinued, resulting in complete resolution of symptoms.4,10) In some cases a clozapine rechallenge was tried, but this strategy is controversial as pericarditis may develop again, even it is not the rule.11,12)\n\nThere is only one report that has investigated the long-acting aripiprazole/clozapine combination in a case of ultra-resistant schizophrenia without insurgence of adverse effects.13) However, in our case, we cannot exclude that this combination may have contributed to cause the observed clozapine-related pericarditis. Moreover, even it has been suggested that valproate-clozapine association may cause eosinophilic effusion,14) we excluded a role of valproate on the matter, because this latter was unaltered for years and any clinically significant pharmacokinetic interaction between these two drugs is likely to happen.15) However, it is worthy to note that, in most cases, antipsychotic and/or other psychotropic polypharmacy may increase the risk of clozapine-related pericarditis and myocarditis2,16,17) and, therefore, a greater attention must be the rule in such cases even in asymptomatic patients.\n\nClozapine-related myocarditis was also excluded since echocardiography, cardiac necrosis markers and brain natriuretic peptide were all negative. Clozapine was a definite causative agent (score of 9) according to the Naranjo probability scale,18) which evaluates single-drug adverse events.\n\nTherefore, we suggest that electrocardiogram, CRP, troponin T, and cardiac ultrasound records should be considered before clozapine introduction and during its titration phase, especially in the case of concomitant treatments (such as, in this case, long-acting aripiprazole and valproate), even if the patients is relatively asymptomatic. This case underlines the importance of early diagnosis of clozapine-related pericarditis and the need to have monitoring protocols to prevent this potentially fatal adverse effect especially when polypharmacy is administered.\n\nFig. 1 Echocardiography documenting a mild pericardial effusion in the right ventricle without cardiac tamponade or myocardial dysfunction.\n==== Refs\nREFERENCES\n1 Curto M Girardi N Lionetto L Ciavarella GM Ferracuti S Baldessarini RJ Systematic review of clozapine cardiotoxicity Curr Psychiatry Rep 2016 18 68 10.1007/s11920-016-0704-3 27222142 \n2 De Berardis D Campanella D Serroni N Rapini G Olivieri L Fornaro M Clozapine-related pericarditis during titration phase in a patient with resistant schizophrenia and concomitant valproate treatment: a case report J Clin Psychopharmacol 2014 34 649 651 10.1097/JCP.0000000000000179 25006818 \n3 De Berardis D Serroni N Campanella D Olivieri L Ferri F Carano A Update on the adverse effects of clozapine: focus on myocarditis Curr Drug Saf 2012 7 55 62 10.2174/157488612800492681 22663959 \n4 Paul I Basavaraju V Narayanaswamy JC Math SB Clozapine-induced pericarditis: an overlooked adverse effect Clin Schizophr Relat Psychoses 2014 8 133 134 25287375 \n5 Rathore S Masani ND Callaghan PO Clozapine-induced effuso-constrictive pericarditis. Case report and review of the literature Cardiology 2007 108 183 185 10.1159/000096666 17085936 \n6 Ronaldson KJ Fitzgerald PB McNeil JJ Clozapine-induced myocarditis, a widely overlooked adverse reaction Acta Psychiatr Scand 2015 132 231 240 10.1111/acps.12416 25865238 \n7 Markovic J Momcilov-Popin T Mitrovic D Ivanovic-Kovacevic S Sekuli S Stojsic-Milosavljevic A Clozapine-induced pericarditis Afr J Psychiatry (Johannesbg) 2011 14 236 238 21863209 \n8 Layland JJ Liew D Prior DL Clozapine-induced cardiotoxicity: a clinical update Med J Aust 2009 190 190 192 19220183 \n9 Körtner K Neuhaus AH Schürer F Dettling M Eosinophilia indicating subclinical clozapine-induced pericarditis J Clin Psychiatry 2007 68 1147 1148 10.4088/JCP.v68n0726d 17685758 \n10 Prisco V Monica P Fiore G Tridente A La Rocca A Catapano F Brain natriuretic peptide as a biomarker of asymptomatic clozapine-related heart dysfunction: a criterion for a more cautious administration Clin Schizophr Relat Psychoses 2016 10.3371/CSRP.PRMO.112316 [Epub ahead of print] 27996318 \n11 Crews MP Dhillon GS MacCabe JH Clozapine rechallenge following clozapine-induced pericarditis J Clin Psychiatry 2010 71 959 961 10.4088/JCP.09l05692yel 20667298 \n12 Manu P Sarpal D Muir O Kane JM Correll CU When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature Schizophr Res 2012 134 180 186 10.1016/j.schres.2011.10.014 22113154 \n13 Sepede G Di Iorio G Spano MC Lorusso M Sarchione F Santacroce R A case of resistant schizophrenia successfully treated with clozapine/long-acting injectable aripiprazole combination Clin Neuropharmacol 2016 39 322 324 10.1097/WNF.0000000000000191 27764052 \n14 Fernández-Pérez R Alvarez-Dobaño JM Suárez-Antelo J Codesido-Barcala R Carballal-Calvo F Arrojo-Romero M Eosinophilic pleural effusion associated with the addition of sodium valproate J Clin Psychopharmacol 2009 29 310 311 10.1097/JCP.0b013e3181a2e1cf 19440094 \n15 Facciolà G Avenoso A Scordo MG Madia AG Ventimiglia A Perucca E Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders Ther Drug Monit 1999 21 341 345 10.1097/00007691-199906000-00017 10365650 \n16 Presecki P Grosić V Silić A Mihanović M Infection or idiosyncratic reaction to antiepileptic drugs? Psychiatr Danub 2010 22 132 134 20305610 \n17 Cadeddu G Deidda A Stochino ME Velluti N Burrai C Del Zompo M Clozapine toxicity due to a multiple drug interaction: a case report J Med Case Rep 2015 9 77 10.1186/s13256-015-0547-2 25890012 \n18 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "16(4)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Clozapine; Drug monitoring; Pericarditis; Polypharmacy; Valproic acid",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
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"pages": "505-507",
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"pmid": "30466225",
"pubdate": "2018-11-30",
"publication_types": "D002363:Case Reports",
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"title": "Clozapine-related Sudden Pericarditis in a Patient Taking Long Acting Aripiprazole and Valproate: A Case Report.",
"title_normalized": "clozapine related sudden pericarditis in a patient taking long acting aripiprazole and valproate a case report"
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"abstract": "This is a case report of a fatal intoxication in Cyprus related to 3,4-methylenedioxypyrovalerone (MDPV) and 2-(methylamino)-1-phenylpentan-1-one (pentedrone) intake combined with antipsychotic and antidepressant substances. A 42- year old man with a history of serious psychiatric illness was found unresponsive in his bed. Seized materials were also found close to his body. The forensic autopsy reported myocardial infarction due to multidrug intoxication. Toxicology screening in blood and urine was applied. Biological specimens were analysed by enzyme immunoassay procedure and GC/MS. MDPV, pentedrone and etizolam detected and quantitated in blood and urine. Other drugs quantitated in blood were also olanzapine, mirtazapine, and ephedrine. This was the first fatal case reported in Cyprus associated with new psychoactive substances. Additionally, this was the first case reported to Early Warning System of the European Monitoring Center of Drugs and Drug Abuse (EMCDDA), related to multidrug intoxication, attributed to the consumption of cathinones, designer benzodiazepines, and other drugs.",
"affiliations": "Department of Forensic Chemistry and Toxicology of the State General Laboratory of Ministry of Health, Nicosia 1451, Cyprus. Electronic address: kliveri@sgl.moh.gov.cy.;Department of Forensic Chemistry and Toxicology of the State General Laboratory of Ministry of Health, Nicosia 1451, Cyprus.;Department of Forensic Chemistry and Toxicology of the State General Laboratory of Ministry of Health, Nicosia 1451, Cyprus.;Department of Forensic Chemistry and Toxicology of the State General Laboratory of Ministry of Health, Nicosia 1451, Cyprus.",
"authors": "Liveri|Katerina|K|;Constantinou|Maria A|MA|;Afxentiou|Maria|M|;Kanari|Popi|P|",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D052117:Benzodioxoles; D008744:Methylamines; D010422:Pentanones; D011759:Pyrrolidines; C572410:pentedrone; C554666:3,4-methylenedioxypyrovalerone",
"country": "Ireland",
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"issn_linking": "0379-0738",
"issue": "265()",
"journal": "Forensic science international",
"keywords": "Bath salts; Designer benzodiazepines; Gas chromatography-mass spectrometry; Multidrug intoxication; Postmortem",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D052117:Benzodioxoles; D003535:Cyprus; D017809:Fatal Outcome; D053593:Forensic Toxicology; D006801:Humans; D008297:Male; D008744:Methylamines; D010422:Pentanones; D011041:Poisoning; D011759:Pyrrolidines",
"nlm_unique_id": "7902034",
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"pages": "160-5",
"pmc": null,
"pmid": "26930452",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A fatal intoxication related to MDPV and pentedrone combined with antipsychotic and antidepressant substances in Cyprus.",
"title_normalized": "a fatal intoxication related to mdpv and pentedrone combined with antipsychotic and antidepressant substances in cyprus"
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"abstract": "BACKGROUND\nSome acute myeloid leukemia (AML) patients present with features mimicking the classical hypergranular subtype of acute promyelocytic leukemia (APL) but without the typical promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement. Herein, we report an AML patient resembling APL but with nucleoporin 98/retinoid acid receptor gamma gene (NUP98/RARG) fusion transcript and Runt-related transcription factor 1 (RUNX1) mutation.\nAn 18-year-old male presented at the hospital with a diagnosis of AML.\nThe patient was diagnosed with bone marrow examination. Bone marrow smear displayed 90.5% promyelocytes. Fluorescence in situ hybridization analysis failed to detect the PML/RARα fusion transcript or RARα amplification. While real-time polymerase chain reaction showed positivity for the NUP98/RARG fusion transcript. G-banding karyotype analysis showed a normal karyotype.\n\n\nMETHODS\nThe patient showed resistance to arsenic trioxide and standard 3 + 7 chemotherapy, but eventually achieved complete remission through the Homoharringtonine, Cytarabine, and Aclarubicin chemotherapy.\n\n\nRESULTS\nThese measures resulted in a rapid response and disease control.\n\n\nCONCLUSIONS\nAcute myeloid leukemia with the NUP98/RARG fusion gene and the RUNX1 mutation may be a special subtype of AML and may benefit from the alkaloid-based regimen.",
"affiliations": "Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun.;Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun.;Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun.;Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun.;Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun.;Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun.;Peking High Trust Diagnostics, Co., Ltd., Peking, China.;Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun.",
"authors": "Wei|Wei|W|;Liu|Qiuju|Q|;Song|Fei|F|;Cao|He|H|;Liu|Mengmeng|M|;Jiang|Yan|Y|;Li|Yanchun|Y|;Gao|Sujun|S|",
"chemical_list": "D050676:Core Binding Factor Alpha 2 Subunit; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; C493728:RUNX1 protein, human; D018168:Receptors, Retinoic Acid; C082926:retinoic acid receptor gamma",
"country": "United States",
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"doi": "10.1097/MD.0000000000022488",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-20-01209\n10.1097/MD.0000000000022488\n22488\n4800\nResearch Article\nClinical Case Report\nAlkaloid-based regimen is beneficial for acute myeloid leukemia resembling acute promyelocytic leukemia with NUP98/RARG fusion and RUNX1 mutation\nA case reportWei Wei MDa Liu Qiuju MSa Song Fei MDa Cao He MDa Liu Mengmeng MDa Jiang Yan MDa Li Yanchun MSb Gao Sujun MSa∗ Saranathan. Maya a Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun\nb Peking High Trust Diagnostics, Co., Ltd., Peking, China.\n∗ Correspondence: Sujun Gao, Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun 130021, China (e-mail: sjgao@jlu.edu.cn).\n02 10 2020 \n02 10 2020 \n99 40 e2248817 2 2020 19 7 2020 1 9 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nSome acute myeloid leukemia (AML) patients present with features mimicking the classical hypergranular subtype of acute promyelocytic leukemia (APL) but without the typical promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement. Herein, we report an AML patient resembling APL but with nucleoporin 98/retinoid acid receptor gamma gene (NUP98/RARG) fusion transcript and Runt-related transcription factor 1 (RUNX1) mutation.\n\nPatient concerns:\nAn 18-year-old male presented at the hospital with a diagnosis of AML.\n\nDiagnoses:\nThe patient was diagnosed with bone marrow examination. Bone marrow smear displayed 90.5% promyelocytes. Fluorescence in situ hybridization analysis failed to detect the PML/RARα fusion transcript or RARα amplification. While real-time polymerase chain reaction showed positivity for the NUP98/RARG fusion transcript. G-banding karyotype analysis showed a normal karyotype.\n\nInterventions:\nThe patient showed resistance to arsenic trioxide and standard 3 + 7 chemotherapy, but eventually achieved complete remission through the Homoharringtonine, Cytarabine, and Aclarubicin chemotherapy.\n\nOutcomes:\nThese measures resulted in a rapid response and disease control.\n\nLessons:\nAcute myeloid leukemia with the NUP98/RARG fusion gene and the RUNX1 mutation may be a special subtype of AML and may benefit from the alkaloid-based regimen.\n\nKeywords\nacute myeloid leukemiachemotherapyNUP98/RARG fusionresembling acute promyelocytic leukemiaDepartment of Science and Technology of Jilin ProvinceProject No 20180101132JC.Sujun GaoOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAcute promyelocytic leukemia (APL) is characterized by the presence of the chromosomal translocation t(15;17)(q24;q21) and/or the resulting PML/RARα chimeric protein.[1] However, approximately 1.3% of acute myeloid leukemia (AML) patients present with features mimicking the classical hypergranular subtype of APL but without the typical PML/RARα rearrangement.[23] Among them, a subtype of retinoic acid receptors (RARs), RARG, has been reported to be fused with at least 3 alternative partner genes, including CPSF6, PML, and NUP98.\n[456] Herein, we report a nucleoporin 98-retinoic acid receptor gamma (NUP98/RARG) gene fusion with a Runt (Runt domain)-related transcription factor 1 (RUNX1) mutation in AML mimicking APL; it was sensitive to aalkaloid-based combination but insensitive to arsenic trioxide (ATO) or anthracycline.\n\n2 Case Report\nAn 18-year-old male was admitted to our department with 2-week fatigue and fever. Laboratory workup revealed a leukocyte count of 5310/μL, a hemoglobin level of 10.1 g/dL, and a platelet count of 43,000/μL with 68% atypical promyelocytes. Bone marrow smear displayed 90.5% promyelocytes with morphologic features resembling the classical hypergranular subtype of acute promyelocytic leukemia (Fig. 1A). These cells were strongly positive for peroxidase upon staining (Fig. 1B). The immunophenotype of the blasts was positive for CD117, CD13, CD33, CD9, CD64, CD123, and cMPO but negative for HLA-DR, CD34, CD38, CD11b, and B-cell and T-cell markers. Based on the typical morphology and immunophenotype, the suspected diagnosis was APL, the patient was submitted to intravenous arsenic trioxide (0.15 mg/kg/d) combined with oral all-trans retinoic acid (ATRA)(25 mg/m2/d) on the first day of his admission. Five days later, the patient complained of weight gain and headache with an increasing white blood cell count, which indicated he might develop retinoic acid differentiation syndrome, and the ATRA treatment was discontinued. However, after collecting the last genetic results 13 days later, we excluded the diagnosis of typical APL. G-banding karyotype analysis showed negativity for the t(15;17) (q24;q21) translocation but a normal karyotype (Fig. 1D and E). Fluorescence in situ hybridization analysis was performed using a PML-RARα dual-color dual-fusion probe (Fig. 1F) according to the manufacturer's protocols, but it failed to detect the PML/RARα fusion transcript or RARα amplification. Multiple nested reverse transcription polymerase chain reactions (PCRs) were performed to detect 43 fusion transcripts, including PML/RARα, PLZF/RARα, NUMA1/RARα, STAT5b/RARα, PAKARIA/RARα, NPM1/RARα, and FIPIL1/RARα, which were negative. Targeted next-generation sequencing of the entire coding sequences of 110 known or putative mutational gene targets in hematologic malignancies identified a 31.69% mutation ratio of the RUNX1: c.319C > A(p.R107S) gene (Fig. 1C). Meanwhile, repeated bone marrow smears and flow cytometry (FCM) analyses still showed the existence of 86% abnormal promyelocytes.\n\nFigure 1 Morphology, karyotyping, FISH, RT-PCR, NGS, and molecular analysis of NUP98/RARG fusion. (A) ×400, May Grunwald-Giemsa stain and (B) POX of a bone marrow smear showing promyelocytes with a hypergranulated cytoplasm; several nuclei are invaginated. C, Next-generation sequencing showed the NM_001754(RUNX1):c.319C > A (p.R107S) mutation. D, A G-banded karyotype of the aberrant clone showing 46, XY. E, Interphase FISH using the PML/RARα dual-color, dual-fusion translocation probe indicated the absence of the normal PML/RARα. C karyotype. F, Schematic representation of the NUP98/RARG fusion protein. It had preserved the DNA binding domain (DBD) and ligand binding domain (LBD). The arrows indicate the breakpoint and fusion sites of the NUP98/RARG gene. G, Electrophoresis of the RT-PCR products from this patient showed NUP98-RARG fusion transcripts. H, Diagram of NUP98-RARG fusion gene. FISH = fluorescence in situ hybridization, NGS = next-generation sequencing, RT-PCR = real-time polymerase chain reaction.\n\nTherefore, we stopped the use of arsenic trioxide and switched to a standard 3 + 7 chemotherapy schedule (60 mg/m2 doxorubicin, d1-3; 100 mg/m2 cytarabine, d1-7 continuously). During this course, he showed fibrinolysis with a mild low serum fibrinogen level. The evaluation of bone marrow morphology showed there were still 44.5% and 81.5% abnormal promyelocytes (Fig. 2A) respectively, on the 14th day and the 21st day after the finish of the chemotherapy. Then, we changed the chemotherapy regimen to Homoharringtonine, Cytarabine and Aclarubicin (HAA) (2 mg/m2 homoharringtonine, d1-7; 14 mg/m2 aclarubicin, d1-7, combined with 100 mg/m2 cytarabine, d1-7 continuously). Meanwhile, another real-time polymerase chain reaction (RT-PCR) showed positivity for the NUP98/RARG fusion transcript (Fig. 1G). The NUP98/RARG mRNA was reverse transcribed into cDNA using random primers, and PCR was performed using the following primers: forward: 5’-GGG CTT GGT GCA GGA TTT GG-3’, and reverse: 5’-TGG GTC CGG TTC AGG GTC AGC-3’ (NUP98: NCBI reference sequence: NM_016320.4; RARG: NCBI reference sequence: NM_001042728.2). These primers were also used to amplify the fusion transcript breakpoints. On the 14th day after the finish of chemotherapy with HAA, morphology showed 12.5% abnormal promyelocytes with differentiation signs (Fig. 2B), and FCM showed 3.97% abnormal myeloid blasts positive for CD117, CD33, CD34, and HLA-DR. At last, both morphology (Fig. 2C) and FCM were negative and CBC had recovered 1 week later. He achieved complete remission with a decreased level of the NUP98/RARG fusion gene (0.1%). Then, the patient received another cycle of HAA followed by 1 cycle of high-dose cytarabine (2 g/m2, q12 h, d1, d3, and d5) as consolidation therapy. During this period, the patient maintained complete reemission (CR) with morphology (Fig. 2D) and MRD negativity with flow cytometry (Fig. 2E). However, because of personal problems, the patient refused to receive any further treatment. Three months later he relapsed with the same morphologic, immunophenotypic, and molecular features displayed at diagnosis but with 8 new point mutations in WT1. He still refused to receive any therapy for his leukemia. Then, he developed an anal abscess with coagulopathy. Ten days later, he died of a severe infection.\n\nFigure 2 CR and MRD after HAA regimen chemotherapy. A–C, Morphology change before chemotherapy and 13 days and 24 days after the chemotherapy. D, E, MRD change during treatment. After CR was induced by HAA, the patient had stayed complete remission and negative for MRD for more than 3 months. CR = complete reemission, HAA = Homoharringtonine, Cytarabine and Aclarubicin.\n\nThe patient provided written informed consent for the publication of these case details, and the consent procedure was approved by the ethic committee of the first hospital of Jilin University.\n\n3 Discussion\nThis was the third human AML case harboring the NUP98/RARG rearrangement to date. It was supposed that the NUP98 5-region encoding the glycine–leucine–phenylalanine–glycine-repeat and the GLE2p-binding Sequence-like motifs were fused to the 3-region of RARG, which included the DNA- and ligand-binding domains of the gene (Fig. 1H). Similar to other RARG fusion gene with AML, this kind of acute leukemia showed the clinical feature with coagulopathy, and the morphology, immunophenotyping were mimicking with APL. But the treatment result was totally different. In this case, our patient showed resistance to the anthracycline-containing regimen, different from the first patient who reached CR with a standard 7 + 3 chemotherapy approach.[6] And the sensitivity to ATRA was controversial. The first patient relapsed with the same features and the researchers did in vitro studies on the relapsed NUP98/RARG fusion and reported that it confers resistance to ATRA treatment.[7] However, another in vivo experiment in murine models showed that cells transformed by the NUP98/RARG fusion were extremely sensitive to ATRA treatment.[89] In our case, similar to the more recently reported case with the PML/RARG and NUP98/RARG fusion gene, the sensitivity to ATRA treatment was not established due to the early discontinuation of ATRA therapy.[5] Among the 7 patients who were reported with the RARG rearrangement,[31011] none showed clear sensitivity to ATRA. But we can confirm the resistance to ATO in this NUP98/RARG fusion gene-positive AML patient, similar to other reports.[34]\n\n\nRUNX1 mutations occur in 13.7% of normal chromosome karyotype AML patients but rarely in APL patients.[13] In AML patients, the RUNX1 mutation is correlated with poor clinical outcomes, even when treatment with intensive therapeutic strategies is performed.[12] Our patient showed resistance to the standard 3 + 7 induction chemotherapy but benefitted from a homoharringtonine (HHT)-based combination. HHT is a natural alkaloid isolated from various Cephalotaxus species. It can bind to and increase the level of myosin-9 in myeloid leukemia to induce the apoptosis of leukemia cells.[13] A recent study showed that HHT treatment alone caused potent inhibition of AML cell growth/survival in vitro and substantial suppression of AML progression in vivo, and such inhibitory effects are likely attributed to HHT-induced cell cycle blockage and apoptosis, as well as enhanced myeloid differentiation.[14] AHHT-based combination regimen was shown to be highly effective in some subtypes (FLT3 and t(8;21)) of AML patients.[1516] Our patient had maintained CR for a half year but relapsed due to early treatment discontinuation.\n\nHow to treat AML patients with NUP98/RARG remains uncertain, but it is challenging because of coagulation abnormality and fatal bleeding risk, which demand a strong supply of blood products to avoid early death. The patient in this report experienced coagulopathy after undergoing chemotherapy with daunorubicin and cytarabine (DA), which suggests some similar characteristics with typical APL. However, the detailed biological function of NUP98/RARG needs to be investigated in the future. In summary, we reported 1 case of acute myeloid leukemia with the NUP98/RARG fusion gene and the RUNX1 mutation that resembled acute promyelocytic leukemia in regards to its morphologic and immunologic features. Herein, we confirm that this is a new subtype of acute myeloid leukemia that is insensitive to ATO and anthracycline, but can benefit from the alkaloid-based regimen.\n\nAcknowledgments\nThis work was supported by the Science and Technology Department of Jilin province, Project No 20180101132JC.\n\nAuthor contributions\nWei Wei, Qiuju Liu, and Sujun Gao contributed to the design of the article. Wei Wei, Qiuju Liu, Fei Song, He Cao, and Mengmeng Liu contributed to the analysis of data and wrote the manuscript. Yan Jiang, and Yanchun Li contributed to the collection of data. Sujun Gao was the research advisor.\n\nAbbreviations: AML = acute myeloid leukemia, APL = acute promyelocytic leukemia, ATO = arsenic trioxide, ATRA = all-trans retinoic acid, CR = complete reemission, DA = daunorubicin and cytarabine, FCM = flow cytometry, HAA = Homoharringtonine, Cytarabine and Aclarubicin, HHT = homoharringtonine, PCR = polymerase chain reaction, PML/RARα = promyelocytic leukemia/retinoic acid receptor α, RARG = retinoid acid receptor gamma gene, RUNX1 = Runt-related transcription factor 1, NUP98 = nucleoporin 98.\n\nHow to cite this article: Wei W, Liu Q, MS, Song F, Cao H, Liu M, Jiang Y, Li Y, Gao S. Alkaloid-based regimen is beneficial for acute myeloid leukemia resembling acute promyelocytic leukemia with NUP98/RARG fusion and RUNX1 mutation: A case report. Medicine. 2020;99:40(e22488).\n\nWW and QL contributed equally to this work.\n\nThe authors have no conflicts of interest to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Fasan A Haferlach C Perglerovà K \nMolecular landscape of acute promyelocytic leukemia at diagnosis and relapse\n. Haematologica \n2017 ;102 :e223 –4\n.\n[2] Grimwade D Biondi A Mozziconacci MJ \nCharacterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party\n. Blood \n2000 ;96 :1297 –308\n.10942371 \n[3] Wen L Xu Y Yao L \nClinical and molecular features of acute promyelocytic leukemia with variant retinoid acid receptor fusions\n. Haematologica \n2019 ;104 :e195 –9\n.30237272 \n[4] Qin YZ Huang XJ Zhu HH \nIdentification of a novel CPSF6-RARG fusion transcript in acute myeloid leukemia resembling acute promyelocytic leukemia\n. Leukemia \n2018 ;32 :2285 –7\n.29568099 \n[5] Ha JS Do YR Ki CS \nIdentification of a novel PML-RARG fusion in acute promyelocytic leukemia\n. Leukemia \n2017 ;31 :1992 –5\n.28555082 \n[6] Such E Cervera J Valencia A \nA novel NUP98/RARG gene fusion in acute myeloid leukemia resembling acute promyelocytic leukemia\n. Blood \n2011 ;117 :242 –5\n.20935257 \n[7] Such E Cordón L Sempere A \nIn vitro all-trans retinoic acid sensitivity of acute myeloid leukemia blasts with NUP98/RARG fusion gene\n. Ann Hematol \n2014 ;93 :1931 –3\n.24728721 \n[8] Marinelli A Bossi D Pelicci PG \nRedundant function of retinoic acid receptor isoforms in leukemogenesis unravels a prominent function of genome topology and architecture in the selection of mutagenic events in cancer\n. Leukemia \n2009 ;23 :417 –9\n.18685608 \n[9] Qiu JJ Zeisig BB Li S \nCritical role of retinoid/rexinoid signaling in mediating transformation and therapeutic response of NUP98-RARG leukemia\n. Leukemia \n2015 ;29 :1153 –62\n.25510432 \n[10] Miller CA Tricarico C Skidmore ZL \nA case of acute myeloid leukemia with promyelocytic features characterized by expression of a novel RARG-CPSF6 fusion\n. Blood Adv \n2018 ;2 :1295 –9\n.29891591 \n[11] Luo H Zhang S Li K \nA novel entity of acute myeloid leukaemia with recurrent RARG-rearrangement resembling acute promyelocytic leukaemia\n. Leuk Res \n2019 ;77 :14 –6\n.30612054 \n[12] Khan M Cortes J Kadia T \nClinical outcomes and co-occurring mutations in patients with RUNX1-mutated acute myeloid leukemia\n. Int J Mol Sci \n2017 ;18 : 1618 .\n[13] Zhang T Shen S Zhu Z \nHomoharringtonine binds to and increases myosin-9 in myeloid leukaemia\n. Br J Pharmacol \n2016 ;173 :212 –21\n.26448459 \n[14] Li C Dong L Su R \nHomoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC\n. Haematologica \n2020 ;105 :148 –60\n.30975912 \n[15] Lam SS Ho ES He BL \nHomoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia\n. Sci Transl Med \n2016 ;8 : 359ra129 .\n[16] Jin J Wang JX Chen FF \nHomoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial\n. Lancet Oncol \n2013 ;14 :599 –608\n.23664707\n\n",
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"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D050676:Core Binding Factor Alpha 2 Subunit; D003937:Diagnosis, Differential; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D028861:Nuclear Pore Complex Proteins; D018168:Receptors, Retinoic Acid",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Alkaloid-based regimen is beneficial for acute myeloid leukemia resembling acute promyelocytic leukemia with NUP98/RARG fusion and RUNX1 mutation: A case report.",
"title_normalized": "alkaloid based regimen is beneficial for acute myeloid leukemia resembling acute promyelocytic leukemia with nup98 rarg fusion and runx1 mutation a case report"
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"abstract": "Whole-genome sequencing was used to examine a persistent Enterococcus faecium bacteremia that acquired heteroresistance to three antibiotics in response to prolonged multidrug therapy. A comparison of the complete genomes before and after each change revealed the emergence of known resistance determinants for vancomycin and linezolid and suggested that a novel mutation in fabF, encoding a fatty acid synthase, was responsible for daptomycin nonsusceptibility. Plasmid recombination contributed to the progressive loss of vancomycin resistance after withdrawal of the drug.",
"affiliations": "Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA harm.vanbakel@mssm.edu.",
"authors": "Chacko|Kieran I|KI|0000-0002-1024-4063;Sullivan|Mitchell J|MJ|;Beckford|Colleen|C|;Altman|Deena R|DR|;Ciferri|Brianne|B|;Pak|Theodore R|TR|0000-0002-1676-2523;Sebra|Robert|R|;Kasarskis|Andrew|A|;Hamula|Camille L|CL|;van Bakel|Harm|H|0000-0002-1376-6916",
"chemical_list": "D014640:Vancomycin; D000069349:Linezolid; D017576:Daptomycin",
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"doi": "10.1128/AAC.02007-17",
"fulltext": "\n==== Front\nAntimicrob Agents ChemotherAntimicrob. Agents ChemotheraacaacAACAntimicrobial Agents and Chemotherapy0066-48041098-6596American Society for Microbiology 1752 N St., N.W., Washington, DC 2933938702007-1710.1128/AAC.02007-17Mechanisms of ResistanceGenetic Basis of Emerging Vancomycin, Linezolid, and Daptomycin Heteroresistance in a Case of Persistent Enterococcus faecium Bacteremia Emerging Heteroresistance during E. faecium BacteremiaChacko et al.https://orcid.org/0000-0002-1024-4063Chacko Kieran I. aSullivan Mitchell J. aBeckford Colleen aAltman Deena R. bCiferri Brianne ahttps://orcid.org/0000-0002-1676-2523Pak Theodore R. aSebra Robert aKasarskis Andrew aHamula Camille L. chttps://orcid.org/0000-0002-1376-6916van Bakel Harm aa Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USAb Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USAc Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USAAddress correspondence to Harm van Bakel, harm.vanbakel@mssm.edu.Citation Chacko KI, Sullivan MJ, Beckford C, Altman DR, Ciferri B, Pak TR, Sebra R, Kasarskis A, Hamula CL, van Bakel H. 2018. Genetic basis of emerging vancomycin, linezolid, and daptomycin heteroresistance in a case of persistent Enterococcus faecium bacteremia. Antimicrob Agents Chemother 62:e02007-17. https://doi.org/10.1128/AAC.02007-17.\n\n16 1 2018 27 3 2018 4 2018 27 3 2018 62 4 e02007-174 10 2017 31 10 2017 20 12 2017 Copyright © 2018 Chacko et al.2018Chacko et al.This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.ABSTRACT\nWhole-genome sequencing was used to examine a persistent Enterococcus faecium bacteremia that acquired heteroresistance to three antibiotics in response to prolonged multidrug therapy. A comparison of the complete genomes before and after each change revealed the emergence of known resistance determinants for vancomycin and linezolid and suggested that a novel mutation in fabF, encoding a fatty acid synthase, was responsible for daptomycin nonsusceptibility. Plasmid recombination contributed to the progressive loss of vancomycin resistance after withdrawal of the drug.\n\nKEYWORDS\nE. faeciumVREdaptomycinfabFheteroresistancelinezolidvancomycinHHS | National Institutes of Health (NIH)https://doi.org/10.13039/100000002F30 AI122673Pak Theodore HHS | National Institutes of Health (NIH)https://doi.org/10.13039/100000002T32 AI07647Altman Deena HHS | National Institutes of Health (NIH)https://doi.org/10.13039/100000002KL2 TR001435Altman Deena HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)https://doi.org/10.13039/100000060R01 AI119145van Bakel Harm New York City Department of Health and Mental Hygiene (DOHMH)https://doi.org/10.13039/100004851ECRIPAltman Deena cover-dateApril 2018\n==== Body\nTEXT\nMultidrug-resistant (MDR) Enterococcus faecium is a common cause of nosocomial infections (1). Resistance to ampicillin or vancomycin occurs in approximately 90% and 80% of nosocomial E. faecium in the United States, respectively (1). Linezolid and daptomycin are currently used as first-line treatment options for vancomycin-resistant E. faecium (VREfm) (2, 3). Although resistance to both agents remains rare among enterococci (<1% for linezolid and <2% for daptomycin) (4, 5), the emergence of resistance during treatment with each drug has been documented in multiple cases (5–7) and can pose significant challenges for infection management. A complication in assessing emerging resistance during infection is that bacterial isolates sometimes show a range of susceptibilities to a particular antibiotic due to genetic, epigenetic, or nongenetic heterogeneity within the isolates; a phenomenon known as “heteroresistance” (8, 9). Heteroresistance can cause significant diagnostic and therapeutic complications, and it has been associated with persistent infections and increased mortality rates (10–13). Nevertheless, the full extent of heteroresistance and its broader clinical relevance remain unclear, and only a few cases have been reported in E. faecium (14–16). In this report, we used complete genome sequencing to characterize the genetic changes underlying emerging vancomycin, linezolid, and daptomycin heteroresistance in a case of persistent E. faecium infection. Note that we will refer to daptomycin resistance throughout for consistency, rather than the accepted term “nonsusceptibility.”\n\nIn 2015, a 65-year-old male was admitted to Mount Sinai Hospital (MSH) who developed an E. faecium bacteremia that spanned 3 months and two hospital stays (Fig. 1). E. faecium was detected in 21 of the 48 blood samples collected from the patient, with additional sporadic detections of Candida glabrata, Stenotrophomonas maltophilia, or Enterobacter cloacae. Automated broth microdilution testing (VITEK2) of single colonies from each isolate culture showed that E. faecium acquired resistance to vancomycin (day 27), daptomycin (day 50), and linezolid (day 86) following treatment with each agent (Fig. 1). After the cessation of vancomycin therapy, vancomycin susceptibility was restored on day 90.\n\nFIG 1 Timeline of antimicrobial treatments and susceptibility changes. Hospital stays and blood culture test results (top) are shown together with antibiotic and antifungal treatment regimes and E. faecium susceptibility profiles (bottom). Positive blood cultures are grouped by pathogen, and the E. faecium isolates selected for sequencing are highlighted in blue and labeled A to F. Automated broth microdilution test results (VITEK2) are shown as colored circles containing MIC values (μg/ml), where available. Red circle outlines indicate instances of acquired or lost resistance. See legend for further details.\n\nTo characterize the susceptibility changes in more detail, we collected six isolates from the original blood cultures before and after each change (Fig. 1, labeled A to F). There were no differences in E. faecium colony morphology within or between isolates. For each isolate, we tested four isogenic strains derived from single colonies, in duplicates, to confirm vancomycin, linezolid, and daptomycin susceptibilities (Table 1). The vancomycin Etest results were consistent with the VITEK2 reports for all isolates except C and E, where susceptibility was restored in two of four strains tested. The mixed susceptibility phenotypes suggested the presence of a vancomycin heteroresistant population; therefore, we performed additional Etests on the original blood isolates, which revealed sparsely distributed isolated colonies within the zones of inhibition for isolates C, E, and F. Isolate A was uniformly susceptible, while B and D were uniformly resistant. The lack of heteroresistance in B and D may be a result of selection pressure due to vancomycin treatment (Fig. 1; see also supplemental material) prior to or at the time of their collection. The linezolid Etests confirmed resistance for isolate F, albeit at lower MICs, and further identified resistance in isolates D and E, for which results had not been reported by the automated broth microdilution. Notably, there was significant variation in MICs among the resistant strains tested for isolates D to F, ranging from 24 to 96 μg/ml. Daptomycin Sensititre assays also showed variability within and between samples. Isolate C tested consistently at the nonsusceptibility threshold MIC of 4 μg/ml, compared to 8 μg/ml by VITEK2, whereas isolates D to F yielded mixed results with MICs ranging from 4 to ≥8 μg/ml. Taken together, our results are consistent with the emergence of an E. faecium population with heteroresistance to vancomycin, linezolid, and daptomycin.\n\nTABLE 1 Vancomycin, linezolid, and daptomycin susceptibilities of patient isolate clones\n\nAgent\tIsolate\tDay\tSusceptibility and MIC (μg/ml) from:a\t\nClinical test (VITEK2)b\tConfirmation test\t\n1c\t2\t3\t4\t\nVancomycind\tA\t9\tS (<0.5)\tS (<1)\tS (<1)\tS (<1)\tS (<1)\t\nB\t27\tR (≥32)\tR (≥256)\tR (≥256)\tR (≥256)\tR (≥256)\t\nC\t75\tR (≥32)\tR (≥256)\tS (<1)\tS (<1)\tR (≥256)\t\nD\t79\tR (≥32)\tR (≥256)\tR (≥256)\tR (≥256)\tR (≥256)\t\nE\t83\tR (≥32)\tS (<1)\tR (≥256)\tS (<1)\tR (≥256)\t\nF\t90\tS (<0.5)\tS (<1)\tS (<1)\tS (<1)\tS (<1)\t\nLinezolidd\tA\t9\tS (2)\tS (2)\tS (2)\tS (2)\tS (2)\t\nB\t27\tS (2)\tS (2)\tS (2)\tS (2)\tS (2)\t\nC\t75\tS (2)\tS (2)\tS (2)\tS (2)\tS (2)\t\nD\t79\t—\tR (48)\tR (24)\tR (24)\tR (32)\t\nE\t83\t—\tR (96)\tR (48)\tR (64)\tR (64)\t\nF\t90\tR (≥256)\tR (64)\tR (64)\tR (24)\tR (96)\t\nDaptomycine\tA\t9\tS (3)\tS (2)\tS (2)\tS (2)\tS (2)\t\nB\t27\tS (3)\tS (2)\tS (2)\tS (2)\tS (2)\t\nC\t75\t— (8)\tS (4)\tS (4)\tS (4)\tS (4)\t\nD\t79\tS (4)\tR (≥8)\tR (≥8)\tS (4)\tR (≥8)\t\nE\t83\t— (8)\tR (≥8)\tR (≥8)\tR (≥8)\tS (4)\t\nF\t90\t— (8)\tR (≥8)\tR (≥8)\tR (≥8)\tS (4)\t\na R, resistant; S, susceptible; —, not reported.\n\nb Maximum tested MIC for vancomycin by automated broth microdilution was 32 μg/ml.\n\nc Strain set selected for complete genome sequencing.\n\nd MICs determined by Etest assays performed in duplicates.\n\ne MICs determined by Sensititre assays performed in duplicates.\n\nWe next performed whole-genome sequencing for strain 1 of each of the six isolates (Table 1) and an additional vancomycin resistant strain from the heteroresistant E isolate (E-VR). Complete genomes were obtained for each strain using PacBio single molecule real-time long-read sequencing and Illumina short-read sequencing. Multilocus sequence typing indicated that all strains were sequence type 736 (ST736). This clone is associated with reduced susceptibility and nonsusceptibility to daptomycin (MIC = 3 to 4 μg/ml) due to the presence of liaS Thr120→Ala and liaR Trp73→Cys substitutions (17). The same substitutions were identified in all sequenced strains (Fig. 2) and presumably explain the low-basal-level daptomycin tolerance exhibited by strains A to C (Table 1) (18, 19). The genomes for each strain were nearly identical, with a maximum of seven single nucleotide variants (SNVs) separating any two genomes (see Table S1). Thus, a single clone of E. faecium was responsible for the infection, and the resistance emerged as a result of genetic changes within this clone. A further comparison of our strain genomes to 27 ST736 E. faecium genomes deposited in GenBank (see Fig. S1) yielded a maximum distance of 88 core genome SNVs between strain A and a 2012 VREfm isolate from Washington, USA. Notably, most ST736 genomes were derived from clinical isolates collected in the New York metropolitan (NYC) area (hospital A, B, and MSH). The small genetic distance between the ST736 genomes relative to the reported mutation rate for VREfm strains of 9.4E−6 substitutions per nucleotide per year (20) suggests that the infection in our patient was part of a larger clonal spread of E. faecium ST736 in the NYC region in recent years.\n\nFIG 2 Resistance determinants and mutations identified in patient strains. Known antibiotic resistance determinants (left) are shown together with all other mutations (right) identified between strains. Connecting lines indicate the location of each determinant or mutation in the strain A genome (center). Locations of prophage insertions and 23S rRNA loci are indicated. Mutations matching the daptomycin susceptibility patterns are boxed in red and highlighted in bold. See legend for further details. CIP, ciprofloxacin; LEVO, levofloxacin; DOX, doxycycline; TET, tetracycline; DAP, daptomycin; AMP, ampicillin; PEN, penicillin; CLI, clindamycin; ERY, erythromycin; LZD, linezolid; GEN, gentamicin; VAN, vancomycin.\n\nWe further examined the genomes for known antibiotic resistance determinants (Fig. 2, left) that matched the susceptibility changes. Each strain contained a 2.86-Mb chromosome and three plasmids of approximately 200 kb (p1), 10 kb (p3), and 4 kb (p4) in size (Table S1 and Fig. S2). An additional 41-kb plasmid (p2) carrying the vanA operon in a 11,654-bp BC1 Tn1546-type transposon (21, 22) was identified in vancomycin-resistant strains only (Fig. 2; see also Table S1 and Fig. S2), explaining the observed susceptibility profiles for this antibiotic. One strain, E-VS, contained an 80-kb plasmid (p5) that was not found in any other strain. The emerging linezolid resistance was accounted for by a G2,576U substitution (23) present in two or three of the six copies of the 23S rRNA in strains D, E-VS, E-VR, and F (Fig. 2). We did not find other determinants associated with linezolid resistance, such as other mutations in the 23S rRNA gene (23–25) or genes encoding ribosomal proteins L3, L4, and L22 (23, 26) or the acquisition of cfr (27, 28) or optrA (29). Consistent with previous observations (24), strains with higher linezolid MICs had more G2,576U mutant 23S rRNA gene copies, indicating that these mutations were responsible for the observed heteroresistance phenotype. Interestingly, we observed consistently higher MICs per 23S rRNA mutant copy than a previous gene dosage study, which reported a maximum MIC of 32 μg/ml for 2 to 3 mutant 23S rRNA copies (24) versus 48 to 96 μg/ml in our strains. This difference may be due to the presence of a 1,417-bp ISEnfa3-like mobile element within domain I of 23S rRNA gene copy III in all four resistant strains (Fig. 2), as disruption of one of the wild-type rRNA genes likely increased the effective dosage of mutant 23S rRNAs.\n\nDaptomycin resistance (≥8 μg/ml MIC) arose concurrently with linezolid resistance in strains D to F. This increase in the MIC could not be explained by known daptomycin resistance determinants (18, 19, 30), indicating that a novel resistance mutation was present in these strains. It is unlikely that the mutations in 23S rRNA genes affected resistance, as daptomycin has been shown to remain effective in linezolid-resistant Enterococci and Staphylococci harboring the G2,576U substitution (31). Moreover, daptomycin MICs were not affected by differences in the numbers of mutant rRNA copies in our strains. Longitudinal genome comparisons between all strains identified 37 additional mutations (Fig. 2; Table S2). Only two other mutations occurred in a pattern consistent with the increase in daptomycin MIC: a nonsynonymous G962A mutation in fabF and an insertion of an IS256-like element in plasmid 1. The IS256-like element was inserted into a noncoding region between two carbohydrate metabolism genes encoding a putative fructokinase and a subunit of a sugar phosphotransferase system. The G962A mutation in fabF resulted in a Gly321→Asp change in the C-terminal domain of the β-ketoacyl-acyl carrier protein synthase it encodes. FabF is involved in membrane fatty acid metabolism (32, 33), consistent with the mechanism of action of daptomycin as a lipopeptide that disrupts the bacterial membrane. Notably, while FabF was not previously associated with daptomycin resistance in enterococci, a Pro137→Leu mutation in its ortholog was implicated in daptomycin resistance in Staphylococcus aureus (34). Taken together, these data suggest that the fabF mutation was responsible for the increased daptomycin MIC, although further studies are needed to confirm these findings and determine the mechanistic basis for its role in resistance.\n\nVancomycin heteroresistance in blood isolate E emerged 12 days after vancomycin treatment was stopped and within 4 days of that in the uniformly resistant D isolate (Fig. 1), prompting us to further examine the mechanism behind the loss of resistance. A comparison of vancomycin-susceptible (E-VS) and -resistant (E-VR) strains obtained from the same patient isolate revealed a recombination event between the 41-kb plasmid containing the vanA resistance gene cluster (p2) and the larger 200-kb plasmid (p1) present in all strains (Fig. 3). This resulted in a new 80-kb plasmid (p5) in strain E-VS that consisted of a 14-kb fragment of p2 and a copy of a 69-kb segment of p1. Notably, E-VS also retained an intact copy of p1, suggesting that the recombination event occurred during or shortly after p1 replication. The p5 plasmid retained the rep17 replicon and ori from p2, whereas the excised 30-kb p2 fragment containing the vanA resistance operon was lost. Further sequence analysis identified homologous regions flanking the recombination sites in p1 and p2, consisting of a 1.3-kb insertion sequence (IS) IS256 on one end and a 49-bp sequence on the other end. The 49-bp conserved sequence in p1 was directly adjacent to the rep17 replicon. Thus, the p5 E-VS plasmid resulted from two separate homologous recombination events between p1 and p2 or from a combination of homologous recombination and IS256 transposition (35).\n\nFIG 3 Excision of the vanA operon by plasmid recombination. Schematic representing recombination events between the 41-kb and 200-kb plasmids. Recombination was driven by the presence of the IS256 insertion sequence and 49-nt sequence flanking each end of the conserved 69-kb and 14-kb regions of plasmids 1 and 2 from patient strain E-VR, respectively. The vanA operon was excised following recombination, resulting in loss of vancomycin resistance in strain E-VS.\n\nThe final vancomycin-susceptible strain from heteroresistant isolate F did not carry the 41-kb p2 plasmid or the p5 recombination product that we identified in E-VS. This suggests a continued loss of p2 elements after treatment ceased, as also evidenced by the smaller fraction of resistant colonies we observed in isolate F than in isolate E. The most likely explanation for this loss is that the presence of the vancomycin resistance plasmid reduces fitness. Indeed, a similar loss of vanA after withdrawal of vancomycin therapy has been described (14), and in vitro studies have shown that carriage of plasmid-mediated resistance incurs fitness costs (36). Nonetheless, a single dose of vancomycin on day 75 was sufficient to uniformly restore resistance in isolate D on day 79, demonstrating that the presence of even a small fraction of resistant bacteria enables rapid adaptation to treatment. Although we did not detect heteroresistance in the original A isolate, it is likely that low-level resistance was already present below the detectable limit. We consider horizontal gene transfer less plausible, especially considering that older ST736 isolates collected at Mount Sinai Hospital (37) all contained nearly identical 41-kb vanA resistance plasmids.\n\nThe present study demonstrates how E. faecium can evolve resistance to antibiotics of last resort through a combination of known and novel genetic mutations, which can ultimately result in treatment failure. Notably, heteroresistance emerged to three different antibiotics, underscoring its clinical relevance during persistent infections and suggesting that it may be more widespread than currently recognized. The clonal spread of ST736 in the NYC region is concerning, as its baseline reduced susceptibility to daptomycin may facilitate the selection of additional resistance variants and reduce the time to emergence of resistance during treatment. As such, the continued dissemination of ST736 and other clones carrying liaFSR mutations should be closely monitored. Notably, it has been shown that the addition of ampicillin can restore daptomycin bactericidal activity when liaFSR mutations are present (19, 38, 39), and combination therapy may help curtail further spread.\n\nThere are some limitations to our study. We did not sequence all colonies, and we may not have captured the full extent of genetic heterogeneity within the bacterial isolates. It is possible that mutations in other genes such as gdpD and cls (18, 19, 30) contributed to daptomycin heteroresistance. Our analyses were also limited to blood isolates, and a primary infection, such as the liver abscess the patient was originally diagnosed with, may have acted as a repository that was less accessible to antibiotics and from which bacteria continued to spread through the bloodstream. This does not detract from our main conclusions and would only serve to demonstrate the contribution of additional intrahost variability.\n\nIn summary, the ineffectiveness of commonly used agents, such as ampicillin and vancomycin, has increased our reliance on and use of last-line and off-label agents. The E. faecium genome has been shown to be highly adaptable, acquiring genes and chromosomal mutations that confer resistance to these last-line agents. We have demonstrated the applicability of complete-genome sequencing of longitudinal samples to comprehensively map all genomic changes responsible for acquired antibiotic resistance. With the increased reliance on newer agents in treating MDR E. faecium infections, there is a need to capture these events on a larger scale to better understand the underlying mechanisms responsible for acquired resistance of commonly used agents and their impact on treatment outcome.\n\nAccession number(s).\nGenome sequences have been deposited in GenBank under BioProject accession number PRJNA407447.\n\nSupplementary Material\nSupplemental material\n Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02007-17.\n\nACKNOWLEDGMENTS\nThis work was funded by NIH/NIAID grant no. R01AI119145. D.R.A. was supported by NIH/NIAID (T32 AI 7647), CTSA/NCATS (KL2 TR001435), and the New York State ECRIP program. T.R.P. was supported by NIH/NIAID F30 fellowship no. 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"fulltext_license": "CC BY",
"issn_linking": "0066-4804",
"issue": "62(4)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "E. faecium; VRE; daptomycin; fabF; heteroresistance; linezolid; vancomycin",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000368:Aged; D016470:Bacteremia; D017576:Daptomycin; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D016984:Enterococcus faecium; D006801:Humans; D000069349:Linezolid; D008297:Male; D008826:Microbial Sensitivity Tests; D014640:Vancomycin; D020713:Vancomycin Resistance",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29339387",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "22143525;19857129;23833178;23959318;22749725;22421879;23114757;21822974;22664970;12234875;24867964;21532521;28348834;27752789;17968832;20569266;27999068;23880167;19489710;6988423;11323048;22964255;24913170;22203597;28301471;25567227;5201887;14727222;17936593;16801432;11751820;23076243;25977397;22123698;21288849;26968883;24468866;18596139",
"title": "Genetic Basis of Emerging Vancomycin, Linezolid, and Daptomycin Heteroresistance in a Case of Persistent Enterococcus faecium Bacteremia.",
"title_normalized": "genetic basis of emerging vancomycin linezolid and daptomycin heteroresistance in a case of persistent enterococcus faecium bacteremia"
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"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-18-04173",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
"abstract": "Brentuximab vedotin (BV) shows a high overall response rate (ORR) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) after autologous transplant (ASCT). The aim of this multicenter study, conducted in nine Hematology Departments of Rete Ematologica Pugliese, was to retrospectively evaluate the efficacy and safety of BV as salvage therapy and as bridge regimen to ASCT or allogeneic transplant (alloSCT) in R/R HL patients. Seventy patients received BV. Forty-five patients (64%) were treated with BV as bridge to transplant:16 (23%) patients as bridge to ASCT and 29 (41%) as bridge to alloSCT. Twenty-five patients (36%), not eligible for transplant, received BV as salvage treatment. The ORR was 59% (CR 26%). The ORR in transplant naïve patients was 75% (CR 31%). In patients treated with BV as bridge to alloSCT, the ORR was 62% (CR 24%). In a multivariate analysis, the ORR was lower in refractory patients (p < 0.005). The 2y-OS was 70%. The median PFS was 17 months. Ten of the 16 (63%) naïve-transplant patients received ASCT, with 50% in CR before ASCT. In the 29 patients treated with BV as bridge to alloSCT, 28 (97%) proceeded to alloSCT with 25% in CR prior to alloSCT. The most common adverse events were peripheral neuropathy (50%), neutropenia (29%) and anemia (12%). These data suggest that BV is well tolerated and very effective in R/R HL, producing a substantial level of CR. BV may also be a key therapeutic agent to achieve good disease control before transplant, improving post- transplant outcomes, also in refractory and heavily pretreated patients, without significant overlapping toxicities with prior therapies.",
"affiliations": "Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase, Italy. sperimentazioniclinichetricase@gmail.com.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase, Italy.;Department of Hematology and Bone Marrow Transplant, University of Bari, Policlinico, Bari, Italy.;Department of Hematology and Bone Marrow Transplant, University of Bari, Policlinico, Bari, Italy.;Department of Hematology and Bone Marrow Transplant, University of Bari, Policlinico, Bari, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital G.Moscati, Taranto, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital G.Moscati, Taranto, Italy.;Department of Hematology, Hospital IRCCS Oncologico, Bari, Italy.;Department of Hematology, Hospital IRCCS Oncologico, Bari, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase, Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Department of Hematology, Hospital Perrino, Brindisi, Italy.;Department of Hematology, Hospital Perrino, Brindisi, Italy.;Department of Hematology, Hospital Vito Fazzi, Lecce, Italy.;Department of Hematology, ASL BT, Barletta, Italy.;Department of Hematology, Hospital University Riuniti, Foggia, Italy.",
"authors": "Pavone|Vincenzo|V|;Mele|Anna|A|;Carlino|Daniela|D|;Specchia|Giorgina|G|;Gaudio|Francesco|F|;Perrone|Tommasina|T|;Mazza|Patrizio|P|;Palazzo|Giulia|G|;Guarini|Attilio|A|;Loseto|Giacomo|G|;Eleonora|Prete|P|;Cascavilla|Nicola|N|;Scalzulli|Potito|P|;Melpignano|Angela|A|;Quintana|Giovanni|G|;Di Renzo|Nicola|N|;Tarantini|Giuseppe|G|;Capalbo|Silvana|S|",
"chemical_list": "D000970:Antineoplastic Agents; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D000079963:Brentuximab Vedotin",
"country": "Germany",
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"issue": "97(10)",
"journal": "Annals of hematology",
"keywords": "Autologous and allogeneic stem cell transplant; Brentuximab vedotin salvage treatment; Relapsed/refractory Hodgkin lymphoma",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064591:Allografts; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000079963:Brentuximab Vedotin; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004341:Drug Evaluation; D005260:Female; D006402:Hematologic Diseases; D006689:Hodgkin Disease; D006801:Humans; D018796:Immunoconjugates; D053208:Kaplan-Meier Estimate; D017730:Ki-1 Antigen; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010523:Peripheral Nervous System Diseases; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D016879:Salvage Therapy; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9107334",
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"pages": "1817-1824",
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"pmid": "30054707",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
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"title": "Brentuximab vedotin as salvage treatment in Hodgkin lymphoma naïve transplant patients or failing ASCT: the real life experience of Rete Ematologica Pugliese (REP).",
"title_normalized": "brentuximab vedotin as salvage treatment in hodgkin lymphoma na ve transplant patients or failing asct the real life experience of rete ematologica pugliese rep"
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"abstract": "Diarrhea, which is common after transplantation, may be due to infections and immunosuppressive therapy. Inflammatory bowel disease (IBD) de novo or as an exacerbation of pre-existent disease is a rare complication after kidney transplantation with pre-existing disease having a less aggressive clinical course than the de novo disease. Cytomegalovirus mismatch, prescription of tacrolimus instead of cyclosporine or mycophenolate mofetil rather than azathioprine as well as low-dose corticosteroid treatments have been linked to an increased incidence of IBD. This series of renal transplant recipients with de novo IBD showed a higher incidence and more aggressive course than that previously described, possibly related to increased use of tacrolimus with minimization of steroids.",
"affiliations": "Department of Nephrology, Centro Hospitalar do Porto, Santo António Hospital, Porto, Portugal. pedronunesazevedo@gmail.com",
"authors": "Azevedo|P|P|;Freitas|C|C|;Aguiar|P|P|;Silva|H|H|;Santos|T|T|;Farrajota|P|P|;Almeida|M|M|;Pedroso|S|S|;Martins|L S|LS|;Dias|L|L|;Vizcaíno|R|R|;Henriques|A Castro|AC|;Cabrita|A|A|",
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"issue": "45(3)",
"journal": "Transplantation proceedings",
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"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0243532",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case series of de novo inflammatory bowel disease after kidney transplantation.",
"title_normalized": "a case series of de novo inflammatory bowel disease after kidney transplantation"
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"abstract": "Prelabor rupture of the membranes (PROM) near the limit of viability is associated with significant risks for both mother and fetus. Preterm labor, intra-amniotic infection, and placental abruption are the immediate risks to the pregnancy; however, the fetus incurs additional risks related to the sequela of persistent oligohydramnios. Transabdominal intra-amniotic infusions have been studied. Results, suggesting that this intervention may prolong the latency period, and potentially, decrease pulmonary hypoplasia in surviving neonates without evidence of increasing risk of intra-amniotic infection. To our knowledge, the use of antibiotic-infused fluid has not been reported in this clinical scenario. Therefore, we present a case of a patient with PROM before the limit of viability who underwent serial transabdominal amnioinfusions with oxacillin-containing normal saline, which resulted in membrane resealing and neonatal survival with no additional maternal morbidity.",
"affiliations": "Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.;Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.;Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.;Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.;Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.;Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.;Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.",
"authors": "Kohari|Katherine|K|;Mehlhaff|Krista|K|;Merriam|Audrey|A|;Abdel-Razeq|Sonya|S|;Grechukhina|Olga|O|;Leon-Martinez|Daisy|D|;Bahtiyar|Mert Ozan|MO|",
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"fulltext": "\n==== Front\nAJP RepAJP Rep10.1055/s-00000169AJP Reports2157-69982157-7005Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. 10.1055/s-0038-1669964180035Case ReportA Novel Approach to Serial Amnioinfusion in a Case of Premature Rupture of Membranes Near the Limit of Viability Kohari Katherine MD1Mehlhaff Krista MD1Merriam Audrey MD1Abdel-Razeq Sonya MD1Grechukhina Olga MD1Leon-Martinez Daisy MD2Bahtiyar Mert Ozan MD11 Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut2 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, ConnecticutAddress for correspondence Katherine Kohari, MD Department of Obstetrics, Gynecology and Reproductive SciencesYale School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063katherine.kohari@yale.edu7 2018 14 9 2018 8 3 e180 e183 06 4 2018 21 7 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.Prelabor rupture of the membranes (PROM) near the limit of viability is associated with significant risks for both mother and fetus. Preterm labor, intra-amniotic infection, and placental abruption are the immediate risks to the pregnancy; however, the fetus incurs additional risks related to the sequela of persistent oligohydramnios. Transabdominal intra-amniotic infusions have been studied. Results, suggesting that this intervention may prolong the latency period, and potentially, decrease pulmonary hypoplasia in surviving neonates without evidence of increasing risk of intra-amniotic infection. To our knowledge, the use of antibiotic-infused fluid has not been reported in this clinical scenario. Therefore, we present a case of a patient with PROM before the limit of viability who underwent serial transabdominal amnioinfusions with oxacillin-containing normal saline, which resulted in membrane resealing and neonatal survival with no additional maternal morbidity.\n\nKeywords\nperiviable PROMserial amnioinfusionpulmonary hypoplasia\n==== Body\nPrelabor rupture of membranes (PROM) is the rupture of membranes before the onset of labor. It is rare for PROM to occur before the onset of viability. Is estimated to occur in approximately 0.37% of all pregnancies, and it presents a challenging clinical dilemma due to high likelihood of poor neonatal outcome, as well as significant risks to maternal health. PROM, before the onset of viability is frequently associated with subclinical intra-amniotic infection.\n1\n2\nPatients with PROM before the onset of viability face significant risks, including development of chorioamnionitis, preterm labor, abruption, and intrauterine demise. After counseling, patients may elect to continue the pregnancy, and in the absence of clinical signs of infection, labor or vaginal bleeding, the mainstay of therapy involves expectant management until the onset of viability. This conservative management typically involves inpatient admission, latency antibiotics, and steroids for fetal lung maturity. This strategy however, does not address the issue of the associated sequela for the fetus, of which include severe pulmonary hypoplasia and compressive limb deformities. The exact incidence of pulmonary hypoplasia is unknown and likely underreported. Pulmonary hypoplasia is potentially lethal for the neonate. Factors that affect the severity of pulmonary hypoplasia in the newborn include gestational age at PROM, duration of latency, and the amount of amniotic fluid present around the developing fetus.\n3\nMore than 20 years ago, serial transabdominal intra-amniotic infusions with warmed saline were proposed as an additive management approach to patients with PPROM (Preterm Prelabor Rupture of Membranes). While the data from these trials have been encouraging, lack of safety data and adequate control groups currently prevent this strategy from becoming widely accepted.\n4\nThe case we present is an example of the novel use of serial transabdominal amnioinfusions using oxacillin infused normal saline, in a patient with PROM before the limit of viability.\n\n\nCase Report\n\nThirty-five year old gravida 3 para 1–0-1–1 was referred to our maternal-fetal medicine office after diagnosis of early midtrimester oligohydramnios. Oligohydramnios was incidentally found during a routine anatomical survey ultrasound examination at 18 weeks of gestation. She was evaluated for preterm prelabor rupture of membranes (pooling of amniotic fluid in posterior vaginal fornix, arborization\nferning\ntesting and\nnitrazine\ntesting); this initial evaluation was negative. Two subsequent assessments again showed no evidence of rupture of amniotic membranes. The patient was offered, but declined intra-amniotic dye infusion testing at that time. An ultrasound at 20\n6/7\nweeks of gestation revealed a single live fetus and an amniotic fluid index of 2.8 cm. There was ultrasound evidence of membrane separation, suggesting a possible membrane rupture distal to the cervical opening (“high amniotic leak”). Fetal kidneys and bladder were seen on ultrasound and appeared normal. Her pregnancy was complicated by a history of gestational diabetes, history of loop electrical excision procedure, herpes simplex type 2, and maternal obesity (prepregnancy body mass index [BMI] 34 kg/m\n2\n). An episode of domestic violence had also been reported. She had early genetic screening with cell free fetal DNA that showed an appropriate fetal fraction, sex chromosomes XY, and low risk for trisomy 13, 18, and 21. A second trimester maternal serum\nα\n-fetoprotein was 2.16 MoM (Multiples of the Median). The patient underwent prenatal counseling with neonatology and maternal-fetal medicine. She expressed wishes for full neonatal resuscitation at 22 weeks and stated an understanding of the prognosis.\n\n\n\nAfter counseling she was offered an amnioinfusion and intra-amniotic dye instillation testing to confirm suspected diagnosis of PPROM. The patient proceeded with amnioinfusion and intra-amniotic dye installation at 21\n6/7\nweeks of gestation. Under ultrasound guidance a 22-gauge-needle was inserted into the intra-amniotic cavity, and 15 mL of clear yellow fluid was removed for purposes of genetic and infection testing. 40 mL of warmed 0.9% sodium chloride solution containing 1,000 mg/L oxacillin was infused at this time. 5 mL of indigo carmine was added for the intra-amniotic dye instillation test. A total of 400 mL of warmed 0.9% sodium chloride solution containing 1,000 mg/L oxacillin was infused. The patient then ambulated for 30 minutes and tampon testing confirmed rupture of fetal membranes. She was admitted to the hospital for latency antibiotics and serial intra-amniotic infusions. Acyclovir prophylaxis was started after clinical exam confirmed no active herpes lesions were seen. She completed a 7-day-course of latency antibiotics consisting of ampicillin and azithromycin. Betamethasone was administered at 23 weeks of gestation.\n\n\n\nAt 22\n6/7\nweeks of gestation, she underwent a second amnioinfusion. At this time, 800 mL of warmed 0.9% sodium chloride solution containing 1,000 mg/L oxacillin were infused to obtain a normal maximum vertical pocket (MVP).\n\n\n\nThe plan was for serial intra-amniotic infusions until 26 weeks of gestation. However, at 23\n6/7\nweeks, the patient denied continued leakage of fluid and MVP was normal. At this time, it was suspected that the amnion had resealed and decision was made to cease further intra-amniotic infusions unless symptoms of leakage of fluid returned or oligohydramnios again developed. Amniotic fluid testing returned with no evidence of intra-amniotic infection. Genetic testing with karyotype and microarray also confirmed no genetic abnormalities in the fetus. At 27 weeks of gestation she developed gestational hypertension without clinical or laboratory evidence for preeclampsia.\n\n\n\nThe patient was expectantly managed in the hospital. Fetal status remained reassuring with appropriate fetal growth on serial ultrasounds. Additionally, the MVP remained normal for the duration of her pregnancy. At 33\n0/7\nweeks, she was given a second course of betamethasone. An external cephalic version was performed at 34 weeks due to breech presentation. She underwent a successful induction of labor at 34\n2/7\nweeks. She was given penicillin in labor for group B streptococcus prophylaxis. She delivered a vigorous male infant, with a birth weight of 2,160 g, Apgar's scores of 9 at 1 and 5 minutes of life. The placenta weighed 390 g and had evidence of moderate acute inflammation (grade 3) at the chorion, but no evidence of inflammation elsewhere on the amnion, or umbilical cord. The newborns initial white blood cell count was 11.7 × 1,000 μL. He was given ampicillin and gentamycin for 48 hours until negative blood cultures per our neonatal intensive care protocol. The newborn stayed in the hospital for 9 days and had no immediate complications.\n\n\nDiscussion\n\nPremature rupture of membranes near the limit of viability occurs in less than 1% of all pregnancies.\n5\nIdentified risk factors for PPROM before the limit of viability include a history of preterm delivery or PPROM in previous pregnancy, short cervical length, cerclage, intra-amniotic procedures, antepartum vaginal bleeding, low body mass index, low socioeconomic status, illicit drug use and tobacco use.\n6\n7\n8\n9\nMost studies of PPROM before the limit of viability are retrospective and only include cases of expectant management. With a paucity of evidence to guide clinical management, this diagnosis creates a challenging clinical dilemma for clinicians and patients alike.\n\n\n\nThe expected clinical course in a patient with rupture of membranes before viability is variable and depends on the gestational age at rupture, the length of latency period, and the presence or absence of oligohydramnios.\n5\nData from an investigation by Falk et al showed that length of latency does not appear to vary by gestational age at rupture. They showed the median latencies of 8 days (range: 1–161 days) with PROM < 20 weeks, 4.5 days (range: 2–106 days) with PROM between 20–21 weeks, and 12.0 days (range: 1–112 days) with PROM between 21–23 weeks.\n10\nPatients, who choose expectant management must be counseled on the serious maternal and perinatal risks. Maternal risks include development of chorioamnionitis (31.8%) and subsequent development of endometritis (1%), abruption (9.3%), sepsis (1%), death (1/619 cases).\n11\nThere is a high rate of perinatal death with 31.6% stillbirth rate, and 29.7% neonatal death rate. Survival for a live birth in the setting of PPROM before the onset of viability is estimated at 44%.\n12\nBeyond high rates of death among the survivors, there is a significant risk for pulmonary hypoplasia and fetal skeletal deformities.\n\n\n\nAfter appropriate counseling, patients that desire conservative management and are absent of clinical signs of infection, labor, or vaginal bleeding, undergo the mainstay of therapy—expectant management until the onset of viability, at which point inpatient admission, latency antibiotics, and steroids are typically recommended.\n2\nThis strategy however, does not address the issue of associated oligo or anhydramnios, or the subsequent fetal sequela of severe pulmonary hypoplasia and compressive limb deformities. The exact incidence of pulmonary hypoplasia is unknown and likely underreported, but some data suggest that it is found in 9 to 20% of newborns delivered after periviable PROM prior to 26 weeks of gestation. Pulmonary hypoplasia is lethal in 50 to 100% of cases.\n3\n13\n14\n15\nFactors that affect the risk of pulmonary hypoplasia in the newborn include gestational age at rupture of membranes, duration of latency, and the amount of remaining amniotic fluid. Although, there are no reliable methods for diagnosing pulmonary hypoplasia in utero, several groups demonstrated association between persistent severe oligohydramnios and worse perinatal outcome.\n12\n\n\n\nThe novel use of serial transabdominal amnioinfusion to prolong latency and prevent the development of pulmonary hypoplasia was first introduced over 20 years ago.\n16\nSince this paper, further studies into this approach have shown promise. The theoretical benefit of amnioinfusion or the introduction of physiologic solution into the amniotic cavity is proposed to be 3-fold. First, it provides a dilution of preexisting intra-amniotic bacteria. Second, it washes out and dilutes inflammatory cells and mediators (prostaglandins, leukotrienes, cytokines, interleukins among others). Lastly, it increases the intra-amniotic fluid volume and intrauterine pressure. In theory, washing out or diluting the preexisting intra-amniotic bacteria and inflammatory cells may be beneficial to prolong the latent period and the presence of fluid may promote lung development and prevent positional contractures.\n17\nSome additional secondary benefits have been proposed and include increasing the ability to test fetal genetics, improving ultrasound imaging and decreasing the risk of cord compression. Recently, a Cochrane review assessed the efficacy of this approach with the data from two randomized control trials and concluded that the small number of subjects in those studies precluded a definitive answer in regards to the efficacy of the intervention.\n4\nA systematic review and meta-analysis suggested a better shortterm prognosis in women with PPROM, who underwent serial amnioinfusion as seen in the reviewed observational studies, but not in the randomized control trials (RCT). The intervention group had significant latency prolongation and improved perinatal and neonatal survival and experienced less pulmonary hypoplasia. These results intensify in the significantly lower gestational ages at rupture of membranes in the intervention group, compared with the control group in the observational studies.\n17\nThese results from the meta-analysis of RCTs, demonstrated a trend toward benefit, but the results were not statistically significant. This is possibly because of lack of power in these studies due to the small number of participants. This review also revealed a large variation in the interventions timing, continuation, and other interventions performed (hospitalization, antepartum monitoring, antibiotic prophylaxis choice, and steroid administration).\n17\n\n\n\nOur case report describes a unique approach to intra-amniotic fluid infusion in a patient with PPROM before the onset of viability. This case adds a novel approach to amnioinfusion with the addition of oxacillin to the intra-amniotic fluid infusion. This technique has been used in other intrauterine intervention procedures such as meningomyelocele repair. Administration of antibiotic in intra-amniotic fluid infusion was used as part of the standard protocol for the Management of Myelomeningocele Study (MOMS) trial and most institutions performing these procedures are using this mixture to replace amniotic fluid prior to completing closure of the hysterotomy.\n18\nThe addition of oxacillin solution may have aided in the significant prolongation of latency for our patient. This conclusion cannot be drawn definitively but should be considered in further study into the potential benefits of serial amnioinfusion are undertaken. While PPROM before the onset of viability remains a rare event, it has serious morbidity for both mother and fetus. Evidence continues to suggest that serial intra-amniotic fluid infusion is a permissible treatment option for well counseled patients choosing to continue their pregnancy.\n\n\nConflict of Interest None.\n==== Refs\nReferences\n1 Kozinszky Z Sikovanyecz J Pásztor N Severe midtrimester oligohydramnios: treatment strategies Curr Opin Obstet Gynecol 2014 26 02 67 76 24614021 \n2 Committee on Practice Bulletins-Obstetrics.ACOG practice bulletin no. 188: prelabor rupture of membranes Obstet Gynecol 2018 131 01 e1 e14 29266075 \n3 Rotschild A Ling E W Puterman M L Farquharson D Neonatal outcome after prolonged preterm rupture of the membranes Am J Obstet Gynecol 1990 162 01 46 52 2301516 \n4 Van Teeffelen S Pajkrt E Willekes C Van Kuijk S M Mol B W Transabdominal amnioinfusion for improving fetal outcomes after oligohydramnios secondary to preterm prelabour rupture of membranes before 26 weeks Cochrane Database Syst Rev 2013 08 CD009952 23913522 \n5 Manuck T A Eller A G Esplin M S Stoddard G J Varner M W Silver R M Outcomes of expectantly managed preterm premature rupture of membranes occurring before 24 weeks of gestation Obstet Gynecol 2009 114 01 29 37 19546755 \n6 Mercer B M Goldenberg R L Meis P J The preterm prediction study: prediction of preterm premature rupture of membranes through clinical findings and ancillary testing Am J Obstet Gynecol 2000 183 03 738 745 10992202 \n7 Berkowitz G S Blackmore-Prince C Lapinski R H Savitz D A Risk factors for preterm birth subtypes Epidemiology 1998 9 03 279 285 9583419 \n8 Harger J H Hsing A W Tuomala R E Risk factors for preterm premature rupture of fetal membranes: a multicenter case-control study Am J Obstet Gynecol 1990 163 (1, Pt 1):130 137 2197863 \n9 Treadwell M C Bronsteen R A Bottoms S F Prognostic factors and complication rates for cervical cerclage: a review of 482 cases Am J Obstet Gynecol 1991 165 03 555 558 1892180 \n10 Falk S J Campbell L J Lee-Parritz A Expectant management in spontaneous preterm premature rupture of membranes between 14 and 24 weeks' gestation J Perinatol 2004 24 10 611 616 15254557 \n11 Moretti M Sibai B M Maternal and perinatal outcome of expectant management of premature rupture of membranes in the midtrimester Am J Obstet Gynecol 1988 159 02 390 396 3407697 \n12 Waters T P Mercer B M The management of preterm premature rupture of the membranes near the limit of fetal viability Am J Obstet Gynecol 2009 201 03 230 240 19733274 \n13 Winn H N Chen M Amon E Leet T L Shumway J B Mostello D Neonatal pulmonary hypoplasia and perinatal mortality in patients with midtrimester rupture of amniotic membranes--a critical analysis Am J Obstet Gynecol 2000 182 06 1638 1644 10871491 \n14 Yang L C Taylor D R Kaufman H H Hume R Calhoun B Maternal and fetal outcomes of spontaneous preterm premature rupture of membranes J Am Osteopath Assoc 2004 104 12 537 542 15653781 \n15 Everest N J Jacobs S E Davis P G Begg L Rogerson S Outcomes following prolonged preterm premature rupture of the membranes Arch Dis Child Fetal Neonatal Ed 2008 93 03 F207 F211 17660215 \n16 Locatelli A Ghidini A Verderio M Predictors of perinatal survival in a cohort of pregnancies with severe oligohydramnios due to premature rupture of membranes at < 26 weeks managed with serial amnioinfusions Eur J Obstet Gynecol Reprod Biol 2006 128 (1,2):97 102 16530921 \n17 Porat S Amsalem H Shah P S Murphy K E Transabdominal amnioinfusion for preterm premature rupture of membranes: a systematic review and metaanalysis of randomized and observational studies Am J Obstet Gynecol 2012 207 05 3930 3.93E13 \n18 Adzick N S Thom E A Spong C Y A randomized trial of prenatal versus postnatal repair of myelomeningocele N Engl J Med 2011 364 11 993 1004 21306277\n\n",
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"title": "A Novel Approach to Serial Amnioinfusion in a Case of Premature Rupture of Membranes Near the Limit of Viability.",
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... |
{
"abstract": "OBJECTIVE\nTo determine from single-centre data the treatment continuation, discontinuation, and reasons for discontinuation among the patients with active rheumatoid arthritis (RA) or spondyloarthropathies (SpA) who were treated with infliximab as their first biological anti-rheumatic drug.\n\n\nMETHODS\nAll (n = 104) RA and SpA patients who were treated with infliximab as their first biological treatment according to the national guidelines in the Centre for Rheumatic Diseases, Tampere University Hospital during 1999-2005 were analysed at baseline and after 6 months of treatment. The treatment was regarded as ineffective if the response was lower than American College of Rheumatology (ACR) response criteria ACR50 in RA or the reduction of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was lower than 50% or 2 cm in SpA.\n\n\nRESULTS\nAfter 6 months, 71% of the patients continued infliximab treatment and the prednisolone dose was diminished by 40%. Infliximab was discontinued in 30 patients and seven of them discontinued due to remission. Eight patients were regarded as poor responders. Thirteen patients discontinued because of adverse events, mainly infections and hypersensitivity reactions. One patient discontinued the treatment because of drug-related leucopaenia and one because of elevated aminotransferases.\n\n\nCONCLUSIONS\nIn this study, infliximab treatment was started in patients who had active disease despite ongoing treatment with combinations of disease-modifying anti-rheumatic drugs (DMARDs). Seventy-eight per cent achieved at least 50% response when infliximab was added to their DMARD treatment. Adverse events, mainly infections and hypersensitivity reactions, were in line with previous reports. Two rare adverse events were reported, one patient with leucopaenia and one with elevated aminotransferases.",
"affiliations": "Medical School, University of Tampere and Research Unit, Tampere University Hospital, Tampere, Finland.",
"authors": "Levälampi|T|T|;Korpela|M|M|;Vuolteenaho|K|K|;Moilanen|E|E|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D005938:Glucocorticoids; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1080/03009740701633337",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9742",
"issue": "37(1)",
"journal": "Scandinavian journal of rheumatology",
"keywords": null,
"medline_ta": "Scand J Rheumatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006967:Hypersensitivity; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D025241:Spondylarthritis; D016896:Treatment Outcome; D016312:Treatment Refusal",
"nlm_unique_id": "0321213",
"other_id": null,
"pages": "6-12",
"pmc": null,
"pmid": "18189188",
"pubdate": "2008",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Infliximab treatment in patients with rheumatoid arthritis and spondyloarthropathies in clinical practice: adverse events and other reasons for discontinuation of treatment.",
"title_normalized": "infliximab treatment in patients with rheumatoid arthritis and spondyloarthropathies in clinical practice adverse events and other reasons for discontinuation of treatment"
} | [
{
"companynumb": "FI-JNJFOC-20080402072",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Despite recent advances and well-known treatment options, cure rates for resistant tuberculosis (TB) cases remain extraordinarily low. We present in first person the case of a patient who suffered from TB for over 7 years, and travelled to four countries in search of a cure. This experience shows how resistance patterns worsen under poor programme conditions and illustrates many of the obstacles faced by patients to obtain appropriate care: late diagnosis, lack of experienced care capacity and drug availability, and absence of psychosocial support during toxic and lengthy regimens. In addition to new tools, patient-centred systems are needed to tackle the drug-resistant TB epidemic.",
"affiliations": "TB-HIV Department, International Union Against Tuberculosis and Lung Disease, Paris, France.;TB-HIV Department, International Union Against Tuberculosis and Lung Disease, Paris, France.;Global Tuberculosis Institute, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.",
"authors": "Delgado|E|E|;Monedero|I|I|;Bhavaraju|R|R|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "France",
"delete": false,
"doi": "10.5588/ijtld.16.0954",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1027-3719",
"issue": "21(6)",
"journal": "The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease",
"keywords": null,
"medline_ta": "Int J Tuberc Lung Dis",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D057210:Delayed Diagnosis; D054908:Extensively Drug-Resistant Tuberculosis; D006801:Humans; D008297:Male; D018802:Patient-Centered Care; D012944:Social Support; D014195:Travel",
"nlm_unique_id": "9706389",
"other_id": null,
"pages": "713-716",
"pmc": null,
"pmid": "28482968",
"pubdate": "2017-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Resilience and extensively drug-resistant tuberculosis: the unlikely ally.",
"title_normalized": "resilience and extensively drug resistant tuberculosis the unlikely ally"
} | [
{
"companynumb": "PHHY2017FR106278",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE\\ISONIAZID\\PYRAZINAMIDE\\RIFAMPIN"
},
... |
{
"abstract": "Familial hypercholesterolaemia (FH) is a primary genetic dyslipidaemia characterized by elevation in serum low-density lipoprotein cholesterol and its deposition in systemic arteries, which causes premature atherosclerosis.\nA 10-year-old girl presented with severe symptomatic coronary artery disease. She demonstrated characteristic morphological features of FH. Despite aggressive medical management and lipid-lowering therapy, her symptoms were not relieved and she had dynamic electrocardiogram changes. Coronary angiography showed a distal left main coronary artery lesion along with significant lesions in ostio-proximal and mid-left circumflex artery which were managed by provisional left main coronary artery to left circumflex artery stenting technique, with good immediate- and short-term results and angina relief.\nTo the best of our knowledge, this is the first reported case of a paediatric patient with FH and acute coronary syndrome treated with percutaneous coronary intervention to left main coronary artery and left circumflex artery using provisional stenting technique. Revascularization strategies for symptomatic coronary artery disease in paediatric patients with FH have multiple unique challenges and remain an unexplored and under-reported subject.",
"affiliations": "Department of Cardiology, Lokmanya Tilak Municipal Medical College and General Hospital (LTMGH), Dr Babasaheb Ambedkar Road, Sion (West), Mumbai 400022, India.;Department of Cardiology, Lokmanya Tilak Municipal Medical College and General Hospital (LTMGH), Dr Babasaheb Ambedkar Road, Sion (West), Mumbai 400022, India.;Department of Cardiology, Lokmanya Tilak Municipal Medical College and General Hospital (LTMGH), Dr Babasaheb Ambedkar Road, Sion (West), Mumbai 400022, India.;Department of Cardiology, Lokmanya Tilak Municipal Medical College and General Hospital (LTMGH), Dr Babasaheb Ambedkar Road, Sion (West), Mumbai 400022, India.",
"authors": "Deshpande|Mrunmayee|M|;Phadke|Milind|M|https://orcid.org/0000-0003-2774-6649;Khan Abid|Talha|T|https://orcid.org/0000-0003-1979-2792;Mahajan|Ajay U|AU|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2514-2119",
"issue": "5(6)",
"journal": "European heart journal. Case reports",
"keywords": "Case report; Coronary artery disease; Familial hypercholesterolaemia; Provisional stenting technique",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytab175",
"pmc": null,
"pmid": "34142008",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "18516203;25983165;22477808;10065027;8640063;32865373;33074152;33123673;17191220;26085769;20213092;8495466;30214904",
"title": "A case report of successful complex percutaneous coronary intervention for acute coronary syndrome in a paediatric patient with familial hypercholesterolaemia.",
"title_normalized": "a case report of successful complex percutaneous coronary intervention for acute coronary syndrome in a paediatric patient with familial hypercholesterolaemia"
} | [
{
"companynumb": "IN-LUPIN LIMITED-2021-22103",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nTo characterize and compare both the outcome and cost of treatment of outpatient (OP) and inpatient (IP) ifosfamide therapy.\n\n\nMETHODS\nA single-center retrospective chart review of patients 18 years and older receiving ifosfamide therapy. The primary endpoint compares and evaluates the side effect profiles of ifosfamide-treated patients in the OP/IP settings. The adverse event grading system was characterized using the CTCAE Version 5.0. The highest grade was documented per cycle. The secondary endpoint of this study compares the costs of OP/IP therapy. It was assumed that the cost of medication was equivalent for IP/OP treatments. The cost saved with OP administration was determined by the average cost of hospital stay for IP admission.\n\n\nRESULTS\nIfosfamide therapy of 86 patients (57 OP, 29 IP) was reviewed. The predominant OP regimens were doxorobucin-ifosfamide-mesna (AIM) with 43.9% and ifosfamide-etoposide (IE) with 29.8%. Grade 4 anemia, thrombocytopenia, and neutropenia were most frequent in IP vs OP therapies (22.9% IP vs 4.3% OP, 21.6% IP vs 9.2% OP, and 22.8% IP vs 19.6% OP respectively). Neutropenic fever (NF) occurred in 20 OP patients which were predominantly treated with AIM or IE and led to average hospital stay of 6 days. Neurotoxicity, treated with methylene blue (MB) occurred in 4 OP patients. OP therapy saved a total of 783 hospital days, leading to a cost savings of $2,103,921.\n\n\nCONCLUSIONS\nTransitioning ifosfamide to the OP setting is feasible for academic and community infusion centers with the OP administration being safe, well-tolerated, and associated with decreased total cost of care. The current processes allow for safe transition of chemotherapy of chemotherapy under times of COVID.",
"affiliations": "The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA.;The University of Arizona Cancer Center, Tucson, AZ, USA. mcbride@pharmacy.arizona.edu.",
"authors": "Banh|Cindy|C|;Valsvik|Kendall|K|;Arredondo|Alejandra|A|;Notbohm|Kassie|K|;Elquza|Emad|E|;Babiker|Hani|H|;Kraft|Andrew|A|;Boiles|Alejandro Recio|AR|;Persky|Daniel|D|;Ortega|Alicia|A|;McBride|Ali|A|http://orcid.org/0000-0002-9430-4675",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-021-06653-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": null,
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Alternative payment model; Ifosfamide; Oncology care model; Outpatient chemotherapy; Supportive care",
"medline_ta": "Support Care Cancer",
"mesh_terms": null,
"nlm_unique_id": "9302957",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34825982",
"pubdate": "2021-11-26",
"publication_types": "D016428:Journal Article",
"references": "7700329;16170162;29691269;27724890;25062721;10894866;29911114;26060221;10387975;8620831;9626808;27127153;26884559;3114435;8879383;7510815;29461916;8925751;28579726;30226791;20808556;15503297;7549123;9552027;17229633;12460784;15928070;30090991;30355027;26979926;12673712;17906705;10646879;19588140",
"title": "Transitioning ifosfamide chemotherapy regimens to the ambulatory setting: reviewing cost savings and safety profile.",
"title_normalized": "transitioning ifosfamide chemotherapy regimens to the ambulatory setting reviewing cost savings and safety profile"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2021US272239",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Oxaliplatin is a platinum compound commonly used in the treatment of advanced colorectal cancer. This report describes two patients who had received repetitive combination chemotherapy including oxaliplatin for the treatment of metastatic colon cancer and who visited the emergency department with acute kidney injury several days after experiencing a hypersensitivity reaction to oxaliplatin. In both cases, the pathologic diagnosis was acute tubulointerstitial nephritis, and corticosteroid therapy resulted in improved renal function. Induction of acute tubulointerstitial nephritis by oxaliplatin has rarely been reported.
