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"abstract": "Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer.\n\n\n\nThis phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured.\n\n\n\n27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least >2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p < 0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03).\n\n\n\nSingle-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.",
"affiliations": "Division of Gynecologic Oncology, Duke Cancer Institute, United States of America. Electronic address: secor002@mc.duke.edu.;Division of Gynecologic Oncology, Virginia Oncology Associates, United States of America.;Division of Gynecologic Oncology, Duke Cancer Institute, United States of America.;Department of Biostatistics and Bioinformatics, Duke Cancer Institute, United States of America.;Division of Gynecologic Oncology, Virginia Oncology Associates, United States of America.;Division of Gynecologic Oncology, Duke Cancer Institute, United States of America.;Division of Gynecologic Oncology, University of Virginia, United States of America.;Department of Medicine, Duke Cancer Institute, Durham, NC 27710, United States of America.;Department of Medicine, Duke Cancer Institute, Durham, NC 27710, United States of America.;Department of Medicine, Duke Cancer Institute, Durham, NC 27710, United States of America.;Division of Gynecologic Oncology, University of Virginia, United States of America.",
"authors": "Secord|Angeles Alvarez|AA|;McCollum|Michael|M|;Davidson|Brittany A|BA|;Broadwater|Gloria|G|;Squatrito|Robert|R|;Havrilesky|Laura J|LJ|;Gabel|Anne C|AC|;Starr|Mark D|MD|;Brady|J Chris|JC|;Nixon|Andrew B|AB|;Duska|Linda R|LR|",
"chemical_list": "D000970:Antineoplastic Agents; D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; C508600:IL6 protein, human; D007211:Indoles; D015850:Interleukin-6; C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; D000068258:Bevacizumab; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C530716:nintedanib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2019.03.246",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "153(3)",
"journal": "Gynecologic oncology",
"keywords": "Nintedanib; Ovarian cancer; Peritoneal cancer",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D015720:5'-Nucleotidase; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D000077216:Carcinoma, Ovarian Epithelial; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005185:Fallopian Tube Neoplasms; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007211:Indoles; D015850:Interleukin-6; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms; D000077982:Progression-Free Survival; D066066:Response Evaluation Criteria in Solid Tumors; D042643:Vascular Endothelial Growth Factor D",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "555-561",
"pmc": null,
"pmid": "30929823",
"pubdate": "2019-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase II trial of nintedanib in patients with bevacizumab-resistant recurrent epithelial ovarian, tubal, and peritoneal cancer.",
"title_normalized": "phase ii trial of nintedanib in patients with bevacizumab resistant recurrent epithelial ovarian tubal and peritoneal cancer"
} | [
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"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-NB-005292",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NINTEDANIB"
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"... |
{
"abstract": "BACKGROUND\nCOPD-related deaths are increasing in Japan, with ~5.3 million people at risk.\n\n\nMETHODS\nThe SHINE was a 26-week, multicenter, randomized, double-blind, parallel-group study that evaluated safety and efficacy of indacaterol (IND)/glycopyrronium (GLY) 110/50 μg once daily (od) compared with GLY 50 μg od, IND 150 μg od, open-label tiotropium (TIO) 18 μg od, and placebo. The primary end point was trough forced expiratory volume in 1 second (FEV1) at Week 26. Other key end points included peak FEV1, area under the curve for FEV1 from 5 minutes to 4 hours (FEV1 AUC5 min-4 h), Transition Dyspnea Index focal score, St George's Respiratory Questionnaire total score, and safety. Here, we present efficacy and safety of IND/GLY in the Japanese subgroup.\n\n\nRESULTS\nOf 2,144 patients from the SHINE study, 182 (8.5%) were Japanese and randomized to IND/GLY (n=42), IND (n=41), GLY (n=40), TIO (n=40), or placebo (n=19). Improvement in trough FEV1 from baseline was 190 mL with IND/GLY and treatment differences versus IND (90 mL), GLY (100 mL), TIO (90 mL), and placebo (280 mL) along with a rapid onset of action at Week 26. IND/GLY showed an improvement in FEV1 AUC5 min-4 h versus all comparators (all P<0.05). All the treatments were well tolerated and showed comparable effect on Transition Dyspnea Index focal score and St George's Respiratory Questionnaire total score. The effect of IND/GLY in the Japanese subgroup was consistent to overall SHINE study population.\n\n\nCONCLUSIONS\nIND/GLY demonstrated superior efficacy and comparable safety compared with its monocomponents, open-label TIO, and placebo and may be used as a treatment option for the management of moderate-to-severe COPD in Japanese patients.",
"affiliations": "Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Novartis Pharma KK, Minato-ku, Tokyo, Japan.;Novartis Pharma KK, Minato-ku, Tokyo, Japan.;Novartis Pharma KK, Minato-ku, Tokyo, Japan.;Novartis Pharma KK, Minato-ku, Tokyo, Japan.;Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.",
"authors": "Hashimoto|Shu|S|;Ikeuchi|Hisataro|H|;Murata|Shujiro|S|;Kitawaki|Tetsuji|T|;Ikeda|Kimitoshi|K|;Banerji|Donald|D|",
"chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004338:Drug Combinations; D007189:Indans; D018727:Muscarinic Antagonists; D015363:Quinolones; C510790:indacaterol; D006024:Glycopyrrolate",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/COPD.S111408",
"fulltext": "\n==== Front\nInt J Chron Obstruct Pulmon DisInt J Chron Obstruct Pulmon DisInternational Journal of COPDInternational Journal of Chronic Obstructive Pulmonary Disease1176-91061178-2005Dove Medical Press 10.2147/COPD.S111408copd-11-2543Original ResearchEfficacy and safety of indacaterol/glycopyrronium in Japanese patients with COPD: a subgroup analysis from the SHINE study Hashimoto Shu 1Ikeuchi Hisataro 2Murata Shujiro 2Kitawaki Tetsuji 2Ikeda Kimitoshi 2Banerji Donald 31 Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan2 Novartis Pharma KK, Minato-ku, Tokyo, Japan3 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USACorrespondence: Shu Hashimoto, Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30-1, Ohyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan, Tel +81 3 3972 7552, Email hashimoto.shu@nihon-u.ac.jp2016 11 10 2016 11 2543 2551 © 2016 Hashimoto et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nCOPD-related deaths are increasing in Japan, with ~5.3 million people at risk.