.",
"affiliations": null,
"authors": "Choi|You-Jung|YJ|;Oh|Kook-Hwan|KH|;Kang|Hye-Ryun|HR|;Lee|Soo-Jin|SJ|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN109131",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "89(2)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000970:Antineoplastic Agents; D003110:Colonic Neoplasms; D004342:Drug Hypersensitivity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "130-134",
"pmc": null,
"pmid": "29231160",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oxaliplatin-induced acute tubulointerstitial nephritis: Two case reports
.",
"title_normalized": "oxaliplatin induced acute tubulointerstitial nephritis two case reports"
} | [
{
"companynumb": "KR-FRESENIUS KABI-FK201801896",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
... |
{
"abstract": "The present study selected two patients with lung cancer and epidermal growth factor receptor (EGFR) mutations who were treated with a programmed cell death protein 1 (PD-1) antibody and an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis. In the first case, a 67-year-old female was diagnosed with lung adenocarcinoma with an EGFR mutation (exon 19 deletion) and Stage IVB disease. Initial treatment with an EGFR mutation-targeted tyrosine kinase inhibitor (TKI), erlotinib, demonstrated a partial response. After disease progression this was followed by carboplatin and pemetrexed with bevacizumab, and re-challenged by erlotinib plus bevacizumab; however, the tumor eventually progressed. Subsequently, the patient was treated with immunomodulatory arabinomannan for 3 months. Immediately after, she was treated with nivolumab and showed a partial response. In the second case, a 57-year-old male with a history of smoking was diagnosed with stage IVB pulmonary adenocarcinoma with an EGFR mutation (exon 19 deletion). He was treated with afatinib, followed by osimertinib when a T790M mutation was identified later. After disease progressed with TKIs, cisplatin plus pemetrexed and re-challenge with erlotinib plus bevacizumab were administered subsequently. Nivolumab was administered for recurrent disease. Although he experienced tumor remission, regrowth of the tumors was observed. Under continuing nivolumab, he was treated by palliative irradiation treatments to the right pelvic bone metastasis and left adrenal metastasis with immunomodulatory arabinomannan. A chest computed tomography scan showed a reduction in the sizes of the primary site and pulmonary metastases, with a decreasing trend of carcinoma embryonic antigen. Overall, these cases may indicate that the immune adjuvant actions of immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis improves the effect of PD-1 antibody treatments.",
"affiliations": "Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.;Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.;Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.;Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.;Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.;Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.;Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.;Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.;Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.",
"authors": "Kobayashi|Kunihiko|K|;Kaira|Kyoichi|K|;Iemura|Hidetoshi|H|;Shinomiya|Shun|S|;Hashimoto|Kosuke|K|;Miura|Yu|Y|;Shiono|Ayako|A|;Nishihara|Fuyumi|F|;Kagamu|Hiroshi|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2390",
"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450\n2049-9469\nD.A. Spandidos\n\nMCO-15-5-02390\n10.3892/mco.2021.2390\nArticles\nCombination of immune check inhibitor and immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis: A case report\nKobayashi Kunihiko\nKaira Kyoichi\nIemura Hidetoshi\nShinomiya Shun\nHashimoto Kosuke\nMiura Yu\nShiono Ayako\nNishihara Fuyumi\nKagamu Hiroshi\nDepartment of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Saitama 350-1298, Japan\nCorrespondence to: Dr Kunihiko Kobayashi, Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan kobakuni@saitama-med.ac.jp\n11 2021\n07 9 2021\n07 9 2021\n15 5 22705 3 2021\n09 7 2021\nCopyright: © Kobayashi et al.\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.\nThe present study selected two patients with lung cancer and epidermal growth factor receptor (EGFR) mutations who were treated with a programmed cell death protein 1 (PD-1) antibody and an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis. In the first case, a 67-year-old female was diagnosed with lung adenocarcinoma with an EGFR mutation (exon 19 deletion) and Stage IVB disease. Initial treatment with an EGFR mutation-targeted tyrosine kinase inhibitor (TKI), erlotinib, demonstrated a partial response. After disease progression this was followed by carboplatin and pemetrexed with bevacizumab, and re-challenged by erlotinib plus bevacizumab; however, the tumor eventually progressed. Subsequently, the patient was treated with immunomodulatory arabinomannan for 3 months. Immediately after, she was treated with nivolumab and showed a partial response. In the second case, a 57-year-old male with a history of smoking was diagnosed with stage IVB pulmonary adenocarcinoma with an EGFR mutation (exon 19 deletion). He was treated with afatinib, followed by osimertinib when a T790M mutation was identified later. After disease progressed with TKIs, cisplatin plus pemetrexed and re-challenge with erlotinib plus bevacizumab were administered subsequently. Nivolumab was administered for recurrent disease. Although he experienced tumor remission, regrowth of the tumors was observed. Under continuing nivolumab, he was treated by palliative irradiation treatments to the right pelvic bone metastasis and left adrenal metastasis with immunomodulatory arabinomannan. A chest computed tomography scan showed a reduction in the sizes of the primary site and pulmonary metastases, with a decreasing trend of carcinoma embryonic antigen. Overall, these cases may indicate that the immune adjuvant actions of immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis improves the effect of PD-1 antibody treatments.\n\nimmune adjuvant\nnivolumab\nMycobacterium tuberculosis\nlung cancer\nimmune checkpoint inhibitor\nFunding: No funding was received.\n==== Body\npmcIntroduction\n\nSequencing of DNA to identify polymorphisms has catalyzed the quest for protein kinase ‘driver’ mutations, which contribute to the transformation of a normal cell to a proliferating cancerous cell. Approximately one-third of patients in Asian populations with non-small cell lung cancer (NSCLC) harbor epidermal growth factor receptor (EGFR) mutations. For these patients, EGFR-targeted tyrosine kinase inhibitors (TKIs) have shown improved efficacy and longer progression-free survival (PFS) than standard chemotherapies (1). Currently, TKI treatment is considered the standard of care for EGFR-mutated NSCLC. However, most patients eventually develop resistance with a PFS from 10 months to 18.9 months (1,2).\n\nFor NSCLC, recent alternative treatments include immune checkpoint inhibitors (ICIs) such as programmed cell death 1 (PD-1) antibody (nivolumab or pembrolizumab) or a programmed cell death 1 ligand (PDL-1) antibody (atezolizumab or durvalumab). ICI monotherapy with nivolumab or pembrolizumab is efficacious for NSCLC, achieving response rates of ~20%, with a 5-year survival rate of ~15%. However, EGFR-mutated NSCLC is insensitive to ICIs (3,4).\n\nPrevious researchers, Coley W and Maruyama C, experienced immune responses to human malignant tumors by erysipelas and tuberculosis, respectively, indicating there might be a relationship between infection and cancer immunity (5,6). Previously, the effect of erysipelas was partially explained via the production of interleukin (IL)-12 and tumor necrosis factor (7). Regarding tuberculosis, Maruyama (6) developed Specific Substance Maruyama (SSM), a hot-water extract from human bacillus tuberculosis containing polysaccharides including arabinomannan and mannan (8). SSM is an immunomodulatory agent and its carcinostatic potential was reported in 1966(6). Later studies indicated that SSM acts as an immune adjuvant, resulting in a change from innate immunity to adaptive immunity (9-12).\n\nNo report has described ICI and immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis in humans.\n\nMaterial and methods\n\nThe two cases presented below gave oral consents as for presenting this case-report, and written consents were also obtained from the families. This manuscript followed a Japanese law, Act on the Protection of Personal Information.\n\nTo produce a hot-water extract from human bacillus tuberculosis, Mycobacterium tuberculosis, Aoyama B strain, grown on the surface of Sauton's media for 5 weeks at 37 degrees Celsius is diluted in distilled water. To extract polysaccharides, it is kept at 100˚C for 120 min, and, after filtering it to delete Mycobacterium tuberculosis, the filtrate is adjusted at the following concentrations (8). There are three types of hot water extracts from human Mycobacterium tuberculosis strain Aoyama B: SSM A at a dose of 2 mg as D-arabinose, SSM B at a dose of 0.2 mg as D-arabinose, and Ancer®, 1 ml ampoule containing Z-100 for subcutaneous injection, at a dose of 20 mg as D-arabinose. Ancer® has been approved in Japan as a granulocyte-macrophage (GM)-colony stimulating factor (CSF) under radiation therapy. SSM and Ancer® are supplied by Zeria Pharmaceutical Co. Ltd.\n\nThe cases were treated in clinical practice, and computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), and measurement of carcinoembryonic antigen (CEA) by a kit of CEA-ABOTT JAPAN were performed when needed in clinical practice. CT was performed by Light Speed VCT (GE, USA), and Biograph mCT 16 (Siemens Healthcare, Erlangen, Germany) was used for PET-CT using 193.8MBq of F-18 FDG.\n\nCase reports\n\nCase one\n\nIn 2016, a 67-year-old woman was diagnosed as NSCLC (adenocarcinoma) harboring a sensitive EGFR mutation, exon 19 deletion of the right lower lung. TNM and staging were cT1bN3M1c (lymph nodes metastasis, bone metastases, and adrenal metastasis) and Stage IVb disease. Thus, an EGFR-TKI, erlotinib, was started in February 2016, and achieved a partial response (PR). However, her disease progressed 10 months after starting the treatment. Second line treatment with carboplatin and pemetrexed with bevacizumab was immediately started, and achieved a PR. As disease progressed again and her tumor had no T790M mutation, erlotinib plus bevacizumab were administered from July 2017, and this maintained stable disease (SD). However, in December 2017, the disease progressed to the neck lymph nodes and left axillary lymph nodes with multiple bone metastases, and bilateral adrenal metastases. At this point, the patient requested to be treated with SSM of her own free will. Between March and May 2018, SSM at doses of 0.2 and 2 mg as D-arabinose were alternatively administered every other day, but the disease progressed further and the SSM treatment stopped. Immediately after it, she was treated with nivolumab as fifth line treatment from June 2018. Nivolumab after SSM treatment achieved a marked PR, resulting in the disappearance of the neck lymph nodes and the left axillary lymph nodes, and decreased the size of the primary site and bone metastases (Fig. 1). Nivolumab treatment was continued for 10 cycles until December 2018. Then, interstitial lung disease of Grade 2 common toxicity criteria occurred, and nivolumab treatment was terminated. Its efficacy continued until February 2019, and then the disease progressed. She was treated by osimertinib due to having T790M, followed by nab-paclitaxel, and died in November 2020.\n\nCase two\n\nA 57-year-old male with a history of smoking was diagnosed with pulmonary adenocarcinoma harboring an EGFR mutation, exon 19 deletion, in the left upper lobe (TNM and staging: cT2aN2M1c (brain metastasis and bone metastases) and Stage IVb disease, respectively) in 2015. Afatinib was initiated in November 2015, and achieved PR. Tumor recurrence and a T790M mutation were found in December 2016; therefore, osimertinib was administered. Six months after its initiation, progressive disease was observed. Then cisplatin plus pemetrexed was administered, and he also received erlotinib plus bevacizumab. However, apparent disease progression was observed in September 2017, and cancer histology by bronchial rebiopsy was changed from adenocarcinoma to undifferentiated carcinoma. Nivolumab was administered for the recurrent disease. Although he experienced tumor remission, regrowth of the primary tumor was observed in December 2019. Adding celecoxib (400 mg/day) due to lumbar pain produced a tentative effect and chest radiography revealed a shrinkage of the primary site (13). However, his disease progressed again in both the primary site and distant metastases in October 2020. He also felt pain and disturbance of motility in the bilateral legs, and it was later diagnosed as leptomeningeal metastases by MRI. Under continuing nivolumab, he was treated with palliative irradiation to the right pelvic bone metastasis at a total dose of 20 Gy in 4 fractions and left adrenal metastasis at a total dose of 30 Gy in 10 fractions with a subcutaneous injection of Ancer® for two months. In December 2020, a chest computed tomography scan showed a reduction in the sizes of the primary site and pulmonary metastases, which were not irradiated, with a decreasing trend in carcinoma embryonic antigen (CEA) blood levels (Fig. 2). However, active treatments stopped and he moved another hospital for palliative care because of progressing leptomeningeal metastases, which made him bed rest in January 2021 and died in late January 2021, indicating that the patient with leptomeningeal metastases could survive for 3 months.\n\nDiscussion\n\nWe experienced two lung cancer patients harboring EGFR mutations in whom the immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis might act as an immune adjuvant under ICI treatment. Although these cases might be considered random or serendipitous, we think these cases provide interesting information. Possible mechanisms to the events described below are shown in Fig. 3.\n\nPolymannan of tuberculosis is an immunogenic ligand for Toll-like receptors (TLRs) (14). Although signaling pathways in DCs by arabinomannan extracted from Mycobacterium tuberculosis is unknown at present, TLR ligands act as adjuvants in adaptive immune responses (15,16). It was reported that SSM induced cluster of differentiation (CD)80, CD86, and major histocompatibility complex (MHC) class II expression on bone marrow-derived dendritic cells (DCs), and that SSM treatment of mice increased the number of activated DCs in target lesions (9-12). Z-100 promoted a change in helper T-cell responses from a type 2 dominant state to a type 1 dominant state via the upregulation of interferon-γ and IL-12 production (9-11). These reports support that arabinomannan extracted from Mycobacterium tuberculosis acts as an immune adjuvant for TLRs on DCs in cancer immunity.\n\nAlthough cancer cells of EGFR-mutated NCSLC often express PDL-1 on their cell-surface, ICIs have a poor therapeutic effect (3,4). This PDL-1 expression is induced directly by activated EGFR signaling, not by tumor immunity (17). Therefore, PDL-1 on cancer cells harboring EGFR mutations is not exposed to any cytokines (18). Type 1 cytokine (IL-2, IFN-γ) production was increased in tumor-bearing mice treated with arabinomannan extracted from Mycobacterium tuberculosis (9,10). In case one, in addition to SSM acting as an immunologic adjuvant, pretreatment with SSM caused tumor cells to be exposed to cytokines.\n\nIt was reported that novel proteins were generated in response to γ-irradiation, resulting in new peptides presented by MHC molecules expressed by DCs (19). Formenti et al hypothesized that ‘abscopal response’ might be related to the radiation-induced exposure of immunogenic mutations to the immune system (20). To produce the abscopal response, both antigen presentation by MHC and co-stimulation by an immunologic adjuvant are critical. A previous study reported the administration of Z-100 in combination with radiation showed the inhibitory action of pulmonary metastasis in tumor-bearing mice model, and prolonged survival time (11). In humans, a phase III placebo-controlled double-blind randomized trial of radiotherapy for stages IIB-IVA cervical cancer with or without Z-100 was reported a trend in the improvement of overall survival (OS) in locally advanced cervical cancer (21). The 5-year OS rate was 75.7% with Z-100 and 65.8% without Z-100 (hazard ratio: 0.65, P=0.07). In our second case receiving nivolumab treatment, palliative irradiation to distant metastases was administered with Ancer®, and effects on the primary site and pulmonary metastases, which were not irradiated, were observed.\n\nIn conclusion, these two cases might indicate immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis has immune adjuvant effects under PD-1 antibody treatment. This treatment strategy should be validated by prospective clinical studies, and the NEJ 046A trial is currently underway.\n\nAcknowledgements\n\nThe authors are especially grateful to Dr Hiroyuki Tajima and Dr Kenji Fukushima (Saitama Medical University, Saitama, Japan) for performing the CT/PET imaging.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\n\nKuK provided the clinical data included in the text and wrote the manuscript draft. KuK, KyK, HI, SS, KH, YM, AS, FN and HK treated the two patients and interpreted the PET-CT, CT imaging and the laboratory test results. KyK critically revised the manuscript and modified the text. KuK and KyK confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.\n\nEthics approval and consent to participate\n\nAll procedures performed in the present case report were in accordance with the ethical standards of Saitama Medical University International Medical Center and with the 1964 Declaration of Helsinki and its later amendments. This manuscript followed a Japanese law, Act on the Protection of Personal Information. The two patients gave oral consent for presenting this case-report, and written consent was also obtained from the families.\n\nPatient consent for publication\n\nWritten consent for publication was provided by the patients' families.\n\nCompeting interests\n\nKuK received research grants from AstraZeneca Co., and Zeria Pharmaceutical Co., and received personal fees from AstraZeneca Co. KyK received personal fees from Ono Pharmaceutical Co., Boehringer Ingelheim Co., Chugai Pharmaceutical Co., Taiho Pharmaceutical Co., Eli Lilly Japan Co., Nihon Medi-Physics Co., and AstraZeneca Co. HK received research grants from AstraZeneca Co., and received personal fees from AstraZeneca Co. All other authors declare that they have no competing interests.\n\nFigure 1 Case A treated with nivolumab immediately after SSM. 18F-FDG-PET before SSM treatment indicated metastases of the left axillar lymph node and vertebral bone (white arrows). After treatment with SSM followed by nivolumab, a markedly reduced uptake on FDG-PET was observed for the left axillar lymph node and vertebral bone. CEA blood levels were markedly reduced after the treatments. 18F-FDG, (18F) fluoro-2-deoxy-D-glucose; PET, positron emission tomography; SSM, Specific Substance Maruyama; CEA, carcinoembryonic antigen.\n\nFigure 2 Case B with distant metastases irradiated with Z-100 under nivolumab treatment. Chest CT on 6 November 2020 revealed progression of the primary lung tumor (dotted arrow) and pulmonary metastases (arrows) under nivolumab treatment. After irradiation to distant metastases of the right pelvic bone metastasis and left adrenal metastasis with Z-100, the sizes of the primary lung tumor and pulmonary metastases were decreased on chest computed tomography by 10 December 2020. CEA blood level was also reduced. CEA, carcinoembryonic antigen.\n\nFigure 3 Enhanced immunity due to immunomodulatory arabinomannan. Immunomodulatory arabinomannan (SSM/Z-100) extracted from Mycobacterium tuberculosis induced CD80, CD86 and MHC expression on bone marrow-derived DCs. SSM/Z-100 promoted a change in helper T cell responses from a type 2 dominant state to a type 1 dominant state via the upregulation of IFN-γ and IL-12 production. MHC, major histocompatibility complex; DC, dendritic cell; pep, peptide; PD-1, programmed cell death protein 1; Th1, T helper 1; TCR, T cell receptor; TLR, toll-like receptor; Ag, antigen.\n==== Refs\nReferences\n\n1 Maemondo M Inoue A Kobayashi K Sugawara S Oizumi S Isobe H Gemma A Harada M Yoshizawa H Kinoshita I Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N Engl J Med 362 2380 2388 2010 10.1056/NEJMoa0909530 20573926\n2 Soria JC Ohe Y Vansteenkiste J Reungwetwattana T Chewaskulyong B Lee KH Dechaphunkul A Imamura F Nogami N Kurata T Osimertinib in Untreated EGFR-mutated advanced non-small-cell lung cancer N Engl J Med 378 113 125 2018 10.1056/NEJMoa1713137 29151359\n3 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Chow LQ Vokes EE Felip E Holgado E Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer N Engl J Med 373 1627 1639 2015 10.1056/NEJMoa1507643 26412456\n4 Reck M Rodríguez-Abreu D Robinson AG Hui R Csőszi T Fülöp A Gottfried M Peled N Tafreshi A Cuffe S Pembrolizumab versus chemotherapy for PD-L1-positive Non-Small-Cell lung cancer N Engl J Med 375 1823 1833 2016 10.1056/NEJMoa1606774 27718847\n5 Busch W Einfluβ von Erysipel Berliner Klin Wschr 3 245 246 1866 (In German)\n6 Maruyama C On the treatment of malignant tumor with an extract from tubercle bacilli Jpn J Dermatol 76 399 404 1966 (In Japanese)\n7 Tsung K Norton JA Lessons from Coley's Toxin Surg Oncol 15 25 28 2006 10.1016/j.suronc.2006.05.002 16814541\n8 Kobatake H Suekane T Murakami Y Niwa S Okahira A Kushida H Studies on hot water extract of Mycobacterium tuberculosis. I. Structural analyses of polysaccharides (author's transl) Yakugaku Zasshi 101 713 722 1981 10.1248/yakushi1947.101.8_713 (In Japanese) 6799639\n9 Oka H Shiraishi Y Sasaki H Yoshinaga K Emori Y Takei M Antimetastatic effect of an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, Z-100, through the production of interleukin-12 Biol Pharm Bull 26 1336 1341 2003 10.1248/bpb.26.1336 12951482\n10 Oka H Emori Y Sasaki H Shiraishi Y Yoshinaga K Kurimoto T Anti-tumor mechanism of Z-100, an immunomodulatory Arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, on pulmonary metastases of B16F10 melanoma: Restoration of helper T cell responses via suppression of glucocorticoid-genesis Microbiol Immunol 46 343 351 2002 10.1111/j.1348-0421.2002.tb02705.x 12139394\n11 Oka H Sasaki H Shiraishi Y Emori Y Yoshinaga K Takei M Z-100, an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, augments anti-tumor activities of X-ray irradiation against B16 melanoma in association with the improvement of type 1 T cell responses Biol Pharm Bull 27 82 88 2004 10.1248/bpb.27.82 14709904\n12 Mitsuishi T Kabashima K Tanizaki H Ohsawa I Oda F Yamada Y Halifu Y Kawana S Kato T Iida K Specific substance of Maruyama (SSM) suppresses immune responses in atopic dermatitis-like skin lesions in DS-Nh mice by modulating dendritic cell functions J Dermatol Sci 63 184 190 2011 10.1016/j.jdermsci.2011.05.007 21708453\n13 Kobayashi K Kaira K Kagamu H Recovery of the sensitivity to Anti-PD-1 antibody by celecoxib in lung cancer Anticancer Res 40 5309 5311 2020 10.21873/anticanres.14537 32878822\n14 Murphy K Weaver C Chapters: 3-5. In: Janeway's Immunobiology. 9th edition. W.W. Norton & Company, Inc., New York, 2017.\n15 Shah RR Hassett KJ Brito LA Overview of vaccine adjuvants: Introduction, history, and current status Methods Mol Biol 1494 1 13 2017 10.1007/978-1-4939-6445-1_1 27718182\n16 Reed SG Orr MT Fox CB Key roles of adjuvants in modern vaccines Nat Med 19 1597 608 2013 10.1038/nm.3409 24309663\n17 Hsu PC Jablons DM Yang CT You L Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC) Int J Mol Sci 20 E3821 2019 10.3390/ijms20153821 31387256\n18 Teng MW Ngiow SF Ribas A Smyth MJ Classifying cancers based on T-cell infiltration and PD-L1 Cancer Res 75 2139 2145 2015 10.1158/0008-5472.CAN-15-0255 25977340\n19 Reits EA Hodge JW Herberts CA Groothuis TA Chakraborty M Wansley EK Camphausen K Luiten RM de Ru AH Neijssen J Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy J Exp Med 203 1259 1271 2006 10.1084/jem.20052494 16636135\n20 Formenti SC Rudqvist NP Golden E Cooper B Wennerberg E Lhuillier C Vanpouille-Box C Friedman K Ferrari de Andrade L Wucherpfennig KW Radiotherapy induces responses of lung cancer to CTLA-4 blockade Nat Med 24 1845 1851 2018 10.1038/s41591-018-0232-2 30397353\n21 Sugiyama T Fujiwara K Ohashi Y Yokota H Hatae M Ohno T Nagai Y Mitsuhashi N Ochiai K Noda K Phase III placebo-controlled double-blind randomized trial of radiotherapy for stage IIB-IVA cervical cancer with or without immunomodulator Z-100: A JGOG study Ann Oncol 25 1011 1017 2014 10.1093/annonc/mdu057 24569914\n\n",
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"keywords": "Mycobacterium tuberculosis; immune adjuvant; immune checkpoint inhibitor; lung cancer; nivolumab",
"medline_ta": "Mol Clin Oncol",
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"title": "Combination of immune check inhibitor and immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis: A case report.",
"title_normalized": "combination of immune check inhibitor and immunomodulatory arabinomannan extracted from mycobacterium tuberculosis a case report"
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"abstract": "Mycoplasma infection may lower the threshold for drug allergy in particular patients. We present a case of drug reaction with eosinophilia and systemic symptoms (DRESS), with drug etiology and non-drug etiology (Mycoplasma infection). Possible synergism between previously known drug allergy and the acute Mycoplasma infection may have led to DRESS eruption. Interferon-γ release test and TNF-α release test yielded different patterns in the present case, suggesting a different role for each in different drug eruption types.",
"affiliations": "Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.;Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.;Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.",
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"fulltext": "\n==== Front\nCase Rep Dermatol\nCase Rep Dermatol\nCDE\nCase Reports in Dermatology\n1662-6567 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\n10.1159/000510706\ncde-0012-0225\nSingle Case\nDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Associated with Mycoplasma pneumoniae Infection\nShalom Guy ab Khoury Raed ab Horev Amir ac* aFaculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel\nbClalit Health Services, Tel-Aviv, Israel\ncPediatric Dermatology Service, Soroka University Medical Center, Beer-Sheva, Israel\n*Amir Horev, Soroka University Medical Center, PO Box 151, Beer-Sheva 84101 (Israel), amirhor@clalit.org.il\nSep-Dec 2020 \n12 11 2020 \n12 11 2020 \n12 3 225 230\n29 4 2020 6 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.Mycoplasma infection may lower the threshold for drug allergy in particular patients. We present a case of drug reaction with eosinophilia and systemic symptoms (DRESS), with drug etiology and non-drug etiology (Mycoplasma infection). Possible synergism between previously known drug allergy and the acute Mycoplasma infection may have led to DRESS eruption. Interferon-γ release test and TNF-α release test yielded different patterns in the present case, suggesting a different role for each in different drug eruption types.\n\nKeywords\nAdverse drug reactionDrug eruptionDrug reaction with eosinophilia and systemic symptoms (DRESS)MycoplasmaInfectionInterferon-γ release test\n==== Body\nCase Report\nA 19-year-old female with an unremarkable medical history, and known drug allergy to penicillin since infancy, was admitted to our department. She suffered from a severe cutaneous eruption, following treatment with cephalosporin for tonsillitis. Her initial treatment was cephalexin (tablet; Cefovit®) 250 mg ×4/day. Two days later, the patient developed mild cutaneous eruption, and the treatment was replaced by cefuroxime (tablet; Zinnat®) 500 mg ×2/day. Under this treatment regimen, her cutaneous eruption was aggravated; thus, the patient was referred to our institution. Physical examination revealed a widespread heterogenic eruption with papular, pustular, erythema target-like lesions and Sweet-like lesions (Fig. 1a, b). Marked facial edema was noted (Fig. 1c). The estimated body surface area involvement was more than 50%. Mild oral erosions were present without any other mucosal involvement. Nikolsky's sign was negative. The patient had a fever of 39°C and bilateral cervical and submandibular lymphadenopathy, larger than 1 cm on palpation. Respiratory auscultation demonstrated bilateral crackles present on both lung bases. A chest X-ray revealed bilateral infiltrates present in both lung bases. Laboratory tests: complete blood count performed upon her admission revealed anemia of 9.3 g/dL, leukocytosis of 30,350 cells/μL, and eosinophilia of 930 cells/μL. The patient had 2% atypical lymphocytes on her peripheral blood smear test. Her creatinine level, liver function tests, and electrolytes were within normal limits, while her albumin level was 2 g/dL. Other ancillary tests revealed hypocomplementemia C3 level of 57 (90–180) and C4 of 4 (10–40). Screening tests for collagen vascular diseases were negative for ANA and RF. Thyroid function tests at baseline were normal. Laboratory investigation screening for viral infections including human herpes virus-6, EBV, CMV, adenovirus, Coxsackie A virus, hepatitis viruses, and varicella zoster virus were all negative. Serologic screening for bacterial infection demonstrated positive IgM and negative IgG for Mycoplasma pneumoniae. Sequential Mycoplasma serology test done 10 days from index day revealed seroconversion: positive for IgM and IgG anti-M. pneumoniae antibodies. Histopathologic examination supported the diagnosis of drug eruption, demonstrating several necrotic keratinocytes in the epidermis, vacuolar changes with interface dermatitis, and an extensive papillary edema (Fig. 2a, b). Perivascular and interstitial mononuclear infiltrate was present admixed with numerous eosinophils (Fig. 2c). Upon her admission, treatment with cefuroxime (tablet; Zinnat®) was discontinued and switched to intravenous azithromycin. Simultaneous treatment with prednisone 60 mg ×1/day was initiated together with topical corticosteroids. Under this treatment regimen, with gradual tapering down of prednisone, a slow, steady improvement was noticed. Five weeks after initiating this treatment regimen, the patient gained complete resolution. One year following her remission, the patient underwent a patch test for drug series (Cutaneous Adverse Drug Reaction Series CAD-1000), which was negative. In vitro tests for cefuroxime (tablet; Zinnat®), penicillin (tablet; Moxypen©), and cephalexin (tablet; Cefovit®) were performed 1 year following the remission, supporting drug reaction with eosinophilia and systemic symptoms (DRESS) diagnosis (Fig. 3).\n\nDiscussion\nOur patient presented with two major medical problems that are closely related: on the one hand, acute M. pneumoniae infection, a diagnosis that was established clinically (“tonsillitis,” systemic symptoms, fever, crackles by auscultation, bilateral lung infiltrate by CXR, and compelling serology tests) and on the other hand, the patient suffered severe drug eruption based on her past medical history (cephalosporin treatments in a patient with penicillin allergy may raise the possibility of cross-reactivity), positive withdrawal test, and positive in vitro tests. Nevertheless, these two problems are probably related. Cutaneous manifestations of Mycoplasma infection include a wide clinical spectrum from exanthematous eruption, erythema multiforme (EM), urticaria, and erythema nodosum to the less common forms of mucositis and Sweet's syndrome [1, 2, 3]. M. pneumoniae-induced rash and mucositis is a relatively recent entity, usually seen in children and young adults. It is characterized by pronounced mucositis, scant or absent cutaneous involvement and generally good prognosis [4]. The current case is characterized by extensive skin and mild mucous membrane involvement, histologic and in vitro test results, as well as the long course of the disease, making M. pneumoniae-induced rash and mucositis diagnosis less favorable. Stevens-Johnson syndrome and toxic epidermal necrolysis are frequently reported to be associated with Mycoplasma infection [5]; nonetheless, drug eruption with systemic symptoms (DRESS) is not commonly reported in association with M. pneumoniae infection as demonstrated in the present case [6]. According to the DRESS validation score established by the REGISCAR group [7], our patient has probable DRESS (4-point score) upon her admission: fever, eosinophilia, atypical lymphocytes, extent >50%, rash suggesting DRESS, in the presence of positive serology for Mycoplasma and negative serologies and blood cultures [7]. The association between DRESS and cephalosporins, as in our case, has been given more attention in the last few years [8, 9]. The EM-like morphology in DRESS is associated with more severe liver involvement [10]; interestingly, our patient had entirely normal liver functions; oral erosions are more compatible with the mycoplasma infection EM variant, hinting for a possible EM-DRESS overlap syndrome. However, a short latency period of less than 5 days, which is allegedly non-consistent with DRESS diagnosis, can be explained by previously known sensitivity to penicillin and a possible cross-reaction, suggesting a lowered threshold for drug allergy and cross-reaction in the presence of Mycoplasma infection. Patch tests are not highly sensitive in the case of DRESS eruptions. Thus, negative results do not rule out this option. In vitro tests supported DRESS diagnosis, incriminating cefuroxime (Zinnat®) more strongly than cephalexin (Cefovit®) as the culprit drug. Interestingly, TNF-α release was significantly increased following exposure to penicillin (Mxypen©) and cefuroxime (Zinnat®) but not to cephalexin (Cefovit®), while interferon-γ release test was significantly positive for all three. This observation may hint at the different roles of TNF-α and interferon-γ. Nevertheless, a general conclusion regarding the role of TNF-α in the pathophysiology of DRESS cannot be made on a solid ground based on a single observation.\n\nIn conclusion, we presented a case of DRESS, with drug etiology and non-drug etiology (bacterial infection). Each of these can serve as a sole etiology for the cutaneous eruption in the present case, yet possible synergism between the two is reasonable. M. pneumoniae infection may lower the threshold for drug allergy in this particular patient with penicillin allergy, triggering a cross-reaction between cephalosporin and penicillin.\n\nStatement of Ethics\nThe patient gave written informed consent for the publication of her case (including publication of images). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNone.\n\nAuthor Contributions\nG.S. collected the data and wrote the initial manuscript draft. R.K. collected the data and revised the manuscript. A.H. evaluated and critically revised the manuscript and is the corresponding author. All authors provided critical feedback and contributed to the final version of the manuscript.\n\nAcknowledgment\nThe authors thank Prof. Sima Halevy.\n\nFig. 1 a Papular, pustular, erythema, and target-like lesions over the trunk. b Papular, pustular, and target-like lesions over the right thigh. c Marked face edema, Sweet-like lesions, and mild oral mucosal involvement.\n\nFig. 2 a Necrotic keratinocytes in the epidermis, vacuolar changes, interface dermatitis in the basal layer (H&E, magnification ×360). b Extensive papillary edema (H&E, magnification ×360). c Perivascular and interstitial mononuclear infiltrate was present admixed with numerous eosinophils (inset) (H&E, magnification ×360).\n\nFig. 3 In vitro tests for cephalexin cefuroxime and penicillin 1 year following the remission. The patient and healthy control subject with no known drug sensitivity: interferon-γ release test (a) and TNF-α release test (b).\n==== Refs\nReferences\n1 Atkinson TP Balish MF Waites KB Epidemiology, clinical manifestations, pathogenesis and laboratory detection of Mycoplasma pneumoniae infections FEMS Microbiol Rev 2008 11 32 (6) 956 73 18754792 \n2 Schalock PC Dinulos JG Mycoplasma pneumoniae-induced cutaneous disease Int J Dermatol 2009 7 48 (7) 673 80 19570071 \n3 Cherry JD Anemia and mucocutaneous lesions due to Mycoplasma pneumoniae infections Clin Infect Dis 1993 8 17 Suppl 1 S47 51 8399937 \n4 Norton SA Diagnosing Mycoplasma pneumoniae-induced rash and mucositis (MIRM) in the emergency room J Am Acad Dermatol 2015 8 73 (2) e67 26184002 \n5 Tay YK Huff JC Weston WL Mycoplasma pneumoniae infection is associated with Stevens-Johnson syndrome, not erythema multiforme (von Hebra) J Am Acad Dermatol 1996 11 35 (5 Pt 1) 757 60 8912572 \n6 Kosseian-Bal I Bocquet H Beneton N Encaoua R Deforges L Roujeau JC Revuz J Hypersensitivity syndrome during Mycoplasma pneumoniae infection Ann Dermatol Venereol 1998 125 (5) 328 330. 152 9747281 \n7 Kardaun S Sidoroff A Valeyrie-Allanore L Halevy S Davidovici BB Mockenhaupt M Roujeau JC Variability in the clinical pattern of cutaneous side- effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007 156 609 611. 156 17300272 \n8 Babu T Panachiyil GM Sebastian J Shastry V Drug Rash With Eosinophilia and Systemic Symptoms (DRESS) Syndrome Probably Related to Cefpodoxime: A Case Report J Pharm Pract 2019 8 897190019866094 31382812 \n9 Karakayalı B Yazar AS Çakir D Cetemen A Kariminikoo M Deliloglu B Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome associated with cefotaxime and clindamycin use in a 6 year-old boy: a case report Pan Afr Med J 2017 11 28 218 29629004 \n10 Walsh S Diaz-Cano S Higgins E Morris-Jones R Bashir S Bernal W Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases Br J Dermatol 2013 2 168 (2) 391 401 23034060\n\n",
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"keywords": "Adverse drug reaction; Drug eruption; Drug reaction with eosinophilia and systemic symptoms (DRESS); Infection; Interferon-γ release test; Mycoplasma",
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{
"abstract": "To define optimal thromboprophylaxis strategy after stent implantation in superior or total cavopulmonary connections.\nStent thrombosis is a rare complication of intravascular stenting, with a perceived higher risk in single-ventricle patients.\nAll patients who underwent stent implantation within superior or total cavopulmonary connections (caval vein, innominate vein, Fontan, or branch pulmonary arteries) were included. Cohort was divided into aspirin therapy alone versus advanced anticoagulation, including warfarin, enoxaparin, heparin, or clopidogrel. Primary endpoint was in-stent or downstream thrombus, and secondary endpoints included bleeding complications.\nA total of 58 patients with single-ventricle circulation underwent 72 stent implantations. Of them 14 stents (19%) were implanted post-superior cavopulmonary connection and 58 (81%) post-total cavopulmonary connection. Indications for stenting included vessel/conduit stenosis (67%), external compression (18%), and thrombotic occlusion (15%). Advanced anticoagulation was prescribed for 32 (44%) patients and aspirin for 40 (56%) patients. Median follow up was 1.1 (25th-75th percentile, 0.5-2.6) years. Echocardiograms were available in 71 patients (99%), and advanced imaging in 44 patients (61%). Thrombosis was present in two patients on advanced anticoagulation (6.3%) and none noted in patients on aspirin (p = 0.187). Both patients with in-stent thrombus underwent initial stenting due to occlusive left pulmonary artery thrombus acutely post-superior cavopulmonary connection. There were seven (22%) significant bleeding complications for advanced anticoagulation and none for aspirin (p < 0.001).\nAntithrombotic strategy does not appear to affect rates of in-stent thrombus in single-ventricle circulations. Aspirin alone may be sufficient for most patients undergoing stent implantation, while pre-existing thrombus may warrant advanced anticoagulation.",
"affiliations": "Division of Cardiology, Children's Healthcare of Atlanta, Atlanta, GA, USA.;Division of Cardiology, Children's Healthcare of Atlanta, Atlanta, GA, USA.;Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.;Division of Cardiology, Children's Healthcare of Atlanta, Atlanta, GA, USA.;Division of Cardiology, Children's Healthcare of Atlanta, Atlanta, GA, USA.;Division of Cardiology, Children's Healthcare of Atlanta, Atlanta, GA, USA.;Division of Cardiology, Children's Healthcare of Atlanta, Atlanta, GA, USA.",
"authors": "Ooi|Yinn K|YK|;Ligon|R Allen|RA|https://orcid.org/0000-0002-1022-3430;Kelleman|Michael|M|;Vincent|Robert N|RN|;Bauser-Heaton|Holly D|HD|;Kim|Dennis W|DW|;Petit|Christopher J|CJ|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1017/S1047951119000969",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "29(7)",
"journal": "Cardiology in the young",
"keywords": "Thromboprophylaxis; anticoagulation; children; single ventricle circulations; stent implantation; superior and total cavopulmonary connections",
"medline_ta": "Cardiol Young",
"mesh_terms": "D000925:Anticoagulants; D001241:Aspirin; D002648:Child; D002675:Child, Preschool; D005260:Female; D005343:Fibrinolytic Agents; D018729:Fontan Procedure; D006083:Graft Occlusion, Vascular; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D015607:Stents; D000080039:Univentricular Heart",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "877-884",
"pmc": null,
"pmid": "31208476",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thromboprophylaxis strategies for children with single-ventricle circulations (superior or total cavo-pulmonary connections) after stent implantation.",
"title_normalized": "thromboprophylaxis strategies for children with single ventricle circulations superior or total cavo pulmonary connections after stent implantation"
} | [
{
"companynumb": "US-PFIZER INC-2019276989",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Hydroxocobalamin is an effective cyanide antidote. While erythema, hypertension, and chromaturia are recognized side effects, methemoglobinemia has not been reported. Methemoglobin levels are most accurately measured by co-oximetry. We describe an extensively burned patient who developed methemoglobinemia within an hour of hydroxocobalamin administration.\n\n\n\nA 47-year old man without genetic deficiencies or abnormal hemoglobin variants presented with 61% body surface area thermal burns and grade 1 inhalation injury sustained during a tugboat engine explosion. On admission, lactate was 9.24 mmol/L, methemoglobin 1%, and carboxyhemoglobin 0.2% by blood gas analysis with co-oximetry. Despite large-volume resuscitation, lactate remained elevated (7-8 mmol/L). Intravenous hydroxocobalamin (5 g) was administered at postburn hour 19 for possible cyanide toxicity. Immediately thereafter, he became hypertensive with reflex bradycardia. Lactate decreased to 5.51 mmol/L, methemoglobin rose to 4.10%, and oxygen saturation by pulse oximetry decreased to 74-80% (despite arterial oxygen saturation of 95% by cooximetry). Methemoglobin concentration peaked at 13.40% at postburn hour 33. Methylene blue was not administered.\n\n\n\nMethemoglobinemia in our patient was temporally associated with hydroxocobalamin administration.",
"affiliations": "a U.S. Army Institute of Surgical Research , Fort Sam Houston , TX , USA.;b Department of Emergency Medicine , University of Colorado School of Medicine , Aurora , CO , USA.;a U.S. Army Institute of Surgical Research , Fort Sam Houston , TX , USA.",
"authors": "Jiwani|Alisha Z|AZ|;Bebarta|Vikhyat S|VS|;Cancio|Leopoldo C|LC|",
"chemical_list": "D000931:Antidotes; D003486:Cyanides; D006879:Hydroxocobalamin",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1377838",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "56(5)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Hydroxocobalamin; burns; co-oximetry; cyanide; methemoglobinemia",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000931:Antidotes; D002056:Burns; D002059:Burns, Inhalation; D003486:Cyanides; D006801:Humans; D006879:Hydroxocobalamin; D008297:Male; D008708:Methemoglobinemia; D008875:Middle Aged",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "370-372",
"pmc": null,
"pmid": "28969436",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired methemoglobinemia after hydroxocobalamin administration in a patient with burns and inhalation injury.",
"title_normalized": "acquired methemoglobinemia after hydroxocobalamin administration in a patient with burns and inhalation injury"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-18-04314",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"dr... |
{
"abstract": "OBJECTIVE\nTumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.\n\n\nOBJECTIVE\nTo determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.\n\n\nMETHODS\nFive men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.\n\n\nMETHODS\nThe primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.\n\n\nRESULTS\nOf the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.\n\n\nCONCLUSIONS\nTargeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.",
"affiliations": "Department of Dermatology, Stanford University, Stanford, California.;Department of Dermatology, Stanford University, Stanford, California2Department of Dermatology, School of Medicine, Stanford University, Stanford, California.;Department of Dermatology, Stanford University, Stanford, California.;Department of Dermatology, School of Medicine, Stanford University, Stanford, California.;Department of Dermatology, Stanford University, Stanford, California.;Department of Dermatology, Stanford University, Stanford, California.;Department of Dermatology, School of Medicine, Stanford University, Stanford, California.;Department of Dermatology, School of Medicine, Stanford University, Stanford, California.;Department of Dermatology, Stanford University, Stanford, California.;Department of Dermatology, Stanford University, Stanford, California2Department of Dermatology, School of Medicine, Stanford University, Stanford, California.;Department of Dermatology, Stanford University, Stanford, California.;Cancer Center, Stanford University, Stanford, California.",
"authors": "Ally|Mina S|MS|;Ransohoff|Katherine|K|;Sarin|Kavita|K|;Atwood|Scott X|SX|;Rezaee|Melika|M|;Bailey-Healy|Irene|I|;Kim|Jynho|J|;Beachy|Philip A|PA|;Chang|Anne Lynn S|AL|;Oro|Anthony|A|;Tang|Jean Y|JY|;Colevas|A Dimitrios|AD|",
"chemical_list": "D001152:Arsenicals; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D010087:Oxides; D012333:RNA, Messenger; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D017964:Itraconazole; D000077237:Arsenic Trioxide",
"country": "United States",
"delete": false,
"doi": "10.1001/jamadermatol.2015.5473",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6068",
"issue": "152(4)",
"journal": "JAMA dermatology",
"keywords": null,
"medline_ta": "JAMA Dermatol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002280:Carcinoma, Basal Cell; D019008:Drug Resistance, Neoplasm; D005500:Follow-Up Studies; D053823:Hedgehog Proteins; D006801:Humans; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010087:Oxides; D012333:RNA, Messenger; D012878:Skin Neoplasms; D014157:Transcription Factors; D016896:Treatment Outcome; D000071676:Zinc Finger Protein GLI1",
"nlm_unique_id": "101589530",
"other_id": null,
"pages": "452-6",
"pmc": null,
"pmid": "26765315",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "19060586;19097774;20385363;20624968;21771911;22670903;22670904;22670922;23291299;23349881;23677097;24127444;24493717;25759020;15356649;7165009",
"title": "Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma.",
"title_normalized": "effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma"
} | [
{
"companynumb": "US-MYLANLABS-2017M1039481",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to investigate the incidence of drug-related pneumonitis during mammalian target of rapamycin (mTOR) inhibitor therapy in patients with neuroendocrine tumours (NET) and characterise radiographic patterns of pneumonitis.\n\n\nMETHODS\nSixty-six patients (39 males, 27 females, age: 22-79 years) with advanced NET treated with mTOR inhibitor, everolimus, were retrospectively studied. Chest computed tomography scans during therapy were reviewed for abnormalities suspicious for drug-related pneumonitis by an independent review of two radiologists. Extent, distributions, and specific findings were evaluated in cases positive for pneumonitis. Radiographic patterns of pneumonitis were classified using the American Thoracic Society/European Respiratory Society classification of interstitial pneumonia.\n\n\nRESULTS\nDrug-related pneumonitis was radiographically detected in 14 patients (21%). Time from the initiation of therapy to pneumonitis was within 6 months of therapy in 10 patients (71%), while it ranged from 1.0 to 27.7 months. Pneumonitis was more common in patients who had never smoked (p=0.03). Lower lungs were more extensively involved than upper and middle lungs. Peripheral and lower distributions were most common (n=8), followed by peripheral and multifocal distributions (n=3). Ground glass and reticular opacities were present in all cases, with consolidation in eight cases. The radiographic pattern of pneumonitis was classified as cryptogenic organising pneumonia (COP) pattern in eight patients, non-specific interstitial pneumonia (NSIP) pattern in five, and hypersensitivity pneumonitis pattern in one patient.\n\n\nCONCLUSIONS\nDrug-related pneumonitis was noted in 21% of the advanced NET patients treated with everolimus. Radiographic pattern of pneumonitis was most commonly COP pattern, followed by NSIP pattern.",
"affiliations": "Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA. Electronic address: Mizuki_Nishino@DFCI.HARVARD.EDU.;Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA; Department of Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02215, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA; Department of Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02215, USA.;Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA; Department of Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02215, USA.;Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA.",
"authors": "Nishino|Mizuki|M|;Brais|Lauren K|LK|;Brooks|Nichole V|NV|;Hatabu|Hiroto|H|;Kulke|Matthew H|MH|;Ramaiya|Nikhil H|NH|",
"chemical_list": "D000970:Antineoplastic Agents; D000068338:Everolimus",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "53()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Computed tomography; Drug toxicity; Neuroendocrine tumours; Pneumonitis; mTOR inhibitor",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000068338:Everolimus; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D010190:Pancreatic Neoplasms; D011014:Pneumonia; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "163-70",
"pmc": null,
"pmid": "26760924",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "24410308;26100356;24245774;24032382;23867634;23388840;22850321;22483544;22468112;22119496;21444868;21306238;20142598;19549709;19648533;18627208;18653228;11790668;11813820;16806903;17538086;24053120;26205737;25117065;25726730;26176400",
"title": "Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors: a radiographic pattern-based approach.",
"title_normalized": "drug related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors a radiographic pattern based approach"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-01887",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"druga... |
{
"abstract": "Cutaneous basosquamous carcinoma is a variant of basal cell carcinoma that is characterized by histopathological features of both basal and squamous cell carcinoma. Due to its local invasiveness, high frequency of recurrence, and its metastatic potential, it is considered to be one of the most aggressive subtypes of basal cell carcinoma. We present the case of an 81-year-old male who was admitted to the hospital with incessant hemorrhage arising from a cutaneous tumor that later proved to be a basosquamous carcinoma. Due to the COVID-19 pandemic at the time, the patient did not seek medical attention as soon as the bleeding was observed, although he did present when the symptom increased in intensity and became incessant. To our knowledge, this is the first case report of a cutaneous basosquamous carcinoma that presents with a massive life-threatening hemorrhage tumor, thus endangering the patient's life. The clinical and histopathological features, the behavior and the treatment of cutaneous basosquamous carcinoma are further reviewed in this article.",
"affiliations": "Department of Thoracic Surgery, 'Carol Davila' University of Medicine and Pharmacy, 050474 Bucharest, Romania.;2nd Department of Dermatology, 'Colentina' Clinical Hospital, 020125 Bucharest, Romania.;2nd Department of Dermatology, 'Colentina' Clinical Hospital, 020125 Bucharest, Romania.;Department of Thoracic Surgery, 'Carol Davila' University of Medicine and Pharmacy, 050474 Bucharest, Romania.;1st Department of Thoracic Surgery, 'Prof. Dr. Marius Nasta' Institute of Pneumophtisiology, 050159 Bucharest, Romania.;Department of Pneumophtisiology, 'Carol Davila' University of Medicine and Pharmacy, 050474 Bucharest, Romania.;2nd Department of Dermatology, 'Colentina' Clinical Hospital, 020125 Bucharest, Romania.;Department of Urology, 'Carol Davila' University of Medicine and Pharmacy, 050474 Bucharest, Romania.",
"authors": "Petreanu|Cornel Adrian|CA|;Șerban|Elena-Daniela|ED|;Constantin|Maria-Magdalena|MM|;Savu|Cornel|C|;Zariosu|Alexandru Victor|AV|;Deleanu|Oana Claudia|OC|;Bucur|Stefana|S|;Constantin|Traian|T|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2021.10592",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "22(4)",
"journal": "Experimental and therapeutic medicine",
"keywords": "COVID-19 pandemic; basal cell carcinoma; basosquamous carcinoma; hemorrhage; life-threatening",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "1158",
"pmc": null,
"pmid": "34504603",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": "31831330;26183979;24332516;28220485;24831322;15541449;27570202;31288208;22251204;27160235;12859383;15929123;22959232;30766448;20484877;29973992;27340741;23607676;20885244;25810014;12100183;10717618;20026854;19103364;7857111;22612571;33116191;29923189",
"title": "Basal cell carcinoma-not always the 'good guy': Case report of a life-threatening basosquamous carcinoma and review of the literature.",
"title_normalized": "basal cell carcinoma not always the good guy case report of a life threatening basosquamous carcinoma and review of the literature"
} | [
{
"companynumb": "RO-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-105865",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APIXABAN"
},
"drugaddit... |
{
"abstract": "Leflunomide (LEF) is an isoxazole derivative used as disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA). It is effective and safe in patients with active RA, in whom standard treatment is insufficient or contraindicated, but it can cause interstitial lung disease (ILD). Identified risk factors for LEF-induced ILD include pre-existing ILD, cigarette smoking, low body weight, and use of loading dose. LEF should be avoided in patients with pre-existing ILD. We present a case of 59-year-old male with RA and a history of smoking and methotrexate (MTX) treatment, who developed dyspnoea, non-productive cough, and fever about two months after the administration of LEF. The clinical and radiological presentation was of acute pneumonia. The patient was treated with methylprednisolone pulse, prednisone, and cyclophosphamide, but he died of respiratory failure.",
"affiliations": "i.siemion@igichp.edu.pl.",
"authors": "Siemion-Szcześniak|Izabela|I|;Bartoszuk|Iwona|I|;Bartosiewicz|Małgorzata|M|;Jakubowska|Lilia|L|;Wesołowski|Stefan|S|;Kuś|Jan|J|",
"chemical_list": "D018501:Antirheumatic Agents; D005938:Glucocorticoids; D007555:Isoxazoles; D000077339:Leflunomide",
"country": "Poland",
"delete": false,
"doi": "10.5603/PiAP.2014.0075",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0867-7077",
"issue": "82(6)",
"journal": "Pneumonologia i alergologia polska",
"keywords": null,
"medline_ta": "Pneumonol Alergol Pol",
"mesh_terms": "D000208:Acute Disease; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005938:Glucocorticoids; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias; D007555:Isoxazoles; D000077339:Leflunomide; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "9302892",
"other_id": null,
"pages": "568-75",
"pmc": null,
"pmid": "25339568",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute interstitial pneumonia in patient with rheumatoid arthritis treated with leflunomide.",
"title_normalized": "acute interstitial pneumonia in patient with rheumatoid arthritis treated with leflunomide"
} | [
{
"companynumb": "PL-SA-2015SA011086",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": null,
... |
{
"abstract": "Gastrointestinal stromal tumor is a rare mesenchymal tumor. Sorafenib is an effective medication in these tumors based on two phase II clinical trials and a retrospective analysis. We report a rare case of a 57-year-old male with acute hepatotoxicity from sorafenib. He was treated conservatively with IV fluids and prednisolone. Liver function tests improved over 2 months. We conclude that sorafenib could cause life-threatening hepatotoxicity and patients taking sorafenib need to be closely monitored.",
"affiliations": "Division of Hematology and Oncology, University of New Mexico Cancer Center, Albuquerque, NM.;Division of Hematology and Oncology, University of New Mexico Cancer Center, Albuquerque, NM.;Division of Hematology and Oncology, University of New Mexico Cancer Center, Albuquerque, NM.",
"authors": "Murad|Waheed|W|;Rabinowitz|Ian|I|;Lee|Fa-Chyi|FC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.2014.19",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2014.1910.14309/crj.2014.19Case ReportLiverSorafenib-Induced Grade Four Hepatotoxicity in a Patient with Recurrent Gastrointestinal Stromal Tumor (GIST): A Case Report and Review of Literature Murad Waheed MDRabinowitz Ian MDLee Fa-Chyi MDDivision of Hematology and Oncology, University of New Mexico Cancer Center, Albuquerque, NMCorrespondence: Waheed Murad, MD, University of New Mexico Cancer Center, 1201 Camino de Salud NE, Albuquerque, NM 87131 (wmurad@salud.unm.edu).1 2014 10 1 2014 1 2 115 117 05 11 2013 02 1 2014 Copyright © Murad et al.2014This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Gastrointestinal stromal tumor is a rare mesenchymal tumor. Sorafenib is an effective medication in these tumors based on two phase II clinical trials and a retrospective analysis. We report a rare case of a 57-year-old male with acute hepatotoxicity from sorafenib. He was treated conservatively with IV fluids and prednisolone. Liver function tests improved over 2 months. We conclude that sorafenib could cause life-threatening hepatotoxicity and patients taking sorafenib need to be closely monitored.\n==== Body\nIntroduction\nMesenchymal tumors including gastrointestinal stromal tumors (GIST) are rare tumors of the GI tract and comprise less than 1% of primary GI tumors. These tumors can involve any part of the GI tract, omentum, and mesentery.1 The primary treatment is surgical resection of a tumor larger than 2 cm.2 The majority of tumors have C-kit mutation and some contain a platelet-derived growth factor receptor polypeptide gene (PDGFR-A) mutation.1 The kit mutation is thought to drive the tumor.3 The risk of progressive disease is high in a tumor larger than 2 cm and >5 mitoses per 50 microscopic high-power field (HPF) in tissue sections.2 There are 3 FDA-approved drugs for metastatic GIST: imatinib, sunitinib, and regorafenib.5 Sorafenib is a recommended treatment option based on National Comprehensive Cancer Network (NCCN) guidelines. We report a case of NCIC common toxicity criteria (CTC) grade 4 hepatotoxicity caused by sorafenib in a patient with GIST and review the literature for sorafenib-induced severe hepatotoxicity.\n\nCase Report\nA 57-year-old Vietnamese male with history of coronary artery disease status post-percutaneous coronary intervention 8 years ago with consequent systolic heart failure (ejection fraction of 35–40%) presented to the hospital with abdominal pain. He did not drink alcohol and his medications include metoprolol, quinapril hydrochloride, tamsulosin, aspirin, and atorvastatin. CT scan of the abdomen demonstrated small bowel obstruction resulting from a 9.9 × 6.4-cm mass arising from the small bowel. During emergent surgery, the tumor was removed with en bloc resection of small bowel, sigmoid colon, and portion of rectum. The pathologic specimen confirmed multifocal GIST with a high Ki-67. The tumor was C-kit (CD 117-stem cell factor receptor) positive.\n\nHe was offered adjuvant imatinib but he declined due to concerns for side effects. Surveillance CT scan 6 months later showed recurrence of disease. He was given imatinib, and, 1 month later, developed severe NCIC CTC grade 3 diarrhea and abdominal pain with normal liver function tests (LFTs). The imatinib was stopped.\n\nSunitinib is often used in patients who are resistant to or intolerant to imatinib, but can worsen underlying heart failure and was avoided in this patient. His LFTs were normal when he was prescribed sorafenib 200 mg twice daily. He reported feeling better after 1 month; side effects included grade 1 fatigue and dizziness but no diarrhea or hand-foot syndrome. His LFTs remained normal.\n\nTwo months later, he noticed darkening of urine color and worsening abdominal pain. He developed frank jaundice within a few days but no mental status alteration. He was admitted to the hospital for supportive care. Blood serology revealed normal alpha 1 antitrypsin, ceruloplasmin, and no evidence of viral hepatitis, Epstein-Barr virus, cytomegalovirus, or autoimmune hepatitis. Triple phase CT showed hepatic steatosis and pelvic masses consistent with his known recurrent GIST. Biopsy of the liver showed moderate acute hepatitis with parenchymal necrosis, prominent canalicular cholestasis, and lymphocytic infiltrate (Figure 1). His ALT and AST levels peaked to 1,193 U/L and 766 U/L, respectively, prior to total bilirubin peak at 23 mg/dL (direct bilirubin 20 mg/dL) after 2 weeks (Figure 2). His prothrombin time increased to 15.7 seconds and INR to 1.25. His alkaline phosphatase increased to 285 U/L.\n\nFigure 1 Morphology of core needle biopsy of the liver showed diffuse acute hepatitis with inflammatory infiltrate containing occasional eosinophils.\n\nFigure 2 Graph of liver function tests showing increase in transaminases over 2 weeks, followed by slow recovery over 2 months. Total bilirubin peaked at 23 mg/dL, and was back to baseline in approximately 2 months after discontinuation of sorafenib. Aspartate aminotransferase (AST; blue circle); alanine aminotransferase (ALT; green square); alkaline phosphatase (turquoise triangle); and bilirubin (red diamond).\n\nHe was treated with IV fluids and prednisolone, and his sorafenib was discontinued. His liver function tests normalized over the course of 10 weeks. He subsequently was given sunitinib after complete normalization of his liver function tests.\n\nDiscussion\nSorafenib (Nexavar®) is a small molecule multi-tyrosine kinase inhibitor (TKI) that inhibits RAF kinase; vascular endothelial factor receptor 1, 2, and 3; and other tyrosine kinases.6 Sorafenib is metabolized primarily by oxidative metabolism in the liver (mediated by CYP3A4) and glucuronidation (mediated by UGT1A9).7 Common side effects (any grade in >30% of patients) are diarrhea, rash, fatigue, and hand-foot syndrome.6 Some of these side effects are dose limiting.\n\nThis agent is commonly used for patients with Child Pugh A and selected patients with Child Pugh B unresectable hepatocellular carcinoma (HCC)8 and metastatic renal cell carcinoma.6 Preclinical studies suggest sorafenib is active in imatinib-resistant GIST. This was thought to be due to activity of sorafenib against secondary Kit mutations.9 There was no NCI CTC grade IV hyperbilirubinemia or elevation of liver enzymes in the phase II study of sorafenib in resistant and refractory GIST patients,9 and this is the first case report of NCI CTC grade IV hepatotoxicity in patients with GIST.\n\nIn a small phase II trial of metastatic GIST resistant to imatinib or sunitinib, sorafenib has shown a disease control rate of 36%. The progression-free survival and overall survival was 4.9 months and 9.7 months, respectively.9 A retrospective analysis of sorafenib as third or fourth line treatment in 124 patients with advanced GIST showed a response rate of 10% and stabilization of disease in 57% of patients.10 In another phase II study, the use of sorafenib in 38 patients with imatinib and sunitinib-resistant GIST resulted in a disease control rate of 68%.11\n\nIn a randomized phase III trial of sorafenib in unresectable HCC, 1% of patients had grade IV liver toxicity, even though most of these patients had baseline Child Pugh A cirrhosis.8 Of patients with hepatocellular carcinoma who received Sorafenib in a large phase III trial, the incidence of grade IV increase in AST was 2%, ALT 1%, and hyperbilirubinemia 2%; however, the experimental arm (brivanib) had the same incidence of hepatotoxicity.12\n\nSorafenib is one of the FDA-approved TKI in renal cell carcinoma; in a pivotal phase III trial, no hepatotoxicity was documented.6 It is possible that these patients in this trial had relatively healthy livers compared to those with hepatocellular carcinoma. This explanation is supported by the absence of hepatotoxicity in a randomized phase III trial of axitinib versus sorafenib in metastatic renal cell cancer.14 Unlike these two large clinical trials, 2% of patients had grade IV increase in AST and ALT when sorafenib was compared to tivazonib.15 Nineteen percent of patients in the sorafenib arm had liver metastases, but the status of liver metastases in patients who had elevation of transaminases is not clear from publication.\n\nGupta-Abramson et al reported a phase II trial of sorafenib in advanced thyroid cancer. One patient developed worsening LFTs 8 weeks after commencement of treatment; despite stopping treatment and supportive care, the patient died 3 months later from liver failure. The patient refused liver biopsy and there were no reported drug–drug interactions or other clear etiology for the liver failure except sorafenib.13 One patient with metastatic renal cell carcinoma who had a normal liver with no metastases when he was given sorafenib as part of SORCE trial developed a severe idiosyncratic reaction 7 weeks after starting treatment. He later on died of fulminant hepatic failure. The autopsy revealed lobular hepatitis and hepatocyte necrosis.16 Our patient's liver toxicity also happened between 6-8 weeks after initiation of the drug.\n\nThis review of literature suggests relative increased risk of hepatotoxicity in patients with underlying liver damage by liver cirrhosis, hepatocellular carcinoma, or hepatic metastases.15 However, our case illustrates that hepatotoxicity is also possible in patients with normal liver function. It is not clear what increases the risk of hepatotoxicity, as the reported phase III RCC trials do not detail whether there were drug interactions, underlying liver metastases, or liver disease in patients who developed hepatotoxicity. Sorafenib is commonly used in hepatocellular and renal cell carcinoma, and we suggest careful, regular monitoring of liver function tests during treatment.\n\nDisclosures\nAuthor contributions: All authors contributed equally to the preparation of this article. W. Murad is the article guarantor.\n\nFinancial disclosure: No relevant potential conflict of interest or funding to disclose.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1 Miettinen M , Lasota J \nGastrointestinal stromal tumors: Definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis . Virchows Arch . 2001 ;438 (1 ):1 –12 .11213830 \n2 Sepe PS , Brugge WR \nA guide for the diagnosis and management of gastrointestinal stromal cell tumors . Nat Rev Gastroenterol Hepatol . 2009 ;6 (6 ):363 –71 .19365407 \n3 Hirota S , Isozaki K , Moriyama Y , et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors . Science . 1998 ;279 (5350 ):577 –80 .9438854 \n4 Dematteo RP , Ballman KV , Antonescu CR , et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial . Lancet . 2009 ;373 (9669 ):1097 –104 .19303137 \n5 Demetri GD , van Oosterom AT , Garrett CR , et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial . Lancet . 2006 ;368 (9544 ):1329 –38 .17046465 \n6 Escudier B , Eisen T , Stadler WM , et al. Sorafenib in advanced clearcell renal cell carcinoma . N Engl J Med . 2007 ;356 (2 ):125 –34 .17215530 \n7 Keating GM , Santoro A \nSorafenib: A review of its use in advanced hepatocellular carcinoma . Drugs . 2009 ;69 (2 ):223 –40 .19228077 \n8 Llovet JM , Ricci S , Mazzaferro V , et al. Sorafenib in advanced hepatocellular carcinoma . N Engl J Med . 2008 ;359 :378 –90 .18650514 \n9 Park SH , Ryu MH , Ryoo BY , et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: A phase II study of Korean gastrointestinal stromal tumors study group . Invest New Drugs . 2012 ;30 (6 ):2377 –83 .22270258 \n10 Montemurro M , Gelderblom H , Bitz U , et al. Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis . Eur J Cancer . 2013 ;49 (5 ):1027 –31 .23140824 \n11 Kindler HL , et al. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): Final results of a University of Chicago Phase II Consortium trial . ASCO Meeting Abstracts . 2011 ;29 (suppl 15 ).\n12 Johnson PJ , Qin S , Park JW , et al. Brivanib versus sorafenib as firstline therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISK-FL study . J Clin Oncol . 2013 ;31 (28 ):3517 –24 .23980084 \n13 Gupta-Abramson V , Troxel AB , Nellore A , et al. Phase II trial of sorafenib in advanced thyroid cancer . J Clin Oncol . 2008 ;26 (29 ):4714 –9 .18541894 \n14 Rini BI , Escudier B , Tomczak P , et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial . Lancet . 2011 ;378 (9807 ):1931 –9 .22056247 \n15 Motzer RJ , Nosov D , Eisen T , et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: Results from a phase III trial . J Clin Oncol . 2013 ;31 (30 ):3791 –9 .24019545 \n16 Fairfax BP , Pratap S , Roberts IS , et al. Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma . BMC Cancer . 2012 ;12 :590 .23231599\n\n",
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"title": "Sorafenib-Induced Grade Four Hepatotoxicity in a Patient with Recurrent Gastrointestinal Stromal Tumor (GIST): A Case Report and Review of Literature.",
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"abstract": "Multiple myeloma (MM) is a hematologic neoplasm characterized by plasma tumor cell proliferation in the bone marrow. It's a rare malignancy before a 40-year-old and it is extremely uncommon during pregnancy. We report the case of a 37-year-old woman with a newly diagnosed IgG λ MM (Durie-Salmon stage IIIA, International Staging System II and good prognosis cytogenetic) at the 27th week of her pregnancy. Our management during pregnancy, the delivery, and initiation of anti-myeloma treatment with bortezomib, lenalidomide, and dexamethasone are published. There are a few reviews reporting the most common features and management of MM during pregnancy. We perform a comprehensive review of all 32 cases reported between 1965 and 2014 in which a MM was diagnosed during pregnancy including score, cytogenetic results, labor characteristics, and response to therapy. About 53% of pregnant women did not start treatment before partum. Cesarean section was the most common form of delivery (82%). About 88% of newborns were healthy, although most of them were premature (73%). Management of a MM diagnosed during pregnancy should be based on the presence of myeloma-related organ damage to secure survival of the mother without fetal adverse effects related to treatment. Serial fetal ultrasound may be helpful in order to avoid complications. The cesarean section may be preferred depending on maternal and fetus prognosis. Whole-body diffusion-weighted imaging minimal response could be an appropriate technique to discard plasmacytomas during pregnancy in critical situations such as the appearance of symptoms of spinal cord compression. Therapeutic choices should be agreed with the pregnant after a thorough discussion of the prognostic factors of the disease and the potential risk for the fetus and the patient. While awaiting partum, dexamethasone is a non-toxic treatment. Triple therapy including a proteasome inhibitor should be started quickly after delivery. Copyright © 2014 John Wiley & Sons, Ltd.",
"affiliations": "Department of Hematology, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Obstetrics, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Hematology, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Hematology, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Obstetrics, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Hematology, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Hematology, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Clinical Analysis, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Clinical Analysis, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Internal Medicine, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Radiology, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Hematology, Virgen de la Arrixaca University Hospital, Murcia, Spain.;Department of Hematology, Virgen de la Arrixaca University Hospital, Murcia, Spain.",
"authors": "Cabañas-Perianes|Valentin|V|;Macizo|Maribel|M|;Salido|Eduardo|E|;Blanquer|Miguel|M|;Araico|Fernando|F|;Melero-Amor|Antonia|A|;Garcia-Candel|Faustino|F|;Muñoz-Garcia|Maria Isabel|MI|;Martinez-Villanueva|Miriam|M|;Muñoz-Esparza|Carmen|C|;Guzmán-Aroca|Florentina|F|;Pérez-López|Raúl|R|;Moraleda|Jose Maria|JM|",
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"keywords": "immunofixation; multiple myeloma; plasma cells; pregnant",
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"pubdate": "2016-06",
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"title": "'Management multiple myeloma during pregnancy: a case report and review'.",
"title_normalized": "management multiple myeloma during pregnancy a case report and review"
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"abstract": "Squamous cell carcinoma of the prostate is rare and represents 0.5% to 1% of prostatic carcinomas. Transformation of prostatic adenocarcinoma into squamous cell carcinoma after LH-RH agonist intake has been reported in only 8 cases in the literature. To our knowledge, our case is the second pure squamous cell carcinoma observed after hormonotherapy and radiotherapy. We reported a case of a patient with prostatic adenocarcinoma treated by radical prostatectomy followed by radiotherapy. Eleven years later, he had a vesical recurrence of prostatic adenocarcinoma. Our patient had an endoscopic resection followed by injections of Triptorelin. Six months later, he developed a local recurrence of a squamous cell carcinoma.",
"affiliations": "Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.;Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie.",
"authors": "Ichaoui|Hamza|H|;Nasr|Sonia Ben|SB|;Gargouri|Faten|F|;Zribi|Aref|A|;Hermi|Amine|A|;Fendri|Sana|S|;Balti|Mehdi|M|;Ayari|Jihen|J|;Khiari|Ramzi|R|;Msakni|Issam|I|;Mansouri|Nada|N|;Ghozzi|Samir|S|;Haddaoui|Abderrazek|A|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone",
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"doi": "10.11604/pamj.2019.34.125.19421",
"fulltext": "\n==== Front\nPan Afr Med J\nPan Afr Med J\nPAMJ\nThe Pan African Medical Journal\n1937-8688 The African Field Epidemiology Network \n\nPAMJ-34-125\n10.11604/pamj.2019.34.125.19421\nCase Report\nTransformation of a prostatic adenocarcinoma into squamous cell carcinoma after luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy treatment\nIchaoui Hamza 12 Nasr Sonia Ben 34& Gargouri Faten 56 Zribi Aref 34 Hermi Amine 12 Fendri Sana 34 Balti Mehdi 34 Ayari Jihen 34 Khiari Ramzi 12 Msakni Issam 56 Mansouri Nada 56 Ghozzi Samir 12 Haddaoui Abderrazek 34 1 Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie\n2 The Military Hospital of Tunis, Department of Urology, Montfleury 1008, Tunis, Tunisia\n3 Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie\n4 The Military Hospital of Tunis, Department of Medical Oncology, Montfleury 1008, Tunis, Tunisia\n5 Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie\n6 The Military Hospital of Tunis, Department of Pathology, Montfleury 1008, Tunis, Tunisia\n& Corresponding author: Sonia Ben Nasr, Université de Tunis El Manar, Faculté de Médecine de Tunis, 1007, Tunis, Tunisie, The Military Hospital of Tunis, Department of Medical Oncology, Montfleury 1008, Tunis, Tunisia\n01 11 2019 \n2019 \n34 12510 6 2019 29 6 2019 © Hamza Ichaoui et al.2019The Pan African Medical Journal - ISSN 1937-8688. 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 work is properly cited.Squamous cell carcinoma of the prostate is rare and represents 0.5% to 1% of prostatic carcinomas. Transformation of prostatic adenocarcinoma into squamous cell carcinoma after LH-RH agonist intake has been reported in only 8 cases in the literature. To our knowledge, our case is the second pure squamous cell carcinoma observed after hormonotherapy and radiotherapy. We reported a case of a patient with prostatic adenocarcinoma treated by radical prostatectomy followed by radiotherapy. Eleven years later, he had a vesical recurrence of prostatic adenocarcinoma. Our patient had an endoscopic resection followed by injections of Triptorelin. Six months later, he developed a local recurrence of a squamous cell carcinoma.\n\nProstatesquamous cell carcinomahormonotherapy\n==== Body\nIntroduction\nProstatic Squamous Cell Carcinoma (SCC) is a rare tumor with aggressive nature and represents 0.5% to 1% of prostatic carcinomas [1,2]. Therefore, clinical presentation, symptoms, treatment and prognosis were reported only in case reports. SCC has a poor response to conventional treatment and results in poor prognosis because of early metastasis to the bone, liver and lungs with an average survival of 14 months [1,2]. Transformation of prostatic adenocarcinoma to SCC after injection of LH-RH agonist or radiotherapy (RT) have been reported in the literature in few cases. We reported a case of prostatic SCC developed in a patient with prostatic ADK following hormonotherapy (HT).\n\nPatient and observation\nA 71-year-old man consulted for a clinically suspected prostate hypertrophy with a serum Prostate-specific antigen (PSA) level within the reference range of 2.7ng/ml (normal: 0-4 ng/mL). Transrectal ultrasound guided needle prostatic biopsy concluded to Gleason 6 (3+3) prostatic adenocarcinoma. Prostatic MRI showed a low signal intensity mass in peripheral zone. Diffusion weighted image showed a high signal intensity mass in peripheral zone without extracapsular extension. Bone scan and Chest, Abdomen and pelvis CT-scan didn't show metastasis. A radical prostatectomy was performed and pathological examination concluded to a Gleason 6 ADK (3 + 3) classified pT2aN0M0 (Figure 1). HT using LHRH analogue (Triptorelin) and antiandrogen agent (bicalutamide) were started, and serum PSA level gradually decreased to a nadir of 0.04ng/ml. The patient had a biological recurrence (PSA at 0.52) after 2 years with a doubling time greater than 12 months. He had a salvage RT (66Gy) and the PSA level didn't exceed 0.08ng/ml over a period of 4 years. Nine years after treatment, patient complained of hematuria with a rise in PSA level between 0.33 and 0.59ng/ml over a period of three years. A cystoscopy objectified a peri-cervical mass of 2 cm whose resection concluded to a vesical localization of a prostatic ADK (Figure 2). HT (Triptorelin and Cyproterone acetate) was done. Six months later, hematuria recurred and cystoscopy objectified a bladder recurrence. Histopathological examination concluded to a bladder squamous cell carcinoma (Figure 3). The patient refused total cystectomy. He had Gemcitabin and Cisplatinum chemotherapy (CT) combined with Triptorelin with partial response after three cycles of CT and good tolerance. The patient is still under treatment.\n\nFigure 1 Gleason 6 (3+3) prostatic ADK: individual well-formed glands\n\nFigure 2 Vesical localization of a prostatic ADK (PSA +): large irregular cribriform massives\n\nFigure 3 Bladder squamous cell carcinoma: massive of atypical squamous cells (PSA-) centered by keratin pearls\n\nDiscussion\nSquamous cell carcinoma of the prostate is a rare tumor (0.5 to 1% of all prostate cancers) with aggressive nature and more frequent extension beyond the prostate gland [2,3]. The average age of onset is 68 years with extremes ranging from 42 to 85 years [2,4]. It differs from common ADK in its therapeutic response and prognosis. This type of tumor has a poor response to conventional treatment resulting in poor prognosis. Due to high degree of malignancy, SCC of the prostate generally metastasizes early to the bone, liver, lungs, and lymph nodes. The bone metastases are usually osteolytic rather than osteoblastic [1,5]. The prostate-specific antigen (PSA) test and Gleason score are of limited value in epidermoid carcinoma diagnosis, and the median survival rate after diagnosis is estimated at 14 months [5-8]. About half of cases occur after the management of prostatic ADK with HT and/or RT. However, they are often associated with an ADK component. Sometimes, patients have no history of prostatic disease, or other locations of SCC, it is then a primitive form of prostate SCC [2,9]. The histological features of prostatic SCC include the presence of cellular metaplasia and local invasion with signs of squamous differentiation: keratinization, the presence of squamous beads and/or many distinct intercellular bridges [10]. It may be challenging to distinguish between SCC and non-neoplastic squamous metaplasia, which may be secondary to infarct, acute or chronic prostatitis, granulomatous prostatitis due to BCG therapy, estrogen therapy or pelvic irradiation [11]. Epidermoid differentiation in prostate cancer can be found either in pure form, or associated with ADK, urothelial carcinoma or sarcoma contingent. The absence of ADK component distinguishes pure SCC from adenosquamous carcinoma [9]. The histogenesis of SCC has always been controversial. The origin may be prostatic or bladder urethral squamous cell, prostatic acini metaplasia, or squamous metaplasia of a prostatic tumor [1,3].Transformation of ADK to SCC occurred secondary to RT or HT. Most case reports of squamous transformation occurring after RT or HT tended to be associated with high grade ADK. Extensive squamous metaplasia, pluripotent stem cells capable of multidirectional differentiation or metaplastic transformation of adenocarcinoma were reported to be possible origins [1]. Lager et al [12] reported SCC developed due to adverse stimuli affecting columnar cells causing them to express normal prostatic antigen such as PSA and prostatic acid phosphatase, although retaining the ability to produce keratin resulting in no elevated serum PSA even in a metastatic disease context.\n\nGiven its possible multiple origins, it may be challenging to decide whether the epidermoid component developed from a divergent differentiation of ADK after RT or HT, or from a squamous differentiation of carcinoma to Transitional cells, or it is just a primitive epidermoid carcinoma, called “De Novo” [1]. Imaging diagnosis of SCC of the prostate is challenging because of its rarity and lack of well-established imaging characteristics. Differential diagnosis of a rapidly growing prostate mass with aggressive nature includes recurred adenocarcinoma and small cell differentiation. If a rapid growth of a prostate mass with a history of RT or HT was noted, squamous transformation of prostate cancer is possible [1]. The treatment is controversial. Various approaches including surgical intervention, CT and RT have been implemented without durable response [1]. In our study, we reported a case of pure SCC that appeared six months after injection of an LH-RH agonist (Triptorelin) and eight years after external beam RT. With did a review of the literature focusing on epidermoid carcinoma that occurred after a radio or hormonotherapy (Table 1). Over seventy cases of prostatic cancer with epidermoid differentiation were reported in English literature [2]. Forty of these cases were caused by the transformation of prostatic ADK into SCC after RT and/or HT. Carcinoma was purely epidermoid in 8 cases and adenosquamous in 32 cases [1,4-6, 9,13-20]. Only seven cases were reported after injection of an LH-RH agonist, among which, only one case was a pure epidermoid carcinoma [5]. To the best of our knowledge, our patient is the second case presenting a pure epidermoid carcinoma resulting from the transformation of a prostatic ADK after injection of a LH-RH agonist. Brazilis et al [6] reported the first case of prostatic ADK transformation into epidermoid carcinoma after injection of an LH-RH agonist. They recommended the report of any other cases to prove the incrimination of LH-RH agonists into the histogenesis of squamous cell carcinomas. Our case should contribute in helping pathologists, oncologists, radiologists and urologists to better understand the nature and pathogenesis of this aggressive tumor to improve its management.\n\nTable 1 Published cases about transformation of prostatic adenocarcinoma into SCC after HT and RT\n\n\tPure epidermoid carcinoma\tAdenosquamous carcinoma\tPrior treatment\t\nWilliams MJ et al. (1956)\t--\t2 cases\tOrchidectomy + Stilbestrol\t\nWernert et al. (1990)\t--\t2 cases\testrogenotherapy\t\nDevaney et al. (1991)\t--\t1 case\testrogenotherapy (Stilbestrol)\t\nBrazilis et al. (1995)\t--\t1 case\t-LHRH analogue (Leuprorelin) + Flutamide\t\nMiller VA et al. (1995)\t1 case\t--\tbrachytherapy\t\nBassler Tj et al. (1999)\t--\t5 cases\tHT and/or RT\t\nHelal M et al. (2000)\t\t2 cases\tRadiotherapy\t\nMohan et al. (2003)\t1 case\t--\tBilateral orchidectomy + RT\t\nParwani et al. (2004)\t3 cases.\nNote: Authors didn’t specify the treatment received for these three patients.\t18 cases\t-LHRH analogue (Leuprorelin) : 4 cases - Estrogenes: 2 cases -4 cases occurred after RT -1 case occurred after RT+HT the remaining cases were not specified\t\nJohn TT et al. (2005)\t1 case\t--\tBilateral Orchidectomy\t\nArva et al. (2011)\t1 case\t--\tbrachytherapy\t\nAL Quasim et al. (2014)\t1 case\t--\t-LHRH analogue (Leuprorelin)\t\nJihyun Lee (2019)\t--\t1 case\tLHRH analogue (goserelin) and antiandrogen agent (bicalutamide)\t\nTotal\t8 cases\t32 cases\t\t\nConclusion\nProstatic SCC is rare. Transformation of a prostatic ADK into SCC after HT with a LH-RH agonist or RT is rarer. As the number of patients treated with LH-RH agonists is growing, it will be interesting to understand the histogenesis of this tumor to improve therapy and prognosis.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAcknowledgments\nWe thank all authors for their contribution to manuscript elaboration.\n\nAuthors’ contributions\nI confirm that all the authors of the manuscript have read and agreed to its content. Hamza Ichaoui, Sonia Ben Nasr, Faten Gargouri, Aref Zribi, Amir Hermi, Sana Fendri and Nada Mansouri wrote the paper. Mehdi Balti, Jihen Ayari , Ramzi Khiari, Issam Msakni, Samir Ghozzi and Abderrazek Haddaoui contributed to quality control and correction of the manuscript before submission.\n==== Refs\nReferences\n1 Jihyun L Transformation of adenocarcinoma of prostate to squamous cell carcinoma following hormonal treatment: A case report and review of the literature Radiology Case Reports 2019 14 14 483 489 30805072 \n2 Bahloul A Charfi S Franck F Jung JL Primary squamous cell carcinoma of the prostate: a case report and review of literature Afr J Urol 2016 22 235 9 \n3 Munoz F Franco P Ciammella P Clerico M Giudici M Filippi AR Squamous cell carcinoma of the prostate: long-term survival after combined chemo-radiation Radiat Oncol 2007 2 15 17407588 \n4 Parwani AV Kronz JD Genega EM Gaudin P Chang S Epstein JI Prostate Carcinoma With Squamous Differentiation: an analysis of 33 Cases Am J Surg Pathol 2004 28 5 651 7 15105655 \n5 Al-Qassim Z Mohammed A Payne D Stocks PJ Khan Z Squamous cell carcinoma of the prostate following treatment with an LHRH-agonist: a rare case of transformation of adenocarcinoma of the prostate Cent European J Urol 2014 67 1 26 8 \n6 Braslis KG Davi RC Nelson E Civantos F Soloway MS Squamous cell carcinoma of the prostate: a transformation from adenocarcinoma after the use of a luteinizing hormone-releasing hormone agonist and flutamide Urology 1995 45 2 329 331 7855985 \n7 Sarma DP Weilbaecher TG Moon TD Squamous cell carcinoma of prostate Urology 1991 37 3 260 262 2000687 \n8 Grignon DJ Unusual subtypes of prostate cancer Mod Pathol 2004 17 3 316 327 14976541 \n9 Arva NC Das K Diagnostic dilemmas of squamous differentiationin prostate carcinoma case report and review of the literature Diagn Pathol 2011 6 46 21627811 \n10 Mott LJ Squamous cell carcinoma of the prostate: report of 2 cases and review of the literature J Urol 1979 121 6 833 5 458967 \n11 Malik RD Dakwar G Hardee ME Sanfilippo NJ Rosenkrantz AB Taneja SS Squamous Cell Carcinoma of the Prostate Rev Urol 2011 13 1 56 60 21826130 \n12 Lager DJ Goeken JA Kemp JD Robinson RA Squamous metaplasia of the prostate. An immunohistochemical study Am J Clin. Pathol 1988 90 5 597 601 2459960 \n13 Williams MJ Klein EI Prostatic adenocarcinoma complicated by the development of epidermoid carcinoma of the urethra; report of two cases J Urol 1956 75 2 314 23 13296133 \n14 Wernert N Goebbels R Bonkhoff H Dhom G Squamous cell carcinoma of the prostate Histopathology 1990 17 4 339 44 1701756 \n15 Devaney DM Dorman A Leader M Adenosquamous carcinoma of the prostate: a case report Hum Pathol 1991 22 10 1046 50 1842377 \n16 Miller VA Reuter V Scher HI Primary squamous cell carcinoma of the prostate after radiation seed implantation for adenocarcinoma Urology 1995 46 1 111 3 7541581 \n17 Bassler TJ Orozco R Bassler IC Boyle LM Bormes T Adenosquamous carcinoma of the prostate: case report with DNA analysis, immunohistochemistry and literature review Urology 1999 53 4 832 4 10197870 \n18 Helal M Diaz JI Tannenbaum A Postradiation therapy adenosquamous cell carcinoma of the prostate Prostate Cancer Prostatic Dis 2000 3 1 53 6 12497163 \n19 Mohan H Bal A Punia RP Bawa AS Squamous cell carcinoma of the prostate Int J Urol 2003 10 2 114 6 12588611 \n20 John TT Bashir J Burrow CT Machin DG Squamous cell carcinoma of the prostate-a case report Int Urol Nephrol 2005 37 2 311 3 16142562\n\n",
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"journal": "The Pan African medical journal",
"keywords": "Prostate; hormonotherapy; squamous cell carcinoma",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D018931:Antineoplastic Agents, Hormonal; D002294:Carcinoma, Squamous Cell; D003131:Combined Modality Therapy; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D011468:Prostatectomy; D011471:Prostatic Neoplasms; D017329:Triptorelin Pamoate",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "125",
"pmc": null,
"pmid": "33708294",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "13296133;17407588;2459960;458967;1842377;1701756;15105655;7855985;7541581;21826130;14976541;12497163;2000687;30805072;16142562;10197870;21627811;24982776;12588611",
"title": "Transformation of a prostatic adenocarcinoma into squamous cell carcinoma after luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy treatment.",
"title_normalized": "transformation of a prostatic adenocarcinoma into squamous cell carcinoma after luteinizing hormone releasing hormone lhrh agonist and radiotherapy treatment"
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"abstract": "Histoplasmosis is a systemic fungal infection caused by dimorphic fungus, Histoplasma capsulatum. Immunocompetent individuals usually have self-limiting or localized disease whereas immunocompromised individuals develop disseminated disease. The occurrence of progressive disseminated histoplasmosis in juvenile systemic lupus erythematosus is extremely rare with only one reported case in literature showing such association. Therefore, we report a case of severe opportunistic fungal infection caused by Histoplasma in a 13-year-old girl who was diagnosed with juvenile lupus erythematosus, subsequently developed septic shock and died of the disease despite of aggressive antifungal therapy.",
"affiliations": "Department of Pathology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.;Department of Pathology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.;Department of Pathology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.",
"authors": "Sarkar|Piyabi|P|;Basu|Keya|K|;Mallick Sinha|Mamata Guha|MG|",
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"fulltext": "\n==== Front\nIndian J DermatolIndian J DermatolIJDIndian Journal of Dermatology0019-51541998-3611Medknow Publications & Media Pvt Ltd India IJD-61-700b10.4103/0019-5154.193710E-IJD Case ReportA Rare Case of Juvenile Systemic Lupus Erythematosus with Disseminated Histoplasmosis Sarkar Piyabi Basu Keya Mallick (Sinha) Mamata Guha From the Department of Pathology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, IndiaAddress for correspondence: Dr. Piyabi Sarkar, Ganapati Enclave, 117A, Santosh Roy Road, Block - A/1, Flat No. 304, Kolkata - 700 008, West Bengal, India. E-mail: piyabi.sarkar@gmail.comNov-Dec 2016 61 6 700 700 2 2016 4 2016 Copyright: © Indian Journal of Dermatology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Histoplasmosis is a systemic fungal infection caused by dimorphic fungus, Histoplasma capsulatum. Immunocompetent individuals usually have self-limiting or localized disease whereas immunocompromised individuals develop disseminated disease. The occurrence of progressive disseminated histoplasmosis in juvenile systemic lupus erythematosus is extremely rare with only one reported case in literature showing such association. Therefore, we report a case of severe opportunistic fungal infection caused by Histoplasma in a 13-year-old girl who was diagnosed with juvenile lupus erythematosus, subsequently developed septic shock and died of the disease despite of aggressive antifungal therapy.\n\nDisseminated histoplasmosisjuvenile systemic lupus erythematosusrare\n==== Body\nIntroduction\nWhat was known?\n\nSystemic lupus erythematosus (SLE), an autoimmune disorder, is commonly associated with bacterial and viral infections. Opportunistic fungal infection like histoplasmosis is uncommon. Progressive disseminated histoplasmosis in SLE is a rare finding and mainly reported in adult population.\n\nSystemic lupus erythematosus (SLE), an autoimmune disorder, is commonly associated with bacterial and viral infections and less frequently with opportunistic fungal infections.[1]\n\nClassical histoplasmosis, also known as Darling's disease, is a deep mycotic infection caused by one of the two thermal dimorphic fungi, Histoplasma capsulatum and Histoplasma duboisii.[2] Affected individuals usually present with pulmonary and primary cutaneous disease. Progressive disseminated histoplasmosis (PDH) which commonly affects immunocompromised patients represents a severe form of the disease.[345]\n\nAn association between SLE and histoplasmosis in adult patients has been published in a recent report which revealed 8 out of 14 patients had PDH.[6] However, only one case of disseminated fungal infections was reported in lupus pediatric population.[1] Therefore, we report a case of PDH in a 13-year-old girl who was diagnosed with juvenile SLE (JSLE).\n\nCase Report\nA 13-year-old girl presented with malar rash [Figure 1a], fever, myalgia, stiffness of hands and knees, and photosensitivity. On physical examination, she appeared febrile (39.5°C), pale (2 + pallor), with heart rate 120/min, respiratory rate of 28 breaths/min, and blood pressure 112/70 mmHg. On auscultation, she had diffuse wheezing, crepitations in lower thirds of lungs, and rhythmic heart sounds without murmurs. Laboratory examination revealed the following results: Hemoglobin (Hb) - 9.0 g/dL; hematocrit - 27%; white blood cell (WBC) count - 2800/mm3 (95% neutrophils, 2% lymphocytes, and 3% monocytes), platelet count - 56,000/mm3; C-reactive protein - 40 mg/L (normal <5.0 mg/L); C3, 35 mg/dL (normal 90–180 mg/dL); C4, 7.0 mg/dL (10–40 mg/dL); antinuclear antibodies (ANAs) by indirect immunofluorescence (1/640 homogenous nuclear pattern). Chest X-ray revealed opacification of both hemithoraces and 24 h proteinuria, 1.0 g (normal <0.5 g/24 h) was also noted. A diagnosis of JSLE was established according to the revised classification criteria proposed by the American College of Rheumatology,[7] based on malar rash, photosensitivity, nonerosive arthritis, positive ANA, serositis (pleural effusion), and hematological disorder (leukopenia, lymphopenia, and thrombocytopenia), and proteinuria. She was treated with oral prednisolone (60 mg/day) and hydroxychloroquine (150 mg/day).\n\nFigure 1 (a) Butterfly (malar) rash of systemic lupus erythematosus. (b) Generalized erythematous maculopapular rash, observed on follow-up\n\nSeven months later, she presented with high fever, severe cough with expectoration, abdominal pain, and distension with generalized erythematous maculopapular rash [Figure 1b]. Routine blood test revealed Hb - 8.5 g/dL; WBC - 2000/mm3; platelet count - 30,000/mm3. Abdominal computed tomography (CT) showed evidence of hepatosplenomegaly and enlarged retroperitoneal lymph nodes with thoracic CT showing bilateral hilar lymphadenopathy. A Doppler echocardiography revealed pulmonary arterial pressure of 64 mmHg.\n\nA punch biopsy was taken from the skin lesion on the forearm, and histopathological examination of the formalin-fixed, paraffin embedded, and hematoxylin-eosin stained sections revealed diffuse infiltration of the dermis with small round to oval organisms surrounded by a clear space resembling spores of Histoplasma sp. [Figure 2a and b]. The organisms were better appreciated in periodic acid-Schiff [Figure 2c] and methenamine silver stains.\n\nFigure 2 (a) Histology of skin showing diffuse infiltration of the dermis by yeast cells of Histoplasma (H and E, ×100). (b) High-power view highlighting spores of Histoplasma in the dermis (H and E, ×400). (c) Periodic acid–Schiff positive spores of Histoplasma in the dermis (periodic acid–Schiff, ×400). (d) Bone marrow aspiration smear showing macrophages containing Histoplasma spores (Leishman's stain, ×400). (e) Bone marrow biopsy section showing yeast cells of Histoplasma (H and E, ×400). (f) Periodic acid–Schiff positive spores of Histoplasma in bone marrow (periodic acid–Schiff, ×400)\n\nBone marrow (BM) aspiration as well as biopsy was done which revealed hypocellular marrow with macrophages containing numerous intracytoplasmic oval organisms with a surrounding clear halo similar to those found in skin biopsy [Figure 2d–f].\n\nCulture from the skin tissue specimen grew white cottony colonies suggestive of H. capsulatum.\n\nThe patient was started on intravenous amphotericin B (1.0 mg/kg/day). Despite this therapy, she died 12 days later due to septic shock. An autopsy revealed the evidence of septic shock and disseminated histoplasmosis involving lung, lymph nodes and BM with no signs of pulmonary thrombosis, and vasculitis.\n\nDiscussion\nWe are reporting a case of JSLE with fatal disseminated histoplasmosis and to the best of our knowledge, only one case with similar findings has been reported in the literature.\n\nHistoplasmosis is caused by Histoplasma sp., which is a dimorphic fungus belonging to ascomycetes class.[1] The disease can be broadly classified into three subtypes: Acute pulmonary form (found in immunocompetent host), chronic pulmonary form (associated with anatomical defect), and disseminated histoplasmosis (seen in immunocompromised individuals).[8]\n\nThis mycotic infection is mostly asymptomatic and has a self-limited course in normal children.[9] Disseminated histoplasmosis is quite rare and is seen in only 10% of patients with histoplasmosis,[4] particularly seen in immunocompromised individuals like those receiving immunosuppressive drugs and corticosteroids after transplantation, or suffering from acquired immunodeficiency syndrome.[9]\n\nIn SLE, both occurrences of localized or diffuse histoplasmosis are unusual and such association is mainly reported in adult patients.[1] Patients with disseminated disease present with nonspecific symptoms such as fever, malaise, anorexia, weight loss, cough, and dyspnea[9] as were noted in our patient. Features meeting the criteria of PDH in our case were persistence of clinical manifestations which did not improve even after 3 weeks of acute infection along with extrapulmonary tissue involvement[9] as confirmed by physical, laboratory, and radiographic evaluation. The presence of Histoplasma infection was confirmed by the histopathological examination of tissue section and culture which are regarded as the gold standard methods.[9] Disseminated disease subtype mainly involves BM and lung[6] as was observed in our case.\n\nPulmonary hypertension was observed in our patient, the cause of which might be due to alveolar hemorrhage caused by histoplasmosis. This severe complication significantly increases mortality in JSLE as compared to adult SLE.[110]\n\nHistoplasmosis mainly affects lupus patients on immunosuppressive drugs such as corticosteroids, cyclophosphamide, azathioprine, and rituximab[6] as was noted in our case. Disseminated histoplasmosis is usually treated with amphotericin B and itraconazole for 3 completed months.[1] In spite of aggressive therapy, there is a high incidence of mortality[6] as was observed in our case.\n\nThe key factors which led to the dismal outcome of our case were delay in diagnosis of histoplasmosis and failure to administer antifungal therapy promptly.\n\nConclusion\nWe report a case of disseminated histoplasmosis in an active JSLE patient who presented with generalized cutaneous rash, lymph nodal, lung, and BM involvement. Histoplasmosis is an uncommon opportunistic infection in an SLE patient. A high degree of clinical suspicion is needed for early diagnosis and prompt management with antifungal drugs should be advocated for favorable prognosis.\n\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nWhat is new?\n\nWe are reporting a case of disseminated histoplasmosis in a juvenile SLE patient which is an exceedingly rare occurrence with only one case in the literature. Symptoms are generally nonspecific which cause delay in the diagnosis. High level of suspicion is necessary for prompt diagnosis and treatment includes aggressive antifungal therapy. A delay in diagnosis usually results in an ominous outcome which we encountered in our case.\n==== Refs\n1 França CM Cavalcante EG Ribeiro AS Oliveira GT Litvinov N Silva CA Disseminated histoplasmosis in a juvenile lupus erythematosus patient Acta Reumatol Port 2012 37 276 9 23348119 \n2 Harnalikar M Kharkar V Khopkar U Disseminated cutaneous histoplasmosis in an immunocompetent adult Indian J Dermatol 2012 57 206 9 22707773 \n3 Ceccato F Gongora V Zunino A Roverano S Paira S Unusual manifestation of histoplasmosis in connective tissue diseases Clin Rheumatol 2007 26 1717 9 17541496 \n4 Joshi SA Kagal AS Bharadwaj RS Kulkarni SS Jadhav MV Disseminated histoplamosis Indian J Med Microbiol 2006 24 297 8 17185853 \n5 Sehgal S Chawla R Loomba PS Mishra B Gastrointestinal histoplasmosis presenting as colonic pseudotumour Indian J Med Microbiol 2008 26 187 9 18445963 \n6 Cairoli E Tafuri J Olivari D Laryngeal histoplasmosis in systemic lupus erythematosus: First reported case Lupus 2010 19 1354 5 20547655 \n7 Hochberg MC Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus Arthritis Rheum 1997 40 1725 \n8 Ubesie AC Okafo OC Ibeziako NS Onukwuli VO Mbanefo NR Uzoigwe JC Disseminated Histoplasmosis in a 13-year-old girl: A case report Afr Health Sci 2013 13 518 21 24235958 \n9 Fischer GB Mocelin H Severo CB Oliveira Fde M Xavier MO Severo LC Histoplasmosis in children Paediatr Respir Rev 2009 10 172 7 19879506 \n10 Araujo DB Borba EF Silva CA Campos LM Pereira RM Bonfa E Alveolar hemorrhage: Distinct features of juvenile and adult onset systemic lupus erythematosus Lupus 2012 21 872 7 22427319\n\n",
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"journal": "Indian journal of dermatology",
"keywords": "Disseminated histoplasmosis; juvenile systemic lupus erythematosus; rare",
"medline_ta": "Indian J Dermatol",
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"title": "A Rare Case of Juvenile Systemic Lupus Erythematosus with Disseminated Histoplasmosis.",
"title_normalized": "a rare case of juvenile systemic lupus erythematosus with disseminated histoplasmosis"
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"abstract": "Cutaneous hyperpigmentation is a recognized adverse effect of chronic minocycline use occurring in up to 50% of patients. In this report we present a rare case of extensive skin hyperpigmentation involving both lower extremities in a patient receiving long term minocycline. The patient was receiving minocycline as suppression for chronic prosthetic joint infection. Risk factors associated with minocycline-induced cutaneous pigmentation (MICH) will be reviewed.",
"affiliations": "Division of Infectious Disease, Mayo Clinic College of Medicine, Rochester, MN, United States.;Division of Infectious Disease, Mayo Clinic College of Medicine, Rochester, MN, United States.;Division of Infectious Disease, Mayo Clinic College of Medicine, Rochester, MN, United States.",
"authors": "Berbari|Hadi|H|;Berbari|Elie F|EF|;Sia|Irene G|IG|",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(16)30120-210.1016/j.idcr.2016.12.003Case ReportDiffuse skin hyperpigmentation associated with chronic minocycline use in a patient with prosthetic joint infection Berbari Hadi Berbari Elie F. Sia Irene G. Sia.Irene@mayo.edu⁎Division of Infectious Disease, Mayo Clinic College of Medicine, Rochester, MN, United States⁎ Corresponding author at: Division of Infectious Disease May Clinic College of Medicine, 2001st Street SW, Rochester, MN 55905, United States. Sia.Irene@mayo.edu19 12 2016 2017 19 12 2016 7 30 31 18 10 2016 15 12 2016 15 12 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cutaneous hyperpigmentation is a recognized adverse effect of chronic minocycline use occurring in up to 50% of patients. In this report we present a rare case of extensive skin hyperpigmentation involving both lower extremities in a patient receiving long term minocycline. The patient was receiving minocycline as suppression for chronic prosthetic joint infection. Risk factors associated with minocycline-induced cutaneous pigmentation (MICH) will be reviewed.\n==== Body\nIntroduction\nCutaneous hyperpigmentation is a recognized adverse effect of chronic minocycline use occurring in up to 50% of patients [1], [2]. In a recent study performed at the Mayo Clinic, 54% of 291 patients receiving long-term minocycline suppression for orthopedic infections developed some degree of hyperpigmentation after a mean follow-up of 4.8 years [1]. In this cohort, the mean duration of minocycline therapy before the onset of hyperpigmentation was 1.5 years. Factors associated with minocycline-induced cutaneous hyperpigmentation (MICH) include a history of vitamin D deficiency, presence of a shoulder prosthesis, noncirrhotic liver pathology, and use of a concurrent medication (e.g., calcium channel blocker) also known to cause hyperpigmentation [1]. MICH is not associated with adverse clinical effects, and it is mostly cosmetic in nature [2]. It typically involves the lower extremity, and is usually limited and localized. We herein present a rare case of extensive skin hyperpigmentation involving both lower extremities in a patient receiving long term minocycline. Risk factors associated with MICH will be reviewed.\n\nCase report\nIn June 2016, a 76-year-old male with a past medical history significant for nephrolithiasis and diverticulitis, presented to the authors’ institution with extensive hyperpigmentation involving both lower extremities. The patient had an extensive orthopedic and orthopedic infectious disease history. He underwent a left total knee arthroplasty in 1988 at an outside institution and underwent revision surgery in 1992. In 2001, he underwent a second revision for fractured patella that was complicated by an infection with a coagulase-negative Staphylococcus. He received six weeks of treatment with parenteral vancomycin followed by oral trimethoprim-sulfamethoxazole. Because of increasing knee pain, in March 2005, the prosthesis was explanted. Operative cultures from the knee grew Enterococcus sp., Prevotella sp, viridans group Streptococcus, as well as Candida parapsilosis. After completing antimicrobial treatment with vancomycin, ertapenem and fluconazole, he underwent reimplantation using a rotating hinged knee arthroplasty in September 2005 (Fig. 1). Unfortunately, operative cultures were positive for coagulase-negative Staphylococcus. Since that time, the patient was maintained on oral minocycline chronic suppression. In 2010, he sustained a periprosthetic fractures that required open reduction and internal fixation.\n\nHis left knee has been clinically quiescent and stable for a number of years. He uses a brace as well as a cane to ambulate. At a follow-up in February 2012, it was noted that he had slight discoloration in the lower extremities. When he was seen again in June 2016, there was extensive blue-gray pigmentation in both cheeks and in the lower extremities (Fig. 2), as well as sub-ungual blue-gray pigmentation in both hands (Fig. 3).\n\nDiscussion\nThere are three types of pigmentation patterns that can result from taking minocycline for long periods of time [3]. Type I is a blue-gray pigmentation occurring around areas that were previously inflamed. Type II has the same appearance as Type I and covers areas of normal skin such as the anterior shins, arms, and ankles. Type III is a muddy brown pigmentation usually occurring on areas of the skin that are exposed to the sun. The blue-gray pigmentation is due to the deposition of iron within the dermal macrophages. The diffuse hyperpigmentation seen in the patient presented in this case report includes both Types I and II. Blue-gray pigmentation is clearly seen around the scar on the left knee from his knee replacement surgery (Type I). Hyperpigmentation is also distinctly seen on the shins of both legs and around the ankles of the patient (Type II).\n\nHyperpigmentation is predominantly seen with minocycline and less likely to occur with other tetracyclines such as doxycycline [4]. Minocycline is five times more lipophilic than doxycycline; hence, central nervous system adverse events are more common with minocycline. Doxycycline may be associated with more gastrointestinal upset and photosensitivity than minocycline [4], [5].\n\nAlthough doxycycline may have a higher incidence of gastrointestinal upset and photosensitivity, minocycline has an increased likelihood of severe and permanent cosmetic adverse events and central nervous system adverse events. In the study of orthopedic patients on long-term minocycline suppression, cutaneous hyperpigmentation occurred in 54% of patients [1]. Furthermore, hyperpigmentation can persist in at least 24% even with medication discontinuation [1]. These side effects are an addition to gastrointestinal adverse effects that can also occur with minocycline. In the absence of data to show that minocycline is superior to doxycycline for long-term suppression of infections including orthopedic infections, the authors propose that doxycycline be looked upon favorably when chronic use is indicated.\n\nConflict of interest\nNo relevant COI to disclose.\n\nFig. 1 Roentgenogram of the left knee revealing a hinged knee with plate and screws in the tibia as well as intramedullary rod in the fibula.\n\nFig. 1Fig. 2 Bilateral lower extremities showing diffuse blue-gray skin hyperpigmentation; a healed incision is noted over the left knee.\n\nFig. 2Fig. 3 Sub-ungual hyperpigmentation.\n\nFig. 3\n==== Refs\nReferences\n1 Hanada Y. Berbari E.F. Steckelberg J.M. Minocycline-induced cutaneous hyperpigmentation in an orthopedic patient population In Open forum infectious diseases vol. 3 2016 Oxford University Press ofv107 No. 1 January \n2 Gordon G. Sparano B.M. Iatropoulos M.J. Hyperpigmentation of the skin associated with minocycline therapy Arch Dermatol 121 5 1985 618 623 3158285 \n3 Mouton R.W. Jordaan H.F. Schneider J.W. A new type of minocycline‐induced cutaneous hyperpigmentation Clin Exp Dermatol 1 January (1) 2004 8 14 29 \n4 Smith K. Leyden J.J. Safety of doxycycline and minocycline: a systematic review Clin Ther 27 September (9) 2005 1329 1342 16291409 \n5 Pepine M. Flowers F.P. Ramos-Caro F.A. Extensive cutaneous hyperpigmentation caused by minocycline J Am Acad Dermatol 28 2 1993 292 295 8436641\n\n",
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"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "30-31",
"pmc": null,
"pmid": "28050350",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "14723711;3158285;26835479;16291409;8436641",
"title": "Diffuse skin hyperpigmentation associated with chronic minocycline use in a patient with prosthetic joint infection.",
"title_normalized": "diffuse skin hyperpigmentation associated with chronic minocycline use in a patient with prosthetic joint infection"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0087129",
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{
"abstract": "OBJECTIVE\nTo present a forme fruste variant of hemorrhagic occlusive retinal vasculitis (HORV) after uncomplicated cataract surgery performed with vancomycin in the irrigating solution.\n\n\nMETHODS\nA report of a single patient who developed HORV; the clinical features and course are described and compared with previously reported cases.\n\n\nRESULTS\nUltra-widefield fluorescein angiography demonstrated an occlusive vasculitis in both eyes 1 week after uncomplicated cataract surgery in which vancomycin was added to the irrigating solution. An extensive systemic evaluation including a hypercoagulable workup, serum electrophoresis, complete blood count, and carotid and cardiac ultrasound was negative. Visual acuity was unaffected, and the patient remained 20/20 in each eye one year after surgery without treatment. This is a markedly different outcome than seen in previously reported cases of HORV.\n\n\nCONCLUSIONS\nUltra-widefield angiography was helpful to confirming the diagnosis of HORV in this milder case example in a patient who maintained excellent vision. This forme fruste variant of HORV after exposure to vancomycin suggests that the incidence of HORV after cataract surgery may be more common than previously reported. Vigilance, close observation, and broad reporting can help further clarify the incidence and potential adverse effects of routinely using intracameral vancomycin during cataract surgery.",
"affiliations": "Bay Area Retina Associates, Walnut Creek, California.;Ophthalmic Consultants of Boston, Boston, Massachusetts.;Ophthalmic Consultants of Boston, Boston, Massachusetts.",
"authors": "Goldberg|Roger A|RA|;Crawford|Courtney|C|;Heier|Jeffrey S|JS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000514",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "12(4)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002387:Cataract Extraction; D005451:Fluorescein Angiography; D006801:Humans; D011183:Postoperative Complications; D012166:Retinal Hemorrhage; D031300:Retinal Vasculitis; D014640:Vancomycin",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "305-306",
"pmc": null,
"pmid": "28045863",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "POSTOPERATIVE HEMORRHAGIC OCCLUSIVE RETINAL VASCULITIS: A FORME FRUSTE VARIANT?",
"title_normalized": "postoperative hemorrhagic occlusive retinal vasculitis a forme fruste variant"
} | [
{
"companynumb": "US-PENTEC HEALTH-2018PEN00054",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
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{
"abstract": "Germ cell tumours (GCT) are the most common malignancy in men between the ages of 15 and 35 years. Pure choriocarcinoma is a very rare entity of non- seminomatous germ cell tumour and comprises only 1% -3% of all the testicular tumours. Choriocarcinoma syndrome is a clinical condition in which haemorrhage occurs from the metastatic sites with elevated level of the Beta-Human Chorionic gonadotropin (Beta -HCG). A 15-year-old adolescent boy presented in with left sided testicular swelling along with dark coloured cutaneous lesions of the scalp, chest and chin for the last one month. He underwent left sided orchiectomy, and the histopathology report showed Pure Choriocarcinoma. Unfortunately, he died after the beginning of chemotherapy due to alveolar haemorrhage.",
"affiliations": "Department of Pediatric Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan.;Department of Pediatric Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan.;Department of Pediatric Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan.",
"authors": "Sindhu|Irfana Ishaq|II|;Noor|Nida|N|;Mansoor|Raheela|R|",
"chemical_list": "D018997:Chorionic Gonadotropin, beta Subunit, Human",
"country": "Pakistan",
"delete": false,
"doi": "10.47391/JPMA.234",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-9982",
"issue": "71(8)",
"journal": "JPMA. The Journal of the Pakistan Medical Association",
"keywords": " Choriocarcinoma syndrome, cutaneous lesions, Cannon Ball metastasis, Alveolar Haemorrhage, Chemotherapy.\n",
"medline_ta": "J Pak Med Assoc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002822:Choriocarcinoma; D018997:Chorionic Gonadotropin, beta Subunit, Human; D005260:Female; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D011247:Pregnancy; D013736:Testicular Neoplasms; D055815:Young Adult",
"nlm_unique_id": "7501162",
"other_id": null,
"pages": "2090-2092",
"pmc": null,
"pmid": "34418038",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Choriocarcinoma syndrome: A rare presentation of testicular germ cell tumour.",
"title_normalized": "choriocarcinoma syndrome a rare presentation of testicular germ cell tumour"
} | [
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"companynumb": "PK-STRIDES ARCOLAB LIMITED-2022SP001594",
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"abstract": "Enterocytozoon bieneusi microsporidiosis is an emerging disease in immunocompromised patients. We report 2 cases of this disease in allogeneic hematopoietic stem cell transplant patients successfully treated with fumagillin. Thrombocytopenia occurred but without major adverse events. Modifications of immunosuppression could be avoided when E. bieneusi is rapidly identified and fumagillin therapy is started promptly.",
"affiliations": null,
"authors": "Bukreyeva|Iryna|I|;Angoulvant|Adela|A|;Bendib|Inès|I|;Gagnard|Jean-Charles|JC|;Bourhis|Jean-Henri|JH|;Dargère|Sylvie|S|;Bonhomme|Julie|J|;Thellier|Marc|M|;Gachot|Bertrand|B|;Wyplosz|Benjamin|B|",
"chemical_list": "D000935:Antifungal Agents; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D007166:Immunosuppressive Agents; D012717:Sesquiterpenes; C026211:fumagillin; D009173:Mycophenolic Acid; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.3201/eid2306.161825",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n28518017\n16-1825\n10.3201/eid2306.161825\nResearch Letter\nResearch Letter\nEnterocytozoon bieneusi Microsporidiosis in Stem Cell Transplant Recipients Treated with Fumagillin\nEnterocytozoon bieneusi Microsporidiosis in Stem Cell Transplant Recipients Treated with Fumagillin1\nEnterocytozoon bieneusi Microsporidiosis in Stem Cell Transplant Recipients Treated with Fumagillin\nBukreyeva Iryna\nAngoulvant Adela\nBendib Inès\nGagnard Jean-Charles\nBourhis Jean-Henri\nDargère Sylvie\nBonhomme Julie\nThellier Marc\nGachot Bertrand\nWyplosz Benjamin\nCentre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicêtre, France (I. Bukreyeva, A. Angoulvant, I. Bendib, J.-C. Gagnard, B. Wyplosz);\nUniversité Paris-Sud, Le Moulon, France (A. Angoulvant);\nInstitut Gustave Roussy, Villejuif, France (J.-H. Bourhis, B. Gachot);\nCentre Hospitalier Universitaire de Caen, Caen, France (S. Dargère, J. Bonhomme);\nCentre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France (M. Thellier);\nUniversité Pierre et Marie Curie, Paris (M. Thellier)\nAddress for correspondence: Benjamin Wyplosz, Service de Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire de Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France; email: benjamin.wyplosz@aphp.fr\n6 2017\n23 6 10391041\nEnterocytozoon bieneusi microsporidiosis is an emerging disease in immunocompromised patients. We report 2 cases of this disease in allogeneic hematopoietic stem cell transplant patients successfully treated with fumagillin. Thrombocytopenia occurred but without major adverse events. Modifications of immunosuppression could be avoided when E. bieneusi is rapidly identified and fumagillin therapy is started promptly.\n\nKeywords:\n\nEnterocytozoon bieneusi\nprotozoa\nmicrosporidia\nmicrosporidiosis\nparasites\nobligate intracellular parasite\ntransplantation\nallogeneic\nhematopoietic stem cell transplant recipients\nimmunocompromised patients\nantiprotozoal drugs\nfumagillin\n==== Body\nEnterocytozoon bieneusi, the most common cause of microsporidiosis in humans (1), causes chronic diarrhea and severe wasting syndrome in immunocompromised patients (2). In 2002, oral fumagillin was established as an effective treatment for E. bieneusi microsporidiosis in HIV-infected and solid organ transplant (SOT) patients (3). In contrast to previous treatments that did not result in parasitologic clearance or clinical remission, fumagillin showed a cure rate of 100%, even for severely immunocompromised patients (2,4–10).\n\nThrombocytopenia is the main adverse event of fumagillin therapy, occurring in up to 33% of patients (3) and raising concerns about fumagillin use in patients with hematologic disorders. We report 2 cases of E. bieneusi microsporidiosis in allogeneic hematopoietic stem cell transplant (HSCT) recipients who were treated with fumagillin and experienced thrombocytopenia.\n\nPatient 1 was a 50-year-old woman admitted to Centre Hospitalier Universitaire de Caen (Caen, France) after profuse watery diarrhea and abdominal discomfort for 3 weeks. She had not traveled abroad. Three years earlier, she received a genoidentical allogeneic HSCT for myeloid leukemia. She recently had cutaneous chronic graft-versus-host disease. Her immunosuppression regimen used was prednisone and mycophenolate mofetil.\n\nAt admission, the patient was dehydrated and had a weight loss of 3 kg. Laboratory analyses showed lymphocytopenia (960 lymphocytes/mm3), reference neutrophil (5,100 cells/mm3) and platelet (408,000 platelets/mm3) counts, and a C-reactive protein level <5 mg/L.\n\nResults of fecal sample analyses were negative for pathogenic bacteria and viruses. Microscopic examination of fecal smears stained with Weber-Green–modified trichrome showed microsporidia. E. bieneusi was identified by using monoclonal antibodies (IFA-MAbs; Bordier Affinity Products, Crissier, Switzerland).\n\nThe mycophenolate mofetil dose was reduced by 50% for 8 days but no benefit was shown. Resolution of symptoms occurred <5 days after initiating fumagillin therapy (60 mg/d for 14 d); fecal smears were negative for microsporidia on day 9, and transient thrombocytopenia (131,000 platelets/mm3) was observed on day 18 (Figure). Fecal smears remained negative for E. bieneusi during the 6-month follow-up. No clinical relapse occurred.\n\nFigure Platelet counts and clinical and parasitologic characteristics during fumagillin therapy and a 1-month follow-up of 2 allogeneic hematopoietic stem cell recipients with Enterocytozoon bieneusi microsporidiosis.\n\nPatient 2 was a 42-year-old man referred to Centre Hospitalier Universitaire de Bicêtre (Le Kremlin-Bicêtre, France) after profuse acute diarrhea for 2 weeks and a weight loss of 10 kg. He had not traveled abroad. Four years earlier, he received a genoidentical allogeneic HSCT for acute leukemia. During the follow-up period, he was given a diagnosis of chronic graft-versus-host disease. He was given extracorporeal phototherapy with mycophenolate mofetil, sirolimus, and prednisolone.\n\nAt admission, the patient was afebrile and dehydrated. Blood analyses showed severe lymphocytopenia (400 lymphocytes/mm3), reference neutrophil (4,680 cells/mm3) and platelet (251,000 platelets/mm3) counts, and a C-reactive protein level <5 mg/L. Results of microbiological analyses of fecal samples were negative for viruses and pathogenic bacteria. Microscopic examination of fecal smears stained with Weber-Green–modified trichrome showed microsporidia. E. bieneusi was identified by using monoclonal antibodies.\n\nThe patient was treated with fumagillin (60 mg/d for 14 d) (Figure). Immunosuppressive therapy was not modified. Clinical symptoms resolved within 5 days. Platelet counts progressively decreased. Fumagillin was withdrawn on day 14, but thrombocytopenia worsened (40,000 platelets/mm3) by day 18. However, the patient spontaneously recovered in 10 days without any bleeding. No relapses were observed. Microsporidia were not detected in fecal samples during the 6-month follow-up.\n\nE. bieneusi is an emerging pathogen in immunocompromised patients (1). Increasing numbers of cases have been reported in SOT patients. We report 2 cases of E. bieneusi microsporidiosis in allogeneic HSCT recipients who were treated with fumagillin without modifying the immunosuppressive regimen for 1 recipient. In France, fumagillin can be obtained from the French National Agency for Medicines and Health Products Safety (Saint-Denis, France) after an individual patient expanded-access request is submitted.\n\nClinical and microbiological responses for the 2 case-patients were similar to those reported for other immunocompromised patients (3). No relapses were observed for 4 HIV-infected patients whose CD4 cell counts remained low, or for 2 SOT recipients who did not receive tapering immunosuppressive therapy (3). In other studies, 15 (70%) of 21 patients treated with fumagillin were cured without modifying immunosuppression regimens (2,6,10); for 6 other patients, immunosuppressive therapy was tapered (n = 4) or withdrawn (n = 2), but reasons for modifying immunosuppression were not specified. For 1 of our patients, the mycophenolate mofetil dose was reduced by 50% to decrease the immunosuppression level. However, no benefit was observed. In contrast, fumagillin led to clinical remission within 5 days.\n\nWe observed thrombocytopenia (platelet count <40,000/mm3) in both patients but no evidence of bleeding. In other non-AIDS patients, thrombocytopenia was reported in 11 (52%) SOT patients receiving fumagillin, including 4 patients with severely low platelet counts (<25,000/mm3) (1,4,6). For these patients, including those we report, thrombocytopenia occurred during the second week of treatment; a minimum value was observed a few days after completing fumagillin therapy. Spontaneous recovery occurred within 2 weeks. Bleeding, hematoma, or requirements for platelet transfusions were not reported. For both patients we report, microsporidia were not detected in fecal samples of both patients during the 6-month follow-up.\n\nIn conclusion, fumagillin was highly efficient in curing E. bieneusi microsporidiosis in 2 allogeneic HSCT recipients. Thrombocytopenia occurred but without major adverse events. Modifications to immunosuppression could be avoided when E. bieneusi is rapidly identified and fumagillin therapy is started promptly.\n\nDr. Bukreyeva is a physician in the Infectious and Tropical Diseases Unit at the Bicêtre University Hospital, Kremlin-Bicêtre, France. Her research interests include prevention and treatment of infections in immunocompromised patients.\n\nSuggested citation for this article: Bukreyeva I, Angoulvant A, Bendib I, Gagnard J-C, Bourhis J-H, Dargère S, et al. Enterocytozoon bieneusi microsporidiosis in stem cell transplant recipients treated with fumagillin. Emerg Infect Dis. 2017 Jun [date cited]. https://dx.doi.org/10.3201/eid2306.161825\n\n1 Results from this study were presented at the 26th European Congress of Clinical Microbiology and Infection Diseases; April 9–12, 2016; Amsterdam, the Netherlands.\n==== Refs\nReferences\n\n1. Didier ES, Weiss LM. Microsporidiosis: current status. Curr Opin Infect Dis. 2006;19 :485–92. 10.1097/01.qco.0000244055.46382.23 16940873\n2. Lanternier F, Boutboul D, Menotti J, Chandesris MO, Sarfati C, Mamzer Bruneel MF, et al. Microsporidiosis in solid organ transplant recipients: two Enterocytozoon bieneusi cases and review. Transpl Infect Dis. 2009;11 :83–8. 10.1111/j.1399-3062.2008.00347.x 18803616\n3. Molina JM, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert JG, et al. ; Agence Nationale de Recherches sur le SIDA 090 Study Group. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med. 2002;346 :1963–9. 10.1056/NEJMoa012924 12075057\n4. Desoubeaux G, Maakaroun-Vermesse Z, Lier C, Bailly E, Morio F, Labarthe F, et al. Successful treatment with fumagillin of the first pediatric case of digestive microsporidiosis in a liver-kidney transplant. Transpl Infect Dis. 2013;15 :E250–9. 10.1111/tid.12158 24298986\n5. Pomares C, Santín M, Miegeville M, Espern A, Albano L, Marty P, et al. A new and highly divergent Enterocytozoon bieneusi genotype isolated from a renal transplant recipient. J Clin Microbiol. 2012;50 :2176–8. 10.1128/JCM.06791-11 22442321\n6. Godron A, Accoceberry I, Couret A, Llanas B, Harambat J. Intestinal microsporidiosis due to Enterocytozoon bieneusi in a pediatric kidney transplant recipient successfully treated with fumagillin. Transplantation. 2013;96 :e66–7. 10.1097/TP.0b013e3182a902e7 24132119\n7. Kicia M, Wesolowska M, Jakuszko K, Kopacz Z, Sak B, Květonova D, et al. Concurrent infection of the urinary tract with Encephalitozoon cuniculi and Enterocytozoon bieneusi in a renal transplant recipient. J Clin Microbiol. 2014;52 :1780–2. 10.1128/JCM.03328-13 24523472\n8. Ghoshal U, Khanduja S, Pant P, Prasad KN, Dhole TN, Sharma RK, et al. Intestinal microsporidiosis in renal transplant recipients: Prevalence, predictors of occurrence and genetic characterization. Indian J Med Microbiol. 2015;33 :357–63. 10.4103/0255-0857.158551 26068335\n9. Bednarska M, Bajer A, Welc-Faleciak R, Czubkowski P, Teisseyre M, Graczyk TK, et al. The first case of Enterocytozoon bieneusi infection in Poland. Ann Agric Environ Med. 2013;20 :287–8.23772577\n10. Champion L, Durrbach A, Lang P, Delahousse M, Chauvet C, Sarfati C, et al. Fumagillin for treatment of intestinal microsporidiosis in renal transplant recipients. Am J Transplant. 2010;10 :1925–30. 10.1111/j.1600-6143.2010.03166.x 20636462\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1080-6040",
"issue": "23(6)",
"journal": "Emerging infectious diseases",
"keywords": "Enterocytozoon bieneusi; allogeneic; antiprotozoal drugs; fumagillin; hematopoietic stem cell transplant recipients; immunocompromised patients; microsporidia; microsporidiosis; obligate intracellular parasite; parasites; protozoa; transplantation",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D003510:Cyclohexanes; D021862:Enterocytozoon; D005231:Fatty Acids, Unsaturated; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D007951:Leukemia, Myeloid; D008297:Male; D016881:Microsporidiosis; D008875:Middle Aged; D009173:Mycophenolic Acid; D010976:Platelet Count; D011241:Prednisone; D012717:Sesquiterpenes; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "9508155",
"other_id": null,
"pages": "1039-1041",
"pmc": null,
"pmid": "28518017",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16940873;20636462;24298986;22442321;12075057;23772577;24132119;24523472;18803616;26068335",
"title": "Enterocytozoon bieneusi Microsporidiosis in Stem Cell Transplant Recipients Treated with Fumagillin",
"title_normalized": "enterocytozoon bieneusi microsporidiosis in stem cell transplant recipients treated with fumagillin"
} | [
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{
"abstract": "Smooth muscle tumors of uncertain malignant potential (STUMP) are mesenchymal uterine tumors lying between benign leiomyomas and leiomyosarcomas. Although lung metastases from uterine leiomyosarcoma are common, \"STUMP\" usually does not metastasize. A case of a 51-year-old woman with progressive dyspnea on exertion and multiple space-occupying lesions in both lungs is presented. She had a history of a total abdominal hysterectomy 3 years ago. Lung biopsy through video-assisted thoracic surgery was consistent with metastatic malignant smooth muscle cell tumor. She received multiple cycles of chemotherapy and died 11 months later. Cell necrosis, atypia and mitotic count are important criteria determining the malignant potential of a uterine smooth muscle tumor. The diagnosis and clinical course of STUMP are not totally and clearly known, and metastasis, especially pulmonary with pleural effusion, is not a common phenomenon. When this occurs, prognosis seems to be poor. Surveillance of these patients should be close and long term.",
"affiliations": "Department of Gynecologic Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece.",
"authors": "Kotsopoulos|Ioannis C|IC|;Barbetakis|Nikolaos|N|;Asteriou|Christos|C|;Voutsas|Markos G|MG|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.4103/0971-5851.103148",
"fulltext": "\n==== Front\nIndian J Med Paediatr OncolIndian J Med Paediatr OncolIJMPOIndian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology0971-58510975-2129Medknow Publications & Media Pvt Ltd India IJMPO-33-17610.4103/0971-5851.103148Case ReportUterine smooth muscle tumor of uncertain malignant potential: A rare cause of multiple pulmonary nodules Kotsopoulos Ioannis C. Barbetakis Nikolaos 1Asteriou Christos 1Voutsas Markos G. 2Department of Gynecologic Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece1 Department of Thoracic Surgery, Theagenio Cancer Hospital, Thessaloniki, Greece2 Department of Histopathology, Theagenio Cancer Hospital, Thessaloniki, GreeceAddress for correspondence: Dr. Christos Asteriou, Department of Thoracic Surgery, Theagenio Cancer Hospital, Al. Simeonidi 2, Thessaloniki 54007, Greece. E-mail: asteriouchris@yahoo.grJul-Sep 2012 33 3 176 178 Copyright: © Indian Journal of Medical and Paediatric Oncology2012This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Smooth muscle tumors of uncertain malignant potential (STUMP) are mesenchymal uterine tumors lying between benign leiomyomas and leiomyosarcomas. Although lung metastases from uterine leiomyosarcoma are common, “STUMP” usually does not metastasize. A case of a 51-year-old woman with progressive dyspnea on exertion and multiple space-occupying lesions in both lungs is presented. She had a history of a total abdominal hysterectomy 3 years ago. Lung biopsy through video-assisted thoracic surgery was consistent with metastatic malignant smooth muscle cell tumor. She received multiple cycles of chemotherapy and died 11 months later. Cell necrosis, atypia and mitotic count are important criteria determining the malignant potential of a uterine smooth muscle tumor. The diagnosis and clinical course of STUMP are not totally and clearly known, and metastasis, especially pulmonary with pleural effusion, is not a common phenomenon. When this occurs, prognosis seems to be poor. Surveillance of these patients should be close and long term.\n\nLeiomyomaleiomyosarcomalungmetastasisuterus\n==== Body\nINTRODUCTION\nSmooth muscle tumors of uncertain malignant potential (STUMP) are mesenchymal uterine tumors lying between benign leiomyomas and leiomyosarcomas. The term “STUMP” contains a heterogeneous group of rare tumors.[1] There is lack of clinicopathologic details and follow-up data of these neoplasms. Histological diagnosis is challenging and usually problematic. The value, in the differential diagnosis, of a number of surface markers, like p16 and p21, has been studied.[2] Natural history of the disease as well as the malignant potential remains uncertain.[3] They are usually clinically benign but, in some cases, recurrence can occur many years following hysterectomy.[1] Little is known about metastasis of these tumors and, until March 2011, there was no case reporting lung metastasis and especially multiple pulmonary nodules and pleural effusion due to STUMP.\n\nOn the other hand, “benign metastasizing leiomyomas” is a clinicopathologic condition where pathologically benign smooth muscle neoplasms derived from uterine leiomyomas metastasize to extrauterine sites, like lung, pelvic lymph nodes or abdomen surfaces.[4]\n\nCASE REPORT\nA case of a 51-year-old woman, gravida 0 - para 0, who was admitted with progressive dyspnea on exertion is presented. The past medical history revealed that 3 years ago and due to persisting menorrhagia, the patient underwent dilatation and curettage. Histopathology report indicated the presence of abnormal endometrial hyperplasia. As the symptoms were persisting, the woman underwent total abdominal hysterectomy. Histopathologically, after thorough gross processing of the specimen, an intramural smooth muscle tumor of the uterus with a diameter measuring 5 cm was identified and six (6) sections from the tumor were obtained. Microscopy showed mild mitotic activity (2–6 MF/10 HPF), moderate nuclear atypia and lack of tumor necrosis [Figure 1]. A second typical leiomyoma, adenomyosis and sparse areas of thin-walled arteriolar type (plexiform) vessels were also identified but with no typical indication of endometrial malignancy present. Immunohistochemistry revealed focally mild immunopositivity regarding Vimentin and CD10. Extensive sampling was done to exclude the possibility of leiomyosarcoma. The absence of necrosis and atypical mitosis made pathologists consider that the tumor belongs to the so-called “grey zone” or STUMP. Therefore, no further treatment was applied and close follow-up was decided.\n\nFigure 1 Uterine smooth muscle tumor with mild mitotic activity (smooth muscle tumors of uncertain malignant potential tumor)\n\nChest X-ray and chest computed tomography (CT) confirmed the presence of bilateral pulmonary nodules [Figure 2]. As multiple metastases due to tumor of unknown origin were suspected, the patient underwent a series of diagnostic tests: brain and abdomen CTs, gastroscopy, colonoscopy, bronchoscopy, mammography, thyroid ultrasound and skeletal scintigraphy, none of which indicated primary extrapulmonary tumor. The patient underwent video-assisted thoracoscopy and multiple lung biopsies were performed. Histopathology and immunohistochemical examination of the specimens showed pulmonary parenchyma with focuses of sarcoma. A metastatic malignant smooth muscle cells neoplasm with uterine origin was diagnosed [Figure 3]. Cell nuclei presented diffuse moderate mitotic activity (6 MF/10 HPF), but there were also some atypical mitoses. The immunohistochemical examination revealed that the tumor was positive in Desmin and smooth muscle actin (SMA) and negative in CD117 and CD34. Pleural fluid was also found positive for metastatic malignancy. Both pathology and cytopathology reports excluded that the condition was associated with benign metastasizing leiomyoma.\n\nFigure 2 Chest computed tomography was consistent with multiple pulmonary nodules and pleural effusion\n\nFigure 3 Pathology was consistent with a metastatic pulmonary leiomyosarcoma\n\nThe patient underwent 14 cycles of chemotherapy, with multiple drug combinations, including ifosfamide, epirubicin, docetaxel, gemcitabine, bevacizumab, cisplatin, cyclophosphamide and vincristine. She died 11 months later due to disease progression.\n\nDISCUSSION\nLeiomyomas are uterine mesenchymal benign tumors derived from smooth muscle cells. These tumors are the most common neoplasm of the uterus.[4] On the other hand, leiomyosarcomas are the most common type of uterine sarcomas, accounting for approximately 30% of them. They usually arise de novo and, only in rare cases, a leiomyoma can be transformed into leiomyosarcoma.[5] Differential diagnostic criteria distinguishing these tumors from benign myomas include coagulative cell necrosis, moderate to severe cytologic atypia and numerous mitotic figures.[4] Furthermore, “STUMP” cannot be classified as benign or malignant.[4] Some researchers described that this heterogeneous category of neoplasms contains more groups like “atypical leiomyomas with limited experience,” “smooth muscle tumor of low malignant potential,” “atypical leiomyoma with low risk of reccurence” and “mitotically active leiomyoma.”[1] “STUMP” diagnosis should be used sparingly and after a detailed clinical, histopathological and immunohistochemical examination.[6]\n\nHematogenous dissemination of uterine leiomyosarcomas is the most common pattern of spread, and lung metastasis occurs in more than half of the patients.[6] However, there is only one case reporting pleural effusion due to sarcoma of the uterine smooth muscle.[7] On the other hand, there is no data about the possible metastatic behavior of uterine “STUMP.”\n\nIn the case presented here, “STUMP” was the initial diagnosis of the uterine tumor. The possibility that the neoplasm was leiomyosarcoma cannot be excluded as the zone between the benign and malignant nature of STUMP is not clear. Also, the hypothesis that the metastatic lung focuses derived from malignant transformation of benign uterine metastasizing leiomyomas cannot be proved but seems to be extremely unlikely. However, all clinical, histopathological and immunohistochemical indications incline to the “STUMP” diagnosis. Furthermore, research on new immunohistochemical markers and histopathological characteristics could have some value in the diagnosis of problematic cases.\n\nFinally, considering the unpredictable clinical behavior of “STUMP” and the fact that the malignant potential of some of them is substantial, patients should receive close and long-term follow-up. Metastasis cannot be excluded and, considering the pattern of metastatic spread of leiomyosarcomas, the lung could be the most common target organ. Clinical history, clinical outcome and treatment approach of these patients are uncertain. Prognosis cannot be determined due to the relative rarity of these tumors and the low experience on chemotherapy effect. However, when metastases occur, prognosis seems to be poor.\n\nSource of Support: Nil,\n\nConflict of Interest: None declared\n==== Refs\nREFERENCES\n1 Ip PP Cheung AN Clement PB Uterine smooth muscle tumors of uncertain malignant potential (STUMP): a clinicopathologic analysis of 16 cases Am J Surg Pathol 2009 33 992 1005 19417585 \n2 Unver NU Acikalin MF Oner U Ciftci E Ozalp SS Colak E Differential expression of P16 and P21 in benign and malignant uterine smooth muscle tumors Arch Gynecol Obstet 2011 284 483 90 20878171 \n3 Ng JS Han A Chew SH Low J A clinicopathologic study of uterine smooth muscle tumours of uncertain malignant potential (STUMP) Ann Acad Med Singapore 2010 39 625 8 20838704 \n4 Kong CS Longacre TA Hendrickson MR Berek JS Hacker NF Pathology Gynecologic Oncology 2010 5th ed Philadelphia Lippincott Williams and Wilkins 166 70 Section I, chapter 5 \n5 Hacker NF Friedlander M Berek JS Hacker NF Uterine Cancer Gynecologic Oncology 2010 5th ed Philadelphia Lippincott Williams and Wilkins 430 2 \n6 Schorge J Schaffer J Halvorson L Hoffman B Brandshaw K Cunningham FG Williams Gynecology 2008 34 1 New York City, U.S McGraw-Hill 708 \n7 Nagata J Nishi H Nakamura A Fukuo S Kosaka J A case of uterine myxoid leiomyosarcoma with positive cytology in pleural effusion Nippon Sanka Fujinka Gakkai Zasshi 1996 48 293 5 8936117\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-5851",
"issue": "33(3)",
"journal": "Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology",
"keywords": "Leiomyoma; leiomyosarcoma; lung; metastasis; uterus",
"medline_ta": "Indian J Med Paediatr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9604571",
"other_id": null,
"pages": "176-8",
"pmc": null,
"pmid": "23248426",
"pubdate": "2012-07",
"publication_types": "D002363:Case Reports",
"references": "19417585;20838704;20878171;8936117",
"title": "Uterine smooth muscle tumor of uncertain malignant potential: A rare cause of multiple pulmonary nodules.",
"title_normalized": "uterine smooth muscle tumor of uncertain malignant potential a rare cause of multiple pulmonary nodules"
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"companynumb": "GR-MYLANLABS-2022M1036369",
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"activesubstancename": "EPIRUBICIN"
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{
"abstract": "BACKGROUND\nAdvances in cancer treatment have led to improved long-term survival after childhood cancer, but often at a price of impaired future fertility. Fertility preservation (FP) in male children and early adolescents poses unique challenges as efficacy is unproven.\n\n\nOBJECTIVE\nTo describe characteristics of testicular tissue cryopreservation (TTCP) specimens taken from paediatric and adolescent patients, stratified by age, and prior chemotherapy, if any, and to demonstrate evidence for germ cells.\n\n\nMETHODS\nRetrospective review of gonadal biopsies and clinical records of patients consented into the Royal Children's Hospital FP programme between 1987 and 2015. Tissue was sliced into blocks, with one section sent for histopathology prior to cryopreservation. In boys ≥12 years where spermatogenesis could be expected, a portion of tissue was disaggregated completely to look for mature sperm and if found, additional tissue was dissected and the resulting suspension frozen.\n\n\nRESULTS\nTesticular tissue cryopreservation specimens in 44 males (0.3-16.8 years) provided an average of 7.8 slices per patient. All the specimens were taken at the same time as another necessary surgical procedure, under one general anaesthesic. There was only one complication of scrotal wound dehiscence. Seven of the forty-four (15.9%) patients had chemotherapy prior to testicular biopsy, while the rest were chemotherapy naïve. Five of these were prepubertal, and two were pubertal patients. Eleven subjects had tissue dissected with mature sperm found in eight. Of these eight patients where sperm were found, all were pubertal with testicular size of more than 10 mL and showing histological evidence of spermatogenesis. No histologic specimen demonstrated any malignant cells.\n\n\nCONCLUSIONS\nTesticular tissue cryopreservation can be performed in young patients without delay, preferably prior to cancer treatment. As testicular tissue contains germ cells from which haploid spermatozoa are ultimately derived, future technologies may allow their utilization for fertility in humans. This may be the only hope for biological offspring in some patients undergoing fertility compromising treatment. Retrieval of mature sperm from some pubertal patients, however, offers realistic hope to these patients of future fertility.",
"affiliations": "Royal Children's Hospital, Melbourne, Vic., Australia.;Melbourne IVF, East Melbourne, Vic., Australia.;Melbourne IVF, East Melbourne, Vic., Australia.;Andrology Unit, Laboratory Services Department, Royal Children's and Royal Women's Hospital, Melbourne, Vic., Australia.;Department of Obstetrics & Gynaecology, Royal Women's Hospital, University of Melbourne, Melbourne, Vic., Australia.;Melbourne IVF, East Melbourne, Vic., Australia.;Melbourne IVF, East Melbourne, Vic., Australia.;Royal Children's Hospital, Melbourne, Vic., Australia.;Monash University, Clayton, Vic., Australia.;Royal Children's Hospital, Melbourne, Vic., Australia.;Royal Children's Hospital, Melbourne, Vic., Australia.;Royal Children's Hospital, Melbourne, Vic., Australia.",
"authors": "Ho|Wei Li Cindy|WLC|;Bourne|Harold|H|;Gook|Debra|D|;Clarke|Gary|G|;Kemertzis|Matthew|M|;Stern|Kate|K|;Agresta|Franca|F|;Heloury|Yves|Y|;Clark|Hannah|H|;Orme|Lisa|L|;Jayasinghe|Yasmin|Y|;Zacharin|Margaret R|MR|;|||",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": "10.1111/cen.13377",
"fulltext": null,
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"issn_linking": "0300-0664",
"issue": "87(3)",
"journal": "Clinical endocrinology",
"keywords": "fertility preservation; gonadotoxic therapy; sperm banking; testicular biopsy",
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D015925:Cryopreservation; D059247:Fertility Preservation; D006801:Humans; D007223:Infant; D007248:Infertility, Male; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies; D013091:Spermatogenesis; D013094:Spermatozoa; D013737:Testis",
"nlm_unique_id": "0346653",
"other_id": null,
"pages": "279-285",
"pmc": null,
"pmid": "28504866",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A short report on current fertility preservation strategies for boys.",
"title_normalized": "a short report on current fertility preservation strategies for boys"
} | [
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"companynumb": "PHHY2018AU051626",
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"abstract": "Propofol is one of the most commonly used sedating agents in critical care units worldwide. It is generally well tolerated and preferred for its pharmacokinetic profile. Here, we describe a rare and devastating adverse effect of propofol, the propofol-related infusion syndrome.",
"affiliations": "Departments of 1Internal Medicine and 2Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR.",
"authors": "Pothineni|Naga Venkata Krishna Chand|NV|;Hayes|Kevin|K|;Deshmukh|Abhishek|A|;Paydak|Hakan|H|",
"chemical_list": "D018686:Anesthetics, Intravenous; D015742:Propofol",
"country": "United States",
"delete": false,
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"issn_linking": "1075-2765",
"issue": "22(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000328:Adult; D018686:Anesthetics, Intravenous; D017809:Fatal Outcome; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D015742:Propofol; D013577:Syndrome",
"nlm_unique_id": "9441347",
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"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Propofol-related infusion syndrome: rare and fatal.",
"title_normalized": "propofol related infusion syndrome rare and fatal"
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"companynumb": "US-TEVA-603490USA",
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{
"abstract": "A six-week-old infant presented in extremis and was diagnosed with dextro-transposition of the great arteries, intact ventricular septum, features of left ventricular deconditioning, and abnormal coronary arteries. Treatment with prostaglandin E1 and balloon atrial septostomy was insufficient, necessitating extracorporeal membrane oxygenation (ECMO). Severe acute respiratory syndrome coronavirus-2 was detected. The arterial switch operation was delayed by eight days because of COVID-19. Although stable on ECMO, the infant was treated with remdesivir. Extracorporeal membrane oxygenation was not required postoperatively with chest closure on day 2 and extubation on day 5.",
"affiliations": "Department of Pediatric Intensive Care, 4593Alder Hey Children's Hospital, Liverpool, United Kingdom.;Department of Pediatric Intensive Care, 4593Alder Hey Children's Hospital, Liverpool, United Kingdom.;Department of Pediatric Infectious Diseases, 4593Alder Hey Children's Hospital, Liverpool, United Kingdom.;Department of Pediatric Cardiology, 4593Alder Hey Children's Hospital, Liverpool, United Kingdom.;Department of Pediatric Cardiology, 4593Alder Hey Children's Hospital, Liverpool, United Kingdom.;Department of Cardiothoracic Surgery, 4593Alder Hey Children's Hospital, Liverpool, United Kingdom.",
"authors": "Nabialek|Tomasz J|TJ|0000-0002-3486-868X;Puppala|Naga K|NK|;Riordan|Andrew|A|;Ramaraj|Ram|R|;Duong|Phuoc|P|;Guerrero|Rafael|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/21501351211000687",
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"issue": "12(4)",
"journal": "World journal for pediatric & congenital heart surgery",
"keywords": null,
"medline_ta": "World J Pediatr Congenit Heart Surg",
"mesh_terms": "D000069278:Arterial Switch Operation; D000086382:COVID-19; D003331:Coronary Vessels; D006801:Humans; D007223:Infant; D000086402:SARS-CoV-2; D014188:Transposition of Great Vessels; D016896:Treatment Outcome",
"nlm_unique_id": "101518415",
"other_id": null,
"pages": "554-556",
"pmc": null,
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"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful Management of a COVID-19 Positive Infant With Transposition of the Great Arteries.",
"title_normalized": "successful management of a covid 19 positive infant with transposition of the great arteries"
} | [
{
"companynumb": "GB-PFIZER INC-2021355450",
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{
"abstract": "Tumour lysis syndrome (TLS) is a potentially fatal complication of malignancy or its treatment. This uncommon syndrome comprises laboratory findings of hyperuricaemia, hypocalcaemia, hyperkalaemia and hyperphosphataemia. A literature search revealed a total of eight patients, with testicular cancer, who had TLS. All these patients had metastatic disease. We present a unique case of a 47-year-old gentleman we saw in clinic, who presented with a rapidly growing right groin mass and acute breathlessness, and discuss the diagnosis and management of TLS. TLS is extremely rare in testicular cancer but necessitates the awareness of urologists. TLS can occur spontaneously in testicular malignancy. Cell lysis in a rapidly proliferating germ cell tumour is a possible mechanism. The prompt identification and institution of management for TLS is crucial to improve clinical outcomes.",
"affiliations": "Department of Urology, Tan Tock Seng Hospital, Singapore.;Department of Urology, Tan Tock Seng Hospital, Singapore.;Department of Urology, Tan Tock Seng Hospital, Singapore.",
"authors": "Chow|Marcus|M|;Yuwono|Arianto|A|;Tan|Ronny|R|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1016/j.ajur.2015.09.005",
"fulltext": "\n==== Front\nAsian J UrolAsian J UrolAsian Journal of Urology2214-38822214-3890Second Military Medical University S2214-3882(15)00113-710.1016/j.ajur.2015.09.005Case ReportTumour lysis syndrome: A rare acute presentation of locally advanced testicular cancer – Case report and review of literature Chow Marcus marcus.chow@mohh.com.sg∗Yuwono Arianto Tan Ronny Department of Urology, Tan Tock Seng Hospital, Singapore∗ Corresponding author. marcus.chow@mohh.com.sg24 10 2015 1 2016 24 10 2015 3 1 49 52 1 7 2015 17 9 2015 28 9 2015 © 2016 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.2016Editorial Office of Asian Journal of UrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Tumour lysis syndrome (TLS) is a potentially fatal complication of malignancy or its treatment. This uncommon syndrome comprises laboratory findings of hyperuricaemia, hypocalcaemia, hyperkalaemia and hyperphosphataemia. A literature search revealed a total of eight patients, with testicular cancer, who had TLS. All these patients had metastatic disease. We present a unique case of a 47-year-old gentleman we saw in clinic, who presented with a rapidly growing right groin mass and acute breathlessness, and discuss the diagnosis and management of TLS. TLS is extremely rare in testicular cancer but necessitates the awareness of urologists. TLS can occur spontaneously in testicular malignancy. Cell lysis in a rapidly proliferating germ cell tumour is a possible mechanism. The prompt identification and institution of management for TLS is crucial to improve clinical outcomes.\n\nKeywords\nTumour lysis syndromeTesticular cancerTesticular malignancy\n==== Body\n1 Introduction\nTumour lysis syndrome (TLS) is an oncological emergency, which is characterized by the derangement of cellular metabolism that can lead to acute renal impairment, metabolic acidosis, cardiac rhythm disturbances, seizures and death [1]. Massive cell lysis results in the release of large amounts of uric acid, potassium and phosphate into the systemic circulation. Hyperkalaemia, if untreated, may cause muscle weakness or paralysis and more significantly, cardiac arrhythmias and ultimately death [1]. Hyperphosphataemia is often associated with hypocalcaemia due to the precipitation of phosphate with the calcium in tissues. The resultant secondary hypocalcaemia may result in neuromuscular symptoms such as tetany, laryngospasm and cardiac arrhythmias. Both hyperuricaemia and hyperphosphataemia potentiate the risk of acute kidney injury by way of uric acid precipitation and calcium phosphate deposition in the renal tubules, further aggravating the electrolyte imbalance [2]. Additionally, the products of cell lysis trigger the release of cytokines, resulting in a systemic inflammatory response syndrome and frequently multiorgan failure [1].\n\nTLS most commonly occurs after the initiation of cytotoxic therapy in patients with aggressive lymphoma or leukaemia. However, it may also occur spontaneously with other types of tumours that have a high proliferative rate, tumour burden or sensitivity to cytotoxic agents. In the setting of testicular cancer, a literature search only revealed eight incidences of TLS in testicular tumours, of which seven were metastatic and one had nodal involvement [3], [4]. TLS occurred spontaneously in three patients, all of who had metastatic testicular seminomas [3]. The presence of metastatic disease would be compatible with an increased tumour burden which consequentially increases the risk of TLS occurring, either spontaneously or after the initiation of chemotherapy.\n\nWe present the case of a 47-year-old gentleman who was referred for a right groin swelling.\n\n2 Case report\nThe patient was referred for progressive right groin swelling of 1-year duration, which had recently rapidly increased in size over the past 2 weeks. He reported a history of an undescended right testis, for which he underwent no previous surgical intervention. He reported good appetite and denied any weight loss. Physical examination revealed a 15 cm × 10 cm firm right groin lump, not extending into the scrotum. The right testis was not palpable in his scrotum. A CT abdomen/pelvis scan done prior to the clinic consultation revealed a 15 cm × 11 cm × 16 cm right groin solid mass, which was partly cystic with septations and calcification, suggestive of gonadal malignancy. There was no lymphadenopathy, metastasis or ascites in the abdomen. The right testis was not seen within the scrotum (Fig. 1). During the consultation, he was noted to be dyspnoeic and tachypnoeic but able to speak in full sentences. Upon further probing, he reported decreased effort tolerance, breathlessness and bilateral lower limb swelling for the past 2 days. He was admitted for an urgent CT pulmonary angiogram (CTPA). The CTPA performed excluded pulmonary embolism and lung metastases.Figure 1 (A) (B) CT abdomen/pelvis revealed a 15 cm × 11 cm × 16 cm right groin mass. There was no lymphadenopathy or metastasis present. (C) CT pulmonary angiogram revealed no pulmonary embolism or lung metastasis.\n\n\n\nAfter admission, he was noted to be more tachypnoeic and struggling to speak in full sentences on the ward. An arterial blood gas (ABG) performed on 4 L/min of oxygen revealed severe metabolic acidosis with a pH of 7.08 and a lactate >10.9 mmol/L. He was promptly transferred to the intensive care unit (ICU) and intubated to provide mechanical ventilatory support. TLS was provisionally diagnosed and subsequently confirmed on laboratory findings. His blood results revealed hyperuricaemia, hyperphosphataemia, hyperkalaemia and an elevated creatinine and urea. Testicular tumour markers revealed a raised lactate dehydrogenase (LDH) >3800 U/L, and β subunit of human chorionic gonadotropin (β-hCG) 37 IU/L, with a normal α-fetoprotein (AFP) 3 μg/L. Post-intubation, he had a decreased level of consciousness, with a Glasgow coma scale score of 3 out of 15 despite receiving no intravenous sedation.\n\nHis electrolyte abnormalities were addressed systematically. For the hyperkalaemia, he received intravenous insulin, calcium gluconate and calcium resonium. For the hyperuricaemia, oral allopurinol via a nasogastric tube and intravenous rasburicase were administered. In view of the refractory hyperkalaemia and worsening metabolic acidosis despite intravenous sodium bicarbonate and multiple fluid challenges, a vascular catheter was inserted in his right internal jugular vein; he was started on continuous renal replacement therapy (CRRT). His systolic blood pressure dropped to 40–60 mmHg during CRRT, from approximately 110 mmHg. It was refractory to intravenous 5% albumin boluses as well as intravenous noradrenaline. CRRT was discontinued after 60 min as the persistently low blood pressure resulted in the formation blood clots in the vascular catheter. Additional inotropic support in the form of intravenous adrenaline was started. Despite the best treatment, the patient had a cardiac arrest and died.\n\n3 Discussion\n3.1 Incidence\nThis case illustrates a rare presentation of a testicular malignancy. To our knowledge, this is the first case of a non-metatstatic testicular malignancy, with no nodal involvement to present with spontaneous TLS. TLS most commonly occurs after initiation of cytotoxic therapy. In the testicular malignancy setting, spontaneous occurrence of TLS is even rarer. In particular, this patient's CT scans showed no regional lymphadenopathy or distant metastasis, unlike previous reported cases where patients with TLS had metastatic testicular malignancy. Of the eight reported cases of TLS resulting from testicular malignancy, there were four patients who had seminomas [5], [6], [7], [8]. All the patients with seminomas had evidence of metastatic disease, either nodal or distant organ metastases. The other tumours reported included testicular choriocarcinoma [5], germ cell tumour and non seminomatous tumour [7], all of which were metastatic. Spontaneous TLS was reported in three of the cases, of which all were seminomas with metastatic disease [6], [8]. Interestingly, a retrospective study done by Kattan et al. [9] failed to show the presence of TLS in 46 cases of germ cell tumours receiving aggressive cisplatin based chemotherapy. Despite not having any evidence of metastasis, factors contributing to our patient's occurrence of TLS would be the size of his tumour and recent rapid rate of growth, favouring a highly proliferative malignancy.\n\n3.2 Diagnosis\nWe arrived at the provisional diagnosis of TLS after taking into account his unique presentation of acute breathlessness, rapidly growing right groin mass, negative findings from CTPA and ABG showing severe metabolic acidosis. Despite the prompt recognition of TLS from the time he was found to be in severe metabolic acidosis and institution of relevant management, he deteriorated and died, less than 24 h after his clinic consultation. The circumstances of his demise necessitated that his case had to be referred to the coroner's office. After reviewing the clinical case and evidence, the coroner's office established that the cause of his death was “Locally Advanced Testicular Malignancy”. A post-mortem was not performed. The history of an undescended right testis, radiological findings of a solid, partly cystic groin mass with septation and calcifications in conjunction with a raised β-hCG point strongly towards a testicular germ-cell tumour. In this case, the most probable diagnosis was a rapidly proliferating testicular germ cell tumour. Testicular lymphoma remains a distant possibility, however it is extremely unlikely as there was no evidence of lymphadenopathy in the chest, abdomen or pelvis. The intravenous contrast from the CT abdomen, pelvis and pulmonary angiogram may have further contributed to renal insult hence aggravating the TLS. Unfortunately, not all of the published case reports described the process in which the diagnosis of TLS was made in these patients with testicular malignancy. A common presentation was progressive dyspnoea that led on to further investigations being performed. Most of them had documented evidence of elevated creatinine, LDH and uric acid.\n\n3.3 Management\nThe occurrence of TLS is multifactorial; attributes such as age, LDH levels, white cell count, baseline creatinine, co-morbidities and cancer type and stage are risk factors [10]. The ideal treatment of TLS is prevention. Risk stratification and initiation of TLS prophylaxis is crucial. Risk stratification for TLS based on the above-mentioned risk factors was developed by Cairo et al. [10] to help indicate which patients required prophylaxis in the form of close monitoring with accurate fluid balance charting, intravenous hydration and medication such as allopurinol or rasburicase. Testicular malignancy, which belongs to the subgroup of solid tumours are classified as low risk and prophylaxis includes close monitoring and intravenous hydration with or without the administration of allopurinol. For patients receiving cytotoxic agents, those at high risk for developing TLS should be assessed for clinical signs and biochemical markers, such as LDH, serum creatinine, uric acid and electrolytes, every 4–6 h after commencement [11]. The most important prophylaxis is the hyperhydration with intravenous fluids. This helps improve renal perfusion and glomerular filtration and minimizes acidosis (which promotes the precipitation of uric acid crystals) [1]. Fluid administration also improves urine output which facilitates the elimination of urates and phosphates [11]. The aim should be to maintain a urine output of greater than 100 mL/h [12]. Secondly, hypouricaemic agents like allopurinol and rasburicase that reduce the level of uric acid are valuable in the prevention of TLS. However, it is important to note that while allopurinol prevents the formation of new uric acid by inhibiting xanthine oxidase, existing uric acid still has to be excreted. Rasburicase is a recombinant urate oxidase enzyme that metabolises uric acid to allantoin, hence reducing high levels of uric acid in addition to preventing hyperuricaemia [1]. Rasburicase is indicated for patients at higher risk of developing TLS.\n\nDespite appropriate prophylactic measures, about 3%–5% of patients receiving cytotoxic chemotherapy will develop TLS [13]. In addition to accurate fluid balance charting, patients should also receive continuous cardiac monitoring together with 4–6 hourly biochemical testing of creatinine, uric acid and electrolytes. Hyperkalaemia is the most dangerous element of TLS as it may cause sudden death secondary to a cardiac arrhythmia. Hyperkalaemia may be corrected with intravenous hydration, sodium polystyrene, sabutamol and intravenous insulin and dextrose. Haemodialysis or hemofiltration to remove the excess potassium is the last resort. Hypocalcaemia may also result in life-threatening dysarrhythmias and neuromuscular irritability. Ensuring that serum phosphate levels are corrected may help avoid hypocalcaemia. If required, symptomatic hypocalcaemia may be treated calcium supplementation at the lowest dose possible to relieve symptoms. Regardless of optimal treatment, severe acute kidney injury may still occur in some patients. Worsening acidosis, severe acute kidney injury and refractory electrolyte abnormalities are indications for renal replacement therapy [14].\n\nPrompt recognition and timely intervention remain the most crucial elements in the successful management of patients with TLS. A case report of a patient with metastatic testicular choriocarcinoma with seminoma, who developed TLS after receiving adjuvant chemotherapy illustrated that aggressive intensive care and prompt intervention led to the prevention of a fatal outcome secondary to TLS [15].\n\n3.4 Learning point\nIn the case of our patient, it was unfortunate that medical attention was sought so late in the course of his disease. Despite arriving at the diagnosis of TLS shortly after hospital admission, the prompt measures we initiated were unable prevent a fatal outcome. His outcome might have improved with earlier surgical intervention such as an orchidectomy, to reduce the tumour burden.\n\n4 Conclusion\nIn conclusion, TLS is extremely rare in untreated, non-metastatic testicular cancer but necessitates the awareness of urologists. It is important to note that TLS can occur spontaneously in malignancy; cell lysis in a rapidly proliferating germ cell tumour is a possible mechanism. The prompt identification and institution of management for TLS is crucial to improve clinical outcomes.\n\nConflicts of interest\nThe authors declare no conflict of interest.\n\nPeer review under responsibility of Shanghai Medical Association and SMMU.\n==== Refs\nReferences\n1 Howard S.C. Jones D.P. Pui C.H. The tumor lysis syndrome Engl J Med 364 2011 1844 1854 \n2 Baeksgaard L. Sørensen J.B. Acute tumor lysis syndrome in solid tumors–a case report and review of the literature Cancer Chemother Pharmacol 51 2003 187 192 12655435 \n3 Mirrakhimov A.E. Ali A.M. Khan M. Barbaryan A. Tumor lysis syndrome in solid tumors: an up to date review of the literature Rare Tumors 6 2014 5389 25002953 \n4 Kobatake K. Kato M. Mita K. Advanced testicular cancer associated with life-threatening tumour lysis syndrome and choriocarcinoma syndrome Can Urol Assoc J 9 2015 62 64 25737760 \n5 Blanke C.D. Hemmer M.P. Witte R.S. Acute tumor lysis syndrome with choriocarcinoma South Med J 93 2000 916 919 11005356 \n6 Pentheroudakis G. O'Neill V.J. Vasey P. Kaye S.B. Spontaneous acute tumour lysis syndrome in patients with metastatic germ cell tumours Support Care Cancer 9 2001 554 557 11680837 \n7 Feres G.A. Salluh J.I. Ferreira C.G. Soares M. Severe acute tumor lysis syndrome in patients with germ-cell tumors Indian J Urol 24 2008 555 557 19468517 \n8 D'Alessandro V. Greco A. Clemente C. Sperandeo M. De Cata A. Di Micco C. Severe spontaneous acute tumor lysis syndrome and hypoglycemia in patient with germ cell tumor Tumori 96 2010 1040 1043 21388073 \n9 Kattan J. Culine S. Tavakoli-Razavi T. Kramar A. Droz J.P. Acute tumor lysis syndrome in poor-risk germ cell tumors: does it exist? Support Care Cancer 2 1994 128 131 7512416 \n10 Cairo M.S. Coiffier B. Reiter A. Younes A. TLS expert panel. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus Br J Haematol 149 2010 578 586 20331465 \n11 Coiffier B. Altman A. Pui C.H. Younes A. Cairo M.S. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review J Clin Oncol 26 2008 2767 2778 18509186 \n12 Pession A. Masetti R. Gaidano G. Tosi P. Rosti G. Aglietta M. Risk evaluation, prophylaxis, and treatment of tumor lysis syndrome: consensus of an Italian expert panel Adv Ther 28 2011 684 697 21779956 \n13 Sarno J. Prevention and management of tumor lysis syndrome in adults with malignancy J Adv Pract Oncol 4 2013 101 106 25031988 \n14 Cairo M.S. Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification Br J Haematol 127 2004 3 11 15384972 \n15 Kawai K. Takaoka E. Naoi M. Mori K. Minami M. Shimazui T. A case of metastatic testicular cancer complicated by tumour lysis syndrome and choriocarcinoma syndrome Jpn J Clin Oncol 36 2006 665 667 16935862\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-3882",
"issue": "3(1)",
"journal": "Asian journal of urology",
"keywords": "Testicular cancer; Testicular malignancy; Tumour lysis syndrome",
"medline_ta": "Asian J Urol",
"mesh_terms": null,
"nlm_unique_id": "101699720",
"other_id": null,
"pages": "49-52",
"pmc": null,
"pmid": "29264163",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports",
"references": "25737760;7512416;18509186;19468517;11680837;25002953;15384972;12655435;21561350;21388073;11005356;21779956;20331465;25031988;16935862",
"title": "Tumour lysis syndrome: A rare acute presentation of locally advanced testicular cancer - Case report and review of literature.",
"title_normalized": "tumour lysis syndrome a rare acute presentation of locally advanced testicular cancer case report and review of literature"
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"activesubstancename": "INSULIN GLARGINE"
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"abstract": "MRI findings of four hemiballism cases are described, and pathophysiology, pathogenesis and treatment of hemiballism are discussed. All cases had no family history. The lesions revealed by MRI and the pathogenesis were different each other. Case 1, a 17 years aged girl with a history of hyperthyroidism and repeated tonsillitis, showed right sided hemiballism which was recovered by prednisolone and haloperidol. Although her involuntary movement was ameliorated by administration of sodium valproate and phenytoin, phenytoin caused allergic agranulocytosis which required prednisolone treatment. T2 weighted MRI at the 31st disease day demonstrated hyperintensities in the left caudate nucleus, putamen, lateral pallidum, perirubral area and substantia nigra. Hyperintensity in the prerubral area suggested involvement of the subthalamic nucleus or its connecting pathway. Fourteen months later, she suffered from convulsion and mental confusion. There were theta wave bursts and delta waves in EEG. No abnormal findings in MRI and positive antinuclear antibody (ANA: X320, speckled type) were observed. Case 2, a 78 year aged woman, suffered from right sided hemiballism. MRI findings at the 58th disease day were the left putaminal infarction and lacunar state in the bilateral caudate nuclei and the deep white matter of the centrum semiovale. There were no abnormal findings in the subthalamic nucleus. Case 3, a 51 year aged man with diabetes mellitus, had right sided hemiballism. X-ray CT at the 8th disease day showed hyperdensity in the left subthalamic nucleus region which could not be observed at the 12th day. Hypointensity in the left subthalamic nucleus region was observed in both T2 weighted and proton density MRI at the 52nd day. Case 4, an 82 year aged woman, had right sided hemiballism which remarkably diminished at the third disease day and disappeared by the fifth day. Any pathogenic lesion concerning to hemiballism was detected by X-ray CT or MRI.(ABSTRACT TRUNCATED AT 250 WORDS)",
"affiliations": "Department of Neurology, Nara Medical University.",
"authors": "Konagaya|M|M|;Nakamuro|T|T|;Sugata|T|T|;Funakawa|I|I|;Takayanagi|T|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0009-918X",
"issue": "30(1)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": null,
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000293:Adolescent; D000368:Aged; D002561:Cerebrovascular Disorders; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders; D013787:Thalamic Nuclei",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "17-23",
"pmc": null,
"pmid": "2331818",
"pubdate": "1990-01",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "MRI study of hemiballism.",
"title_normalized": "mri study of hemiballism"
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"activesubstancename": "VALPROATE SODIUM"
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"abstract": "Objective The treatment of refractory lupus nephritis (LN) remains challenging for clinicians because these patients either do not respond to conventional therapy or relapse during the maintenance treatment period. The aim of this study was to investigate the efficacy and safety of bortezomib combined with glucocorticoids in refractory lupus patients. Methodology Five refractory LN patients aged 21 to 43 years (four females and one male) with biopsy-proven diagnosis (four with type IV and one with type V+IV) were recruited. These patients received bortezomib therapy for four cycles (1.3 mg per square meter of body surface area as an intravenous bolus on days 1, 4, 8, and 11 of 21-day cycles) and glucocorticoids (methylprednisolone 0.5 g/d intravenously for three days, followed by prednisone 0.6 mg/kg/d orally for four weeks, with gradual tapering to 10 mg/d). Proteinuria, serum albumin and creatinine, and immunological parameters were assessed, and adverse effects were also evaluated. Results After two to four bortezomib treatment cycles, four patients achieved partial remission with decreases in SLE disease activity index scores from the range of 12-16 to that of 4-8. The patients also exhibited a decline in proteinuria and an elevation of albumin level after treatment. SCr level was decreased in three of five patients with elevated SCr at baseline. The anti-autoantibodies and complements were also improved. Adverse events were of grades 1-2 and included transient thrombocytopenia, gastrointestinal symptoms and acroesthesia. During a 6- to 24-month follow-up period, three patients achieved complete remission, and one had partial remission. However, one patient received renal replacement therapy. Conclusion Bortezomib combined with glucocorticoids reduces proteinuria, improves renal function and decreases anti-autoantibodies, with good tolerance and mild adverse events, thus representing an alternative therapy for refractory LN and warranting further study.",
"affiliations": "National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Clinical School of Second Military Medical University, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Clinical School of Second Military Medical University, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Clinical School of Second Military Medical University, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Clinical School of Second Military Medical University, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Clinical School of Second Military Medical University, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Clinical School of Second Military Medical University, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Clinical School of Second Military Medical University, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Clinical School of Second Military Medical University, Nanjing University School of Medicine, Nanjing, China.",
"authors": "Zhang|H|H|;Liu|Z|Z|;Huang|L|L|;Hou|J|J|;Zhou|M|M|;Huang|X|X|;Hu|W|W|;Liu|Z|Z|",
"chemical_list": "D000970:Antineoplastic Agents; D001323:Autoantibodies; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000069286:Bortezomib; D011241:Prednisone; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1177/0961203316686703",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "26(9)",
"journal": "Lupus",
"keywords": "Lupus nephritis; adverse effect; bortezomib; efficacy",
"medline_ta": "Lupus",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000970:Antineoplastic Agents; D001323:Autoantibodies; D000069286:Bortezomib; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D008181:Lupus Nephritis; D008297:Male; D008775:Methylprednisolone; D011241:Prednisone; D011507:Proteinuria; D012074:Remission Induction",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "952-958",
"pmc": null,
"pmid": "28059023",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The short-term efficacy of bortezomib combined with glucocorticoids for the treatment of refractory lupus nephritis.",
"title_normalized": "the short term efficacy of bortezomib combined with glucocorticoids for the treatment of refractory lupus nephritis"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1055813",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "BACKGROUND\nComplex injuries to the central part of the face are difficult to reconstruct with the current plastic surgery methods. The ultimate one-staged approach to restore anatomy and vital facial functions is to perform a vascularized composite allotransplantation (VCA).\n\n\nMETHODS\nA 54-year-old man suffered from a high-energy ballistic injury, resulting in a large central facial defect. A temporary reconstruction was performed with a free plicated anterolateral thigh (ALT) flap. Considering the goal to optimally restore facial function and aesthetics, VCA was considered as an option for facial reconstruction. A multidisciplinary team approach, digital planning, and cadaver sessions preceded the transplantation.\n\n\nRESULTS\nA digitally planned facial VCA was performed involving the bilateral maxillae, the hard palate, a part of the left mandible, and the soft tissues of the lower two-thirds of the face. Due to meticulous preparations, minimal adjustments were necessary to achieve good fitting in the recipient. At week 17, a grade 4 rejection was successfully treated; sensory and motor recovery was noted to occur from the fourth postoperative month. Several serious infectious and medical problems have occurred until 15-months postoperatively; following that, the clinical situation has remained stable. Two years postoperatively, the patient and his family are very satisfied with the overall outcome and social reintegration in the community is successful.\n\n\nCONCLUSIONS\nThe first face transplant in Belgium (#19 worldwide) was successful because of a meticulous 3-year preparation by a large multidisciplinary team. In our experience, preparatory cadaver dissections and three-dimensional (3D) computed tomographic (CT) modeling were valuable tools for an optimal intraoperative course and good alignment of the bony structures. Continuous long-term multidisciplinary follow-up is mandatory for surveillance of the complications associated with the immunosuppressive regime and for functional assessment of the graft.",
"affiliations": "Department of Plastic and Reconstructive Surgery, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: nathalie.roche@ugent.be.;Department of Head and Neck Surgery, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.;Department of Plastic and Reconstructive Surgery, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.;Department of Plastic and Reconstructive Surgery, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.;Center for Craniofacial Epithetics, Guldendelle 35, 1930 Zaventem, Belgium.;Department of Speech, Language and Hearing Sciences, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.;Department of Transplant Surgery, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.;Department of Transplant Surgery, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.;Department of Nephrology, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.;Department of Psychiatry and Medical Psychology, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.;Department of Plastic and Reconstructive Surgery, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.",
"authors": "Roche|Nathalie A|NA|;Vermeersch|Hubert F|HF|;Stillaert|Filip B|FB|;Peters|Kevin T|KT|;De Cubber|Jan|J|;Van Lierde|Kristiane|K|;Rogiers|Xavier|X|;Colenbie|Luc|L|;Peeters|Patrick C|PC|;Lemmens|Gilbert M D|GM|;Blondeel|Phillip N|PN|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1748-6815",
"issue": "68(3)",
"journal": "Journal of plastic, reconstructive & aesthetic surgery : JPRAS",
"keywords": "3D CT modeling; Face transplant; Multidisciplinary team approach; Vascularized composite allotransplantation",
"medline_ta": "J Plast Reconstr Aesthet Surg",
"mesh_terms": "D064591:Allografts; D001530:Belgium; D005151:Facial Injuries; D054445:Facial Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D025321:Surgery, Computer-Assisted; D014057:Tomography, X-Ray Computed; D014948:Wounds, Gunshot",
"nlm_unique_id": "101264239",
"other_id": null,
"pages": "362-71",
"pmc": null,
"pmid": "25488328",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complex facial reconstruction by vascularized composite allotransplantation: the first Belgian case.",
"title_normalized": "complex facial reconstruction by vascularized composite allotransplantation the first belgian case"
} | [
{
"companynumb": "PHHY2015BE041189",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
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"drugadditional": null,
"dr... |
{
"abstract": "A 32-year-old Indian female 38 weeks pregnant, with a history of multiple sclerosis since 2008 was admitted in obstetric ward for safe confinement. She had a history of diminution of vision in both eyes and limb weakness, relapsing - remitting type with movement-induced muscle spasms, in all the four limbs. Her symptoms were usually diplopia, difficulty in vision and ataxic gait. Sh was then treated with methylprednisolone. She was on oral dimethyl fumarate trial, which was stopped at the beginning of pregnancy. Presently, she was completely asymptomatic. Epidural anesthesia with an indwelling catheter was administered with 15 ml of 0.25% bupivacaine in 5 ml increments. A total of 3 mg of epidural morphine was given for post-operative analgesia. The surgery evolved without any intercurrences and patient was discharged from the hospital 72 h after surgery without worsening of her symptoms. We report a safe anesthetic management of a patient with MS undergoing cesarean section with low dose epidural bupivacaine with the addition of morphine for post-operative analgesia.",
"affiliations": "Department of Anesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Anesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Sethi|Sameer|S|;Kapil|Sonia|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/1658-354X.136633",
"fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Medknow Publications & Media Pvt Ltd India SJA-8-40210.4103/1658-354X.136633Case ReportAnesthetic management of a patient with multiple sclerosis undergoing cesarean section with low dose epidural bupivacaine Sethi Sameer Kapil Sonia Department of Anesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Chandigarh, IndiaAddress for correspondence: Dr. Sameer Sethi, Department of Anesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, India. E-mail: sethi.sameer@rediffmail.comJul-Sep 2014 8 3 402 405 Copyright: © Saudi Journal of Anaesthesia2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 32-year-old Indian female 38 weeks pregnant, with a history of multiple sclerosis since 2008 was admitted in obstetric ward for safe confinement. She had a history of diminution of vision in both eyes and limb weakness, relapsing – remitting type with movement-induced muscle spasms, in all the four limbs. Her symptoms were usually diplopia, difficulty in vision and ataxic gait. Sh was then treated with methylprednisolone. She was on oral dimethyl fumarate trial, which was stopped at the beginning of pregnancy. Presently, she was completely asymptomatic. Epidural anesthesia with an indwelling catheter was administered with 15 ml of 0.25% bupivacaine in 5 ml increments. A total of 3 mg of epidural morphine was given for post-operative analgesia. The surgery evolved without any intercurrences and patient was discharged from the hospital 72 h after surgery without worsening of her symptoms. We report a safe anesthetic management of a patient with MS undergoing cesarean section with low dose epidural bupivacaine with the addition of morphine for post-operative analgesia.\n\nCesarean sectionepidural anesthesiamultiple sclerosisopioid\n==== Body\nINTRODUCTION\nMultiple sclerosis (MS) is an acquired disease of the central nervous system characterized by inflammation and demyelination in the brain and spinal cord.[123] It is an autoimmune disease that seems to affect genetically susceptible patients after exposure to the environmental factors[2456] with a greater incidence in women.[24] The disease evolves with periods of exacerbations and remissions at the unpredictable intervals[478] and when only the pregnant patients are taking into consideration, more than half of the exacerbations happen after delivery[49] especially in the first 3 months.[4] Prevalence, increases with latitude, is rare in Asian countries, highest in North Scotland, Northern Europe and Northern United States and in Canada.[1] We report a safe anesthetic management of a patient with MS undergoing cesarean section with low dose epidural bupivacaine with the addition of morphine for post-operative analgesia.\n\nCASE REPORT\nA 32-year-old Indian female 38 weeks pregnant, weighing 50 kg with a history of MS since 2008 was admitted in obstetric ward for safe confinement. She had a history of diminution of vision in both eyes and limb weakness, relapsing — remitting type with movement-induced muscle spasms, in all the four limbs. Her symptoms were usually diplopia, difficulty in vision and ataxic gait. Bowel and bladder function was normal. There was no history of seizures, difficulty in speech, swallowing and breathing. She was then treated with methylprednisolone. She was on oral dimethyl fumarate trial which was stopped at the beginning of pregnancy. Presently, she was completely asymptomatic. Her respiratory system and blood gas analysis was normal. Autonomic system was tested with heart rate response to deep breathing and was found to be normal. Laboratory investigations (routine hematological, liver and kidney function, serum electrolytes), chest X-ray and electrocardiogram were normal. Magnetic resonance imaging scan showed patchy bright signals within the cord on T2-weighed images from C1 to T10 vertebral levels suggesting demyelination. Patient was preloaded with 500 ml of normal saline. Epidural anesthesia (EA) with an indwelling catheter was administered with 15 ml of 0.25% bupivacaine in 5 ml increments. Anesthesia up to T6 level was confirmed and surgery was started. 3 mg of epidural morphine was given for the post-operative pain. The surgery evolved without any intercurrences and patient was discharged from the hospital 72 h after delivery without worsening of her symptoms.\n\nShe was followed-up for 4 months and during that period she had no remission of the disease.\n\nDISCUSSION\nMS is characterized by periods of exacerbation and remission. The disease may usually remain quiescent during pregnancy, but the incidence of recurrence is 3 times higher than in non-pregnant women, in the first 3 months after pregnancy.\n\nOther factors, which have been implicated in the exacerbation of the disease are emotional stress, trauma, surgery, water and electrolyte balance, fever and infection.[6710]\n\nGeneral anesthesia (GA)[9] and anesthesia of the neuroaxis[11] can induce recurrences although it is still a matter of controversy.[5712131415] Perlas and Chan[5] and many other recent data[1013141516] stated that although the post-operative and post-partum recurrences are controversial, they are not affected by the choice of the anesthetic technique and all the techniques can be safely used in these patients.\n\nPerioperative stress or anesthesia and post-operative pain are often implicated as causes of exacerbation of a disease.[1317] Pre-operative counseling of patient for post-operative exacerbations should be done.\n\nThe pre-operative anesthetic assessment in a patient should involve pre- operative documentation of the neurological deficit, respiratory system involvement, autonomic nervous system dysfunction, potential drug interactions. The anesthetic personnel must carefully choose the anesthetic technique, anesthetic drugs (inhalational/intravenous [IV]). Apart from the routine monitoring of the patient intraoperative neuromuscular monitoring and temperature monitoring should take precedence.[18]\n\nDue to the motor weakness and cervical cord involvement leading to diaphragmatic paralysis some authors recommend pulmonary function tests.[1920]\n\nThe test was not carried out in our patient as it was an emergency lower segment caesarean section and the clinical assessment did not indicated any respiratory system involvement.\n\nCare of the pregnant patient with MS is challenging because of multiple physiological changes associated with pregnancy and the need to consider the impact of any intervention on fetus.[16]\n\nRegarding the relationship between pregnancy and MS, the incidence and frequency of MS relapses are same in multipara as well as in nullipara. Fertility is not altered in early stages. In mild cases or in remissions, the pregnant patient does well. Pregnancy has no untoward effect on the course of disease and the incidence of obstetric complication is not increased and the method of delivery depends entirely on the obstetric considerations.[16]\n\nThe literature regarding anesthetic management contains use of GA, spinal and epidural techniques. GA and epidural with low concentrations of local anesthetic (LA) are considered safe.[2517]\n\nUntil a decade ago, subarachnoid anesthesia has been implicated in post-operative exacerbation,[411] so also epidurals with higher concentrations and longer duration,[214] but the recent data suggests that it is safe in these patients[3131415]\n\nEA can also be successfully administered to those patients[2122] It has been considered the most innocuous technique[8] because the concentration of the LA in the white matter of the spinal cord is 3-4 times lower than with subarachnoid anesthesia.[791123] and the reports of relapses after EA may be related to higher concentrations of bupivacaine (>0.25%)[24] administered for longer periods of time.\n\nPasto et al. conducted a prospective study in 423 pregnant patients with MS and concluded that there was no significant correlation in the EA and post-partum exacerbation of the disease. There was no information on the type and dosage of anesthetic used for EA.[22]\n\nThe addition of opioid to EA is useful for post-operative pain control, which can be helpful in limiting the stress response due to pain and surgery and thus minimizing the chances of relapse. In our patient, we used epidural morphine for post-operative analgesia.\n\nThe obstetric patient seems to be more resistant to late post-operative respiratory depression after the administration of hydrophilic opioids to the neuroaxis.[3] This protective effect is due to the increased minute ventilation observed during pregnancy secondary to the direct stimulation of the respiratory centers and/or to the increased sensitivity to carbon dioxide caused by progesterone.[3] Most cases of severe depression affect patients who received concomitant parenteral opioids or sedatives. The addition of opioids to the neuroaxis favors anesthesia in patients with MS.[25] In the context of patients with MS, the side-effects of morphine do not seem to be exacerbated.[13]\n\nAdequate preloading prior to EA was performed as the involvement of autonomic nervous system makes these patients more prone to marked hypotension[17] and reduced response to IV fluid and vasopressor therapy.\n\nMedications used to treat MS may have anesthetic implications. Recent steroid use must be elicited and supplemental steroids should be given per operatively to avoid adrenal insufficiency.[17] Our patient was not on any steroid so we did not administer supplementary steroid.\n\nChronic steroid use may lead to muscle wasting and osteoporosis and increase the risk of injury during positioning.\n\nGA can also be used in these patients[10] and there is no preference as regards to the induction agent (inhalational/IV). The use of nitrous oxide is avoided owing to its inhibition of vitamin B12 and relation to myopathy. On the contrary, neuromuscular agents should be used carefully. Succinylcholine seems to be a relative contraindication due to the risk of hyperkalemia as a result of denervation sensitivity by upregulation of acetylcholine receptors.[4]\n\nDenervation with upregulation of acetylcholine receptors may increase resistance to non-depolarizing neuromuscular blockers as seen with patients receiving anticonvulsants such as carbamazepine or phenytoin. On the other hand, muscle weakness and decreased muscle mass in patients on baclofen may be associated with increased sensitivity.[26] So dose titration must be performed with neuromuscular monitoring.\n\nTemperature monitoring must be done and care must be done to prevent hyperpyrexia as even an increase of 0.5°C in body temperature is capable of reducing temporarily the neurological function.[21718] Use of IV fluids at room temperature should be done.[27] Maintenance of operation theater temperature and temperature monitoring was done in our patient. We used IV fluids at room temperature in the perioperative period and 1 g IV paracetamol was given round the clock to prevent any hyper-pyrexia in the post-operative period.\n\nDeep vein thrombosis must be considered as one of the post-operative risk factor in a patient with MS who has to stay for a longer period in bed because of leg paralysis. The preventive measures such as use of anticoagulants, wearing compression stockings, intermittent external pneumatic compression and early ambulation after surgery must be taken.[28] Our patient was completely asymptomatic and we ensured early ambulation of patient.\n\nOur patient did not show any post-operative exacerbation of the symptoms following EA. Thus, EA with careful preoperative assessment and care can be successfully used in patients with MS.\n\nSource of Support: Nil\n\nConflict of Interest: None declared\n==== Refs\nREFERENCES\n1 Harser SL Goodin DS Multiple sclerosis and demyelinating diseases. Harrison's Principles of Internal Medicine Harrison's Principles of Internal Medicine 2008 2 7th ed New York, London McGraw Hill Medical 2611 20 \n2 Dierdoff SF Walton JS Barash PG Cullen BF Stoelting RK Anesthesia for patients with rare and co-existing diseases Clinical Anesthesia 2006 5th ed Philadelphia Lippincott Williams & Wilkins 510 1 \n3 Barbosa FT Bernardo RC Cunha RM Pedrosa Mdo S Subarachnoid anesthesia for cesarean section in a patient with multiple sclerosis: Case report Rev Bras Anestesiol 2007 57 301 6 19466365 \n4 Stoelting RK Dierdorf SF Stoelting RK Dierdorf SF Diseases of the nervous system Anesthesia and Coexisting Disease 2002 4th ed New York Churchill Livingstone 233 98 \n5 Perlas A Chan VW Neuraxial anesthesia and multiple sclerosis Can J Anaesth 2005 52 454 8 15872120 \n6 al Satli RA Samarkandi AH Anesthesia for multiple sclerosis in a patient undergoing correction of ASD — A case report Middle East J Anesthesiol 1999 15 91 8 10068974 \n7 Martz DG Jr Schreibman DL Matjasko MJ Benumof JL Neurologic diseases Anesthesia and Uncommon Diseases 1998 4th ed Philadelphia WB Saunders 3 37 \n8 Iglesias-González JL Barredo-Abellón J García-Velasco P Alaejos-Estébanez A Perucho A Multiple sclerosis and anesthesia Rev Esp Anestesiol Reanim 1997 44 334 9424691 \n9 Warren TM Datta S Ostheimer GW Lumbar epidural anesthesia in a patient with multiple sclerosis Anesth Analg 1982 61 1022 3 7149297 \n10 Lee KH Park JS Lee SI Kim JY Kim KT Choi WJ Anesthetic management of the emergency laparotomy for a patient with multiple sclerosis — A case report Korean J Anesthesiol 2010 59 359 62 21179301 \n11 Finucane BT Terblanche OC Prolonged duration of anesthesia in a patient with multiple sclerosis following paravertebral block Can J Anaesth 2005 52 493 7 15872128 \n12 Leigh J Fearnley SJ Lupprian KG Intrathecal diamorphine during laparotomy in a patient with advanced multiple sclerosis Anesthesia 1990 45 640 2 \n13 Vercauteren M Heytens L Anaesthetic considerations for patients with a pre-existing neurological deficit: Are neuraxial techniques safe? Acta Anaesthesiol Scand 2007 51 831 8 17488315 \n14 Hebl JR Horlocker TT Shroeder DR Neuraxial anesthesia and analgesia in patients with pre-existing central nervous system disorders Anesth Analg 2006 103 223 8 16790657 \n15 Martucci G Di Lorenzo A Polito F Acampa L A 12-month follow-up for neurological complication after subarachnoid anesthesia in a parturient affected by multiple sclerosis Eur Rev Med Pharmacol Sci 2011 15 458 60 21608443 \n16 Malhotra D Alex M Bengtsson J Anesthetic management of pregnant patient with multiple sclerosis Internet J Anesthesiol 2011 28 DOI:10.5580/1488 \n17 Dorotta IR Schubert A Multiple sclerosis and anesthetic implications Curr Opin Anaesthesiol 2002 15 365 70 17019227 \n18 Kulkarni LM Sanikop C Shilpa H Vinayan A Anaesthetic management in a patient with multiple sclerosis Indian J Anaesth 2011 55 64 7 21431057 \n19 Aisen M Arlt G Foster S Diaphragmatic paralysis without bulbar or limb paralysis in multiple sclerosis Chest 1990 98 499 501 2376189 \n20 Smeltzer SC Skurnick JH Troiano R Cook SD Duran W Lavietes MH Respiratory function in multiple sclerosis. Utility of clinical assessment of respiratory muscle function Chest 1992 101 479 84 1735276 \n21 Wang A Sinatra RS Epidural anesthesia for cesarean section in a patient with von Hippel-Lindau disease and multiple sclerosis Anesth Analg 1999 88 1083 4 10320174 \n22 Pastò L Portaccio E Ghezzi A Hakiki B Giannini M Razzolini L Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: The Italian cohort study BMC Neurol 2012 12 165 23276328 \n23 Bader AM Hunt CO Datta S Naulty JS Ostheimer GW Anesthesia for the obstetric patient with multiple sclerosis J Clin Anesth 1988 1 21 4 3272740 \n24 Pasternak JJ Lanier WL Jr Hines RL Marschall KE Spinal cord disorders Stoelting's Anesthesia and Co-existing Disease 2008 5th ed New York Churchill Livingstone 230 1 \n25 Dalmas AF Texier C Ducloy-Bouthors AS Krivosic-Horber R Obstetrical analgesia and anesthesia in multiple sclerosis Ann Fr Anesth Reanim 2003 22 861 4 14644367 \n26 Brett RS Schmidt JH Gage JS Schartel SA Poppers PJ Measurement of acetylcholine receptor concentration in skeletal muscle from a patient with multiple sclerosis and resistance to atracurium Anesthesiology 1987 66 837 9 3592284 \n27 Guthrie TC Nelson DA Influence of temperature changes on multiple sclerosis: Critical review of mechanisms and research potential J Neurol Sci 1995 129 1 8 7751837 \n28 Arpaia G Bavera PM Caputo D Mendozzi L Cavarretta R Agus GB Risk of deep venous thrombosis (DVT) in bedridden or wheelchair-bound multiple sclerosis patients: A prospective study Thromb Res 2010 125 315 7 19640570\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "8(3)",
"journal": "Saudi journal of anaesthesia",
"keywords": "Cesarean section; epidural anesthesia; multiple sclerosis; opioid",
"medline_ta": "Saudi J Anaesth",
"mesh_terms": null,
"nlm_unique_id": "101500601",
"other_id": null,