\n\nMethods\nThe SHINE was a 26-week, multicenter, randomized, double-blind, parallel-group study that evaluated safety and efficacy of indacaterol (IND)/glycopyrronium (GLY) 110/50 μg once daily (od) compared with GLY 50 μg od, IND 150 μg od, open-label tiotropium (TIO) 18 μg od, and placebo. The primary end point was trough forced expiratory volume in 1 second (FEV1) at Week 26. Other key end points included peak FEV1, area under the curve for FEV1 from 5 minutes to 4 hours (FEV1 AUC5 min–4 h), Transition Dyspnea Index focal score, St George’s Respiratory Questionnaire total score, and safety. Here, we present efficacy and safety of IND/GLY in the Japanese subgroup.\n\nResults\nOf 2,144 patients from the SHINE study, 182 (8.5%) were Japanese and randomized to IND/GLY (n=42), IND (n=41), GLY (n=40), TIO (n=40), or placebo (n=19). Improvement in trough FEV1 from baseline was 190 mL with IND/GLY and treatment differences versus IND (90 mL), GLY (100 mL), TIO (90 mL), and placebo (280 mL) along with a rapid onset of action at Week 26. IND/GLY showed an improvement in FEV1 AUC5 min–4 h versus all comparators (all P<0.05). All the treatments were well tolerated and showed comparable effect on Transition Dyspnea Index focal score and St George’s Respiratory Questionnaire total score. The effect of IND/GLY in the Japanese subgroup was consistent to overall SHINE study population.\n\nConclusion\nIND/GLY demonstrated superior efficacy and comparable safety compared with its monocomponents, open-label TIO, and placebo and may be used as a treatment option for the management of moderate-to-severe COPD in Japanese patients.\n\nKeywords\nSHINE studyJapanese subgroupCOPDindacaterol/glycopyrroniumopen-label tiotropium\n==== Body\nIntroduction\nCOPD was the tenth most common cause of disease-related deaths in Japan in 2014, and it was found that the number of COPD-related deaths is increasing.1 An epidemiological survey in Japanese population revealed that the prevalence of physician-diagnosed COPD in Japan is increasing, and ~8.6% of the patients aged ≥40 years are suffering from COPD. An estimated population of 5.3 million Japanese are now at risk of developing COPD; however, only a small proportion (9.4%) were diagnosed to have COPD.2,3\n\nDecline in quality of life due to breathlessness is the major challenge in the management of COPD that demands sustained improvement in lung function.4 Long-acting bronchodilators of different pharmacological classes, either as monotherapy or in combination, are now the preferred choice and proven cornerstone for treating compromised airflow in patients with COPD.4 In situations where a single bronchodilator fails to provide the desired effect, both Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy and Japanese Respiratory Society (JRS) guidelines recommend the use of a fixed-dose combination of a long-acting β2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) for management of symptomatic patients with COPD.4,5 A fixed-dose LABA/LAMA combination, indacaterol (IND)/glycopyrronium (GLY), was evaluated in 14 controlled trials as maintenance treatment for patients with COPD. Outcomes of these studies demonstrated better efficacy of IND/GLY in terms of improving lung function and quality of life, with a comparable safety profile versus placebo,6–8 LAMA, open-label tiotropium (TIO),9 and a combination of LABA/inhaled corticosteroid (ICS) and salmeterol/fluticasone (50/500 μg) in patients with moderate-to-severe COPD. Most of these trials have been conducted in Caucasian patients; however, two studies, SHINE and ARISE, evaluated the efficacy of IND/GLY in a Japanese patient subgroup as well.10,11 In the overall population of the SHINE study, IND/GLY showed superior improvements in lung function and health status compared with placebo, IND, GLY, and open-label TIO with a similar safety profile in patients with COPD.10 Here, we report the efficacy and safety of IND/GLY in the Japanese subgroup of patients from the SHINE study.\n\nMethods\nSHINE was a 26-week, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled study (www.ClinicalTrial.gov identifier NCT01202188).10 After the eligibility assessments, patients were randomized (2:2:2:2:1) to receive once daily (od) IND/GLY 110/50 μg, IND 150 μg, GLY 50 μg, open-label TIO 18 μg, or matching placebo. IND/GLY, IND, GLY, and placebo were administered via the Breezhaler® device, whereas TIO was delivered via the HandiHaler® device. Men and women aged ≥40 years with moderate-to-severe stable COPD and a smoking history of ≥10 pack-years who had a postbronchodilator forced expiratory volume in 1 second (FEV1) ≥30% and <80% of predicted normal value and a postbronchodilator FEV1/forced vital capacity ratio <0.70 were included in the study. The key exclusion criterion was COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous), or hospitalization during 6 weeks prior to screening or before randomization. During the study, salbutamol/albuterol was permitted as a rescue medication. Informed consent was taken from all the eligible patients. The study was performed in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and all applicable regulatory requirements and was approved by the Ministry of Health, Labor and Welfare, Japan, as well as all relevant national and local ethics review boards (Table S1).\n\nAssessments\nThe primary end point of the study was trough FEV1 (mean of FEV1 values measured at 23 hours 15 minutes and 23 hours 45 minutes) after IND/GLY administration at Week 26 versus IND and GLY. Other key end points included peak FEV1, area under the curve for FEV1 from 5 minutes to 4 hours (FEV1 AUC5 min–4 h), and trough FEV1 throughout the study period. Nonspirometric analysis included the Transition Dyspnea Index (TDI) focal score and St George’s Respiratory Questionnaire (SGRQ) total score at Week 26. Safety was assessed by monitoring adverse events (AEs) and serious AEs over the 26-week study period.\n\nStatistical analysis\nData were analyzed using a linear mixed model, which included FEV1 as the dependent variable, treatment as an fixed effect, the variables (FEV1, ICS use, FEV1 reversibility components, and smoking status) at baseline as covariates, and centre as a random effect. The estimated treatment differences were presented as least-squares mean with standard errors and the associated 95% confidence interval. The secondary efficacy variables, which included peak FEV1, FEV1 AUC5 min–4 h, trough FEV1 over 26 weeks, TDI focal score, and SGRQ total score, were also analyzed using the same mixed model as specified for the analysis of the primary variable, with the appropriate baseline measurement included as a covariate.10 In addition, the proportions of patients who achieved a clinically important improvement in the SGRQ and TDI focal score were analyzed using logistic regression as specified for the analysis of the primary variable, with the appropriate baseline measurement included as a covariate.