"pages": "402-5",
"pmc": null,
"pmid": "25191198",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports",
"references": "15872120;10068974;3272740;16790657;15872128;21179301;2400074;21431057;9424691;17488315;19640570;7751837;1735276;7149297;23276328;17019227;21608443;2376189;10320174;19466365;3592284;14644367",
"title": "Anesthetic management of a patient with multiple sclerosis undergoing cesarean section with low dose epidural bupivacaine.",
"title_normalized": "anesthetic management of a patient with multiple sclerosis undergoing cesarean section with low dose epidural bupivacaine"
} | [
{
"companynumb": "IN-BIOGENIDEC-2014BI091202",
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"occurcountry": "IN",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "DIMETHYL FUMARATE"
},
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{
"abstract": "Opioids are utilized frequently for the treatment of moderate to severe acute pain in the perioperative setting, as well as in the treatment of cancer-related pain. When prescribing chronic opioid therapy to patients with chronic pain, it is crucial for the practitioner to be aware not only of the issues of tolerance and withdrawal, but also to have knowledge of the possibility for opioid-induced hyperalgesia (OIH). An understanding of the differences between tolerance and OIH when escalating opioid therapy allows the titration of opioid as well as nonopioid analgesics in order to obtain maximum control of both chronic and acute pain. A case study is described to highlight the importance of judicious utilization of opioids in the treatment of cancer-related pain. In this case, high-dose opioid therapy did not improve chronic pain and contributed to a hyperalgesic state in which a young man experienced severe intractable pain postoperatively after two routine thoracotomies, despite aggressive pharmacologic measures to manage his perioperative pain. Furthermore, it illustrates the potential advantages of opioid rotation to methadone when OIH is suspected.",
"affiliations": null,
"authors": "Carullo|Veronica|V|;Fitz-James|Ingrid|I|;Delphin|Ellise|E|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "England",
"delete": false,
"doi": "10.3109/15360288.2015.1082006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "29(4)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "acute or chronic pain; cancer pain; hyperalgesia; multimodal pain management; opioid; opioid-induced androgen deficiency; physical dependence; tolerance",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000701:Analgesics, Opioid; D006801:Humans; D006930:Hyperalgesia; D008297:Male; D059408:Pain Management; D010149:Pain, Postoperative; D019990:Perioperative Care",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "378-84",
"pmc": null,
"pmid": "26523869",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Opioid-Induced Hyperalgesia: A Diagnostic Dilemma.",
"title_normalized": "opioid induced hyperalgesia a diagnostic dilemma"
} | [
{
"companynumb": "US-ZYDUS-010333",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE"
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{
"abstract": "There are limited data on the incidence of delirium in children with cancer. We performed a retrospective chart review of all pediatric oncology admissions over a 1 year period to determine the incidence of delirium in this population. We identified seven patients with delirium (10% incidence). Delirium is associated with significant morbidity and mortality, and is likely under-recognized in this population. Improved diagnosis and treatment of delirium may improve outcomes in children with cancer.",
"affiliations": "Department of Pediatrics, University of Arizona, Tucson, Arizona.",
"authors": "Combs|Daniel|D|;Rice|Sydney A|SA|;Kopp|Lisa M|LM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25107",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(11)",
"journal": "Pediatric blood & cancer",
"keywords": "altered mental status; confusion; delirium; oncology; pediatric",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003693:Delirium; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "2094-5",
"pmc": null,
"pmid": "24938869",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence of delirium in children with cancer.",
"title_normalized": "incidence of delirium in children with cancer"
} | [
{
"companynumb": "US-MYLANLABS-2015M1040374",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo assess effectiveness and safety of certolizumab PEGol (CZP) in rheumatoid arthritis (RA) patients after 12 months of treatment and to detect predictors of response.\n\n\nMETHODS\nObservational longitudinal prospective study of RA patients from 35 sites in Spain. Variables (baseline, 3- and 12-month assessment): sociodemographics, previous Disease Modifying Anti-Rheumatic Drug (DMARD) and previous Biological Therapies (BT) use; TJC, SJC, ESR, CRP, DAS28, SDAI. Response variables: TJC, SJC, CRP, ESR, and steroids dose reductions, EULAR Moderate/Good Response, SDAI response and remission, DAS28 remission. Safety variables: discontinuation due to side-effects. Descriptive, comparative and Logistic regression analyses were performed.\n\n\nRESULTS\nWe included 168 patients: 79.2% women, mean age 54.5 years (±13.2 SD), mean disease duration 7.5 years (±7.3 SD). Mean number of prior DMARD: 1.4 (±1.2 SD), mean number of prior BT was 0.8 (±1.1). Mean time on CZP was 9.8 months (±3.4 SD). A total of 71.4% were receiving CZP at 12-month assessment. Baseline predictors of response: lower prior number DMARD; low number prior BT; higher CRP, ESR, TJC, SJC, DAS28 and SDAI (p < 0.05) scores. A 25/46.4% Moderate/Good Response, a 20% SDAI remission, and a 44% DAS28 remission were observed. We observed 48 discontinuations (28.6%), 31 due to partial or complete ineffectiveness, and 17 due to side-effects.\n\n\nCONCLUSIONS\nCZP showed benefit in severe RA patients, with significant reduction of all effectiveness parameters, despite the high prevalence of previous BT exposure in our series. We found CRP, ESR, prior DMARD/BT number, TJC, SJC, DAS28, and SDAI as baseline predictors of response. CZP was mostly well tolerated.",
"affiliations": "a Rheumatology Department , Hospital General Hospitalet-Sant Joan Despí Moisès Broggi , Catalunya , Spain.;b Rheumatology Department , Hospital Can Misses , Ibiza , Spain.;c Rheumatology Department , Complejo Hospital Universitario Lucus Augusti , Lugo , Spain.;d Rheumatology Department , Hospital General Universitario de Elche , Elche , Spain.;e Rheumatology Department , Hospital Universitario Virgen del Rocío , Sevilla , Spain.;f Rheumatology Department , Hospital de la Ribera , Alzira , Spain.;g Rheumatology Department , Hospital Universitario de Guadalajara , Guadalajara , Spain.;h Rheumatology Department , Hospital Universitario de Ceuta , Ceuta , Spain.;i Rheumatology Department , Hospital General Hospitalet-Sant Joan Despí Moisès Broggi , Sant Joan Despí , Spain.;a Rheumatology Department , Hospital General Hospitalet-Sant Joan Despí Moisès Broggi , Catalunya , Spain.;i Rheumatology Department , Hospital General Hospitalet-Sant Joan Despí Moisès Broggi , Sant Joan Despí , Spain.;j Rheumatology Department , Hospital Santa Creu i Sant Pau , Barcelona , Spain.;k Rheumatology Department , Hospital de Viladecans , Viladecans , Spain.;l Rheumatology Department , Hospital Universitario del Henares , Alcalá de Henares , Spain.;m Rheumatology Department , Hospital Comarcal de Laredo , Laredo , Spain.;n Rheumatology Department , Hospital Univeristario Reina Sofia , Córdoba , Spain.;o Rheumatology Department , Hospital Fuenlabrada , Fuenlabrada , Spain.;p Rheumatology Department , Complejo Hospital Universitario A Coruña , A Coruña , Spain.;d Rheumatology Department , Hospital General Universitario de Elche , Elche , Spain.;e Rheumatology Department , Hospital Universitario Virgen del Rocío , Sevilla , Spain.;q Rheumatology Department , Hospital Sant Bernabé , Berga , Spain.;r Rheumatology Department , Hospital Público LluisAlcanyis de Xátiva , Valencia , Spain.;s Rheumatology Department , Hospital Universitario de Getafe , Getafe , Spain.;t Rheumatology Department , Hospital Comarcal Mora d'Ebre , Mora d'Ebre , Spain.;u Rheumatology Department , Hospital General MateuOrfila , Mahó , Spain.;v Rheumatology Department , Hospital Universitari de Reus , Reus , Spain.;w Rheumatology Department , Clínica Dr. Rivas , Segovia , Spain.;x Rheumatology Department , Hospital General de Castellón , Castellón de la Plana , Spain.;y Rheumatology Department , Hospital Virgen de la Victoria de Málaga , Málaga , Spain.;z Rheumatology Department , Hospital Universitario Arnau de Vilanova , Lleida , Spain.;v Rheumatology Department , Hospital Universitari de Reus , Reus , Spain.;aa Rheumatology Department , ClinicaQuiron Valencia , Valencia , Spain.;ab Rheumatology Department , Hospital Clínico Valencia , Valencia , Spain.;ac Rheumatology Department , Hospital Sierrallana , Torrelavega , Spain.;ad Rheumatology Department , EOXI CHU A Coruña , A Coruña , Spain.;ae Rheumatology Department , Hospital de Fuenlabrada , Madrid , Spain , and.;af Rheumatology Department , Hospital Universitario de Móstoles , Móstoles , Spain.",
"authors": "Torrente-Segarra|Vicenç|V|;Urruticoechea Arana|Ana|A|;Sánchez-Andrade Fernández|Amalia|A|;Tovar Beltrán|Juan Víctor|JV|;Muñoz Jiménez|Alejandro|A|;Martínez-Cristóbal|Anna|A|;González Ferrández|José Antonio|JA|;Fernández Prada|Manuel|M|;Vázquez Fuentes|Noelia|N|;Corominas|Hèctor|H|;García-Díaz|Sílvia|S|;Acosta Pereira|Asunción|A|;Ruiz Martín|José Miguel|JM|;Lamua Riazuelo|José Ramón|JR|;Expósito Moliner|Rosa|R|;Ruiz Vilchez|Desireé|D|;Veiga Cabello|Raúl|R|;Fernández|Jesús Carlos|JC|;Noguera Pons|José Raúl|JR|;Garrido Puñal|Noemí Patricia|NP|;Giralt Celiméndiz|Pedro|P|;Cortés Verdú|Raúl|R|;Aragón Díez|Angel|A|;Tomás Roura|Carlos|C|;Moll Turudi|Concepción|C|;Taverner Torrent|Delia|D|;Rivas Santirso|Felipe Joaquín|FJ|;Lerma Garrido|Juan José|JJ|;García Portales|Rosa|R|;Ordoñez Palau|Sergi|S|;Paredes González-Albo|Silvia|S|;Gracia Pérez|Antonio|A|;Conesa Mateos|Arantxa|A|;Calvo Alén|Jaime|J|;Graña Gil|Jenaro|J|;Navarro Alonso|María Pilar|MP|;Martínez Blasco|María Jesús|MJ|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/14397595.2015.1101200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "26(3)",
"journal": "Modern rheumatology",
"keywords": "Certolizumab PEGol; Clinical practice; Efficacy; Rheumatoid arthritis; Safety; Spanish population; Survival rate",
"medline_ta": "Mod Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "336-341",
"pmc": null,
"pmid": "26418571",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "RENACER study: Assessment of 12-month efficacy and safety of 168 certolizumab PEGol rheumatoid arthritis-treated patients from a Spanish multicenter national database.",
"title_normalized": "renacer study assessment of 12 month efficacy and safety of 168 certolizumab pegol rheumatoid arthritis treated patients from a spanish multicenter national database"
} | [
{
"companynumb": "ES-UCBSA-2015032313",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CERTOLIZUMAB PEGOL"
},
"drugadditional": null,
... |
{
"abstract": "Reporting of new or unexpected adverse drug reactions of medicines that are subject to additional monitoring (\"black triangle\" label), such as the antipsychotic drug cariprazine, is of paramount importance to improve pharmacotherapy safety.",
"affiliations": "Institute for Clinical Pharmacology Hannover Medical School Hannover Germany.;Department of Psychiatry Social Psychiatry and Psychotherapy Hannover Medical School Hannover Germany.;Institute for Clinical Pharmacology Hannover Medical School Hannover Germany.;Institute for Clinical Pharmacology Hannover Medical School Hannover Germany.;Department of Psychiatry Social Psychiatry and Psychotherapy Hannover Medical School Hannover Germany.;Department of Psychiatry Social Psychiatry and Psychotherapy Hannover Medical School Hannover Germany.;Department of Psychiatry and Psychotherapy Georg August University of Göttingen Göttingen Germany.;Department of Psychiatry and Psychotherapy Georg August University of Göttingen Göttingen Germany.;University Clinic for Psychiatry and Psychotherapy Brandenburg Medical School Immanuel Klinik Rüdersdorf Germany.;Department of Psychiatry and Psychotherapy Ludwig Maximilian University of Munich Munich Germany.;Department of Psychiatry and Psychotherapy Ludwig Maximilian University of Munich Munich Germany.;Department of Psychiatry Social Psychiatry and Psychotherapy Hannover Medical School Hannover Germany.;Department of Psychiatry and Psychotherapy Ludwig Maximilian University of Munich Munich Germany.;Department of Psychiatry Social Psychiatry and Psychotherapy Hannover Medical School Hannover Germany.",
"authors": "Heck|Johannes|J|https://orcid.org/0000-0002-5382-3014;Seifert|Johanna|J|https://orcid.org/0000-0002-8678-7419;Stichtenoth|Dirk O|DO|;Schroeder|Christoph|C|;Groh|Adrian|A|https://orcid.org/0000-0002-4407-3557;Szycik|Gregor R|GR|;Degner|Detlef|D|;Adamovic|Ivana|I|;Schneider|Michael|M|https://orcid.org/0000-0002-3275-294X;Glocker|Catherine|C|https://orcid.org/0000-0003-0821-8533;Rüther|Eckart|E|;Bleich|Stefan|S|;Grohmann|Renate|R|;Toto|Sermin|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4084",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4084\nCCR34084\nCase Report\nCase Reports\nA case series of serious and unexpected adverse drug reactions under treatment with cariprazine\nHECK et al.\nHeck Johannes https://orcid.org/0000-0002-5382-3014\n1 heck.johannes@mh-hannover.de\n\nSeifert Johanna https://orcid.org/0000-0002-8678-7419\n2\nStichtenoth Dirk O. 1 3\nSchroeder Christoph 1 4\nGroh Adrian https://orcid.org/0000-0002-4407-3557\n2\nSzycik Gregor R. 2\nDegner Detlef 5\nAdamovic Ivana 5\nSchneider Michael https://orcid.org/0000-0002-3275-294X\n6\nGlocker Catherine https://orcid.org/0000-0003-0821-8533\n7\nRüther Eckart 7 8\nBleich Stefan 2\nGrohmann Renate 7\nToto Sermin 2\n1 Institute for Clinical Pharmacology Hannover Medical School Hannover Germany\n2 Department of Psychiatry Social Psychiatry and Psychotherapy Hannover Medical School Hannover Germany\n3 Drug Commissioner of Hannover Medical School Hannover Germany\n4 Head of Pharmacovigilance of Hannover Medical School Hannover Germany\n5 Department of Psychiatry and Psychotherapy Georg August University of Göttingen Göttingen Germany\n6 University Clinic for Psychiatry and Psychotherapy Brandenburg Medical School Immanuel Klinik Rüdersdorf Germany\n7 Department of Psychiatry and Psychotherapy Ludwig Maximilian University of Munich Munich Germany\n8 Prosomno Klinik und Poliklinik für Schlafmedizin Munich Germany\n* Correspondence\nJohannes Heck, Institute for Clinical Pharmacology, Hannover Medical School, Carl‐Neuberg‐Str. 1, 30625 Hannover, Germany.\nEmail: heck.johannes@mh-hannover.de\n\n04 5 2021\n5 2021\n9 5 10.1002/ccr3.v9.5 e0408415 2 2021\n18 1 2021\n14 3 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nReporting of new or unexpected adverse drug reactions of medicines that are subject to additional monitoring (“black triangle” label), such as the antipsychotic drug cariprazine, is of paramount importance to improve pharmacotherapy safety.\n\nReporting of new or unexpected adverse drug reactions of medicines that are subject to additional monitoring (“black triangle” label), such as the antipsychotic drug cariprazine, is of paramount importance to improve pharmacotherapy safety.\n\nadverse drug reactions\ncariprazine\ndopamine supersensitivity psychosis\ndrug safety\nhyperprolactinemia\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.05.2021\nHeck J , Seifert J , Stichtenoth DO , et al. A case series of serious and unexpected adverse drug reactions under treatment with cariprazine. Clin Case Rep. 2021;9 :e04084. 10.1002/ccr3.4084\n\nJohannes Heck and Johanna Seifert have contributed equally to this work.\n==== Body\n1 INTRODUCTION\n\nCariprazine is a dopamine receptor partial agonist (DRPA) that was approved for the treatment of schizophrenia in adult patients in Germany in 2017. 1 Cariprazine has proven especially effective in the treatment of negative symptoms of schizophrenia with regard to self‐care, interpersonal relationships, and socially useful activities. 2 In the United States (US), where cariprazine has been on the pharmaceutical market since 2015, the substance is additionally approved for the treatment of manic or mixed episodes associated with bipolar I disorder in adults. 3 , 4 Cariprazine is currently being investigated as an adjunctive treatment for unipolar major depressive disorder. 5 The pharmacological class of DRPAs currently comprises three drugs (aripiprazole, brexpiprazole, and cariprazine) among which cariprazine displays the highest affinity to the dopamine D3 receptor. 6 In fact, cariprazine has an even higher affinity to D3 receptors than endogenous dopamine itself. 7 Dopamine D3 receptors are considered to play an important role in mediating negative and cognitive symptoms of schizophrenia. 2 Cariprazine also binds to dopamine D2 receptors with high affinity. Cariprazine displays either agonistic or antagonistic activity, depending on the functional status of a neuronal system. In systems with normal or increased dopaminergic transmission, cariprazine acts as an antagonist. Conversely, in systems with low dopaminergic transmission, cariprazine exerts agonistic activity. 8 Apart from dopamine receptors, cariprazine also binds to serotonin 5‐HT2B receptors with high affinity and to serotonin 5‐HT1A and 5‐HT2A receptors with moderate affinity. 5 , 9 Cariprazine exerts little to no anticholinergic activity. 6\n\nCariprazine is primarily metabolized via the cytochrome P450 isoenzyme (CYP) 3A4 and, to a lesser extent, by CYP2D6. 10 Two active metabolites of cariprazine, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), substantially contribute to the drug's antipsychotic activity. 10 While cariprazine displays a half‐life of 2‐4 days, its major metabolite DDCAR has a half‐life of up to 3 weeks, the longest of any atypical antipsychotic. 5 The extended half‐life can be favorable since missing doses even over several days may not necessarily lead to a recurrence of the underlying psychiatric condition. On the other hand, the long half‐life may be disadvantageous as adverse drug reactions (ADRs) can persist for weeks after discontinuation.\n\nAkathisia has been described as the clinically most relevant ADR of DRPAs. 6 According to the German summary of product characteristics (SPC), common ADRs of cariprazine (affecting 1%‐10% of treated patients) include—but are not limited to—sedation, blurred vision, and arterial hypertension. In comparison, akathisia and Parkinsonism both constitute very frequent ADRs of cariprazine (affecting >10% of treated patients). 1 Similarly, the US SPC agrees that extrapyramidal symptoms (EPS), especially akathisia, belong to the clinically most relevant ADRs of cariprazine, along with sedation, dyspepsia, vomiting, and restlessness. 3 In this article, we present four ADRs of cariprazine, including two previously unreported ADRs: exacerbation of psychosis and hyperprolactinemia.\n\nAll presented cases have been documented in “Arzneimittelsicherheit in der Psychiatrie” (“Drug Safety in Psychiatry”; AMSP), a trinational postmarketing pharmacovigilance program comprising 52 participating psychiatric hospitals in Germany, Austria, and Switzerland. 11 Since 1993, AMSP has been systematically monitoring the occurrence of serious, new, and unexpected ADRs of psychotropic drugs in the routine treatment of psychiatric inpatients. In accordance with the Guideline for Good Clinical Practice (GCP) of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), 12 a serious ADR within the AMSP program is defined as an ADR that (a) results in death, (b) is life‐threatening, (c) requires inpatient hospitalization or prolongation of existing hospitalization, (d) results in persistent or significant disability/incapacity, or (e) is a congenital anomaly/birth defect. Three of the four ADRs presented in this case series were classified as serious, while one ADR was considered unexpected. Written informed consent for patient information to be published was provided by all patients or a legally authorized representative.\n\nThe aim of this article is to disseminate existing and newly acquired knowledge about the side‐effect profile of cariprazine to other healthcare professionals in psychiatry and beyond in order to facilitate recognition of (serious) ADRs of cariprazine and improve patient safety in the future.\n\n2 CASE PRESENTATIONS\n\n2.1 Case 1\n\nA 30‐year‐old female patient suffering from an exacerbation of paranoid schizophrenia with persecutory delusions and distortions of self‐experience was admitted to the hospital. The psychiatric condition had been diagnosed 3 years earlier and had previously been treated with quetiapine 900 mg per day (mg/d) and aripiprazole 20 mg/d. Moreover, the patient was suffering from a substance use disorder of alcohol and amphetamines for which she tested positive upon admission. The patient had discontinued her medication 4 months before hospitalization.\n\nSince quetiapine had been well tolerated in the past, treatment with quetiapine 300 mg/d was resumed. Despite displaying significant clinical improvement of her psychotic symptoms, however, the patient requested to discontinue quetiapine. The reduction and subsequent termination of quetiapine triggered an exacerbation of psychotic symptoms which again required antipsychotic medication. Eight days after admission to the hospital, treatment with cariprazine 1.5 mg/d was commenced and increased to 3 mg/d 5 days later. Due to increased drive with euphoric affect, aggressive behavior, and sleeplessness, treatment with quetiapine 300 mg/d was reinitiated 1 day prior to the dosage increase of cariprazine from 1.5 to 3 mg/d. Twelve days after treatment initiation with cariprazine, 7 days after the restart of quetiapine, and 6 days after the dosage increase of cariprazine to 3 mg/d, the patient complained of restlessness in her lower extremities, anxiety, and an uncontrollable urge to move around. The patient paced back and forth along the hospital ward, being unable to sit still. While the patient's psychotic symptoms appeared significantly improved, the described symptoms of akathisia caused the patient great distress and impairment. Therefore, cariprazine was reduced to 1.5 mg/d 3 days after the onset of akathisia. Another 2 days later, cariprazine was stopped. On the other hand, treatment with quetiapine was maintained for 21 days thereafter, with no effect on akathisia. Three days after the discontinuation of cariprazine, the patient complained of persisting akathisia—albeit slightly improved—for another 5 weeks; then, the patient appeared calmer and less distressed. However, some degree of akathisia persisted for the remainder of her inpatient treatment (ie, another 3 weeks).\n\nAlternatively, antipsychotic treatment with risperidone was started with the aim to establish monthly risperidone injections. Under risperidone 5 mg/d, the patient developed Parkinsonism, again necessitating a change of medication. Treatment with amisulpride was established and titrated to 500 mg/d and augmented with lamotrigine 100 mg/d as well as quetiapine 150 mg/d under which the patient's mental status stabilized significantly, albeit without achieving full remission.\n\n2.2 Case 2\n\nA 22‐year‐old male patient was admitted to the hospital due to paranoid schizophrenia, from which he had been suffering since the age of 17 years. The patient had previously been treated with various antipsychotic drugs but was unmedicated when admitted to inpatient care. Antipsychotic treatment was initiated with risperidone 0.5 mg/d and gradually increased to 3 mg/d over the course of two and a half weeks. As the patient displayed a multitude of negative symptoms, including blunted affect, asociality, and avolition, treatment with cariprazine 1.5 mg/d was instituted 1 week after the introduction of risperidone and further increased to 3 mg/d after 2 weeks. Eighteen days after the start of treatment with risperidone and 11 days after the start of cariprazine, the patient developed hypokinesia with a forward‐flexed posture and reduced arm swing when walking. Hence, the patient was prescribed biperiden 4 mg/d. Despite the treatment with biperiden, however, hypokinesia progressed. Twenty and 13 days after the start of treatment with risperidone and cariprazine, respectively, the patient showed symptoms of severe Parkinsonism with bradykinesia, postural instability, dysdiadochokinesia, difficulty raising from a sitting or supine into a standing position, rigor of his extremities, and pronounced tremor of his hands, leading to an inability to drink from a glass or bottle without spilling fluid. Due to his extreme immobility, the patient repeatedly wet himself. He required substantial assistance from the nursing staff for nearly all activities of daily living. Symptoms were most prominent 3 days after the dosage increase of cariprazine from 1.5 to 3 mg/d. Magnetic resonance imaging did not reveal any signs of organic brain disorder. Furthermore, electroencephalography was inconclusive. After excluding alternative causes and a continuous progression of symptoms, the described Parkinsonism was suspected as ADR of the antipsychotic treatment.\n\nConsequently, risperidone was decreased to 1 mg/d which did not result in an improvement of symptoms. The patient was treated with cariprazine at an unaltered dose of 3 mg/d for another 10 days before the dosage was reduced to 1.5 mg/d. Treatment with risperidone was fully discontinued 14 days later (ie, 25 days after the onset of Parkinsonism). The patient was also treated with biperiden 4 mg/d for a total of 5 weeks. The reduction and ultimately termination of risperidone, the reduction of cariprazine, and the administration of biperiden led to a slow but full recovery of the patient over 5 weeks. Cariprazine 1.5 mg/d was maintained as antipsychotic therapy.\n\n2.3 Case 3\n\nA 52‐year‐old male patient with a 30‐year history of paranoid schizophrenia was admitted to the hospital due to the exacerbation of psychotic symptoms following the patient's decision to discontinue his antipsychotic medication (haloperidol 5 mg/d and aripiprazole 15 mg/d). Besides presenting with delusional content, the patient also displayed disorganized behavior during acute psychosis. The patient was unable to recollect when precisely he had stopped taking his medication. Since the patient had suffered from severe negative symptoms of paranoid schizophrenia in the past, an antipsychotic treatment with cariprazine 1.5 mg/d was established. Additionally, the patient was treated with pipamperone 40 mg/d, taking advantage of the drug's sedating effects. One week later, cariprazine was increased to 3 mg/d and another 5 days later to 4.5 mg/d. The patient benefitted from this drug regimen as he appeared more structured in his behavior, was able to sleep during the night, and less frequently reported delusional content. One day after the last dosage increase of cariprazine, however, the patient suddenly appeared extremely restless, especially at night, and displayed an inappropriate, bizarre behavior. For instance, he emptied a garbage can, poured water over it, and subsequently spread the trash all over the lawn of the hospital garden. Moreover, he sprayed shaving cream on a tree. Six days after the onset of this bizarre behavior, olanzapine 10 mg/d was added to the patient's medication regimen, while pipamperone was discontinued. In response, the patient's sleep disturbances significantly improved and the patient was able to sleep throughout the entire night. Furthermore, the patient appeared much calmer than during previous days, and the bizarre behavior had vanished.\n\nThe patient's legal guardian, who had accompanied him for almost the entire duration of his psychiatric condition, confirmed that the behavior the patient had displayed after the increment of cariprazine to 4.5 mg/d had been very much reminiscent of previous episodes of acute psychosis. After the behavioral changes had subsided, the patient was asked to reflect on his actions. The patient merely replied that his actions had been “just for fun” and that now he no longer experienced the urge to perform such actions, stating that he felt mentally stable. The patient was discharged from the hospital with a medication consisting of cariprazine 4.5 mg/d and olanzapine 10 mg/d. At discharge, the patient did not appear to be suffering from acute psychosis or substantial negative symptoms.\n\n2.4 Case 4\n\nA 22‐year‐old female patient, who had first been diagnosed with paranoid schizophrenia 3 years earlier, was treated with risperidone 2 mg/d after a complete diagnostic work‐up had not revealed any physical abnormalities. Even though prolactin levels were normal, the patient developed amenorrhea and Parkinsonism. The medication was changed to aripiprazole 20 mg/d. Unfortunately, this did not provide sufficient control of her psychotic symptoms and she experienced imperative voices for the first time. Consequently, her medication was reevaluated. During cross‐titration from aripiprazole to amisulpride, elevated levels of prolactin were detected (max. 3554 µU/mL, reference value <496 µU/mL) under aripiprazole 10 mg/d and amisulpride 250 mg/d. After excluding prolactinoma via magnetic resonance imaging, the patient's medication was switched to monotherapy with cariprazine. This was a precautionary measure because the patient had a positive family history of breast cancer. Following discontinuation of amisulpride, prolactin levels normalized. Treatment with cariprazine was initiated with 1.5 mg/d and increased to 3 mg/d, 4.5 mg/d, and 6 mg/d after 2, 4, and 12 weeks, respectively. Thirteen months after the start of treatment with cariprazine, elevated prolactin levels (2449 µU/mL) were detected in a routine control. Due to the uncommon relationship with a DRPA, further diagnostic work‐up of hyperprolactinemia was initiated. Again, magnetic resonance imaging was performed, but remained inconclusive. As the patient did not suffer from galactorrhea or amenorrhea, the medication was continued under regular gynecological and endocrinological surveillance.\n\n3 DISCUSSION\n\nAs of January 2021, cariprazine is subject to additional monitoring in the European Union (EU), indicated by the “black triangle” label in the drug's SPC and package leaflet. 13 Generally speaking, medicinal products labeled with a black inverted triangle are under additional monitoring in the EU because they are new to the pharmaceutical market, and comparatively, little information is available on their long‐term use. 14 For this reason, reporting newly recognized ADRs of cariprazine—such as exacerbation of psychosis (case 3) and hyperprolactinemia (case 4)—is particularly important in order to improve drug safety. Furthermore, ADRs of cariprazine, which are in principle known from previous clinical trials (such as EPS), 6 but whose severity exceeds the usually expected intensity (cases 1 and 2) should be shared with the medical community.\n\nCases 1‐3 have in common that the dosage of cariprazine was increased at a rather fast pace. In case 1, the dosage of cariprazine was raised to 3 mg/d 5 days after treatment initiation, as was the case in the dose escalation from 3 to 4.5 mg/d in case 3. In case 2, an increment in dose of 1.5 mg/d was performed after 1 week. The German SPC of cariprazine remains surprisingly vague on how quickly the dosage should be increased, stating only that this should be done “slowly”. 1 The US SPC of cariprazine, on the other hand, is more precise, recommending increasing the dose from 1.5 to 3 mg/d as early as on day 2 of treatment. 3\n\nDue to the long half‐life of cariprazine's active metabolites, especially DDCAR, it may take up to 3 weeks for a steady state to be reached. 3 Therefore, changes in dose will not be fully reflected in plasma concentrations for several weeks. Furthermore, it must be considered that the time for DDCAR to reach a steady state shows an appreciable interindividual variability. After administration of 1 mg cariprazine, DDCAR remains detectable in plasma for 8 weeks. 1 , 3 Accordingly, dose adjustments should be performed with great caution and prescribers should monitor patients for ADRs and treatment response for several weeks after the start of treatment. Considering the long half‐life of DDCAR, 3 it seems reasonable to recommend that the dosage of cariprazine should not be increased earlier than 1 week after treatment initiation. Some patients may require an even more cautious approach, increasing the dosage of cariprazine only 2‐4 weeks after the start of treatment or last increase of dosage.\n\nIn the following, the presented ADRs will be analyzed from both a pharmacological and a pharmacovigilance viewpoint. The evaluation of the relationship between cariprazine and the suspected ADRs will be performed in accordance with the World Health Organization—Uppsala Monitoring Centre (WHO‐UMC) system for standardized case causality assessment. 15\n\n3.1 Cases 1 and 2—extrapyramidal symptoms\n\nIn general, EPS are very common ADRs of antipsychotic drugs even though the exact pathophysiology still remains poorly understood. Alongside other postulated mechanisms, blockade of dopamine D2 receptors in basal ganglia is thought to play a decisive role in EPS development. In contrast, antagonism of serotonin 5‐HT2A receptors may lower the risk of akathisia and ameliorate EPS. 16 High‐potency first‐generation antipsychotics such as haloperidol or benperidol are infamous for causing severe movement disorders due to their high affinity for dopamine D2 receptors where they exert antagonistic effects. 17 However, EPS may also arise during treatment with second‐ or third‐generation antipsychotics and have been reported as a very frequent ADR of cariprazine, affecting ≥10% of treated patients. 1 All three DRPAs—aripiprazole, brexpiprazole, and cariprazine—display a high affinity for dopamine D2 receptors where they act as partial agonists. Cariprazine has the lowest intrinsic D2 receptor activity and, therefore, most likely exerts antagonistic effects. Aripiprazole, on the other hand, shows higher intrinsic D2 receptor activity and, therefore, higher D2 agonism. 6 EPS arising under treatment with cariprazine most commonly manifest as akathisia. 6 In general, EPS show a dose‐dependent relationship. 18 Studies have suggested that efficacious antipsychotic activity of cariprazine can be obtained by using lower doses than those required to trigger EPS. 9\n\n3.2 Case 1—akathisia\n\nThe akathisia described in case 1 was classified as a serious ADR since it required cessation of cariprazine and led to a prolongation of inpatient care. 12 Among DRPAs, cariprazine is most likely to induce akathisia. 6 Akathisia is characterized by a subjective feeling of inner restlessness in combination with an irrepressible urge to move around and may cause great distress to affected patients. In fact, akathisia has even been associated with aggressive and suicidal behavior 6 and commonly necessitates discontinuation of the causative drug(s). Akathisia most frequently presents during the first weeks of antipsychotic treatment. 6\n\nIn case 1, the patient was treated with both cariprazine and quetiapine at the onset of akathisia. Cariprazine had been increased to 3 mg/d 1 week prior to the start of symptoms, which is in line with the assumption that akathisia is a dose‐dependent ADR. 6 Quetiapine had been added to the patient's medication 8 days earlier. Even though quetiapine had been well tolerated in the past, that is, without occurrence of akathisia or other EPS, a pharmacodynamic interaction between cariprazine and quetiapine cannot be ruled out. In general, quetiapine appears to have a lower overall risk of akathisia than cariprazine 6 ; nevertheless, reports of severe quetiapine‐induced akathisia do exist. 19 Because akathisia persisted despite the discontinuation of cariprazine, the other antipsychotic drugs the patients was treated with (ie, risperidone and amisulpride) seem to have contributed to the persistence of symptoms.\n\nAccording to the WHO‐UMC system, 15 the causality between cariprazine and the development of akathisia in case 1 was judged as possible because there was a reasonable time relationship to the intake of cariprazine although the symptom could also be explained by other antipsychotics.\n\n3.3 Case 2—Parkinsonism\n\nThe Parkinsonism described in case 2 was classified as a serious ADR because it had resulted in significant handicap and led to the prolongation of inpatient care. 12 Parkinsonism occurs in approximately 10% of patients treated with cariprazine. 20 While advanced age is generally considered a risk factor for drug‐induced Parkinsonism, 21 , 22 case 2 describes the onset of Parkinsonism in a 22‐year‐old adult. Since EPS also represent a very common ADR of risperidone (affecting ≥10% of treated patients), 23 a pharmacodynamic interaction between risperidone and cariprazine seems likely and may have played a decisive role in the presented case as both drugs exert antagonistic effects on dopamine D2 receptors. 17 An exacerbation of symptoms after dose escalation of cariprazine is consistent with the aforementioned dose‐dependent nature of cariprazine‐induced EPS. However, because the patient showed full remission of symptoms under continuation of treatment with cariprazine 1.5 mg/d, it cannot be fully excluded that Parkinsonism was primarily caused by risperidone and would have progressed to this extent without the addition of cariprazine. Parkinsonism persisted at an unaltered intensity after the initial dose reduction of risperidone and did not improve until the dosage of cariprazine was lowered. Symptoms improved continuously over the course of several weeks, which is best explained by the long half‐life of cariprazine and its active metabolites, 5 whereas the longest half‐life of risperidone's active metabolites is approximately 24 hours, 23 suggesting that symptoms would have improved much more rapidly if they had solely been evoked by risperidone.\n\nThe extent of Parkinsonism was so debilitating that the patient required assistance even for basic activities of daily living such as personal hygiene. Symptoms persisted for nearly 1 month after discontinuation of risperidone and reduction of cariprazine, which may be a consequence of the long half‐life of cariprazine's major metabolite, DDCAR.\n\nAccording to the WHO‐UMC system, 15 the causality between cariprazine and the development of Parkinsonism in case 2 was assessed as possible because of the reasonable time relationship to the intake of cariprazine. However, the symptom could also have been caused at least partly by risperidone.\n\n3.4 Case 3—exacerbation of psychosis\n\nThe patient's bizarre behavior and psychotic symptoms in case 3 necessitated urgent medical intervention (ie, treatment with olanzapine) and led to the prolongation of inpatient care. Accordingly, the suspected ADR was classified as serious. 12 Since the patient immediately responded to treatment with olanzapine, the described symptoms were interpreted as an exacerbation of his underlying schizophrenia. Of course, it is impossible to attribute the observed psychotic exacerbation to cariprazine with absolute certainty as psychotic symptoms are also intrinsic to paranoid schizophrenia itself. While the patient appeared to have taken his antipsychotic medication as prescribed, nonadherence to the psychopharmacological regimen cannot be fully excluded, which might have left him potentially unmedicated at the time of symptom onset. However, considering the long half‐life of cariprazine and its active metabolites, missed doses for even several days in a row would not exclude the drug's involvement in a psychotic exacerbation. Even though not explicitly stated in the German SPC, aripiprazole has been implicated in the exacerbation of psychotic symptoms under certain circumstances. 24 Higher doses of aripiprazole may exert an increasing dopamine‐agonistic activity. 24 A similar rationale may apply to cariprazine.\n\nAnother aspect that should be discussed is the role of pipamperone. Pipamperone was discontinued, upon which the patient's psychotic symptoms subsided, therefore showing a clear temporal relationship to the improvement of psychosis. However, induction of psychosis is not a known ADR of pipamperone and therefore seems highly unlikely to have triggered the patient's psychotic symptoms.\n\nPrior treatment with the high‐potency antipsychotic haloperidol in case 3 may have further increased the risk of psychotic exacerbation. 25 Recent use of antipsychotic drugs with a high affinity to dopamine D2 receptors can lead to an upregulation of D2 receptors, causing supersensitivity of neurons to dopamine. 26 The addition of cariprazine may then trigger an abrupt exacerbation of psychosis by over‐proportionately stimulating D2 receptors via partial‐agonistic effects, 24 a phenomenon that has been termed “dopamine supersensitivity psychosis” by Nakata and colleagues. 26 Even though it remained unclear when exactly the patient had discontinued treatment with haloperidol, the onset of dopamine supersensitivity psychosis has been described with a latency of up to 6 weeks after discontinuation of previous antipsychotic treatment. 26\n\nSimilar to cases 1 and 2, a possible causality between cariprazine and the exacerbation of psychosis in case 3 according to the WHO‐UMC system 15 was assumed because of the reasonable time relationship to the intake of cariprazine although it cannot be excluded that the symptom was evoked by the underlying disease (ie, paranoid schizophrenia).\n\n3.5 Case 4—hyperprolactinemia\n\nThe hyperprolactinemia described in case 4 was assessed as an unexpected ADR of cariprazine because it is not listed in the SPC. It was classified as nonserious, as no seriousness criterium was met. Blockade of dopamine D2 receptors on lactotroph cells of the pituitary gland causes hyperprolactinemia due to removal of the main inhibitory influence, that is, dopamine. 6 DRPAs are thought to have a low risk of hyperprolactinemia due to their partial‐agonistic effects. DRPAs have even proven effective in lowering prolactin concentrations in patients with hyperprolactinemia induced by other (antipsychotic) drugs. 6 Compared to high‐potency first‐generation antipsychotic drugs, which cause treatment‐emergent prolactin elevation in 40%‐90% of treated patients, 6 prevalence of hyperprolactinemia under treatment with aripiprazole is 3.1%‐9.0%. 27 To the best of our knowledge, this is the first published case of hyperprolactinemia under monotherapy with cariprazine. In a post hoc analysis of two 48‐week open‐label, flexible‐dose extension studies to evaluate the long‐term safety of cariprazine, mean prolactin levels showed a decrease among all dose groups. 28 In the case presented here, an alternative cause for the elevated prolactin levels could not be identified despite thorough investigation. Based on the time relationship and the lack of alternative explanations, the causality between cariprazine and the development of hyperprolactinemia in case 4 was judged as probable, according to the WHO‐UMC system. 15 The correlation might be similar to cases of hyperprolactinemia under treatment with aripiprazole—unexpected but not exclusionary. Cases such as case 4 underscore the importance of prolactin monitoring during psychopharmacological treatment, even if the applied substance rarely leads to elevated prolactin levels or has not at all been implicated in hyperprolactinemia thus far.\n\n4 LIMITATIONS AND CONCLUSION\n\nLimitations of this case series mainly arise from the comedication and the differential diagnoses, making it difficult—if not impossible—to attribute the presented ADRs solely and undoubtedly to cariprazine. However, within the field of pharmacovigilance, it is neither necessary nor reasonable to merely report cases in which an adverse event can be ascribed to a single agent with absolute certainty. On the contrary, reporting of suspected ADRs—as in this case series—fulfills an important purpose, namely the detection of risk signals. 29 This is especially true for medicines under additional monitoring, 13 such as cariprazine. 1\n\nOur case series reports on four suspected ADRs of cariprazine, namely akathisia, Parkinsonism, exacerbation of psychosis, and hyperprolactinemia. To the best of our knowledge, exacerbation of psychosis and hyperprolactinemia have not previously been described as ADRs of cariprazine in the literature. Further pharmacovigilance surveillance is needed to assess their frequency. Reporting newly recognized and/or unusually severe ADRs to the medical community remains a cornerstone of pharmacovigilance. We would like to share our observations with healthcare professionals in the field of psychiatry and beyond in order to promote the timely detection of (serious) ADRs of cariprazine in the future, thus pursuing the ultimate goal of improving patient safety.\n\nCONFLICT OF INTEREST\n\nJS took part in an educational event sponsored by Otsuka/Lundbeck. ST is a member of the advisory board for Otsuka and Janssen‐Cilag and has received speaker's honoraria from Janssen‐Cilag, Lundbeck/Otsuka, and Servier. As Drug Commissioner of Hannover Medical School, DOS is an independent expert and not affiliated with AMSP. DOS, JH, AG, CG, DD, GRS, IA, MS, RG, ER, CS, and SB state that they have no conflicts of interest to declare. The AMSP drug safety project is facilitated by nonprofit associations in Germany, Austria, and Switzerland. The AMSP project has been supported with unrestricted educational and research grants since 1993 by the following companies: German companies: Abbott GmbH & Co. KG, AstraZeneca GmbH, Aventis Pharma Deutschland GmbH GE–O/R/N, Bayer Vital GmbH, Boehringer Mannheim GmbH, Bristol‐Myers‐Squibb, Ciba Geigy GmbH, Desitin Arzneimittel GmbH, Duphar Pharma GmbH & Co. KG, Eisai GmbH, Esparma GmbH Arzneimittel, GlaxoSmithKline Pharma GmbH & Co. KG, Hoffmann‐La Roche AG Medical Affairs, Janssen‐Cilag GmbH, Janssen Research Foundation, Knoll Deutschland GmbH, Lilly Deutschland GmbH Niederlassung Bad Homburg, Lundbeck GmbH & Co. KG, Novartis Pharma GmbH, Nordmark Arzneimittel GmbH, Organon GmbH, Otsuka‐Pharma Frankfurt, Pfizer GmbH, Pharmacia & Upjohn GmbH, Promonta Lundbeck Arzneimittel, Recordati Pharma GmbH, Rhone‐Poulenc Rohrer, Sanofi‐Synthelabo GmbH, Sanofi‐Aventis Deutschland, Schering AG, SmithKlineBeecham Pharma GmbH, Solvay Arzneimittel GmbH, Synthelabo Arzneimittel GmbH, Dr Wilmar Schwabe GmbH & Co., Thiemann Arzneimittel GmbH, Troponwerke GmbH & Co. KG, Upjohn GmbH, Wander Pharma GmbH, and Wyeth‐Pharma GmbH. Austrian companies: Astra Zeneca Österreich GmbH, Boehringer Ingelheim Austria, Bristol‐Myers Squibb GmbH, CSC Pharmaceuticals GmbH, Eli Lilly GmbH, Germania Pharma GmbH, GlaxoSmithKline Pharma GmbH, Janssen‐Cilag Pharma GmbH, Lundbeck GmbH, Novartis Pharma GmbH, Pfizer Med Inform, and Wyeth Lederle Pharma GmbH. Swiss companies: AHP (Schweiz) AG, AstraZeneca AG, Bristol‐Myers Squibb AG, Desitin Pharma GmbH, Eli Lilly (Suisse) SA, Essex Chemie AG, GlaxoSmithKline AG, Janssen‐Cilag AG, Lundbeck (Suisse) AG, Organon AG, Pfizer AG, Pharmacia, Sanofi‐Aventis (Suisse) SA, Sanofi‐Synthelabo SA, Servier SA, SmithKlineBeecham AG, Solvay Pharma AG, Wyeth AHP (Suisse) AG, and Wyeth Pharmaceuticals AG.\n\nAUTHOR CONTRIBUTIONS\n\nJH, JS, AG, CG, and ST: involved in writing the first draft of manuscript. CS: contributed special expertise in pharmacovigilance. DOS, CS, GRS, DD, IA, MS, RG, ER, and SB: commented on previous versions of the manuscript. All authors: read and approved the final manuscript.\n\nETHICAL APPROVAL\n\nEvaluations based on the AMSP database have been approved by the Ethics Committee of Ludwig Maximilian University of Munich and by the Ethics Committee of Hannover Medical School (No. 8100_BO_S_2018). This study adheres to the Declaration of Helsinki and its later amendments. The AMSP project is a continuous observational postmarketing drug surveillance program that does not interfere with the ongoing clinical treatment of the patients under surveillance.\n\nACKNOWLEDGMENTS\n\nPublished with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nREFERENCES\n\n1 Reagila® Hartkapseln [Summary of product characteristics] 2017. Ulm, Germany: Recordati Pharma GmbH; 2017.\n2 Nemeth G , Laszlovszky I , Czobor P , et al. 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Harmonised Guideline Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). 2016: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed December 08, 2020.\n13 European Medicines Agency . Medicines under additional monitoring. https://www.ema.europa.eu/en/human‐regulatory/post‐authorisation/pharmacovigilance/medicines‐under‐additional‐monitoring. Accessed December 08, 2020.\n14 Bundesinstitut für Arzneimittel und Medizinprodukte . Black Triangle. https://www.bfarm.de/SharedDocs/Glossareintraege/EN/B/BlackTriangle.html#:~:text=The%20black%20triangle%20indicates%20that%20this%20medicine%20is,the%20summary%20of%20product%20characteristics%20%28the%20so‐called%20%22Fachinformation%22%29. Accessed December 08, 2020.\n15 World Health Organization . The use of the WHO‐UMC system for standardised case causality assessment. https://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf. Accessed February 08, 2021.\n16 Demyttenaere K , Detraux J , Racagni G , Vansteelandt K . Medication‐induced akathisia with newly approved antipsychotics in patients with a severe mental illness: a systematic review and meta‐analysis. CNS Drugs. 2019;33 :549‐566.31065941\n17 Benkert O , Hippius H . Kompendium der Psychiatrischen Pharmakotherapie, 12th edn. Berlin, Germany: Springer‐Verlag GmbH; 2019.\n18 Earley W , Durgam S , Lu K , et al. Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double‐blind, placebo‐controlled studies. Int Clin Psychopharmacol. 2017;32 :319‐328.28692485\n19 Catalano G , Grace JW , Catalano MC , et al. Acute akathisia associated with quetiapine use. Psychosomatics. 2005;46 :291‐301.16000672\n20 Cutler AJ , Durgam S , Wang Y , et al. Evaluation of the long‐term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1‐year open‐label study. CNS Spectr. 2018;23 :39‐50.28478771\n21 López‐Sendón JL , Mena MA , de Yébenes JG . Drug‐Induced Parkinsonism in the Elderly. Drugs Aging. 2012;29 :105‐118.22250585\n22 Bondon‐Guitton E , Perez‐Lloret S , Bagheri H , et al. Drug‐induced parkinsonism: a review of 17 years' experience in a regional pharmacovigilance center in France. Mov Disord. 2011;26 :2226‐2231.21674626\n23 Risperdal® Filmtabletten [Summary of product characteristics] 2019. Neuss, Germany: Janssen‐Cilag GmbH; 2019.\n24 Ramaswamy S , Vijay D , William M , et al. Aripiprazole possibly worsens psychosis. Int Clin Psychopharmacol. 2004;19 :45‐48.15101571\n25 Adan‐Manes J , Garcia‐Parajua P . Aripiprazole in combination with other antipsychotic drugs may worsen psychosis. J Clin Pharm Ther. 2009;34 :245‐246.19250146\n26 Nakata Y , Kanahara N , Iyo M . Dopamine supersensitivity psychosis in schizophrenia: concepts and implications in clinical practice. J Psychopharmacol. 2017;31 :1511‐1518.28925317\n27 Tewksbury A , Olander A . Management of antipsychotic‐induced hyperprolactinemia. Ment Health Clin. 2016;6 :185‐190.29955468\n28 Nasrallah HA , Earley W , Cutler AJ , et al. The safety and tolerability of cariprazine in long‐term treatment of schizophrenia: a post hoc pooled analysis. BMC Psychiatry. 2017;17 :305.28836957\n29 Waller P , Harrison‐Woolrych M . An Introduction to Pharmacovigilance, 2nd edn. Hoboken, NJ: John Wiley & Sons, Inc.; 2017.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "9(5)",
"journal": "Clinical case reports",
"keywords": "adverse drug reactions; cariprazine; dopamine supersensitivity psychosis; drug safety; hyperprolactinemia",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "e04084",
"pmc": null,
"pmid": "34084502",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "19250146;28692485;20093397;29955468;29955527;21674626;32110377;29722587;32246399;22250585;28478771;15101571;28836957;16000672;31065941;23320989;28925317;29915922;28185672",
"title": "A case series of serious and unexpected adverse drug reactions under treatment with cariprazine.",
"title_normalized": "a case series of serious and unexpected adverse drug reactions under treatment with cariprazine"
} | [
{
"companynumb": "DE-MACLEODS PHARMACEUTICALS US LTD-MAC2021032911",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugad... |
{
"abstract": "BACKGROUND\nFour direct oral anticoagulants (DOACs) have been licensed for the treatment of atrial fibrillation (AF); efficacy and safety have been shown in clinical trials, but its real use in elderly and very elderly people is still unclear.\n\n\nOBJECTIVE\nTo evaluate the impact of DOACs in our patients (pts) aged ≥75 years and switched from other treatments.\n\n\nMETHODS\nFrom September 2013 to May 2015, all consecutive pts aged ≥75 years, males and females, in treatment for AF and switched to DOACs are considered in this study. Follow-up (FU) was scheduled after 3 and 6 months by phone and after 12 months by visit.\n\n\nRESULTS\nTwo hundred thirty-two pts in treatment for AF were switched to DOACs, among these 143 (61.6%) pts aged ≥75 years (mean age, 81 years). The medium FU was 9.6 months, during which 4 minor bleedings in 4 different pts and 1 clinically relevant nonmajor bleeding were reported, all treated with temporary cessation or reduction in DOACs. Two strokes occurred in pts in treatment with dabigatran 110 mg, both resolved without serious sequelae; 2.8% of pts had nausea, itching, vomiting, or discomfort, half of these returned to acenocumarol, and the remaining switched to other DOAC. Four pts died, but the deaths were not related to anticoagulation.\n\n\nCONCLUSIONS\nAs reported for general people, also in our elderly population, DOACs resulted in a good alternative to old antithrombotic therapies. Efficacy and safety associated with a higher compliance by pts bring these drugs to be the first choice for long-term anticoagulation.",
"affiliations": "Center for Hemorrhagic and Thrombotic Diseases, University Hospital of Udine, Udine, Italy sampasca@alice.it.;Center for Hemorrhagic and Thrombotic Diseases, University Hospital of Udine, Udine, Italy.;Center for Hemorrhagic and Thrombotic Diseases, University Hospital of Udine, Udine, Italy.;Center for Hemorrhagic and Thrombotic Diseases, University Hospital of Udine, Udine, Italy.",
"authors": "Pasca|Samantha|S|;Venturelli|Ugo|U|;Bertone|Antonella|A|;Barillari|Giovanni|G|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1177/1076029615619485",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-0296",
"issue": "23(1)",
"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": "anticoagulants; bleeding; cardiology; stroke",
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D005260:Female; D006801:Humans; D008297:Male",
"nlm_unique_id": "9508125",
"other_id": null,
"pages": "58-63",
"pmc": null,
"pmid": "26620417",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Direct Oral Anticoagulants for Very Elderly People With Atrial Fibrillation: Efficacy and Safe Enough?",
"title_normalized": "direct oral anticoagulants for very elderly people with atrial fibrillation efficacy and safe enough"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-69593BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Primary Mediastinal B cell lymphoma (PMBCL) is a biologically and clinically distinct subset of diffuse large B cell lymphoma. We analysed the outcomes of our cohort of PMBCL patients treated with Dose adjusted (DA)-R-EPOCH regimen.\nThis is a retrospective analysis of consecutive PMBCL patients who received chemotherapy consisting of DA-R-EPOCH with filgrastim support. Survival analysis was done using Kaplan-Meier method. All calculations were performed using SPSS version 20 for windows.\nA total of 43 consecutive suspected PMBCL patients were reviewed for this study, 6 patients were excluded as diagnosis of PMBCL could not be established. All patients except one (97.3%) received 6 cycles of R-DA-EPOCH regimen. Median age of the patients was 27 years (range 15-58). Bulky disease (> 7 cm) was present in 97% patients and 54% patients had extranodal disease. With a median follow up of 40 months, 3-year overall survival was 80.6% (95% CI: 74.0-87.2). The 3-year event free survival was 78.4% (95% CI: 71.6-85.2). There were 6 (16.2%) relapses, 1 (2.7%) primary progression and 7 (23%) deaths. Mediastinal radiotherapy was administered to 17 (45.9%) patients. All the deaths were due to disease progression. Grade III/IV toxicities were seen in 28 (75.7%) patients, febrile neutropenia being the most common one.\nDA-R-EPOCH regimen is an effective and tolerable regimen in PMBCL patients even with adverse features.",
"affiliations": "Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National University, E. Borges Marg, Parel, Mumbai, Maharashtra 400012 India.;Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National University, E. Borges Marg, Parel, Mumbai, Maharashtra 400012 India.;Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National University, E. Borges Marg, Parel, Mumbai, Maharashtra 400012 India.;Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National University, E. Borges Marg, Parel, Mumbai, Maharashtra 400012 India.;Medical Oncologist, Cytecare hospital, Bengaluru, India.;Department of Pathology, Tata Memorial Hospital, Mumbai, India.;Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India.;Department of Nuclear Medicine, Tata Memorial Hospital, Mumbai, India.;Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India.;Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India.;Department of Nuclear Medicine, Tata Memorial Hospital, Mumbai, India.;Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National University, E. Borges Marg, Parel, Mumbai, Maharashtra 400012 India.;Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National University, E. Borges Marg, Parel, Mumbai, Maharashtra 400012 India.;Department of Pathology, Tata Memorial Hospital, Mumbai, India.;Department of Pathology, Tata Memorial Hospital, Mumbai, India.",
"authors": "Jain|Hasmukh|H|0000-0002-9947-7065;Kapoor|Akhil|A|;Sengar|Manju|M|;Chanana|Raajit|R|;Menon|Hari|H|;Sridhar|Epari|E|;Laskar|Siddhartha|S|;Agarwal|Archi|A|;Shastri|Jayant|J|;Khanna|Nehal|N|;Rangarajan|Venkatesh|V|;Bagal|Bhausaheb|B|;Thorat|Jayashree|J|;Shet|Tanuja|T|;Gujral|Sumeet|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-020-01372-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0971-4502",
"issue": "37(3)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "Chemo-immunotherapy; Dose adjusted R-EPOCH; Mediastinal lymphoma; Mediastinal radiotherapy; Survival outcomes",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "379-385",
"pmc": null,
"pmid": "34267455",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "16236753;33707856;23137070;22282906;16720849;31606909;17379431;19858058;23574119;18378569;29082519;31264808;11929754;22133772",
"title": "Outcomes of Patients with Primary Mediastinal B-Cell Lymphoma Treated with Dose Adjusted R-EPOCH Regimen: A Single Centre Experience.",
"title_normalized": "outcomes of patients with primary mediastinal b cell lymphoma treated with dose adjusted r epoch regimen a single centre experience"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-328874",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"dru... |
{
"abstract": "BACKGROUND\nFocusing on glomerular thrombotic microangiopathy (TMA), we detected urinary podocytes to evaluate podocyte damage following glomerular endothelial cell injury.\n\n\nMETHODS\nWe analyzed the relationship between urinary podocytes as biomarkers for podocyte injuries and clinical manifestations in five patients of anti-cancer-drug-induced glomerular TMA.\n\n\nRESULTS\nCancer in all five patients was advanced, including 4 cases of renal cell carcinoma treated with tyrosine kinase inhibitor, and one with intrahepatic bile duct carcinoma treated with gemcitabine. Urinary podocytes were detected in 2 cases that rapidly developed acute kidney injury (AKI) and nephrotic syndrome, while they were not detected in 3 cases of slowly progressive chronic renal failure. One case with AKI, presenting sequential manifestations of urinary podocytes, showed the decrease and disappearance of urinary podocytes in accordance with the cessation of the anti-cancer drug, followed by improvement in renal function and in clinical symptoms such as hypertension.\n\n\nCONCLUSIONS\nThese findings indicate that severe endothelial cell dysfunction during the acute phase of glomerular TMA leads to podocyte loss.",
"affiliations": null,
"authors": "Usui|Joichi|J|;Yokoyama|Chie|C|;Hagiwara|Masahiro|M|;Hirayasu|Kai|K|;Kojima|Takahiro|T|;Yoshino|Takayuki|T|;Nishiyama|Hiroyuki|H|;Hara|Masanori|M|;Yamagata|Kunihiro|K|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "Germany",
"delete": false,
"doi": "10.7754/Clin.Lab.2016.160525",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1433-6510",
"issue": "62(12)",
"journal": "Clinical laboratory",
"keywords": null,
"medline_ta": "Clin Lab",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009404:Nephrotic Syndrome; D050199:Podocytes; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies; D057049:Thrombotic Microangiopathies; D013997:Time Factors; D016482:Urinalysis; D014556:Urine",
"nlm_unique_id": "9705611",
"other_id": null,
"pages": "2413-2417",
"pmc": null,
"pmid": "28164557",
"pubdate": "2016-12-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "The Detection of Urinary Podocytes from Drug-Induced Glomerular Thrombotic Microangiopathy in Advanced Cancer Patients.",
"title_normalized": "the detection of urinary podocytes from drug induced glomerular thrombotic microangiopathy in advanced cancer patients"
} | [
{
"companynumb": "JP-ACCORD-048670",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Fungemia caused by uncommon Candida species (UCS) (other than C.albicans, C.glabrata, C.parapsilosis, C.tropicalis, C.krusei) is a rare but emerging threat with their potential to exhibit reduced susceptibility or resistance to antifungal agents. We identified 25 patients with UCS fungemia (9 C.kefyr, 8 C.lusitaniae, 4 C.dubliniensis, 2 C.guilliermondii, 1 C.pelliculosa, 1 C.rugosa) through January 2011 and August 2018. Echinocandins were the most common administered agents, followed by fluconazole. Overall mortality was 44%. Echinocandins and voriconazole showed sufficient activity against all tested isolates. High fluconazole MICs among C.guilliermondii, C.pelliculosa, and C.rugosa were determined. MIC value of C.pelliculosa was above the epidemiological cut-off proposed for fluconazole.",
"affiliations": "Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Hacettepe University, 06100, Sihhiye, Ankara, Turkey. alpsehnaz@gmail.com.;Faculty of Medicine, Department of Medical Microbiology, Hacettepe University, Ankara, Turkey.;Faculty of Medicine, Department of Internal Medicine, Hacettepe University, Ankara, Turkey.;Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Hacettepe University, 06100, Sihhiye, Ankara, Turkey.;Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Hacettepe University, 06100, Sihhiye, Ankara, Turkey.;Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Hacettepe University, 06100, Sihhiye, Ankara, Turkey.;Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Hacettepe University, 06100, Sihhiye, Ankara, Turkey.;Faculty of Medicine, Department of Medical Microbiology, Hacettepe University, Ankara, Turkey.;Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Hacettepe University, 06100, Sihhiye, Ankara, Turkey.",
"authors": "Alp|Sehnaz|S|http://orcid.org/0000-0001-9424-8346;Gulmez|Dolunay|D|;Kardas|Rıza Can|RC|;Karahan|Gizem|G|;Tas|Zahit|Z|;Gursoy|Gamze|G|;Ayaz-Ceylan|Caglayan Merve|CM|;Arikan-Akdagli|Sevtap|S|;Akova|Murat|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-020-04147-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-9723",
"issue": "40(7)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": "Antifungal susceptibility; Antifungal treatment; Breakthrough fungemia; Epidemiological cut-off value; Fungemia; Uncommon Candida species",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D002175:Candida; D058387:Candidemia; D003428:Cross Infection; D005260:Female; D006785:Hospitals, University; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D014421:Turkey",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "1539-1545",
"pmc": null,
"pmid": "33495941",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "26488845;31254420",
"title": "Expect the unexpected: fungemia caused by uncommon Candida species in a Turkish University Hospital.",
"title_normalized": "expect the unexpected fungemia caused by uncommon candida species in a turkish university hospital"
} | [
{
"companynumb": "TR-PFIZER INC-202101419388",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "4",
... |
{
"abstract": "In this report, we describe two patients with white globe appearance in the non-cancerous stomach. The patient in Case 1 was an 82-year-old Japanese man who had been taking vonoprazan, dimethicone, acotiamide, sitagliptin, candesartan, dutasteride, etizolam and zolpidem. The patient in Case 2 was a 74-year-old Japanese woman who had been taking esomeprazole, rebamipide, sitagliptin, candesartan, ezetimibe, mirabegron, levocetirizine, zolpidem and lactobacillus preparation. In both cases, endoscopy revealed multiple white spots in the stomach. Magnifying endoscopy and blue laser imaging revealed a slightly elevated, round, white substance. Biopsied specimens from the lesions contained parietal cell protrusions and fundic gland cysts. Intraglandular necrotic debris was absent. Consequently, microscopic features in these cases were different from those reported previously for white globe appearance observed in gastric cancer lesions. These results indicate that white globe appearance can be observed in non-cancerous stomach. Although the macroscopic features could be confusing or misleading, thorough endoscopic observation and pathological analysis of white globe appearance will aid oncologists and endoscopists in differentiating between cancer-related lesions and non-cancerous lesions.",
"affiliations": "Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.;Department of Pathology, Okayama University Hospital, Okayama 700-8558, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.;Department of Endoscopy, Okayama University Hospital, Okayama 700-8558, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.",
"authors": "Iwamuro|Masaya|M|;Tanaka|Takehiro|T|;Sakae|Hiroyuki|H|;Yamasaki|Yasushi|Y|;Kanzaki|Hiromitsu|H|;Kawano|Seiji|S|;Kawahara|Yoshiro|Y|;Okada|Hiroyuki|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3332/ecancer.2018.856",
"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2018.856can-12-856Case ReportTwo cases of white globe appearance in non-cancerous stomach Iwamuro Masaya 1Tanaka Takehiro 2Sakae Hiroyuki 1Yamasaki Yasushi 1Kanzaki Hiromitsu 1Kawano Seiji 1Kawahara Yoshiro 3Okada Hiroyuki 1\n1 Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan\n2 Department of Pathology, Okayama University Hospital, Okayama 700-8558, Japan\n3 Department of Endoscopy, Okayama University Hospital, Okayama 700-8558, JapanCorrespondence to: Masaya Iwamuro. iwamuromasaya@yahoo.co.jp2018 07 8 2018 12 85628 3 2018 © the authors; licensee ecancermedicalscience.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.In this report, we describe two patients with white globe appearance in the non-cancerous stomach. The patient in Case 1 was an 82-year-old Japanese man who had been taking vonoprazan, dimethicone, acotiamide, sitagliptin, candesartan, dutasteride, etizolam and zolpidem. The patient in Case 2 was a 74-year-old Japanese woman who had been taking esomeprazole, rebamipide, sitagliptin, candesartan, ezetimibe, mirabegron, levocetirizine, zolpidem and lactobacillus preparation. In both cases, endoscopy revealed multiple white spots in the stomach. Magnifying endoscopy and blue laser imaging revealed a slightly elevated, round, white substance. Biopsied specimens from the lesions contained parietal cell protrusions and fundic gland cysts. Intraglandular necrotic debris was absent. Consequently, microscopic features in these cases were different from those reported previously for white globe appearance observed in gastric cancer lesions. These results indicate that white globe appearance can be observed in non-cancerous stomach. Although the macroscopic features could be confusing or misleading, thorough endoscopic observation and pathological analysis of white globe appearance will aid oncologists and endoscopists in differentiating between cancer-related lesions and non-cancerous lesions.\n\nwhite globe appearanceintraglandular necrotic debrisgastric canceracid secretion inhibitor\n==== Body\nIntroduction\nWhite globe appearance was first reported in 2015 by Doyama et al [1] as a small, white lesion in the gastric mucosa. Doyama et al suggested that the finding pathologically corresponded to a dilated gastric gland containing eosinophilic material with necrotic epithelial fragments, called intraglandular necrotic debris [1, 2]. It is noteworthy that the white globe appearance is found within the margin of the cancerous gastric epithelium.\n\nThe presence of white globe appearance in the stomach has been reported to be highly indicative of cancer [1]. However, it can also be observed in non-cancerous gastric mucosa, albeit rarely [3]. To our knowledge, endoscopic pictures and detailed pathological features of the white globe appearance in patients without gastric cancer have not been described thus far. Here, we present two patients with multiple white spots in the non-cancerous gastric mucosa, which were consistent with the known features of the white globe appearance. Here, we discuss differences in the pathological features of white globe appearance in gastric cancer versus non-cancerous stomach.\n\nCase presentation\nCase 1\nAn 82-year-old Japanese man underwent esophagogastroduodenoscopy for a routine health checkup. The patient had been taking vonoprazan, dimethicone, acotiamide, sitagliptin, candesartan, dutasteride, etizolam and zolpidem for reflux esophagitis, functional dyspepsia, diabetes, hypertension, benign prostatic hyperplasia and insomnia. Physical examination revealed no abnormalities in his abdomen. All laboratory findings were within the normal ranges, except for elevation of plasma glucose (256 mg/dL), haemoglobin A1c (7.1%) and gastrin levels (844 pg/mL, normal range: 42–200 pg/mL). He tested negative for Helicobacter pylori (H. pylori) IgG antibody.\n\nEndoscopy revealed multiple white spots in the fornix (Figure 1a) and body (Figure 1b) of the stomach. Magnifying endoscopy observation (Figure 1c) and blue laser imaging (Figure 1d) showed a slightly elevated, round, white substance. Microvasculature was also seen on its surface, suggesting deposition of the white substance within the mucosa. Atrophic gastritis was also observed during esophagogastroduodenoscopy. No inflammation was observed in the oesophageal mucosa. Biopsy from the gastric mucosa that contained white spots revealed cystic dilation of the gastric fundal gland with a 400 μm diameter (Figure 2a, b). Parietal cell protrusion was also noted (Figure 2c, arrows). Xanthoma cells were absent in the biopsied specimen.\n\nCase 2\nA 74-year-old Japanese woman underwent esophagogastroduodenoscopy for investigation of epigastric pain and throat discomfort. She had been taking esomeprazole, rebamipide, sitagliptin, candesartan, ezetimibe, mirabegron, levocetirizine, zolpidem and lactobacillus preparation for reflux esophagitis, diabetes, hypertension, hyperlipidaemia, urticaria and insomnia. The patient had also been using flurbiprofen poultice for chronic lumbar pain. She is allergic to multiple medications, including antibiotics. Although the patient underwent eradication treatment for H. pylori 2 years previously, she discontinued taking the medication due to epigastric discomfort, and eradication failed. Physical examination revealed no abnormalities in her abdomen. Laboratory findings revealed elevated levels of total cholesterol (254 mg/dL), triglyceride (130 mg/dL), haemoglobin A1c (7.7%) and immunoglobulin E (598 IU/mL, normal range: 0–170 IU/mL). Gastrin levels were not measured in this patient. H. pylori IgG antibody was positive.\n\nEsophagogastroduodenoscopy revealed multiple white spots in the gastric fornix (Figure 3a, arrows), body (Figure 3b, post-indigo carmine spraying) and antrum. Magnifying endoscopy observation (Figure 3c) and blue laser imaging (Figure 3d) showed small, round, white deposits that were similar to the substances observed in case 1. Other endoscopic findings included atrophic gastritis and oesophageal hiatal hernia. Cystic dilation of the gastric fundal gland was identified in the biopsied specimen obtained from the white spots, which contained debris in the dilated duct (Figure 4a, b). The dilated duct was approximately 600 μm in diameter. In addition, parietal cell protrusions and dilated glands forming microcysts were present (Figure 4c).\n\nDiscussion\nIn the presented two patients, white substance was deposited in a slightly elevated, circular fashion within the gastric mucosa, and microvasculature was observed on its surface. The white substance pathologically consisted of cystic dilation of the duct with a 400–600 μm diameter. Doyama et al defined the white globe appearance as a small (<1 mm) white lesion of globular shape that is found underneath the gastric epithelium and can be clearly visualised using magnifying endoscopy with narrow-band imaging [1, 4]. Microvessels overlying the white substance, reflecting the white substance existing underneath the gastric epithelium and subepithelial microvessels, have been reported to be useful for identifying the white globe appearance [3]. The endoscopic features observed in the presented two cases fit these definitions. As described earlier, to the best of our knowledge, this report is the first to present detailed endoscopic and pathologic images of the white globe appearance in cases without gastric cancer.\n\nAs described earlier, Doyama et al described the white globe appearance as a novel marker to correctly diagnose early gastric cancer [1, 3]. Figure 5 shows the typical images of the white globe appearance observed in a 78-year-old Japanese man with gastric cancer.\n\nTiny white substances were observed in the periphery of the cancer lesion (Figure 5a, arrows). In an endoscopically resected specimen, eosinophilic materials with necrotic epithelial fragments were identified within the lumen of the dilated glands (Figure 5b, c), which are called intraglandular necrotic debris [1–3]. Meanwhile, neither eosinophilic materials nor necrotic epithelial fragments were identified in the two presented cases. We speculate that the deposited material was mucus in Case 1 and degenerated epithelial cells and mucus in Case 2. White globe features in the present two cases seemed to be more elevated and whiter than those in gastric cancer. In addition, the distribution of white globe appearance was patchy in the present two cases. Such differences of the endoscopic and pathological features between cases with and without cancer lesions probably reflect different underlying pathogeneses of the white globe appearance.\n\nYoshida et al [3] described three cases of patients without gastric cancer who showed white globe appearance in the stomach. One patient had a benign open ulcer, another had gastritis, and the other had low-grade adenoma with an ulcer scar. Because two of the three patients had a gastric ulcer, the authors speculated that ulceration is associated with the pathogenesis of the white globe appearance. However, no ulceration was detected endoscopically or pathologically in the two presented cases. In addition, the white globe appearance was distributed in wide areas (the fornix and body in Case 1 and the fornix, body and antrum in Case 2).\n\nSeveral possible mechanisms can be hypothesised for the white globe appearance in the two cases. First, an acid secretion inhibitor might induce such features. The patient in Case 1 had been taking vonoprazan, a potassium-competitive acid blocker, and the patient in Case 2 had been taking esomeprazole, a proton-pump inhibitor. These acid secretion inhibitors lead to hypergastrinemia, which causes parietal cell enlargement and a serrated or tongue-like internal gland profile, that is, parietal cell protrusion [5]. Subsequently, parietal cell protrusion would obstruct outflow from the gland, finally resulting in intramucosal cyst formation of dilated glands, which is called fundic gland cysts [6]. We speculate that fluid in the fundic gland cysts was observed as the white globe appearance. The presence of parietal cell protrusion in the biopsied specimen of the presented cases supports this hypothesis. Hatano et al [7] recently reported black spots as a novel gastric finding, which was potentially induced by proton-pump inhibitor use. Among 64 patients, 44 (68.8%) were taking proton-pump inhibitors. Parietal cell protrusions and fundic gland cysts were pathologically identified in 26 (76.5%) and 23 (64.1%) cases, respectively. The authors speculated that the brownish pigmentation retained in the fundic gland cysts was responsible for the black spots. Although the colour was apparently different between black spots reported by Hatano et al and white spots observed in the presented two cases, they shared common macroscopic and microscopic features; both of them presented with small punctiform lesions in the stomach and had parietal cell protrusions and fundic gland cysts. Therefore, a common ethology may exist between the black spots and white globe appearance in the non-cancerous stomach.\n\nThe second hypothesis is that medications other than acid secretion inhibitors or underlying diseases might cause the white globe appearance. For example, both patients in Cases 1 and 2 had been taking sitagliptin, candesartan and zolpidem. Moreover, both patients had diabetes mellitus. Any of these drugs or diabetes mellitus might be involved in the pathogenesis of the white spots. Third, H. pylori-associated chronic gastritis might contribute to the formation of white globe appearance. The patient in Case 2 had active H. pylori infection and white globe appearance was observed at the border of the atrophic gastric mucosa. In Case 1, although H. pylori was serologically and pathologically negative, and the white globe appearance was observed in the non-atrophic gastric mucosa, the presence of atrophic gastritis meant past H. pylori infection. Inflammation and alteration of gastric mucosa due to H. pylori may promote or facilitate the formation of white spots in the stomach. Because the pathogenesis of white globe appearance has not been described thus far, further investigations are warranted.\n\nConclusions\nWe present two cases with white globe appearance observed in the non-cancerous gastric mucosa. Pathologically, parietal cell protrusion and fundic gland cysts existed, whereas intraglandular necrotic debris was absent. The results of the present study reinforce that white globe appearance can be observed in non-cancerous stomach. Although the macroscopic features could be confusing or misleading, thorough endoscopic observation and pathological analysis of white globe appearance will aid oncologists and endoscopists in differentiating between cancer-related lesions and non-cancerous lesions.\n\nConflicts of interest\nThe authors declare that they have no conflicts of interest regarding the publication of this paper.\n\nFunding\nThe authors did not receive any funding for this work.\n\nFigure 1. Endoscopic images of Case 1. Multiple white spots are seen in the gastric fornix (a) and body (b). Magnifying endoscopy observation (c) and blue laser imaging (d) show deposition of slightly elevated, round, white substance and microvasculature on its surface, which are consistent with reported features of white globe appearance.\nFigure 2. Pathology images of Case 1. Biopsied specimen reveals cystic dilatation of the gastric fundal gland that had a 400 μm diameter (a, b). Parietal cell protrusion is also noted (c, arrows) along with dilated duct (c, asterisk).\nFigure 3. Endoscopic images of Case 2. Multiple white spots are identified in the gastric fornix (a, arrows) and body (b, post-indigo carmine spraying). Magnifying endocopy observation (c) and blue laser imaging (d) show small, round, white deposits.\nFigure 4. Pathology images of Case 2. The biopsied specimen shows cystic dilatation of the gastric fundal gland of approximately 600 μm diameter (a, b). Parietal cell protrusions and dilated glands forming microcysts are also seen (c).\nFigure 5. Representative images of white globe appearance observed in a patient with gastric cancer. Tiny white substances are observed in the periphery of the cancer lesion (a, arrows). Intraglandular necrotic debris is seen in the resected specimen (b, c).\n==== Refs\nReferences\n1. Doyama H Yoshida N Tsuyama S The “white globe appearance” (WGA): a novel marker for a correct diagnosis of early gastric cancer by magnifying endoscopy with narrow-band imaging (M-NBI) Endosc Int Open 2015 3 2 E120 E124 10.1055/s-0034-1391026 26135651 \n2. Watanabe Y Shimizu M Itoh T Intraglandular necrotic debris in gastric biopsy and surgical specimens Ann Diagn Pathol 2001 5 3 141 147 10.1053/adpa.2001.25405 11436167 \n3. Yoshida N Doyama H Nakanishi H White globe appearance is a novel specific endoscopic marker for gastric cancer: a prospective study Dig Endosc 2016 28 1 59 66 10.1111/den.12519 26227666 \n4. Omura H Yoshida N Hayashi T Interobserver agreement in detection of “white globe appearance” and the ability of educational lectures to improve the diagnosis of gastric lesions Gastric Cancer 2017 20 4 620 628 10.1007/s10120-016-0676-3 27915451 \n5. Stolte M Bethke B Rühl G Omeprazole-induced pseudohypertrophy of gastric parietal cells Z Gastroenterol 1992 30 2 134 138 1553828 \n6. Cats A Schenk BE Bloemena E Parietal cell protrusions and fundic gland cysts during omeprazole maintenance treatment Hum Pathol 2000 31 6 684 690 10.1053/hupa.2000.7637 10872661 \n7. Hatano Y Haruma K Ayaki M Black spot, a novel gastric finding potentially induced by proton pump inhibitors Intern Med 2016 55 21 3079 3084 10.2169/internalmedicine.55.6974 27803398\n\n",
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"title": "Two cases of white globe appearance in non-cancerous stomach.",
"title_normalized": "two cases of white globe appearance in non cancerous stomach"
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"abstract": "Lithium is an effective mood stabiliser used to treat bipolar affective disorder (BPAD); however, it can also adversely affect the kidneys, causing acute toxic effects, nephrogenic diabetes insipidus, chronic renal dysfunction and end-stage kidney disease (ESKD) in a minority of patients. We describe the case of a man with a 34-year history of BPAD type-1 and a 2-year history of ESKD secondary to lithium-induced nephropathy who experienced a manic relapse. He previously responded well to lithium but, following a deterioration in kidney function, was switched to olanzapine and sodium valproate. This precipitated a period of instability, which culminated in a treatment-resistant manic episode requiring hospital admission. After a multidisciplinary team discussion, lithium therapy was restarted and provided remission. This was achieved safely through a reduced dosing schedule of three times a week post dialysis, slow dose titration and blood level monitoring prior to each dialysis session.",
"affiliations": "Hounslow Crisis Assessment & Treatment Team, West London Mental Health NHS Trust, Isleworth, UK.;Renal and Transplant, Imperial College Healthcare NHS Trust, London, UK emma.salisbury@nhs.net.",
"authors": "Topp|Sam|S|;Salisbury|Emma|E|http://orcid.org/0000-0002-4357-3787",
"chemical_list": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D014635:Valproic Acid; D008094:Lithium",
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"journal": "BMJ case reports",
"keywords": "bipolar i disorder; chronic renal failure; dialysis; psychiatry (drugs and medicines)",
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"mesh_terms": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001714:Bipolar Disorder; D006801:Humans; D007674:Kidney Diseases; D008094:Lithium; D008297:Male; D019964:Mood Disorders; D009364:Neoplasm Recurrence, Local; D006435:Renal Dialysis; D014635:Valproic Acid",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Lithium use in a patient on haemodialysis with bipolar affective disorder and lithium-induced nephropathy.",
"title_normalized": "lithium use in a patient on haemodialysis with bipolar affective disorder and lithium induced nephropathy"
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"abstract": "BACKGROUND\nThe aim of this study was to report an unusual case of chronic postoperative endophthalmitis following cataract surgery, secondary to Ochrobactrum anthropi that was found to be resistant to vancomycin.\n\n\nRESULTS\nAnterior chamber paracentesis cultures grew gram negative bacilli Ochrobactrum anthropi. The patient was treated with a series of intracameral injections of moxifloxacin, with adjuvant oral moxifloxacin. Posterior sub-Tenon and oral corticosteroids were used to treat cystoid macular edema. Explantation of the intraocular lens (IOL)-capsular bag complex was avoided.\n\n\nCONCLUSIONS\nChronic postoperative endophthalmitis is a rare entity, often due to indolent pathogens that sequester in the capsular bag. Aggressive surgical intervention may be avoided with the use of adequate intraocular antibiotic, provided that the offending organism demonstrates appropriate antibiotic susceptibilities.",
"affiliations": "Department of Ophthalmology, Max Rady College of Medicine, University of Manitoba, M264-99 Cornish Ave., Winnipeg, MB, R3C 1A2, Canada.;Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 440, Chicago, IL, 60611, USA.;Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 440, Chicago, IL, 60611, USA.;Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 440, Chicago, IL, 60611, USA. debrgold@yahoo.com.",
"authors": "Kanjee|Raageen|R|;Koreishi|Anjum F|AF|;Tanna|Angelo P|AP|;Goldstein|Debra A|DA|",
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"doi": "10.1186/s12348-016-0094-z",
"fulltext": "\n==== Front\nJ Ophthalmic Inflamm InfectJ Ophthalmic Inflamm InfectJournal of Ophthalmic Inflammation and Infection1869-5760Springer Berlin Heidelberg Berlin/Heidelberg 9410.1186/s12348-016-0094-zBrief ReportChronic postoperative endophthalmitis after cataract surgery secondary to vancomycin-resistant Ochrobactrum anthropi: case report and literature review Kanjee Raageen kanjeer@myumanitoba.ca Koreishi Anjum F. akoreishi@gmail.com Tanna Angelo P. atanna@northwestern.edu Goldstein Debra A. 312-908-8152debrgold@yahoo.com Department of Ophthalmology, Max Rady College of Medicine, University of Manitoba, M264-99 Cornish Ave., Winnipeg, MB R3C 1A2 Canada Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 440, Chicago, IL 60611 USA 15 7 2016 15 7 2016 2016 6 2525 4 2016 28 6 2016 © 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.Background\nThe aim of this study was to report an unusual case of chronic postoperative endophthalmitis following cataract surgery, secondary to Ochrobactrum anthropi that was found to be resistant to vancomycin.\n\nFindings\nAnterior chamber paracentesis cultures grew gram negative bacilli Ochrobactrum anthropi. The patient was treated with a series of intracameral injections of moxifloxacin, with adjuvant oral moxifloxacin. Posterior sub-Tenon and oral corticosteroids were used to treat cystoid macular edema. Explantation of the intraocular lens (IOL)-capsular bag complex was avoided.\n\nConclusions\nChronic postoperative endophthalmitis is a rare entity, often due to indolent pathogens that sequester in the capsular bag. Aggressive surgical intervention may be avoided with the use of adequate intraocular antibiotic, provided that the offending organism demonstrates appropriate antibiotic susceptibilities.\n\nKeywords\nEndophthalmitisOchrobactrum anthropiCataract extractionDrug therapyGram-negative bacterial infectionDrug resistanceMicrobialissue-copyright-statement© The Author(s) 2016\n==== Body\nCase\nA 60-year-old female underwent uncomplicated bilateral cataract surgery in Colombia, 1 month apart, in 2013. Past ocular history was significant for laser in situ keratomileusis in 2006 and past medical history was unremarkable. One month after cataract surgery in the left eye, vision was reduced to 20/80 with an inflammatory response. After an initial non-contributory anterior chamber paracentesis, she underwent a vitreous tap and intravitreal vancomycin injection without improvement. Two pars plana vitrectomies with intravitreal vancomycin failed to improve vision or inflammation, and all cultures were negative. In January 2014, she returned to the USA and was treated by a retinal specialist, who performed intravitreal and sub-Tenon triamcinolone acetonide injections without improvement and with marked elevation of intraocular pressure (IOP).\n\nFindings\n At referral to a tertiary care uveitis clinic in December 2014, best corrected visual acuity (BCVA) was counting fingers in the left eye and 20/15 in the unaffected right eye. IOP in the left eye, despite maximally tolerated topical and systemic therapy was 42 mmHg. Slit lamp examination demonstrated hundreds of large granulomatous KP and 1+ anterior chamber cell (Fig. 1). Gonioscopy revealed an open angle with no peripheral anterior synechiae, but the view was limited. Fundus examination was limited. Ultrasound biomicroscopy and B-scan of the left eye demonstrated an intraocular lens (IOL) centered in the capsular bag with no retained lens fragments, no significant vitritis, and no retinal detachment.Fig. 1 Appearance at presentation: multiple large granulomatous KP\n\n\n\nIntraocular pressure was urgently treated with implantation of an Ahmed FP-7 glaucoma valve (AGV), resulting in postoperative IOP in the mid-teens and improved BCVA of 20/125. An intraoperative sample of aqueous humor was sent for culture and PCR for 16-s eubacterial and 18-s fungal primers, but was not processed due to laboratory error. An initial work-up for sarcoidosis (lysozyme, angiotensin-converting enzyme, chest X-ray), syphilis (Treponema pallidum Ab, RPR), and tuberculosis (QuantiFERON®-TB Gold) was negative. Oral prednisone was started 1 day postoperatively.\n\nAt the 1-week postoperative follow-up, intraocular inflammation was noted to have worsened, with 3+ anterior chamber cell, new granulomatous iris nodules, and the appearance of golden-brown “strings of pearls” in the anterior chamber (Fig. 2). A 0.3-cm3 sample of aqueous humor was again sent for PCR and culture. Intracameral moxifloxacin (160 μg/0.1 cm3) was administered, and oral prednisone was tapered. Gram stain revealed gram negative bacilli, and bacterial cultures were positive for Ochrobactrum anthropi, resistant to vancomycin, and sensitive to moxifloxacin.Fig. 2 Presentation after initiation of oral steroids post-Ahmed glaucoma valve implantation (superotemporal): new granulomatous iris nodules and anterior chamber fibrin\n\n\n\nOver the subsequent 3 months, six intracameral moxifloxacin injections (160 μg/0.1 cm3, 0.1–0.2 cm3) were administered every 1 to 3 weeks based on clinical findings, in conjunction with oral moxifloxacin (400 mg) until aqueous cultures were negative. Oral moxifloxacin was continued at frequencies ranging from daily to three times per week over the subsequent year. Oral prednisone was tapered from 60 mg every 1 to 2 weeks based on clinical response.\n\nWithin 3 months of this treatment regimen, the nodules and fibrin improved (Fig. 3). However, new granulomatous nodules developed along the intracameral portion of the AGV tube and progressed into the subconjunctival portion of the tube, necessitating explantation of the entire device, including the plate (Fig. 4). Cultures from this procedure were negative, and the eye was thoroughly irrigated with moxifloxacin intraoperatively. BCVA improved to 20/50 with a quiet anterior chamber (Fig. 5).Fig. 3 Significant improvement was noted after intracameral moxifloxacin injections. Note the strands were connected to the tube and the suture (right)\n\nFig. 4 Granulomatous nodules at entrance of Ahmed glaucoma valve tube (left), extending toward plate (right)\n\nFig. 5 Appearance after removal of Ahmed glaucoma valve\n\n\n\nThe view of the fundus improved, and the retina appeared normal, with the exception of cystoid macular edema (CME). This was treated with increased oral prednisone and moxifloxacin, and a subsequent series of posterior sub-Tenon triamcinolone injections (0.5–0.6 cc of 40 mg/cc of triamcinolone), after a thorough discussion of the risk of worsening any residual infection. The CME responded well, and oral moxifloxacin and prednisone were tapered. A year after the AGV was removed, IOP was noted to be unacceptably high despite maximally tolerated medical therapy, and a Baerveldt BG 103–250 glaucoma drainage device was implanted, with subsequent improvement in IOP control. As of this writing, BCVA is stable at 20/25 and IOP is 27 on dorzolamide/timolol, atropine, and prednisolone drops. There have been no recurrences 7 months after oral moxifloxacin was discontinued.\n\nDiscussion\nO. anthropi is an aerobic gram-negative bacillus, first described in 1988 [9]. It is typically found in water sources, both in the community and in hospitals [7]. While not typically pathogenic, O. anthropi has been implicated in conditions such as pancreatic abscess and catheter-associated sepsis [2, 7]. It demonstrates a high affinity for implanted medical devices, such as silicone products and other foreign materials [1].\n\nA PubMed literature search (keywords “ochrobactrum anthropi AND (cornea OR cataract OR vitreous OR retina)”) yielded 22 reported cases of ocular infection caused by O. anthropi. Another two articles were identified through a similar Web of Science™ search; in total, 23 cases were of chronic postoperative endophthalmitis [3–6, 8, 10, 12, 14, 16] and one case was of microbial keratitis [11]. Of those with endophthalmitis, 19 occurred following cataract surgery [4, 8, 12, 14, 16], one after Boston type 1 keratoprosthesis implantation [5], and three were likely endogenous in origin [3, 6, 10]. For those cases following cataract surgery, the most common treatment involved a combination of vitrectomy with intravitreal antibiotics and capsulectomy with IOL explantation. Antibiotic selection can be challenging, given broad resistance patterns. Table 1 describes reported resistance and sensitivity patterns. In those cases reporting sensitivities, O. anthropi has been variably resistant to β-lactams, cephalosporins, aminoglycosides, sulfonamides, and trimethoprim. It is usually sensitive to fluoroquinolones and tetracyclines, though sensitivities to other classes have been noted. While visual acuities on presentation have typically been poor (20/100 or worse), with adequate treatment most cases recovered to 20/60 or better (Table 1).Table 1 Antibiotic profiles reported in cases of O. anthropi endophthalmitis\n\nReport\tCases\tSensitivities\tResistances\tPresenting VA\n\tFinal VA\n\t\nBraun, [4]\t1\tAmikacin\nCiprofloxacin\nImipenem\nTetracycline\tCephalosporins\nPenicillins\nSulfamethoxazole\nTobramycin\nTrimethoprim\t20/100\t20/30\t\nGreven, [8]\t1\tCiprofloxacin\nImipenem\nTMP-SMX\tCeftazidime\nGentamycin\tCF\t20/25\t\nKim, [12]\t1\tAmikacin\nCiprofloxacin\nImipenem\nMeropenem\tAztreonam\nCeftazidime\nGentamycin\nSulperazone\nPiperacillin\t20/100\t20/25\t\nSong, [16]\t9\tImipenem\nQuinolones\nTMP-SMX\tAminoglycosides\n\nβ-lactams\t20/200\nor worse\t20/60\nor better\t\nChiang, [6]\t1\tCeftazidime\nCiprofloxacin\nImipenem\nTrimethoprim\tNR\t20/100\t20/200\t\nMattos, [14]\t7\tNR\tNR\tNR\tNR\t\n\nNR not reported, TMP-SMX trimethoprim-sulfamethoxazole, V\nA visual acuity\n\n\n\nTwo epidemics of postoperative endophthalmitis have been reported. Nine cases were attributed to irrigating solution during phacoemulsification in Korea [16], and seven cases were thought to be caused by phacoemulsification machine tubing in Brazil [14]. In two cases, preceding non-ocular surgery with implanted medical devices was noted: one patient with a mitral valvuloplasty [10] and one patient with percutaneous transluminal angioplasty [6].\n\nChronic postoperative endophthalmitis is a rare entity, significantly less common than acute postoperative endophthalmitis [13]. The most frequently identified bacterial agent is Propionibacterium acnes, a gram positive bacillus [15]. Many such indolent pathogens, including O. anthropi, may sequester in the capsular bag, necessitating its removal [4, 6, 8, 16].\n\nPrior to aggressive surgical intervention, chronic postoperative endophthalmitis is often treated with intravitreal injections of vancomycin, given its excellent activity against P. acnes. It is important to note that in our case, O. anthropi was resistant to vancomycin, which contributed to the complexity of management. While initial surgical interventions were unsuccessful, aggressive treatment with intracameral and oral moxifloxacin resulted in a good visual outcome. There was a significant delay in making an accurate diagnosis in this case, despite intraocular infection being investigated at many steps. It is unclear why initial cultures performed in Colombia were negative. Previous reports have suggested that O. anthropi should grow on culture media within 6 days of inoculation [16].\n\nAs O. anthropi has a high affinity for foreign material, there remains concern for its persistent sequestration on implanted medical devices such as IOLs. In the present case, our patient wanted to maintain the IOL if at all possible, and this was achieved with aggressive intraocular and systemic antibiotic therapy. The intraocular inflammation has remained controlled, and CME has not recurred despite discontinuation of oral moxifloxacin. If CME or inflammation recurs, explanation of the IOL and capsular bag will likely be necessary.\n\nWhile chronic postoperative endophthalmitis continues to be a rare event following cataract surgery, its outcomes may be devastating. O. anthropi is a rare causative organism, but should be included in the differential diagnosis, particularly in light of its possible resistance to vancomycin. It may present indolently, similarly to P. acnes and atypical mycobacteria. In culture-proven cases with adequate antibiotic sensitivity patterns, a trial of repeated intracameral antibiotic injections and oral antibiotic therapy may control the infection and obviate the need for IOL explantation.\n\nAbbreviations\nAGV, Ahmed glaucoma valve; BCVA, best-corrected visual acuity; CME, cystoid macular edema; IOL, intraocular lens; IOP, intraocular pressure; PCR, polymerase chain reaction; RPR, rapid plasma regain\n\nAuthors’ contributions\nRK, AFK, and DAG were involved in data acquisition and analysis. All authors were involved in manuscript drafting and critical revisions. APT and DAG were involved in supervision. All authors approved the final manuscript.\n\nAuthors’ information\nRK is a senior ophthalmology resident at the University of Manitoba. AFK is a uveitis fellow at the Northwestern University Feinberg School of Medicine. APT is the Director of the Glaucoma Service and Associate Professor at the Northwestern University Feinberg School of Medicine. DAG is the Director of the Uveitis Service and Professor at the Northwestern University Feinberg School of Medicine.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nConsent was received from the reported patient for use of their clinical images and data.\n==== Refs\nReferences\n1. Alnor D Frimodt-Møller N Espersen F Frederiksen W Infections with the unusual human pathogens Agrobacterium species and Ochrobactrum anthropi Clin Infect Dis 1994 18 914 920 10.1093/clinids/18.6.914 8086552 \n2. Applebaum PC Campbell DB Pancreatic abscess associated with Achromobacter group Vd biovar-1 J Clin Microbiol 1980 12 282 283 7229011 \n3. Berman AJ Del Priore LV Fischer CK Endogenous Ochrobactrum anthropi endophthalmitis Am J Ophthalmol 1997 123 560 562 10.1016/S0002-9394(14)70190-4 9124261 \n4. Braun M Jonas JB Schönherr U Naumann GO Ochrobactrum anthropi endophthalmitis after uncomplicated cataract surgery Am J Ophthalmol 1996 122 272 273 10.1016/S0002-9394(14)72025-2 8694102 \n5. Chan CC Holland EJ Infectious keratitis after Boston type 1 keratoprosthesis implantation Cornea 2012 31 1128 1134 10.1097/ICO.0b013e318245c02a 22960647 \n6. Chiang C Tsai Y Lin J Chen W Chronic endophthalmitis after cataract surgery secondary to Ochrobactrum anthropi Eye (Lond) 2009 23 1237 1238 10.1038/eye.2008.137 18483495 \n7. Cieslak TJ Robb ML Drabick CJ Fischer GW Catheter-associated sepsis caused by Ochrobactrum anthropi: report of a case and review of related nonfermentative bacteria Clin Infect Dis 1992 14 902 907 10.1093/clinids/14.4.902 1576286 \n8. Greven CM Nelson KC Chronic postoperative endophthalmitis secondary to Ochrobactrum anthropi Retina 2001 21 279 280 10.1097/00006982-200106000-00021 11421027 \n9. Holmes B Popoff M Kiredjian M Kersters K Ochrobactrum anthropi gen. nov., sp. nov. from human clinical specimens and previously known as group vd Int J Syst Bacteriol 1988 38 406 416 10.1099/00207713-38-4-406 \n10. Inoue K Numaga J Nagata Y Ochrobactrum anthropi endophthalmitis after vitreous surgery Br J Ophthalmol 1999 83 502 10434878 \n11. Kent HD Cohen EJ Laibson PR Arentsen JJ Microbial keratitis and corneal ulceration associated with therapeutic soft contact lenses CLAO J 1990 16 49 52 2306853 \n12. Kim KS Han JW Lee WK A case of Ochrobactrum anthropi endophthalmitis after cataract surgery J Korean Ophthalmol Soc 2003 44 1943 1947 \n13. Kresloff MS Castellarin AA Zarbin MA Endophthalmitis Surv Ophthalmol 1998 43 193 224 10.1016/S0039-6257(98)00036-8 9862309 \n14. Mattos FB Saraiva FP Angotti-Neto H Passos AF Outbreak of Ochrobactrum anthropi endophthalmitis following cataract surgery J Hosp Infect 2013 83 337 340 10.1016/j.jhin.2012.11.027 23415718 \n15. Meisler DM Zakov ZN Bruner WE Endophthalmitis associated with sequestered intraocular Propionibacterium acnes Am J Ophthalmol 1987 104 428 429 10.1016/0002-9394(87)90240-6 3499078 \n16. Song S Ahn JK Lee GH Park YG An epidemic of chronic pseudophakic endophthalmitis due to Ochrobactrum anthropi: clinical findings and managements of nine consecutive cases Ocul Immunol Inflamm 2007 15 429 434 10.1080/09273940701798546 18085486\n\n",