\n\nResults\nPatient characteristics\nOf the total 2,144 patients randomized in the SHINE study, 182 (8.5%) were Japanese and randomized to receive IND/GLY 110/50 μg (n=42), IND 110 μg (n=41), GLY 50 μg (n=40), open-label TIO 18 μg (n=40), and matching placebo (n=19). The baseline demographic and clinical characteristics of the patients were comparable across all the groups (Table 1). More than 90% of the patients in the Japanese cohort were men aged >68 years, and their mean percentage of predicted postbronchodilator FEV1 was ~60%, with only 19% reversibility of FEV1 after bronchodilation. More than 75% of patients had moderate-to-severe COPD according to the GOLD 2009 guidelines, and almost 10% of patients in the Japanese subgroup were having a history of COPD exacerbation in the previous year and ~25% were using ICS at baseline. In total, 160 patients (87.9%) completed the study; the major reasons for discontinuation from the study were AEs and withdrawal of consent by the patients (Figure 1).\n\nLung function\nThe primary efficacy end point of the SHINE study was achieving a 190 mL improvement in trough FEV1 from baseline with IND/GLY in Japanese patients. Improvement in lung function was greater in Japanese patients treated using IND/GLY compared with IND (90 mL), GLY (100 mL), TIO (90 mL), and placebo (280 mL; Figure 2).10 The spirometric profile in terms of trough FEV1 with IND/GLY was superior compared with TIO and placebo on Day 2 and Week 26, with treatment differences ranging from 90 mL to 290 mL (Figure 3). IND/GLY showed greater improvements in peak FEV1 from 5 minutes to 4 hours compared with IND, GLY, TIO, and placebo at Week 26, with treatment differences ranging from 100 mL to 390 mL (all P<0.01; Figure 4). In addition, an improvement in lung function was also observed with IND/GLY in terms of FEV1 AUC5 min–4 h compared with IND, GLY, TIO, and placebo, at the end of study, with treatment differences ranging from 90 mL to 380 mL (all P<0.05; Figure 5).\n\nPatient-reported outcomes\nDyspnea control in terms of improvement in TDI focal score in the Japanese subgroup was comparable across all treatment groups. Treatment differences between IND/GLY versus placebo were 0.67 units and versus IND, GLY, TIO were 0.69 units, 0.03 units, and 0.65 units, respectively. A higher proportion of patients achieved a clinically meaningful improvement in the TDI focal score (≥1 unit) with IND/GLY versus IND (odds ratio [OR], 1.60), GLY (OR, 1.01), TIO (OR, 1.16), and placebo (OR, 1.15).\n\nImprovement in health status assessed via reduction in the SGRQ total score was similar across all treatment groups in the Japanese patient subgroup. Treatment differences in the SGRQ total score between IND/GLY vs placebo, IND, GLY, and TIO were −1.31 units, −0.48 units, −3.75 units, and −0.96 units, respectively. The proportion of patients achieving a clinically meaningful improvement in the SGRQ total score (≥4-unit reduction) was highest with IND/GLY compared to IND (OR, 1.69), GLY (OR, 3.13), TIO (OR, 2.36), and placebo (OR, 0.86).\n\nSafety\nThe overall incidence of AEs was similar across the five treatment groups, and the lowest incidence was reported for patients treated with IND/GLY (21 (50%); IND, 27 (65.9%); GLY, 24 (60.0%); TIO, 31 (77.5%); and placebo, 12 (63.2%); Table 2). COPD exacerbations were found to be the frequent AEs in all treatment groups, with their lowest occurrence in patients treated with IND/GLY (~12%). Serious AEs were comparable across all treatment groups. Moreover, no cardiovascular AEs, major adverse cardiac events, cerebro–cardiovascular AEs, abnormal changes from baseline QTc in resting ECG was obtained using Bazett’s formula (QTcB), Fridericia’s formula (QTcF) (<10 mlliseconds) or heart rate, or imbalance in hematocrit values was observed in the Japanese subgroup.\n\nDiscussion\nThe aim of this post hoc analysis was to explore the efficacy and safety profile of IND/GLY in the Japanese subgroup of the SHINE study. Based on the overall results of the SHINE study, the efficacy of IND/GLY was superior to that of placebo, with comparable safety.10 The results of this analysis support our claim that IND/GLY improves lung function and health status in patients with moderate-to-severe COPD with compromised airflow according to the GOLD guidelines, irrespective of ethnicity. The fourth edition of the JRS guidelines, which is customized for the Japanese scenario, recommend LAMA/LABA for the management of moderate-to-severe COPD with symptoms and the use of ICS in combination with LABA or LAMA only if the condition does not improve.4,5,12 GOLD strategy that considers diverse ethnicity as well as various COPD phenotypes differs from the JRS guidelines, which are specific for the Japanese population, in terms of prescribing ICS.4,5 The difference in the recommendations may be due to the fact that Japanese patients with COPD experience fewer COPD exacerbations compared to Caucasians.12 In the Japanese subgroup of the SHINE study, we observed greater improvements in lung function with IND/GLY versus IND, GLY, and TIO mono-therapies, although the improvement in quality of life was comparable across all groups. The results of this subgroup analysis were similar to those observed in the entire study population.10 The small sample size is perhaps responsible for the lower baseline FEV1 observed in the TIO group (1.22 L) than the IND/GLY group (1.36 L), which was at least partially responsible for the 90 mL “treatment effect” of IND/GLY versus TIO at the end of 26 weeks. However, baseline FEV1 was used as a covariate in the statistical analysis, and the treatment effect was adjusted to account for the baseline difference in FEV1 between the IND/GLY and TIO groups. The aforementioned findings were similar to those reported in another study, wherein baseline FEV1 affected the treatment efficacy of a bronchodilator, which showed a smaller change from baseline FEV1 value in patients with lower baseline FEV1.13 In addition to the observed improvements in trough FEV1, our study also demonstrated rapid bronchodilation with IND/GLY in terms of FEV1 AUC5 min–4 h compared to the monotherapy components, TIO, and placebo. In previous studies, spirometric outcomes of IND/GLY treatment showed a comparable reduction in the rate of COPD exacerbations, along with superior improvement in lung function versus its monotherapy components, TIO, and salmeterol/fluticasone and without considerable variations in the TDI focal score and SGRQ total score among different treatment groups.9,11,14,15 In our study, the results of the Japanese subgroup analysis showed comparable improvements in the TDI focal score and SGRQ total score, which is consistent with the results of a previous study.14 A higher proportion of patients from the IND/GLY group achieved minimal clinically important differences for TDI and SGRQ compared with the other treatment groups. Moreover, the number of patients in the Japanese subgroup was small to determine the significant improvement in the TDI focal score and SGRQ total score.\n\nThe SHINE study demonstrated that safety profile of IND/GLY in Japanese patients with COPD was consistent with the overall study population.10 The most frequently reported AE was COPD exacerbation in the Japanese subgroup, and the occurrence was ~12%, which was lower compared with TIO (25%) and placebo (~32%). Furthermore, the incidents of exacerbations were lesser in the Japanese subgroup than the overall study population, where ~39% exacerbations were reported. This fact was supported by the results of a previous study that demonstrated that IND/GLY was superior in preventing moderate-to-severe COPD exacerbations compared with TIO, with concomitant improvements in lung function and health status.9 A pooled analysis of 14 randomized clinical trials with data from 11,404 patients with COPD demonstrated that IND/GLY did not increase the risk of investigated safety end points and had a comparable safety profile as its monocomponents, TIO, and placebo.16\n\nConclusion\nBased on the results of this subgroup analysis, we can conclude that the efficacy and safety of IND/GLY in the Japanese population were similar to that in the overall study population of the SHINE study; thus, IND/GLY may be considered as a treatment option for the management of Japanese patients with moderate-to-severe COPD.\n\nSupplementary material\nTable S1 List of relevant national and local ethics review boards\n\n 1.\tUnited States: Food and Drug Administration\t\n 2.\tArgentina: Administracion Nacional de Medicamentos, Alimentos y TecnologiaMedica\t\n 3.\tArgentina: Human Research Bioethics Committee\t\n 4.\tArgentina: Ministry of Health\t\n 5.\tAustralia: Department of Health and Ageing Therapeutic Goods Administration\t\n 6.\tAustralia: Human Research Ethics Committee\t\n 7.\tAustralia: National Health and Medical Research Council\t\n 8.\tBulgaria: Bulgarian Drug Agency\t\n 9.\tBulgaria: Ministry of Health\t\n10.\tCanada: Health Canada\t\n11.\tChina: Food and Drug Administration\t\n12.\tFinland: Ethics Committee\t\n13.\tFinland: Ministry of Social Affairs and Health\t\n14.\tFinland: Finnish Medicines Agency\t\n15.\tFrance: Afssaps - Agencefrançaise de sécurité sanitaire des produits de santé (Saint-Denis)\t\n16.\tFrance: Direction Générale de la Santé\t\n17.\tFrance: French Data Protection Authority\t\n18.\tFrance: Haute Autorité de Santé Transparency Commission\t\n19.\tFrance: Institutional Ethical Committee\t\n20.\tFrance: Ministry of Health\t\n21.\tFrance: National Consultative Ethics Committee for Health and Life Sciences\t\n22.\tGermany: Ethics Commission\t\n23.\tGermany: Federal Institute for Drugs and Medical Devices\t\n24.\tGermany: Federal Ministry of Education and Research\t\n25.\tGermany: Federal Ministry of Food, Agriculture and Consumer Protection\t\n26.\tGermany: German Institute of Medical Documentation and Information\t\n27.\tGermany: Ministry of Health\t\n28.\tGermany: Paul-Ehrlich-Institut\t\n29.\tGuatemala: MSPAS - Ministerio de SaludPública y Asistencia Social: Programa Nacional de Farmacovigilancia\t\n30.\tHungary: Research Ethics Medical Committee\t\n31.\tHungary: National Institute of Pharmacy\t\n32.\tIndia: Central Drugs Standard Control Organization\t\n33.\tIndia: Department of Atomic Energy\t\n34.\tIndia: Drugs Controller General of India\t\n35.\tIndia: Indian Council of Medical Research\t\n36.\tIndia: Institutional Review Board\t\n37.\tIndia: Ministry of Health\t\n38.\tIndia: Ministry of Science and Technology\t\n39.\tIndia: Science and Engineering Research Council\t\n40.\tJapan: Ministry of Health, Labor and Welfare\t\n41.\tMexico: Ethics Committee\t\n42.\tMexico: Federal Commission for Protection Against Health Risks\t\n43.\tMexico: Federal Commission for Sanitary Risks Protection\t\n44.\tMexico: Ministry of Health\t\n45.\tMexico: National Council of Science and Technology\t\n46.\tMexico: National Institute of Public Health, Health Secretariat\t\n47.\tThe Netherlands: Independent Ethics Committee\t\n48.\tThe Netherlands: Dutch Health Care Inspectorate\t\n49.\tThe Netherlands: Medical Ethics Review Committee (METC)\t\n50.\tThe Netherlands: Medicines Evaluation Board (MEB)\t\n51.\tThe Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)\t\n52.\tPanama: Ministry of Health\t\n53.\tPhilippines: Department of Health\t\n54.\tPhilippines: Bureau of Food and Drugs\t\n55.\tPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products\t\n56.\tPoland: Ministry of Health\t\n57.\tPoland: Ministry of Science and Higher Education\t\n Acknowledgments\nThe authors would like to thank their colleagues who were involved in the planning, execution, and analysis of the SHINE study and all the study participants. This study was sponsored by Novartis Pharma AG, Basel, Switzerland. The authors were assisted in the preparation of this manuscript by Kevin Roche and Santanu Bhadra of Novartis Healthcare Pvt. Ltd., Hyderabad, India.\n\nAuthor contributions\n\nAll authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nSH had received grants and/or lecture fees from Astellas Pharma Inc., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., KYORIN Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Torii Pharmaceutical Co. Ltd., and Novartis Pharma K.K. within the last 3 years. SM, TK, KI, and DB are employees of the study sponsor Novartis. The authors report no other conflicts of interest in this work.\n\nFigure 1 Patient disposition.\n\nNote: n, number of patients.\n\nAbbreviations: IND, indacaterol; GLY, glycopyrronium; od, once daily; TIO, tiotropium; ol, open label.\n\nFigure 2 Trough FEV1 (L) after 26 weeks in the Japanese subgroup.\n\nNotes: Data are presented as LSM (standard error). Trough FEV1 is defined as the average of the post dose 23 hours 15 minutes and 23 hours 45 minutes FEV1 values (excluding values taken outside 22 hours 45 minutes and 24 hours 15 minutes post dose) at Day 2.\n\nAbbreviations: FEV1, forced expiratory volume in 1 second; LSM, least-squares mean; IND, indacaterol; GLY, glycopyrronium; od, once daily; TIO, tiotropium; ∆, treatment difference.\n\nFigure 3 Trough FEV1 (L) over 26 weeks in the Japanese subgroup.\n\nNote: Data are presented as LSM (standard error).\n\nAbbreviations: FEV1, forced expiratory volume in 1 second; LSM, least-squares mean; IND, indacaterol; GLY, glycopyrronium; od, once daily; TIO, tiotropium.\n\nFigure 4 Peak FEV1 (L) from 5 minutes to 4 hours at Week 26 in the Japanese subgroup.\n\nNotes: Data are presented as LSM (standard error). Peak FEV1 is defined as the maximum FEV1 during the first 4 hours after dosing.\n\nAbbreviations: FEV1, forced expiratory volume in 1 second; LSM, least-squares mean; IND, indacaterol; GLY, glycopyrronium; od, once daily; TIO, tiotropium; ∆, treatment difference.\n\nFigure 5 FEV1 AUC5 min–4 h (L) at Week 26 in the Japanese subgroup.\n\nNote: Data are presented as LSM (standard error).\n\nAbbreviations: FEV1 AUC5 min-4 h, area under the curve for FEV1 from 5 minutes to 4 hours; FEV1, forced expiratory volume in 1 second; LSM, least-squares mean; IND, indacaterol; GLY, glycopyrronium; od, once daily; TIO, tiotropium; ∆, treatment difference.