"fulltext_license": "CC BY",
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"keywords": "Cataract extraction; Drug resistance; Drug therapy; Endophthalmitis; Gram-negative bacterial infection; Microbial; Ochrobactrum anthropi",
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"title": "Chronic postoperative endophthalmitis after cataract surgery secondary to vancomycin-resistant Ochrobactrum anthropi: case report and literature review.",
"title_normalized": "chronic postoperative endophthalmitis after cataract surgery secondary to vancomycin resistant ochrobactrum anthropi case report and literature review"
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"abstract": "Papulopustular rash, an acneiform rash, appears on the seborrheic region during the first to second week of treatment with an epidermal growth factor receptor inhibitor (EGFRi). The rash gradually disappears after the fourth week; however, it persists or newly develops in other regions during EGFRi treatment. Because Staphylococcus aureus is frequently isolated from late-phase papulopustular rash, we assessed the incidence of bacterial infection and treatment outcomes of patients with late-phase papulopustular rash. Sixty-four cases treated with an EGFRi over 4 weeks who presented with papulopustular rash were assessed retrospectively. The median duration of EGFR inhibitor treatment was 5 months. Grade 2 and 3 papulopustular rash was observed in 47 and eight cases, respectively. Bacterial culture was performed in 51 cases, 50 of which yielded positive results: methicillin-sensitive S. aureus in 29, methicillin-resistant S. aureus in 14, Staphylococcus species in five, Pseudomonas aeruginosa in three, and other in four cases. Of the S. aureus isolates, 42% were resistant to minocycline and 40% to levofloxacin. After treatment with topical and/or oral antibiotics without topical corticosteroids, the papulopustular rash rapidly improved by an average of 2.9 ± 3.4 weeks. However, use of a combination of antibiotics and a topical corticosteroid prolonged the recovery period to an average of 18.9 ± 11.4 weeks. In conclusion, folliculitis that develops over 4 weeks after the initiation of EGFRi treatment is typically caused by staphylococcal infection. Bacterial culture is necessary due to the high rate of antibiotic resistance. It is important to distinguish late- from early-phase papulopustular rash and to treat using different approaches.",
"affiliations": "Department of Dermatology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Infectious Disease and Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Head and Neck Surgery, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.",
"authors": "Tohyama|Mikiko|M|https://orcid.org/0000-0003-4756-0155;Hamada|Makoto|M|;Harada|Daijiro|D|;Kozuki|Toshiyuki|T|;Nogami|Naoyuki|N|;Monden|Nobuya|N|;Kajiwara|Takeshi|T|;Nishina|Tomohiro|T|",
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"title": "Clinical features and treatment of epidermal growth factor inhibitor-related late-phase papulopustular rash.",
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"abstract": "The proliferation signal inhibitors (PSIs)-sirolimus, everolimus, and temsirolimus-have been associated with a noninfectious pneumonitis characterized by lymphocytic alveolitis and bronciolitis obliterans with organizing pneumonia (BOOP). This condition usually occurs within the first year. Herein we presented a case of a deceased donor renal transplant with interstitial pneumonitis developing 6 years after a switch from tacrolimus to sirolimus due to chronic graft dysfunction. After the addition of intravenous pentamidine due to the suspicion of Pneumocystis pneumonia, there was marked clinical deterioration requiring intubation. Open lung biopsy revealed sirolimus-induced pulmonary toxicity (BOOP) with the additional finding of a drug-induced phospholipidosis (DIPL) that we ascribe to pentamidine treatment. After cessation of both drugs and application of corticosteroid therapy, there was only partial improvement. Eight months later the residual interstitial fibrosis demands supplemental home oxygen. We review the literature on PSI-induced pneumonitis and discuss the pathophysiology of a potential interaction with pentamidine. We caution against its use in the setting of PSI-induced pneumonitis. It is currently unknown whether these concerns also apply to prescription of other more commonly used medications associated with DIPL, eg, amiodarone and aminoglycosides.",
"affiliations": "Department of Medicine, Thomas Jefferson University, Philadelphia, PA, 19145, USA. kidneys@comcast.net",
"authors": "Filippone|E J|EJ|;Carson|J M|JM|;Beckford|R A|RA|;Jaffe|B C|BC|;Newman|E|E|;Awsare|B K|BK|;Doria|C|C|;Farber|J L|JL|",
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"title": "Sirolimus-induced pneumonitis complicated by pentamidine-induced phospholipidosis in a renal transplant recipient: a case report.",
"title_normalized": "sirolimus induced pneumonitis complicated by pentamidine induced phospholipidosis in a renal transplant recipient a case report"
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"abstract": "We report a case of a 36-year-old man with a medical history of human immunodeficiency virus (HIV) infection who presented with hypomimia, hypophonia, bradykinesia, rigidity, and freezing of gait. His clinical presentation and magnetic resonance imaging were consistent with HIV encephalopathy with involvement of the bilateral basal ganglia and diffuse leukoencephalopathy. We initiated a trial of carbidopa-levodopa. The dose was escalated to 1050 mg levodopa daily. Amantadine was also started. The patient was closely monitored for behavioral, neurological, or systemic side effects. He tolerated therapy well without adverse effects. The patient's neurological status significantly improved with levodopa, including hypomimia, hypophonia, bradykinesia, and fluidity of gait. This case demonstrates that carbidopa-levodopa can be safely utilized to manage parkinsonism in an adult patient with HIV encephalopathy.",
"affiliations": "Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Devine|M F|MF|;Herrin|C|C|;Warnack|W|W|;Dubey|D|D|",
"chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D000547:Amantadine; D002230:Carbidopa",
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"fulltext": "\n==== Front\nJ Postgrad MedJ Postgrad MedJPGMJournal of Postgraduate Medicine0022-38590972-2823Medknow Publications & Media Pvt Ltd India 28862245JPGM-64-5310.4103/jpgm.JPGM_674_16Case ReportNovel use of levodopa in human immunodeficiency virus encephalopathy-mediated parkinsonism in an adult Devine MF 1Herrin C 1Warnack W 1Dubey D 121 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA2 Department of Neurology, Mayo Clinic, Rochester, Minnesota, USAAddress for correspondence: Dr. Devine MF, E-mail: Michelle.Devine@phhs.orgJan-Mar 2018 64 1 53 55 12 11 2016 07 1 2017 27 2 2017 Copyright: © 2018 Journal of Postgraduate Medicine2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.We report a case of a 36-year-old man with a medical history of human immunodeficiency virus (HIV) infection who presented with hypomimia, hypophonia, bradykinesia, rigidity, and freezing of gait. His clinical presentation and magnetic resonance imaging were consistent with HIV encephalopathy with involvement of the bilateral basal ganglia and diffuse leukoencephalopathy. We initiated a trial of carbidopa-levodopa. The dose was escalated to 1050 mg levodopa daily. Amantadine was also started. The patient was closely monitored for behavioral, neurological, or systemic side effects. He tolerated therapy well without adverse effects. The patient's neurological status significantly improved with levodopa, including hypomimia, hypophonia, bradykinesia, and fluidity of gait. This case demonstrates that carbidopa-levodopa can be safely utilized to manage parkinsonism in an adult patient with HIV encephalopathy.\n\nKEY WORDS\nAIDS dementia complexgait apraxiahuman immunodeficiency viruslevodopaparkinsonian disorder\n==== Body\nIntroduction\nMovement disorders, including parkinsonism, are known complications of human immunodeficiency virus (HIV) infection. There is viral infiltration of the basal ganglia[1] leading to calcification, a common radiographic abnormality identified in pediatric patients.[2] Children with HIV-1 have altered dopamine activity in the central nervous system, including reduced levels of enzymes critical to dopamine synthesis in the substantia nigra.[1]\n\nEarly initiation of highly active anti-retroviral therapy (HAART) can help delay or prevent the onset of neurological manifestations in HIV-infected patients.[3] There is, however, no proven management of parkinsonian features in adult patients with HIV encephalopathy.\n\nOliver Sacks demonstrated transient benefits of levodopa in reducing parkinsonian symptoms afflicting patients with encephalitis lethargica.[4] In addition, a small case series of five children with HIV-related extrapyramidal symptoms managed with levodopa showed sustained neurological improvement.[5]\n\nWe report an adult case of HIV encephalopathy and extrapyramidal dysfunction successfully treated with carbidopa-levodopa therapy without significant adverse effects.\n\nCase Report\nA 36-year-old male with a medical history of HIV presented to our institution with behavioral changes characterized by decreased responsiveness. He had been diagnosed with HIV after routine screening 14 years prior. His HAART regimen consisted of abacavir-lamivudine, atazanavir, and ritonavir. At baseline, he was able to ambulate and converse without difficulty. Four months before presentation, the patient was noted to have stiffening of his neck and back. During this time, the patient also developed decreased verbal output. When the patient's family first noticed these symptoms, the patient was transferred from his previous residence in a group home into his parents’ house. While residing with his parents, the patient stopped taking his HAART. His mother reported that his symptoms initially improved, but he later developed further worsening of his speech and gait. His mother restarted his HAART, however, the patient continued to worsen to the point of multiple falls and virtually no verbal output. This prompted his family to bring the patient to the emergency room. When admitted to an internal medicine service, he was found to have minimal verbal output, minimal responsiveness to verbal stimuli, and decreased movements. The patient was continued on his HAART. Empiric acyclovir was started to cover possible viral encephalitis. Psychiatry was consulted for possible catatonia. He was given lorazepam without improvement. After failure of this benzodiazepine challenge, neurology was consulted.\n\nOn our neurology team's initial assessment, the patient was awake and alert but was minimally verbally or physically responsive. He would mouth words, without audible response. He had rigidity in all extremities, more severe in his lower extremities. There was no significant tremor. He also had diffuse hyperreflexia and sustained bilateral ankle clonus. He required assistance to stand, had difficulty initiating movements, had stooped posture, and had a magnetic gait.\n\nMagnetic resonance imaging (MRI) brain showed extensive leukoencephalopathy with periventricular involvement and subcortical extension in the bilateral frontal and parietal lobes [Figure 1]. Given the symmetry of leukoencephalopathy, degree of global cerebral atrophy, and lack of gadolinium enhancement, this likely represented sequela of HIV encephalopathy. The patient also had subtle mineralization of bilateral basal ganglia. MRI spine was unremarkable. His absolute CD4 count was 208 cells/mcL, and HIV viral load was 36378 copies/mL. Serum analysis revealed a borderline thiamine level at 64 nmol/L. Otherwise serum analysis was unremarkable, including normal ammonia, Vitamin-B12, and folate level. Serum toxoplasma antibodies and rapid plasma reagin were negative. Blood bacterial cultures and mycobacterial cultures were negative.\n\nFigure 1 (a) MRI Brain T2 fluid attenuated inversion recovery (FLAIR) with diffuse white mater disease. (b) MRI Brain T2 fluid attenuated inversion recovery (FLAIR) with white matter disease and hypointensity in bilateral basal ganglia (arrows). (c) MRI Brain susceptibility weighted imaging (SWI) sequence with calcification of basal ganglia. Physiologic calcification would be less likely given patient's young age of 36 years old\n\nCerebral spinal fluid (CSF) analysis revealed 94 mg/dL protein, 58 mg/dL glucose, 2 white blood cells/mcL, and <1 red blood cell/mcL. Serum and CSF cryptococcal antigen were negative. CSF herpes simplex virus, varicella virus, and John Cunningham virus polymerase chain reactions were negative. CSF West Nile virus IgM and IgG were negative. CSF cultures were negative, including bacterial, mycobacterial, and fungal.\n\nGiven the patient's clinical presentation and radiographic findings, the patient was started on carbidopa-levodopa. This was initiated at 12.5–50 mg TID with gradual titration up to 87.5–350 mg TID (total levodopa 1050 mg daily). With titration of levodopa to 1050 mg daily, the patient had improved extrapyramidal signs and symptoms. He had increased facial expression and improved fluidity and spontaneity of speech. His bradykinesia and gait apraxia also improved significantly. He was also started on amantadine 100 mg twice per day as recommended by the physical medicine and rehabilitation physicians to optimize participation with rehabilitation. Before initiation of amantadine, the patient had already reached the optimal carbidopa-levodopa dose (total levodopa 1050 mg daily) and had shown significant symptomatic benefit. The patient was discharged on HAART, amantadine, trimethoprim-sulfamethoxazole prophylaxis, thiamine, and carbidopa-levodopa 87.5–350 mg TID.\n\nThe patient was evaluated in clinic 3 months after discharge. He was compliant with the carbidopa-levodopa regimen. He retained the level of functionality he had regained at discharge. Furthermore, he did not display any adverse effects, specifically no dyskinesias or any adverse psychological reactions.\n\nDiscussion\nWe report a case of successful carbidopa-levodopa trial in an adult patient with HIV-related leukoencephalopathy and parkinsonism. Due to our patient's significant extrapyramidal dysfunction, we initiated a trial of levodopa. We concurrently continued his HAART to limit further disease progression and viral accumulation. After titration of levodopa therapy to 1050 mg daily, the patient began to display improvement of his parkinsonian symptoms. After 3 months of continued levodopa therapy, sustained improvement was observed. The patient also did not demonstrate any dyskinetic or psychiatric side effects. Our patient had not previously received dopamine antagonists that may incite similar symptoms. There was also no evidence of opportunistic infection. His symptoms were, therefore, likely from neuronal loss related to viral infiltration of the basal ganglia.[3]\n\nHIV virus has been shown to have a direct causal or toxic relationship in the pathophysiology of parkinsonism associated with HIV encephalopathy. Gp120 viral envelope protein has been associated with excitotoxicity and dopaminergic dysfunction.[6] Another viral protein Tat reduces the expression of tyrosine hydroxylase as well as synthesis and release of dopamine.[1] Histopathology studies have demonstrated multinucleate giant cells and microglial infiltration in caudate and putamen.[78] However, typical pathological changes of Parkinson's disease, such as development of Lewy bodies have not been reported.\n\nAs with Parkinson's disease, treating extrapyramidal dysfunction in HIV-infected patients has been associated with severe side effects, both psychiatric (psychosis, mania, worsening confusion, etc.) and dyskinetic.[78910] In particular, Caparros-Lefebvre et al. demonstrated that the combination of carbidopa-levodopa and protease inhibitors (indinavir) were associated with peak-dose ballistic dyskinesias. This association is thought to be related to the inhibitory effects of protease inhibitors on the cytochrome p450 system.[9] Another concern is activation of HIV by levodopa, leading to increased viral load as shown in simian immunodeficiency virus-infected macaque model.[11] Knowing the potential side effects, one must weigh the risks and benefits before initiating levodopa trials in HIV patients with parkinsonism.\n\nThe case we describe above supports the utility and safety of a levodopa trial in patients with HIV-induced extrapyramidal dysfunction. This should be further evaluated in larger studies.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Fitting S Booze RM Mactutus CF HIV-1 proteins, Tat and gp120, target the developing dopamine system Curr HIV Res 2015 13 21 42 25613135 \n2 Kauffman WM Sivit CJ Fitz CR Rakusan TA Herzog K Chandra RS CT and MR evaluation of intracranial involvement in pediatric HIV infection: A clinical-imaging correlation AJNR Am J Neuroradiol 1992 13 949 57 1590197 \n3 Webb KM Mactutus CF Booze RM The ART of HIV therapies: Dopaminergic deficits and future treatments for HIV pediatric encephalopathy Expert Rev Anti Infect Ther 2009 7 193 203 19254168 \n4 Sacks OW Awakenings 1973 UK Duckworth & Co 408 \n5 Mintz M Tardieu M Hoyt L McSherry G Mendelson J Oleske J Levodopa therapy improves motor function in HIV-infected children with extrapyramidal syndromes Neurology 1996 47 1583 5 8960752 \n6 Kieburtz KD Epstein LG Gelbard HA Greenamyre JT Excitotoxicity and dopaminergic dysfunction in the acquired immunodeficiency syndrome dementia complex. Therapeutic implications Arch Neurol 1991 48 1281 4 1845034 \n7 Koutsilieri E Sopper S Scheller C ter Meulen V Riederer P Parkinsonism in HIV dementia J Neural Transm (Vienna) 2002 109 767 75 12111466 \n8 Tse W Cersosimo MG Gracies JM Morgello S Olanow CW Koller W Movement disorders and AIDS: A review Parkinsonism Relat Disord 2004 10 323 34 15261874 \n9 Caparros-Lefebvre D Blond S Feltin MP Pollak P Benabid AL Improvement of levodopa induced dyskinesias by thalamic deep brain stimulation is related to slight variation in electrode placement: Possible involvement of the centre median and parafascicularis complex J Neurol Neurosurg Psychiatry 1999 67 308 14 10449551 \n10 Kobylecki C Silverdale MA Varma A Dick JP Kellett MW HIV-associated Parkinsonism with levodopa-induced dyskinesia and response to highly-active antiretroviral therapy Mov Disord 2009 24 2441 2 19908326 \n11 Czub S Koutsilieri E Sopper S Czub M Stahl-Hennig C Müller JG Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs Acta Neuropathol 2001 101 85 91 11271377\n\n",
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"title": "Novel use of levodopa in human immunodeficiency virus encephalopathy-mediated parkinsonism in an adult.",
"title_normalized": "novel use of levodopa in human immunodeficiency virus encephalopathy mediated parkinsonism in an adult"
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"abstract": "BACKGROUND\nSAPHO (synovitis, acne, pustolosis, hyperostosis and osteitis) syndrome is a rare autoinflammatory chronic disorder, presenting with non-infectious osteitis, sterile joint inflammation and skin manifestations including palmoplantar pustolosis and severe acne. It could be often misdiagnosed for its heterogeneous clinical presentation. Treatment is challenging and, due to the rarity of this syndrome, no randomized controlled clinical trials have been conducted. Empirical treatments, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibiotics and bisphosphonates and disease-modifying anti-rheumatic drugs (DMARDs) could be quite effective. Anti-tumor necrosis factor-alpha (anti-TNF-α) agents and interleukin-1 (IL-1) antagonists have shown promising results in refractory patients. Isotretinoin, commonly used for severe acne, has been rarely described as possible trigger of osteo-articular manifestations, in particular sacroiliitis.\n\n\nMETHODS\nThe case of a boy, affected by acne fulminans and depression, who presented with sacroiliitis after a 10-week treatment with isotretinoin is presented. After SAPHO diagnosis, NSAIDs therapy was started but the onset of bilateral gluteal hidradenitis suppurativa required the switch to a TNF-α antagonist (Adalimumab) with the achievement of a good control of the disease. Despite specific therapy with sertraline, the patient continued to complains severe depression.\n\n\nCONCLUSIONS\nOur case reports a temporal association between the onset of osteo-articular symptoms and the introduction of isotretinoin, as previously described. However, this timeline is not sufficient to establish a causal role of this drug into the pathogenesis of sacroiliitis. At this regard, further studies are required. The occurrence of hidradenitis suppurativa during SAPHO course supported the introduction of TNF-α blockers with a favourable result, as reported in a few cases in literature. The association between SAPHO syndrome and depressive mood disorders is already reported. Our patient experienced severe depression whose trend seems to be independent from the course of the main disease. Currently, it is not clarified if depression could be considered reactive to the underling disease or if it forms an integral part of the autoinflammatory disorder.",
"affiliations": "Post-Graduate School of Pediatrics, University of Florence, Florence, Italy. michele.luzzati@unifi.it.;Department of NEUROFARBA, University of Florence, Florence, Italy.;Dermatology Department, Meyer Children's University Hospital, Florence, Italy.;Rheumatology Department, Meyer Children's University Hospital, Florence, Italy.;Department of Health Science, University of Florence, Florence, Italy.",
"authors": "Luzzati|Michele|M|http://orcid.org/0000-0002-1999-4389;Simonini|Gabriele|G|;Filippeschi|Cesare|C|;Giani|Teresa|T|;Trapani|Sandra|S|",
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"doi": "10.1186/s13052-020-00933-1",
"fulltext": "\n==== Front\nItal J Pediatr\nItal J Pediatr\nItalian Journal of Pediatrics\n1824-7288 BioMed Central London \n\n933\n10.1186/s13052-020-00933-1\nCase Report\nSAPHO syndrome: the supposed trigger by isotretinoin, the efficacy of adalimumab and the specter of depressive disorder: a case report\nhttp://orcid.org/0000-0002-1999-4389Luzzati Michele michele.luzzati@unifi.it 1 Simonini Gabriele gabriele.simonini@unifi.it 23 Filippeschi Cesare cesare.filippeschi@meyer.it 4 Giani Teresa teresa.giani@meyer.it 3 Trapani Sandra sandra.trapani@unifi.it 5 1 grid.8404.80000 0004 1757 2304Post-Graduate School of Pediatrics, University of Florence, Florence, Italy \n2 grid.8404.80000 0004 1757 2304Department of NEUROFARBA, University of Florence, Florence, Italy \n3 grid.411477.00000 0004 1759 0844Rheumatology Department, Meyer Children’s University Hospital, Florence, Italy \n4 grid.411477.00000 0004 1759 0844Dermatology Department, Meyer Children’s University Hospital, Florence, Italy \n5 grid.8404.80000 0004 1757 2304Department of Health Science, University of Florence, Florence, Italy \n13 11 2020 \n13 11 2020 \n2020 \n46 16926 3 2020 26 10 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\nSAPHO (synovitis, acne, pustolosis, hyperostosis and osteitis) syndrome is a rare autoinflammatory chronic disorder, presenting with non-infectious osteitis, sterile joint inflammation and skin manifestations including palmoplantar pustolosis and severe acne.\n\nIt could be often misdiagnosed for its heterogeneous clinical presentation. Treatment is challenging and, due to the rarity of this syndrome, no randomized controlled clinical trials have been conducted. Empirical treatments, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibiotics and bisphosphonates and disease-modifying anti-rheumatic drugs (DMARDs) could be quite effective. Anti-tumor necrosis factor-alpha (anti-TNF-α) agents and interleukin-1 (IL-1) antagonists have shown promising results in refractory patients. Isotretinoin, commonly used for severe acne, has been rarely described as possible trigger of osteo-articular manifestations, in particular sacroiliitis.\n\nCase presentation\nThe case of a boy, affected by acne fulminans and depression, who presented with sacroiliitis after a 10-week treatment with isotretinoin is presented. After SAPHO diagnosis, NSAIDs therapy was started but the onset of bilateral gluteal hidradenitis suppurativa required the switch to a TNF-α antagonist (Adalimumab) with the achievement of a good control of the disease. Despite specific therapy with sertraline, the patient continued to complains severe depression.\n\nConclusions\nOur case reports a temporal association between the onset of osteo-articular symptoms and the introduction of isotretinoin, as previously described. However, this timeline is not sufficient to establish a causal role of this drug into the pathogenesis of sacroiliitis. At this regard, further studies are required. The occurrence of hidradenitis suppurativa during SAPHO course supported the introduction of TNF-α blockers with a favourable result, as reported in a few cases in literature. The association between SAPHO syndrome and depressive mood disorders is already reported. Our patient experienced severe depression whose trend seems to be independent from the course of the main disease. Currently, it is not clarified if depression could be considered reactive to the underling disease or if it forms an integral part of the autoinflammatory disorder.\n\nKeywords\nIsotretinoinDepressionAdalimumabOsteitisHidradenitis suppurativaAcne fulminanshttp://dx.doi.org/10.13039/501100004434Università degli Studi di Firenzeissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nSynovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome is an uncommon disease, characterized by chronic inflammatory osteoarticular and dermatological lesions. Its prevalence (< 1 in 10.000) is recognised as being underestimated [1]. The SAPHO syndrome is often misdiagnosed for its heterogeneous clinical presentation. Anterior chest wall and axial skeleton joints are the most commonly involved osteoarticular sites. Cutaneous manifestations include various acneiform and neutrophilic dermatoses: palmoplantar pustolosis is the most commonly reported lesion; moderate to severe acne, including acne conglobate and acne fulminans, and hidradenitis suppurativa (HS) occur approximately in 25% of patients [2]. Finally, patients may have the potential to develop depressive symptoms [3].\n\nThe pathogenesis of SAPHO syndrome is not defined, but likely includes a combination of genetic, infectious and immunological components leading to the activation of innate and cell-mediate immune system [4]. Therefore, it is classified as an autoinflammatory disorder [5].\n\nIsotretinoin, representing the first-choice treatment for severe acne in adolescents, has been reported as potential trigger of osteoarticular symptoms, although its pathogenesis remains unclear. Conversely, osteoarticular involvement triggered by isotretinoin has been very rarely described in SAPHO [6]. Since SAPHO syndrome is rare and no therapeutic trials are available, the therapy is aimed to modify the inflammatory process and control symptoms. Conventional first-line treatments include various drugs such as NSAIDs, corticosteroids, DMARDs and bisphosphonates. Moreover, the use of anti-TNF agents has been proved to be a valid therapeutic regimen for unresponsive cases [7]. The use of adalimumab (ADA), a tumour necrosis factor (TNF)-α antagonist, has been proved to be a valid therapeutic regimen for cases of refractory SAPHO or complicated with HS [8]. Recently, non-anti-TNF- α agents have revealed as effective alternative treatments. Tocilizumab has been proposed for its known activity on osteoclasts and Ustekinumab for its efficacy against palmoplantar psoriasis [9].\n\nWe report a case of severe SAPHO syndrome complicated by HS, successfully treated with ADA. Despite the good control of disease, a depressive mood disorder persisted.\n\nCase presentation\nA Caucasian 15-year old male complained of severe acne and low back pain with inability to walk. His previous medical history was unremarkable except for the onset of acne vulgaris during his puberty. Three months before admission, he had showed a dramatic worsening of acne characterized by several cystic skin lesions with extensive ulcerating and inflammatory components, assuming a form of acne fulminans. Therefore, a course of systemic isotretinoin therapy was administered at the dose of 0.5 mg/kg/daily without any benefit. In addition, the boy developed depressive symptoms associated with insomnia and irritability. Thus, sertraline therapy was started.\n\nTen weeks after starting isotretinoin, the patient experienced increasing low-back pain with progressive inability to walk and restriction of daily activities. At admission to the emergency department, he was suffering and unable to walk. Physical examination revealed a decreased axial range of movement, sacroiliac pain and severe nodulocystic acne with abscesses on face, neck and thorax. Laboratory investigations revealed systemic inflammation (CPR 7.15 mg/dl [normal range < 0.5 mg/dl], ESR 84 mm/h [normal range < 30 mm/h], WBC 14,950/mmc, 70% neutrophils). All rheumatologic parameters including complement and autoantibodies were within normal range. The patient tested negative for HLA-B27 typing. Culture of the pustular lesions was positive for Staphylococcus aureus. Antibiotic therapy with clindamycin was introduced and isotretinoin was interrupted. Pelvis and hip X-ray was unremarkable. Magnetic resonance imaging (MRI) showed moderate bone marrow oedema and osteitis of transverse process of fifth lumbar vertebra (Fig. 1a) and symmetrical sacroiliitis (Fig. 1b). The association of acne fulminans and osteitis suggested the diagnosis of SAPHO syndrome. Whole body MRI confirmed this hypothesis revealing anterior chest wall, in particular coronal views showed sternoclavicular and costoclavicular osteitis, and axial involvement, including sacroiliac joint and spine. Consequently, intravenous antibiotics were interrupted and, NSAIDs and oral rifampicin were started, in order to control the inflammatory status and the cutaneous lesions, respectively. Despite the specific treatment, the depressive disorder was persisting along with the other complaints. Nevertheless, during the following weeks osteoarticular involvement and cutaneous manifestations worsened and gluteal bilateral HS appeared. Therefore, ADA was subcutaneously administered at the dosage of 40 mg/dose every 2 weeks. After 4 weeks of treatment a progressive improvement both of cutaneous lesions and osteoarticular symptoms was reported and ADA administration interval (at the same dose of 40 mg) was extended to 4 weeks. After six months of favourable ADA treatment, the boy experimented a relapse of osteoarticular symptoms. Therefore, ADA was administered again every 2 weeks obtaining a long-lasting remission. An MRI performed 12 months later, has shown no evidence of abnormal vertebral bone marrow signal (Fig. 1a), sterno-clavear or sacroiliac effusions (Fig. 1b). After 24-months treatment with ADA, the disease maintains complete remission. In Fig. 2 we show cutaneous lesions on the face, on the back and on the sternal region before and after ADA treatment. On the contrary, the depressive mood disorder persists and negatively affects the quality of patient’s life.\nFig. 1 MRI STIR images of lumbar osteitis and sacroiliac involvement before (upside) and after ADA treatment (downside)\n\nFig. 2 Cutaneous lesions on the face, back and sternal region before (upside) and after (downside) ADA treatment\n\n\n\nDiscussion and conclusions\nSAPHO syndrome is an uncommon auto inflammatory disease. Its pathogenesis could be the consequence of the complex interactions between polygenic and exogenous factors triggering the disease burden [2].\n\nIn our case acne fulminans had preceded the onset of sacroiliitis. As previously reported skin manifestations may precede the onset of osteoarticular symptoms in 30 to 50% of patients [5, 10].\n\nHowever, a few cases documented that isotretinoin was as a possible causing factor for articular symptoms. Two different case reports described the development of symmetrical sacroiliitis in two boys one and three months after the introduction of isotretinoin. Their symptoms improved with the concurrent isotretinoin interrumption and NSAIDs starting [11, 12]. Furthermore, Coskun et al. in a review of 21 cases concluded that sacriliitis could be a rare complication of isotretinoin treatment [13].\n\nPrevious studies supported the hypothesis that isotretinoin has detergent-like properties and could alter cell membrane structures, promoting the degenerative process of joints [14]. Moreover, retinol and acid retinoic has been shown to induce metalloproteinases activity, which increase degradation of membranes [6, 14, 15].\n\nHowever, isotretinoin remains a valuable and effective treatment of severe acne, its use is supported in combination with corticosteroids also to treat acne fulminans [16].\n\nOur patient experienced osteoarticular symptoms 10 weeks after being on isotretinoin. Indeed, only a temporal association between the onset of osteo-articular symptoms and the introduction of this drug has been demonstrated. Moreover, SAPHO syndrome may present a remitting and relapsing course, and skin manifestations could precede osteoarticular symptoms in almost an half of cases. Hence, these timeline is not sufficient to establish a causal role of this drug into the pathogenesis of sacroiliitis.\n\nConsidering that the available data about the role of isotretinoin regard a small sample of patients, further studies are required. Awaiting for new evidences, we suggest a wise approach in case of adolescents suffering from acne and osteoarticular symptoms, particularly with axial skeleton involvement, in order to examine a trigger role of previous isotretinoin administration.\n\nIn our case due to the onset of HS we decide to introduce ADA treatment. HS is a chronic, suppurative skin manifestantion associated to SAPHO syndrome. It is characterized by the involvement of the apocrine glands, in particular of the axillae and groin.\n\nTo our knowledge there are only few cases reporting a favourable effect of ADA in the treatment of HS associated to SAPHO syndrome [17–19]. ADA is considered the first-choice biologic agent in moderate/severe HS after failure of conventional treatments and in refractory SAPHO syndrome [8, 17]. Our patient experimented a rapid clinical and radiological improvement with ADA administration every 2 weeks at 12 and 24 month follow-up period.\n\nUnfortunately, the boy who had complained depression since the worsening of acne, still maintained a severe psychiatric disorder in the following years, despite the sertraline therapy and the dermatological and rheumatological stable remission.\n\nThe association between many immuno-mediated inflammatory diseases and depressive mood disorders is already reported [20]. There is no related literature concerning psychiatric symptoms in SAPHO patients, out of a recent study by Lu et al., revealing a high prevalence (46%) of depression in SAPHO patients. Twenty-eight SAPHO patients underwent to psychiatric evaluation and MRI scans. The study confirmed the great prevalence of depressive mood disorders and revealed an abnormal brain activity at functional MRI sequences suggesting that SAPHO patients may potentially develop depression.\n\nConsidering the psychological impact that skin manifestations could have especially during adolescence it is not clarified if depression could be considered reactive to the underling disease or if it forms an integral part of the autoinflammatory disorder.\n\nIn conclusion, the temporal association between isotretinoin and sacroiliitis has been already described but a real pathogenetic mechanism is not proved. In severe cases of SAPHO syndrome Adalimumab therapy demonstrated persistent clinical remission, even in cases complicated by HS. SAPHO patients may develop depressive symptoms, but further studies should investigate its pathogenesis.\n\nAbbreviations\nNSAIDsNonsteroidal anti-inflammatory drugs\n\nHSHidradenitis suppurativa\n\nADAAdalimumab\n\nDMARDsDisease modifying antirheumatic drugs\n\nCRPC-Reactive protein\n\nESRErythrocyte sedimentation rate\n\nWBCWhite blood cells\n\nMRIMagnetic resonance imaging\n\nTNFTumour necrosis factor\n\nILInterleukin\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 read and approved the final manuscript. ML collected all clinical data and reviewed the medical chart of the patient. CF and TG contributed to analyze the case. ST supervised the project and help in writing the manuscript.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nThis study has been approved by the institutional reviewed board of the Meyer Children Hospital.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the parent of the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Carneiro S Sampaio-Barros PD SAPHO syndrome Rheum Dis Clin North Am 2013 39 2 401 418 10.1016/j.rdc.2013.02.009 23597971 \n2. Cianci F Zoli A Gremese E Ferraccioli G Clinical heterogeneity of SAPHO syndrome: challenging diagnose and treatment Clin Rheumatol 2017 36 9 2151 2158 10.1007/s10067-017-3751-1 28725947 \n3. Lu J Duan Y Zuo Z Depression in patients with SAPHO syndrome and its relationship with brain activity and connectivity Orphanet J Rare Dis 2017 12 1 103 10.1186/s13023-017-0658-5 28545486 \n4. Li C Cao Y Zhang W Clinical heterogeneity of SAPHO syndrome: Challenge of diagnosis Mod Rheumatol 2018 28 3 432 434 10.1080/14397595.2017.1416733 29251057 \n5. Zimmermann P Curtis N Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome - A challenging diagnosis not to be missed J Infect 2016 72 Suppl S106 114 10.1016/j.jinf.2016.04.030 27263075 \n6. Alkan S Kayiran N Zengin O Isotretinoin-induced Spondyloarthropathy-related Symptoms: A Prospective Study J Rheumatol 2015 42 11 2106 2109 10.3899/jrheum.150013 26472411 \n7. Freira S Fonseca H Ferreira PD Vasconcelos P Fonseca JE SAPHO syndrome in an adolescent: a clinical case with unusual severe systemic impact J Adolesc Health Off Publ Soc Adolesc Med 2014 55 2 304 306 10.1016/j.jadohealth.2014.02.004 \n8. Garcovich S Amelia R Magarelli N Valenza V Amerio P Long-term treatment of severe SAPHO syndrome with adalimumab: case report and a review of the literature Am J Clin Dermatol 2012 13 1 55 59 10.2165/11593250-000000000-00000 22007948 \n9. Figueiredo ASB Oliveira AL Caetano A Moraes-Fontes MF SAPHO: has the time come for tailored therapy? Clin Rheumatol 2020 39 1 177 187 10.1007/s10067-019-04675-2 31312988 \n10. Li C Zuo Y Wu N Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients Rheumatology 2016 55 6 1023 1030 10.1093/rheumatology/kew015 26917545 \n11. Geller ASB Alagia RFN Sacroiliitis after use of oral isotretinoin–association with acne fulminans or adverse effect? An Bras Dermatol 2013 88 6 Suppl 1 193 196 10.1590/abd1806-4841.20132500 24346917 \n12. Levinson M Gibson A Stephenson G Sacroiliitis secondary to isotretinoin: Sacroiliitis secondary to isotretinoin Australas J Dermatol 2012 53 4 298 300 10.1111/j.1440-0960.2011.00841.x 23157782 \n13. Coskun BN Yagiz B Pehlivan Y Dalkilic E Isotretinoin-induced sacroiliitis in patients with hidradenitis suppurativa: a case-based review Rheumatol Int 2019 39 12 2159 2165 10.1007/s00296-019-04434-1 31455984 \n14. Burrage PS Matrix Metalloproteinases: Role In Arthritis Front Biosci 2006 11 1 529 10.2741/1817 16146751 \n15. Dalmolin RJS Zanotto-filho A De oliveira RB Duarte RF Pasquali MAB Moreira JCF Retinol and retinoic acid increase MMP-2 activity by different pathways in cultured Sertoli cells Free Radic Res 2007 41 12 1338 47 10.1080/10715760701717427 18075836 \n16. Greywal T Zaenglein AL Baldwin HE Evidence-based recommendations for the management of acne fulminans and its variants J Am Acad Dermatol 2017 77 1 109 117 10.1016/j.jaad.2016.11.028 28619551 \n17. Vekic DA Woods J Lin P Cains GD SAPHO syndrome associated with hidradenitis suppurativa and pyoderma gangrenosum successfully treated with adalimumab and methotrexate: a case report and review of the literature Int J Dermatol 2018 57 1 10 18 10.1111/ijd.13740 28884797 \n18. Genovese G Caorsi R Moltrasio C Marzano AV Successful treatment of co- existent SAPHO syndrome and hidradenitis suppurativa with adalimumab and methotrexate J Eur Acad Dermatol Venereol 2019 33 S6 40 41 10.1111/jdv.15849 31535768 \n19. Crowley EL, O’Toole A, Gooderham MJ. Hidradenitis suppurativa with SAPHO syndrome maintained effectively with adalimumab, methotrexate, and intralesional corticosteroid injections. SAGE Open Med Case Rep 2018;6:2050313X1877872.\n20. Varan Ö Babaoğlu H Göker B Associations between Depressive Disorders and Inflammatory Rheumatic Diseases Curr Top Med Chem 2018 18 16 1395 1401 10.2174/1568026618666180516100805 29766809\n\n",
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"keywords": "Acne fulminans; Adalimumab; Depression; Hidradenitis suppurativa; Isotretinoin; Osteitis",
"medline_ta": "Ital J Pediatr",
"mesh_terms": "D000152:Acne Vulgaris; D020083:Acquired Hyperostosis Syndrome; D000068879:Adalimumab; D000293:Adolescent; D000893:Anti-Inflammatory Agents; D003866:Depressive Disorder; D003879:Dermatologic Agents; D006801:Humans; D015474:Isotretinoin; D008297:Male",
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"title": "SAPHO syndrome: the supposed trigger by isotretinoin, the efficacy of adalimumab and the specter of depressive disorder: a case report.",
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"abstract": "Here, we present a somewhat unusual suicide attempt where, despite an unbelievable overdose with transdermal fentanyl patches, the patient survived. The patient-a woman aged 70 years, who has suffered from chronic back pain despite starting transdermal fentanyl patches in 2007. The unconventional method of attempted suicide was based on online research into deaths from fentanyl patch toxicity. She had gradually accumulated 100 µg fentanyl patches from repeat prescriptions, applying 14 patches with fatal intent, alongside 2 45 mg mirtazapine tablets, and concurrent therapeutic doses of tramadol and morphine sulfate oral solution. However, after 24 hours, she awoke from a deep sleep to the sound of the telephone ringing, somewhat amazed her drastic efforts had failed. During admission to Great Western hospital, she was seen by liaison psychiatry and subsequently transferred to the care of the pain management team, to which she had already been referred.",
"affiliations": "Faculty of Health Sciences, University of Bristol, Bristol, UK.;Faculty of Health Sciences, University of Bristol, Bristol, UK.;Great Western Hospitals NHS Foundation Trust, Swindon, UK.",
"authors": "Trist|Adam Joseph|AJ|;Sahota|Hardeep|H|;Williams|Lucy|L|",
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"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D001416:Back Pain; D059350:Chronic Pain; D062787:Drug Overdose; D005260:Female; D005283:Fentanyl; D006801:Humans; D013406:Suicide, Attempted; D057968:Transdermal Patch",
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"title": "Not so patchy story of attempted suicide…leading to 24 hours of deep sleep and survival!",
"title_normalized": "not so patchy story of attempted suicide leading to 24 hours of deep sleep and survival"
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"abstract": "BACKGROUND\nEffects of mechanical cardiac support on renal function in children with end-stage heart failure are unknown. The objective of this study was to investigate the impact of ventricular assist device (VAD) and extracorporeal membrane oxygenation (ECMO) on renal function in children.\n\n\nMETHODS\nWe performed a single center retrospective observational study in children with end-stage heart failure supported on pediatric mechanical cardiac support. The patient population was divided into three groups: the VAD group included patients receiving ventricular assist device support; the ECMO group included patients receiving extracorporeal membrane oxygenation membrane support for more than 14 days; and the ECMO+VAD group included patients receiving ECMO followed by VAD support. Comparison of baseline characteristics, duration of mechanical cardiac support, and renal function was made between the three groups.\n\n\nRESULTS\nDuring the study period, there were 23 patients in the VAD group, 16 patients in the ECMO+VAD group, and 37 patients in the ECMO group. The patients in the ECMO group were significantly younger and smaller than the patients in the VAD and ECMO+VAD groups. There was a steady improvement in eGFR in the VAD group and the ECMO+VAD group until day 7 after which there was a decline in renal function. In the ECMO group, the improvement in eGFR continued until day 28 after which there was a steady decline in eGFR. Improvement in eGFR in the VAD group and the ECMO+VAD group was much higher than in the ECMO group in the first 7 days.\n\n\nCONCLUSIONS\nOn the basis of these data, we demonstrate that renal dysfunction improves early after mechanical cardiac support.",
"affiliations": "Division of Pediatric Cardiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Division of Pediatric Critical Care, University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Division of Pediatric Cardiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Division of Pediatric Critical Care, University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Section of Biostatistics, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Section of Medical Education, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Division of Pediatric Cardiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Department of Cardiothoracic Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Division of Pediatric Cardiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Division of Pediatric Critical Care, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Electronic address: pgupta2@uams.edu.",
"authors": "Prodhan|Parthak|P|;Bhutta|Adnan T|AT|;Gossett|Jeffrey M|JM|;Dodgen|Andrew L|AL|;Seib|Paul M|PM|;Imamura|Michiaki|M|;Gupta|Punkaj|P|",
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"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparative effects of ventricular assist device and extracorporeal membrane oxygenation on renal function in pediatric heart failure.",
"title_normalized": "comparative effects of ventricular assist device and extracorporeal membrane oxygenation on renal function in pediatric heart failure"
} | [
{
"companynumb": "US-MYLANLABS-2015M1007589",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "L-asparaginase is frequently used in combination therapy for the treatment of lymphoid malignancies. We report 5 children aged between 8 and 14 years with neurologic complications presenting with headache and seizures during the first three weeks of L-asparaginase treatment. Three patients had venous thrombosis, one presented a parenchymal hemorrhage, and one showed a peculiar encephalopathy with extended cortical and subcortical lesions suggesting a neurotoxic reaction. Decreased fibrinogen and antithrombin III levels were found. Early MRI is critical even in cases with mild neurologic symptoms. Diagnosis should be followed by early cessation of l-asparaginase application.",
"affiliations": "Department of Pediatric Neurology, Johann Wolfgang Goethe University, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany. matthias.kieslich@kgu.de",
"authors": "Kieslich|Matthias|M|;Porto|Luciana|L|;Lanfermann|Heinrich|H|;Jacobi|Gert|G|;Schwabe|Dirk|D|;Böhles|Hansjosef|H|",
"chemical_list": "D000970:Antineoplastic Agents; D000990:Antithrombin III; D005340:Fibrinogen; D001215:Asparaginase",
"country": "United States",
"delete": false,
"doi": "10.1097/00043426-200306000-00011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "25(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D000990:Antithrombin III; D001215:Asparaginase; D001921:Brain; D001927:Brain Diseases; D002543:Cerebral Hemorrhage; D002648:Child; D005260:Female; D005340:Fibrinogen; D006261:Headache; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012640:Seizures; D020246:Venous Thrombosis",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "484-7",
"pmc": null,
"pmid": "12794528",
"pubdate": "2003-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cerebrovascular complications of L-asparaginase in the therapy of acute lymphoblastic leukemia.",
"title_normalized": "cerebrovascular complications of l asparaginase in the therapy of acute lymphoblastic leukemia"
} | [
{
"companynumb": "DE-JAZZ-2016-DE-021964",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe effect of individual dose adjustment of 5-fluorouracil (5-FU) based on pharmacokinetic monitoring on the outcome of FOLFOX for metastatic colorectal cancer was analyzed retrospectively.\n\n\nMETHODS\nTwenty patients with metastatic colorectal cancer underwent FOLFOX chemotherapy from January 2005 to December 2013 at the Niitsu Medical Center Hospital. The sample group included 11 patients in whom 5-FU doses were adjusted individually based on pharmacokinetic monitoring according to an algorithm to maintain the area under the curve (AUC) in the range of 20-25 mg·h/L (Group A) and 9 patients in whom 5-FU doses were adjusted conventionally based on body surface area (Group B).\n\n\nRESULTS\nThe objective response rate was 63% and 33% in Group A and Group B, respectively (p=0.174). The median overall survival was 34 months and 14 months in Group A and Group B, respectively (p=0.036). There were 4 cases of Grade 3 toxicity (2 in Group A, 2 in Group B; p=0.636) and no cases of Grade 4 toxicity or treatment-related death.\n\n\nCONCLUSIONS\nPharmacokinetically guided dose adjustment of 5-FU may improve the outcome of FOLFOX for metastatic colorectal cancer.",
"affiliations": "Dept. of Surgery, Niitsu Medical Center Hospital.",
"authors": "Muneoka|Katsuki|K|;Shirai|Yoshio|Y|;Sasaki|Masataka|M|;Sakata|Jun|J|;Kanda|Junkichi|J|;Wakabayashi|Hiroyuki|H|;Wakai|Toshifumi|T|",
"chemical_list": "D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(3)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D012004:Rectal Neoplasms; D012008:Recurrence; D012189:Retrospective Studies",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "323-6",
"pmc": null,
"pmid": "27067847",
"pubdate": "2016-03",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Individual Dose Adjustment of 5-Fluorouracil Based on Pharmacokinetic Monitoring May Improve the Outcome of FOLFOX for Metastatic Colorectal Cancer.",
"title_normalized": "individual dose adjustment of 5 fluorouracil based on pharmacokinetic monitoring may improve the outcome of folfox for metastatic colorectal cancer"
} | [
{
"companynumb": "JP-ACCORD-040033",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nHepatitis C infection is highly prevalent worldwide and has a well-known association with B-cell lymphoid malignancies. Antiviral therapy has successfully decreased the rate of liver cirrhosis and improved the outcome in patients with hepatitis C-associated lymphomas. However, although there are a few case reports of aggressive lymphomas after successful hepatitis C therapy, the mechanism behind this association remains unclear.\n\n\nMETHODS\nWe present the case of a 55-year-old man with chronic hepatitis C infection and liver cirrhosis who received antiviral therapy with sofosbuvir and ribavirin and achieved a sustained complete virological response. One year after successful therapy, there was an unexplained decline of his liver function and atypical liver nodularity, which led to the diagnosis of a primary liver diffuse large B-cell lymphoma.\n\n\nCONCLUSIONS\nWe review the evidence supporting possible mechanisms of lymphomagenesis after successful hepatitis C therapy, particularly involving late \"second-hit\" mutations after viral-induced DNA damage and antiviral therapy facilitating the emergence of latent malignant B-cell clones by decreasing local inflammation and immune surveillance. More reports may help elucidate any association between hepatitis C antiviral therapy and late lymphoid malignancies.",
"affiliations": "Department of Medicine, John H. Stroger Jr. Hospital, Chicago, IL, USA.",
"authors": "Andrade|Xavier A|XA|;Paz|Luis H|LH|;Nassar|Mo''ath|M|;Oramas|Diana M|DM|;Fuentes|Harry E|HE|;Kovarik|Paula|P|;Mishra|Satya|S|;Singh|Anshu|A|",
"chemical_list": "D000998:Antiviral Agents; D015415:Biomarkers; D014408:Biomarkers, Tumor",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000484653",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "139(2)",
"journal": "Acta haematologica",
"keywords": "Diffuse large B-cell lymphoma; Direct antiviral therapy; Hepatitis C; Ribavirin; Sofosbuvir",
"medline_ta": "Acta Haematol",
"mesh_terms": "D000998:Antiviral Agents; D015415:Biomarkers; D014408:Biomarkers, Tumor; D001706:Biopsy; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019562:Viral Load",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "77-80",
"pmc": null,
"pmid": "29393087",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy.",
"title_normalized": "primary liver diffuse large b cell lymphoma following complete response for hepatitis c infection after direct antiviral therapy"
} | [
{
"companynumb": "US-009507513-1802USA005913",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadditional": null,
... |
{
"abstract": "Beta-lactam (BL) antibiotics are the most frequent cause of drug hypersensitivity in children, inducing both immediate and non-immediate reactions. Here we report a case of a 4-year-old child with a disseminated maculopapular exanthema 7 days after the first dose of amoxicillin-clavulanate, referred to our paediatric allergy department. Skin prick tests were negative. Intradermal tests were performed and, after 10 hours, indurated wheals larger than 10×10 mm with progressive erythema and disseminated maculopapular eruption were developed, related to amoxicillin and amoxicillin-clavulanate. Systemic reactions to BL skin tests are rarely reported and the majority are immediate reactions. This case illustrates a rare example of a non-immediate systemic reaction to intradermal tests, underlying the importance of skin testing before drug provocation tests in cases of moderate to severe non-immediate reactions.",
"affiliations": "Pediatric Department, Local Health Unit of Matosinhos, EPE, Senhora da Hora, Portugal joana.teixeiracarvalho@gmail.com.;Pediatric Department, Local Health Unit of Matosinhos, EPE, Senhora da Hora, Portugal.",
"authors": "Carvalho|Joana|J|http://orcid.org/0000-0001-6561-2153;Oliveira|Georgeta|G|",
"chemical_list": "D000900:Anti-Bacterial Agents; D047090:beta-Lactams",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "allergy; asthma; paediatric prescribing; paediatrics; pharmacology and therapeutics",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D006801:Humans; D006968:Hypersensitivity, Delayed; D007428:Intradermal Tests; D012882:Skin Tests; D047090:beta-Lactams",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33674286",
"pubdate": "2021-03-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Systemic reaction during intradermal skin tests with beta-lactams.",
"title_normalized": "systemic reaction during intradermal skin tests with beta lactams"
} | [
{
"companynumb": "PT-TEVA-2021-PT-1898138",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nSynergism between gemcitabine and platinum is known clinically. Bevacizumab in combination with single-agent chemotherapy has demonstrated significant clinical activity in platinum-resistant recurrent ovarian cancer in AURELIA study. However, the efficacy of platinum-gemcitabine-bevacizumab (PGA) has not been investigated in the platinum-resistant population.\n\n\nMETHODS\nA retrospective chart review was conducted in all patients with platinum-resistant/refractory ovarian cancer treated with triplet combination therapy containing a platinum agent, gemcitabine, and bevacizumab between July 2011 and December 2013.\n\n\nRESULTS\nIn total, 13 patients met the selection criteria, including ten patients with resistant disease (10/13, 77%) and three patients with refractory disease (3/13, 23%). Most of the patients were heavily pre-treated, having received over three lines of prior chemotherapy regimens on average (range 1-11). All patients had previously received taxane therapy; four patients received gemcitabine, seven patients failed combination regimens including bevacizumab, and three patients progressed on chemotherapy including both gemcitabine and bevacizumab. Ten patients responded biochemically to the therapy (defined by CA-125 declined by at least 50%). Of ten responders, one patient achieved CR for 24 months (8%), six patients achieved PR for 6.8 months (46%), three had stable disease for 6.7 months (23%), and three patients had PD (23%) by RECIST 1.1 criteria. The regimen was well-tolerated. One patient (8%) developed grade 3 neutropenia and neutropenic fever, requiring hospitalization, two patients developed grade 3 thrombocytopenia, two patients (15%) developed thrombosis in internal jugular vein, requiring discontinuation of bevacizumab, one patient (8%) experienced skin ulcer, and two patients developed thrombosis in internal jugular vein, requiring discontinuation of bevacizumab.\n\n\nCONCLUSIONS\nCombination of PGA appears to be safe and very active against platinum-resistant/refractory ovarian cancer and merits further evaluation prospectively. A randomized phase II study (NCTO 1936974) is currently under way to confirm this important finding.",
"affiliations": null,
"authors": "Niu|J|J|;Kundranda|M N|MN|;Markman|M|M|;Farley|J|J|",
"chemical_list": "D000970:Antineoplastic Agents; D017671:Platinum Compounds; D003841:Deoxycytidine; D000068258:Bevacizumab; C056507:gemcitabine",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-2936",
"issue": "38(1)",
"journal": "European journal of gynaecological oncology",
"keywords": null,
"medline_ta": "Eur J Gynaecol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D003841:Deoxycytidine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D017671:Platinum Compounds; D012189:Retrospective Studies",
"nlm_unique_id": "8100357",
"other_id": null,
"pages": "40-44",
"pmc": null,
"pmid": "29767862",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Platinum-Gemcitabine-Avastin (PGA) for platinum-resistant/refractory ovarian cancer.",
"title_normalized": "platinum gemcitabine avastin pga for platinum resistant refractory ovarian cancer"
} | [
{
"companynumb": "US-PFIZER INC-2017135346",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We report the case of an 18-year-old woman with personality disorders who was hospitalized a few hours after suicidal ingestion of acetaminophen, quetiapine, acetylsalicylic acid, and ethanol. Twelve hours after admission, severe liver damage was evident, but the patient was stable and awaiting hepatic transplantation. Electrolytes were successfully controlled. The condition of the liver stabilized. Cardiac biomarkers then deteriorated unexpectedly. Localized ST-segment elevations were noted on electrocardiogram, but angiography ruled out myocardial infarction. A computed tomographic scan ruled out cerebral edema. The patient died of irreversible cardiac arrest 40 hours after admission. Heart failure remained unexplained, and the body underwent forensic autopsy.At autopsy, histologic findings were indicative of acute toxic myocarditis and were concluded to be caused by acetaminophen intoxication. Acetaminophen overdose is common and typically leads to liver failure requiring supportive treatment and emergency liver transplantation. Toxic myocarditis is an extremely rare complication of acetaminophen overdose. It has only been reported 4 times in the literature despite the widespread use and misuse of acetaminophen. Toxic myocarditis remains a possibility in many cases of overdose but can be overlooked in a clinical picture dominated by hepatorenal failure and encephalopathy. Clinicians and forensic pathologists should be aware of this rare potential complication.",
"affiliations": "From the Laboratoire de Sciences Judiciaires et de Médecine Légale, Montréal, Québec, Canada.",
"authors": "Gosselin|Maxime|M|;Dazé|Yann|Y|;Mireault|Pascal|P|;Crahes|Marie|M|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014150:Antipsychotic Agents; D002492:Central Nervous System Depressants; D000069348:Quetiapine Fumarate; D000082:Acetaminophen; D000431:Ethanol; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1097/PAF.0000000000000339",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "38(4)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014150:Antipsychotic Agents; D001241:Aspirin; D001883:Borderline Personality Disorder; D002492:Central Nervous System Depressants; D062787:Drug Overdose; D000431:Ethanol; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006333:Heart Failure; D006801:Humans; D009205:Myocarditis; D000069348:Quetiapine Fumarate; D013405:Suicide",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "349-352",
"pmc": null,
"pmid": "28795995",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic Myocarditis Caused by Acetaminophen in a Multidrug Overdose.",
"title_normalized": "toxic myocarditis caused by acetaminophen in a multidrug overdose"
} | [
{
"companynumb": "CA-AUROBINDO-AUR-APL-2017-39428",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nMethadone is a standard treatment for opioid dependence in pregnancy; however, its impact on maternal corrected QT interval (QTc) has not been evaluated. We studied the association between methadone dose and enantiomer-specific plasma concentrations and QTc among pregnant and postpartum women and newborns. We assessed the relevance of QTc screening guidelines for pregnant women and infants.\n\n\nMETHODS\nFrom 2006 to 2008, plasma methadone concentrations were measured during pregnancy, postpartum, and in cord blood in women treated for opioid dependence at a single treatment program. Electrocardiograms (ECGs) were obtained at peak methadone concentrations in mothers and within 48 hours of birth for infants. Pearson correlations were performed at each time point for QTc and R-methadone, S-methadone, and total methadone concentrations and ratio of R-methadone/S-methadone concentrations.\n\n\nRESULTS\nMean (SD) daily methadone dose for the 25 women was 94.2 (39.1) mg during pregnancy and 112.5 (46.6) mg postpartum. During the third trimester, higher methadone dose and R-methadone concentration correlated with longer QTc (Pearson r = 0.67, P < .001 and Pearson r = 0.49, P = .02, respectively), while S-methadone concentration, R-methadone/S-methadone concentration ratio, and total methadone concentration did not. Postpartum, QTc did not significantly correlate with dose or enantiomer concentrations. Infant QTc did not correlate with maternal dose at delivery or enantiomer-specific cord methadone concentrations. In pregnant and postpartum women, 13% and 17%, respectively, had QTc ≥ 450 ms, as did 19% of infants.\n\n\nCONCLUSIONS\nQTc correlated with dose and R-methadone concentration during the third trimester. However, longer QTc was common among women during and after pregnancy. Given the relatively high rate of QTc > 450 ms, an ECG before and after methadone initiation is advisable for pregnant and postpartum women.",
"affiliations": "University of Pittsburgh School of Medicine, Division of General Academic Pediatrics, Children's Hospital of Pittsburgh, 3414 Fifth Ave, CHOB 3rd floor, Pittsburgh, PA 15213. bogendl@upmc.edu.;Department of Pediatrics, University of Pittsburgh School of Medicine, Division of General Academic Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.;Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, USA.;Department of Pediatrics, University of Pittsburgh School of Medicine, Division of Pediatric Cardiology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.;Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.",
"authors": "Bogen|Debra L|DL|;Hanusa|Barbara H|BH|;Perel|James M|JM|;Sherman|Frederick|F|;Mendelson|Marla A|MA|;Wisner|Katherine L|KL|",
"chemical_list": "D009294:Narcotics; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "78(8)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000328:Adult; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D004562:Electrocardiography; D005260:Female; D005312:Fetal Blood; D006207:Half-Life; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome; D008691:Methadone; D009294:Narcotics; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D049590:Postpartum Period; D011247:Pregnancy; D011248:Pregnancy Complications; D011263:Pregnancy Trimester, Third; D013223:Statistics as Topic; D014481:United States",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "e1013-e1019",
"pmc": null,
"pmid": "28994902",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "23656339;26467074;27286724;21857233;23909865;17376175;21348770;11069437;11736879;24685459;21371149;18762507;12820821;17349890;16338275;17329992;7823756;9490239;22926004;22512363;21081591;22546608;27889436;12405865;9341416;18984955;24653586;22123351;19220239;11911622;9851480;10910367;23689766;16740817;19153406;9431829;16801510",
"title": "Corrected QT Interval and Methadone Dose and Concentrations in Pregnant and Postpartum Women.",
"title_normalized": "corrected qt interval and methadone dose and concentrations in pregnant and postpartum women"
} | [
{
"companynumb": "US-SPECGX-T202001010",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nPrevious observational studies in the US suggest that opioid analgesic use increases the risk of cardiovascular (CV) events. The current study provides additional background event rates for five prespecified CV outcomes of interest in patients from three countries.\n\n\nMETHODS\nThree observational cohort studies were conducted in patients from the US (N = 17,604), the UK (N = 9,823), and Germany (N = 9,412). Patients were new opioid users who had undergone ≥6 months of chronic, continuous therapy. De-identified data were collated from electronic healthcare databases in the respective countries. Demographics, clinical characteristics, and opioid use were examined. Overall rates, prevalence rates in patients with established CV disease, and incidence rates in patients without established CV disease were determined for myocardial infarction (MI), stroke, transient ischemic attack, unstable angina, and congestive heart failure (CHF).\n\n\nRESULTS\nCardiovascular disease at baseline was more prevalent in US and German patients. Back pain and depression were prevalent preexisting comorbidities. The majority of patients were using various weak opioids (based on receptor affinities), CV medications, and antidepressants. Overall rates by individual CV outcome per 1,000 patient-years by country were greatest for CHF (US 37.2, 95% CI 24.1-40.5), unstable angina (UK 8.2, 95% CI 7.0-9.6), and stroke (Germany 5.3, 95% CI 4.1-6.7). Overall rates for MI were: US, 10.7 (95% CI 9.1-12.5), UK, 6.7 (95% CI 5.6-8.0), and Germany, 2.7 (95% CI 1.9-3.7). Overall rates for each CV outcome, prevalence rates in patients with preexisting CV disease, and incidence rates in patients without established CV disease differed by country. Rates were higher in patients with preexisting CV disease.\n\n\nCONCLUSIONS\nCV risk for new opioid users with ≥6 months of therapy was increased in patients with established CV disease compared with those without established CV disease, and the risk for specific outcomes differed by country. Assessment of CV safety events of new therapies introduced to chronic opioid users should consider sample size and population heterogeneity in the design of an observational study.",
"affiliations": "AstraZeneca, Wilmington, DE, USA, robert.locasale@astrazeneca.com.",
"authors": "LoCasale|Robert|R|;Kern|David M|DM|;Chevalier|Pierre|P|;Zhou|Siting|S|;Chavoshi|Soheil|S|;Sostek|Mark|M|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.1007/s12325-014-0131-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-238X",
"issue": "31(7)",
"journal": "Advances in therapy",
"keywords": null,
"medline_ta": "Adv Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D002318:Cardiovascular Diseases; D015331:Cohort Studies; D005260:Female; D005858:Germany; D006333:Heart Failure; D006801:Humans; D002546:Ischemic Attack, Transient; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010146:Pain; D015995:Prevalence; D012306:Risk; D020521:Stroke; D013997:Time Factors; D006113:United Kingdom; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "8611864",
"other_id": null,
"pages": "708-23",
"pmc": null,
"pmid": "25033926",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Description of cardiovascular event rates in patients initiating chronic opioid therapy for noncancer pain in observational cohort studies in the US, UK, and Germany.",
"title_normalized": "description of cardiovascular event rates in patients initiating chronic opioid therapy for noncancer pain in observational cohort studies in the us uk and germany"
} | [
{
"companynumb": "US-JNJFOC-20140908742",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
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{
"abstract": "Systemic retinoids such as isotretinoin and acitretin are associated with numerous side effects but are therapeutically valuable in dermatological practice. Several studies have reported the wound-healing effects of treatment with concurrent systemic retinoids in addition to surgical treatments. Herein, we describe two patients with scar dehiscence that developed after initiation of systemic retinoid treatment following cutaneous surgery. In Case 1, isotretinoin was thought to decrease collagen production to a greater degree than did degradation during the wound remodeling phase, which resulted in wound dehiscence. In Case 2, acitretin was thought to decrease fibroblast proliferation and collagen production during the proliferation phase of wound healing, which resulted in wound dehiscence. Based on the two presented cases, it is advisable to postpone systemic retinoid treatment for 6 months to 1 year following cutaneous surgery, located especially in cosmetically important sites.",
"affiliations": "Department of Plastic and Reconstructive Surgery, Bahcesehir University, Istanbul, Turkey.;Department of Dermatology, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey.;Department of Dermatology, Faculty of Medicine, Aksaray University, Aksaray, Turkey.",
"authors": "Aksoy|Hasan Mete|HM|;Aksoy|Berna|B|;Çalikoglu|Emel|E|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijd.IJD_148_18",
"fulltext": "\n==== Front\nIndian J DermatolIndian J DermatolIJDIndian Journal of Dermatology0019-51541998-3611Medknow Publications & Media Pvt Ltd India IJD-64-6810.4103/ijd.IJD_148_18Case ReportSystemic Retinoids and Scar Dehiscence Aksoy Hasan Mete 12Aksoy Berna 34Çalikoglu Emel 51 From the Department of Plastic and Reconstructive Surgery, Bahcesehir University, Istanbul, Turkey2 Plastic, Reconstructive and Aesthetic Surgery Clinic, VM Medicalpark Kocaeli Hospital, Aksaray, Turkey3 Department of Dermatology, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey4 Dermatology Clinic, VM Medicalpark Kocaeli Hospital Kocaeli, Aksaray, Turkey5 Department of Dermatology, Faculty of Medicine, Aksaray University, Aksaray, TurkeyAddress for correspondence: Dr. Berna Aksoy, VM Medicalpark Kocaeli Hospital, Ovacik Discreet, Beside D-100 Highway, No: 36, Basiskele, Kocaeli, Turkey. E-mail: bmaksoy@mynet.com, bernaaaksoy@gmail.comJan-Feb 2019 64 1 68 70 4 2018 10 2018 Copyright: © 2019 Indian Journal of Dermatology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Systemic retinoids such as isotretinoin and acitretin are associated with numerous side effects but are therapeutically valuable in dermatological practice. Several studies have reported the wound-healing effects of treatment with concurrent systemic retinoids in addition to surgical treatments. Herein, we describe two patients with scar dehiscence that developed after initiation of systemic retinoid treatment following cutaneous surgery. In Case 1, isotretinoin was thought to decrease collagen production to a greater degree than did degradation during the wound remodeling phase, which resulted in wound dehiscence. In Case 2, acitretin was thought to decrease fibroblast proliferation and collagen production during the proliferation phase of wound healing, which resulted in wound dehiscence. Based on the two presented cases, it is advisable to postpone systemic retinoid treatment for 6 months to 1 year following cutaneous surgery, located especially in cosmetically important sites.\n\nKEY WORDS:\nAcitretindehiscenceisotretinoinretinoidscarwound healing\n==== Body\nIntroduction\nSystemic retinoids such as isotretinoin and acitretin are essential for dermatological therapy but are associated with numerous side effects. Isotretinoin induces thinning of the skin.[1] It also decreases collagenase action and enhances hypertrophic or keloidal scarring following mechanical dermabrasion surgery and ablative laser treatment performed during, immediately after, and before isotretinoin treatment.[123] Findings in the literature concerning the adverse effects of systemic isotretinoin on wound healing are reported to be inconsistent.[1] Isotretinoin, when used in therapeutic dosages (≤2 mg/kg/d), does not seem to impair wound healing.[1] Moreover, the optimal timing for surgery in patients taking systemic isotretinoin remains unclear.[1] A comprehensive review of isotretinoin treatment and concurrent surgical procedures was inconclusive in this context.[2] Another consensus report concluded that there is insufficient evidence to recommend delaying cutaneous surgery not involving muscles in patients on isotretinoin treatment or in those who recently completed such treatment.[3] Another study reported that it is doubtful that isotretinoin can affect wound healing negatively, but there is a small risk that it may.[2] Surgical outcome in patients taking isotretinoin during the perioperative period was reported to be no different than in those not taking isotretinoin.[4] A study on organ transplant recipients undergoing surgical treatment for skin cancers reported there were no differences in wound-healing complications between those taking and not taking acitretin chemoprophylaxis;[5] however, only one study examined the outcome of previous surgical procedures during subsequent retinoid treatment.[6] Herein, we describe two cases of scar dehiscence that developed after initiation of systemic retinoid treatment following cutaneous surgery.\n\nCase Reports\n\nCase 1\nAn otherwise healthy 17-year-old male undergone excision of an inflamed sebaceous cyst located on his right cheek. The patient presented again with nodulocystic acne and began treatment with oral isotretinoin 1 mg/kg/d. On day 29 of the treatment, he hit his right cheek and the incision scar (approximately 130 day old) was dehisced [Figure 1]. It was followed by local wound dressings while continuing oral isotretinoin treatment. The wound healed by secondary intention in about 2.5 months, leaving an atrophic depressed scar [Figure 2].\n\nFigure 1 Scar dehiscence on the right cheek in Case 1 on day 29 of isotretinoin treatment\n\nFigure 2 In Case 1, the wound healed through secondary intention in about 2.5 months, leaving an atrophic scar on the right cheek\n\nCase 2\nAn 81-year-old male was operated for squamous cell carcinoma (SCC) located on the left ear helical border. A new tumoral nodule was detected on the right side of the midline of the forehead and excised 40 day later, and the histopathological diagnosis was again well-differentiated SCC. Oral acitretin 25 mg/d was initiated for chemoprevention of new SCC and treatment of widespread actinic keratoses. On day 8 of treatment, the surgical scar on the patient's forehead (25 day old) was dehisced. During the next few days, the left helical scar widened. Scar dehiscence on the forehead healed in about 7 weeks via secondary intention with wound dressings.\n\nDiscussion\nThe literature includes only three patients reported to have developed complications of surgical procedures that occurred during or subsequent use of isotretinoin.[6] All three of these patients underwent septorhinoplasty before starting oral isotretinoin treatment in the previous 2 years and all developed nasal tip deformities within 6 months of the initiation of isotretinoin treatment. Authors concluded that nasal tip deformity had developed due to isotretinoin's creation of imbalance between collagen production and degradation, as well as the accentuated “shrink and wrap” phenomenon associated with the abnormally thin nasal epidermis, and recommended postponing isotretinoin treatment for a minimum of 2 years following rhinoplasty;[6] however, Cobo and Vitery[7] reported that concomitant initiation of isotretinoin treatment with rhinoplasty helped to define the nasal tip and improved the surgical outcome in thick-skinned patients.\n\nShigematsu and Tajima[8] reported that 13-cis-retinoic acid and etretinate inhibited collagen and noncollagenous protein synthesis in fibroblast cell cultures, although 13-cis-retinoic acid did so to a greater degree (66% reduction in collagen synthesis). Etretinate, but not 13-cis-retinoic acid, was reported to inhibit DNA synthesis (by 45%), and therefore, inhibited fibroblast proliferation; the researchers concluded that 13-cis-retinoic acid was the more valuable compound for the treatment of fibrotic disorders.[8] Ohta et al.[9] noted that all-trans-retinal (vitamin A aldehyde) (final collagenase activity was 14.3% of control) and all-trans-retinoic acid (final collagenase activity was 39.4% of control) were potent inhibitors of collagenase (MMP-1) production, but that 13-cis-retinoic acid (final collagenase activity was 57.7% of control) inhibited collagenase production to a lesser extent in human mononuclear cells in culture.\n\nIn Case 1, isotretinoin was thought to decrease collagen synthesis to a greater degree than collagen degradation during the postoperative wound remodeling phase. Due to this decrease in collagen synthesis, the patient's scar contained less collagen than normal scar at that age and was therefore weak, and dehiscence occurred following subsequent minor trauma. In Case 2, acitretin was started during the proliferation phase of wound healing. As acitretin inhibited both fibroblast proliferation and collagen synthesis, the patient's surgical wound was thought to get less cellular, with a decrease in collagen content and wound strength than normal scar at that age. Subsequently, the patient's scar dehisced spontaneously. The helical scar in Case 2 was older than that in Case 1 and was enlarged due to a decrease in collagen synthesis during the 3rd month of the wound remodeling phase. Since acitretin impaired collagen synthesis to a lesser degree in comparison with isotretinoin, it was thought that dehiscence was not observed in helical scar of Case 2. Acitretin was reported to delay secondary wound healing in rats.[10] Both of the presented cases experienced delayed secondary wound healing of dehisced scars while treatment with systemic retinoids was ongoing. Case 2 had an uneventful recovery following abdominal surgery and his third skin cancer excision.\n\nBased on our experience with the presented cases, it is recommended that it may be beneficial to postpone systemic retinoid treatment for 6 months to 1 year following cutaneous surgery, located especially in cosmetically important sites. We concluded so because the remodeling phase of the wound healing process was generally completed in 1 year. Wound tensile strength is also related to this phase of wound healing and the maximum tensile strength of the wound is achieved in 3–6 months following creation of a wound.\n\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgments\nThe authors would like to thank Scott Barry Evans for his assistance in native English language correction.\n==== Refs\n1 Ungarelli LF Hetem CM Farina Junior JA Is it safe to operate on patients taking isotretinoin? Aesthetic Plast Surg 2016 40 139 48 26686845 \n2 Wootton CI Cartwright RP Manning P Williams HC Should isotretinoin be stopped prior to surgery? A critically appraised topic Br J Dermatol 2014 170 239 44 24547720 \n3 Spring LK Krakowski AC Alam M Bhatia A Brauer J Cohen J Isotretinoin and Timing of Procedural Interventions: A Systematic Review With Consensus Recommendations JAMA Dermatol 2017 153 802 9 28658462 \n4 Tolkachjov SN Sahoo A Patel NG Lohse CM Murray JA Tollefson MM Surgical outcomes of patients on isotretinoin in the perioperative period: A single-center, retrospective analysis J Am Acad Dermatol 2017 77 159 61 28619552 \n5 Tan SR Tope WD Effect of acitretin on wound healing in organ transplant recipients Dermatol Surg 2004 30 667 73 15061853 \n6 Allen BC Rhee JS Complications associated with isotretinoin use after rhinoplasty Aesthetic Plast Surg 2005 29 102 6 15803349 \n7 Cobo R Vitery L Isotretinoin use in thick-skinned rhinoplasty patients Facial Plast Surg 2016 32 656 61 28033642 \n8 Shigematsu T Tajima S Modulation of collagen synthesis and cell proliferation by retinoids in human skin fibroblasts J Dermatol Sci 1995 9 142 5 7772577 \n9 Ohta A Louie JS Uitto J Retinoid modulation of collagenase production by adherent human mononuclear cells in culture Ann Rheum Dis 1987 46 357 62 3036026 \n10 Gunes Bilgili S Calka O Akdeniz N Bayram I Metin A The effects of retinoids on secondary wound healing: Biometrical and histopathological study in rats J Dermatolog Treat 2013 24 283 9 22646471\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0019-5154",
"issue": "64(1)",
"journal": "Indian journal of dermatology",
"keywords": "Acitretin; dehiscence; isotretinoin; retinoid; scar; wound healing",
"medline_ta": "Indian J Dermatol",
"mesh_terms": null,
"nlm_unique_id": "0370750",
"other_id": null,
"pages": "68-70",
"pmc": null,
"pmid": "30745640",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "15061853;15803349;22646471;24547720;26686845;28033642;28619552;28658462;3036026;7772577",
"title": "Systemic Retinoids and Scar Dehiscence.",
"title_normalized": "systemic retinoids and scar dehiscence"
} | [
{
"companynumb": "TR-GLAXOSMITHKLINE-TR2019012198",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACITRETIN"
},
"drugadditional": "3",
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{
"abstract": "It is relatively unknown that some of the possible side effects of antibiotic treatment can be transient psychotic episodes and other encephalopathies such as seizure disorders. Since these are rare events, there have not been many studies about them, nor is there a clear understanding of the underlying basis for these symptoms. This phenomenon was recently brought to our attention by a patient whose case history is discussed here. For the past few years, he has been diagnosed at different times with schizophrenia, schizoaffective disorder, bipolar disorder with psychosis, temporal lobe epilepsy, and psychogenic nonepileptic seizures. He was seen by a neurologist and placed on carbamazepine, which by his admittance helped him tremendously. During this same time period, psychiatrists placed him on various antipsychotic medications as well. The patient researched many medical conditions and came to the conclusion that his symptoms are caused by a large dose of an \"antibiotic\" given to him on his first day of basic training for the military, the so called \"peanut butter shot\", although he has not been able to convince his physicians of this theory. Whether or not this patient has a chronic schizophrenia-like illness or an adverse reaction to antibiotics, this case is presented so that clinicians are aware that neurological and psychiatric side effects can occur as rare reactions to antibiotic therapy and that treatment with an anti-seizure drug concurrently used as a mood stabilizer may be warranted in such cases.",
"affiliations": "Harvard South Shore Residency Training Program, Brockton, MA, United States; VA Boston Healthcare System, Brockton Division, 940 Belmont Avenue, Brockton, MA, United States.;Harvard South Shore Residency Training Program, Brockton, MA, United States; VA Boston Healthcare System, Brockton Division, 940 Belmont Avenue, Brockton, MA, United States; Department of Psychiatry, Harvard Medical School, Brockton Campus, MA, United States. Electronic address: Lynn.DeLisi@VA.gov.",
"authors": "Ly|Duy|D|;DeLisi|Lynn E|LE|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.schres.2017.01.041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-9964",
"issue": "189()",
"journal": "Schizophrenia research",
"keywords": "Antibiotics; Psychosis; Schizophrenia",
"medline_ta": "Schizophr Res",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D006801:Humans; D008297:Male; D011605:Psychoses, Substance-Induced; D014728:Veterans",
"nlm_unique_id": "8804207",
"other_id": null,
"pages": "204-207",
"pmc": null,
"pmid": "28185785",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Can antibiotics cause a psychosis?: Case report and review of the literature.",
"title_normalized": "can antibiotics cause a psychosis case report and review of the literature"
} | [
{
"companynumb": "US-SHIRE-US201703667",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nWe aimed to investigate the longitudinal changes in bone metabolic markers and bone mineral density (BMD) after starting or switching from bisphosphonate (BP) to romosozumab (ROMO) or denosumab (DENO) therapies over 12 months and to determine predictors that establish associations with changes in BMD among the patients received the ROMO therapy.\n\n\nMETHODS\nPostmenopausal osteoporosis patients with a high risk of fracture-154 in total-were recruited; their therapies were switched to ROMO or DENO from BP/naïve or vitamin D (ND) (ND-ROMO: 43, BP-ROMO: 38, ND-DENO: 38, and BP-DENO: 35). Longitudinal changes in bone metabolic markers and BMD were evaluated.\n\n\nRESULTS\nROMO groups showed significant increases in BMD of the lumbar spine at 6 and 12 months and femoral neck at 12 months compared to the DENO groups. Although BP-ROMO showed significant increase in the lumbar spine BMD compared to BP-DENO, there were no significant differences in femoral neck and total hip BMDs between BP-ROMO and BP-DENO. Among the ROMO groups, % changes of BMD from baseline to 12 months were associated with bone metabolic markers at baseline and changes in TRACP-5b from baseline to 3 months.\n\n\nCONCLUSIONS\nROMO continuously increased BMD for 12 months and performed better than DENO. On the other hand, effects of ROMO switched from BP on BMD of femoral neck and total hip were almost same with DENO. Bone metabolic markers at baseline and changes in TRACP-5b from baseline to 3 months may predict the efficacy of ROMO after 12 months of administration.",
"affiliations": "Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. simitom@wg8.so-net.ne.jp.;Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Orthopaedic Surgery, Wajyokai Sapporo Hospital, Sapporo, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.",
"authors": "Shimizu|Tomohiro|T|http://orcid.org/0000-0001-6760-3066;Arita|Kosuke|K|;Murota|Eihiro|E|;Hiratsuka|Shigeto|S|;Fujita|Ryo|R|;Ishizu|Hotaka|H|;Asano|Tsuyoshi|T|;Takahashi|Daisuke|D|;Takahata|Masahiko|M|;Iwasaki|Norimasa|N|",
"chemical_list": "D000911:Antibodies, Monoclonal; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C557282:romosozumab; D000069448:Denosumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00774-021-01226-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0914-8779",
"issue": "39(5)",
"journal": "Journal of bone and mineral metabolism",
"keywords": "Bone metabolic marker; Denosumab; Postmenopausal osteoporosis; Romosozumab",
"medline_ta": "J Bone Miner Metab",
"mesh_terms": "D000911:Antibodies, Monoclonal; D015519:Bone Density; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D006801:Humans; D007564:Japan; D015663:Osteoporosis, Postmenopausal; D017698:Postmenopause",
"nlm_unique_id": "9436705",
"other_id": null,
"pages": "868-875",
"pmc": null,
"pmid": "33847831",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": "16983459;26018089;20593411;24382002;27055223;27641143;28892457;28755782;22543469;32777516;32979066;23203733;23553500;12510801;20461422;15613428;8237484;25524021;28687496;31168657;33057807;31707465;32548215",
"title": "Effects after starting or switching from bisphosphonate to romosozumab or denosumab in Japanese postmenopausal patients.",
"title_normalized": "effects after starting or switching from bisphosphonate to romosozumab or denosumab in japanese postmenopausal patients"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2021063000",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROMOSOZUMAB"
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"drugadditional": "3",
... |
{
"abstract": "Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.",
"affiliations": "Vanderbilt Medical Scientist Training Program, Vanderbilt University Medical Center, 2nd Floor Eskind Biomedical Library and Learning Center, Vanderbilt University School of Medicine, 2209 Garland Avenue, Nashville, TN 37240, United States of America.;Vanderbilt Medical Scientist Training Program, Vanderbilt University Medical Center, 2nd Floor Eskind Biomedical Library and Learning Center, Vanderbilt University School of Medicine, 2209 Garland Avenue, Nashville, TN 37240, United States of America.;Department of Thoracic Surgery, Vanderbilt University Medical Center, Room 609 Oxford House, 1313 21st Avenue South, Nashville, TN 37232, United States of America.;Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st St SW, Rochester, MN 55902, United States of America.;Program for Metabolic Bone Disorders at Vanderbilt, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, 8210 Medical Center East, 1215 21st Avenue South, Nashville, TN 37232-8148, United States of America.",
"authors": "Colazo|Juan M|JM|;DeCorte|Joseph A|JA|;Gillaspie|Erin A|EA|;Folpe|Andrew L|AL|;Dahir|Kathryn M|KM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bonr.2020.100744",
"fulltext": "\n==== Front\nBone Rep\nBone Rep\nBone Reports\n2352-1872 Elsevier \n\nS2352-1872(20)30504-0\n10.1016/j.bonr.2020.100744\n100744\nCase Report\nHiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia\nColazo Juan M. BScjuan.m.colazo@vanderbilt.edua1 DeCorte Joseph A. BSjoseph.a.decorte@vanderbilt.edua1 Gillaspie Erin A. MD, MPHerin.a.gillaspie@vumc.orgb Folpe Andrew L. MDfolpe.andrew@mayo.educ Dahir Kathryn M. MDkathryn.dahir@vumc.orgd⁎ a Vanderbilt Medical Scientist Training Program, Vanderbilt University Medical Center, 2nd Floor Eskind Biomedical Library and Learning Center, Vanderbilt University School of Medicine, 2209 Garland Avenue, Nashville, TN 37240, United States of America\nb Department of Thoracic Surgery, Vanderbilt University Medical Center, Room 609 Oxford House, 1313 21st Avenue South, Nashville, TN 37232, United States of America\nc Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st St SW, Rochester, MN 55902, United States of America\nd Program for Metabolic Bone Disorders at Vanderbilt, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, 8210 Medical Center East, 1215 21st Avenue South, Nashville, TN 37232-8148, United States of America\n⁎ Corresponding author. kathryn.dahir@vumc.org1 These authors contributed equally.\n\n\n24 12 2020 \n6 2021 \n24 12 2020 \n14 1007445 10 2020 14 12 2020 21 12 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.\n\nGraphical abstract\n(A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity). (E) Post-operative image of 9th right rib removed during the second, successful surgery. White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown histologically in F and G. (F) Histological appearance of the Phosphaturic Mesenchymal Tumor (PMT) specifically showing infiltration of rib bone and proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. (G) FGF23 Chromogenic in situ hybridization (CISH) of the PMT.Unlabelled Image\n\nHighlights\n• TIO is caused by FGF23 hypersecretion by phosphaturic mesenchymal tumors (PMTs).\n\n• TIO can go undiagnosed and/or be misdiagnosed with similar disorders (e.g. XLH).\n\n• Family history, biochemistry, gene panels, and imaging may help distinguish TIO.\n\n• FN1-FGF1 and FN1-FGFR1 are transcribed and synthesized by the majority of PMTs.\n\n• Burosumab (anti-FGF23) and FGF/R inhibitors show promise; resection is preferred.\n\n\n\nKeywords\nTumor-induced osteomalaciaTIOFibroblast growth factor 23FGF23ParaneoplasticPhosphaturic mesenchymal tumor68Ga-DOTATATEBurosumabChromogenic in situ hybridizationRNA sequencingX-linked hypophosphatemic ricketsXLHPHEXFN1-FGFR1fibronectinFN1Fibroblast growth factor receptor 1FGFR1phosphorousphosphate wasting disorders\n==== Body\n1 Introduction\nOsteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).\n\nX-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.\n\nIn particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.\n\n2 Case presentation\nA 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.\n\nDespite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.\n\nFig. 1\n\nDespite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.\n\nTeriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.\n\nThe patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.\n\nAt our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.\n\nFig. 2\n\nAdditionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.\n\nTable 1Gene\tPrimary location(s) of expression\tType of mutation precipitating disease\tAssociated hypophosphatemic/osteomalacic disease\t\nALPL\tOsteoblasts\tLoss of function\tHypophosphatasia\t\nCLCN5\tProximal renal tubule\tLoss of function\tX-linked recessive hypophosphatemic rickets\t\nCYP27B1\tMany cell types\tLoss of function\tAR VDDR type 1A\t\nCYP2R1\tHepatocytes\tLoss of function\tAR VDDR type 1B\t\nDMP1\tOsteoblasts, osteocytes\tLoss of function\tAR hypophosphatemic rickets\t\nENPP1\tChondrocytes, osteocytes, plasma cells\tLoss of function\tAR hypophosphatemic rickets\t\nFAH\tHepatocytes\tLoss of function\tAR tyrosinemia type 1\t\nFAM20C\tOsteoblasts, osteocytes\tLoss of function\tAR osteosclerotic bone dysplasia (Raine syndrome)\t\nFGF23\tOsteoblasts, osteocytes\tGain of function\tAD hypophosphatemic rickets\t\nFGFR1\tMany cell types\tGain of function\tAD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors\t\nPHEX\tOsteoblasts\tLoss of function, X-linked\tXLH, increased FGF23 secretion\t\nSLC34A3\tProximal renal tubule\tLoss of function\tAR hypophosphatemic rickets with hypercalciuria\t\nVDR\t\tLoss of function\tCalcitriol resistance, VDDR type 2A\t\n\n\nDue to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).\n\nFig. 3\n\nSome TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.\n\nIntra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.\n\nFig. 4\n\nThese findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.\n\nFig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).\n\nFig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.\n\nFig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.\n\nTable 2Laboratory value\tNormal range\tPre-Op 1 (on Burosumab)\tPost-Op 1, Pre-Op 2\tPost-Op 2 (3 months after 9th right rib resection)\t\nSerum phosphorus\t2.3–4.7 mg/dL\t2.5\t1.4\t3.7\t\nCalcium\t8.4–10.5 mg/dL\t9.7\t9.3\t10.4\t\nTotal vitamin D\t25–80 ng/mL\t40\t38\t35\t\n1,25 dihydroxyvitamin D\t19.9–79.3 pg/mL\t333\t15\t327\t\nAlkaline phosphatase\t40–150 U/L\t168\t111\t130\t\nChloride\t96–106 mmol/L\t108\t109\t105\t\nPTH\t16–77 pg/mL\t189\tNot collected\t194\t\nFGF23\t<180 RU/mL\t36,900\t1532\t245\t\n\n\n3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.\n\n3 Discussion\nTIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.\n\nDiagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.\n\nPatients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).\n\nPatient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).\n\nTable 3Phosphate wasting disorders with low FGF23\tPhosphate wasting disorders with high or “inappropriately normal” FGF23\t\nFanconi syndrome\tX-linked hypophosphatemia (XLH)\t\nHyperparathyroidism\tTumor-induced osteomalacia (TIO)\t\nDiuretics (e.g. acetazolamide)\tAutosomal dominant/autosomal recessive rickets\t\nMyeloma\tMcCune Albright syndrome\t\nCopper disorders (Menkes)\tCutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)\t\nAlcohol consumption\tIron use (iron polymaltose infusions)\t\nGenetic disorders (e.g. Npt2a mutations)\t\t\n\n\nFinally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.\n\nSuspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.\n\nMisdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).\n\nWhile diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.\n\nTo date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.\n\nIndeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.\n\nIn this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.\n\n4 Conclusion\nTumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.\n\nWe highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.\n\nThe following are the supplementary data related to this article.Video 1\nPre-operative functionality of patient\n\nVideo 1 Video 2\nPost-operative functionality of patient\n\nVideo 2 \n\nTransparency document\nTransparency document.\n\nImage 1 \n\nAcknowledgments\nTwo of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\n\nThe Transparency document associated with this article can be found, in online version.\n==== Refs\nReferences\nBeck-Nielsen S.S. FGF23 and its role in X-linked hypophosphatemia-related morbidity Orphanet Journal of Rare Diseases 14 2019 58 30808384 \nCarpenter T.O. New perspectives on the biology and treatment of X-linked hypophosphatemic rickets Pediatr. Clin. N. Am. 44 1997 443 466 \nM. P. Carpenter T.O., Weber T., Peacock M., Ruppe M., Insogna K., Osei S., Luca D., Skrinar A., San Martin J. (2016) Effects of KRN23, and anti-FGF23 antibody, in patients with tumor induced osteomalacia and epidermal nevus syndrome: results from an ongoing phase 2 study. in Jan De Beur S. Annual Meeting of the American Society for Bone and Mineral Research 1098.\nCarter J.M. Caron B.L. Dogan A. Folpe A.L. A novel chromogenic in situ hybridization assay for FGF23 mRNA in phosphaturic mesenchymal tumors Am. J. Surg. Pathol. 39 2015 75 83 25025444 \nJ. M. Colazo, R. C. Thompson, N. V. Covington, K. M. Dahir, An Intracranial Mass Causing Tumor-induced Osteomalacia (TIO): Rapid and Complete Resolution of Severe Osteoporosis After Surgical Resection. doi:10.1016/j.radcr.2020.01.039 .\nDay A.L. Gutiérrez O.M. Guthrie B.L. Saag K.G. Burosumab in tumor-induced osteomalacia: a case report Joint Bone Spine 87 2020 81 83 31382017 \nDurmaz E. Novel and de novo PHEX mutations in patients with hypophosphatemic rickets Bone 52 2013 286 291 23079138 \nFeng J. The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases Endocr. J. 64 2017 675 683 28450684 \nFolpe A.L. Phosphaturic mesenchymal tumors: a review and update Semin. Diagn. Pathol. 36 2019 260 268 31301876 \nHartley I.R. Targeted FGFR blockade for the treatment of tumor-induced osteomalacia N. Engl. J. Med. 383 2020 1387 1389 32905668 \nHautmann A.H. Hautmann M.G. Kölbl O. Herr W. Fleck M. Tumor-induced osteomalacia: an up-to-date review Curr. Rheumatol. Rep. 17 2015 37 \nHofman M.S. Lau W.F. Hicks R.J. Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation Radiographics 35 2015 500 516 25763733 \nHouang M. Phosphaturic mesenchymal tumors show positive staining for somatostatin receptor 2A (SSTR2A) Hum. Pathol. 44 2013 2711 2718 24060005 \nImel E.A. Econs M.J. Approach to the hypophosphatemic patient The Journal of Clinical Endocrinology & Metabolism 97 2012 696 706 22392950 \nJagtap V.S. Hypophosphatemic rickets Indian J Endocrinol Metab 16 2012 177 182 22470852 \nJan de Beur S.M. Tumor-induced osteomalacia JAMA 294 2005 1260 1267 16160135 \nS. Jan De Beur et al., OR13-1 Burosumab improves the biochemical, skeletal, and clinical symptoms of tumor-induced osteomalacia syndrome. Journal of the Endocrine Society 3 (2019).\nLee J.C. Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors Mod. Pathol. 29 2016 1335 1346 27443518 \nLee B.N. Jung H.Y. Chang H.S. Hwang Y.C. Oh W.M. Dental management of patients with X-linked hypophosphatemia Restor Dent Endod 42 2017 146 151 28503481 \nLiu S. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX J. Biol. Chem. 278 2003 37419 37426 12874285 \nLloyd S.E. A common molecular basis for three inherited kidney stone diseases Nature 379 1996 445 449 8559248 \nMartin A. David V. Quarles L.D. Regulation and function of the FGF23/Klotho endocrine pathways Physiol. Rev. 92 2012 131 155 22298654 \nMartinez A.P. Histiocyte-rich rhabdomyoblastic tumor: rhabdomyosarcoma, rhabdomyoma, or rhabdomyoblastic tumor of uncertain malignant potential? A histologically distinctive rhabdomyoblastic tumor in search of a place in the classification of skeletal muscle neoplasms. Mod Pathol 32 2019 446 457 30287926 \nR. MD, \"X-Linked hypophosphatemia\" in GeneReviews [Internet], A. H. Adam MP, Pagon RA, et al., Ed. (University of Washington, Seattle, WA, 2012).\nMichigami T. Skeletal mineralization: mechanisms and diseases Ann Pediatr Endocrinol Metab 24 2019 213 219 31905439 \nPayne R.B. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation Ann. Clin. Biochem. 35 Pt 2 1998 201 206 9547891 \nC. M. Priante G, Terrin L, Gianesello L, Quaggio F, Del Prete D, Anglani F., \"Understanding the pathophysiology of nephrocalcinosis\" in Updates and Advances in Nephrolithiasis - Pathophysiology, Genetics, and Treatment Modalities. (InTech Open, 2017).\nRoot A.W. Genetic disorders of calcium, phosphorus, and bone homeostasis Translational Science of Rare Diseases 3 2018 1 36 \nSchober H.-C. Kneitz C. Fieber F. Hesse K. Schroeder H. Selective blood sampling for FGF-23 in tumor-induced osteomalacia Endocrinol Diabetes Metab Case Rep 2017 2017 17-0006 \nM. K. Takeda R, Takagi M, Goto M, Ariyasu D, Izawa M, Igaki J, Suzuki E, Nakamura Y, Hasegawa Y, TmP/GFR is a useful marker in making a clinical diagnosis of X-linked hypophosphataemic rickets caused by the PHEX gene mutation. ESPE Abstracts 84 (2015).\nYin Z. Du J. Yu F. Xia W. Tumor-induced osteomalacia Osteoporos Sarcopenia 4 2018 119 127 30775554 \nZhang J. 68Ga DOTATATE PET/CT is an accurate imaging modality in the detection of culprit tumors causing osteomalacia Clin. Nucl. Med. 40 2015 642 646 26053726 \nZoller H. Schaefer B. Glodny B. Iron-induced hypophosphatemia: an emerging complication Curr. Opin. Nephrol. Hypertens. 26 2017 266 275 28399017\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-1872",