\n\nTable 1 Demographic and baseline clinical characteristics of the Japanese subgroup\n\n\tIND/GLY (n=42)\tIND (n=41)\tGLY (n=40)\tTIO* (n=40)\tPlacebo (n=19)\t\nAge, years\t71.0 (6.92)\t69.2 (5.96)\t69.0 (8.87)\t67.8 (9.25)\t68.9 (5.22)\t\nSex, male, n (%)\t42 (100)\t40 (97.6)\t38 (95.0)\t37 (92.5)\t18 (94.7)\t\nBody mass index, kg/m2\t22.4 (3.35)\t22.7 (3.17)\t22.2 (3.05)\t22.8 (3.54)\t24.3 (1.86)\t\nSmoking history, pack-years\t64.7 (25.21)\t59.9 (27.71)\t69.8 (33.36)\t64.7 (38.25)\t52.3 (20.20)\t\nSmoking status, n (%)\t\t\t\t\t\t\n Ex-smoker\t31 (73.8)\t31 (75.6)\t31 (77.5)\t29 (72.5)\t17 (89.5)\t\n Current smoker\t11 (26.2)\t10 (24.4)\t9 (22.5)\t11 (27.5)\t2 (10.5)\t\nICS use at baseline, n (%)\t\t\t\t\t\t\n No\t31 (73.8)\t30 (73.2)\t28 (70.0)\t29 (72.5)\t14 (73.7)\t\n Yes\t11 (26.2)\t11 (26.8)\t12 (30.0)\t11 (27.5)\t5 (26.3)\t\nNumber of COPD exacerbations in the previous year, n (%)\t\t\t\t\t\t\n 0\t39 (92.9)\t32 (78.0)\t31 (77.5)\t33 (82.5)\t17 (89.5)\t\n 1\t2 (4.8)\t9 (22.0)\t8 (20.0)\t7 (17.5)\t1 (5.3)\t\n ≥2\t1 (2.4)\t0\t1 (2.5)\t0\t1 (5.3)\t\nSeverity of COPD (GOLD 2008), n (%)\t\t\t\t\t\t\n Moderate COPD\t32 (76.2)\t31 (75.6)\t35 (87.5)\t28 (70.0)\t14 (73.7)\t\n Severe COPD\t10 (23.8)\t10 (24.4)\t4 (10.0)\t12 (30.0)\t5 (26.3)\t\nDuration of COPD, years\t3.6 (3.23)\t3.9 (5.01)\t4.0 (3.80)\t3.4 (2.10)\t3.2 (2.78)\t\nFEV1, prebronchodilator, L\t1.36 (0.44)\t1.32 (0.43)\t1.35 (0.41)\t1.22 (0.42)\t1.27 (0.38)\t\nFEV1, postbronchodilator, L\t1.60 (0.42)\t1.54 (0.46)\t1.56 (0.42)\t1.48 (0.45)\t1.47 (0.46)\t\nFEV1 (L) postbronchodilator (% predicted FEV1)\t61.357 (13.0941)\t60.268 (14.8594)\t61.300 (11.4672)\t57.600 (12.8797)\t57.474 (13.1376)\t\nFEV1 reversibility after inhalation of bronchodilator (%)\t20.167 (13.3543)\t18.829 (13.6874)\t17.000 (12.7481)\t23.800 (15.4026)\t15.737 (9.4331)\t\nNote: Data are represented as mean (standard deviation) unless otherwise specified.\n\n* Open label.\n\nAbbreviations: IND, indacaterol; GLY, glycopyrronium; TIO, tiotropium; ICS, inhaled corticosteroid; FEV1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease.\n\nTable 2 Summary of AEs and SAEs by preferred terms in the Japanese subgroup\n\n\tIND/GLY (n=42)\tIND (n=41)\tGLY (n=40)\tTIO (n=40)\tPlacebo (n=19)\t\nTotal AEs\t21 (50.0)\t27 (65.9)\t24 (60.0)\t31 (77.5)\t12 (63.2)\t\nAEs ≥2 incidences in any group\t\n COPDa\t5 (11.9)\t7 (17.1)\t6 (15.0)\t10 (25.0)\t6 (31.6)\t\n Nasopharyngitis\t4 (9.5)\t10 (24.4)\t9 (22.5)\t9 (22.5)\t5 (26.3)\t\n Cough\t2 (4.8)\t2 (4.9)\t0\t0\t0\t\n Productive cough\t2 (4.8)\t0\t0\t0\t0\t\n Constipation\t2 (4.8)\t2 (4.9)\t3 (7.5)\t0\t0\t\n Bronchitis\t1 (2.4)\t0\t0\t3 (7.5)\t1 (5.3)\t\n Upper respiratory tract infection\t1 (2.4)\t1 (2.4)\t0\t2 (5.0)\t1 (5.3)\t\n GERD\t0\t2 (4.9)\t1 (2.5)\t0\t0\t\n Back pain\t0\t0\t3 (7.5)\t0\t0\t\nDrug-related AEs\t7 (16.7)\t5 (12.2)\t4 (10.0)\t5 (12.5)\t0\t\nAEs leading to permanent discontinuation of study drugs\t\n Total SAEs\t1 (2.4)\t5 (12.2)\t2 (5.0)\t1 (2.5)\t2 (10.5)\t\nNotes: Data are presented as number of patients (percentage).\n\na Includes COPD exacerbation or COPD worsening.\n\nAbbreviations: AEs, adverse events; SAEs, serious adverse events; IND, indacaterol; GLY, glycopyrronium; TIO, tiotropium; GERD, gastroesophageal reflux disease.\n==== Refs\nReferences\n1 Vital Statistics, Ministry of Health, Labor Welfare Japan 2014 Available from: http://www.mhlw.go.jp/english/new-info/ Accessed December 12, 2015 \n2 Fukuchi Y Fernandez L Kuo HP Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial Respirology 2011 16 5 825 835 21539680 \n3 Ishikawa N Hattori N Kohno N Kobayashi A Hayamizu T Johnson M Airway inflammation in Japanese COPD patients compared with smoking and nonsmoking controls Int J Chron Obstruct Pulmon Dis 2015 10 185 192 25670894 \n4 Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Global Initiative for Chronic Obstructive Lung Disease (GOLD 2016) Available from: http://www.goldcopd.com Accessed January 6, 2016 \n5 Japanese Respiratory Society Guidelines for the Diagnosis and Treatment of COPD 4th edition Japanese Respiratory Society 2013 Available from: https://www.jrs.or.jp/modules/guidelines/index.php?content_id=1 Accessed December 12, 2015 \n6 Beeh KM Korn S Beier J Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study Respir Med 2014 108 4 584 592 24534204 \n7 Dahl R Chapman KR Rudolf M Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study Respir Med 2013 107 10 1558 1567 23867808 \n8 Mahler DA Decramer M D’Urzo A Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study Eur Respir J 2014 43 6 1599 1609 24176997 \n9 Wedzicha JA Decramer M Ficker JH Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study Lancet Respir Med 2013 1 3 199 209 24429126 \n10 Bateman ED Ferguson GT Barnes N Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study Eur Respir J 2013 42 6 1484 1494 23722616 \n11 Asai K Minakata Y Hirata K QVA149 once-daily is safe and well tolerated and improves lung function and health status in Japanese patients with COPD: The ARISE study European Respiratory Society Annual Congress 2013 Barcelona, Spain 2013 P3392 \n12 Horita N Kaneko T Role of combined indacaterol and glycopyrronium bromide (QVA149) for the treatment of COPD in Japan Int J Chron Obstruct Pulmon Dis 2015 10 813 822 25960646 \n13 Calverley P Pauwels RA Jones PW Anderson JA Vestbos J The severity of airways obstruction as a determinant of treatment response in COPD Int J Chron Obstruct Pulmon Dis 2006 1 3 209 218 18046858 \n14 Vogelmeier CF Bateman ED Pallante J Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study Lancet Respir Med 2013 1 1 51 60 24321804 \n15 Zhong N Wang C Zhou X LANTERN Investigators LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD Int J Chron Obstruct Pulmon Dis 2015 10 1015 1026 26082625 \n16 Wedzicha JA Dahl R Buhl R Pooled safety analysis of the fixed-dose combination of indacaterol and glycopyrronium (QVA149), its monocomponents, and tiotropium versus placebo in COPD patients Respir Med 2014 108 10 1498 1507 25135743\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-9106",
"issue": "11()",
"journal": "International journal of chronic obstructive pulmonary disease",
"keywords": "COPD; Japanese subgroup; SHINE study; indacaterol/glycopyrronium; open-label tiotropium",
"medline_ta": "Int J Chron Obstruct Pulmon Dis",
"mesh_terms": "D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists; D000368:Aged; D019540:Area Under Curve; D001993:Bronchodilator Agents; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005541:Forced Expiratory Volume; D006024:Glycopyrrolate; D006801:Humans; D007189:Indans; D007564:Japan; D008168:Lung; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists; D011237:Predictive Value of Tests; D029424:Pulmonary Disease, Chronic Obstructive; D015363:Quinolones; D012372:ROC Curve; D020127:Recovery of Function; D012720:Severity of Illness Index; D013147:Spirometry; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D014797:Vital Capacity",
"nlm_unique_id": "101273481",
"other_id": null,
"pages": "2543-2551",
"pmc": null,
"pmid": "27785010",
"pubdate": "2016",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "24176997;25135743;25670894;24534204;26082625;21539680;23867808;24321804;18046858;25960646;17507545;24429126;23722616",
"title": "Efficacy and safety of indacaterol/glycopyrronium in Japanese patients with COPD: a subgroup analysis from the SHINE study.",
"title_normalized": "efficacy and safety of indacaterol glycopyrronium in japanese patients with copd a subgroup analysis from the shine study"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-076076",
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"occurcountry": "JP",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIOTROPIUM BROMIDE MONOHYDRATE"
... |
{
"abstract": "NMOSD develops primarily in women of childbearing age, and several previous studies have shown that the disorder may increase the risk of miscarriage. However, there are no reports, to our knowledge, of fetal malformation, other than neonatal hydrocephalus, related to NMOSD. We report a 30-year-old woman who experienced recurrent neuritis and who was seropositive for AQP4-IgG. She became pregnant, and the fetus was found to have ectrodactyly. Histological analysis of the placenta showed moderate inflammatory infiltration; however, whether fetal malformation in NMOSD is related to inflammation and AQP4-IgG remains to be determined.",
"affiliations": "Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: changyyu@163.com.;Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: shuyaqing@126.com.;Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: sister_555@163.com.;Department of Obstetrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: lindaxu2011@qq.com.;Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: hedan76@126.com.;Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: lingf0313@qq.com.;Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: chen931691670@qq.com.;Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: hxq245600@qq.com.;Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Department of Neurology, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Nedlands, Perth, Western Australia, Australia; Institute of Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia. Electronic address: kermode@me.com.;Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: qiuwei120@vip.163.com.",
"authors": "Chang|Yanyu|Y|;Shu|Yaqing|Y|;Sun|Xiaobo|X|;Xu|Chengfang|C|;He|Dan|D|;Fang|Ling|L|;Chen|Chen|C|;Hu|Xueqiang|X|;Kermode|Allan|A|;Qiu|Wei|W|",
"chemical_list": "C496030:AQP4 protein, human; D051401:Aquaporin 4",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2017.11.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "19()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "AQP4-IgG; Ectrodactyly; Fetal malformation; Neuromyelitis optica spectrum disorder",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D051401:Aquaporin 4; D002680:Chin; D005260:Female; D006801:Humans; D017880:Limb Deformities, Congenital; D009471:Neuromyelitis Optica; D010920:Placenta; D011247:Pregnancy; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "70-72",
"pmc": null,
"pmid": "29149698",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ectrodactyly in a Chinese patient born to a mother with neuromyelitis optica spectrum disorder.",
"title_normalized": "ectrodactyly in a chinese patient born to a mother with neuromyelitis optica spectrum disorder"
} | [
{
"companynumb": "PHHY2017CN185349",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nSkin grafting has been evolving as an important application in reconstructive surgery. Mixed reports about the survival of allogeneic and xenogeneic keratinocytes require further substantiation to determine the role of these cells in wound healing.\n\n\nMETHODS\nRabbit and rat skins were recovered and cultured in vitro. Full-thickness wounds were created on the dorsum of rabbits (2 cm × 2 cm; n = 4). Cultured epithelial autograft, allograft, and xenograft cells were sprayed onto 3 freshly created wounds, with 1 wound acting as a control. The wounds were monitored every 2 days for 4 weeks. After 4 weeks, the rabbits were killed; skin biopsies were taken from each healed wound and stained with hematoxylin and eosin, and epidermal thickness was measured.\n\n\nRESULTS\nAll examined grafts showed favorable healing outcomes because the wounds appeared similar to normal skin upon healing. The only observed significant difference was the thickness of the epidermis layer, which was thinner in the xenograft (P = .002) than the autograft or allograft. Morphologic evaluation of the skin surface showed that the rat skin was thinner than the rabbit skin. The graft that achieved the best result was the autograft because the thickness was similar to and mimicked normal skin.\n\n\nCONCLUSIONS\nAll 3 grafts (autograft, allograft, and xenograft) have the potential to reconstitute epithelial defects. This approach can overcome the limitation of autologous skin donor sites, especially in burn cases.",
"affiliations": "From the Department of Nephrology, Seth G. S. Medical College and K. E. M. Hospital, Acharya Donde Marg, Parel, Mumbai, Maharashtra, India.",
"authors": "Keskar|Vaibhav|V|;Jamale|Tukaram|T|;Karegar|Manjusha|M|;Parikh|Hardik|H|;Jawale|Sunil|S|;Mahajan|Dinesh|D|;Hase|Niwrutti|N|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D000077562:Valganciclovir; D015774:Ganciclovir",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2013.0301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "13(3)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000328:Adult; D064591:Allografts; D000998:Antiviral Agents; D001706:Biopsy; D003586:Cytomegalovirus Infections; D005260:Female; D015774:Ganciclovir; D005756:Gastritis; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D009894:Opportunistic Infections; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D000077562:Valganciclovir",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "279-82",
"pmc": null,
"pmid": "25019524",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late-Onset Cytomegalovirus Gastritis in Low-Risk Renal Allograft Recipients.",
"title_normalized": "late onset cytomegalovirus gastritis in low risk renal allograft recipients"
} | [
{
"companynumb": "IN-MYLANLABS-2015M1047247",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Post-transplant complications are common among patients receiving immunosuppressive medications, including pain syndromes. Recently, a pain syndrome, calcineurin-inhibitor induced pain syndrome (CIPS) has been described. To our knowledge, this article is the second report of tacrolimus-associated CIPS, and the first report in the pediatric setting.",
"affiliations": "Department of Pharmacy, University of North Carolina Hospitals, 101 Manning Drive, Campus Box 7600, Chapel Hill, NC 27514, USA. re_dupuis@unc.edu",
"authors": "Malat|G E|GE|;Dupuis|R E|RE|;Kassman|B|B|;Rhoads|J M|JM|;Freeman|K|K|;Lichtman|S|S|;Johnson|M W|MW|;Gerber|D|D|;Andreoni|K|K|;Fair|J|J|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1034/j.1399-3046.2002.02030.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "6(5)",
"journal": "Pediatric transplantation",
"keywords": null,
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D009437:Neuralgia; D011183:Postoperative Complications; D013577:Syndrome; D016559:Tacrolimus",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "435-8",
"pmc": null,
"pmid": "12390434",
"pubdate": "2002-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tacrolimus-induced pain syndrome in a pediatric orthotopic liver transplant patient.",
"title_normalized": "tacrolimus induced pain syndrome in a pediatric orthotopic liver transplant patient"
} | [
{