"issue": "14()",
"journal": "Bone reports",
"keywords": "68Ga-DOTATATE; Burosumab; Chromogenic in situ hybridization; FGF23; FGFR1; FN1; FN1-FGFR1; Fibroblast growth factor 23; Fibroblast growth factor receptor 1; PHEX; Paraneoplastic; Phosphaturic mesenchymal tumor; RNA sequencing; TIO; Tumor-induced osteomalacia; X-linked hypophosphatemic rickets; XLH; fibronectin; phosphate wasting disorders; phosphorous",
"medline_ta": "Bone Rep",
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"pmid": "33490314",
"pubdate": "2021-06",
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"references": "28503481;8559248;32140194;27443518;24060005;12874285;22298654;9547891;29026610;16160135;23079138;26053726;30287926;22392950;30775554;32905668;9130929;31301876;30808384;31382017;28450684;22470852;25900190;25025444;28399017;31905439;25763733",
"title": "Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.",
"title_normalized": "hiding in plain sight gene panel and genetic markers reveal 26 year undiagnosed tumor induced osteomalacia of the rib concurrently misdiagnosed as x linked hypophosphatemia"
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"abstract": "BACKGROUND Cardioversion is a safe, commonly used procedure throughout the world. It is performed over 30 000 times per year in the United States, specifically for atrial fibrillation. Procedural risks from cardioversion include clot dislodgement, sedation effects, site pain, burns, hypotension, dysrhythmias, or heart failure. Generally, back pain is considered to be simple muscle soreness, and cardioversion consents therefore do not include discussion of back injuries. CASE REPORT A 46-year-old man with no prior back pain or injury history underwent a planned synchronized cardioversion for atrial fibrillation. He immediately reported new back pain following the procedure. No unusual event such as a fall occurred near the time of the procedure, but upon evaluation, he was found to have a new lumbar compression fracture that caused incapacitating pain for more than 6 weeks. CONCLUSIONS Cardioversion has been found to be a safe, effective treatment for atrial fibrillation. Adverse effects are generally minor, and the frequency of adverse effects appear to be low overall. The case reported here represents a rare, but possibly underreported adverse effect, namely, lumbar compression fracture due to cardioversion. Patients should be counseled on the possibility of back injury, even compression fracture, as a result of cardioversion. It would also be prudent to broaden the differential diagnosis possibilities should a patient complain of back pain after cardioversion.",
"affiliations": "Banholzer Clinic, Malcolm Grow, Joint Base Andrews, MD, USA.",
"authors": "Koda|Erik K|EK|",
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"doi": "10.12659/AJCR.927064",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n33170832\n10.12659/AJCR.927064\n927064\nArticles\nLumbar Compression Fracture Caused by Cardioversion\nKoda Erik K. BEF Banholzer Clinic, Malcolm Grow, Joint Base Andrews, MD, U.S.A.\nCorresponding Author: Erik K. Koda, e-mail: erik.k.koda.civ@mail.milAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n10 11 2020 \n21 e927064-1 e927064-3\n26 6 2020 10 9 2020 28 9 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 46-year-old\n\nFinal Diagnosis: Lumbar compression fracture\n\nSymptoms: Low back pain\n\nMedication:—\n\nClinical Procedure: Cardioversion\n\nSpecialty: Family Medicine\n\nObjective:\nDiagnostic/therapeutic accidents\n\nBackground:\nCardioversion is a safe, commonly used procedure throughout the world. It is performed over 30 000 times per year in the United States, specifically for atrial fibrillation. Procedural risks from cardioversion include clot dislodgement, sedation effects, site pain, burns, hypotension, dysrhythmias, or heart failure. Generally, back pain is considered to be simple muscle soreness, and cardioversion consents therefore do not include discussion of back injuries.\n\nCase Report:\nA 46-year-old man with no prior back pain or injury history underwent a planned synchronized cardioversion for atrial fibrillation. He immediately reported new back pain following the procedure. No unusual event such as a fall occurred near the time of the procedure, but upon evaluation, he was found to have a new lumbar compression fracture that caused incapacitating pain for more than 6 weeks.\n\nConclusions:\nCardioversion has been found to be a safe, effective treatment for atrial fibrillation. Adverse effects are generally minor, and the frequency of adverse effects appear to be low overall. The case reported here represents a rare, but possibly underreported adverse effect, namely, lumbar compression fracture due to cardioversion. Patients should be counseled on the possibility of back injury, even compression fracture, as a result of cardio-version. It would also be prudent to broaden the differential diagnosis possibilities should a patient complain of back pain after cardioversion.\n\nMeSH Keywords:\nElectric CountershockFractures, CompressionIntraoperative Complications\n==== Body\nBackground\nApproximately 30 000 cardioversion procedures are performed annually in the United States for atrial fibrillation alone [1]. Cardioversion is generally safe, and it is well indicated for several cardiac conditions. Procedural risks from cardioversion include clot dislodgement, sedation effects, site pain, burns, hypotension, dysrhythmias, or heart failure. Typically, a transesophageal echocardiogram is done prior to the procedure to ensure that no clots are present within the heart. Postprocedural back pain is often considered to be simple muscle soreness. Therefore, cardioversion consents do not include a discussion of potential back injuries. This case highlights a possible major adverse effect that should be considered in the differential diagnosis of pain that occurs after cardioversion.\n\nCase Report\nA 46-year-old man with frequent atrial fibrillation symptoms that were refractory to medical management underwent synchronized cardioversion. He presented with palpitations and a heart rate in the range of 120 to 130 beats per minute. His vital signs were otherwise normal. His weight was weighed 137 kg, his height was 1.9 m, and his body mass index was 38.9 kg/m2. Laboratory test results on the morning of the procedure revealed normal values for calcium, magnesium, creatinine, hematocrit, troponin, and international normalized ratio. Following an unremarkable transesophageal echocardiogram, he was cardioverted with pads placed on the anterior chest and midback to a normal sinus rhythm with 1 shock at 200 J. The procedure and recovery were uneventful, but immediately upon coming out of procedural sedation, he reported new severe low back pain. The procedure had not been complicated by any mishap, fall, or traumatic injury.\n\nThe patient’s past medical history included atrial fibrillation and nephrolithiasis. He had no history of back pain, and his electronic medical record did not show any medical encounters for back issues in the previous 12 years. His only surgery was cholecystectomy. The medication list included diltiazem 240 mg (extended release) daily and apixaban 5 mg twice a day. He used smokeless tobacco (one-quarter tin daily), and his alcohol use was normal based on his AUDIT-C score.\n\nDifferential diagnoses included lumbar back strain, myofascial pain, preexisting condition, herniated disc, pathological fracture, and injury-related lumbar fracture.\n\nThe initial assessment suggested probable back spasms while the patient was recovering from sedation, and he was treated with acetaminophen, transdermal lidocaine, and cyclobenzaprine. He later tried diclofenac gel and injectable ketorolac without any relief. Auricular acupuncture and cupping provided relief so that he could stand and walk relatively pain free. Diazepam helped slightly for sleeping, but his sleep was poor due to pain associated with any sitting or lying position.\n\nHe continued to have severe pain regardless of position. Due to the ongoing, poorly relieved symptoms, an X-ray was obtained and showed an L1 vertebral anterior wedge compression fracture with 30% compression. No bony tumor was seen. On X-ray, the bones appeared normal, and owing to the patient’s history, sex, and body habitus, osteoporosis did not appear to be a factor. Lumbar magnetic resonance imaging confirmed the L1 compression fracture with 50% anterior to mid-vertebral body loss of height, marrow edema in the upper 50% of L1, endplate edema, and L4–L5 mild disc bulge with mild left foraminal stenosis (Figure 1). No osteoporotic change, pathologic lesion, or posterior compromise was noted. Testing for testosterone, 25-hydroxy vitamin D, thyroid functions, hemoglobin A1C, and glucose repeat yielded normal results.\n\nThe patient needed diazepam or hydrocodone and acetaminophen in order to get any sleep for over 6 weeks after the procedure. Even after 6 weeks, he was unable to sleep well or to tolerate any pressure against the L1 vertebra due to pain. Furthermore, he had progressive L1–L2 bilateral sensory neuropathy that worsened over time and spread to his thighs and testicles. As a consequence, he was referred to neurosurgery and treated with gabapentin. The severe pain started to subside after 7 weeks.\n\nConclusions\nCardioversion is commonly performed for atrial fibrillation to reduce the risk of stroke and is successful in 67% to 91% of cases [2], with variability related to the amount of energy delivered and duration of symptoms. The risks commonly associated with cardioversion include clot dislodgement potentially resulting in a stroke; sedation adverse effects, such as aspiration or respiratory depression; shock site pain; burns; transient hypotension; other dysrhythmias; heart failure or injury; or skin damage. A recent assessment of the safety of cardio-version for acute atrial fibrillation indicated that among 419 cases, iatrogenic hyponatremia occurred in 1 case, but there were no reports of strokes, major bleeding, serious dysrhythmias, or peripheral thromboembolism [3]. The study noted 9 first- or second-degree burns, which were attributed to a batch of faulty pads. Typical risk factors for vertebral compression fractures are osteoporosis, estrogen deficiency, falls, trauma, low body mass index, tobacco use, frailty, impaired eyesight and impaired physical activity increasing fall risk, malignancy, calcium deficiency, and vitamin D deficiency [4]. Tonic-clonic seizures have also been known to cause lumbar compression fractures. The patient in the current report had none of these risk factors other than light tobacco use.\n\nLumbar compression fractures are most commonly caused by osteoporosis or trauma, such as from falls or accidents. The only 2 cases of vertebral fractures from electrical energy found on a PubMed literature search were a 1987 case in Italy due to a direct current defibrillation for ventricular fibrillation [5] and a 1983 case in Brazil, which had no available English abstract [6]. One other case found via an online search was from 1968; it involved 21 shocks, most at maximal energy settings [7]. The first shock in that case was for a slow idioventricular rhythm, and the last 20 were for ventricular fibrillation. Of the 2 reviewable cases in the literature, both involved treatments for ventricular fibrillation and stronger defibrillation energies.\n\nCardioversion for atrial fibrillation is overall a safe, effective procedure. The case presented here is unique in that a rare complication of cardioversion occurred with the delivery of much lower electrical energy than in prior reported cases. It is possible that this adverse effect of cardioversion occurs periodically, but it is not reported. Counseling patients on this possible, rare adverse effect would be prudent, especially in patients at higher risk, such as those with low bone density. Vertebral compression fracture should be included in the differential diagnoses for severe back pain after cardioversion procedures.\n\nStatement\n\nThe views expressed in this article do not represent the views of the United States Air Force or the Department of Defense.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Magnetic resonance imaging scan illustrating the patient’s lumbar compression fracture.\n==== Refs\nReferences:\n1. Martin-Doyle W Essebag V Zimetbaum P Reynolds MR Trends in U.S. hospitalization rates and rhythm control therapies following publication of the AFFIRM and RACE trials J Cardiovasc Electrophysiol 2011 22 5 548 53 21087329 \n2. Lévy S Lauribe P Dolla E A randomized comparison of external and internal cardioversion of chronic atrial fibrillation Circulation 1992 86 5 1415 20 1423954 \n3. Bonfanti L Annovi A Sanchis-Gomar F Effectiveness and safety of electrical cardioversion for acute-onset atrial fibrillation in the Emergency Department: A real-world 10-year singe center experience Clin Exp Emerg Med 2019 6 1 64 69 30944291 \n4. Old JL Calvert M Vertebral compression fractures in the elderly Am Fam Physician 2004 69 1 111 16 14727827 \n5. Giacomoni P Cremonini R Cristoferi E [Vertebral fracture caused by electric cardioversion] G Ital Cardiol 1987 17 6 543 45 [in Italian] 3666381 \n6. Xavier SS Vertebral fracture during electric cardioversion. Report of a case Arq Bras Cardiol 1983 40 5 337 39 6651568 \n7. Okel BB Vertebral fracture from cardioversion shock JAMA 1968 203 5 369\n\n",
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"journal": "The American journal of case reports",
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"mesh_terms": "D001281:Atrial Fibrillation; D004554:Electric Countershock; D050815:Fractures, Compression; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008875:Middle Aged; D016103:Spinal Fractures",
"nlm_unique_id": "101489566",
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"pubdate": "2020-11-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21087329;6651568;14727827;30944291;1423954;3666381",
"title": "Lumbar Compression Fracture Caused by Cardioversion.",
"title_normalized": "lumbar compression fracture caused by cardioversion"
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"abstract": "The recently revised ISSVA classification approved in Melbourne in April 2014 recognizes generalized lymphatic anomaly and lymphatic malformation in Gorham-Stout disease. The 2 entities can overlap in presentation, as both are characterized by destructive lymphatic vessel invasion of the axial skeleton and surrounding soft tissues. At least at present, no standard therapeutic options exist, and due to the rarity of the disease, no clinical trials are available. We present 2 patients, 1 with generalized lymphatic anomaly and 1 with lymphatic malformation in Gorham-Stout disease, with severe exacerbation during puberty. The first child presented in florid pulmonary failure and pleural effusion, the other with severe pain due to bone destruction of the pelvis and inability to walk. Both were treated using individualized protocols. The manuscript describes the rationale for choosing sunitinib in combination with low-dose (metronomic) taxol. Both patients experienced clinical and radiologic response without major toxicities, suggesting that patients with rare conditions may benefit from individualized, molecularly based therapies.",
"affiliations": "*Division of Pediatric Hematology/Oncology †Division of Pediatric Radiology ‡Institute of General Pathology, University Hospital of Freiburg, Freiburg §Institute of Pathology, Charité University Medicine Berlin, Berlin, Germany ∥Pediatric Hematology Oncology ¶Newman Lakka Institute for Personalized Cancer Care, Floating Hospital for Children at Tufts Medical Center, Boston, MA.",
"authors": "Rössler|Jochen|J|;Saueressig|Ulrich|U|;Kayser|Gian|G|;von Winterfeld|Moritz|M|;Klement|Gianoula L|GL|",
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"fulltext": "\n==== Front\nJ Pediatr Hematol OncolJ. Pediatr. Hematol. OncolMPHJournal of Pediatric Hematology/Oncology1077-41141536-3678Lippincott Williams & Wilkins 10.1097/MPH.000000000000043600019Online Articles: Original ArticlesPersonalized Therapy for Generalized Lymphatic Anomaly/Gorham-Stout Disease With a Combination of Sunitinib and Taxol Rössler Jochen MD*Saueressig Ulrich MD†Kayser Gian MD‡von Winterfeld Moritz MD§Klement Gianoula L. MD, FRCP(C)∥¶* Division of Pediatric Hematology/Oncology† Division of Pediatric Radiology‡ Institute of General Pathology, University Hospital of Freiburg, Freiburg§ Institute of Pathology, Charité University Medicine Berlin, Berlin, Germany∥ Pediatric Hematology Oncology¶ Newman Lakka Institute for Personalized Cancer Care, Floating Hospital for Children at Tufts Medical Center, Boston, MAReprints: Giannoula L. Klement, MD, FRCP(C), Division of Pediatric Hematology Oncology, Floating Hospital for Children at Tufts Medical Center, 800 Washington Street, Boston, MA 02115 (e-mail: glakkaklement@tuftsmedicalcenter.org).11 2015 26 10 2015 37 8 e481 e485 10 5 2015 29 8 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.Supplemental Digital Content is available in the text.\n\nThe recently revised ISSVA classification approved in Melbourne in April 2014 recognizes generalized lymphatic anomaly and lymphatic malformation in Gorham-Stout disease. The 2 entities can overlap in presentation, as both are characterized by destructive lymphatic vessel invasion of the axial skeleton and surrounding soft tissues. At least at present, no standard therapeutic options exist, and due to the rarity of the disease, no clinical trials are available. We present 2 patients, 1 with generalized lymphatic anomaly and 1 with lymphatic malformation in Gorham-Stout disease, with severe exacerbation during puberty. The first child presented in florid pulmonary failure and pleural effusion, the other with severe pain due to bone destruction of the pelvis and inability to walk. Both were treated using individualized protocols. The manuscript describes the rationale for choosing sunitinib in combination with low-dose (metronomic) taxol. Both patients experienced clinical and radiologic response without major toxicities, suggesting that patients with rare conditions may benefit from individualized, molecularly based therapies.\n\nKey Words:\nGorham-Stout Diseasegeneralized lymphatic anomalylymphatic malformationtreatmentmanagementsunitinibtaxolmetronomic chemotherapylymphangiogenesischylothoraxSDCTOPEN-ACCESSTRUESTATUSONLINE-ONLY\n==== Body\nThis manuscript presents 2 types of systemic lymphatic malformations described in the recently revised ISSVA classification approved in Melbourne in April 2014.1 Generalized lymphatic anomaly (GLA) is characterized by multifocal lymphatic malformation affecting the skin and superficial soft tissues, viscera of the abdominal and thoracic cavities, and bone. The bone disease in GLA usually spares the bone cortex, and does not progress with time. GLA can present with acute or persistent pericardial, pleural, or peritoneal effusions. Although the lymphatic malformation in Gorham-Stout disease (GSD) is also characterized by lymphatic malformation affecting a single or multiple bones and adjacent soft tissues, the osteolysis is progressive and invades the bone cortex. It was originally described in the orthopedic literature as disappearing or vanishing bone disease.2–4 The progression of GSD often includes visceral progression with thoracic and abdominal involvement leading to effusions and ascites. Pathologic fractures occur in both GLA and GSD, even though they are more frequent in GSD.\n\nThe older literature can be confusing as clinicians often describe involvement of soft tissues and visceral organs by lymphatics as “congenital lymphangiomatosis,” “disseminated lymphangiomatosis,” or “multifocal lymphangiomatosis.” These terms are better to be avoided because they are not very helpful for prognostication or in guiding future medical management.\n\nIn addition to the skeleton, systemic lymphatic disease often includes aggressive unremitting proliferation of lymphatic vessels in lungs, spleen, and other visceral organs.5–7 This aggressive disease benefits from early intervention. In contrast, many patients with GLA can be safely observed, and timely management depends on correct diagnosis. At least at present, there are no molecular markers or radiologic features that can identify the patient at risk for progression. Some clinicians feel that multiple lesions with distinct sclerotic edges may suggest disease that will remain stable for years, and that the presence of a soft tissue component and/or pleural effusion may identify disease more likely to progress,7 but even for experts, defining an incipient progression is difficult.\n\nNotable are also the differences in the character of the disease across the life span. Commonly, a previously quiescent disease is exacerbated by puberty,8,9 suggesting an anabolic effect of sex-specific steroids on the lymphatic vasculature. Although in early childhood most GLA/GSD diagnoses are incidental findings of a lytic lesion during a trauma evaluation, the diagnoses of GSD/GLA during puberty/adolescence are usually due to symptoms associated with disease progression.9,10\n\nFor those pediatricians working without the help of a vascular anomalies expert, it is often difficult to recognize an acute exacerbation of systemic lymphatic lesions such as GLA/GSD and recommend the most appropriate early intervention. GLA, because of its resemblance to metastatic lesions is often referred to oncology, whereas GSD is usually evaluated by orthopedics. The referral to a vascular anomalies center is often delayed and the window of opportunity is often missed until the disease gathers an unremitting course, involving multiple organs leading eventual cardiovascular collapse. Even though there are no standard therapies for GLA, early case reports indicate that stabilization of the disease and/or remission can be achieved. As is the case with many rare diseases, a large spectrum of interventions has been used and includes: glucocorticoids, radiation, bisphosphonates, combination of radiation and bisphosphonates, pegylated-interferon, regular interferon and heparin, bevacizumab, or thalidomide.\n\nThe treatment varies widely. A retrospective analysis of 67 cases (64 published in Chinese and 3 in English) from 54 publications were analyzed,11 and the treatment varied from surgery (n=27, 40.3%), radiation therapy (n=6, 9.0%), surgery combined with radiation therapy (n=2, 3.0%), and medical therapy (n=7, 10.4%), such as interferon (n=2), bisphosphonates (n=1), calcium/vitamin D (n=1), cyclophosphamide/5FU (n=2), and calcitonin/alendronate (n=1). The few available larger case series10,12 also included cases before the emergence of molecular markers and the efficacy of the used oncological therapies could not be assessed. Recently, a successful use of bevacizumab, an antibody against vascular endothelial growth factor (VEGF), in a Gorham-Stout disease patient was reported.13\n\nAs oncology embraces molecularly based therapeutics, many promising antiangiogenic agents and combinations that may be useful in GLA/GSD are being accepted, and sharing these strategies is extremely important. In absence of evidence-based, disease-modifying, curative therapy for GLA/GSD, this manuscript provides a rational approach to individualizing the treatments of patients with GLA/GSD on the basis known biology, and their tissue-specific molecular markers. We used a synergistic combination of sunitinib, a direct inhibitor of angiogenesis, and low-dose metronomic schedule14 of taxol to minimize toxicity in this nonmalignant disease.\n\nCASE REPORTS\nThe patients and their guardians were informed of the risks, benefits, and therapeutic alternatives before treatment on an individualized protocol. It was stressed that their lesions were not amenable to more standard therapeutic approaches such as surgery or sclerotherapy, and they understood that the goal of the therapy was disease stabilization rather than cure.\n\nThe first patient was initially diagnosed with GLA at the age of 7 years. He presented with recurrent coughing leading to the diagnosis of a left-sided chylothorax requiring multiple drains. The effusion did not recede despite a medium chain triglyceride (MCT) diet. The child’s pulmonary disease was exacerbated as he entered puberty. By 13 years, he had severe pulmonary insufficiency, and large persistent bilateral chylous pleural effusions due to the presence of bilateral paravertebral lymphatic malformation extending from third to seventh thoracic vertebrae. He had undergone external drainage of the pleural effusion followed by pleurodesis, with minimal improvement in symptoms. Immunohistochemistry of this pleural biopsy showed D2-40 and CD31+ endothelium with expression of PDGFR and VEGFR1 (Fig. 1). At the time of this child’s diagnosis, there was no clinically applicable antibody for VEGFR2, but there was sufficient overlap between VEGFR1 and 2 and 3 using the ZYTOMED Systems (GmbH, Berlin) antibody to justify its use. The choice of PDGFR was based on previously published data on its expression in Gorham disease.15 The child ultimately required tracheostomy for long-term airway management, and a gastroduodenostomy to facilitate low fat, MCT diet. It was at this late point of the disease progression that he was referred to the oncologist. He was initially treated with sarcoma-like therapy with 2 cycles of cyclophosphamide (1500 mg/m2) and vincristine (1.5 mg/m2). Despite severe side effects such as neutropenia, sepsis, and candidiasis, this regimen provided no benefit. After 2 months on mechanical ventilation, and no standard therapeutic options, we reviewed the tissue markers with hope to develop new approaches for this child. Although it is not always possible to do colocalization studies to establish that lymphatic endothelium is positive for tyrosine kinase receptors such as VEGFR and PDGFR in clinical setting, the pleural biopsy showed D2-40+ and CD31+ endothelium, with PDGFR+ and VEGFR-1/2+ expression in the same vascular pattern (Fig. 1) providing some reassurance about the histologic configuration. The goals of the therapy, namely disease stabilization and extubation, were clearly identified to parents, and consents obtained before initiation of treatment. The child’s therapy was then changed to sunitinib 12.5 mg daily and taxol 10 mg/m2/once weekly. The dose of taxol was increased every 4 weeks up to 60 mg/m2/once weekly, and was tittered to avoid myelosuppression. There were no significant toxicities with this regimen, no peripheral neuropathy, no neutropenia, and no increase in infections. Over the subsequent 12 months, he was weaned off mechanical ventilation, extubated, and weaned from 8 to 10 L of O2 to room air (supplemental data, Table 1, Supplemental Digital Content 1, http://links.lww.com/JPHO/A111). He had both clinical and radiologic regression of the pulmonary infiltration, as well as of the soft tissue lesions (Fig. 2). Unfortunately, the patient later relapsed on therapy, required reintubation, and ultimately succumbed to the disease.\n\nFIGURE 1 Immunhistochemistry of pleural biopsy in case 1 (A), and of left ileosacral soft tissue in case 2 (B). Formalin-fixed, paraffin-embedded archival tissues were processed using standard IHC methods and stained with anti-VEGFR-1, anti-PDGFR, and anti-podoplanin (D2-40) antibodies (all from ZYTOMED Systems; GmbH) at 1:20 dilution. In both cases the CD34+ endothelium was also positive for D2-40 confirming its lymphatic origin. Further support for the therapy was the positive staining for PDGFR and VEGFR-1 tyrosine kinases, both targets of sunitinib. All images were taken at ×20 magnification with the exception of PDGFR and VEGFR in case B (ileosacral soft tissue), which was captured with ×40 lens. VEGFR indicates vascular endothelial growth factor receptor.\n\nFIGURE 2 Radiologic findings. For both patients T2-weighted magnetic resonance imaging at baseline (before initiation of therapy), at 6 and 18 months on therapy. In both, the thorax images for case 1 (A), and the pelvis images in case 2 (B) there is a marked reduction of the pathologic lymphatic tissue burden, as well as of the accompanying edema.\n\nThe second patient was diagnosed with GSD at the age of 14 years, after an episode of severe pain and swelling in the lower back after a football injury. The magnetic resonance imaging revealed a diffuse osteolytic lesion in the left ileosacral articulation, ileum, and sacrum, as well as in several vertebral bodies. The difficulty with histologic diagnosis necessitated 3 consecutive biopsies, leading to a recalcitrant lymphatic leak for over 3 weeks. This child also received MCT diet. The ileosacral articulation was stabilized by a supportive corset, which also provided some degree of vascular compression. As the lesion continued to progress, the decision was made to escalate therapy, but no standard therapeutic options were available. We again discussed with parents and clearly identified the goal of the potential targeted therapy, namely disease stabilization. We summarized this in a consent that included the risk, benefits, and goals of the various therapies used in the past. We then initiated a combination therapy with sunitinib 12.5 mg PO daily and intravenous taxol 10 mg/m2/once weekly. The child completed 12 months of therapy, and experienced gradual improvement in both clinical and radiologic measures (Fig. 2). There were no significant toxicities with this regimen, no peripheral neuropathy, no neutropenia, and no increase in infections. The therapy was stopped after a year, and he has remained stable for over 4 years.\n\nDISCUSSION\nThe classification of lymphatic lesions has recently been updated.1 By this new ISSVA classification, case 1 carries the diagnosis of “GLA” because pulmonary effusion was the first pathologic finding, and the second case with a large aggressively osteolytic lesion in the sacrum is a “lymphatic malformation in Gorham-Stout disease.” The purpose of this manuscript is to introduce new therapeutic options for GLA/GSD rather than review classification, and we refer the reader to recent publications discussing the differences between the 2 entities.7 Whether one views GSD/GLA as a continuum ranging from a single lymphatic malformation of the bone (monostotic), multiple but nonprogressive lytic lesions of the bone (polyostotic), to disseminated lymphangiomatosis with pulmonary compromise,6,16 the diagnostic distinction is important for management. Recognizing which lesion is likely to progress is more likely to lead to a timely referral to an experienced multidisciplinary team familiar with the disorder, and to institution of a timely and effective therapy.\n\nThe etiology of GLA/GSD remains unclear, even though the triggering effect of inflammation, puberty, and trauma is quite established. There are early indications that at least some of these osteolytic bone lesions are due to genetic mutations.17 The V-MAF—musculoaponeurotic fibrosarcoma oncogene family protein B was described in 11 cases of multicentric carpotarsal osteolysis syndrome by the Australian group of Zankl and Duncan,18 the lymphoedema-distichiasis syndrome described in 74 patients with FOXC2 mutation,19 the Nonne-Milroy syndrome in patients with FLT4/VEGFR3 mutation,20 hypotrichosis-lymphedema-telangiectasia in patients with SOX18,21,22 and primary GLA (Hennekam lymphangiectasia-lymphedema syndrome) in patients with CCBE1 mutation.23 It is very likely that with time additional genetic mutations will further clarify the spectrum of lymphatic malformations of the bone. Although the genetic alterations may be both germinal and/or somatic, neither GLA nor GSD are presently associated with a risk of malignant transformation.7\n\nThe pathogenesis of GLA/GSD is also unclear. Although some investigators believe that there is minimal cell turnover in the pathologic lesions of GLA or GSD, the disease is in fact characterized by an active proliferation of lymphatic endothelium,24 by platelet derived growth factor pathway activation,15 and by upregulation of a number of lymphangiogenesis stimulating pathways.5 A recent analysis of the cellular and humoral mechanisms underlying GSD25 compared the numbers and sensitivity to osteoclastogenic factors between age/sex-matched controls and a GSD patient. They found that even though the number of circulating osteoclast progenitors was not increased, the osteoclast precursors showed an increased sensitivity to IL-1β, IL-6/sIL-6R, and TNFα, leading to increased osteoclastic activity.\n\nIt is unclear whether the lymphatic vessel proliferation in GLA/GSD is a secondary or a primary event. Although physiologically normal, healthy lymphatic endothelium serves to decompress tissues by returning lymphatic fluid to venous circulation, its pathologic counterpart looses this directional flow and transforms into a leaky, invasive, and proliferative vascular meshwork. These types of leaky lymphatic endothelial cells have been well described in other lesions with pathologic lymphangiogenesis such as in Klippel-Trenaunay syndrome and kaposiform lymphangiomatosis, as well as in many malignancies. The invasive nature and bone destruction within these lesions can be surmised from the increased acid phosphatase activity in mononuclear phagocytes, multinuclear osteoclasts, and vascular endothelium.26 Furthermore, because lymphatic vessels are not present in healthy intact bones,27 lesions in both GLA and GSD are likely to represent a manifestation of systemic disease with either primary or secondary bone and soft tissue activation. In either way, activated lymphatic endothelium can be inhibited by a combination of metronomic therapy and antiangiogenic agent.14 The inhibition of activated stroma using this approach may be further amplified by inhibition of alternative pathways such as the PI3K/Akt/mTOR pathway by sirolimus. The efficacy of sirolimus in complex vascular anomalies such as kaposiform hemangioendothelioma and diffuse microcystic lymphangiogenesis has recently been published,28 but its efficacy had not been established at the time we needed intervention for our 2 patients. It should be pointed out here that the inhibition of the ras/raf/MAPK pathway by sunitinib had equivalent outcome to the inhibition of PI3K/Akt/mTOR pathway (extubation and stabilization of disease), suggesting that these 2 pathways are alternatives and inhibition of both would have synergistic effect.\n\nThe lack of understanding of the etiology and pathogenesis of GLA/GSD has been the biggest hindrance in developing effective therapeutic approaches. Although gene therapy may be possible one day for those sybtypes of systemic lymphatic malformations where a single genetic defect has been identified single gene mutations, many GLA/GSD patients will need therapy before then. Because both GLA and GSD are difficult to treat by surgery alone, systemic therapies need to be directed to minimizing the process of lymphangiogenesis, stromal invasion, and at maximizing bone restoration. Even though these lesions are not cancers, or even tumors, they grow and progress. Thus, even though they have not been historically thought to be proliferative, and are therefore presumed not to respond to traditional high-dose chemotherapy, they do grow and proliferate24 and are highly dependent on growth factors15 and can therefore be treated with biological agents. Because the target of metronomic chemotherapy is the tumor stroma rather than the cancer cell, the combination of low-dose metronomic chemotherapy and a direct angiogenesis inhibitor provides a good, minimally toxic therapeutic alternative for lymphatic malformations. The strategy has shown efficacy in preclinical and clinical settings.29 The rationale of using this particular combination of a tubulin inhibitor and direct anti-angiogenic agent was supported by the extreme sensitivity of endothelial cells (both lymphatic and microvascular) to tubulin inhibitors,30 and on the presence of increased levels of PDGFR and VEGFR1/2 in the patient tissues (Fig. 1). Unlike tumor cells, endothelial cells rely on cytoskeleton for both adhesion and polarization, and cannot grow in anchorage independent manner. Endothelial cells are also exquisitely dependent on continuous supply of growth factors and the combination of a direct angiogenesis inhibitor with low-dose tubulin inhibitor has been shown to lead to vascular collapse.14 The combination is particularly attractive in cases of histologically benign, but aggressively invasive disease such as GLA, because a long-term minimally toxic treatment is usually needed and because the likelihood of causing secondary malignancies with this regimen is extremely low.\n\nThe radiologic and clinical responses observed in the 2 patients presented in this manuscript support the applicability of this approach in GLA and severe progressive GSD. In our first case, an argument can be made that an earlier application of this therapeutic combination may have prevented the end-organ damage resulting from a long-standing pathologic lymphatic infiltration of pulmonary vasculature. He was diagnosed at 7 years of age, and as expected, his disease was exacerbated by puberty leading to irreversible respiratory compromise. Despite the chronicity of the pulmonary disease, he experienced a marked radiologic and clinical improvement on the combination regimen. It should also be noted that he required long-term therapy. Because long-term anti-angiogenic therapy has been shown to lead to tolerance,31 one is left to wonder if a drug holiday, or a change to an alternative regimen may have resulted in a better outcome for this child. Even though the damage caused by many years of chronic disease would not have been reversed, it is possible that a long-term quiescence may have ensued with changing the regimen.\n\nBoth of the cases presented in this manuscript showed with disease exacerbation during puberty. Although many experts in the vascular anomalies field have made this observation, there is paucity of studies on the topic. The frequency of disease exacerbation during puberty, pregnancy, and other conditions involving hormonally unstable states is consistent with the preclinical evidence of testosterone and estrogen having anabolic effect on the vasculature.32 The second inciting stimulus often observed in clinic is trauma. In the case of the second child, the inflammation accompanying an acute injury may have contributed to an exacerbation of otherwise quiescent disease. The inflammation associated with injury tends to disturb the balance of stimulators and inhibitors of lymphangiogenesis and can lead to progressive disease. A reinduction of disease quiescence and adequate control of the lymphatic endothelium proliferation using a combination of sunitinib and low-dose taxol, can reinstitute disease stability. Indeed, after only a year of therapy, the child has remained stable for over 3 years.\n\nIn conclusion, a timely referral to vascular anomalies centers with expertise in diagnosis and management of GLA and GSD, leads to timely therapy. In these rare diseases, tailoring the therapy to the underlying biology represents a very rational alternative. Because large randomized double blind clinical trials would be difficult, it will be essential to share both positive and negative experiences with specific molecularly based therapies, and record the outcomes obtained with specific individualized protocols. As more and more angiogenesis inhibitors and biological response modifiers are becoming available in an “off label” setting, collaborative consortia should be used to share these strategies and define the best future approaches.\n\nSupplementary Material\nSUPPLEMENTARY MATERIAL\n Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.jpho-online.com.\n\nG.L.K. was funded by NIH RO1 GM93050, and by philanthropic funding of Newman Lakka Cancer Foundation.\n\nThe authors declare no conflict of interest.\n==== Refs\nREFERENCES\n1 Wassef M Blei F Adams D \nVascular anomalies classification: recommendations from the international society for the study of vascular anomalies . Pediatrics . 2015 ;136 :e203 –e214 .26055853 \n2 Gorham LW Stout AP \nMassive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone); its relation to hemangiomatosis . Bone Joint Surg Am . 1955 ;37-A :985 –1004 .\n3 Pastakia B Horvath K Lack EE \nSeventeen year follow-up and autopsy findings in a case of massive osteolysis . Skeletal Radiol . 1987 ;16 :291 –297 .3616668 \n4 Klein M Metelmann HR Gross U \nMassive osteolysis (Gorham-Stout syndrome) in the maxillofacial region: an unusual manifestation . Int J Oral Maxillofac Surg . 1996 ;25 :376 –378 .8961021 \n5 Radhakrishnan K Rockson SG \nGorham’s disease: an osseous disease of lymphangiogenesis? \nAnn N Y Acad Sci . 2008 ;1131 :203 –205 .18519972 \n6 Radhakrishnan K Rockson SG \nThe clinical spectrum of lymphatic disease . Ann N Y Acad Sci . 2008 ;1131 :155 –184 .18519969 \n7 Lala S Mulliken JB Alomari AI \nGorham-Stout disease and generalized lymphatic anomaly—clinical, radiologic, and histologic differentiation . Skeletal Radiol . 2013 ;42 :917 –924 .23371338 \n8 Batt RE Michalski SR Mahl T \nPostmenarchal development of chylous ascites in acrocephalosyndactyly with congenital lymphatic dysplasia . Obstet Gynecol . 2001 ;97 (pt 2 ):829 –831 .11336770 \n9 Hassanein AH Mulliken JB Fishman SJ \nLymphatic malformation: risk of progression during childhood and adolescence . J Craniofac Surg . 2012 ;23 :149 –152 .22337394 \n10 Heritier S Le Merrer M Jaubert F \nRetrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009 . Orphanet J Rare Dis . 2010 ;5 :3 .20128925 \n11 Hu P Yuan XG Hu XY \nGorham-Stout syndrome in mainland China: a case series of 67 patients and review of the literature . J Zhejiang Univ Sci B . 2013 ;14 :729 –735 .23897792 \n12 Lopez-Gutierrez JC Miguel M Diaz M \nOsteolysis and lymphatic anomalies: a review of 54 consecutive cases . Lymphat Res Biol . 2012 ;10 :164 –172 .23215742 \n13 Grunewald TG Damke L Maschan M \nFirst report of effective and feasible treatment of multifocal lymphangiomatosis (Gorham-Stout) with bevacizumab in a child . Ann Oncol . 2010 ;21 :1733 –1734 .20605931 \n14 Klement G Baruchel S Rak J \nContinuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity . J Clin Invest . 2000 ;105 :R15 –R24 .10772661 \n15 Hagendoorn J Padera TP Yock TI \nPlatelet-derived growth factor receptor-beta in Gorham’s disease . Nat Clin Pract Oncol . 2006 ;3 :693 –697 .17139320 \n16 Rockson SG \nThe lymphatic continuum revisited . Ann N Y Acad Sci . 2008 ;1131 :ix –x .18519954 \n17 Brouillard P Boon L Vikkula M \nGenetics of lymphatic anomalies . J Clin Invest . 2014 ;124 :898 –904 .24590274 \n18 Zankl A Duncan EL Leo PJ \nMulticentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB . Am J Hum Genet . 2012 ;90 :494 –501 .22387013 \n19 Brice G Mansour S Bell R \nAnalysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24 . J Med Genet . 2002 ;39 :478 –483 .12114478 \n20 Ghalamkarpour A Morlot S Raas-Rothschild A \nHereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations . Clin Genet . 2006 ;70 :330 –335 .16965327 \n21 Moalem S Brouillard P Kuypers D \nHypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene . Clin Genet . 2015 ;87 :378 –382 .24697860 \n22 Irrthum A Devriendt K Chitayat D \nMutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia . Am J Hum Genet . 2003 ;72 :1470 –1478 .12740761 \n23 Gabrielli O Catassi C Carlucci A \nIntestinal lymphangiectasia, lymphedema, mental retardation, and typical face: confirmation of the Hennekam syndrome . Am J Med Genet . 1991 ;40 :244 –247 .1897580 \n24 Meijer-Jorna LB van der Loos CM de Boer OJ \nMicrovascular proliferation in congenital vascular malformations of skin and soft tissue . J Clin Pathol . 2007 ;60 :798 –803 .16816171 \n25 Hirayama T Sabokbar A Itonaga I \nCellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease . J Pathol . 2001 ;195 :624 –630 .11745700 \n26 Dickson GR Mollan RA Carr KE \nCytochemical localization of alkaline and acid phosphatase in human vanishing bone disease . Histochemistry . 1987 ;87 :569 –572 .3692922 \n27 Edwards JR Williams K Kindblom LG \nLymphatics and bone . Hum Pathol . 2008 ;39 :49 –55 .17904616 \n28 Hammill AM Wentzel M Gupta A \nSirolimus for the treatment of complicated vascular anomalies in children . Pediatr Blood Cancer . 2011 ;57 :1018 –1024 .21445948 \n29 Kareva I Waxman DJ Lakka Klement G \nMetronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance . Cancer Lett . 2015 ;358 :100 –106 .25541061 \n30 Wang J Lou P Lesniewski R \nPaclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly . Anticancer Drugs . 2003 ;14 :13 –19 .12544254 \n31 Kerbel RS Yu J Tran J \nPossible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches . Cancer Metastasis Rev . 2001 ;20 :79 –86 .11831651 \n32 Shweiki D Itin A Neufeld G \nPatterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis . J Clin Invest . 1993 ;91 :2235 –2243 .7683699\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1077-4114",
"issue": "37(8)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D059250:Administration, Metronomic; D000293:Adolescent; D002648:Child; D059350:Chronic Pain; D003131:Combined Modality Therapy; D004041:Dietary Fats; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D006801:Humans; D007211:Indoles; D044148:Lymphatic Abnormalities; D008297:Male; D010015:Osteolysis, Essential; D017239:Paclitaxel; D010384:Pelvic Bones; D010996:Pleural Effusion; D057285:Precision Medicine; D011758:Pyrroles; D011859:Radiography; D012008:Recurrence; D012074:Remission Induction; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D000077210:Sunitinib; D014280:Triglycerides",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e481-5",
"pmc": null,
"pmid": "26458155",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "23215742;23371338;23897792;24590274;25541061;24697860;10772661;7683699;8961021;16965327;17139320;16816171;17904616;18519954;18519969;18519972;20128925;20605931;21445948;22337394;22387013;13263344;26055853;11336770;11745700;11831651;12114478;12544254;12740761;3616668;3692922;1897580",
"title": "Personalized Therapy for Generalized Lymphatic Anomaly/Gorham-Stout Disease With a Combination of Sunitinib and Taxol.",
"title_normalized": "personalized therapy for generalized lymphatic anomaly gorham stout disease with a combination of sunitinib and taxol"
} | [
{
"companynumb": "US-BAXTER-2015BAX063465",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe the off-label medication use in a cohort of pregnant women.\n\n\nMETHODS\nWe performed a multicenter prospective longitudinal observational study in the Haute-Vienne department (France) called the NéHaVi cohort (\"Né en Haute-Vienne\" meaning \"born in Haute-Vienne\"). Women who had given birth to a viable baby in one of three maternity wards in the Haute-Vienne were included in the study after giving their informed consent. Data on the progress and outcome of pregnancies, childbirth, and drug or toxic exposure during pregnancy were collected. Drugs were classified, according to the labeling of the summary of product characteristics (SmPC) regarding the use in pregnancy, as follows: on-label, off-label at risk, and off-label contra-indicated.\n\n\nRESULTS\nDuring their pregnancy, the 397 included women gave birth to 400 viable babies (209 boys, 191 girls, 3 sets of twins). All women had used at least 1 health product: 3,533 (92%) drugs, 298 (7.5%) homeopathic products, and 18 (0.5%) herb derivatives. The mean number of different drugs taken was 8.9 ± 5.3 (min 1, max 31). All pregnant women used at least 1 drug either with a license or considered as safe to take during pregnancy. Among the 2,538 (71.6%) on-label drugs, the most frequently used were analgesics (n = 611, 24.1%) (acetaminophen (n = 566)), antianemia preparations (n = 528, 20.8%), drugs for functional gastrointestinal disorder (n = 269, 10.6%), vitamins (n = 192, 7.5%), drugs for acid-related disorders (n = 148, 5.8%), and antibacterials (n = 118, 4.6%). In total, 321 (80.9%, 95% CI: 77.0 - 84.7) pregnant women used at least 1 off-label drug; and more precisely, 285 (71.8%, 95% CI: 67.4 - 76.2) used at least 1 off-label high-risk drug, and 189 (47.6%, 95% CI: 42.7 - 52.5) at least 1 contra-indicated drug. Among the 995 off-label drugs (28.2%), 760 (21.5%) were considered high-risk, including vasoprotectives (n = 156, 20.5%) (treatment of hemorrhoids (n = 147)), antithrombotic agents (n = 91, 11.6%) (heparins (n = 88)), and calcium channel blockers (n = 88, 11.6%). Lastly, 235 (6.7%) off-label drugs used were contraindicated medications (non-steroidal anti-inflammatory drugs during the 3rd trimester (n = 231)). Five babies were born with malformations not related to the drugs used during pregnancy.\n\n\nCONCLUSIONS\nWe showed for the first time the magnitude of off-label prescription during pregnancy in France. Women and health professionals should be made more aware of the potential drug-induced risk during pregnancy. Drug adverse effects during pregnancy should be evaluated through an improved notification in pharmacovigilance and appropriate pharmacoepidemiologic studies in order to change SmPC labelings as early as possible, when necessary.",
"affiliations": null,
"authors": "Laroche|Marie-Laure|ML|;Blin|Aurora|A|;Coubret|Anne|A|;Grau|Muriel|M|;Roux|Barbara|B|;Aubard|Yves|Y|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "58(4)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D011307:Drug Prescriptions; D005260:Female; D005602:France; D006801:Humans; D008137:Longitudinal Studies; D056687:Off-Label Use; D011247:Pregnancy; D011446:Prospective Studies",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "198-208",
"pmc": null,
"pmid": "31933473",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Off-label prescribing during pregnancy in France: the NéHaVi cohort
.",
"title_normalized": "off label prescribing during pregnancy in france the n havi cohort"
} | [
{
"companynumb": "FR-ALKEM LABORATORIES LIMITED-FR-ALKEM-2020-00239",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYZINE HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nGanciclovir (GCV) is effective for prevention of cytomegalovirus (CMV) disease. In animals it may cause some teratogenicity. There is little information on the effect of GCV on a human fetus.\n\n\nMETHODS\nThe chart of a liver transplant recipient who received oral GCV during the first trimester was reviewed as was the published literature.\n\n\nRESULTS\nThere was no evidence of teratogenicity in the baby or in a case reported elsewhere.\n\n\nCONCLUSIONS\nGCV has been used in a few female transplant recipients without untoward effects. The still uncertain risk of short term and long term teratogenicity, however, must be weighed against the risk of CMV disease in the recipient and the development of congenital CMV in the baby.",
"affiliations": "Department of Surgery, Indiana University, Indianapolis 46202-5253, USA.",
"authors": "Pescovitz|M D|MD|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "United States",
"delete": false,
"doi": "10.1097/00007890-199903150-00021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "67(5)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents; D005260:Female; D005333:Fetus; D015774:Ganciclovir; D006084:Graft Rejection; D006801:Humans; D016031:Liver Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First; D012092:Replantation",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "758-9",
"pmc": null,
"pmid": "10096536",
"pubdate": "1999-03-15",
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"abstract": "Idiopathic pulmonary hemosiderosis is characterized by the triad of hemoptysis, iron deficiency anemia and pulmonary infiltrates. Though idiopathic pulmonary hemosiderosis has classically been described as a childhood disease, survival into adulthood is possible. Treatment options for advanced and/or refractory disease is limited, and in our unique case of idiopathic pulmonary hemosiderosis with precapillary pulmonary hypertension, lung transplantation has had a favorable short-term outcome. We also demonstrate that disease recurrence of idiopathic pulmonary hemosiderosis following lung transplantation is possible.",
"affiliations": "Department of Medicine, University of Alberta, Edmonton, Canada.;Department of Medicine, University of Alberta, Edmonton, Canada.;Department of Laboratory Medicine, University of Alberta, Edmonton, Canada.;Department of Surgery, University of Alberta, Edmonton, Canada.;Department of Medicine, University of Alberta, Edmonton, Canada.",
"authors": "Ross|Bryan|B|;Halloran|Kieran|K|;Adam|Benjamin|B|;Laing|Bryce|B|;Hirji|Alim|A|",
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"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30280-X\n10.1016/j.rmcr.2020.101128\n101128\nCase Report\nDisease recurrence after lung transplantation for idiopathic pulmonary hemosiderosis\nRoss Bryan bryan.ross@mail.mcgill.caad Halloran Kieran kieran.halloran@ualberta.caa Adam Benjamin baadam@ualberta.cab Laing Bryce blaing@ualberta.cac Hirji Alim ahirji@ualberta.caa∗ a Department of Medicine, University of Alberta, Edmonton, Canada\nb Department of Laboratory Medicine, University of Alberta, Edmonton, Canada\nc Department of Surgery, University of Alberta, Edmonton, Canada\nd Department of Medicine, McGill University, Montreal, Canada\n∗ Corresponding author. University of Alberta, 11350 83rd Street, 3-114F Clinical Sciences Building, Edmonton, Alberta, T6G 2G3, Canada. ahirji@ualberta.ca\n10 6 2020 \n2020 \n10 6 2020 \n30 10112826 5 2020 9 6 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Idiopathic pulmonary hemosiderosis is characterized by the triad of hemoptysis, iron deficiency anemia and pulmonary infiltrates. Though idiopathic pulmonary hemosiderosis has classically been described as a childhood disease, survival into adulthood is possible. Treatment options for advanced and/or refractory disease is limited, and in our unique case of idiopathic pulmonary hemosiderosis with precapillary pulmonary hypertension, lung transplantation has had a favorable short-term outcome. We also demonstrate that disease recurrence of idiopathic pulmonary hemosiderosis following lung transplantation is possible.\n\nKeywords\nIdiopathic pulmonary hemosiderosisPulmonary hypertensionLung transplantHemoptysisDisease recurrence\n==== Body\n1 Case presentation\nA 26-year-old female diagnosed with idiopathic pulmonary hemosiderosis (IPH) since age 5 presented for lung transplantation evaluation. She originally presented with childhood hemoptysis and underwent a comprehensive rheumatological and infectious workup including lung and kidney biopsy to rule out vasculitis and other potential etiologies. Without a secondary cause, she was diagnosed with idiopathic pulmonary hemosiderosis. To manage intermittent bouts of hemoptysis, she was maintained on prednisone and azathioprine, and treated with high-dose glucocorticoids during exacerbations.\n\nInto adulthood she developed progressive hypoxic respiratory failure with severe precapillary pulmonary hypertension (mean pulmonary arterial pressure 63 mmHg) requiring treatment with tadalafil and ambrisentan, as well as continuous subcutaneous treprostinil. Computed tomography images revealed extensive basal-predominant ground glass opacities (see Fig. 1).Fig. 1 Pre-transplant computed tomography images showing a dilated pulmonary artery suggestive of pulmonary hypertension (left) and extensive, basal-predominant, centrilobular ground glass opacities with smooth septal thickening (right).\n\nFig. 1\n\nPulmonary function revealed worsening forced vital capacity and diffusion capacity. At the age of 26, she underwent bilateral lung transplant. She developed severe primary graft dysfunction requiring veno-venous extracorporeal membrane oxygenation (vv-ECMO) support on day 2 post-transplant, and was eventually decannulated and liberated from ventilation one week post-transplant. Explant pathology revealed end-stage disease, diffuse alveolar septal fibrosis, extensive interstitial and airspace hemosiderin deposition, and marked fibrointimal thickening and medial hyperplasia of the pulmonary arteries (see Fig. 2).Fig. 2 Gross (left) and microscopic (right) pathology from explanted native lungs revealing diffuse homogeneous alveolar septal fibrosis with clusters of alveolar hemosiderin-laden macrophages and interstitial hemosiderin deposition.\n\nFig. 2\n\nLung function and oxygen saturations normalized post-transplant with no residual impairment in functional status. At 1.5 years post-transplant she experienced low-volume hemoptysis. Computed tomography revealed new lingular ground glass, and bronchoscopic samples revealed only hemosiderin-laden macrophages with negative microbiologic cultures. Repeat rheumatologic serology was negative and her presentation was deemed to be recurrence of her primary disease. Immunosuppression was augmented, by maintaining mycophenolate mofetil at 1000mg BID, tacrolimus target levels between 8 and 10 and prednisone increased to 30mg for 10 days followed by her standard dose of 5mg daily. With this management alone, her radiographic findings resolved. At 2.5 years post-transplant she developed a macular rash on her palms and soles and pulmonary nodules on chest x-ray. Rapid plasma reagin and syphilis enzyme immunoassay testing were reactive and she was diagnosed with pulmonary syphilis. Bronchoscopy cultures were negative, however alveolar hemosiderin deposits were again noted on cytological examination. She however has had no further bouts of hemoptysis and the syphilitic infection was successfully treated with IV penicillin.\n\n2 Discussion\nIPH is a rare cause of alveolar hemorrhage with an estimated incidence of approximately 0.24 [1]-1.23 [2] per million children. It is characterized by a triad of hemoptysis, iron deficiency anemia and pulmonary infiltrates [3]. 80% of cases are diagnosed in childhood, with a variable clinical trajectory [4,5]. Progressive hemosiderin-laden macrophage deposition occurs with recurrent alveolar bleeding episodes, ultimately leading to lung fibrosis. Although in general the prognosis of IPH is considered to be poor with a mean survival period of 2.5 years after diagnosis, long-term survival into adulthood is also observed [4]. A variety of imaging findings have been documented in the adult patient with IPH. Ground glass opacities and consolidation are typically observed in acute phases, while interlobular septal thickening and pulmonary fibrosis characterizes the chronic phase [6].\n\nVarious autoimmune, allergic, environmental and genetic mechanisms have been postulated [3,7]. The clinical response to immunosuppressive therapy additionally implicates immune processes in the pathogenesis of disease. The cornerstone of management of IPH remains chronic corticosteroids, with increased dosing during acute episodes. The evidence regarding the use of alternative therapeutic classes is lacking [8].\n\nThis is the first reported case of lung transplantation for IPH with concomitant pulmonary hypertension. To our knowledge, only two prior cases [9,10] have documented recurrence of IPH in the transplanted lung. The overall prognosis of IPH following lung transplantation is unknown. The present case demonstrates that these patients are at risk of severe group 3 pulmonary hypertension, and that successful outcomes are feasible following lung transplantation, and transplant should be considered if patients develop significant hypoxemia or functional limitation, despite maximal medical therapy. Lastly, disease recurrence remains a possibility following lung transplantation in this patient population, but can be successfully managed with augmented immunosuppression.\n\nConflict of Interest Statement\nNone of the authors have any conflicts of interest to disclose.\n\nSubmission declaration and verification\nThe work described has not been published previously and is not under consideration for publication elsewhere. Its publication is approved by all authors.\n\nAuthor contributions\nBR collected the relevant data, images and wrote the first draft of the manuscript. KH and BL helped collect data and write and review the manuscript. BA retrieved relevant pathology slides and reviewed the manuscript. AH helped collect data and write, review and finalize the manuscript.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nConsent\nInformed consent was obtained from the patient prior to submission for publication.\n\nDeclaration of competing interest\nNone.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2020.101128.\n==== Refs\nReferences\n1 Kjellman B. Elinder G. Garwicz S. Svan H. Idiopathic pulmonary haemosiderosis in Swedish children Acta Paediatr. Scand. 73 1984 584 588 6485774 \n2 Ohga S. Takahashi K. Miyazaki S. Kato H. Ueda K. Idiopathic pulmonary haemosiderosis in Japan: 39 possible cases from a survey questionnaire Eur. J. Pediatr. 154 1995 994 995 8801109 \n3 Taytard J. Nathan N. de Blic J. Fayon M. Epaud R. Deschildre A. Troussier F. Lubrano M. Chiron R. Reix P. Cros P. Mahloul M. Michon D. Clement A. Corvol H. New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare® cohort Orphanet J. Rare Dis. 8 2013 161 167 24125570 \n4 Le Clainche L. Le Bourgeois M. Fauroux B. Forenza N. Dommergues J.P. Desbois J.C. Bellon G. Derelle J. Dutau G. Marguet C. Pin I. Tillie-Leblond I. Scheinmann P. De Blic J. Long-term outcome of idiopathic pulmonary hemosiderosis in children Medicine 79 2000 318 326 11039080 \n5 Saeed M.M. Woo M.S. Mac Laughlin E.F. Margetis M.F. Keens T.G. Prognosis in pediatric idiopathic pulmonary hemosiderosis Chest 116 1999 721 725 10492278 \n6 Khorashadi L. Wu C.C. Betancourt S.L. Carter B.W. Idiopathic pulmonary haemosiderosis: spectrum of thoracic imaging findings in the adult patient Clin. Radiol. 70 2015 459 465 25515792 \n7 Ioachimescu O. Sieber S. Kotch A. Idiopathic pulmonary haemosiderosis revisited Eur. Respir. J. 24 2004 162 170 15293620 \n8 Chin C.I.C. Kohn S.L. Keens T.G. Margetis M.F. Kato R.M. A physician survey reveals differences in management of idiopathic pulmonary hemosiderosis Orphanet J. Rare Dis. 10 2015 98 26289251 \n9 Wroblewski B.M. Stefanovic C.R. McDonough V.M. Kidik P.J. The challenges of idiopathic pulmonary hemosiderosis and lung transplantation Crit. Care Nurse 17 1997 39 44 \n10 Calabrese F. Giacometti C. Rea F. Loy M. Sartori F. Di Vittorio G. Abudureheman A. Thiene G. Valente M. Recurrence of idiopathic pulmonary hemosiderosis in a young adult patient after bilateral single-lung transplantation Transplantation 74 2002 1643 1645 12490803\n\n",
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"keywords": "Disease recurrence; Hemoptysis; Idiopathic pulmonary hemosiderosis; Lung transplant; Pulmonary hypertension",
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"title": "Disease recurrence after lung transplantation for idiopathic pulmonary hemosiderosis.",
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"abstract": "Rhodococcus equi is a gram positive bacterium most commonly presenting clinically as pneumonia, however can disseminate to cause disease in virtually any human tissue. Although it is predominantly an opportunistic pathogen, a number of case series have described infection occurring among individuals with a normal immune system. We describe two cases of Rhodococcus equi infection which highlight the diversity of disease presentations of this rare organism.",
"affiliations": "Infectious Diseases Service, Department of Medicine, Sunshine Coast University Hospital, QLD, Australia.;Infectious Diseases Service, Department of Medicine, Sunshine Coast University Hospital, QLD, Australia.;Microbiology Department, Pathology Queensland, Sunshine Coast University Hospital, QLD, Australia.;Respiratory Medicine, Department of Medicine, Sunshine Coast University Hospital, QLD, Australia.;Infectious Diseases Service, Department of Medicine, Sunshine Coast University Hospital, QLD, Australia.",
"authors": "Stewart|Adam|A|;Sowden|David|D|;Caffery|Michael|M|;Bint|Michael|M|;Broom|Jennifer|J|",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30222-110.1016/j.idcr.2019.e00487e00487ArticleRhodococcus equi infection: A diverse spectrum of disease Stewart Adam adm_stewart@hotmail.coma⁎Sowden David abCaffery Michael bBint Michael cBroom Jennifer ada Infectious Diseases Service, Department of Medicine, Sunshine Coast University Hospital, QLD, Australiab Microbiology Department, Pathology Queensland, Sunshine Coast University Hospital, QLD, Australiac Respiratory Medicine, Department of Medicine, Sunshine Coast University Hospital, QLD, Australiad University of Queensland, School of Medicine, QLD, Australia⁎ Corresponding author at: Infectious Diseases Service, Department of Medicine, Sunshine Coast University Hospital, 6 Doherty St, Birtinya, QLD, 4575, Australia. adm_stewart@hotmail.com08 1 2019 2019 08 1 2019 15 e004876 12 2018 4 1 2019 4 1 2019 © 2019 Published by Elsevier Ltd.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Rhodococcus equi infection primarily causes pneumonia but can disseminate to cause disease in virtually any human tissue.\n\n• Increasing recognition that this pathogen can cause disease in both immunocompetent and immunocompromised hosts.\n\n• Two cases of invasive R. equi infection at both ends of the spectrum in terms of susceptibility and severity of disease.\n\n• High index of suspicion in a broad range of settings and communication with microbiologist is essential for early diagnosis.\n\n\n\nRhodococcus equi is a gram positive bacterium most commonly presenting clinically as pneumonia, however can disseminate to cause disease in virtually any human tissue. Although it is predominantly an opportunistic pathogen, a number of case series have described infection occurring among individuals with a normal immune system. We describe two cases of Rhodococcus equi infection which highlight the diversity of disease presentations of this rare organism.\n\nKeywords\nRhodococcus equiHuman immunodeficiency virusOpportunistic infectionCavitating pneumoniaSoft tissue infection\n==== Body\nIntroduction\nRhodococcus equi is a zoonotic organism which is a frequent cause of disease in a number of animals, including being the most common cause of pneumonia in foals [1]. It is a non-motile gram positive coccoid or bacillary organism found in high numbers on dry surface soil of farming and livestock properties [1]. Despite being a well-recognized pathogen in veterinary medicine, it has been known also to cause human disease, particularly in immunocompromised hosts [2]. Currently, infection remains a rare occurrence even among immunocompromised individuals [3]. Although pneumonia accounts for roughly 80% of clinical manifestations, R. equi can also cause wound infection, isolated bacteremia and abscesses in virtually any organ system [4]. There is increasing recognition that this pathogen can cause disease in both immunocompetent and immunocompromised individuals, but little is known about the human immunological response to this pathogen, or deficits which may predispose to clinical infection [5]. Due to the rarity and heterogeneity of disease, treatment recommendations for R. equi infection remain largely anecdotal and are often complicated frequent disease recurrences and clinical treatment failures [2]. In addition, there are reports of increasing antimicrobial resistance, particularly to rifampin and macrolides, and ideal treatment regimens in resistant cases are not clear [2]. We present two cases of invasive R. equi infection at both ends of the spectrum in terms of immunological susceptibility and severity of disease.\n\nCase 1\nA 33 year-old human immunodeficiency virus (HIV)-positive male who lived on a property with cattle and horses presented to a regional hospital with one month of fever, dry cough, six-kilogram weight loss, sweats and anorexia. He was not on antiretroviral therapy (due to CD4 + T cell counts previously >350/mm3 consistent with clinical practice standards at that time) for five years and had failed to attend a recent clinic appointment. Initial blood tests revealed a CD4+ T cell count drop to 20/mm3, HIV viral load >100 000 copies/mL, and an abnormal liver profile (GGT 352 IU/L, ALT 540 IU/L, AST 403 IU/L, ALP 99 IU/L). A chest x-ray showed a left lower lobe cavitating lung lesion. Further imaging with computed tomography (CT) showed a five cm cavitating lesion (Fig. 1) with an irregular thickened wall in the left lower lobe with adjacent interstitial opacification. A CT guided lung aspirate and biopsy was performed and sent for routine bacterial, fungal and mycobacterial culture. Rod-like organisms were seen within one macrophage on tissue staining. Rhodococcus equi was subsequently grown from the lung aspirate and blood cultures. Intravenous (IV) meropenem 1 g three times daily and vancomycin 1.25 g twice daily therapy were initiated.Fig. 1 Computed Tomography (CT) chest of Rhodococcus equi cavitating pneumonia in an HIV positive male with Acquired Immunodeficiency Syndrome (AIDS) (Case 1).\n\nFig. 1\n\nHe remained unwell with persistent fevers and progressive pancytopenia. He underwent a bone marrow aspirate and trephine that revealed a mildy hypercellular marrow with reactive changes and ample megakaryocytes; fungal and mycobacterial culture negative and no organisms were seen. Vancomycin was discontinued following concerns regarding drug-induced cytopenias, and the patient was temporarily supported with granulocyte-colony stimulating factor (G-CSF) 300 μg on alternate days. Oral ciprofloxacin 750 mg twice daily was added. Antiretroviral therapy was commenced and consisted of atazanavir 300 mg daily, ritonavir 100 mg daily and tenofovir/emtricitabine 300/200 mg daily six days after admission. Pulmonary consolidation worsened significantly after ART introduction, raising the possibility of an immune reconstitution inflammatory response. After an extended inpatient stay, he was discharged on home IV ertapenem 1 g daily, oral ciprofloxacin 750 mg twice daily, antiretroviral therapy, and prophylactic trimethoprim/sulfamethoxazole 80/400 mg daily and azithromycin 1 g weekly.\n\nOne month after discharge from hospital he was readmitted with headache, fevers and vomiting and a CT chest showed worsening left lower lobe consolidation and new multiple pulmonary nodules with cavitation of the larger nodules and a moderate left sided pleural effusion. His CRP had increased to 188 mg/L and his CD4+T cell count had increased to 210/mm3. A bronchoscopy and bronchoalveolar lavage (BAL) was performed which cultured Mycobacterium avium intracellulare. Combination therapy for Mycobacterium avium intracellulare infection included rifabutin 300 mg thrice weekly, ethambutol 800 mg daily, and clarithromycin 250 mg twice daily. Ertapenem was continued to make up three months total therapy for pulmonary R. equi infection before discontinuation; ciprofloxacin was continued for approximately two years. His respiratory symptoms improved and repeat CT chest six months after his original presentation to hospital showed significant improvement in left lower lobe consolidation and lymphadenopathy.\n\nCase 2\nA 53 year-old female teacher developed a small area of superficial redness and blistering over the dorsum of her left foot. She lived in an urban setting without exposure to farming or any animals, including horses. The patient had no relevant past medical history, regular medications, had never smoked nor consumed alcohol. She did not use recreational drugs. Her skin lesion was attributed to a friction injury secondary to new footwear. The lesion (Fig. 2) enlarged with more prominent erythema and swelling, and began to ulcerate over a three week period. She was systemically well and had no other skin lesions or lymphadenopathy.Fig. 2 Left foot Rhodococcus equi skin and soft tissue infection in an immunocompetent host (Case 2).\n\nFig. 2\n\nShe presented to her primary care physician and was prescribed multiple courses of oral β-lactam antimicrobials including amoxicillin and cephalexin for a presumed bacterial soft tissue infection, without improvement. Initial wound swabs failed to culture a pathogen and a punch biopsy revealed only granulation tissue. At this stage, the lesion had formed a verruciform erythematous plaque. The patient was reviewed by a dermatologist who performed a repeat biopsy and culture of the lesion and commenced treatment with doxycycline 100 mg twice daily. Histopathology results showed an acute suppurative neutrophilic inflammatory process suggestive of infection, with subsequent culture growing Rhodococcus equi. Fungal and mycobacterial cultures, and Mycobacterium ulcerans PCR, were all negative. Her chest x-ray, full blood count, liver and renal function were normal, and she had a negative HIV antibody test. In addition, her lymphocyte subsets, neutrophil function and immunoglobulin levels were within normal range. Doxycycline was discontinued and she commenced on oral ciprofloxacin 500 mg twice daily however this was ceased prematurely due to the development of a right Achilles tendinopathy. She was then started on oral rifampin 600 mg daily and clarithromycin 500 mg twice daily. Despite this, her left foot lesion began to worsen and she was admitted to hospital for further management, including plastic surgery and dermatology consultation. Left foot magnetic resonance imaging (MRI) did not reveal evidence of osteomyelitis or abscess formation. A decision was made to surgically excise the lesion and to apply a split skin graft. Her antimicrobial therapy consisted of oral azithromycin 500 mg daily and rifampicin 600 mg daily on admission with a plan for three months of total therapy. At outpatient review, her skin graft had taken well with evidence of good wound healing.\n\nDiscussion\nRhodococcus equi is an aerobic acid-fast gram positive coccobacilliary organism described first in the lungs of foals with pyogranulomatous pneumonia [6]. The first case of human infection was described in 1967 where a young male with autoimmune hepatitis on a corticosteroid and 6-mercaptopurine who worked on a stockyard fell ill with a cavitating pneumonia [7]. Cases of Rhodococcus equi infection remained remarkably rare until the early 1980s where HIV-related immunosuppression and solid organ transplantation became more common [8]. Improved microbiological laboratory identification techniques during this time undoubtedly also played a role. Rhodococcus equi can be cultured from water and soil worldwide and exposure to farm soil, animals or manure has frequently been reported to cause human cases of disease by inhalation, ingestion or direct inoculation [9]. A thick walled cavitating pneumonia is common and can be complicated by lung abscess, empyema, pneumothorax and mediastinitis [10]. R. equi can also cause a wide spectrum of disease and has been cultured from a variety of human tissues including heart valves, cerebrospinal fluid, skin, lymph nodes, bone and peritoneal fluid [11].\n\nThe immunological response and individual susceptibility to R. equi infection remains largely unknown. Most infected individuals have some defect in their cell mediated immune response [4]. Poor outcomes occur in CD4+ and CD8 T+ cell deficient mice with R. equi infection [12]. Infection involves HIV-infected individuals (primarily in patients with CD4+ T cell count <100/mm3), organ transplant recipients and individuals receiving chemotherapy for a malignancy, corticosteroids or anti-TNF antibody therapy. Increased risk is seen in those with diabetes, excessive alcohol intake, chronic kidney disease, hematological malignancy, lung cancer, and sarcoidosis [2,4]. Disease in immunocompetent individuals has been documented. The largest reported case series of R. equi infection in immunocompetent hosts evaluated 19 patients with a broad spectrum of disease apart from skin or soft tissue infections [5]. Although milder localized disease represented a higher proportion of illness in this series, invasive severe infections were still observed.\n\nExposure to livestock or contaminated soil appears to be important as an epidemiological link to disease. However, this may not be necessary for acquisition of R. equi infection [5]. As demonstrated in a large case series, 9 out of 19 patients did not provide such a history, as in Case 2 [5]. Exposures are more evident when the patient is immunocompromised, as noted in numerous case series involving HIV infected individuals and solid organ transplant recipients [2]. There has been one documented case of human-to-human transmission of pulmonary R. equi infection in two HIV infected males living together [13].\n\nRhodococcus sp. belongs to the family Nocardiaeceae, order Actinomycetes that includes Nocardia sp. and Mycobacterium sp [3]. It grows optimally at 30°C and classically produces pale salmon-pink colonies on solid media. Microbiological identification using standard culture techniques can be troublesome with R. equi occasionally being misidentified as Nocardia. Moreover, because it is partially acid fast, it can also be mistaken for a Mycobacterium [14]. Given that patients with impaired cell mediated immunity are susceptible to infection from all of these organisms, co-infection is possible (as in Case 1) and high clinical suspicion, close observation and accurate laboratory identification is needed. Identification of Rhodococcus sp. using molecular techniques such as the 16S rRNA sequencing method provides accurate identification [15]. Quantitative PCR testing has been used in the veterinary medicine setting with success but is yet to become standard practice in humans [16]. MALDI-TOF has been used to provide rapid and accurate identification of R. equi. Ultimately, early communication with the microbiology laboratory regarding clinical suspicion is essential to expedite accurate diagnosis.\n\nTreating R. equi infection is difficult, complicated by antimicrobial resistance, frequent treatment failures, and clinical relapses [2]. Little systematic data exists and treatment recommendations rely largely on animal studies and expert opinion. Available evidence suggests that combination therapy (at least two or three active agents) is superior to monotherapy [17]. This was indeed true in Case 2 where monotherapy led to treatment failure. Animal studies suggest that vancomycin, imipenem and rifampicin are most effective [18]. Bacterial clearance is dependent on the degree of immunocompromise and success of treatment often relies on immune reconstitution. A prolonged course of both intravenous and oral antimicrobial therapy is recommended [2]. Oral short course regimens have been used successfully in localised disease in immunocompetent individuals [5]. Surgical resection of local lesions should be considered early where treatment failure is likely and immune reconstitution unlikely.\n\nImmune reconstitution inflammatory syndrome (IRIS) after introduction of antiretroviral therapy (ART) in HIV positive patents with Rhodococcus equi pneumonia is described [19]. Patient 1 had significant worsening of his pneumonia following the introduction of antiretroviral therapy, raising the question of possible IRIS. The role of corticosteroids or anti-inflammatory agents in the management of this is unclear.\n\nConclusion\nRhodococcus equi infection is a rare and sometimes elusive disease affecting mainly those with impaired cellular immunity. This bacterium is known to reside in high numbers in dry farm soil and animal manure, with this epidemiological exposure often being a clue to diagnosis. However, cases where infection occurs in immunocompetent hosts without typical exposure histories are being documented. In addition, the full spectrum of disease ranging from mild localised infection to disseminated multiorgan disease with bacteraemia has been observed in both immunocompetent and immunocompromised hosts. These cases highlight that a high index of suspicion in a broad range of clinical settings, together with early communication with the microbiology department, is essential for diagnosis and institution of effective treatment for R. equi infection.\n\nConflict of interest\nNone.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Cohen N.D. Rhodococcus equi foal pneumonia Vet Clin North Am Equine Pract 30 3 2014 609 622 25282322 \n2 Yamshchikov A.V. Schuetz A. Lyon G.M. Rhodococcus equi infection Lancet Infect Dis 10 5 2010 350 359 20417417 \n3 Prescott J.F. Rhodococcus equi: an animal and human pathogen Clin Microbiol Rev 4 1 1991 20 34 2004346 \n4 Weinstock D.M. Brown A.E. Rhodococcus equi: an emerging pathogen Clin Infect Dis 34 10 2002 1379 1385 11981734 \n5 Kedlaya I. Ing M.B. Wong S.S. Rhodococcus equi infections in immunocompetent hosts: case report and review Clin Infect Dis 32 3 2001 E39 E46 11170969 \n6 Magnusson H. Spezilfi sche infektiose pneumonie beim fohlen: ein neuer eitererreger beim pferd Arch Wiss Prakt Tierheilkd 50 1923 22 38 \n7 Golub B. Falk G. Spink W.W. Lung abscess due to Corynebacterium equi. Report of first human infection Ann Intern Med 66 6 1967 1174 1177 6067513 \n8 Torres-Tortosa M. Prognosis and clinical evaluation of infection caused by Rhodococcus equi in HIV-infected patients: a multicenter study of 67 cases Chest 123 6 2003 1970 1976 12796176 \n9 Vazquez-Boland J.A. Rhodococcus equi: the many facets of a pathogenic actinomycete Vet Microbiol 167 1–2 2013 9 33 23993705 \n10 Muntaner L. Radiologic features of Rhodococcus equi pneumonia in AIDS Eur J Radiol 24 1 1997 66 70 9056153 \n11 Antinori S. Disseminated Rhodococcus equi infection initially presenting as foot mycetoma in an HIV-positive patient AIDS 6 7 1992 740 742 1503695 \n12 Kanaly S.T. Hines S.A. Palmer G.H. Failure of pulmonary clearance of Rhodococcus equi infection in CD4+ T-lymphocyte-deficient transgenic mice Infect Immun 61 11 1993 4929 4932 8104903 \n13 Arlotti M. Rhodococcus equi infection in HIV-positive subjects: a retrospective analysis of 24 cases Scand J Infect Dis 28 5 1996 463 467 8953675 \n14 Walsh R.D. Schoch P.E. Cunha B.A. Rhodococcus Infect Control Hosp Epidemiol 14 5 1993 282 287 8496585 \n15 Bharadwaj R. Clinical impact of the use of 16S rRNA sequencing method for the identification of \"difficult-to-identify\" bacteria in immunocompromised hosts Transpl Infect Dis 14 2 2012 206 212 22093075 \n16 Shaw S.D. Estimating the Sensitivity and Specificity of Real-Time Quantitative PCR of Fecal Samples for Diagnosis of Rhodococcus equi Pneumonia in Foals J Vet Intern Med 29 6 2015 1712 1717 26436545 \n17 Tse K.C. Rhodococcus lung abscess complicating kidney transplantation: successful management by combination antibiotic therapy Transpl Infect Dis 10 1 2008 44 47 17428277 \n18 Nordmann P. Kerestedjian J.J. Ronco E. Therapy of Rhodococcus equi disseminated infections in nude mice Antimicrob Agents Chemother 36 6 1992 1244 1248 1416823 \n19 Ferretti F. Disseminated Rhodococcus equi infection in HIV infection despite highly active antiretroviral therapy BMC Infect Dis 11 2011 343 22168333\n\n",
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"pubdate": "2019",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "17428277;22168333;8496585;20417417;25282322;22093075;6067513;2004346;1503695;12796176;8953675;9056153;11981734;1416823;8104903;26436545;11170969;23993705",
"title": "Rhodococcus equi infection: A diverse spectrum of disease.",
"title_normalized": "rhodococcus equi infection a diverse spectrum of disease"
} | [
{
"companynumb": "PHHY2019AU038378",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nPhotodynamic therapy (PDT) is an effective treatment of pachychoroid spectrum disease. PDT can cause a rare complication known as PDT-associated exudative maculopathy (PAEM). Treatments including intravitreal anti-vascular endothelial growth factor (anti-VEGF) medications, local or systemic steroids, and observation have been attempted with variable success to address this complication.\n\n\nMETHODS\nA thorough literature review was performed using the PubMed database on search terms aimed at treatments of PAEM. These cases were compared with each other and a novel case of PAEM in polypoidal choroidal vasculopathy (PCV) treated with oral prednisone by the authors.\n\n\nRESULTS\nFifteen patients were compared; 11 were treated with anti-VEGF alone or in combination with intravitreal steroid and/or vitrectomy, one was treated with topical steroid, one was observed, one was treated with intravenous methylprednisolone, and one was treated with oral prednisone. The two cases treated with systemic steroids were given adjunctive sub-tenon's triamcinolone acetonide (STTA) after a favorable response was observed. Most cases had anatomic resolution of serous retinal detachment with stability of vision between 16 days and 2 months, with the most rapid resolution occurring in a patient with PCV treated with oral prednisone and STTA.\n\n\nCONCLUSIONS\nReported treatment of PAEM includes intravitreal anti-VEGF agents with or without local or systemic steroids. Oral steroids may be advantageous in cases where there is concern regarding the risk profile of periocular steroids, intravitreal steroids or anti-VEGF agents. However, data describing the various treatments of this rare complication is limited, precluding firm conclusions regarding relative safety and efficacy.",
"affiliations": "Loma Linda University Eye Institute, Loma Linda, CA, USA.;Loma Linda University Eye Institute, Loma Linda, CA, USA.;Loma Linda University Eye Institute, Loma Linda, CA, USA.;Loma Linda University Eye Institute, Loma Linda, CA, USA. Electronic address: dsierpina@llu.edu.",
"authors": "Sumnicht|Andrew J|AJ|;Chalam|Kakarla V|KV|;Alset|Adel E|AE|;Sierpina|David I|DI|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D017319:Photosensitizing Agents; D013256:Steroids; D042461:Vascular Endothelial Growth Factor A",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.pdpdt.2021.102390",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1572-1000",
"issue": "35()",
"journal": "Photodiagnosis and photodynamic therapy",
"keywords": "Idiopathic polypoidal choroidal vasculopathy; Oral prednisone; Photodynamic therapy-induced acute exudative maculopathy",
"medline_ta": "Photodiagnosis Photodyn Ther",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D005451:Fluorescein Angiography; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D012189:Retrospective Studies; D013256:Steroids; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "101226123",
"other_id": null,
"pages": "102390",
"pmc": null,
"pmid": "34119709",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "The role of oral steroids in the treatment of photodynamic therapy-associated exudative maculopathy, a case report and review of the literature.",
"title_normalized": "the role of oral steroids in the treatment of photodynamic therapy associated exudative maculopathy a case report and review of the literature"
} | [
{
"companynumb": "US-BAUSCH-BL-2021-034646",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERTEPORFIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nHemophagocytic syndrome (HPS) is an infrequent complication of transplantation caused by an inflammatory response with a benign proliferation of macrophages and defective lytic capability of T lymphocytes and NK cells that can lead to multiorgan failure. Transplant patients are particularly exposed as a result of the increased risk of both infections and malignancies derived from immunosuppressive drugs. There is no consensus for therapy or immunosuppression; mortality is high. We report a case and present a review of all cases of HPS occurring in solid organ transplant recipients. CASE REPORT: We report two cases of infection by Toxoplasma gondii transmitted by the kidney allograft. One of the recipients was seronegative before transplantation and developed disseminated primary toxoplasmosis. An immune reaction compatible with an HPS ensued. Both were treated with Trimethoprim/sulfamethoxazole, immunosuppression was tapered, and after a 2-week period a complete response was obtained.\n\n\nCONCLUSIONS\nHPS presents therapeutic challenges in the context of transplantation. If HPS is suspected, the search of a very likely underlying infection should be central to the management.",
"affiliations": "Nephrology Department, Clínico San Carlos University Hospital, Madrid, Spain.;Nephrology Department, Clínico San Carlos University Hospital, Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Clínico San Carlos University Hospital, Madrid, Spain.;Nephrology Department, Clínico San Carlos University Hospital, Madrid, Spain.;Nephrology Department, Clínico San Carlos University Hospital, Madrid, Spain.;Nephrology Department, Clínico San Carlos University Hospital, Madrid, Spain.;Nephrology Department, Clínico San Carlos University Hospital, Madrid, Spain.;Nephrology Department, Clínico San Carlos University Hospital, Madrid, Spain.",
"authors": "Valdés Francí|Elena|E|https://orcid.org/0000-0002-5836-5868;Perez Flores|Isabel|I|;Candel|Francisco Javier|FJ|;Moreno de la Higuera|María Angeles|MA|;Romero|Natividad Calvo|NC|;Rodríguez Cubillo|Beatriz|B|;Lucena Valverde|Rafael|R|;Sánchez Fructuoso|Ana Isabel|AI|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13732",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": null,
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "donor-transmitted toxoplasmosis; hemophagocytic syndrome; transplant complications",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13732",
"pmc": null,
"pmid": "34533259",
"pubdate": "2021-09-17",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Hemophagocytic syndrome triggered by donor-transmitted toxoplasmosis as a complication in same-donor recipients of renal transplantation: Case report and review of the literature.",
"title_normalized": "hemophagocytic syndrome triggered by donor transmitted toxoplasmosis as a complication in same donor recipients of renal transplantation case report and review of the literature"
} | [
{
"companynumb": "ES-SA-2021SA343834",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BELATACEPT"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Safinamide (SF) is a third-generation monoamine-oxidase-B inhibitor that proved efficacy as add-on to levodopa in fluctuating Parkinson's disease (PD) patients. Despite the high prevalence of complicated PD in older population, the data on the tolerability, safety and efficacy of SF in elderly patients are rather poor. Here we studied retrospectively the consequences of add-on with SF in PD patients older than 65 years. Fifty-three fluctuating PD patients were included (30 subjects aged between 65 and 75 years, the remaining 23 subjects aged > 75 years). Patients were treated with either 50 (n = 27) or 100 mg (n = 26) SF for at least 6 months. In all patients, fluctuations were identified by the report of a Wearing-Off-Questionnaire-19 (WOQ-19) score ≥ 3 at baseline. Add-on with SF was well tolerated and safe. Adverse events occurred in 30% of patients and led to drug discontinuation in 11% of cases. At follow-up visits, 60% of patients reported lowering of the WOQ-19 score to ≤ 2. There were no significant differences related to age or daily drug dose in tolerability, safety or efficacy. The results of this study provide evidence of the efficacy, tolerability and safety of SF in elderly PD patients.",
"affiliations": "Dipartimento Di Neuroscienze, Salute Mentale E Organi Di Senso \"Sapienza, Università Di Roma, Via di Grottarossa, 1035, 00189, Roma, Italy.;Dipartimento Di Neuroscienze, Salute Mentale E Organi Di Senso \"Sapienza, Università Di Roma, Via di Grottarossa, 1035, 00189, Roma, Italy.;Dipartimento Di Neuroscienze, Salute Mentale E Organi Di Senso \"Sapienza, Università Di Roma, Via di Grottarossa, 1035, 00189, Roma, Italy.;Dipartimento Di Neuroscienze, Salute Mentale E Organi Di Senso \"Sapienza, Università Di Roma, Via di Grottarossa, 1035, 00189, Roma, Italy.;Dipartimento Di Neuroscienze, Salute Mentale E Organi Di Senso \"Sapienza, Università Di Roma, Via di Grottarossa, 1035, 00189, Roma, Italy.;Dipartimento Di Neuroscienze, Salute Mentale E Organi Di Senso \"Sapienza, Università Di Roma, Via di Grottarossa, 1035, 00189, Roma, Italy.;UOC Di Neurologia, Azienda Ospedaliera-Universitaria Sant'Andrea, Roma, Italy.;Dipartimento Di Neuroscienze, Salute Mentale E Organi Di Senso \"Sapienza, Università Di Roma, Via di Grottarossa, 1035, 00189, Roma, Italy. fe.pontieri@gmail.com.",
"authors": "Rinaldi|Domiziana|D|;Bianchini|Edoardo|E|;Sforza|Michela|M|;Alborghetti|Marika|M|;Galli|Silvia|S|;Salvetti|Marco|M|;Giovannelli|Morena|M|;Pontieri|Francesco E|FE|http://orcid.org/0000-0002-8693-8432",
"chemical_list": "D000978:Antiparkinson Agents; D001596:Benzylamines; C092797:safinamide; D000409:Alanine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s40520-020-01648-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1594-0667",
"issue": "33(6)",
"journal": "Aging clinical and experimental research",
"keywords": "Elderly; Parkinson’s disease; Safinamide; Wearing-off",
"medline_ta": "Aging Clin Exp Res",
"mesh_terms": "D000368:Aged; D000409:Alanine; D000978:Antiparkinson Agents; D001596:Benzylamines; D006801:Humans; D010300:Parkinson Disease; D012189:Retrospective Studies",
"nlm_unique_id": "101132995",
"other_id": null,
"pages": "1689-1692",
"pmc": null,
"pmid": "32681474",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "21696087;32529595",
"title": "The tolerability, safety and efficacy of safinamide in elderly Parkinson's disease patients: a retrospective study.",
"title_normalized": "the tolerability safety and efficacy of safinamide in elderly parkinson s disease patients a retrospective study"
} | [
{
"companynumb": "IT-MDD US OPERATIONS-E2B_00003389",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOPAMINE HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "Skin cancers are the most common malignancies in renal transplant recipients, with squamous-cell and basal-cell cancers accounting for the majority of all skin cancer cases. Melanoma is relatively rare in this group of patients. From 1973 to May 2017, out of 1889 patients who received allografts at our institution, 4 developed melanoma. After the mean follow-up of 11.5 months, 2 patients died and 2 are still alive with functioning allografts. Malignancies were localized in the legs in both female patients, and in the neck and head in 1 male patient each. Compared to the general population of Croatia, renal transplant recipients from our cohort have 6.85 times higher risk for development of melanoma. Regular screenings and patient education are mandatory, especially in Mediterranean countries.",
"affiliations": "Prof. Nikolina Bašić-Jukić, MD, PhD, Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia; nina_basic@net.hr.",
"authors": "Borlinić|Tajana|T|;Knežević|Tamara|T|;Gellineo|Lana|L|;Franceschi|Maja|M|;Bukvić Mokos|Zrinka|Z|;Bašić-Jukić|Nikolina|N|",
"chemical_list": null,
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1330-027X",
"issue": "25(4)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D000368:Aged; D017523:Croatia; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D012189:Retrospective Studies; D012878:Skin Neoplasms",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "281-284",
"pmc": null,
"pmid": "30064600",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Melanomas in Renal Transplant Recipients: A Single-center Study.",
"title_normalized": "melanomas in renal transplant recipients a single center study"
} | [
{
"companynumb": "HR-MYLANLABS-2018M1029626",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Congenital factor XIII deficiency is a very rare bleeding disorder affecting 33 patients in France. Besides its role in fibrin clot stabilization, factor XIII is involved in placental attachment. Fetal miscarriages represent a frequent and concerning issue for these patients. The aim of the present study was to describe clinical characteristics of women presenting severe congenital FXIII deficiency in France, to focus on gynecological and obstetrical events, and to report the management of these rare situations.\n\n\n\nWe conducted a retrospective study in the French Hemophilia Comprehensive Care and Clinical Hemostasis Centers. Women between 15 and 65 years with factor XIII activity <10 IU dL-1 were included. Biological, clinical and therapeutic events that occurred to these patients during their gynecological and obstetrical period were recorded.\n\n\n\nAmong 31 centers, eleven patients were included. The median age at diagnosis was 1.5 years (range: 0-35), and at inclusion it was 30 years (range: 15-63). Fetal miscarriage was the primary manifestations in 2 (18%) patients, the remaining were diagnosed during hemorrhage. Menorrhagias were reported by 2 women (27%), 13 pregnancies were reported by 9 women including one abortion. Every pregnancy was conducted under factor XIII substitution, no hemorrhagic episode was reported. Four patients (36%) experienced at least one fetal miscarriage with a total amount of 30 miscarriages with 6 occurring during substitution.\n\n\n\nAltogether, our data confirmed the high incidence of miscarriage in women with factor XIII deficiency. Good outcome of pregnancies required prophylaxis in accordance with international guidelines.",
"affiliations": "Hospices Civils de Lyon, Unité Hémostase Clinique, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France. Electronic address: lucia.rugeri@chu-lyon.fr.;Department of Medical Biology, Military Medical Center Percy, Clamart, France.;Centre de Traitement de l'Hémophilie, CHU Angers, Angers, France.;Unité Hémostase et Centre Régional de Traitement des maladies Hémorragiques, Institut de Biologie Clinique, Hôpital Charles Nicolle, Rouen, France.;Centre for Bleeding Disorders, Pediatric Haematology Oncology Department, University Hospital La Timone, AP-HM, and Aix Marseille Univ, INSERM, INRA, C2VN, Marseille, France.;Service d'Hématologie, Hôpital de Valence, Valence, France.;Centre de Traitement de l'Hémophilie, CHU Strasbourg, Strasbourg, France.;Hemophilia Care Centre, Hematology Unit, Hôpital Universitaire Necker Enfants Malades, Paris, France.;FranceCoag, University Hospital La Timone, AP-HM, Marseille, France.;Unité Hémostase Service hématologie, CHU Brest, Brest, France.;Hospices Civils de Lyon, Unité Hémostase Clinique, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France.",