"companynumb": "US-PFIZER INC-2019013785",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "Paclitaxel (PTX) and/or cisplatin (CDDP), as important cytotoxic anti-cancer agents, are widely used to treat various solid tumors. Both may cause moderate or severe neurotoxicity, but ocular neurotoxicity is also occasionally reported. A patient diagnosed with nasopharyngeal cancer suffering acute ocular neurotoxicity 10 days after paclitaxel and CDDP administration at the recommended dose is described in the present case report, and PTX- and/or CDDP-induced ocular neurotoxicity are summarized according to previous reports. Possible mechanisms and the potential diagnostic, therapeutic and predictive strategies of PTX- and/or CDDP-induced ocular neurotoxicity are reviewed, to help the oncologist to take the infrequent toxicity of cytotoxic drugs into account and improve patient safety during anti-cancer therapy.",
"affiliations": "Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, People's Republic of China.;Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, People's Republic of China.;Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, People's Republic of China.;Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, People's Republic of China.;Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, People's Republic of China.",
"authors": "Li|Ying|Y|;Li|Yanping|Y|;Li|Junyu|J|;Pi|Guoliang|G|;Tan|Wenyong|W|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S65774",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S65774ott-7-1361Case ReportPaclitaxel- and/or cisplatin-induced ocular neurotoxicity: a case report and literature review Li Ying *Li Yanping *Li Junyu Pi Guoliang Tan Wenyong Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, People’s Republic of ChinaCorrespondence: Wenyong Tan, Department of Radiation Oncology, Hubei Cancer Hospital, 116 South Road, Zhuodaoquan, Wuhan 430079, People’s Republic of China, Tel +86 28 8767 1353, Fax +86 28 8767 0469, Email tanwyym@hotmail.com*These authors contributed equally to this work\n\n2014 31 7 2014 7 1361 1366 © 2014 Li et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Paclitaxel (PTX) and/or cisplatin (CDDP), as important cytotoxic anti-cancer agents, are widely used to treat various solid tumors. Both may cause moderate or severe neurotoxicity, but ocular neurotoxicity is also occasionally reported. A patient diagnosed with nasopharyngeal cancer suffering acute ocular neurotoxicity 10 days after paclitaxel and CDDP administration at the recommended dose is described in the present case report, and PTX- and/or CDDP-induced ocular neurotoxicity are summarized according to previous reports. Possible mechanisms and the potential diagnostic, therapeutic and predictive strategies of PTX- and/or CDDP-induced ocular neurotoxicity are reviewed, to help the oncologist to take the infrequent toxicity of cytotoxic drugs into account and improve patient safety during anti-cancer therapy.\n\nKeywords\ncytotoxic drugsPTXCDDPoncologychemotherapy\n==== Body\nIntroduction\nPaclitaxel (PTX) + cisplatin (CDDP) or PTX + carboplatin have frequently been used in combination to treat various solid tumors. Though the toxicities inevitably increased, the toxicitic profile usually remained unchanged. Rare and severe toxicities, such as ocular neurotoxicity, warrant more attention due to their negative impact on the quality of life of patients who received various anti-cancer therapies. PTX- and/or CDDP-induced ocular neurotoxicity (PCION) have rarely been reported in the literature.1–4 Herein, we describe a patient with nasopharyngeal cancer who suffered PCION after chemoradiotherapy, and review the clinical manifestations, diagnostic and therapeutic strategies, and the possible molecular mechanisms which improve patient safety during anti-cancer therapy.\n\nCase presentation\nThe patient provided written informed consent for this case report. A 56-year-old male patient was diagnosed pathologically with a low-differentiated non-keratinized squamous cell via a nasopharyngeal biopsy performed using electronic nasopharyngeal endoscopy. The primary tumor had invaded locally, including the cervical lymph nodes. Based on the 2010 American Joint Committee on Cancer staging system, the tumor was stage III with T2N2M0. Intensity-modulated radiotherapy (IMRT) was delivered at three doses from July to August 2013 according to our departmental protocol (Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, People’s Republic of China).5 The radiation dose to gross primary tumor and positive lymph nodes in the neck, high-risk region, and low-risk elective nodal region were 70 Gy, 60.3 Gy, and 54 Gy, respectively. IMRT was delivered with 30 daily fractions in 6 weeks (five fractions per week). The maximal radiation dose to the optic chiasm and the left and right optic nerves were 32.1 Gy, 16.7 Gy, and 17.7 Gy, respectively (Figure 1). Complete response was confirmed by both magnetic resonance imaging (MRI) and electronic nasopharyngeal endoscope 2 months after completing radiotherapy. In addition, patient also has well controlled primary hypertension and chronic hepatitis B.\n\nBased on our institutional guidelines, the patient was administered adjuvant chemotherapy comprising PTX (150 mg/m2) (Harbin Pharmaceutical Group Bioengineering Co, Ltd, Harbin, People’s Republic of China) and CDDP (75 mg/m2) (Supertrack Biopharmaceutical Co, Ltd, Yunnan, People’s Republic of China) on the day immediately following the post-radiotherapy evaluation. During the initial chemotherapy, he suffered grade 2 gastrointestinal (nausea and vomiting) and grade 4 hematological (neutropenia) toxicity, as described by the Common Terminology Criteria for Adverse Events Version 4.0,6 but he recovered after receiving antiemetic and granulocyte-colony stimulating factor medications.\n\nTen days after the chemotherapeutic drugs were administered, he complained of severe headache, nausea, and vomiting. Fourteen hours after his first complaint, he reported blurred vision with transitory lightning scotoma in the left eye and right hand numbness. After 22 hours, he gradually lost central vision in the left eye. A detailed physical examination, complete blood count, liver and renal biochemistry, blood glucose, and serum electrolyte concentration were measured and all the result showed no clinical abnormality. His vital signs including body temperature, pulse rate, blood pressure, and respiratory rate were of normal, and no other significant physical signs were found when the patient was cooperative, conscious, and reasonably fluent during the examinations. Computed tomography (CT) and MRI were performed immediately, but there was no significant tumor recurrence or radiation-associated damage observed.\n\nSeveral ophthalmic examinations were performed after the patient became blind; the best-corrected visual acuities were 0.3 on the right and only slight light perception on the left. The intraocular pressures were normal bilaterally at 11 mmHg on the left and 13 mmHg on the right. The pattern visual-evoked potentials (VEPs) and transient, flash electroretinograms (ERGs) were abnormal (Figure 2A and C). Non-specific waves were found in his left eye (Figure 2A and C), but the VEP and ERG were normal in his right eye (Figure 2B and C). The direct ophthalmoscopic examination of the fundus, retina, and vitreous humor was normal bilaterally. The right eye had a normal visual field; the left eye visual field could not be assessed due to its loss of light perception (Figure 3). A temporal hemianopsia, and a nasal peripheral visual field defect were found in the right eye (Figure 3).