"authors": "Rugeri|Lucia|L|;Martinaud|Christophe|C|;Beurrier|Philippe|P|;Borg|Yvonne|Y|;Chambost|Hervé|H|;Chirila-Hetsch|Mirela|M|;Desprez|Dominique|D|;Harroche|Annie|A|;Milien|Vanessa|V|;Pan-Petesch|Brigitte|B|;Meunier|Sandrine|S|",
"chemical_list": "D005176:Factor XIII",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2020.04.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "191()",
"journal": "Thrombosis research",
"keywords": "Factor XIII deficiency; Menorrhagia; Miscarriages; Pregnancy outcome",
"medline_ta": "Thromb Res",
"mesh_terms": "D000022:Abortion, Spontaneous; D005176:Factor XIII; D005177:Factor XIII Deficiency; D005260:Female; D005602:France; D006470:Hemorrhage; D006801:Humans; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "22-25",
"pmc": null,
"pmid": "32360976",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Gynecological and obstetric outcome in the French cohort of women with factor XIII deficiency.",
"title_normalized": "gynecological and obstetric outcome in the french cohort of women with factor xiii deficiency"
} | [
{
"companynumb": "FR-BEH-2020117765",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FACTOR XIII CONCENTRATE (HUMAN)"
},
"drugadditional"... |
{
"abstract": "Topiramate is an anticonvulsant that has been widely used in psychiatric conditions. The most common treatment-related adverse effects of topiramate were diarrhea, nausea, loss of appetite, fatigue, paresthesia, cognitive impairment, and metabolic acidosis. The following is a case report intended to draw attention to a rarely reported adverse effect of topiramate. A male patient treated with topiramate developed urinary incontinence that was considered drug associated because of the temporal relationship between its appearance and the commencement of topiramate, its resolution upon topiramate discontinuation, and its recurrence with topiramate rechallenge. Urinary incontinence, although not life threatening, can be a distressing problem with a profound impact on quality of life. This case reminds that physicians prescribing topiramate should be aware of this possible adverse effect and communicate it to patients and their caregivers.",
"affiliations": "*Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, and †Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.",
"authors": "Wang|Cheng-Fa|CF|;Ho|Pei-Shen|PS|;Tseng|Yu-Ting|YT|;Liang|Chih-Sung|CS|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "37(5)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D005632:Fructose; D006801:Humans; D008297:Male; D015203:Reproducibility of Results; D000077236:Topiramate; D014549:Urinary Incontinence",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "149-50",
"pmc": null,
"pmid": "25229172",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Topiramate-associated urinary incontinence: a case verified by rechallenge.",
"title_normalized": "topiramate associated urinary incontinence a case verified by rechallenge"
} | [
{
"companynumb": "TW-WATSON-2015-12304",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSystemic chemotherapy is the main treatment of diffuse and/or aggressive classic Kaposi's sarcoma (KS) but there are no standard treatment guidelines and published literature regarding vinorelbine is lacking.\n\n\nOBJECTIVE\nTo assess the safety and effectiveness of intravenous vinorelbine in the treatment of classic KS.\n\n\nMETHODS\nWe performed a retrospective study of a departmental database in histologically proven classic KS.\n\n\nRESULTS\nTwenty patients received intravenous vinorelbine as cycles of 20 mg/m(2) once every two weeks for 5 cycles and subsequently at a dose of 30 mg/m(2) once every three weeks. Of 19 assessable patients, three (16%) had a complete remission and 11 (58%) had a partial response, for an overall response rate of 74%. The remaining 5 patients had a stable disease (26%). Grade 3 or 4 toxicities were neutropenia (3/20 patients), deep vein thrombosis (1/20 patients) and constipation (1/20 patients). The median progression-free survival from the start of therapy until the development of progressive disease was 35.1 months.\n\n\nCONCLUSIONS\nVinorelbine is an effective and overall well tolerated treatment for classic KS.",
"affiliations": "U.O. Dermatologia, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, via Pace 9, 20122 Milano, Italy.;U.O. Dermatologia, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, via Pace 9, 20122 Milano, Italy.;U.O. Dermatologia, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, via Pace 9, 20122 Milano, Italy.",
"authors": "Brambilla|Lucia|L|;Recalcati|Sebastiano|S|;Tourlaki|Athanasia|A|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D011838:Radiation-Sensitizing Agents; D014747:Vinblastine; D000077235:Vinorelbine",
"country": "France",
"delete": false,
"doi": "10.1684/ejd.2015.2659",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1167-1122",
"issue": "25(6)",
"journal": "European journal of dermatology : EJD",
"keywords": "Kaposi's sarcoma; chemotherapy; intravenous vinorelbine; treatment",
"medline_ta": "Eur J Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents; D012189:Retrospective Studies; D012514:Sarcoma, Kaposi; D012867:Skin; D012878:Skin Neoplasms; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "9206420",
"other_id": null,
"pages": "535-8",
"pmc": null,
"pmid": "26552718",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Vinorelbine therapy in classic Kaposi's sarcoma: a retrospective study of 20 patients.",
"title_normalized": "vinorelbine therapy in classic kaposi s sarcoma a retrospective study of 20 patients"
} | [
{
"companynumb": "IT-ACTAVIS-2016-12166",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE"
},
"drugadditi... |
{
"abstract": "The early intravesical Instillation of mitomycin C (MMC) is accepted as safe adjuvant therapy after TURBT by non-muscle- invasive bladder cancer if there is no perforation. In our case we report a female patient undergoing resection of papillary recurrent tumor on the anterior bladder wall. In the early postoperative period had the patient no complaints regarding to Instillation of MMC. The clinical manifestation of the necrosis of the anterior bladder wall appeared after one week requiring a long extended unsuccessful conservative therapy in order to save the bladder. Finally we performed a radical cystectomy. This complication is reported by some authors in literature.",
"affiliations": "Department of Urology in Borromäus Hospital Leer, Germany.;Department of Urology in Borromäus Hospital Leer, Germany.",
"authors": "Hatem|Humam|H|;Leifeld|Jörg|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2019.100955",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(19)30131-710.1016/j.eucr.2019.100955100955OncologyA rare complication of intravesical early instillation of mitomycin C after TURBT Hatem Humam dr.h.hatem@hotmail.de∗Leifeld Jörg Department of Urology in Borromäus Hospital Leer, Germany∗ Corresponding author. dr.h.hatem@hotmail.de26 6 2019 9 2019 26 6 2019 26 10095511 4 2019 11 6 2019 25 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/).The early intravesical Instillation of mitomycin C (MMC) is accepted as safe adjuvant therapy after TURBT by non-muscle- invasive bladder cancer if there is no perforation. In our case we report a female patient undergoing resection of papillary recurrent tumor on the anterior bladder wall. In the early postoperative period had the patient no complaints regarding to Instillation of MMC. The clinical manifestation of the necrosis of the anterior bladder wall appeared after one week requiring a long extended unsuccessful conservative therapy in order to save the bladder.\n\nFinally we performed a radical cystectomy. This complication is reported by some authors in literature.\n==== Body\nIntroduction\nBladder cancer is a common urologic cancer. A transurethral resection of bladder tumor (TURBT) is the primary procedure for diagnosing and treating visible tumors. A single intravesical instillation of mitomycin C (MMC) within 24 hour after TURBT has been shown to reduce recurrence. This adjuvant postoperative instillation therapy is considered safe. Necrosis of the bladder wall is a rare complication that has been reported in some studies as in our case.\n\nCase presentation\nWe report a 74-year-old female patient with a history of bladder cancer (low-grade pTa diagnosed in 2005). Except for arterial hypertension, there were no comorbidities, and there was no medical history of abdominal or pelvic operations. The preoperative laboratory values were normal (creatinine 0.8 mg/dl; CRP 0.1 mg/dl; negative urine culture).\n\nIn May 2018, the patient was admitted to our department to receive a TURBT due to tumor recurrence. A multifocal papillary tumor on the bladder roof (each one smaller than 3 mm) was resected without endoscopic evidence of perforation. Postoperatively, an early instillation of MMC was performed without complaint. After two days, the indwelling catheter was removed and the patient was discharged. Six days after discharge, the patient complained of persistent abdominal pain and dysuria. On the tenth day, she was again admitted to our department. Ultrasound revealed free prevesical fluid, and a follow-up abdominal CT demonstrated an urgent suspicion of perforation with evidence of air bubbles in the bladder wall and in the pelvis (Fig. 1).Fig. 1 Shows air bubbles in the bladder wall and in the pelvis.\n\nFig. 1\n\nNo improvement was observed in after the insertion of a urinary catheter; therefore, we performed an extraperitoneal laparotomy. Extremely edematous inflammation of the whole anterior bladder wall was found without sure evidence of a bladder defect, and we inserted a drain. Later, the patient suffered a fever and was in poor general condition. Another CT showed the same recent findings.\n\nAccording to a positive blood culture for E. coli, we started broad-spectrum antibiotic therapy, and the serum infection parameter declined. We removed the drain once the drain output stopped. Before discharge, we exchanged the urinary catheter. It should be removed in two weeks depending on retrograde cystography.\n\nAfter five days, the patient returned with a purulent secretion from the still opened channel of the removed drainage in addition to being in poor general condition. We performed a renewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, and vacuum-assisted closure (VAC) therapy. At this time, the anterior bladder wall and the prevesical fat were convoluted into a necrotic fibrotic plate with definite extravasation. In an attempt to preserve the urinary bladder, we performed complete drainage of urine through mono-J ureteral stents and nephrostomy. Unfortunately, these maintenance attempts failed after several changes in the VAC system.\n\nIn July 2018, we performed a radical cystectomy with a urinary diversion through ureterocutaneostomy. We avoided carrying out an ileum conduit due to pronounced infection in the pelvic area. The pathological finding revealed focal transmural wall necrosis of the anterior bladder wall with high-grade acute exudative phlegmonous inflammation of the perivesical fat as well as a remaining pTa low-grade urothelial cancer at the anterior bladder right pN0 (0/12); L0, V0, R0. After one year of surveillance, no recurrence was found. We regularly changed her ureteral catheter in our department.\n\nDiscussion\nThe most common side effects reported in randomized trials are irritative symptoms (10%) and allergic skin reactions (3%).1 Weizer et al.2 showed that dysuria is the most frequent (17%) complaint requiring intervention.\n\nRare complications such as bladder wall necrosis or even bladder perforation after early instillation have seldom been reported in the literature. In our case, the operator had intraoperatively no concerns about bladder perforation. Furthermore, the early instillation of MMC was symptom-free. It is unclear whether the urinary bladder perforation happened as a consequence of the instillation or a covered perforation was unnoticeable. We assume that necrosis of the detrusor occurred due to the instillation of the MMC, which later led to a secondary perforation with superinfection. Perforation of the bladder after early MMC transvesical instillation has been reported by some authors.\n\nPenna et al.3 reported a 77-year-old Caucasian male who received an early MMC instillation after TURBT. This patient complained of urinary retention after the removal of an indwelling catheter. Conservative therapy through an indwelling catheter and antibiotics were sufficient, and there was no need for surgical exploration. In this case, the authors felt that the MMC instillation led to weakening of the site of the resection, which indirectly caused a late perforation following bladder overdistension after removal of the indwelling catheter. The authors attributed the risk factors to the following: a) delayed diagnosis of the perforation and b) bladder overdistension, particularly in the elderly with existent outflow obstruction.\n\nLim et al.4 reported a 79-year-old man with a history of recurrent TaG2 bladder cancer managed by TURBT and immediate postoperative instillation of intravesical MMC. One day after removing the catheter, the patient complained of severe abdominal pain due to extraperitoneal perforation. Conservative management, with an indwelling catheter for three weeks, was unsuccessful. Because of fever, the patient underwent an explorative laparotomy, which revealed an abscess and necrotic defect in the anterior bladder wall. This defect was closed and a drain inserted. Similar to our case, transurethral placement of a ureteral catheter was performed. These procedures were sufficient to heal the bladder. The indwelling catheter was removed after one month.\n\nIn contrast, in our case, this conservative management, besides the nephrostomy and the VAC system, failed to heal the necrotic defect. Lim et al.4 thought that the patient's preexisting peripheral vascular disease and suboptimal tissue oxygenation may have led to poor healing.\n\nAlthough the immediate instillation of MMC after TURBT is still strongly advisable, some studies comparing overnight bladder irrigation after TURBT with immediate intravesical chemotherapy have shown no difference between both procedures regarding early recurrence. Bladder irrigation after TURBT might be an alternative to the early instillation of chemotherapy after TURBT for less complications, especially if there is an unrecognized bladder perforation.5\n==== Refs\nReferences\n1 Sylvester R.J. Oosterlinck W. van der Meijden A.P.M. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta-T1 bladder cancer: a meta-analysis of published results of randomized clinical trials J Urol 171 2004 2186 2190 ([PubMed]) 15126782 \n2 Filson Christopher P. Montgomery Jeffrey S. Dailey Stephen M. Crossley Heather S. Lentz Heidi Tallman Christopher T. He Chang Weizer Alon Z. Complications associated with single-dose, perioperative mitomycin-C for patients undergoing bladder tumor resection Urol Oncol 32 1 2014 Jan 40.e1–40.e8. Published online 2013 Jun 17 \n3 Penna M. Mistry K. Pal P. Sudhanshu C Intravesical instillation of mitomycin C: a cause of delayed bladder perforation? Case Rep Urol. 2012 2012:576519, Epub 2012 Dec 23 \n4 Lim D.1 Izawa J.I. Middlebrook P. Chin J.L. Bladder perforation after immediate postoperative intravesical instillation of mitomycin C Can Urol Assoc J 4 1 2010 Feb E1 E3 20174483 \n5 Mahran A. Bukavina L. Mishra K. Bladder irrigation after transurethral resection of superficial bladder cancer: a systematic review of the literature Can J Urol 25 6 2018 Dec 9579 9584 30553282\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "26()",
"journal": "Urology case reports",
"keywords": null,
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "100955",
"pmc": null,
"pmid": "31334032",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "15126782;20174483;23326749;23787296;30553282",
"title": "A rare complication of intravesical early instillation of mitomycin C after TURBT.",
"title_normalized": "a rare complication of intravesical early instillation of mitomycin c after turbt"
} | [
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"abstract": "OBJECTIVE\nIntoxications with the tricyclic antidepressant amitriptyline frequently occur in the clinical setting and require immediate treatment. Although various poisonings can be counteracted with specific remedies, treatment options for amitriptyline intoxication remain sparse. Besides conventional approaches, a new haemoadsorption device might represent an opportunity for therapeutic detoxification.\n\n\nMETHODS\nWe report on two patients who were admitted as an emergency case with suspected amitriptyline overdose. Due to potentially life-threatening intoxication, the decision was made to initiate continuous renal replacement therapy (CRRT) together with CytoSorb haemoadsorption. As a result, drug-level measurements showed fast and efficient reduction of amitriptyline levels in the blood (case 1 from 186 µg/l to 54.7 µg/l, case 2 from 844 µg/l to 290 µg/l) and helped to stabilize a critical situation.\n\n\nCONCLUSIONS\nWe were able to quickly and efficiently reduce amitriptyline to non-toxic serum levels and to stabilize a critical situation using the CytoSorb adsorber. Therefore, in the absence of other proven beneficial treatment regimen, the use of CytoSorb haemoadsorption could represent a potential treatment modality for severe amitriptyline intoxication.",
"affiliations": "Department of Anesthesiology and Intensive Care Medicine, Marktredwitz Hospital, Marktredwitz, Germany.",
"authors": "Paland|Michael|M|https://orcid.org/0000-0001-8312-118X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13373",
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"issn_linking": "0269-4727",
"issue": "46(5)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": null,
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "1476-1479",
"pmc": null,
"pmid": "33768556",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Use of CytoSorb in cases of acute amitriptyline intoxication.",
"title_normalized": "use of cytosorb in cases of acute amitriptyline intoxication"
} | [
{
"companynumb": "NVSC2021DE084829",
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"occurcountry": "DE",
"patient": {
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"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
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"drugadditional": "3",
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{
"abstract": "BACKGROUND\nThe role of PI3K/AKT/mTOR pathway hyperactivation in localized brain overgrowth is evolving. We describe two patients with focal cortical dysplasia (FCD) who demonstrated somatic mutations in TSC1 and TSC2 genes in the dysplastic brain tissue but not peripheral blood.\n\n\nMETHODS\nPaired whole-exome sequencing was performed on genomic DNA extracted from blood and excised brain tissue in two children with FCD who underwent excision of dysplastic tissue.\n\n\nRESULTS\nPatient 1, a 14-year boy, had drug-resistant focal epilepsy with onset at 20 months. His brain MRI showed abnormalities suggestive of FCD in the left superior and middle frontal lobes. Patient 2 presented at the age of 10 years with pharmaco-resistant focal epilepsy (onset at six years). His MRI suggested FCD in the left insular lobe. Both patients underwent surgical excision of FCD, and excised tissues were pathologically confirmed to have type IIb FCD. For patient 1, a missense mutation (c.64C > T; p.Arg22Trp) was detected in the TSC1 gene in DNA of dysplastic brain tissue but not peripheral blood lymphocytes. Similarly, for patient 2, a frameshift mutation (c.4258_4261delCAGT; p.Ser1420GlyfsTer55) in the TSC2 gene was identified in the brain tissue but not blood. Both gene variants are likely pathogenic and cause mTOR pathway activation.\n\n\nCONCLUSIONS\nOur report of TSC1/TSC2 somatic mutations in patients with non-syndromic FCD suggests that localized hyperactivation of the mTOR pathway can cause focal malformations during cortical development and presents pharmacological targets for precision therapy in FCD management.",
"affiliations": "Department of Pediatrics, Armed Forces Medical College, Pune, India.;Department of Pediatrics, Armed Forces Medical College, Pune, India.;Department of Radiodiagnosis, Armed Forces Medical College, Pune, India.;Department of Neurosurgery, Aditya Birla Memorial Hospital, Pune, India.;Department of Pediatrics, Armed Forces Medical College, Pune, India. Electronic address: vishalsondhi@gmail.com.",
"authors": "Jha|Ruchika|R|;Kurup|Arjun|A|;Kovilapu|U B|UB|;Ranjan|Rakesh|R|;Sondhi|Vishal|V|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2021.10.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": null,
"journal": "Brain & development",
"keywords": "Cortical malformations; Drug-resistant epilepsy; Epilepsy; mTOR, AKT, PI3K",
"medline_ta": "Brain Dev",
"mesh_terms": null,
"nlm_unique_id": "7909235",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34756499",
"pubdate": "2021-10-27",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Somatic mutations involving TSC 1 and TSC2 genes in two children with focal cortical dysplasia.",
"title_normalized": "somatic mutations involving tsc 1 and tsc2 genes in two children with focal cortical dysplasia"
} | [
{
"companynumb": "IN-CIPLA LTD.-2022IN03239",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": "3",
... |
{
"abstract": "Catecholamine-induced cardiomyopathy due to chronic excess of endogenous catecholamines has been recognized for decades as a clinical phenomenon. In contrast, reports of myocardial dysfunction due to acute iatrogenic overdose are rare. A 35-year-old woman whose cervix uteri was inadvertently injected with 8 mg of epinephrine developed myocardial stunning that was characterized by severe hemodynamic compromise, profound, albeit transient, left ventricular systolic and diastolic dysfunction, and only modestly elevated biochemical markers of myocardial necrosis. Our case illustrates the serious consequences of medical errors that can be avoided through improved medication labeling and staff supervision.",
"affiliations": "Department of Medicine, New Jersey Medical School, Newark, New Jersey, USA.",
"authors": "Budhwani|Navin|N|;Bonaparte|Kenneth L|KL|;Cuyjet|Aloysius B|AB|;Saric|Muhamed|M|",
"chemical_list": "D014662:Vasoconstrictor Agents; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-6550",
"issue": "5(2)",
"journal": "Reviews in cardiovascular medicine",
"keywords": null,
"medline_ta": "Rev Cardiovasc Med",
"mesh_terms": "D000282:Administration, Intravaginal; D000328:Adult; D062787:Drug Overdose; D004837:Epinephrine; D005260:Female; D006801:Humans; D008508:Medication Errors; D009515:New Jersey; D014662:Vasoconstrictor Agents; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "100960007",
"other_id": null,
"pages": "130-3",
"pmc": null,
"pmid": "15188772",
"pubdate": "2004",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe reversible left ventricular systolic and diastolic dysfunction due to accidental iatrogenic epinephrine overdose.",
"title_normalized": "severe reversible left ventricular systolic and diastolic dysfunction due to accidental iatrogenic epinephrine overdose"
} | [
{
"companynumb": "US-PFIZER INC-2017132059",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
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{
"abstract": "OBJECTIVE\nTo assess the relationship between Takayasu arteritis (TAK) and pregnancy outcome.\n\n\nMETHODS\nThis study included 240 pregnancies in 96 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK and/or the 1994 Chapel Hill Consensus Conference nomenclature/criteria for vasculitis. We analyzed obstetric and maternal outcomes in women who were pregnant before and/or at the same time as or after TAK diagnosis. We assessed factors associated with complicated pregnancy.\n\n\nRESULTS\nOne hundred forty-two pregnancies occurred in 52 patients before TAK diagnosis (median age at pregnancy 26 years [interquartile range 23-30 years]), and 98 pregnancies occurred in 52 patients concomitant with or after TAK diagnosis (median age at pregnancy 28 years [interquartile range 26-31 years]). Pregnancies concomitant with or after TAK diagnosis had a 13-fold higher rate of obstetric complications compared to pregnancies before TAK diagnosis (odds ratio 13 [95% confidence interval 5-33], P < 0.0001). TAK was associated with a 40% frequency of obstetric complications, including preeclampsia/eclampsia (24 pregnancies [24%]), premature delivery (8 pregnancies [8%]), and intrauterine fetal growth restriction or death (5 pregnancies [5%]). Maternal complications of TAK occurred during 39% of pregnancies and included mainly new-onset or worsening hypertension (26 pregnancies [27%]). In multivariate analysis, smoking (odds ratio 6.15 [95% confidence interval 1.31-28.8]) and disease activity of TAK (a National Institutes of Health score of >1) (odds ratio 28.7 [95% confidence interval 7.89-104.7]) were independently associated with obstetric and maternal complications.\n\n\nCONCLUSIONS\nTAK negatively affects pregnancy outcomes. Disease activity increases the risk of obstetric and maternal complications, mainly due to arterial hypertension.",
"affiliations": "AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, and Université Pierre et Marie Curie, Paris 6, Paris, France.;AP-HP, Hôpital Européen Georges-Pompidou, INSERM UMR970, PARCC, Centre de Référence des Maladies Vasculaires Rares, Hôpitaux Universitaires Paris Ouest, and Université Paris Descartes, Paris 5, Sorbonne Paris Cité, Paris, France.;AP-HP, SBIM, Hôpital Saint-Louis and Université Paris Diderot, Paris 7, INSERM, CRESS UMR-S 1153, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière and Sorbonne Universités, Université Pierre et Marie Curie, Paris 6, CNRS UMR 7222, INSERM U1150, Paris, France.;Hôpital Claude Huriez, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre Hospitalier Régional Universitaire de Lille, and Université de Lille 2, Lille, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, and Université Pierre et Marie Curie, Paris 6, Paris, France.;Hôpital Claude Huriez, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre Hospitalier Régional Universitaire de Lille, and Université de Lille 2, Lille, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière and Université Pierre et Marie Curie, Paris 6, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière and Université Pierre et Marie Curie, Paris 6, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière and Université Pierre et Marie Curie, Paris 6, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière and Université Pierre et Marie Curie, Paris 6, INSERM-CNRS-LIB, Paris, France.;AP-HP, Hôpital Européen Georges-Pompidou, INSERM UMR970, PARCC, Centre de Référence des Maladies Vasculaires Rares, Hôpitaux Universitaires Paris Ouest, and Université Paris Descartes, Paris 5, Sorbonne Paris Cité, Paris, France.;AP-HP, SBIM, Hôpital Saint-Louis and Université Paris Diderot, Paris 7, INSERM, CRESS UMR-S 1153, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, and Université Pierre et Marie Curie, Paris 6, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, and Université Pierre et Marie Curie, Paris 6, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, and Université Pierre et Marie Curie, Paris 6, Paris, France.",
"authors": "Comarmond|C|C|;Mirault|T|T|;Biard|L|L|;Nizard|J|J|;Lambert|M|M|;Wechsler|B|B|;Hachulla|E|E|;Chiche|L|L|;Koskas|F|F|;Gaudric|J|J|;Cluzel|P|P|;Messas|E|E|;Resche-Rigon|M|M|;Piette|J C|JC|;Cacoub|P|P|;Saadoun|D|D|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/art.39335",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2326-5191",
"issue": "67(12)",
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": null,
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D002585:Cesarean Section; D015331:Cohort Studies; D005260:Female; D005317:Fetal Growth Retardation; D006801:Humans; D046110:Hypertension, Pregnancy-Induced; D015999:Multivariate Analysis; D016017:Odds Ratio; D011225:Pre-Eclampsia; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D047928:Premature Birth; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012907:Smoking; D013625:Takayasu Arteritis; D020246:Venous Thrombosis; D055815:Young Adult",
"nlm_unique_id": "101623795",
"other_id": null,
"pages": "3262-9",
"pmc": null,
"pmid": "26315109",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Takayasu Arteritis and Pregnancy.",
"title_normalized": "takayasu arteritis and pregnancy"
} | [
{
"companynumb": "AT-NOVARTISPH-NVSC2021AT236879",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": "3",
... |
{
"abstract": "Female sex workers (FSW) have increased risk of HIV infection. Antiretroviral treatment (ART) can improve HIV outcomes and prevent HIV transmission. We analyzed antiretroviral (ARV) drug use and HIV drug resistance among HIV-positive FSW in the Dominican Republic and Tanzania.\n\n\n\nPlasma samples collected at study entry with viral loads >1,000 copies/mL were tested for ARV drugs and HIV drug resistance. ARV drug testing was performed using a qualitative assay that detects 22 ARV drugs in five classes. HIV genotyping was performed using the ViroSeq HIV-1 Genotyping System. Phylogenetic analyses were performed to determine HIV subtype and assess transmission clusters.\n\n\n\nAmong 410 FSW, 144 (35.1%) had viral loads >1,000 copies/mL (DR: n = 50; Tanzania: n = 94). ARV drugs were detected in 36 (25.0%) of 144 samples. HIV genotyping results were obtained for 138 (95.8%) cases. No transmission clusters were observed in either country. HIV drug resistance was detected in 54 (39.1%) of 138 samples (31/35 [88.6%] with drugs detected; 23/103 [22.3%] without drugs detected); 29/138 (21.0%) had multi-class resistance (MCR). None with MCR had integrase strand transfer inhibitor resistance. In eight cases, one or more ARV drug was detected without corresponding resistance mutations; those women were at risk of acquiring additional drug resistance. Using multivariate logistic regression, resistance was associated with ARV drug detection (p<0.001), self-reported ART (full adherence [p = 0.034]; partial adherence [p<0.001]), and duration of HIV infection (p = 0.013).\n\n\n\nIn this cohort, many women were on ART, but were not virally suppressed. High levels of HIV drug resistance, including MCR, were observed. Resistance was associated with detection of ARV drugs, self-report of ART with full or partial adherence, and duration of HIV infection. These findings highlight the need for better HIV care among FSW to improve their health, reduce HIV drug resistance, and decrease risk of transmission to others.",
"affiliations": "Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.;Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland, United States of America.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.;Department of Psychiatry, Muhimibili University of Health and Allied Sciences, Dar es Salaam, Tanzania.;Department of Psychiatry, Muhimibili University of Health and Allied Sciences, Dar es Salaam, Tanzania.;Department of Microbiology and Immunology, Muhimibili University of Health and Allied Sciences, Dar es Salaam, Tanzania.;Unidad de Investigacion de Vacunas, Instituto Dermatologico y Cirugia de la Piel, Santo Domingo, Dominican Republic.;Unidad de Investigacion de Vacunas, Instituto Dermatologico y Cirugia de la Piel, Santo Domingo, Dominican Republic.;Department of Health Behavior, University of North Carolina, Chapel Hill, North Carolina, United States of America.;Center on Health, Risk and Society, American University, Washington, District of Columbia, United States of America.;Center on Health, Risk and Society, American University, Washington, District of Columbia, United States of America.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.",
"authors": "Grant-McAuley|Wendy|W|;Fogel|Jessica M|JM|;Galai|Noya|N|;Clarke|William|W|;Breaud|Autumn|A|;Marzinke|Mark A|MA|;Mbwambo|Jessie|J|;Likindikoki|Samuel|S|;Aboud|Said|S|;Donastorg|Yeycy|Y|;Perez|Martha|M|;Barrington|Clare|C|;Davis|Wendy|W|;Kerrigan|Deanna|D|;Eshleman|Susan H|SH|0000-0002-4587-791X",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "United States",
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"doi": "10.1371/journal.pone.0240890",
"fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nplosone\nPLoS ONE\n1932-6203 Public Library of Science San Francisco, CA USA \n\n10.1371/journal.pone.0240890\nPONE-D-20-18624\nResearch Article\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nImmunodeficiency Viruses\nHIV\nBiology and life sciences\nOrganisms\nViruses\nRNA viruses\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nMedicine and Health Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nMedicine and Health Sciences\nPublic and Occupational Health\nPreventive Medicine\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nMedicine and health sciences\nEpidemiology\nHIV epidemiology\nMedicine and Health Sciences\nPharmacology\nDrug Adherence\nPeople and Places\nGeographical Locations\nAfrica\nTanzania\nBiology and Life Sciences\nGenetics\nGene Identification and Analysis\nMutation Detection\nMedicine and health sciences\nMedical conditions\nInfectious diseases\nViral diseases\nHIV infections\nMedicine and Health Sciences\nPharmacology\nDrugs\nAntimicrobials\nAntivirals\nAntiretrovirals\nBiology and Life Sciences\nMicrobiology\nMicrobial Control\nAntimicrobials\nAntivirals\nAntiretrovirals\nBiology and Life Sciences\nMicrobiology\nVirology\nAntivirals\nAntiretrovirals\nAntiretroviral drug use and HIV drug resistance in female sex workers in Tanzania and the Dominican Republic\nARV drug use and HIV drug resistance in FSWGrant-McAuley Wendy ConceptualizationInvestigationVisualizationWriting – original draftWriting – review & editing1 Fogel Jessica M. ConceptualizationInvestigationProject administrationSupervisionVisualizationWriting – original draftWriting – review & editing1 Galai Noya Data curationFormal analysisVisualizationWriting – original draftWriting – review & editing23 Clarke William MethodologySupervisionWriting – review & editing1 Breaud Autumn InvestigationWriting – review & editing1 Marzinke Mark A. ConceptualizationWriting – review & editing1 Mbwambo Jessie InvestigationResourcesSupervisionWriting – review & editing4 Likindikoki Samuel InvestigationResourcesWriting – review & editing4 Aboud Said InvestigationResourcesSupervisionWriting – review & editing5 Donastorg Yeycy InvestigationResourcesSupervisionWriting – review & editing6 Perez Martha InvestigationResourcesWriting – review & editing6 Barrington Clare InvestigationProject administrationWriting – review & editing7 Davis Wendy InvestigationProject administrationWriting – review & editing8 Kerrigan Deanna ConceptualizationFunding acquisitionSupervisionWriting – review & editing8 https://orcid.org/0000-0002-4587-791XEshleman Susan H. ConceptualizationFunding acquisitionMethodologyProject administrationSupervisionVisualizationWriting – original draftWriting – review & editing1* 1 \nDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America\n2 \nDepartment of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland, United States of America\n3 \nDepartment of Statistics, University of Haifa, Mt Carmel, Israel\n4 \nDepartment of Psychiatry, Muhimibili University of Health and Allied Sciences, Dar es Salaam, Tanzania\n5 \nDepartment of Microbiology and Immunology, Muhimibili University of Health and Allied Sciences, Dar es Salaam, Tanzania\n6 \nUnidad de Investigacion de Vacunas, Instituto Dermatologico y Cirugia de la Piel, Santo Domingo, Dominican Republic\n7 \nDepartment of Health Behavior, University of North Carolina, Chapel Hill, North Carolina, United States of America\n8 \nCenter on Health, Risk and Society, American University, Washington, District of Columbia, United States of America\nBlackard Jason Editor University of Cincinnati College of Medicine, UNITED STATES\nCompeting Interests: None of the authors have a financial or personal relationship with other people or organizations that could inappropriately influence (bias) their work, with the following exceptions: Susan Eshleman has collaborated on research studies with investigators from Abbott Diagnostics; Abbott Diagnostics has provided reagents for collaborative research studies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.\n\n* E-mail: seshlem@jhmi.edu\n29 10 2020 \n2020 \n15 10 e024089017 6 2020 5 10 2020 © 2020 Grant-McAuley et al2020Grant-McAuley et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objective\nFemale sex workers (FSW) have increased risk of HIV infection. Antiretroviral treatment (ART) can improve HIV outcomes and prevent HIV transmission. We analyzed antiretroviral (ARV) drug use and HIV drug resistance among HIV-positive FSW in the Dominican Republic and Tanzania.\n\nMethods\nPlasma samples collected at study entry with viral loads >1,000 copies/mL were tested for ARV drugs and HIV drug resistance. ARV drug testing was performed using a qualitative assay that detects 22 ARV drugs in five classes. HIV genotyping was performed using the ViroSeq HIV-1 Genotyping System. Phylogenetic analyses were performed to determine HIV subtype and assess transmission clusters.\n\nResults\nAmong 410 FSW, 144 (35.1%) had viral loads >1,000 copies/mL (DR: n = 50; Tanzania: n = 94). ARV drugs were detected in 36 (25.0%) of 144 samples. HIV genotyping results were obtained for 138 (95.8%) cases. No transmission clusters were observed in either country. HIV drug resistance was detected in 54 (39.1%) of 138 samples (31/35 [88.6%] with drugs detected; 23/103 [22.3%] without drugs detected); 29/138 (21.0%) had multi-class resistance (MCR). None with MCR had integrase strand transfer inhibitor resistance. In eight cases, one or more ARV drug was detected without corresponding resistance mutations; those women were at risk of acquiring additional drug resistance. Using multivariate logistic regression, resistance was associated with ARV drug detection (p<0.001), self-reported ART (full adherence [p = 0.034]; partial adherence [p<0.001]), and duration of HIV infection (p = 0.013).\n\nConclusions\nIn this cohort, many women were on ART, but were not virally suppressed. High levels of HIV drug resistance, including MCR, were observed. Resistance was associated with detection of ARV drugs, self-report of ART with full or partial adherence, and duration of HIV infection. These findings highlight the need for better HIV care among FSW to improve their health, reduce HIV drug resistance, and decrease risk of transmission to others.\n\nhttp://dx.doi.org/10.13039/100000025National Institute of Mental HealthR01-MH110158Kerrigan Deanna http://dx.doi.org/10.13039/100000002National Institutes of HealthUM1-AI068613https://orcid.org/0000-0002-4587-791XEshleman Susan H. This work was supported by the National Institute of Mental Health (NIMH, http://www.nimh.nih.gov); R01-MH110158 (DK). Additional support was provided by the HIV Prevention Trials Network (HPTN, http://www.hptn.org) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID, http://www.niaid.nih.gov), National Institute on Drug Abuse (NIDA, http://www.drugabuse.gov), and Office of AIDS Research (http://www.oar.nih.gov), of the National Institutes of Health (NIH); UM1-AI068613 (SHE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityGenBank accession numbers for HIV sequences reported in this study are MN978752 - MN978889 (HIV protease/RT) and MN978890 - MN978916 (HIV integrase). All other relevant data are within the manuscript and its Supporting Information files.Data Availability\nGenBank accession numbers for HIV sequences reported in this study are MN978752 - MN978889 (HIV protease/RT) and MN978890 - MN978916 (HIV integrase). All other relevant data are within the manuscript and its Supporting Information files.\n==== Body\nIntroduction\nThe HIV epidemic is a global public health crisis, with approximately 37.9 million people living with HIV and 1.7 million new infections per year [1]. Female sex workers (FSW) are at higher risk of HIV infection compared to women in the general population, with an overall global prevalence of 10.4% [2–4]. This disparity has been documented in sub-Saharan Africa and the Caribbean, where HIV prevalence among FSW is 36.9% and 6.1% respectively, compared to 7.4% and 0.38% among the general population of cisgender women [2, 3]. Female sex work also plays an important role in HIV transmission dynamics and is the probable source of ~15% of HIV infections in women worldwide [5]. In addition, data from more than 70 countries indicate that HIV prevalence among FSW serves as the greatest indicator of national HIV prevalence [6]. Research with FSW living with HIV has been limited by difficulties in study recruitment due to sex-work related stigma, population mobility, and criminalization of sex work [7–10]. Available data suggest that FSW across the globe struggle to engage effectively with programs for HIV diagnosis and treatment [11–15]. Poor engagement of FSW in care has been associated with several factors, including low socioeconomic status, gender discrimination, and stigma associated with HIV infection and sex work [13–16]. Ineffective HIV care and treatment negatively impact viral suppression in the FSW population, increasing the risk of HIV transmission to others [4, 13, 14].\n\nHIV drug resistance can limit the ability to achieve viral suppression among HIV-positive people on antiretroviral therapy (ART) [17, 18]. Drug-resistant HIV can also emerge during ART, especially with suboptimal adherence, leading to treatment failure and limiting treatment options [17, 18]. Drug-resistant HIV can also be transmitted to others [18, 19]. To date, relatively few studies have evaluated ART failure and HIV drug resistance among FSW [11, 12, 19, 20]. Many FSW are not virally suppressed, despite high levels of self-reported ART adherence [12, 19, 20], and a high prevalence of drug resistance has been observed in HIV-positive FSW regardless of their treatment status [19, 20]. Data on ARV drug use among FSW are also limited and have been based primarily on self-report [19, 20], which may be unreliable [21–25]. Participants in research studies may over-report ARV drug use for a variety of reasons (e.g., because they misunderstand questionnaires or prefer to give socially-desirable answers) [25, 26]. ARV drug use may also be underreported in order to meet study eligibility requirements or to hide prior knowledge of HIV status [27]. Some individuals may also use ARV drugs for reasons other than ART, such as pre-exposure prophylaxis (PrEP, in those who are not aware that they are infected), hepatitis treatment, or recreational use [28, 29]; these data would not be captured in questionnaires that ask only about ARV drug use for HIV treatment.\n\nGiven the heightened burden of disease among FSW and their integral role in the on-going global HIV epidemic, there is a clear need for a comprehensive evaluation of ARV drug use and HIV drug resistance among FSW living with HIV. In this study, we evaluated ARV drug use and HIV drug resistance among FSW in two geographically and epidemically distinct settings.\n\nMethods\nStudy cohort\nFSW living with HIV were recruited for study participation in two areas with high HIV burden among FSW: the Iringa region of Tanzania and the Dominican Republic (DR). Participants were enrolled in 2017 and 2018 in a study focused on social determinants of HIV outcomes. Participants in the DR (Abriendo Puertas [13]) were recruited largely through use of peer navigators, while those in Tanzania (Project Shikamana [14]) were recruited using venue time-location sampling. Plasma samples and social demographic, behavioral, and clinical data were collected from participants at enrollment and at six- and twelve-month follow-up visits. In this study, ARV drug testing and HIV genotyping were performed using baseline samples from participants who had viral loads >1,000 copies/mL at study entry.\n\nLaboratory testing\nViral load testing was performed at the at the study sites (Muhimbili University of Health and Allied Sciences [MUHAS] in Iringa, Tanzania; Instituto Dermatológico y Cirugía de la Piel [IDCP] in Santo Domingo, DR) using the Roche Amplicor HIV-1 Monitor test [13, 14]. All other testing was performed retrospectively at Johns Hopkins University (Baltimore, MD). Plasma samples were analyzed using a qualitative multi-drug assay based on high-performance liquid chromatography coupled with high resolution mass spectrometry [30]. This assay detects 22 ARV drugs in five drug classes (nine protease inhibitors [PIs], six nucleoside/nucleotide reverse transcriptase inhibitors [NRTIs], three non-nucleoside reverse transcriptase inhibitors [NNRTIs], three integrase strand transfer inhibitors [INSTIs], and one CCR5 receptor antagonist); analyte lower limits of detection are drug-specific and range from 2–20 ng/mL. HIV genotyping was performed using the ViroSeq HIV-1 Genotyping System, v2.0 (Abbott Molecular, Des Plaines, IL); this assay produces a 1302 base pair sequence which encodes HIV protease and the first 335 amino acids of HIV reverse transcriptase. Samples with both NRTI and NNRTI resistance were also tested using the ViroSeq HIV-1 Integrase Genotyping Kit, RUO (Abbott Molecular, Des Plaines, IL); this assay produces an 864 base pair sequence encoding HIV integrase. HIV drug resistance was assessed using the ViroSeq HIV-1 Genotyping Software, v.3.0 and ViroSeq Integrase Software 1.0.\n\nPhylogenetic analysis\nHIV subtyping was performed using two automated online tools (REGA HIV Subtyping tool v3.0 and the Recombination Identification Program); HIV subtypes were confirmed by phylogenetic analysis using FastTree v2.1.10 with HIV subtype reference sequences from the Los Alamos National Laboratory’s HIV Sequence Database [31]. For cases with conflicting subtype results, subtype was assigned based on agreement using two of three subtyping methods.\n\nPhylogenetic trees were constructed for cluster analysis using HIV pol sequences from study samples. Up to ten similar background sequences per study sequence were identified with BLAST [32]. After duplicate sequences were removed, the remaining background sequences were obtained from the LANL HIV Sequence Database [31]. Recombination breakpoints were identified with RDP4 [33]; sequences with breakpoints were excluded from the analysis. Multiple pairwise sequence alignment was performed with MAFFT v6.864 [34]. Trees were constructed with the randomized accelerated maximum-likelihood (RAxML) v8.2.12 method, accessed via the CIPRES Science Gateway [35]. Potential clusters were identified with Cluster Picker [36], using a maximum genetic distance threshold setting of 4.5% and a bootstrap support value threshold setting of ≥90% [37]. Phylogenetic tree graphics were created with the Interactive Tree of Life (iTOL) software v5.6.3 [38].\n\nStatistical analysis\nIn univariate analyses, social demographic, behavioral, and clinical factors associated with HIV drug resistance were evaluated using Chi-square tests and simple logistic regression, stratified by country and combined. The initial multivariate model included covariates that were either p<0.3 in the univariate analyses or hypothesized to be potentially related to resistance. The final multivariate logistic regression model was determined by applying backward stepwise procedures. The same methods were applied for stratification by country.\n\nEthical considerations\nVerbal informed consent was obtained from all individuals who were screened for participation in the parent study; all participants were compensated ~$USD5 at each study visit. The study was approved by the institutional review boards of MUHAS Health and the National Institute for Medical Research in Tanzania, the IDCP in the DR, and the Johns Hopkins Bloomberg School of Public Health in the United States.\n\nGenBank accession numbers\nGenBank accession numbers for HIV sequences reported in this study are MN978752—MN978889 (HIV protease/RT) and MN978890—MN978916 (HIV integrase).\n\nResults\nSamples analyzed\nThe parent study enrolled 410 HIV-positive FSW (209 from Tanzania, 201 from the DR). Plasma samples collected at enrollment were available for 405 (98.8%) of the 410 participants (204 from Tanzania, 201 from the DR). HIV viral load was >1,000 copies/mL at enrollment for 144 (35.6%) of the 405 participants (94/204 [46.1%] from Tanzania, 50/201 [24.9%] from the DR); these samples were included in the analysis of ARV drug use and HIV drug resistance (Fig 1).\n\n10.1371/journal.pone.0240890.g001Fig 1 Overview of antiretroviral drug testing and HIV drug resistance testing.\nThe figure shows an overview of the samples used for testing and a summary of the test results. Abbreviations: FSW: female sex workers; VL, viral load; mL, milliliter; ARV, antiretroviral.\n\nHIV phylogenetic analysis\nHIV subtypes were determined by phylogenetic analysis of pol region sequences obtained from HIV genotyping. HIV genotyping results were obtained for 138 (95.8%) of the 144 cases (88 from Tanzania, 50 from the DR). The subtypes detected in Tanzania were C (55.7%); A1 (25.0%); CD recombinant (6.8%); D (5.7%); and A1C recombinant (5.7%). One sample was an A1D recombinant (1.1%). In the DR, 98.0% were subtype B, and one sample (2.0%) was a BF recombinant. Transmission cluster analysis was performed separately for each country (Fig 2). The analysis included 85 study sequences and 480 background sequences from Tanzania and 50 study sequences and 165 background sequences from the DR. The study sequences were dispersed among the background sequences with no evidence of transmission clusters in either country.\n\n10.1371/journal.pone.0240890.g002Fig 2 Phylogenetic trees of HIV pol sequences from Tanzania (Panel A), and the Dominican Republic (Panel B).\nPhylogenetic trees were constructed using study sequences from Tanzania (Panel A) and the Dominican Republic (Panel B) to identify potential transmission clusters. Dots at branch tips denote study sequences; plain branch tips denote background sequences. Sequences are color-coded according to HIV subtype. Background sequences that were most similar to study sequences from Tanzania were from Uganda (17.7%), Tanzania (14.2%), and South Africa (11.5%). Background sequences that were most similar to study sequences from the Dominican Republic were from the United States (66.7%), Spain (10.3%), and Canada (3.6%); only one background sequence originated from the Dominican Republic. There was no evidence of transmission clusters among sequences from either site, using a maximum genetic distance threshold of 4.5% and a bootstrap support value threshold of ≥90%.\n\nDetection of ARV drugs\nAt least one ARV drug was detected in samples from 36 (25.0%) of 144 participants (19/94 [20.2%] from Tanzania, 17/50 [34.0%] from the DR, Figs 1 and 3). Table 1 shows the data from the 36 samples with ARV drugs detected. NNRTIs were detected in 27 (18.8%) of the samples, NRTIs were detected in 30 (20.8%) of the samples, and PIs were detected in five (3.5%) of the samples. An INSTI was detected in one sample from the DR. Of note, three samples from Tanzania had one or more NRTIs detected alone; one had lamivudine, one had lamivudine and zidovudine, and one had lamivudine, stavudine, and zidovudine.\n\n10.1371/journal.pone.0240890.g003Fig 3 Detection of antiretroviral drugs and HIV drug resistance in samples from female sex workers with viral loads >1,000 copies/mL.\nThe figure shows a summary of results from antiretroviral (ARV) drug testing (Panel A) and HIV drug resistance testing (Panel B). Results are shown for each site and for the two sites combined. Numbers above each bar indicate the number of samples with a positive test result (Panel A: one or more ARV drug detected; Panel B: one or more major drug resistance mutation detected). Abbreviations: DR: Dominican Republic; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside/nucleotide reverse transcriptase inhibitor; PI; protease inhibitor; INSTI: integrase strand transfer inhibitor.\n\n10.1371/journal.pone.0240890.t001Table 1 Antiretroviral drugs and major drug resistance mutations detected in samples from female sex workers with viral loads >1,000 copies/mL.\n#\tSite\tARV drugs detected\tMajor drug resistance mutations detected\t\n\t\tNNRTI\tNRTI\tPI/INSTI\tNNRTI\tNRTI\tPI\t\n1\tTZ\t\tFTC\tATV\tK103N\tM184V\ta\t\n2\tTZ\tEFV\t3TC, TFV\t\tL100I, K101E, G190A\tK65R, M184V, K219E\t\t\n3\tTZ\tEFV\t3TC, TFV\t\tL100I, K103N\tK65R, M184V\t\t\n4\tTZ\tEFV\t3TC, TFV\t\tK103N\tD67N, K70R, M184V, K219E\t\t\n5\tTZ\tEFV\t3TC\t\tL100I, Y181C, G190A\tD67N, K70R, L74I, M184V, T215F, K219E/Q\t\t\n6\tTZ\tEFV\t3TC\t\tK103N, Y181C, G190A\tK70R, M184V, K219E/Q\t\t\n7\tTZ\tEFV\t3TC\t\tL100I, K103N\tK65R, M184V, T215Y\t\t\n8\tTZ\tEFV\t3TC\t\tK103N, Y181C\tM184V, T215F\t\t\n9\tTZ\tEFV\t3TC\t\tK103N\tK70E, M184V\t\t\n10\tTZ\tEFV\t3TC\t\tK103N\tM184V\t\t\n11\tTZ\tEFV\t\t\tK103N, Y181C\tM184V\t\t\n12\tTZ\tNVP\t3TC, ZDV\t\tK101E, G190A\tM41L, K70R, M184V, T215Y\t\t\n13\tTZ\tNVP\t3TC\t\tK103N, Y181C\tM184V\t\t\n14\tTZ\t\t3TC, d4T, ZDV\t\tK103N\tM184V\t\t\n15\tTZ\t\t3TC, ZDV\t\tK103N\tM184V\t\t\n16\tTZ\t\t3TC\t\t\tM184V\t\t\n17\tDR\t\t3TC\tLPV, RTV\tY188L, G190A\tD67N, K70R, M184V, K219E\tV82A, L90M\t\n18\tDR\tEFV\t3TC\t\tK103N\tK70R, M184V\tL90M\t\n19\tDR\tEFV\t3TC, TFV\t\tK101E, Y181C, G190S\tK65R, M184V\t\t\n20\tDR\tNVP\t3TC, ZDV\t\tY188L\tM41L, M184V, L210W, T215Y\t\t\n21\tDR\tEFV\tABC, 3TC\t\tK103N, Y188L\tM41L, D67N, K70R, M184V, T215F, K219Q\t\t\n22\tDR\tEFV\t\t\tK101E, G190S\tK65R, M184V\t\t\n23\tDR\tEFV\t\t\tK103N\tK65R, L74I, M184V\t\t\n24\tDR\tEFV\t3TC, TFV\t\tK103N, Y181C, G190A\tL74I, M184V, T215F\t\t\n25\tDR\tEFV\t\t\tK103N, G190A\tM184V\t\t\n26\tDR\tNVP\t3TC\t\tY181C\tM41L, M184V, L210W, T215Y\t\t\n27\tDR\tEFV\t\t\tK103N\t\t\t\n28\tDR\tEFV\t3TC, TFV\t\tK103N\ta\t\t\n29\tDR\tEFV\t\t\tK101E, K103N, G190A\t\t\t\n30\tDR\t\t3TC\tLPV, RTV\t\tM184V\ta\t\n31\tDR\t\t3TC, TFV\tRLV\t\tM184V\ta\t\n32\tTZ\tEFV\t3TC, TFV\t\ta\ta\t\t\n33\tTZ\tEFV\t3TC, TFV\t\ta\ta\t\t\n34\tTZ\tEFV\t3TC\t\t\tFailed genotyping\t\t\n35\tDR\t\tFTC, TFV\tATV, RTV\t\ta\ta\t\n36\tDR\t\t3TC, TFV\tATV, RTV\t\ta\ta\t\n37\tTZ\t\t\t\tK103N\tM184V\t\t\n38\tTZ\t\t\t\tK103N\t\t\t\n39\tTZ\t\t\t\tK103N\t\t\t\n40\tTZ\t\t\t\tK103N\t\t\t\n41\tTZ\t\t\t\tK103N\t\t\t\n42\tTZ\t\t\t\tK103N\t\t\t\n43\tTZ\t\t\t\tK103N\t\t\t\n44\tTZ\t\t\t\tG190E\tD67N\t\t\n45\tTZ\t\t\t\tK103N\t\t\t\n46\tTZ\t\t\t\tK103N\t\t\t\n47\tTZ\t\t\t\tK103N\t\t\t\n48\tDR\t\t\t\tK103N\tK65R, M184V\t\t\n49\tDR\t\t\t\tL100I, K103N\tK65R\t\t\n50\tDR\t\t\t\tK103N\t\t\t\n51\tDR\t\t\t\tV106M\t\t\t\n52\tDR\t\t\t\tK103N\t\t\t\n53\tDR\t\t\t\tK103N\t\t\t\n54\tDR\t\t\t\tK103S\t\t\t\n55\tDR\t\t\t\tK103R\t\t\t\n56\tDR\t\t\t\tL100I, K103N\t\t\t\n57\tDR\t\t\t\tK103N\t\t\t\n58\tDR\t\t\t\tY181C\t\t\t\n59\tDR\t\t\t\tL100I, K103N\t\t\t\nThe table shows the pattern of ARV drugs and HIV drug resistance mutations detected in the subset of 59 samples that were positive with one or both assays. Resistance mutations shown in italics are thymidine analog mutations (TAMs).\n\na Indicates the risk for developing additional resistance (detection of one or more ARV drugs without the corresponding resistance mutations).\n\nAbbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; ARV, antiretroviral; d4T, stavudine; DR, Dominican Republic; EFV, efavirenz; FTC, emtricitabine; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; NVP, nevirapine; RLV, raltegravir; RTV, ritonavir; TFV, tenofovir; TZ, Tanzania; ZDV, zidovudine.\n\nAmong 78 of the participants who reported that they were on ART, only 35 (44.9%) had ARV drugs detected (18/41 [43.9%] from Tanzania, 17/37 [45.9%] from the DR). In addition, one (1.5%) of 66 FSW who reported that they were not on ART had ARV drugs detected (efavirenz and lamivudine; 1/53 [1.9%] from Tanzania, 0/13 [0%] from the DR). Of the 35 women who reported they were on ART, 29 were considered adherent to ART based on a cumulative score from four questions regarding adherence. Of those 29 women, only 18 (62.1%) had ARV drugs detected (7/13 [53.8%] from Tanzania and 11/16 [68.8%] from the DR).\n\nAnalysis of HIV drug resistance\nHIV drug resistance was detected in 54 (39.1%) of 138 cases (27/88 [30.7%] from Tanzania, 27/50 [54.0%] from the DR; Fig 2). NNRTI resistance was detected in 51 (37.0%) of 138 cases (26/88 [29.5%] from Tanzania, 25/50 [50.0%] from the DR). NRTI resistance was detected in 32 (23.2%) of 138 cases (18/88 [20.5%] from Tanzania, 14/50 [28.0%] from the DR). PI resistance was detected in one case from the DR (0.7%). Multi-class resistance (MCR; resistance to more than one ARV drug class) was detected in 29 (21.0%) of 138 cases (17/88 [19.3%] from Tanzania, 12/50 [24.0%] from the DR). Of these 29 cases, all had NNRTI and NRTI resistance; one case from the DR also had PI resistance. INSTI resistance was assessed for the 29 samples with MCR; none of these samples had INSTI resistance.\n\nTable 1 shows the patterns of major drug resistance mutations detected in the 54 samples noted above. Forty-seven (87.0%) of the 54 samples had the NNRTI resistance mutations K103N, Y181C, Y188L, or G190A/S mutations alone or in combination. Thirty-one (57.4%) of the 54 samples had the NRTI resistance mutations M184V or K65R alone or in combination. Many samples also had one or more thymidine analog mutation (TAM) detected (n = 13). PI resistance mutations were detected in two (3.7%) of the 54 samples (one had V82A and L90M; one had L90M alone). No INSTI resistance mutations were detected.\n\nRelationship between ARV drug use and HIV drug resistance\nThe prevalence of HIV drug resistance was higher among the participants with ARV drugs detected compared to those with no drugs detected (31/35 [88.6%] vs. 23/103 [22.3%], p<0.001; Fig 1, Table 2). In most cases, the mutations detected corresponded to the drugs detected in the same sample. Of note, only two of those with a TAM had zidovudine detected, and none had stavudine detected. HIV from eight samples with one or more ARV drugs detected lacked corresponding resistance mutations, indicating that those women were at risk of acquiring additional drug resistance.\n\n10.1371/journal.pone.0240890.t002Table 2 Factors associated with HIV drug resistance among female sex workers with viral loads >1,000 c/mL.\nCharacteristics\tTotal n = 138\tUnivariate\tMultivariate\t\nResistance Detected\tOR\tP-value\tAOR\t95% CI\tP-value\t\nNo n = 84\tYes n = 54\t\nStudy site\t\t\t\t\t\t\t\t\t\n Tanzania\t88\t61 (69.3%)\t27 (30.7%)\t0.38\t0.007\t\t\t\t\n Dominican Republic\t50\t23 (46.0%)\t27 (54.0%)\t1.00\t\t\t\t\t\nDuration of HIV infection, mean (SD)\t5.2 (5.3)\t3.7 (4.3)\t7.8 (5.8)\t1.17\t<0.001\t1.14\t1.03, 1.27\t0.013\t\nCurrently on ART (self-report)\t\t\t\t\t<0.001\t\t\t\t\n No\t62\t58 (93.6%)\t4 (6.5%)\t1.00\t\t\t\t\t\n Yes\t76\t26 (34.2%)\t50 (65.8%)\t27.88\t\t\t\t\t\nSelf-reported adherence levela\t\t\t\t\t<0.001\t\t\t\t\n No ART/No adherenceb\t71\t63 (88.7%)\t8 (11.3%)\t1.00\t\t\t\t\t\n Partial adherence\t39\t12 (30.8%)\t27 (69.2%)\t17.72\t\t13.37\t3.35, 53.37\t<0.001\t\n Full adherence\t28\t9 (32.1%)\t19 (67.9%)\t16.62\t\t6.14\t1.15, 32.80\t0.034\t\nARV drugs detected in blood\t\t\t\t\t<0.001\t12.79\t3.35, 48.77\t<0.001\t\n No\t103\t80 (77.7%)\t23 (22.3%)\t1.00\t\t\t\t\t\n Yes\t35\t4 (11.4%)\t31 (88.6%)\t26.96\t\t\t\t\t\nAge in years, mean (SD)\t31.7 (8.4)\t29.2 (6.4)\t35.9 (9.9)\t1.11\t<0.001\t\t\t\t\nMarital status, single\t\t\t\t\t0.001\t\t\t\t\n No\t78\t38 (48.7%)\t40 (51.3%)\t1.00\t\t\t\t\t\n Yes\t60\t46 (76.7%)\t14 (23.3%)\t0.29\t\t\t\t\t\nNumber of live births\t\t\t\t\t0.005\t\t\t\t\n 0\t12\t9 (75.0%)\t3 (25.0%)\t1.00\t\t\t\t\t\n 1-2\t77\t54 (70.1%)\t23 (29.9%)\t1.28\t\t\t\t\t\n 3+\t49\t21 (42.9%)\t28 (57.1%)\t4.00\t\t\t\t\t\nSeen provider at ANC last pregnancy\t\t\t\t\t0.005\t\t\t\t\n No\t23\t20 (87.0%)\t3 (13.0%)\t1.00\t\t\t\t\t\n Yes\t115\t64 (55.7%)\t51 (44.4%)\t5.31\t\t\t\t\t\nTravel (past 6 months)\t\t\t\t\t0.263\t\t\t\t\n No\t84\t48 (57.1%)\t36 (42.9%)\t1.00\t\t\t\t\t\n Yes\t54\t36 (66.7%)\t18 (33.3%)\t0.67\t\t\t\t\t\nNumber new/regular clients (past 30 days)\t\t\t\t\t0.295\t\t\t\t\n ≤4\t69\t45 (65.2%)\t24 (34.8%)\t1.00\t\t\t\t\t\n >4\t69\t39 (56.5%)\t30 (43.5%)\t1.44\t\t\t\t\t\nInconsistent condom use with new/regular clients (past 30 days)\t\t\t\t\t0.028\t\t\t\t\n No\t84\t45 (53.6%)\t39 (46.4%)\t1.00\t\t\t\t\t\n Yes\t54\t39 (72.2%)\t15 (27.8%)\t0.44\t\t\t\t\t\nAlcohol (≥4 days per week)\t\t\t\t\t0.774\t\t\t\t\n No\t90\t54 (60.0%)\t36 (40.0%)\t1.00\t\t\t\t\t\n Yes\t48\t30 (62.5%)\t18 (37.5%)\t0.92\t\t\t\t\t\nDrug use (ever)\t\t\t\t\t0.375\t\t\t\t\n No\t110\t69 (62.7%)\t41 (37.3%)\t1.00\t\t\t\t\t\n Yes\t28\t15 (53.6%)\t13 (46.4%)\t1.46\t\t\t\t\t\nSex work stigmac\t\t\t\t\t\t\t\t\t\n <36\t91\t58 (63.7%)\t33 (36.3%)\t1.00\t0.337\t\t\t\t\n ≥36\t47\t26 (55.3%)\t21 (44.7%)\t1.42\t\t\t\t\t\nGender-based violence (past 6 months)\t\t\t\t\t0.823\t\t\t\t\n No\t91\t56 (61.5%)\t35 (38.5%)\t1.00\t\t\t\t\t\n Yes\t47\t28 (59.6%)\t19 (40.4%)\t1.09\t\t\t\t\t\nThe table shows factors associated with HIV drug resistance in univariate models and a multivariate model generated by backwards selection (see text); the multivariate model included data from 132 cases. The initial model used for multivariate analysis included the following variables: country, age, being single, travel in the last 6 months, having ≥3 live births, visiting an ANC during last pregnancy, having >4 clients per week on average, consistent condom use, HIV duration, self-reported ART adherence level, and detection of ARV drugs. Self-reported current ART correlated with self-reported ART adherence and therefore was not included in the initial multivariate model.\n\na The level of self-reported ART adherence was the sum of four adherence measures (adherence in last 4 days, always take on schedule, always follow instructions, and not skipped last weekend). Responses were scored as full adherence (4), partial adherence (1–3), no ART/no adherence (0).\n\nb This included nine participants who reported that they were “currently on ART”.\n\nc The stigma score was calculated as the sum of a 13-item Likert type scale [14].\n\nAbbreviations: OR, odds ratio; CI, confidence interval; SD, standard deviation; ANC, antenatal clinic; STI, sexually transmitted infection; ART, antiretroviral treatment; ARV, antiretroviral.\n\nFactors associated with HIV drug resistance\nWe examined the relationship between HIV drug resistance and social demographic, behavioral, and clinical factors (Table 2). Univariate analysis demonstrated that resistance was associated with study site (higher prevalence in the DR), older age, marital status, higher number of live births, engagement at an antenatal clinic (ANC) during the last pregnancy, consistent condom use, longer duration of HIV infection, current ART by self-report, self-reported partial or full ART adherence, and detection of ARV drugs. There was no significant association between resistance and recent travel, number of new clients, alcohol or substance use, sex-work stigma, or gender-based violence.\n\nIn a multivariate logistic model, HIV drug resistance was independently associated with longer duration of HIV infection (adjusted odds ratio [aOR]: 1.14, 95% confidence interval [CI]: 1.03, 1.27), self-reported partial (aOR: 13.37, 95%CI: 3.35, 53.37) or full ART adherence (aOR: 6.14, 95%CI: 1.15, 32.80) (vs. no ART/no adherence), and detection of ARV drugs (aOR: 12.79, 95%CI: 3.35, 48.77). The model had an area under the curve (AUC, or c-statistics) of 91.2%, indicating a very high ability to discriminate between cases with vs. without resistance. In multivariate models stratified by site, duration of HIV infection and detection of ARV drugs were independently associated with resistance at both sites. Self-reported partial ART adherence was independently associated with resistance in Tanzania only (S1 Table).\n\nDiscussion\nThis study evaluated patterns of ARV drug use and HIV drug resistance in FSW in Tanzania and the DR. At enrollment, over one third of the women had viral loads >1,000 copies/mL and one quarter of those women had ARV drugs detected in study samples. The drug combinations detected mostly reflected first-line ART regimens used in each country at the time the study was performed (2 NRTIs + 1 NNRTI or 2 NRTIs + 1 PI) [39–41]. In Tanzania, first-line drugs included zidovudine, stavudine, lamivudine, emtricitabine, tenofovir, nevirapine, and efavirenz [39]; in the DR, first-line drugs included zidovudine, lamivudine, nevirapine, and efavirenz [41]. At the time of this study, universal ART was not available in the DR; instead, ART initiation was based on CD4 cell count and other AIDS-defining criteria [41]. The DR has since adopted universal ART [42] with dolutegravir-based first-line regimens [43].\n\nOnly one participant had an INSTI detected. In Tanzania, three participants had one or more NRTIs detected without drugs from other classes. This may reflect sub-optimal ART adherence or continued use of regimens previously used in sub-Saharan Africa, including triple NRTI regimens [44, 45]. Notably, only 45% of those who reported that they were currently on ART had ARV drugs detected. Similar discrepancies between self-reported ART and objective measures of ARV drug use using laboratory testing have been reported in other cohorts and settings [25, 46, 47]. For example, in a retrospective analysis of a subset of participants from the HPTN 052 study, 29% of participants who self-reported being ARV drug naive had ARV drugs detected [25]. In the HPTN 074 study, ARV drugs were detected in only 75% of those who self-reported being on ART and in 8% of those who reported not being on ART [46].\n\nHIV drug resistance was detected in ~40% of those tested and many had resistance to more than one class of ARV drugs. INSTI resistance was not observed among any of those with MCR. Drug resistance was most strongly associated with detection of ARV drugs and self-reported full or partial adherence to ART (vs. no ART/no adherence). Drug resistance was detected in nearly 90% of the FSW who had ARV drugs detected. This is higher than the proportion that has been observed in other cohorts and settings [22, 23, 48]. Further studies are underway using quantitative ARV assays to evaluate whether HIV drug resistance among FSW is associated with sub-optimal ART adherence.\n\nThe frequency of virologic failure, HIV drug resistance, and MCR were all higher in this cohort compared to data from a recent, smaller study of FSW from Uganda [19]. In this study, eight participants were also identified who were at risk of developing additional drug resistance. These findings indicate that treatment options for many FSW are limited. The low prevalence of PI resistance and the lack of detection of INSTI resistance in this cohort suggest that PI- and INSTI-based regimens, including those with long-acting drugs, should be considered for HIV treatment in this population.\n\nDrug resistance was also observed in samples from 22% of women in this study who did not have ARV drugs detected. This may reflect lapses in ART due to inconsistent access to care, but could also reflect prior exposure to ARV drugs for HIV treatment or other indications, or infection with drug-resistant HIV. Transmitted drug resistance was not assessed in this study since many FSW in this cohort were previously diagnosed with HIV (mean duration of infection: 5 years) and may have had prior exposure to ARV drugs. A recent study of a smaller cohort of FSW in Brazil found that approximately half of the participants who reported that they were ART-naïve had drug resistance mutations [49]. Further studies are needed to assess the frequency of transmitted HIV drug resistance among FSW.\n\nPhylogenetic cluster analysis was also performed for each study site; this analysis revealed no evidence of HIV transmission networks. Sequences most similar to those from study participants in Tanzania were from several countries in sub-Saharan Africa. Given Iringa’s proximity to the Tanzam Highway and the known migratory aspect of sex work, it is likely that FSW from this region are involved in both local and international transmission networks [14]. Sequences are available from several studies focused on HIV transmission networks in Hispaniola [50–52]; these sequences were not included as background sequences in this analysis, since they did not meet the criteria for similarity to study sequences. In this study, sequences most similar to those from study participants in the DR were mostly from the United States, which may indicate that tourism plays a role in HIV transmission among FSWs in this region.\n\nOne limitation of this study is that it only included FSW with viral load >1,000 copies/mL; women with lower viral loads may also have had drug-resistant HIV. Also, this study used population sequencing to detect drug resistance mutations; these methods do not detect low-frequency drug resistance mutations, which can also contribute to treatment failure [53]. Another limitation is that INSTI resistance was only assessed among participants with MCR and not the whole cohort. In addition, the assay used for ARV drug testing only detects recent exposure to ARV drugs; ARV use outside of the detection window was not captured. For these reasons, the rates of ARV use and HIV drug resistance reported in this study should be considered to be minimum estimates. Finally, the qualitative drug assay does not provide information on ART adherence; results from quantitative ARV testing will be used to evaluate the relationship between ART adherence and HIV drug resistance in participants who had ARV drugs detected with viral loads >1,000 copies/mL.\n\nConclusions\nIn summary, FSW are at heightened risk for HIV infection, are more likely to experience poor HIV outcomes, and play a critical role in the on-going global HIV epidemic. The findings of this report, including infrequent ART, high rates of resistance and MCR, and lack of viral suppression among many FSW using ARV drugs, highlight the urgent need for improved HIV care and treatment in this vulnerable population. Durable viral suppression would have health benefits for these women and would also reduce transmission to others, potentially reducing HIV incidence in the general population.\n\nSupporting information\nS1 Table Factors associated with HIV drug resistance among HIV-positive female sex workers stratified by study site.\nThe table shows results from univariate analyses of factors associated with resistance for each study site. Multivariate analyses were also performed by study site (not shown in the table). The initial model used for multivariate analysis included the following variables: country, age, being single, travel in the last 6 months, having ≥3 live births, visiting an ANC during last pregnancy, having >4 clients per week on average, consistent condom use, HIV duration, ART adherence level and detection of ARV drugs. Self-reported current ART correlated with self-reported adherence and therefore was not included in the initial multivariate model. Among 82 women from Tanzania, the following factors were independently associated with resistance: duration of HIV infection (odds ratio [OR], 95% confidence interval [CI]: 1.22, 1.01–1.47, p = 0.045), self-reported partial adherence (OR, 95% CI: 8.35, 1.66–42.03, p = 0.010), and detection of ARV drugs (OR, 95% CI: 18.41, 2.88–117.59, p = 0.002). Among 50 women from the DR, the following variables were independently associated with resistance: duration of HIV infection (OR, 95% CI: 1.15, 1.01–1.31, p = 0.032) and detection of ARV drugs (OR, 95% CI: 15.98, 2.80–91.33, p = 0.002). a The level of self-reported ART adherence was the sum of four adherence measures (adherence in last 4 days, always take on schedule, always follow instructions, and not skipped last weekend). Responses were scored as full adherence (4), partial adherence (1–3), no ART/no adherence (0). b This included nine participants who reported that they were “currently on ART”. c The stigma score was calculated as the sum of a 13-item Likert type scale [14]. Abbreviations: OR, odds ratio; CI, confidence interval; SD, standard deviation; ANC, antenatal clinic; STI, sexually transmitted infection; ART, antiretroviral treatment; ARV, antiretroviral.\n\n(DOCX)\n\nClick here for additional data file.\n\n The authors thank the study team and the study participants for providing the samples and data used in this study.\n\nDisclaimer: Some of the work in this manuscript was presented at the Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, March 8–11, 2020. Abstract 537.\n==== Refs\nReferences\n1 UNAIDS Global HIV & AIDS statistics—2019 fact sheet. 2019. https://www.unaids.org/en/resources/fact-sheet. 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[Accessed September, 2019].\n41 Protocolos Nacionales de Atencion Clinica y Esquemas Terapeuticos del Programa Nacional de Atencion Integral de VIH/SIDA. 2004. https://www.who.int/hiv/pub/guidelines/dominican_art.pdf?ua=1. [Accessed September, 2019].\n42 “Treatment for All” Strategy for HIV Adopted in the Dominican Republic. 2018. https://www.hfgproject.org/treatment-for-all-strategy-for-hiv-adopted-in-the-dominican-republic/#:~:text=Until%20July%202018%2C%20the%20Dominican,regardless%20of%20their%20viral%20status. [Accessed September, 2019].\n43 Dominican Republic Country Operational Plan (COP/ROP) 2019 Strategic Direction Summary. April 1, 2019. https://www.state.gov/wp-content/uploads/2019/09/Dominican-Republic_COP19-Strategic-Directional-Summary_public.pdf. [Accessed September, 2019].\n44 Boulle A , Orrel C , Kaplan R , Van Cutsem G , McNally M , Hilderbrand K , et al\nSubstitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort\n. Antivir Ther . 2007 ;12 (5 ):753 –760\n. 17713158 \n45 Gulick RM , Ribaudo HJ , Shikuma CM , Lustgarten S , Squires KE , Meyer WA 3rd, et al\nTriple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection\n. N Engl J Med . 2004 ;350 (18 ):1850 –1861\n. 10.1056/NEJMoa031772 \n15115831 \n46 Fogel JM , Zhang Y , Palumbo PJ , Guo X , Clarke W , Breaud A , et al\nUse of Antiretroviral Drug Testing to Assess the Accuracy of Self-reported Data from HIV-Infected People Who Inject Drugs\n. 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AIDS Res Hum Retroviruses . 2019 \n10.1089/AID.2019.0243 \n31724429 \n50 Bello G , Arantes I , Lacoste V , Ouka M , Boncy J , Césaire R , et al\nPhylogeographic Analyses Reveal the Early Expansion and Frequent Bidirectional Cross-Border Transmissions of Non-pandemic HIV-1 Subtype B Strains in Hispaniola\n. Front Microbiol . 2019 ;10 :1340 \n10.3389/fmicb.2019.01340 \n31333594 \n51 Cabello M , Mendoza Y , Bello G . Spatiotemporal dynamics of dissemination of non-pandemic HIV-1 subtype B clades in the Caribbean region\n. PLoS One . 2014 ;9 (8 ):e106045 \n10.1371/journal.pone.0106045 \n25148215 \n52 López P , Rivera-Amill V , Paulino-Ramirez R , Yamamura Y . Short Communication: HIV-1 Subtype B in the Dominican Republic: Evolution and Molecular Epidemiology\n. 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"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D004293:Dominican Republic; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D010802:Phylogeny; D060386:Sex Workers; D013636:Tanzania; D019562:Viral Load; D055815:Young Adult",
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"title": "Antiretroviral drug use and HIV drug resistance in female sex workers in Tanzania and the Dominican Republic.",
"title_normalized": "antiretroviral drug use and hiv drug resistance in female sex workers in tanzania and the dominican republic"
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"abstract": "Scopolamine is an alkaloid which acts as competitive antagonists to acetylcholine at central and peripheral muscarinic receptors. We report the case of a 41-year-old male convict with a 27-year history of cannabis abuse who suddenly died in the bed of his cell after having smoked buscopan® tablets. Since both abuse of substances and recent physical assaults had been reported, we opted for a comprehensive approach (post-mortem computed tomography CT (PMCT), full forensic autopsy, and toxicology testing) to determine which was the cause of the death. Virtopsy found significant cerebral edema and lungs edema that were confirmed at the autopsy and at the histopathological examination. Scopolamine was detected in peripheral blood at the toxic concentration of 14 ng/mL in blood and at 263 ng/mL in urine, and scopolamine butyl bromide at 17 ng/mL in blood and 90 ng/mL in urine. Quetiapine, mirtazapine, lorazepam, diazepam, and metabolites and valproate were also detected (at therapeutic concentrations). Inmates, especially when they have a history of drug abuse, are at risk to use any substance they can find for recreational purposes. In prisons, active surveillance on the management and assumption of prescribed drugs could avoid fatal acute intoxication.",
"affiliations": "Section of Legal Medicine, Department of Health Surveillance and Bioethics, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.;Section of Legal Medicine, Department of Health Surveillance and Bioethics, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.;Unit of Forensic Pathology, SAIMLAL Department, Sapienza University of Rome, Rome, Italy.;Section of Legal Medicine, Department of Health Surveillance and Bioethics, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.;Section of Legal Medicine, Department of Health Surveillance and Bioethics, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.;Section of Legal Medicine, Department of Health Surveillance and Bioethics, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy. Antonio.oliva@unicatt.it.",
"authors": "Strano-Rossi|Sabina|S|;Mestria|Serena|S|;Bolino|Giorgio|G|;Polacco|Matteo|M|;Grassi|Simone|S|;Oliva|Antonio|A|http://orcid.org/0000-0001-7112-9096",
"chemical_list": "D002086:Butylscopolammonium Bromide; D012601:Scopolamine",
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"doi": "10.1007/s00414-021-02583-2",
"fulltext": "\n==== Front\nInt J Legal Med\nInt J Legal Med\nInternational Journal of Legal Medicine\n0937-9827\n1437-1596\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33890166\n2583\n10.1007/s00414-021-02583-2\nCase Report\nScopolamine fatal outcome in an inmate after buscopan® smoking\nStrano-Rossi Sabina 1\nMestria Serena 1\nBolino Giorgio 2\nPolacco Matteo 1\nGrassi Simone 1\nhttp://orcid.org/0000-0001-7112-9096\nOliva Antonio Antonio.oliva@unicatt.it\n\n1\n1 grid.8142.f 0000 0001 0941 3192 Section of Legal Medicine, Department of Health Surveillance and Bioethics, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy\n2 grid.7841.a Unit of Forensic Pathology, SAIMLAL Department, Sapienza University of Rome, Rome, Italy\n23 4 2021\n23 4 2021\n2021\n135 4 14551460\n27 1 2021\n16 3 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/.\nScopolamine is an alkaloid which acts as competitive antagonists to acetylcholine at central and peripheral muscarinic receptors. We report the case of a 41-year-old male convict with a 27-year history of cannabis abuse who suddenly died in the bed of his cell after having smoked buscopan® tablets. Since both abuse of substances and recent physical assaults had been reported, we opted for a comprehensive approach (post-mortem computed tomography CT (PMCT), full forensic autopsy, and toxicology testing) to determine which was the cause of the death. Virtopsy found significant cerebral edema and lungs edema that were confirmed at the autopsy and at the histopathological examination. Scopolamine was detected in peripheral blood at the toxic concentration of 14 ng/mL in blood and at 263 ng/mL in urine, and scopolamine butyl bromide at 17 ng/mL in blood and 90 ng/mL in urine. Quetiapine, mirtazapine, lorazepam, diazepam, and metabolites and valproate were also detected (at therapeutic concentrations). Inmates, especially when they have a history of drug abuse, are at risk to use any substance they can find for recreational purposes. In prisons, active surveillance on the management and assumption of prescribed drugs could avoid fatal acute intoxication.\n\nKeywords\n\nScopolamine\nScopolamine N-butylbromide\nForensic toxicology\nPoisoning\nPMCT\nhttp://dx.doi.org/10.13039/501100005743 Università Cattolica del Sacro Cuore R4124500772 Oliva Antonio Università Cattolica del Sacro CuoreOpen access funding provided by Università Cattolica del Sacro Cuore within the CRUI-CARE Agreement.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nScopolamine is one of the main alkaloids, together with atropine, contained in many plants from the Solanaceae family such as Datura species, Hyoscyamus, and Atropa belladonna. Tropane Solanaceae alkaloids are contained mainly in the seeds, flowers, and leaves. They have strong anticholinergic activity and act as competitive antagonists to acetylcholine at central and peripheral muscarinic receptors. They penetrate the blood–brain barrier and bind to acetylcholine receptors in the cortex and subcortical regions of the brain. At low doses, tropane alkaloids cause peripheral anticholinergic signs including decreased salivation and sweating, mydriasis, loss of accommodation, increased pulse rate, and sinus tachycardia. As the dose increases, ileus, urinary retention, and elevated temperature occur followed by the beginning of central nervous system (CNS) effects (confusion, agitation). High doses of belladonna alkaloids produce delirium, hallucination, and coma, with higher activity of scopolamine compared to atropine [1].\n\nBuscopan® is a pharmaceutical product containing the quaternary ammonium derivative scopolamine N-butylbromide. It acts primarily on parasympathetic ganglia in the walls of the viscera, with antispasmodic action on smooth muscle in the gastrointestinal, biliary, and urinary tracts. It is indicated in the symptomatic treatment of spastic-painful manifestations of the gastroenteric and genitourinary tract and is produced as tablets, suppositories, and injectable solutions [2]. Overdose symptoms include tachycardia, hypotension, drowsiness, urinary retention, dry mouth, skin redness, inhibition of gastrointestinal motility, transient visual disturbances, and respiratory paralysis. The effects can be increased by concomitant use of other anticholinergic or central acting drugs. Scopolamine N-butylbromide does not pass the blood–brain barrier. No scopolamine is detected in biological fluids after buscopan intake [3].\n\nThe formation of scopolamine from its N-butyl bromide after treatment at high temperature via microwaves or after smoking has been described [3, 4]. The habit of smoking buscopan® tablets by inmates, due to its hallucinogenic effects, was described in previous reports, and the intoxication symptoms were attributed to scopolamine, formed by the pyrolysis of the N-butylbromide derivative, as demonstrated by the experimental study [3, 5].\n\nWe report the case of a male convict who suddenly died in the bed of his cell. Since both abuse of substances (buscopan® tablets smoking) and recent physical assaults had been reported, we opted for a comprehensive approach (post-mortem CT (PMCT), full forensic autopsy, and toxicology testing) to determine which was the cause of the death.\n\nCase presentation and PMCT/autopsy findings\n\nA 41-year-old male convict (height: 165 cm; weight: 72 kg; body mass index: 26,4) with a 27-year history of cannabis abuse was found dead in the bed of his cell. Other inmates reported that he had recently smoked an undefined number of buscopan® tablets, obtained by a cellmate. Depakin® (natrium valproate), seroquel® (quetiapine), and remeron® (mirtazapine) tablets were found on the floor of his cell. Four days and the day before his death, he had been assaulted, suffering multiple bruises on face, chest, epigastric area and lower limbs, a wound above the left eyebrow, and fractures of six left ribs (from the second to the seventh), and seven right ribs (from the second to the eight). A public prosecutor requested a full forensic autopsy to evaluate whether the death had been caused by the assaults or by a drug intoxication. We performed a CT scan using a Somatom Sensation 16 CT scanner (Siemens®, Munich, Germany). We adopted these parameters: 140 kVp, 160 mAs, 24-mm feed/rotation, 1-mm slice collimation, 1-mm slice width, and 10–30-40–70-80 reconstruction kernel. After data processing, axial, coronal and sagittal two- dimensional (2D) reconstructions and a 3D-reconstruction with volume rendering (VR) and shaded surface display (SSD) were performed. Virtopsy found significant cerebral edema (Fig. 1) and lungs edema (Fig. 2).Fig. 1 CT image showing massive cerebral edema\n\nFig. 2 CT image showing massive edema of the lungs\n\nVirtopsy also confirmed the fractures caused by the assaults and did not find any possible cause of the death. Post-mortem nasal and pharyngeal swabs were performed in accordance with current guidelines [6] and excluded a SARS-CoV-2 infection. Hence, we performed a full forensic autopsy and, then, a histopathologic examination of the organs, which confirmed the PMCT findings.\n\nToxicological analyses\n\nMaterials and methods\n\nChemicals and reagents\n\nScopolamine hydrochloride, chloroform, ethyl acetate, methanol, formic acid, ammonium formate, bis-trimethylsylil trifluoroacetamide (BSTFA), and ultrapure water were supplied by Sigma-Aldrich (Milan, Italy). Scopolamine butyl bromide and sodium valproate were obtained by Sanofi (Milan, Italy) as 20 and 200 mg/mL solutions, respectively. Zolpidem-D6 (Internal standard) was purchased from Lipomed AG (Arlesheim, Switzerland) as 0.1 µg/mL solution. One µg/mL solutions were prepared and used as working solutions to prepare the calibration curves.\n\nSamples preparation\n\nUrine samples were analyzed by LC–MS/MS using a dilute and shoot approach. One hundred microliter of urine were diluted with 400 μL of 0.1% aqueous formic acid, added with a mixture of deuterated internal standards (0.1 µg/mL) and directly injected in the UHPLC-MS/MS system. For the analysis of benzodiazepines another aliquot of sample prepared as described above was preliminary submitted to enzymatic hydrolysis by β-glucuronidase in acidic medium.\n\nPeripheral blood samples (0.5 mL) were analyzed and quantified by LC–MS/MS after DLLME (dispersive liquid/liquid microextraction) or after deproteinisation with 0.5 mL of methanol and ultracentrifugation (for scopolamine butylbromide). Detailed analytical conditions for the analysis of blood samples and methods validations are reported elsewhere [7, 8].\n\nValproic acid determination was performed by GC–MS after liquid/liquid extraction of 2 mL of samples in acidic conditions with ethyl acetate. The extracts were collected, evaporated to dryness, and derivatized with BSTFA (50 μL). One microliter of the extract was injected into the GC port. Calibration curve was in the range 10–100 g/L.\n\nInstruments\n\nLC–MS/MS\n\nThe UHPLC instrument was an Agilent 1290 Infinity system: binary pump with integrated vacuum degasser, high-performance well-plate autosampler, and thermostated column compartment modules. The detection system was an Agilent 6460 triple quadrupole mass spectrometer (Agilent Technologies, Santa Clara, CA, USA) with a Jet-Stream electrospray ionization source in positive mode. Instrumental parameters were set as follows: gas temp 350 °C, gas flow 9 mL/min, nebulizer 40 psi, column flow 0.4 mL/min, sheath gas heater 400 °C, sheath gas flow 11 psi, and capillary voltage 4000 V. Chromatographic separation was achieved using a superficially porous Raptor C18 column (2.7 μm, 100 × 2.1 mm from Restek, Milan, Italy), mobile phase A: H2O 0.1% HCOOH/0.1% ammonium formate and B: MeOH 0.1% HCOOH, with a gradient from 10 to 90% B in 14 min. MRM transitions for the detected drugs were the following: Scopolamine 304 156, 138, 103; Scopolamine butyl bromide 360 194, 138; Quetiapine 384 279, 253, 221; Diazepam 285 257, 222, 154; Nordiazepam 271 208, 165, 140; OH-triazolam 359 331, 239, 176; Triazolam 343 315, 308, 239; Oxazepam 287 269, 242, 163; Lorazepam 321 275, 229, 163 Temazepam 301 255, 177, 199; Mirtazapine 266 209, 195, 72.\n\nMRM transitions for the deuterated standards were the following: Zolpidem D6 314 235, 263; Alprazolam D5 314 286, 210; Diazepam D5 290 154, 227; Nordiazepam D5 276 140, 165; Triazolam D4 347 312, 319; Oxazepam D5 292 246, 109 Lorazepam D4 325 279, 233. Underlined ions were used for quantitation.\n\nThe limits of detection were 0.2 ng/mL for scopolamine and 1 ng/mL for scopolamine butyl bromide, and the limits of quantitation (LOQ) were 0.5 ng/mL for scopolamine and 2 ng/mL for scopolamine butyl bromide. The method was linear in the range from the LOQ to 200 ng/mL for both the substances, giving correlation coefficients of the curves > 0.99 for scopolamine and > 0.98 for scopolamine butyl bromide. The accuracy, intended as %E, was < 15% for scopolamine at 2 and 50 ng/mL and < 20% at 2 ng/mL and < 15% at 50 ng/mL for scopolamine butyl bromide. The validation parameters for the other analytes detected are reported elsewhere [5].\n\nGC–MS\n\nThe GC–MS system was an Agilent 7890 gas chromatograph coupled to an Agilent 5975c quadrupole mass detector (Agilent Technologies Italia, Milan, Italy) operating at 70 eV in electron ionization mode. The chromatographic conditions were the following: J&W 5% phenyl-methylsilicone capillary column (17 m × 0.2 mm i.d., 0.33-µm film thickness, CPS Analitica, Milan, Italy). Helium was used as carrier gas at a constant flow of 1 mL/min. The oven temperature was held at 75 °C for 2 min, increased to 270 °C at 15 °C/min, and increased to 310 °C at 50 °C/min (held for 4 min). The injection port was set at 270 °C in splitless mode. The mass detector was operated in SIM mode for valproic acid-TMS determination (acquired ions are m/z 174, 201, 191, and 145 for valproic acid and m/z 206 and 233 for GHB-D6, I.S.).\n\nToxicological findings\n\nToxicological analyses allowed the detection of different drugs in the biological samples of the deceased. Scopolamine was detected at the toxic concentration of 14 ng/mL in blood and at 263 ng/mL in urine, and scopolamine butyl bromide at 17 ng/mL in blood and 90 ng/mL in urine. The other drugs identified included benzodiazepines (diazepam and active metabolites nordiazepam, oxazepam and temazepam, triazolam, lorazepam), antipsychotic drugs (quetiapine), and antidepressant drugs (mirtazapine and valproic acid). All of them were in therapeutic or subtherapeutic concentrations. The analytical findings are summarized in Table 1. The extracted ion chromatograms of characteristic transitions of scopolamine and scopolamine N-butylbromide in the urine of the victim and in a reference positive sample at 100 ng/mL are depicted in Fig. 3. The anti-inflammatory drug ibuprofen was also detected in the blood and urine of the deceased.Table 1 Substances detected in blood and urine from the deceased subject (ng/mL)\n\nSubstance\tPeripheral blood\tUrine\t\nScopolamine N-butylbromide (buscopan®)\t17\t90\t\nScopolamine\t14\t263\t\nQuetiapine\t247\t234\t\nMirtazapine\t26\t165\t\nTriazolam\t7\t6\t\nLorazepam\t68\t609\t\nDiazepam\t103\tBelow LOQ\t\nNordiazepam\t190\t1549\t\nTemazepam\t35\tBelow LOQ\t\nOxazepam\t67\tBelow LOQ\t\nValproic Acid\t25,000\t12,000\t\n\nFig. 3 Extracted ionic chromatograms of scopolamine and scopolamine butyl bromide characteristic transitions in the urine of the deceased (a) and in a reference positive sample (b)\n\nDiscussion\n\nWe report the case of a convict who suddenly died in his cell. Since a traumatic cause of death was suspected because of two recent assaults, we performed a PMCT and then a full forensic autopsy, as recommended by the scientific literature [9, 10]. Both PMCT and autopsy did not find any possible cause of the death, only revealing cerebral and lungs edema. Since a recent abuse of substances (buscopan® tablets), valproic acid (depakin®) (natrium valproate), seroquel® (quetiapine), and remeron® (mirtazapine) was suspected, we performed toxicological testing that found significant levels of scopolamine and scopolamine butyl bromide in blood and urine, thus indicating a fatal acute intoxication by scopolamine. The concentrations of quetiapine, mirtazapine, triazolam, hydroxy-triazolam, lorazepam, diazepam, and metabolites and valproic acid were in the therapeutic ranges [11].\n\nScopolamine and atropine intake are generally performed by ingestion of an infusion of the leaves or of the seeds of some plants of the Solanaceae family, such as Datura stramonium, Atropa belladonna, or Mandragora officinalis. This way of administration causes intoxications with hallucinations, which are the desired effect. Severe complications are often associated with this habit, as anticholinergic and psychotic-like symptoms, but they rarely have a lethal outcome. Cases of paralysis and convulsions following ingestion of flowers of plants of the genus Datura are reported [1, 12, 13]. Severe poisonings and at least one death after the ingestion of Datura stramonium seeds or wheat contaminated with seeds were reported. In cases of severe non-fatal intoxications, blood concentrations ranging from 0.5 to 0.8 ng/mL 3 h after the intake were reported; in one case of hypoxemia and coma, blood and urine concentrations were 1.2 and 132 ng/mL, respectively [14]. In non-fatal, severe intoxications occurred in 21 adults after drinking a tea containing scopolamine, an average serum value of 13 ng/mL was detected, similarly to the present case [13]. Scopolamine was detected in serum at 2.0 and 0.5 ng/mL in two subjects that ingested scopolamine obtained by the pyrolysis of buscopan in a microwave oven, while urinary concentrations were, respectively, 83 and 20 ng/mL after more than 12 h from the ingestion. One of them presented uncontrolled, clonic movements, non-sensical speech, flushed and dry skin, symmetric mydriasis, and intermittent aggressive behavior [3].\n\nUnlike other cases reported in the literature, in which the way of administration was ingestion, in the present case, scopolamine was administered by smoking crushed buscopan® tablets. The pyrolytic transformation of scopolamine N-butylbromide into scopolamine and its inhalation presumably caused the rapid absorption of a toxic amount of the drug, compatible with a lethal intoxication, as for the high concentration of scopolamine in peripheral blood (14 ng/mL) and in urine (263 ng/mL). After therapeutic use, scopolamine concentrations are in fact reported between 0.1 and 0.3 ng/mL while are considered toxic/lethal concentrations from 1.2 ng/mL [11]. Nevertheless, in a fatal scopolamine intoxication, the drug concentration in blood reached 1890 ng/mL [14].\n\nIn the described case, the presence of other central acting drugs such as valproate, benzodiazepines, mirtazapine, and quetiapine, although in therapeutic concentrations, may have contributed to the fatal outcome by a central depression and alteration of the cardiac rhythm.\n\nThe misuse of an easily available over the counter drug, considered as essential medicine by WHO, being one of the efficacious, safe, and cost-effective medicines for priority conditions [15], must be carefully considered as a possible health risk, especially for inmates. In this population, the search of psychotropic effects by off-label use of psychotropic medicines, which can be more easily available in jail, may happen [16, 17].\n\nConclusions\n\nIn this paper, we report the death of a convict caused by an acute intoxication of scopolamine in association to valproate, benzodiazepines, mirtazapine, and quetiapine (in therapeutic concentrations). Inmates, especially when they have a history of drug abuse, are at risk of using any substance they can find for recreational purposes [17]. Therefore, in prisons, the active surveillance on the management and assumption of prescribed drugs could avoid fatal acute intoxication.\n\nFunding\n\nOpen access funding provided by Università Cattolica del Sacro Cuore within the CRUI-CARE Agreement. This work has been supported by Fondi di Ateneo, Linea D1—Università Cattolica del Sacro Cuore, grant no. R4124500772, to A.O.\n\nData Availability\n\nAccess to data is possible on reasonable request.\n\nCode availability\n\nNot applicable.\n\nDeclarations\n\nEthics approval\n\nNot needed.\n\nConsent to participate and consent for publication\n\nNot needed.\n\nConflict of interest\n\nNone.\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. Barceloux DG Medical toxicology of natural substances 2008 Hoboken John Wiley & Sons Inc\n2. Agenzia Italiana del Farmaco AIFA. https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=006979. Accessed 14 Jan 2021\n3. Kummer S Rickert A Daldrup T Mayatepek E Abuse of the over-the-counter antispasmodic butylscopolamine for the home synthesis of psychoactive scopolamine Eur J Pediatr 2016 175 1019 1021 10.1007/s00431-015-2683-5 26691719\n4. Jalali F Afshari R Babaei A Smoking crushed hyoscine/scopolamine tablets as drug abuse Subst Use Misuse 2014 49 793 797 10.3109/10826084.2014.880178 24494624\n5. Frascht M Schneider S Schuman M Wennig R Formation of scopolamine from n-butyl-scopolammonium bromide in cigarettes J Anal Toxicol 2007 31 220 223 10.1093/jat/31.4.220 17555646\n6. Aquila I Sacco MA Abenavoli L Severe acute respiratory syndrome coronavirus 2 pandemic: review of the literature and proposal for safe autopsy practice Arch Pathol Lab Med 2020 144 1048 1056 10.5858/arpa.2020-0165-SA 32383963\n7. Fisichella M Odoardi S Strano-Rossi S High-throughput dispersive liquid/liquid microextraction (DLLME) method for the rapid determination of drugs of abuse, benzodiazepines and other psychotropic medications in blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and application to forensic cases Microchem J 2015 123 33 41 10.1016/j.microc.2015.05.009\n8. Odoardi S Fisichella M Romolo FS Strano-Rossi S High-throughput screening for new psychoactive substances (NPS) in whole blood by DLLME extraction and UHPLC–MS/MS analysis J Chromatogr B 2015 1000 57 68 10.1016/j.jchromb.2015.07.007\n9. Ampanozi G Halbheer D Ebert LC Postmortem imaging findings and cause of death determination compared with autopsy: a systematic review of diagnostic test accuracy and meta-analysis Int J Legal Med 2020 134 321 337 10.1007/s00414-019-02140-y 31455980\n10. Oliva A Grassi S Grassi VM Postmortem CT and autopsy findings in nine victims of terrorist attack Int J Legal Med 2021 10.1007/s00414-020-02492-w 33890166\n11. Schulz M Schmoldt A Andresen-Streichert H Iwersen-Bergmann S Revisited: therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics Crit Care 2020 24 195 10.1186/s13054-020-02915-5 32375836\n12. Cummins BM Belladonna Poisoning as a facet of psychodelia JAMA J Am Med Assoc 1968 204 1011 10.1001/jama.1968.03140240067029\n13. Hall RC Popkin MK Mchenry LE Angel’s Trumpet psychosis: a central nervous system anticholinergic syndrome Am J Psychiatry 1977 134 312 314 10.1176/ajp.134.3.312 842711\n14. Dr. Randall Dr. Baselt (2017) Disposition of toxic drugs and chemicals in Man, Baselt, 11th edition. Biomedical Pubns, Seal Beach, pp 1930–1932\n15. WHO model list of essential medicines, 18th edition. In: April 2013, Revis. Oct 2013. http://www.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1. Accessed 26 Feb 2021\n16. Bukten A Lund IO Kinner SA Factors associated with drug use in prison – results from the Norwegian offender mental health and addiction (NorMA) study Heal Justice 2020 8 10 10.1186/s40352-020-00112-8\n17. Salinas Rosillo C Ortega Basanta L Rubio Flores A Jiménez Sánchez JA Utilización de Neurolépticosatípicosen el Centro Penitenciario de Málaga Rev Española SanidPenit 2007 9 21 25 10.4321/S1575-06202007000100004\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0937-9827",
"issue": "135(4)",
"journal": "International journal of legal medicine",
"keywords": "Forensic toxicology; PMCT; Poisoning; Scopolamine; Scopolamine N-butylbromide",
"medline_ta": "Int J Legal Med",
"mesh_terms": "D000328:Adult; D001344:Autopsy; D002086:Butylscopolammonium Bromide; D004487:Edema; D017809:Fatal Outcome; D053593:Forensic Toxicology; D006801:Humans; D008297:Male; D011329:Prisoners; D012601:Scopolamine; D015813:Substance Abuse Detection",
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"pages": "1455-1460",
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"pubdate": "2021-07",
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"references": "26691719;24494624;17555646;32383963;31455980;33890166;32375836;842711",
"title": "Scopolamine fatal outcome in an inmate after buscopan® smoking.",
"title_normalized": "scopolamine fatal outcome in an inmate after buscopan smoking"
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"abstract": "BACKGROUND\nTreatment with biological agents such as anti-tumor necrosis factors (TNFs) has become standard of care in moderate to severe pediatric inflammatory bowel disease (IBD). However, a significant proportion of patients experience loss of response to anti-TNFs, need treatment escalation, or develop side effects. There is no data in the literature regarding combination of biological agents in pediatric IBD.\n\n\nMETHODS\nAt our hospital, which is a tertiary referral center, we have combined the anti-TNF infliximab with either vedolizumab or ustekinumab in patients with severe pediatric IBD. The indications for dual biological therapy were insufficient efficacy of infliximab or vedolizumab monotherapy, or side effects such as psoriasis due to anti-TNFs.\n\n\nRESULTS\nEight patients (four boys) aged 14-17.5 years received a combination of infliximab and vedolizumab due to only a partial response to infliximab, four with Crohn's disease (CD) and four with ulcerative colitis (UC). Clinical remission was achieved in four patients (3 UC) and four had a colectomy (3 CD, 1 UC). Five CD patients (3 girls) aged 11-17 years, on maintenance therapy with infliximab, developed psoriasis resistant to topical treatment. A combination of infliximab and ustekinumab resulted in clinical remission of CD without skin symptoms. No serious adverse events occurred in any of the patients on combination therapy. Thirteen publications report on combining biologicals, all in adult IBD.\n\n\nCONCLUSIONS\nIn pediatric IBD, combining biological agents seems to be safe and beneficial in selected patients. The safety should be addressed in long-term follow-up studies.",
"affiliations": "Department of Pediatric and Adolescent Medicine, Akershus University Hospital, 1478, Lørenskog, Norway. chrisolb@gmail.com.;Department of Pediatric and Adolescent Medicine, Akershus University Hospital, 1478, Lørenskog, Norway.;Institute of Clinical Medicine, University of Oslo, Oslo, Norway.",
"authors": "Olbjørn|Christine|C|;Rove|Jon Bergreen|JB|;Jahnsen|Jørgen|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D001685:Biological Factors; D014409:Tumor Necrosis Factor-alpha; C543529:vedolizumab; D000069285:Infliximab",
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"doi": "10.1007/s40272-020-00396-1",
"fulltext": "\n==== Front\nPaediatr Drugs\nPaediatr Drugs\nPaediatric Drugs\n1174-5878 1179-2019 Springer International Publishing Cham \n\n396\n10.1007/s40272-020-00396-1\nOriginal Research Article\nCombination of Biological Agents in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Case Series and Review of the Literature\nOlbjørn Christine chrisolb@gmail.com 12 Rove Jon Bergreen 1 Jahnsen Jørgen 23 1 grid.411279.80000 0000 9637 455XDepartment of Pediatric and Adolescent Medicine, Akershus University Hospital, 1478 Lørenskog, Norway \n2 grid.5510.10000 0004 1936 8921Institute of Clinical Medicine, University of Oslo, Oslo, Norway \n3 grid.411279.80000 0000 9637 455XDepartment of Gastroenterology, Akershus University Hospital, Lørenskog, Norway \n7 5 2020 \n7 5 2020 \n2020 \n22 4 409 416\n© The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.Background\nTreatment with biological agents such as anti-tumor necrosis factors (TNFs) has become standard of care in moderate to severe pediatric inflammatory bowel disease (IBD). However, a significant proportion of patients experience loss of response to anti-TNFs, need treatment escalation, or develop side effects. There is no data in the literature regarding combination of biological agents in pediatric IBD.\n\nMethods\nAt our hospital, which is a tertiary referral center, we have combined the anti-TNF infliximab with either vedolizumab or ustekinumab in patients with severe pediatric IBD. The indications for dual biological therapy were insufficient efficacy of infliximab or vedolizumab monotherapy, or side effects such as psoriasis due to anti-TNFs.\n\nResults\nEight patients (four boys) aged 14–17.5 years received a combination of infliximab and vedolizumab due to only a partial response to infliximab, four with Crohn’s disease (CD) and four with ulcerative colitis (UC). Clinical remission was achieved in four patients (3 UC) and four had a colectomy (3 CD, 1 UC). Five CD patients (3 girls) aged 11–17 years, on maintenance therapy with infliximab, developed psoriasis resistant to topical treatment. A combination of infliximab and ustekinumab resulted in clinical remission of CD without skin symptoms. No serious adverse events occurred in any of the patients on combination therapy. Thirteen publications report on combining biologicals, all in adult IBD.\n\nConclusion\nIn pediatric IBD, combining biological agents seems to be safe and beneficial in selected patients. The safety should be addressed in long-term follow-up studies.\n\nissue-copyright-statement© Springer Nature Switzerland AG 2020\n==== Body\nKey Points\nIn pediatric inflammatory bowel disease patients, there are no publications on combining biological therapies.\t\nWe have treated eight patients with a combination of infliximab and vedolizumab, and five patients with infliximab in combination with ustekinumab in order to gain clinical remission or to treat side effects such as psoriasis caused by infliximab.\t\nWe experienced no serious adverse events and in nine of the 13 patients, clinical remission was achieved and the side effects managed with the combination of biologicals.\t\n\n\nIntroduction\nPediatric inflammatory bowel disease (PIBD) is often aggressive with a high inflammatory burden at diagnosis and a complicated disease course [1]. Treatment with biological agents such as anti-tumor necrosis factors (TNFs) has improved the clinical outcome and has become standard of care in moderate to severe PIBD. However, patients develop side effects and up to 40% experience loss of response to anti-TNFs, which necessitates treatment escalation [2]. Psoriasis due to TNF blocker treatment is increasingly recognized in patients with IBD [3]. Considering that increased levels of TNFα play a key role in the pathogenesis of psoriasis, the occurrence under anti-TNF therapy seems to be paradoxical. New biological drugs for the treatment of IBD offer the possibility of combining agents that antagonize different pathways, potentially resulting in an additive effect for refractory disease and management of side effects. Vedolizumab (VDZ) and ustekinumab (UST) are such biological drugs, each with a different mode of action to anti-TNFs. These agents have demonstrated efficacy in IBD and can be used in patients failing or losing response to anti-TNFs [4–6].\n\nVDZ is a humanized monoclonal antibody that specifically recognizes the α4β7 integrin receptor on lymphocytes and blocks the migration from the bloodstream to the intestinal mucosa, which reduces the white cell influx to inflamed tissue. This gut-selective mechanism of action differentiates it from the other biologics, which all have a more systemic influence on the immune system [7]. VDZ is not approved for pediatric patients, but use in PIBD has shown clinical efficacy with remission rates in ulcerative colitis (UC) and Crohn’s disease (CD) reaching 76% and 42%, respectively. The drug is well tolerated with a lack of serious adverse events [8–13].\n\nUST is approved for the treatment of moderate-to-severe psoriasis in adolescents (aged 12 years and older) as well as for adult CD and UC [14–16]. UST is a human monoclonal antibody directed against the p40 subunit of interleukin (IL)-12 and IL-23 and exerts its anti-inflammatory effects by inhibiting these cytokines and their downstream pro-inflammatory signals, and inhibits Th1 and Th2 lymphocytes. Off-label use in the PIBD population is increasing and is reported to be safe and efficacious [17–19].\n\nThere are no publications on combining biological agents in PIBD, and data on combining biological agents with different modes of action in adult IBD is limited. We present our experience with combining biological agents in pediatric patients with IBD and give a review of the literature regarding the combination of biologicals in adult IBD patients.\n\nMethods\nCase Reports\nWe describe our experience with combining biological agents in PIBD between May 2014 and March 2020 in our hospital, a tertiary referral center and University Hospital.\n\nPIBD patients who had insufficient response to infliximab (IFX) were treated with a combination of IFX and VDZ. Before adding VDZ, adequate drug levels of IFX were ensured with trough level measurements and IFX was optimized with dose or interval adjustments. Disease activity was assessed with fecal calprotectin, laboratory work up, endoscopy, and magnetic resonance imaging (MRI).\n\nUST was added to IFX in patients who developed paradoxical psoriasis not responding to topical treatment. All patients were evaluated by a dermatologist. During the combination therapy we continuously screened the patients for adverse events.\n\nLiterature Review\nA literature search of the PubMed database and Web of Science was performed using relevant terms and keywords related to combining biological drugs in the treatment of IBD.\n\nResults\nCombination Therapy in Response to Insufficient Effect of Infliximab (IFX) or Vedolizumab (VDZ) Alone\nEight patients (four boys and four girls, aged 14–17.5 years) received a combination of IFX and VDZ. Four of the patients had CD, four had UC (Table 1). They had been treated with IFX for a median of 2 years (range 4 months to 7 years), but experienced a flare that continued after optimizing IFX treatment. Before escalating therapy, active inflammation was confirmed endoscopically and histologically in all patients. Infectious gastroenteritis including Clostridium difficile, Cytomegalovirus, and Epstein Barr virus was excluded. Other treatment options—exclusive enteral nutrition (EEN) in CD, immunomodulators (azathioprine or methotrexate), and corticosteroids—were tried without inducing remission. In the first two CD patients, we stopped IFX and switched to VDZ, but VDZ was not effective as monotherapy. One patient experienced a flare of both her CD and concomitant rheumatoid arthritis without IFX, the other CD patient developed a perianal fistula on VDZ monotherapy. In both patients, IFX was reintroduced after 4 and 5 months due to lack of disease control. The remaining six patients had active disease and some effect of IFX, and after the experience with IBD flares after IFX discontinuation in the two previous patients we continued IFX infusions in six patients every 4–6 weeks while VDZ was initiated. Other immunomodulator therapy was stopped except in two patients who continued methotrexate. We used an induction scheme of VDZ 300 mg intravenously in weeks 0, 2, 6, and 10, and continued infusions every 6–8 weeks, following trough level measurements. Three of the eight patients achieved complete clinical and biochemical remission on combination therapy, all three with UC. None of these patients were using methotrexate. After a mean combination treatment duration of 6.5 months (range 4–10 months), the patients were switched to monotherapy with VDZ; in two patients, this was due to the development of antibodies to IFX. They have both been in remission on VDZ monotherapy since, for more than 15 months. One UC patient developed elevated transaminases while on VDZ and IFX combination therapy, and IFX was stopped. This patient continued having slightly elevated transaminases, and is being evaluated for possible primary sclerosing cholangitis (PSC) and a liver biopsy is scheduled. His UC is in remission with VDZ monotherapy. One CD girl is in clinical remission, but has ongoing inflammation with an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). She has concomitant PSC. IFX was stopped after 4 months’ combination therapy due to severe eczema on the face, scalp, and body. The eczema was thought to be due to IFX as it resolved after cessation of IFX. Altogether, four patients (3 CD, 1 UC) had a colectomy due to failure of achieving remission with combination therapy. No infections or serious adverse events of the combination therapy were noted.Table 1 Characteristics of patients treated with a combination of infliximab and vedolizumab due to need for treatment escalation\n\nGender (age in years), diagnosis\tPhenotype\tPrevious therapy\tFecal calprotectin, mg/kg\tCRP, mg/L\tESR, mm/h\tPUCAI/wPCDAI score\tDuration of combination therapy\tOutcome\tAdverse events\tOngoing therapy\t\nBoy (17.5), CD, celiac disease\tL3, B3p\tEEN, MTX, AB, CS, IFX\t>3000\t38\t48\t87.5\t6 months\tColectomy\tNone\t\t\nGirl (17.5), UC\tE4\tAZA, CS, 5-ASA, IFX\t1500\t1\t2\t27.5\t4 months\tRemission\tATI\tVDZ\t\nBoy (17), UC\tE4\t5-ASA, CS, MTX, IFX\t1246\t2\t9\t65\t8 months\tRemission\tATI\tVDZ\t\nBoy (15), UC\tE4\t5-ASA, AZA, CS, IFX\t2709\t1\t7\t70\t10 months\tRemission\tElevated transaminases\tVDZ\t\nBoy (17.5), UC\tE4\t5-ASA, CS, AB, MTX, IFX\t > 1500\t5\t9\t85\t2 months\tColectomy\tNone\t\t\nGirl (14), CD\tL4, L2, B3\tEEN, AZA, CS, IFX\t > 3000\t6\t59\t65\t34 months\tColectomy\tNone\tIFX\t\nGirl (14), CD, RA\tL4, L2, B1\tEEN, CS, AB, IFX\t > 3000\t47\t27\t65\t8 months\tColectomy\tNone\tIFX\t\nGirl (17), CD+ PSC\tL4, L3, B1\tEEN,5-ASA, CS, IFX\t > 2000\t14\t53\t72.5\t4 months\tRemission\tEczema\tVDZ\t\n5-ASA 5-aminosalicylic acid, AB antibiotics, ATI antibodies to infliximab, AZA azathioprine, B1 inflammatory disease, B3 penetrating disease, CD Crohn’s disease, CRP C-reactive protein, CS corticosteroids, EEN exclusive enteral nutrition, ESR erythrocyte sedimentation rate, IFX infliximab, L2 colonic disease, L3 ileocolonic disease, L4 upper gastrointestinal disease, MTX methotrexate, p perianal, PSC primary sclerosing cholangitis, PUCAI pediatric ulcerative colitis activity index, RA rheumatoid arthritis, UC ulcerative colitis, UST ustekinumab, VDZ vedolizumab, wPCDAI weighted pediatric Crohn’s disease activity index\n\n\n\nCombining IFX and Ustekinumab (UST) in Response to Side Effects of IFX\nFive CD patients (three girls and two boys, aged 11–17 years), on maintenance therapy with IFX, developed severe paradoxical psoriasis resistant to topical treatment (Table 2). The psoriasis was mainly located in the periauricular region and on the scalp, with severe hair loss in three patients. One boy and one girl had additional palmoplantar psoriasis; another girl had concomitant anogenital psoriasis. These patients had been treated with IFX for a median of 2 years (range 7 months to 7 years) and were in clinical and biochemical remission with trough levels within target range (5–8 μg/mL) [20] (Table 3). In the first two patients with hair loss and scalp psoriasis, we switched treatment from IFX to subcutaneous UST 90 mg, with an induction regimen of weekly injections for 4 weeks, and every 8 weeks thereafter. The skin lesions and hair loss improved, but their CD flared with abdominal pain, diarrhea, weight loss, and elevated fecal calprotectin levels. Reintroduction of IFX was initiated. With the combination of IFX every 6–8 weeks and UST every 8–12 weeks, remission of CD was regained without re-occurrence of the psoriasis. One girl received combination treatment for 7 years and then continued with IFX monotherapy. On monotherapy she developed a rectovaginal fistula and abscess. She still has some psoriatic lesions, but no hair loss and the psoriasis is managed with topical treatment. The other female patient with CD on combination therapy went into CD remission without psoriasis. After 2 years on dual therapy, she received monotherapy with UST, but had another CD flare, and was switched to adalimumab and methotrexate. Both her CD and psoriasis flared, and she was again treated with IFX and UST. After 1 year she developed plantar pustulosis psoriatic lesions and was therefore switched to VDZ monotherapy. On VDZ monotherapy she developed several small bowel strictures.Table 2 Characteristics of patients treated with combination therapy with infliximab and ustekinumab due to anti-TNF-induced psoriasis\n\nGender (age) duration of combination therapy\tCD phenotype\tPsoriasis distribution\tFecal calprotectina, mg/kg\tCRPa, mg/L\tESRa mm/h\twPCDAIa score\tIFX TLa, mg/L\tAdverse events\tOutcome\tOngoing therapy\t\nGirl (15)\n\n6 years\n\n\tL4, L3, B1\tFace, scalp, hair loss, palmoplantar\t > 3000\t32\t86\t80\t9.3\tNo\tCD flare with UST alone, remission with combo\tADA + VDZ\t\nGirl (17)\n\n7 years\n\n\tL3, B3\tScalp, hair loss\t > 1500\t90\t92\t80\t8\tNo\tCD flare with UST alone, remission with combo\tIFX + AZA\t\nBoy (16)\n\n12 months\n\n\tL2, B3p\tScalp, hair loss\t56\t3\t17\t7.5\t6\tNo\tRemission\tUST\t\nBoy (11)\n\n21 months\n\n\tL4, L3, B1\tScalp, palmoplantar\t294\t1\t14\t7.5\t5\tNo\tRemission\tIFX\t\nGirl (15.5)\n\n25 months\n\n\tL4, L3, B1\tScalp, face, anogenital\t1000\t4\t58\t42.5\t8.8\tSkin infection, otitis externa\tRemission\tVDZ\t\nADA adalimumab, AZA azathioprine, B1 inflammatory disease, B3 penetrating disease, CD Crohn’s disease, combo combination therapy, CRP C-reactive protein, ESR erythrocyte sedimentation rate, IFX infliximab, IFX TL infliximab trough level, L2 colonic disease, L3 ileocolonic disease, L4 upper gastrointestinal disease, p perianal, UST ustekinumab, VDZ vedolizumab, wPCDAI weighted pediatric Crohn’s disease activity index\n\naAt time of starting dual therapy\n\nTable 3 Publications on combination of biologicals in the treatment of inflammatory bowel disease\n\nStudy\tYear\tStudy type\tDisease\tNo. of subjects\tMedication\tEfficacy\tAdverse events\t\nSands et al. [24]\t2007\tRCT\tCD\t52\tNAT + IFX\tGood\tHeadache, CD exacerbation, nausea, nasopharyngitis\t\nHirten et al. [25]\t2015\tCase report\tCD\t1\tIFX + VDZ\tBenefit\tNo\t\nAfzali and Chiorean [26]\t2016\tCase report\tCD\t1\tADA + VDZ\tRemission\tNo\t\nFischer et al. [29]\t2016\tCase report\tUC\t1\tCER + VDZ\tRemission\tNo\t\nYzet et al. [23]\t2016\tCase report\tCD/UC/PS\t3\tIFX + UST\tNot effective for psoriasis\tNo\t\nBethge et al. [32]\t2017\tCase report\tPouchitis/SpA\t1\tETA + VDZ\tRemission\tNo\t\nLiu and Loomes [28]\t2017\tCase report\tCD\t1\tVDZ + UST\tRemission\tNo\t\nHuff-Hardy et al. [27]\t2017\tCase report\tCD\t1\tUST + VDZ\tRemission\tRotavirus\t\nRoblin et al. [30]\t2018\tCase report\tUC\t1\tVDZ + GOL\tRemission\tNo\t\nBuer et al. [21]\t2018\tCase series\tCD/UC\t10\t9 IFX + VDZ\n\n1 ADA + UST\n\n\tRemission\t3 UAI\t\nMao et al. [31]\t2018\tCase series\tCD\t4\t1 ETA + UST/VDZ\n\n1 VDZ + UST\n\n2 VDZ + GOL\n\n\tRemission in 3/4\tHFMD, influenza, Clostridium difficile\t\nElmoursi et al. [33]\t2020\tCase report\tCD\t1\tUST + VDZ\tRemission\tNo\t\nKwapisz et al. [22]\t2020\tCase series\tCD/UC\t15\t8 VDZ + TNF\n\n5 VDZ + UST\n\n2 UST + TNF\n\n\t11/15 clinical improvement\tSalmonella, Clostridium difficile, 4 infections, arthralgia\t\nAll reports were limited to adult patients\n\nADA adalimumab, CD Crohn’s disease, CER certolizumab, ETA etanercept, GOL golimumab, HFMD hand, foot, and mouth disease, IFX infliximab, NAT natalizumab, PS psoriasis, RCT randomized controlled trial, SpA spondyloarthritis, TNF tumor necrosis factor inhibitor, UAI upper airway infections, UC ulcerative colitis, UST ustekinumab, VDZ vedolizumab\n\n\n\nThe two boys were treated for 2 years with a combination of IFX and UST. Thereafter, they were managed with monotherapy, one with UST every 8 weeks subcutaneously, the other with IFX. Both are in CD remission without psoriasis. The girl with anogenital psoriasis received combination therapy and went into clinical remission, but with endoscopic inflammation and elevated inflammatory markers. She experienced a skin infection and an external otitis that were successfully treated with antibiotics. After 2.5 years she was switched to VDZ monotherapy, initially supported by corticosteroids, and is in remission. No other adverse events were noted.\n\nLiterature Search\nData on combining biological agents with a different mode of action is limited. We found no publications reporting the use of a combination of biological agents (TNF antagonists, VDZ or UST) in PIBD. However, we did identify 13 publications (most of them case series) (Table 3) describing the use of a combination of biological agents in adult patients with IBD [21–33]. One of the studies was a randomized controlled trial (RCT) comparing IFX and IFX in combination with natalizumab (a humanized monoclonal IgG4 antibody against α4β1 integrin) in the treatment of active CD [24]. There was a trend toward clinical improvement with the combination and rates of infections and adverse events were comparable between the two treatment arms. The other studies are case reports including 1–15 patients, both UC and CD. In 2019, Ribaldone et al. published a pooled analysis that included seven of these reports, involving a total of 18 patients. A clinical improvement was obtained in all patients, with endoscopic improvement in 93% without any serious adverse events [34]. In another study, three adult patients in remission received the combination of a TNF antagonist and UST for paradoxical psoriasis resistant to topical therapy and methotrexate [23]. The combination therapy was well tolerated but was terminated after 2 months due to lack of effect on the psoriasis. In a case series from the Mayo Clinic including 15 patients (14 CD, 1 UC), combination therapy with biological agents was used due to disease worsening [22]. Eleven patients had symptomatic improvement and the authors conclude that combining biologics with different mechanisms of action may be safe and effective in the treatment of IBD. Finally, there is one ongoing RCT investigating the potential effect of triple therapy with VDZ, adalimumab, and oral methotrexate on endoscopic remission in newly diagnosed adult CD patients at high risk for complications [ClinicalTrials.gov identifier NCT02764762].\n\nDiscussion\nWe have experienced improved clinical efficacy combining biologicals in selected moderate to severe PIBD patients without the occurrence of serious adverse events. The indications for this treatment strategy in our patients were partial effect of IFX and therefore a need for treatment escalation, or side effects such as paradoxical psoriasis. To our knowledge, this is the first report of combining biological agents in PIBD.\n\nAccording to a recent study, patients co‐exposed to anti‐TNF while receiving VDZ induction therapy did not experience higher rate of adverse events compared with patients exposed to VDZ alone, indicating there is no need for a waiting interval before starting VDZ in patients who recently stopped anti‐TNF [35]. Combining a TNF antagonist that has a rapid systemic effect with a slower acting gut-specific agent like VDZ seems very attractive and adult experience in combining VDZ with IFX in IBD patients indicate that the combination is safe and efficacious [34]. In patients with only a partial improvement with anti-TNF, this combination may also act as a bridge to monotherapy with VDZ. In addition, corticosteroids can be avoided, which is of special interest in children [36].\n\nMost IBD patients have inactive or mild disease activity when paradoxical psoriasis appears [37]. This was also the case in our patients. UST has been proven to be effective in treating anti-TNF-induced psoriasis and psoriasiform alopecia [35, 38, 39]. In most cases, topical treatment is sufficient, and few patients need to end the anti-TNF therapy. In our patients, the psoriasis was extensive, not controlled by topical treatments, and involved hair loss. A switch to monotherapy with UST was tried in two patients, resulting in a flare of CD. Maybe we would have obtained a better result if we had used an intravenous loading dose with UST, which is recommended in IBD [5, 40], but that was not available at the time. Combination therapy with UST and IFX due to paradoxical psoriasis may not be an indefinite treatment. Two of our patients have discontinued combination therapy and have stayed in clinical remission with IFX or UST monotherapy for > 3 years without reoccurrence of psoriasis.\n\nThe combination treatments with biologicals were well tolerated in our patients. This is consistent with several published case series in adult patients [21–23]. Among our patients, one girl with CD and PSC developed severe eczema on the face and body, and in one boy with UC, elevated transaminases were detected after induction of clinical remission with VDZ and IFX combination therapy. In both patients, the treatment with IFX was stopped. The eczema was most probably due to IFX as it resolved after IFX discontinuation and the elevated transaminases were most likely related to PSC. Two patients developed antibodies to IFX but remained in remission with VDZ monotherapy. Apart from a skin infection and an external otitis in one patient, we did not notice any other adverse events.\n\nImmunogenicity with the formation of anti-drug antibodies seems to have little or no importance when using UST or VDZ in the treatment of IBD and, in contrast to anti-TNFs, co-medication with immunosuppressants is usually not recommended [41]. We stopped the use of immunosuppressants in all except two of our patients, since there is an increased risk of severe adverse events related to extensive immune suppression. Development of antibodies to IFX in two patients in whom concomitant immunosuppression was stopped was probably a consequence of this; therefore, there might still be a need for immunosuppression in patients receiving anti-TNFs as part of the combination. Such triple regimens are probably less problematic when using VDZ because of the gut-selective mode of action of this agent. However, most importantly, in every patient the risks of extensive immune suppression must be weighed against the severity of the disease.\n\nIn two of our patients, their IBD got worse when we tried monotherapy with VDZ and it was evident that they needed the combination treatment. In the other six patients who received combination with IFX, VDZ monotherapy might have induced remission. Among those patients who experienced anti-TNF-induced psoriasis, there were two patients who received monotherapy with subcutaneous UST with good effect on the skin lesions, but insufficient effect on the IBD. When switching to another class of biologics due to failure of monotherapy with IFX (and other anti-TNF drugs), monotherapy with the next biological is still our routine until RCTs have provided evidence for the opposite.\n\nThis is a small case report. The results must be interpreted with caution, especially with respect to the safety data. An obvious weakness of our study is the retrospective nature. Other therapeutic options had been tried, but not systematically in all patients. For example, as previously mentioned, monotherapy with UST or VDZ was not tried in all patients before combining biologicals. A strength of or study is that all patients treated with IFX and VDZ were well characterized by endoscopic evaluation, laboratory work-up, fecal calprotectin, drug levels, and measurements of anti-drug antibodies (see Table 1) to verify inflammation and optimize ongoing therapy.\n\nConclusions\nIn patients with moderate to severe IBD who lose response to an anti-TNF agent or develop side effects such as paradoxical psoriasis, combining the anti-TNF with another biological agent with a different mode of action may be beneficial. We did not experience any severe adverse events when combining IFX with VDZ or UST in PIBD patients. Our findings should, however, be addressed in larger studies with a long-term follow-up.\n\nOpen Access funding provided by Akershus University Hospital (AHUS).\n\nAuthor contributions\nAll authors have made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.\n\nCompliance with Ethical Standards\nConflict of interest\nCO has served as a speaker, consultant, or advisory board member for AbbVie, Nutricia, Norgine, Tillotts Pharma, and Mead Johnson. JJ has served as a speaker, consultant, or advisory board member for Abbie, Astro Pharma, Boehringer Ingelheim, BMS, Ferring, Celltrion, Hikma, Janssen, Meda, MSD, Napp Pharma, Norgine, Novartis, Orion Pharma, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts, and Sandoz. JBR has no conflicts of interest to disclose.\n\nEthics approval\nThe study was approved as a quality assurance study by the Data Protection Official for Research at Akershus University Hospital and good clinical practice guidelines were followed. Written informed consent is not required in quality assurance studies.\n==== Refs\nReferences\n1. Grover Z Predicting and preventing complications in children with inflammatory bowel disease Transl Pediatr 2019 8 1 70 76 10.21037/tp.2019.01.03 30881900 \n2. Tarnok A Kiss Z Kadenczki O Veres G Characteristics of biological therapy in pediatric patients with Crohn's disease Exp Opin Biolog Ther 2019 19 3 181 196 10.1080/14712598.2019.1564034 \n3. Sridhar S Maltz RM Boyle B Kim SC Dermatological manifestations in pediatric patients with inflammatory bowel diseases on anti-TNF therapy Inflamm Bowel Dis. 2018 24 2086 2092 10.1093/ibd/izy112 29718343 \n4. Sandborn WJ Gasink C Gao LL Blank MA Johanns J Guzzo C Ustekinumab induction and maintenance therapy in refractory Crohn's disease N Engl J Med 2012 367 16 1519 1528 10.1056/NEJMoa1203572 23075178 \n5. Feagan BG Rutgeerts P Sands BE Hanauer S Colombel JF Sandborn WJ Vedolizumab as induction and maintenance therapy for ulcerative colitis N Engl J Med 2013 369 8 699 710 10.1056/NEJMoa1215734 23964932 \n6. Shim HH Chan PW Chuah SW Schwender BJ Kong SC Ling KL A review of vedolizumab and ustekinumab for the treatment of inflammatory bowel diseases J Gastroenterol Hepatol Open 2018 2 5 223 234 \n7. Wyant T Fedyk E Abhyankar B An overview of the mechanism of action of the monoclonal antibody vedolizumab J Crohn's & colitis 2016 10 12 1437 1444 10.1093/ecco-jcc/jjw092 27252400 \n8. Singh N Rabizadeh S Jossen J Pittman N Check M Hashemi G Multi-center experience of vedolizumab effectiveness in pediatric inflammatory bowel disease Inflamm Bbowel Dis 2016 22 9 2121 2126 10.1097/MIB.0000000000000865 \n9. Conrad MA Stein RE Maxwell EC Albenberg L Baldassano RN Dawany N Vedolizumab therapy in severe pediatric inflammatory bowel disease Inflamm Bowel Dis 2016 22 10 2425 2431 10.1097/MIB.0000000000000918 27598742 \n10. Schneider AM Weghuber D Hetzer B Entenmann A Muller T Zimmermann G Vedolizumab use after failure of TNF-alpha antagonists in children and adolescents with inflammatory bowel disease BMC Gastroenterol 2018 18 1 140 10.1186/s12876-018-0868-x 30219028 \n11. Hamel B Wu M Hamel EO Bass DM Park KT Outcome of tacrolimus and vedolizumab after corticosteroid and anti-TNF failure in paediatric severe colitis BMJ Open Gastroenterol 2018 5 1 e000195 10.1136/bmjgast-2017-000195 \n12. Ledder O Assa A Levine A Escher JC de Ridder L Ruemmele F Vedolizumab in paediatric inflammatory bowel disease: a retrospective multi-centre experience from the paediatric IBD Porto Group of ESPGHAN J Crohn's Colitis 2017 11 10 1230 1237 10.1093/ecco-jcc/jjx082 28605483 \n13. Russell RK Hansen R Turner D New treatments for ulcerative colitis: do we have pediatric data? Exp Rev Clin Immunol 2016 12 7 701 704 10.1080/1744666X.2016.1177459 \n14. Landells I Marano C Hsu MC Li S Zhu Y Eichenfield LF Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study J Amer Acad Dermatol 2015 73 4 594 603 10.1016/j.jaad.2015.07.002 26259989 \n15. Feagan BG Sandborn WJ Gasink C Jacobstein D Lang Y Friedman JR Ustekinumab as induction and maintenance therapy for Crohn's disease New Engl J Med 2016 375 20 1946 1960 10.1056/NEJMoa1602773 27959607 \n16. Sands BE Sandborn WJ Panaccione R O'Brien CD Zhang H Johanns J Ustekinumab as induction and maintenance therapy for ulcerative colitis New Engl J Med 2019 381 13 1201 1214 10.1056/NEJMoa1900750 31553833 \n17. Bishop C Simon H Suskind D Lee D Wahbeh G Ustekinumab in pediatric Crohn disease patients J Pediatr Gastroenterol Nutr 2016 63 3 348 351 10.1097/MPG.0000000000001146 26854655 \n18. Dayan JR Dolinger M Benkov K Dunkin D Jossen J Lai J Real world experience with ustekinumab in children and young adults at a tertiary care pediatric inflammatory bowel disease center J Pediatr Gastroenterol Nutr. 2019 69 61 67 10.1097/MPG.0000000000002362 31058718 \n19. Chavannes M Martinez-Vinson C Hart L Kaniki N Chao CY Lawrence S Management of paediatric patients with medically refractory Crohn's disease using ustekinumab: a multi-centred cohort study J Crohn's Colitis 2019 13 5 578 584 10.1093/ecco-jcc/jjy206 30541021 \n20. van Hoeve K Dreesen E Hoffman I Van Assche G Ferrante M Gils A Higher infliximab trough levels are associated with better outcome in paediatric patients with inflammatory bowel disease J Crohn's Colitis 2018 12 11 1316 1325 10.1093/ecco-jcc/jjy111 30239644 \n21. Buer LCT Hoivik ML Warren DJ Medhus AW Moum BA Combining anti-TNF-alpha and vedolizumab in the treatment of inflammatory bowel disease: a case series Inflamm Bowel Dis 2018 24 5 997 1004 10.1093/ibd/izx110 29668901 \n22. Kwapisz L, Raffals LE, Bruining DH, Pardi DS, Tremaine WJ, Kane SV, et al. Combination biologic therapy in inflammatory bowel disease: experience from a tertiary care center. Clin Gastroenterol Hepatol. 2020 (in press).\n23. Yzet C Dupas JL Fumery M Ustekinumab and anti-TNF combination therapy in patients with inflammatory bowel disease Am J Gastroenterol 2016 111 5 748 749 10.1038/ajg.2016.66 27151127 \n24. Sands BE Kozarek R Spainhour J Barish CF Becker S Goldberg L Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab Inflamm Bowel Dis 2007 13 1 2 11 10.1002/ibd.20014 17206633 \n25. Hirten R Longman RS Bosworth BP Steinlauf A Scherl E Vedolizumab and infliximab combination therapy in the treatment of Crohn's disease Am J Gastroenterol 2015 110 12 1737 1738 10.1038/ajg.2015.355 26673509 \n26. Afzali A Chiorean M Combination of biologic agents in the management of severe refractory Crohn's disease: a case report of concomitant treatment with vedolizumab and adalimumab: 1725 Am J Gastroenterol 2016 111 S823 S824 10.14309/00000434-201610001-01725 \n27. Huff-Hardy K Bedair M Vazquez R Burstein E Efficacy of combination vedolizumab and ustekinumab for refractory Crohn's disease Inflamm Bowel Dis 2017 23 10 E49 10.1097/MIB.0000000000001232 \n28. Liu EY Loomes DE Ustekinumab and vedolizumab dual biologic therapy in the treatment of Crohn's disease Case Rep Med 2017 2017 5264216 29250117 \n29. Fischer S Rath T Geppert CI Manger B Schett G Neurath MF Long-term combination therapy with anti-TNF plus vedolizumab induces and maintains remission in therapy-refractory ulcerative colitis Am J Gastroenterol 2017 112 10 1621 1623 10.1038/ajg.2017.242 \n30. Roblin X Paul S Ben-Horin S Co-treatment with golimumab and vedolizumab to treat severe UC and associated spondyloarthropathy J Crohn's Colitis 2018 12 3 379 380 10.1093/ecco-jcc/jjx142 29088342 \n31. Mao EJ Lewin S Terdiman JP Beck K Safety of dual biological therapy in Crohn's disease: a case series of vedolizumab in combination with other biologics BMJ Open Gastroenterol 2018 5 1 e000243 10.1136/bmjgast-2018-000243 \n32. Bethge J Meffert S Ellrichmann M Conrad C Nikolaus S Schreiber S Combination therapy with vedolizumab and etanercept in a patient with pouchitis and spondylarthritis BMJ Open Gastroenterol 2017 4 1 e000127 10.1136/bmjgast-2016-000127 \n33. Elmoursi A Perry C Barrett T Deep remission with double biologic therapy: a successful case of combination ustekinumab and vedolizumab for severe refractory Crohn's disease Gastroenterology 2020 158 3 S117 S118 10.1053/j.gastro.2019.11.269 \n34. Ribaldone DG Pellicano R Vernero M Caviglia GP Saracco GM Morino M Dual biological therapy with anti-TNF, vedolizumab or ustekinumab in inflammatory bowel disease: a systematic review with pool analysis Scand J Gastroenterol 2019 54 4 407 413 10.1080/00365521.2019.1597159 30945576 \n35. Ben-Horin S Zhao Y Guo J Mao R Novack L Sergienko R Efficacy of biological drugs in short-duration versus long-duration inflammatory bowel disease: a protocol for a systematic review and an individual-patient level meta-analysis of randomised controlled trials BMJ Open 2019 9 1 e024222 10.1136/bmjopen-2018-024222 \n36. Rutgeerts PJ Review article: the limitations of corticosteroid therapy in Crohn's disease Alim Pharmacol Ther 2001 15 10 1515 1525 10.1046/j.1365-2036.2001.01060.x \n37. Melo FJ Magina S Clinical management of Anti-TNF-alpha-induced psoriasis or psoriasiform lesions in inflammatory bowel disease patients: a systematic review Int J Dermatol 2018 57 12 1521 1532 10.1111/ijd.14072 30028008 \n38. Tillack C Ehmann LM Friedrich M Laubender RP Papay P Vogelsang H Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-gamma-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment Gut 2014 63 4 567 577 10.1136/gutjnl-2012-302853 23468464 \n39. Eickstaedt JB Killpack L Tung J Davis D Hand JL Tollefson MM Psoriasis and psoriasiform eruptions in pediatric patients with inflammatory bowel disease treated with anti-tumor necrosis factor alpha agents Pediatr Dermatol 2017 34 3 253 260 10.1111/pde.13081 28211161 \n40. Sandborn WJ Feagan BG Rutgeerts P Hanauer S Colombel JF Sands BE Vedolizumab as induction and maintenance therapy for Crohn's disease N Engl J Med 2013 369 8 711 721 10.1056/NEJMoa1215739 23964933 \n41. Tamilarasan AG Cunningham G Irving PM Samaan MA Recent advances in monoclonal antibody therapy in IBD: practical issues Frontline Gastroenterol 2019 10 4 409 416 10.1136/flgastro-2018-101054 31656567\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1174-5878",
"issue": "22(4)",
"journal": "Paediatric drugs",
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"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D001685:Biological Factors; D001691:Biological Therapy; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "100883685",
"other_id": null,
"pages": "409-416",
"pmc": null,
"pmid": "32378002",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "28858074;28243458;27959607;29718343;23964932;27151127;23468464;29250117;30483594;30601083;28211161;27074695;27598742;32068149;28605483;30028008;29088342;26259989;11563990;27542130;30782731;31656567;30945576;31058718;23964933;26673509;27252400;29668901;30239644;30538822;31553833;23075178;17206633;28978957;29527316;30541021;30219028;30881900;26854655",
"title": "Combination of Biological Agents in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Case Series and Review of the Literature.",
"title_normalized": "combination of biological agents in moderate to severe pediatric inflammatory bowel disease a case series and review of the literature"
} | [
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"companynumb": "NO-CELLTRION INC.-2019NO022733",
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"abstract": "We investigated efficacy and safety of rabbit anti-thymocyte globulin (rATG), cyclosporine and granulocyte colony-stimulating factor (G-CSF) as first-line therapy for patients with aplastic anemia (AA) and low or intermediate-1 or hypoplastic myelodysplastic syndrome (MDS). rATG 3.5 mg/kg (or 2.5 mg/kg per day for patients >or=55 years with MDS) was given for 5 days. Cyclosporine (5 mg/kg) and G-CSF (5 microg/kg) were given daily and continued for up to 6 months or longer. Responses were assessed about 3 and 6 months after therapy. Thirty-six patients have been enrolled on study and 32 patients treated; 25 were evaluable for a response (13 with AA, 12 with MDS); the rest are too early. The median age was 62 years (range, 20-83) for patients with AA and 63 (range, 42-80) for patients with MDS. Of 13 patients, 12 (92%) patients with AA responded (5 complete response (CR), 7 partial response (PR)), whereas of 12 patients, 4 (33%) patients with MDS responded (1 CR, 3 PR). For patients with AA, the median time to response (TTR) was 93 days (range, 79-623), whereas in the MDS group the median TTR was 111 days (range, 77-139). Grade III/IV toxicities were mainly cytopenias and neutropenic fever. Combination of rATG, cyclosporine and G-CSF is safe and effective as first-line treatment of AA and has significant activity in low-risk MDS.",
"affiliations": "Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.",
"authors": "Garg|R|R|;Faderl|S|S|;Garcia-Manero|G|G|;Cortes|J|J|;Koller|C|C|;Huang|X|X|;York|S|S|;Pierce|S|S|;Brandt|M|M|;Beran|M|M|;Borthakur|G|G|;Kantarjian|H|H|;Ravandi|F|F|",
"chemical_list": "D000961:Antilymphocyte Serum; D016179:Granulocyte Colony-Stimulating Factor; D016572:Cyclosporine",
"country": "England",
"delete": false,
"doi": "10.1038/leu.2009.28",
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"issn_linking": "0887-6924",
"issue": "23(7)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000741:Anemia, Aplastic; D000818:Animals; D000961:Antilymphocyte Serum; D016572:Cyclosporine; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D011817:Rabbits",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1297-302",
"pmc": null,
"pmid": "19242494",
"pubdate": "2009-07",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10498555;10583220;15276395;12588356;11926789;8371581;17124044;9488634;9134878;14712285;7756640;8558211;15377466;10676908;12160363;11090046;16704434;12176872;9699230;12393680;7532040;11039659;7746977;16670072",
"title": "Phase II study of rabbit anti-thymocyte globulin, cyclosporine and granulocyte colony-stimulating factor in patients with aplastic anemia and myelodysplastic syndrome.",
"title_normalized": "phase ii study of rabbit anti thymocyte globulin cyclosporine and granulocyte colony stimulating factor in patients with aplastic anemia and myelodysplastic syndrome"
} | [
{
"companynumb": "US-AMGEN-USASP2021172065",
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"activesubstancename": "FILGRASTIM"
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{
"abstract": "Inverse psoriasis is a rare form of psoriasis characterized by the involvement of skin fold areas rather than the more common psoriatic involvement of the extensor surfaces of the extremities, trunk, and scalp. In addition, it requires a modified therapeutic approach because it is often less responsive to standard treatment regimens. Current treatment recommendations for inverse psoriasis mainly consist of topical agents, including corticosteroids, calcipotriol, and immunomodulating agents, whereas systemic medications remain insufficiently studied. Although adalimumab, a TNF-α inhibitor, has been approved for the treatment of moderate to severe plaque psoriasis, some reports indicate that TNF-α inhibitors may sometimes trigger psoriatic lesions, including inverse psoriasis. However, we present a case of inverse psoriasis and psoriatic arthritis unresponsive to standard treatment that was successfully treated with adalimumab.",
"affiliations": "Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia. Department of Dermatovenereology, University Medical Centre Ljubljana, Ljubljana, Slovenia. Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. Corresponding author: matija.tomsic@guest.arnes.si.",
"authors": "Ješe|Rok|R|;Perdan-Pirkmajer|Katja|K|;Dolenc-Voljč|Mateja|M|;Tomšič|Matija|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab",
"country": "Slovenia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1318-4458",
"issue": "23(1)",
"journal": "Acta dermatovenerologica Alpina, Pannonica, et Adriatica",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Alp Pannonica Adriat",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D015535:Arthritis, Psoriatic; D006801:Humans; D008297:Male; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "9422563",
"other_id": null,
"pages": "21-3",
"pmc": null,
"pmid": "24638868",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of inverse psoriasis successfully treated with adalimumab.",
"title_normalized": "a case of inverse psoriasis successfully treated with adalimumab"
} | [
{
"companynumb": "SI-ROXANE LABORATORIES, INC.-2014-RO-01446RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "SI",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nSmall-cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation typically manifests as a transformation occurring after EGFR tyrosine kinase inhibitor therapy for adenocarcinoma with EGFR mutation, whereas primary small-cell lung cancer showing EGFR mutation is extremely rare. Second biopsy of EGFR-mutated tumor has been broadly recognized as necessary, but is not always performed in daily practice, mainly due to the imbalance between the potential risk of the diagnostic procedure and the therapeutic impact of the biopsy result.\n\n\nMETHODS\nA 70-year-old woman who had never smoked was referred to our hospital with chief complaints of cough and back pain. Transbronchial lung biopsy from the primary tumor of the left upper lobe revealed combined small-cell lung cancer and adenocarcinoma, a subtype of small-cell lung cancer. EGFR L861Q mutation was detected in both small-cell lung cancer and adenocarcinoma components. Given the staging of cT2aN3M1b (Stage IV) and histological diagnosis, first-line chemotherapy with cisplatin plus irinotecan was initiated, and partial response was achieved. Seven months after initial diagnosis, the primary tumor enlarged again, and a second biopsy from the enlarged lesion detected only adenocarcinoma with the L861Q mutation. Erlotinib was started, but multiple brain metastases and enlarged mediastinal lymph nodes subsequently appeared. Whole-brain radiation therapy was performed, and endobronchial ultrasonography-guided transbronchial biopsy from the lymph node revealed reverse transformation to small-cell lung cancer with the L861Q mutation. Amrubicin therapy achieved partial response after two cycles, with the shrinkage lasting for eight months. Serum sialyl Lewis X antigen level increased when the adenocarcinoma component was dominant, whereas plasma pro-gastrin-releasing peptide level increased when the small-cell lung cancer component became dominant.\n\n\nCONCLUSIONS\nTransformation of the tumor correlates with the difference between small-cell lung cancer and adenocarcinoma in sensitivity to therapies, so repeated biopsies are beneficial for choosing appropriate treatments. Noninvasively obtainable parameters such as tumor markers can support the need for biopsy.",
"affiliations": "Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. ytakagi-tmd@umin.net.",
"authors": "Takagi|Yusuke|Y|;Nakahara|Yoshiro|Y|;Hosomi|Yukio|Y|;Hishima|Tsunekazu|T|",
"chemical_list": "D066246:ErbB Receptors",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2407-13-529",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central 1471-2407-13-5292419546810.1186/1471-2407-13-529Case ReportSmall-cell lung cancer with a rare epidermal growth factor receptor gene mutation showing “wax-and-wane” transformation Takagi Yusuke 1ytakagi-tmd@umin.netNakahara Yoshiro 1yoshironakaharakomagome@yahoo.co.jpHosomi Yukio 1yhosomi@cick.jpHishima Tsunekazu 2hishima@cick.jp1 Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan2 Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan2013 7 11 2013 13 529 529 6 6 2013 4 11 2013 Copyright © 2013 Takagi et al.; licensee BioMed Central Ltd.2013Takagi 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\nSmall-cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation typically manifests as a transformation occurring after EGFR tyrosine kinase inhibitor therapy for adenocarcinoma with EGFR mutation, whereas primary small-cell lung cancer showing EGFR mutation is extremely rare. Second biopsy of EGFR-mutated tumor has been broadly recognized as necessary, but is not always performed in daily practice, mainly due to the imbalance between the potential risk of the diagnostic procedure and the therapeutic impact of the biopsy result.\n\nCase presentation\nA 70-year-old woman who had never smoked was referred to our hospital with chief complaints of cough and back pain. Transbronchial lung biopsy from the primary tumor of the left upper lobe revealed combined small-cell lung cancer and adenocarcinoma, a subtype of small-cell lung cancer. EGFR L861Q mutation was detected in both small-cell lung cancer and adenocarcinoma components. Given the staging of cT2aN3M1b (Stage IV) and histological diagnosis, first-line chemotherapy with cisplatin plus irinotecan was initiated, and partial response was achieved. Seven months after initial diagnosis, the primary tumor enlarged again, and a second biopsy from the enlarged lesion detected only adenocarcinoma with the L861Q mutation. Erlotinib was started, but multiple brain metastases and enlarged mediastinal lymph nodes subsequently appeared. Whole-brain radiation therapy was performed, and endobronchial ultrasonography-guided transbronchial biopsy from the lymph node revealed reverse transformation to small-cell lung cancer with the L861Q mutation. Amrubicin therapy achieved partial response after two cycles, with the shrinkage lasting for eight months. Serum sialyl Lewis X antigen level increased when the adenocarcinoma component was dominant, whereas plasma pro-gastrin-releasing peptide level increased when the small-cell lung cancer component became dominant.\n\nConclusions\nTransformation of the tumor correlates with the difference between small-cell lung cancer and adenocarcinoma in sensitivity to therapies, so repeated biopsies are beneficial for choosing appropriate treatments. Noninvasively obtainable parameters such as tumor markers can support the need for biopsy.\n\nAdenocarcinomaBiopsyEpidermal growth factor receptorErlotinibMutationPro-gastrin releasing peptideSialyl Lewis X antigenSmall-cell lung cancerTransformationTumor marker\n==== Body\nBackground\nEpidermal growth factor receptor (EGFR) gene mutation is one of the most pervasive driver mutations in non-small cell lung cancer (NSCLC), particularly in adenocarcinoma\n[1]. Activating mutations in EGFR occur in exons 18 to 21, and most of the mutations in exons 18, 19 and 21 are regarded as sensitizing mutations for EGFR tyrosine kinase inhibitors (TKIs)\n[2]. Of these, exon 19 deletions and the exon 21 L858R point mutation account for more than 80% of mutations detected in tumors with EGFR mutations\n[2,3]. EGFR-TKI therapy for NSCLC with an EGFR mutation shows a significantly higher response rate, longer progression-free survival, and better quality of life when compared with platinum-doublet chemotherapy\n[4,5]. First-line treatment with EGFR-TKI is thus recommended for EGFR mutation-bearing NSCLC in recent clinical practice guidelines\n[6,7]. In contrast, EGFR mutation is rarely detected in small-cell lung cancer (SCLC). EGFR mutations in SCLC mostly manifest as a “transformation” after EGFR-TKI therapy in EGFR-mutated adenocarcinoma\n[8], whereas primary SCLC with EGFR mutation is extremely rare. Some case reports have described EGFR-mutated SCLC treated using EGFR-TKI, but responses to EGFR-TKI differ\n[9,10]. To date, whether EGFR-TKIs or cytotoxic chemotherapy should be administered for SCLC with an EGFR mutation remains unclear. A case of SCLC with a rare EGFR mutation that showed “wax-and-wane” transformation is presented, and EGFR mutations in SCLC are comprehensively reviewed.\n\nCase presentation\nA 70-year-old Japanese woman was referred to our hospital with chief complaints of cough and back pain. She had never smoked and had no history of malignancy. Computed tomography (CT) revealed a 4-cm-diameter mass in the left upper lobe, enlargement of mediastinal lymph nodes, and left pleural dissemination (Figure \n1). Asymptomatic brain metastasis was also detected on magnetic resonance imaging. A transbronchial lung biopsy (TBLB) specimen from the left upper lobe showed combined SCLC and adenocarcinoma (Figure \n2), and the TNM classification of the tumor was cT2aN3M1b(BRA). The TBLB specimens were analyzed using a peptide nucleic acid-locked nucleic acid PCR clamp test, and EGFR exon 21 L861Q mutations were detected in both SCLC and adenocarcinoma components (Figure \n3).\n\nFigure 1 Computed tomography at the time of initial diagnosis. A) Primary lung cancer lesion in the upper lobe of the left lung. B) Enlargement of the mediastinal lymph nodes. C) Left pleural dissemination.\n\nFigure 2 Histopathology of combined small-cell lung cancer. A) Transbronchial lung biopsy from the primary lesion shows adenocarcinoma (hematoxylin and eosin staining, marked with arrow). The insets show that this tumor is positive for TTF-1 and negative for synaptophysin and chromogranin. B) Another slice from the same biopsy specimen shows small-cell lung cancer (hematoxylin and eosin staining, marked with arrow). The insets show that this tumor is positive for TTF-1, synaptophysin, and chromogranin. chr, chromogranin; syn, synaptophysin; TTF, TTF-1.\n\nFigure 3 EGFR L861Q amplification curve for each specimen by the peptide nucleic acid-locked nucleic acid PCR clamp test. A) Small-cell lung cancer component of the specimen at the time of initial diagnosis. B) Adenocarcinoma component of the specimen at the time of initial diagnosis. C) Adenocarcinoma at the time of disease progression after cisplatin-irinotecan therapy. D) Small-cell lung cancer at the time of disease progression after erlotinib therapy.\n\nThe patient underwent four cycles of chemotherapy comprising cisplatin (60 mg/m2) and irinotecan (60 mg/m2). The total effect of chemotherapy was partial response, and symptoms resolved. Serum sialyl Lewis X antigen (SLX) level decreased from 35 U/mL at the initiation of chemotherapy to 5.2 U/mL after four cycles of chemotherapy, and plasma levels of pro-gastrin releasing peptide (pro-GRP) also decreased from 695 pg/mL to 102 pg/mL. Complete remission of the brain metastasis was also achieved, and whole-brain radiation therapy (WBRT) was postponed at the request of the patient.\n\nSeven months after initial diagnosis, disease progression with enlargement of the primary tumor and lymph nodes was observed. Serum SLX level was elevated to 14 U/mL, while plasma pro-GRP level remained stable (102 pg/mL). TBLB of the primary tumor was performed again, and only adenocarcinoma with the EGFR L861Q mutation was detected (Figure \n3). Treatment with erlotinib (150 mg daily) was thus started.\n\nAfter two months of disease stabilization, multiple brain metastases developed without any symptoms. The patient underwent WBRT of 30 Gy. Soon after the completion of WBRT, mediastinal lymph node enlargement occurred again. Serum SLX level was decreased (9.1 U/mL), but plasma pro-GRP level increased to 133 pg/mL. Endobronchial ultrasonography-guided transbronchial biopsy was performed. At that time, only SCLC with the EGFR L861Q mutation was identified (Figure \n3). PIK3CA mutation analysis of the second (adenocarcinoma) and third (SCLC) biopsy specimens was performed, but no mutation was detected from either sample. Erlotinib was stopped, and chemotherapy with amrubicin (35 mg/m2) achieved partial response after two cycles. This treatment was therefore continued for nine cycles without disease progression. SLX and pro-GRP levels both decreased, to <2.5 U/mL and 79.8 pg/mL, respectively. However, chemotherapy was terminated when performance status decreased after lumbar vertebral compression without bone metastasis. Chemotherapy was then terminated. The patient remains alive as of 21 months after diagnosis.\n\nConclusions\nFew case reports have described primary EGFR-mutated adenocarcinoma transforming to SCLC and then reverse-transforming to adenocarcinoma\n[8,11]. As far as we can determine, this represents the first report of initially diagnosed SCLC with an EGFR mutation that showed transformations in both directions. EGFR L861Q mutation was detected from all specimens obtained on each occasion. Taking the rarity of L861Q mutation among EGFR activating mutations\n[2] into account, it appears very likely that both the SCLC and adenocarcinoma components shared a common origin. Relatively good response to cytotoxic chemotherapy was observed throughout the course of treatment. Tumor markers such as SLX and pro-GRP reflected the pathological changes in the tumor.\n\nAlthough the objective response to erlotinib therapy was modest, the dominant component of the tumor in the present case changed from adenocarcinoma to SCLC after EGFR-TKI therapy. Generally, histological examination of TBLB specimens can provide the histology of only a part of the disease, but all biopsies were performed from enlarging lesions, reflecting the dominant component of the progressing disease. We suggest that responsiveness to EGFR-TKI varies between SCLC and adenocarcinoma, and the SCLC component that did not respond to erlotinib progressed selectively. In a similar manner, most cases of SCLC with EGFR mutations have been reported as developing acquired resistance to EGFR-TKI, and were initially diagnosed as NSCLC\n[8,11-15]. In general, lung adenocarcinoma and SCLC show different genetic characteristics\n[15,16]. In mouse models, concomitant knockout of Rb and p53 causes a high incidence of SCLC, whereas mice with somatic inactivation of p53 alone develop adenocarcinomas\n[17]. A previous study showed an acquired PIK3CA mutation in SCLC transformed from EGFR-mutated adenocarcinoma after EGFR-TKI therapy\n[8]. Unfortunately, it was not possible to detect concomitant molecular alterations in the present case, but oncogenic drivers out of EGFR may explain the resistance to EGFR-TKI in EGFR-mutated SCLC.\n\nSCLC with an EGFR mutation is often resistant to EGFR-TKI, as mentioned above, whereas most cytotoxic chemotherapies achieve good response (Table \n1). Second biopsy after cytotoxic chemotherapy for SCLC with an EGFR mutation revealed transformation to adenocarcinoma in various reports\n[8,11], indicating that the SCLC component is more sensitive to cytotoxic chemotherapy than the adenocarcinoma component. The differences in effectiveness of therapeutic regimens between histological types strongly support the indication of repeated biopsies at the time of each treatment change.\n\nTable 1 Small-cell lung cancer with EGFR mutations and treatment outcomes\n\nPrior TKI\tMutation\tChemotherapy\tPFS\tHist after Tx\tRef.\t\nNone\tL861Q\tCDDP + CPT-11\t7 mo\tAdenocarcinoma\t*\t\nE\tL861Q\tAMR\t8 mo\tN/A\t*\t\nNone\tG719A\tG\tN/A (PR)\tN/A\t[9]\t\nNone\tEx19del\tCRT\t7 mo\tN/A\t[10]\t\nNone\tEx19del\tCDDP + VP-16\t6 mo\tN/A\t[10]\t\nG\tEx19del\tG\t5 mo\tN/A\t[18]\t\nG, E\tEx19del\tG + VP-16\tN/A (PD)\tN/A\t[12]\t\nG\tEx19del\tCDDP + CPT-11\t6 mo\tAdenocarcinoma\t[11]\t\nG, E\tL858R\tTOP\t>4 mo (CR)\tN/A\t[13]\t\nE\tL858R\tCRT\t6 mo\tAdenocarcinoma\t[8]\t\nE\tL858R\tCDDP + VP-16\tN/A (PR)\tN/A\t[8]\t\nG\tL858R\tCDDP + VP-16\tN/A (PR)\tN/A\t[14]\t\nReports without sufficient information about treatment are not included on this table.\n\n*, present case; AMR, Amrubicin; CDDP, Cisplatin; CPT-11, Irinotecan; CR, Complete response; CRT, Combined chemoradiotherapy; E, Erlotinib; Ex19del, Exon 19 deletions; G, Gefitinib; Hist after Tx, Histology after treatment; mo, Months; N/A, Not assessed; PFS, Progression-free survival; PR, Partial response; Ref., Reference; TKI, Epidermal growth factor receptor tyrosine kinase inhibitor; TOP, Topotecan; VP-16, Etoposide.\n\nIn this case, transitions in tumor markers (SLX and pro-GRP) appeared to occur in parallel with histological transformation. Second biopsy has been broadly recognized as necessary\n[8], but has not always been carried out in daily practice. This is mainly attributable to the imbalance between the potential risk of the diagnostic procedure and the therapeutic impact of the biopsy result. Given the sensitivity of EGFR-mutated SCLC to cytotoxic chemotherapies, re-biopsy for detecting tumor transformation can prove highly beneficial for patients. Noninvasive methods, including tumor markers, circulating tumor cells\n[19], and highly sensitive mutation detection using plasma samples\n[20] may play an important role in guiding the decisions of physicians and patients for the next diagnostic step, particularly when an invasive procedure is needed for obtaining tumor samples.\n\nIn conclusion, the optimal regimen for SCLC with an EGFR mutation cannot be uniformly defined, and should be decided according to the dominant histology at each point in the treatment course. Repeated biopsies are sometimes difficult in daily practice, but noninvasively obtainable parameters such as tumor markers can support the need for diagnostic procedures. Detailed examination of combined SCLC and adenocarcinoma, including comprehensive genome analysis, may reveal the factors that determine the histological and clinical characteristics of these tumors.\n\nEthics statement\nThis case study was approved by the ethics committee of Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital (Tokyo, Japan), and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nYT was responsible for clinical management of the patient, acquisition of data, and drafting the manuscript; YN, YH and TH were responsible for interpretation of data and critical revision of the manuscript. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-2407/13/529/prepub\n==== Refs\nKris MG Johnson BE Kwiatkowski DJ Iafrate AJ Wistuba II Aronson SL Engelman JA Shyr Y Khuri FR Rudin CM Garon EB Pao W Schiller JH Haura EB Shirai K Giaccone G Berry LD Kugler K Minna JD Bunn PA Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI’s Lung Cancer Mutation Consortium (LCMC) J Clin Oncol 2011 29 Suppl-May CRA7506 \nde Pas T Toffalorio F Manzotti M Fumagalli C Spitaleri G Catania C Delmonte A Giovannini M Spaggiari L de Braud F Barberis M Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations J Thorac Oncol 2011 6 1895 1901 10.1097/JTO.0b013e318227e8c6 21841502 \nPao W Chmielecki J Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer Nat Rev Cancer 2010 10 760 774 10.1038/nrc2947 20966921 \nMaemondo M Inoue A Kobayashi K Sugawara S Oizumi S Isobe H Gemma A Harada M Yoshizawa H Kinoshita I Fujita Y Okinaga S Hirano H Yoshimori K Harada T Ogura T Ando M Miyazawa H Tanaka T Saijo Y Hagiwara K Morita S Nukiwa T North-East Japan Study Group: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N Eng J Med 2010 362 2380 2388 10.1056/NEJMoa0909530 \nRosell R Carcereny E Gervais R Vergnenegre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A de Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial Lancet Oncol 2012 13 239 246 10.1016/S1470-2045(11)70393-X 22285168 \nPeters S Adjei AA Gridelli C Reck M Kerr K Felip E ESMO Guidelines Working Group: Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2012 23 Suppl 7 vii56 vii64 10.1093/annonc/mds226 22997455 \nde Marinis F Rossi A di Maio M Ricciardi S Gridelli C Italian Association of Thoracic Oncology: Treatment of advanced non-small-cell lung cancer: Italian Association of Thoracic Oncology (AIOT) clinical practice guidelines Lung Cancer 2011 73 1 10 10.1016/j.lungcan.2011.02.022 21440325 \nSequist LV Waltman BA Dias-Santagata D Digumarthy S Turke AB Fidias P Bergethon K Shaw AT Gettinger S Cosper AK Akhavanfard S Heist RS Temel J Christensen JG Wain JC Lynch TJ Vernovsky K Mark EJ Lanuti M Iafrate AJ Mino-Kenudson M Engelman JA Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors Sci Transl Med 2011 3 75ra26 10.1126/scitranslmed.3002003 21430269 \nTatematsu A Shimizu J Murakami Y Horio Y Nakamura S Hida T Mitsudomi T Yatabe Y Epidermal growth factor receptor mutations in small cell lung cancer Clin Cancer Res 2008 14 6092 6096 10.1158/1078-0432.CCR-08-0332 18829487 \nShiao TH Chang YL Yu CJ Chang YC Hsu YC Chang SH Shih JY Yang PC Epidermal growth factor receptor mutations in small cell lung cancer: a brief report J Thorac Oncol 2011 6 195 198 10.1097/JTO.0b013e3181f94abb 21178714 \nMorinaga R Okamoto I Furuta K Kawano Y Sekijima M Dote K Satou T Nishio K Fukuoka M Nakagawa K Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation Lung Cancer 2007 58 411 413 10.1016/j.lungcan.2007.05.014 17601631 \nZakowski MF Ladanyi M Kris MG Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group: EGFR mutations in small-cell lung cancers in patients who have never smoked N Eng J Med 2006 355 213 215 10.1056/NEJMc053610 \nAlam N Gustafson KS Ladanyi M Zakowski MF Kapoor A Truskinovsky AM Dudek AZ Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung Clin Lung Cancer 2010 11 E1 E4 10.3816/CLC.2010.n.046 20837450 \nMa AT Chan WK Ma ES Cheng T Cheng PN Small cell lung cancer with an epidermal growth factor receptor mutation in primary gefitinib-resistant adenocarcinoma of the lung Acta Oncol 2012 51 557 559 10.3109/0284186X.2011.636757 22129360 \nImielinski M Berger AH Hammerman PS Hernandez B Pugh TJ Hodis E Cho J Suh J Capelletti M Sivachenko A Sougnez C Auclair D Lawrence MS Stojanov P Cibulskis K Choi K de Waal L Sharifnia T Brooks A Greulich H Banerji S Zander T Seidel D Leenders F Ansén S Ludwig C Engel-Riedel W Stoelben E Wolf J Goparju C Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing Cell 2012 150 1107 1120 10.1016/j.cell.2012.08.029 22980975 \nPeifer M Fernández-Cuesta L Sos ML George J Seidel D Kasper LH Plenker D Leenders F Sun R Zander T Menon R Koker M Dahmen I Müller C di Cerbo V Schildhaus HU Altmüller J Baessmann I Becker C de Wilde B Vandesompele J Böhm D Ansén S Gabler F Wilkening I Heynck S Heuckmann JM Lu X Carter SL Cibulskis K Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer Nat Genet 2012 44 1104 1110 10.1038/ng.2396 22941188 \nMeuwissen R Linn SC Linnoila RI Zevenhoven J Mooi WJ Berns A Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model Cancer Cell 2003 4 181 189 10.1016/S1535-6108(03)00220-4 14522252 \nAraki J Okamoto I Suto R Ichikawa Y Sasaki J Efficacy of the tyrosine kinase inhibitor gefitinib in a patient with metastatic small cell lung cancer Lung Cancer 2005 48 141 144 10.1016/j.lungcan.2004.10.012 15777982 \nMaheswaran S Sequist LV Nagrath S Ulkus L Brannigan B Collura CV Inserra E Diederichs S Iafrate AJ Bell DW Digumarthy S Muzikansky A Irimia D Settleman J Tompkins RG Lynch TJ Toner M Haber DA Detection of mutations in EGFR in circulating lung-cancer cells N Eng J Med 2008 359 366 377 10.1056/NEJMoa0800668 \nTaniguchi K Uchida J Nishino K Kumagai T Okuyama T Okami J Higashiyama M Kodama K Imamura F Kato K Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas Clin Cancer Res 2011 17 7808 7815 10.1158/1078-0432.CCR-11-1712 21976538\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "13()",
"journal": "BMC cancer",
"keywords": null,
"medline_ta": "BMC Cancer",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009154:Mutation; D055752:Small Cell Lung Carcinoma; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
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"pages": "529",
"pmc": null,
"pmid": "24195468",
"pubdate": "2013-11-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22997455;20966921;20573926;15777982;21178714;22941188;21430269;22980975;22285168;20837450;21976538;21841502;14522252;17601631;18829487;16837691;18596266;22129360;21440325",
"title": "Small-cell lung cancer with a rare epidermal growth factor receptor gene mutation showing \"wax-and-wane\" transformation.",
"title_normalized": "small cell lung cancer with a rare epidermal growth factor receptor gene mutation showing wax and wane transformation"
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"companynumb": "JP-CIPLA LTD.-2016JP17546",
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"abstract": "OBJECTIVE\nPatients being treated with anti-tumor necrosis factor-alpha (anti-TNF-alpha) agents were reported to have better prognosis related to COVID-19. We evaluated the factors affecting the frequency, clinical course, and outcome of COVID-19 in patients treated with anti-TNF-alpha agents.\n\n\nMETHODS\nPatients with rheumatoid diseases and chronic inflammatory bowel diseases treated with anti-TNF-alpha agents were evaluated retrospectively. The laboratory data in routine visits, frequency of COVID-19, pneumonia, hospitalization and/or intensive care unit (ICU) follow-up and, mortality were recorded. The factors related to COVID-19 frequency and clinical outcome were evaluated.\n\n\nRESULTS\nA total of 324 patients (177 males [54.6%] and 147 females [45.4%], mean age: 45.3±12.16 years) was included in the study. In all, 44 (13.6%) patients had COVID-19; of these, 11 (25%) developed pneumonia, 7 (15.9%) were hospitalized, and 1 (2.3%) was followed up in ICU. There was no mortality. The patients with COVID-19 pneumonia were older (mean age: 52±11 years versus 41±12 years, p=0.01), had hypertension and coronary artery disease more frequently (5 cases [55.6%] versus 4 cases [44.4], p=0.02 and 2 cases [100%] versus 0 cases [0%], p=0.014, respectively), and lower eosinophil % (1.35±1.79% versus 2.3±1.45%, p=0.016). The diabetes mellitus was more frequent (66.7 versus 33.3%, p=0.013), and mean eosinophil % was lower among inpatients compared with outpatients (1.29±2.22% versus 2.19±1.37%, p=0.02).\n\n\nCONCLUSIONS\nWe concluded that the patients treated with anti-TNF-alpha agents having COVID-19 might have mild clinical course and better prognosis.",
"affiliations": "Umraniye Training and Research Hospital, Department of Pulmonology - Istanbul, Turkey.;Umraniye Training and Research Hospital, Department of Rheumatology - Istanbul, Turkey.",
"authors": "Baslılar|Seyma|S|http://orcid.org/0000-0003-1495-6508;Pehlivan|Ozlem|O|http://orcid.org/0000-0002-6887-1801",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1806-9282.20210568",
"fulltext": null,
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"issn_linking": "0104-4230",
"issue": "67(9)",
"journal": "Revista da Associacao Medica Brasileira (1992)",
"keywords": null,
"medline_ta": "Rev Assoc Med Bras (1992)",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "9308586",
"other_id": null,
"pages": "1286-1292",
"pmc": null,
"pmid": "34816922",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of factors affecting the frequency and clinical course of COVID-19 in patients using anti-TNF-alpha agents.",
"title_normalized": "evaluation of factors affecting the frequency and clinical course of covid 19 in patients using anti tnf alpha agents"
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"companynumb": "TR-AMGEN-TURSP2022010302",
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"abstract": "OBJECTIVE\nThe combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patients.\n\n\nMETHODS\nPatients with advanced adenocarcinoma of the pancreas were enrolled. Eligible patients had a WHO performance status 0-2 and adequate hepatic and renal functions. The treatment regimen consisted of capecitabine 1000 mg/m(2) BID day 1-14 and everolimus 10 mg daily (5 mg BID) in a continuous 21-day schedule. Tumor assessment was performed with CT-scan every three cycles. Primary endpoint was response rate (RR) according to RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and 1-year survival rate.\n\n\nRESULTS\nIn total, 31 patients were enrolled. Median (range) treatment duration with everolimus was 76 days (1-431). Principal grade 3/4 toxicities were hyperglycemia (45 %), hand-foot syndrome (16 %), diarrhea (6 %) and mucositis (3 %). Prominent grade 1/2 toxicities were anemia (81 %), rash (65 %), mucositis (58 %) and fatigue (55 %). RR was 6 %. Ten patients (32 %) had stable disease resulting in a disease control rate of 38 %. Median overall survival was 8.9 months (95 % CI 4.6-13.1). Progression-free survival was 3.6 months (95 % CI 1.9-5.3).\n\n\nCONCLUSIONS\nThe oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer, with an acceptable toxicity profile at the applied dose level.",
"affiliations": "Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands, silkordes@gmail.com.",
"authors": "Kordes|S|S|;Klümpen|H J|HJ|;Weterman|M J|MJ|;Schellens|J H M|JH|;Richel|D J|DJ|;Wilmink|J W|JW|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; D000069287:Capecitabine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil; D020123:Sirolimus",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-015-2730-y",
"fulltext": "\n==== Front\nCancer Chemother Pharmacol\nCancer Chemother Pharmacol\nCancer Chemotherapy and Pharmacology\n0344-5704\n1432-0843\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n25822310\n2730\n10.1007/s00280-015-2730-y\nOriginal Article\nPhase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer\nKordes S. +31 20 5665955 silkordes@gmail.com\n\n1\nKlümpen H. J. 1\nWeterman M. J. 1\nSchellens J. H. M. 234\nRichel D. J. 1\nWilmink J. W. 1\n1 Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands\n2 Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands\n3 Department of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands\n4 Division of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, University Utrecht, Universiteitsweg 99, Utrecht, The Netherlands\n31 3 2015\n31 3 2015\n2015\n75 6 11351141\n14 1 2015\n17 3 2015\n© The Author(s) 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nPurpose\n\nThe combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patients.\n\nMethods\n\nPatients with advanced adenocarcinoma of the pancreas were enrolled. Eligible patients had a WHO performance status 0–2 and adequate hepatic and renal functions. The treatment regimen consisted of capecitabine 1000 mg/m2 BID day 1–14 and everolimus 10 mg daily (5 mg BID) in a continuous 21-day schedule. Tumor assessment was performed with CT-scan every three cycles. Primary endpoint was response rate (RR) according to RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and 1-year survival rate.\n\nResults\n\nIn total, 31 patients were enrolled. Median (range) treatment duration with everolimus was 76 days (1–431). Principal grade 3/4 toxicities were hyperglycemia (45 %), hand-foot syndrome (16 %), diarrhea (6 %) and mucositis (3 %). Prominent grade 1/2 toxicities were anemia (81 %), rash (65 %), mucositis (58 %) and fatigue (55 %). RR was 6 %. Ten patients (32 %) had stable disease resulting in a disease control rate of 38 %. Median overall survival was 8.9 months (95 % CI 4.6–13.1). Progression-free survival was 3.6 months (95 % CI 1.9–5.3).\n\nConclusions\n\nThe oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer, with an acceptable toxicity profile at the applied dose level.\n\nKeywords\n\nmTOR\nPancreatic cancer\nCapecitabine\nPhase II\nTargeted therapy\nEverolimus\nissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2015\n==== Body\nIntroduction\n\nThe PI3K/Akt pathway is an important intracellular signaling pathway that is often dysregulated in cancer [1]. Signal transduction of activated PI3K/Akt is transmitted through several downstream targets, including the mammalian target of rapamycin (mTOR) [2, 3]. Everolimus, an oral mTOR inhibitor, has demonstrated antitumor properties in vitro and in vivo including inhibition of cell proliferation, cell survival and angiogenesis and showed additive as well as synergistic effects when combined with other anticancer agents such as 5-fluorouracil (5-FU) [4–11].\n\nSingle-agent everolimus has been investigated in phase I–III clinical trials in patients with various types of advanced solid tumors [12–19]. These trials demonstrated that treatment with everolimus at 10 mg daily was well tolerated and showed clinical activity in some malignancies with an acceptable toxicity profile, consisting mainly of stomatitis and fatigue.\n\nClinical trials investigating everolimus in combination with other anticancer drugs have been performed or are ongoing, in short, confirming preclinical evidence that everolimus may be more efficacious when used in combination with other anticancer drugs [20–25]. Recently, a phase II study with the combination of low-dose capecitabine (650 mg/m2 BID day 1–14) and everolimus (5 mg BID) showed effectivity in heavily pretreated gastric cancer patients, and with an acceptable toxicity profile [26]. Previously, we demonstrated the safety and feasibility of the combination of capecitabine 1000 mg/m2 BID day 1–14 and continuous everolimus 5 mg BID in a 21-day schedule [27]. In this phase I study, two out of three patients with pancreatic cancer achieved a partial remission (PR).\n\nIn the pre-FOLFIRINOX era, gemcitabine was considered standard therapy for first-line treatment of pancreatic cancer patients, because of a significant improvement of the clinical benefit response, although the survival advantage was <1 month, in comparison with 5-FU [28, 29]. Although studies with the oral 5-FU analogue capecitabine in direct comparison with 5-FU or gemcitabine in patients with pancreatic cancer are not available, capecitabine seems to have comparable activity in this patient group [30].\n\nIn the present phase II study, we explored the activity of capecitabine and everolimus combination treatment as first- and second-line therapy in patients with advanced pancreatic cancer.\n\nMaterials and methods\n\nPatient population\n\nEligible patients were aged ≥18 years, with histologically or cytologically confirmed advanced pancreatic cancer, and measurable lesions according to Response Evaluation Criteria in Solid Tumors (RECIST 1.0) [31]. Patients who had prior chemotherapy in the adjuvant setting or for metastatic disease were eligible. Adjuvant patients were considered second line if the chemotherapy free interval was <6 months before start study. Other eligibility criteria included WHO performance status ≤2, estimated life expectancy of ≥3 months, adequate bone marrow (white blood cell count ≥ 3.0 × 109/L, platelets ≥ 100 × 109/L) and adequate hepatic and renal function (serum bilirubin ≤ 1.5 × upper limit of normal (ULN), ALAT/ASAT ≤ 2.5 × ULN or in case of liver metastases ≤ 5 × ULN and serum creatinine ≤ 150 μmol/L). Patients were ineligible if they had established alcohol abuse, drug addiction and/or psychotic disorders that made adequate follow-up unlikely. Women who were pregnant or lactating were also excluded. All patients gave written informed consent. The study was approved by the Medical Ethics Committee of the Academic Medical Center Amsterdam and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The trial was registered online (ClinicalTrials.gov identifier: NCT01079702).\n\nStudy design and treatment\n\nThis was a phase II, open-label, single-center study to assess the antitumor activity and safety of the combination of everolimus and capecitabine. The primary endpoint was response rate. The study was conducted at the Amsterdam Medical Center, The Netherlands. Everolimus was administered continuously at an oral dose of 5 mg BID. The first 7 days of treatment patients were treated with single-agent everolimus to reach steady-state drug concentrations. Treatment with capecitabine 1000 mg/m2 BID started on day 8 and was given twice daily for 14 days in a three weekly cycle. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and was assessed every treatment cycle [32]. Tumor measurements were performed at baseline and every three cycles, and responses were evaluated in accordance with RECIST 1.0 [31]. Patients continued treatment until disease progression, withdrawal of consent or in case of intolerability. Overall survival was defined from start of study treatment until death. Progression-free survival was defined from start of study to clinical or radiological progression or death. When treatment was discontinued due to other reasons, date of last documented assessment was used and censored.\n\nStatistical analysis\n\nFor sample size calculations, the two-stage design according to Gehan for estimating the response rate was used [33]. In the first stage, 14 patients were entered. If no responses were observed in the first stage, then the trial would be terminated because the absence of response (0/14) has a probability <0.05 if the true response rate is 0.20. We choose for an estimate with approximately a 10 % standard error, with an accrual of 11 patients in the second stage. For the evaluation of the safety, efficacy parameters descriptive statistics were applied using SPSS statistics. Intention to treat analysis was used.\n\nResults\n\nIn total, 31 patients with advanced pancreatic cancer were enrolled between June 2010 and November 2011. After a partial response in the first stage of 14 patients, 11 patients were enrolled in the second stage. Six additional patients were enrolled to ensure 25 patients receiving at least one full cycle of the treatment combination for a complete safety analysis (see below).\n\nPatient characteristics are listed in Table 1. The majority of patients had metastatic adenocarcinoma and a WHO performance status of 0–1. The study group consisted of 15 first-line patients and 16 second-line patients. Eighteen patients received prior gemcitabine-based chemotherapy; 11 in palliative setting, six adjuvant (five patients with chemotherapy free interval <6 months) and 1 as part of neoadjuvant chemoradiotherapy.Table 1 Patient characteristics\n\n\tN\t%\t\nNo. of patients\t31\t\t\nGender\t\n Male\t15\t48\t\n Female\t16\t52\t\nRace\t\n Caucasian\t30\t97\t\n Asian\t1\t3\t\nMedian age (years)\t63\t\t\n Range\t37–77\t\t\nStage\t\n Metastatic\t29\t94\t\n Locally advanced\t2\t6\t\nWHO performance status\t\n 0\t16\t52\t\n 1\t11\t35\t\n 2\t4\t13\t\nHistology\t\n Adenocarcinoma\t30\t97\t\n Acinar cell carcinoma\t1\t3\t\nPrior therapy\t\n First line\t15\t48\t\n Neoadjuvant CRT\t1\t3\t\n Adjuvant gemcitabine\t1\t3\t\n Second line\t16\t52\t\n Adjuvant gemcitabinea\t5\t16\t\n Palliative\t11\t35\t\nWHO World Health Organization, CRT chemoradiotherapy\n\naProgression during or within 6 months after adjuvant treatment\n\nOverall, a total of 147 treatment cycles were given, with a median (range) of 3 (1–9) cycles per patient. Median (range) treatment duration with everolimus was 76 (1–431) days (Table 2). Six patients temporarily interrupted treatment with everolimus due to adverse events. Following treatment interruption, five patients received a 50 % dose reduction of everolimus and the other continued treatment at the full dose of everolimus. Due to adverse events, treatment with capecitabine was interrupted in 15 patients resulting in dose reductions for capecitabine in 14 patients.Table 2 Treatment administration of the combination of everolimus and capecitabine\n\nEvaluable patients (N = 31)\t\nNo. of treatment cycles\t\n Median\t3\t\n Range\t1–15\t\nNo. of treatment days with everolimus\t\n Mean ± SD\t104 ± 93\t\n Median\t76\t\n Range\t1–431\t\nEverolimus dose delivery\t\nNo. of patients (%)\t\n Dose reduction due to toxicity\t5 (16)\t\n Temporary treatment disruption due to toxicity\t6 (19)\t\nCapecitabine dose delivery\t\nNo. of patients (%)\t\n Dose reduction due to toxicity\t14 (45)\t\n Temporary treatment disruption due to toxicity\t15 (48)\t\nSD standard deviation\n\nSafety\n\nSix patients did not receive a complete cycle of the treatment combination; two patients refusal, three patients had early clinical progression, and one patient died of non-treatment-related septic cholangitis. Treatment-related toxicities of these patients were included in the intention to treat toxicity analysis.\n\nTable 3 lists the treatment-related CTC grade 1–2 and grade 3–4 adverse events. The most frequently reported clinical toxicities of any grade included mucositis, skin reactions, fatigue, nausea and diarrhea. Severe clinical toxicities were not frequent. Grade 3–4 hand-foot syndrome was observed in five patients, diarrhea in two patients, stomatitis, skin rash and vomiting in one patient. Three patients developed grade 3 hematological toxicity (thrombocytopenia and anemia). Hyperglycemia of any grade was the most frequently reported biochemical toxicity, resulting in clinical relevance (grade 3) in fourteen patients. Grade 3 levels of alkaline phosphatase, hypokalemia and hyperbilirubinemia occurred in two, five and one patients, respectively.Table 3 Treatment-related grade 1–2 and grade 3–4 adverse events\n\n\tTotal [n (%)]\t\nNo. of patients\tN = 31 (100)\t\nCTC grade\tGrade 1–2\tGrade 3–4\t\nAdverse event\t\nMucositisa\t18 (58)\t1 (3)\t\nFatigue\t17 (55)\t\t\nHand-foot syndrome\t9 (29)\t5 (16)\t\nDiarrhea\t13 (42)\t2 (6)\t\nNausea\t16 (52)\t\t\nSkinb\t20 (65)\t1 (3)\t\nAnorexia\t8 (26)\t\t\nVomiting\t12 (39)\t1 (3)\t\nNeuropathy\t7 (23)\t\t\nConstipation\t4 (13)\t\t\nAnkle edema\t5 (16)\t\t\nEpistaxis\t4 (13)\t\t\nInfection\t3 (10)\t\t\nHematology\t\nAnemia\t25 (81)\t1 (3)\t\nThrombocytopenia\t14 (45)\t2 (6)\t\nNeutropenia\t12 (39)\t\t\nClinical chemistry\t\nHyperglycemiac\t13 (42)\t14 (45)\t\nAP\t19 (61)\t2 (6)\t\nASAT\t11 (35)\t\t\nALAT\t12 (39)\t\t\nHypokalemia\t10 (32)\t5 (16)\t\nHyponatremia\t7 (23)\t\t\nHypertriglyceridemia\t7 (23)\t\t\nGGT\t13 (42)\t9 (29)\t\nBilirubin\t4 (13)\t1 (3)\t\nHypercholesteremia\t3 (10)\t\t\nGGT gamma-glutamyltransferase, ASAT aspartate aminotransferase, ALAT alanine aminotransferase, AP alkaline phosphatase\n\naMucositis including aphthous ulcers and stomatitis\n\nbSkin toxicity includes rash, itching, color and nail changes\n\ncNon-fasting glucose\n\nAntitumor activity\n\nA total of 31 participating patients had measurable disease according to RECIST 1.0 at start of treatment. Nine of these 31 patients were not available for radiological response evaluation due to early discontinuation of the study medication prior to the first planned radiological evaluation time point and were considered as progressive. Two patients had a partial response (6.5 %). Ten patients had stable disease (32 %), and nineteen patients were progressive (61 %) (Table 4).Table 4 Response rates for the entire cohort (N = 31)\n\nType of response\tEntire cohort (n = 31)\tFirst line (n = 15)\tSecond line (n = 16)\t\nPR\t2\t65 %\t2\t13 %\t0\t0 %\t\nSD\t10\t32 %\t8\t53 %\t2\t13 %\t\nPD\t19\t61 %\t5\t33 %\t14\t87 %\t\nPer protocol radiological response evaluable patients (N = 22). Nine patients discontinued the study before radiological tumor response evaluation was performed (PD)\n\nPD progressive disease, PR partial remission, SD stable disease\n\nIn first-line patients, PR and SD were seen in 2 (13 %) and 8 (53 %), respectively. In second-line patients, no patients had PR and 2 (13 %) patients had SD. The waterfall plot shows radiologic responses for all radiologic evaluable patients (Fig. 1).Fig. 1 Best confirmed change from baseline in sum of longest diameters of target lesion size (%), by RECIST 1.0\n\nAmong the nine patients who discontinued treatment early and who were not available for the first radiological response evaluation, two patients refused further therapy, three patients had clinical progressive disease and one patient developed grade 3 diarrhea and had deterioration of the performance status. Three patients died before radiological evaluation, two patients due to tumor progression and one patient died of non-treatment-related septic cholangitis during the first cycle\n\nAt the time of the intention to treat analysis, one patient was still alive. For the entire cohort, the one-year survival rate was 38.7 % and the median overall survival was 8.9 months (95 % CI 4.6–13.1 months) (Fig. 2). Overall survival was 12.4 months (95 % CI 10.2–14.6) and 5.9 months (95 % CI 1.6–10.2) in first (n = 15)- and second-line patients (n = 16), respectively. Median progression-free survival (PFS) was 3.6 months (95 % CI 1.9–5.3), 5.7 months (95 % CI 2.0–9.5) and 2.3 months (95 % CI 2.2–2.5) for all, first- and second-line patients, respectively.Fig. 2 Kaplan–Meier curve of overall survival\n\nDiscussion\n\nIn this phase II study, exploring the combination of capecitabine with the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer moderate treatment activity was observed with a response rate (RR) of 6.5 % and an overall survival (OS) of 8.9 months.\n\nAs a single-arm phase II study, the contribution of everolimus in this treatment regimen is difficult to determine. However, our results can be compared with previous studies using capecitabine as monotherapy. A RR of 7.1 % was seen in a study of capecitabine (1250 mg/m2 BID) in 42 patients with advanced pancreatic cancer as first-line treatment [30]. A randomized phase II study with pre-treated pancreatic cancer patients showed a RR of 9.4 % for the 32 patients in the capecitabine (1250 mg/m2 BID) control arm [34].\n\nThe endpoint OS in non-randomized phase II studies, should be used with care, because of the constraints of historical control groups and inadequate sample sizes, especially in subgroup analyses. Nevertheless, the median OS of 8.9 months in the entire cohort, 12.4 months in first-line patients and 5.9 months in second-line patients reported in this study are encouraging. The overall survival for capecitabine monotherapy in first-line patients reported by Cartwright et al. [30] was 5.9 months (95 % CI 2.8–9.0 months). And OS in second-line patients, reported by Bodoky et al. [34] was 5.0 months. Therefore, the addition of everolimus to capecitabine might enhance efficacy of capecitabine monotherapy, especially in first-line patients.\n\nThe most commonly reported treatment-related clinical side effects were stomatitis, fatigue and hand-foot syndrome. Although stomatitis is a common adverse event of both capecitabine and everolimus as single agent, this overlapping toxicity remained mild to moderate in severity in this study and led to dose reduction in only one patient. We assume at most marginally additive toxicity of capecitabine to everolimus since the frequency of stomatitis in this study was similar to that in studies with single-agent everolimus [30, 34, 35]. The frequency of fatigue was increased compared with single-agent studies of either agent, suggesting an additive toxic effect of the combination. An alternative explanation for the increased incidence of fatigue might be disease related. Patients with pancreatic cancer have a high probability to develop disease-related fatigue [36]. Hand-foot syndrome can be solely attributed to capecitabine, since this has not been observed before in single-agent everolimus trials. This well-known side effect of capecitabine resulted in dose reductions of capecitabine in 45 % of the patients, which is only 10 % higher than in a previous study with colorectal cancer patients receiving capecitabine monotherapy and might be related to the combinatory effects of the study drugs [37]. Grade 3 hyperglycemia was seen in 45 % of the patients in the non-fasting blood draws, which is more than seen in everolimus monotherapy in this patient group (18 %), but it mostly remained at manageable levels and did not lead to dose reductions [14]. Other adverse events included diarrhea, anorexia, taste loss, neuropathy and skin rash, but remained non-severe. The frequency and severity of toxicity confirmed the data from our previous phase I study [27].\n\nIn contrast to the outlined acceptable toxicity findings, a prior phase I study that combined the mTOR inhibitor temsirolimus and 5-FU demonstrated dose limiting stomatitis and hematological toxicity, and in the expansion cohort, two patients died due to mucositis with bowel perforation [38]. An explanation for this difference could be dose related. The dose of temsirolimus in the expansion cohort of that phase I study was 45 mg/m2 per week, while the recommended dose used as monotherapy in renal cell carcinoma is 25 mg per week. The phase II study of capecitabine (650 mg/m2 BID) and everolimus (5 mg BID) in gastric cancer patients, showed less toxicity, especially in all grade hand-foot syndrome (35 vs 13 %), fatigue (55 vs 6 %) and diarrhea (48 vs 22 %) [26]. This is probably due to the lower dose of capecitabine and the different disease.\n\nRecently, the combination of conventional chemotherapy (gemcitabine) with everolimus is examined as first-line treatment for pancreatic cancer patients [39]. Everolimus 5 mg BID could not be combined with full-dose gemcitabine, as the maximum tolerated dose was already met at 400 mg/m2 [39]. In comparison with the present study, this might indicate that for combining everolimus with conventional chemotherapy, capecitabine is easier to administer at therapeutical doses.\n\nIn conclusion, we showed that continuous everolimus 5 mg BID combined with capecitabine 1000 mg/m2 for 14 days every 3 weeks is a feasible and moderately efficacious outpatient oral treatment regimen, but only in first-line pancreatic cancer patients.\n\nThis work was supported by the Academic Medical Center Amsterdam. Everolimus was supplied free of charge by Novartis.\n\nConflict of interest\n\nH.J. Klumpen declares to currently conduct research which is sponsored by Novartis, the manufacturer of everolimus. All other authors declare no conflict of interest. Novartis had no role in the study design, the collection, analysis and interpretation of data, the writing of the manuscript or in the decision to submit the manuscript for publication.\n\nS. Kordes and H. J. Klümpen have contributed equally to this work.\n==== Refs\nReferences\n\n1. Faivre S Kroemer G Raymond E Current development of mTOR inhibitors as anticancer agents Nat Rev Drug Discov 2006 5 8 671 688 10.1038/nrd2062 16883305\n2. LoPiccolo J Blumenthal GM Bernstein WB Dennis PA Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations Drug Resist Updat 2008 11 1–2 32 50 10.1016/j.drup.2007.11.003 18166498\n3. 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Deenen MJ Klumpen HJ Richel DJ Sparidans RW Weterman MJ Beijnen JH Phase I and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies Invest New Drugs 2011 30 4 1557 1565 10.1007/s10637-011-9723-4 21809026\n28. Conroy T Desseigne F Ychou M Bouché O Guimbaud R FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 364 19 1817 1825 10.1056/NEJMoa1011923 21561347\n29. Burris HA 3rd Moore MJ Andersen J Green MR Rothenberg ML Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial J Clin Oncol 1997 15 6 2403 2413 9196156\n30. Cartwright TH Cohn A Varkey JA Chen YM Szatrowski TP Cox JV Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer J Clin Oncol 2002 20 1 160 164 10.1200/JCO.20.1.160 11773165\n31. Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst 2000 92 3 205 216 10.1093/jnci/92.3.205 10655437\n32. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). http://ctep.cancer.gov/reporting/ctc_v30.html\n33. Gehan EA The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent J Chronic Dis. 1961 13 346 353 10.1016/0021-9681(61)90060-1 13704181\n34. Bodoky G Timcheva C Spigel DR La Stella PJ Ciuleanu TE Pover G A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy Invest New Drugs 2011 30 3 1216 1223 10.1007/s10637-011-9687-4 21594619\n35. Yao JC Shah MH Ito T Bohas CL Wolin EM Van CE Everolimus for advanced pancreatic neuroendocrine tumors N Engl J Med 2011 364 6 514 523 10.1056/NEJMoa1009290 21306238\n36. Labori KJ Hjermstad MJ Wester T Buanes T Loge JH Symptom profiles and palliative care in advanced pancreatic cancer: a prospective study Support Care Cancer 2006 14 11 1126 1133 10.1007/s00520-006-0067-0 16601947\n37. Cassidy J Twelves C Van CE Hoff P Bajetta E Boyer M First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin Ann Oncol 2002 13 4 566 575 10.1093/annonc/mdf089 12056707\n38. Punt CJ Boni J Bruntsch U Peters M Thielert C Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors Ann Oncol 2003 14 6 931 937 10.1093/annonc/mdg248 12796032\n39. Joka M Boeck S Zech CJ Seufferlein T Wichert GV Combination of antiangiogenic therapy using the mTOR-inhibitor everolimus and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: a dose-finding study Anticancer Drugs 2014 25 9 1095 1101 10.1097/CAD.0000000000000146 25029236\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0344-5704",
"issue": "75(6)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": null,
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D003841:Deoxycytidine; D018572:Disease-Free Survival; D000068338:Everolimus; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D047428:Protein Kinase Inhibitors; D020123:Sirolimus; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1135-41",
"pmc": null,
"pmid": "25822310",
"pubdate": "2015-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10655437;20975068;11773165;12056707;12796032;15014039;9196156;21306238;21561347;21594619;21809026;24013904;25029236;13704181;15797377;16652094;16883305;16601947;17310129;17634556;17577220;17713840;18332469;18332470;18166498;18075305;18653228;19047305;19127256;19306412;19380449;19549709;19687332;19783551;19764996;20564157;11134523",
"title": "Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer.",
"title_normalized": "phase ii study of capecitabine and the oral mtor inhibitor everolimus in patients with advanced pancreatic cancer"
} | [
{
"companynumb": "NL-ROCHE-1563871",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Adverse reactions with an outcome of death are inherently important for pharmacovigilance organizations to evaluate. Prior efforts to systematically evaluate individual case safety reports (ICSRs) with an outcome of death have been limited to high-level summaries.\n\n\n\nThe aim of this study was to characterize ICSRs with an outcome of death contained in the US FDA Adverse Event Reporting System (FAERS) database.\n\n\n\nAll ICSRs received through 31 December 2017 reporting an outcome of death were characterized by patient demographics, suspect product(s), adverse events, and reporter type. Using the ICSR's narrative and reporter information, we classified ICSRs by source to include those from industry-sponsored programs, poison control centers, specialty pharmacies, and litigation. Additionally, a random sample of ICSRs was evaluated for completeness of structured data fields and manually reviewed for the availability of key information in the narrative (i.e. cause of death, medical history, and causality assessment).\n\n\n\nOverall, 1,053,716 ICSRs with a death outcome were received in the study period. Ten medications treating conditions for malignancies, pain, and kidney disease accounted for nearly 20% of all fatal ICSRs. ICSRs originating from industry-sponsored programs, poison control centers, litigation, and specialty pharmacies accounted for 14%, 6.5%, 5.0%, and 3.3% of all fatal ICSRs, respectively. ICSRs in which the only adverse event coded was 'death' were more likely to be missing structured data and less likely to include key information in the narrative.\n\n\n\nUnderstanding the origins and characteristics of ICSRs with an outcome of death supports meaningful evaluations and interpretations of FAERS data. A wide variability in ICSR quality exists, even in those reports with the most serious outcome.",
"affiliations": "Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.;Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.;Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.;Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.;Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA. monica.munoz@fda.hhs.gov.",
"authors": "Marwitz|Kathryn|K|0000-0001-5907-538X;Jones|S Christopher|SC|0000-0002-0478-0978;Kortepeter|Cindy M|CM|0000-0002-7774-1443;Dal Pan|Gerald J|GJ|0000-0003-4874-5864;Muñoz|Monica A|MA|0000-0001-9754-1986",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-020-00908-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "43(5)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D002423:Cause of Death; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D060735:Pharmacovigilance; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "457-465",
"pmc": null,
"pmid": "31981082",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": "29952714;31098918;23033257;30569267;30798791;9555760;23280652;28913827;31190237;17846394;29556685;31912439",
"title": "An Evaluation of Postmarketing Reports with an Outcome of Death in the US FDA Adverse Event Reporting System.",
"title_normalized": "an evaluation of postmarketing reports with an outcome of death in the us fda adverse event reporting system"
} | [
{
"companynumb": "US-ACTELION-A-CH2020-205698",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BOSENTAN"
},
"drugadditional": "3",
... |
{
"abstract": "Oral ulceration is a non-specific clinical finding with many potential causes. The persistence of oral ulcers in the context of a patient post-SOT is concerning for PTLD. There is growing evidence that SOT recipients may also be at higher risk of autoimmune diseases. This case report describes a pediatric patient with persistent oral ulcers after heart transplant, who underwent an extensive workup for PTLD, including repeat investigations, with a subsequent diagnosis of Behçet's disease.",
"affiliations": "School of Clinical Medicine, University of Cambridge, Cambridge, UK.;Division of Hematology and Oncology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.;Division of Rheumatology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.;Division of Rheumatology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.;Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.;Division of Hematology and Oncology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.",
"authors": "Asmar|Namir|N|0000-0002-8272-3602;Geerlinks|Ashley V|AV|0000-0002-8142-3886;Laxer|Ronald M|RM|;Tse|Shirley M L|SML|0000-0002-3027-7866;Dipchand|Anne|A|;Punnett|Angela|A|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13264",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "22(7)",
"journal": "Pediatric transplantation",
"keywords": "Behçet's disease; pediatric autoimmune; pediatric transplant; post-transplant lymphoproliferative disease",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D001528:Behcet Syndrome; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D019226:Oral Ulcer; D011183:Postoperative Complications; D012008:Recurrence",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13264",
"pmc": null,
"pmid": "30003623",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent oral ulcerations following heart transplant in a pediatric patient: A diagnostic dilemma.",
"title_normalized": "recurrent oral ulcerations following heart transplant in a pediatric patient a diagnostic dilemma"
} | [
{
"companynumb": "PHHY2018GB048018",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
"druga... |
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