\n\nTwo days after losing his left-sided vision, hypopsia appeared in the right eye, and 72 hours later, he developed complete blindness bilaterally. Numerous therapies were administered, including glucocorticoids (methylprednisolone), calcium antagonists (flunarizine), vasodilators, and neuro-nutrition drugs over the following 2 weeks, but his sight did not improve in the 6 months following adjuvant chemotherapy, and he had a very poor quality of life.\n\nDiscussion\nAnti-cancer drug-induced ocular neurotoxicity is extremely rare. Some of these toxicities are irreversible and might worsen the patient’s quality of life, or even cause patient disability. In the following, we will discuss the clinical manifestation, possible pathogenesis, diagnosis, and therapeutic strategies against PCION.\n\nClinical manifestations\nChemotherapeutic agent-induced ocular neurotoxicity is commonly associated with interferon.7 The main clinical manifestations have been described previously4,8–16 and are summarized in Table 1. Ocular neurotoxicity generally presents as 1) blepharitis and conjunctivitis; 2) hemianopia, homonymous or bi-temporal visual field defects; 3) periorbital edema with firm eyelid swelling and ocular pain; 4) retinal toxicity with maculopathy characterized by pigmentary changes resulting from localized retinal pigment disturbances, altered color perception attributable to cone dysfunction, or mild retinal ischemic changes such as cotton-wool spots and posterior pole intraretinal hemorrhage; and 5) some other rare ocular toxicities.\n\nCisplatin-associated neurotoxicity is dose-dependent.17 Although it occurs infrequently, the previous studies indicated that visual impairment may occur secondary to CDDP-related neurotoxicity.17 The severe neurotoxicity was extremely uncommon at a cumulative dose below 400 mg/m2, but the incidence increased at a 600–800 mg/m2 cumulative dose.17 Children, young patients, and those with renal dysfunction seem to be the highest risk groups for cisplatin-related neurotoxicity.7 The visual alterations might also result from the optic neuritis and cortical blindness, which may be accompanied by seizure activity.7,18 Wang et al11 reported that occlusion of a retinal artery branch and bilateral blindness is associated with high-dose cytotoxic agents such as carmustine and CDDP. In a report by Kwan et al,4 severe macular ischemia and retinal neovascularization occurred in a patient who received CDDP-contained chemotherapy.\n\nPaclitaxel-induced neurotoxicity has been reported previously.19 The patients typically complained of a transient and scintillating scotoma, visual impairment, or bilateral cystoid macular edema. The majority of these symptoms occurred within the first 30 minutes of drug administration and completely resolved within 3 hours. These symptoms occurred more frequently in patients who received doses greater than 250 mg/m2.20,21 Tan et al10 described two patients with breast and ovarian cancer who suffered ocular toxicity after the administration of PTX and carboplatin. Though the underlying causes remained unknown, the authors surmised that PTX was the primary agent. Bakbak et al22 assessed CDDP- and PTX-associated toxicities in the optic nerve by measuring the retinal nerve fiber layer (RNFL) thickness and visual field changes in patients with lung cancer who received systemic CDDP and PTX. They found the peripapillary RNFL thicknesses and visual field indices changed based on frequency-doubling technology (FDT) perimetry.\n\nPossible mechanisms\nThe mechanism of ocular neurotoxicity remains unknown, and neither the ischemic nor electrophysiological hypotheses could fully explain the pathogenesis of PCION in the previous study.23 A study by Scaioli et al24 suggested that the visual symptoms and electrophysiological changes following intravenous PTX administration were likely caused by retinal vascular dysregulation or optic nerve ischemia. Because the cystoid macular edema occurred after treatment of PTX, one theory is that Müller cell toxicity results subsequent to intracellular fluid accumulation and subclinical extracellular fluid leakage. In patients with reversible scotoma, the abnormal visual-evoked potential was comparable to those with changes observed in ischemic neuropathies, which suggested that the target of anti-cancer drugs such as PTX was within the optic nerve.19 Brain irradiation and/or surgery are high risk factors because cystoid macular edema can result in disruption of the normal blood–retinal barrier.16,24\n\nCisplatin or PTX may affect optic nerve function, and the combination of CDDP with PTX may synergistically increase the neurotoxicity risk to the optic nerve. In our case, however, the primary cause of the patient’s ocular symptoms and blindness remain unknown. The cause may potentially be attributed to CDDP administration alone, PTX alone, the combination of PTX with CDDP, or the interaction of cytotoxic drugs with radiation. To investigate the exact cause of the loss of eyesight, both CT and MRI scanning of head and neck, and laboratory biochemical examination including serum electrolyte, were performed. The potential causes that could result in ocular disease were excluded by various examinations. They included the uncontrolled primary tumor, radiation-induced brain and nerve damage, the central neural and cerebrovascular disease, chemotherapeutic drug-related myelosuppression, imbalance of serum electrolyte, and so on. For the patient in our report, the possible cause of PCION included cytotoxic drugs, radiation, and the patient’s concomitant diseases (hypertension and chronic hepatitis B). The possibility of both radiation treatment and concomitant diseases causing PCION was extremely low because all the concomitant diseases were well controlled. Additionally, the maximal radiation dose to the optical nerves and chiasm was <32 Gy, which is far below the tolerance to the radiation. Though we could not accurately ascertain the exact cause of our patient’s blindness, and did not know the precise interaction of cytotoxic agent and radiation or the variation of the normal tissue’s response to anti-cancer therapy during the complicated context of chemoradiotherapy, we could still infer cytotoxicity of PTX and/or CDDP as the primary cause.\n\nStrategies for detection, treatment and prediction\nBecause of its scarcity, PCION was usually underestimated or considered minor when compared to other life-threatening complications.17 Oncologists should take all potential severe toxicities into consideration prior to initial treatment and be familiar with their pathogenesis and management. Despite the lack of consensus outlining routine ophthalmologic monitoring and ocular toxicity management at present, for some drugs with potential ocular toxicity a baseline ophthalmologic examination and regular monitoring is strongly recommended before treatment. The monitoring examinations could include visual acuity, tonometry, fundoscopy, color vision test, automated perimetry, retinal photography, and others.17 Potential treatment options including warm compress, eyelid hygiene, corticosteroids, topical anti-inflammatory medications and lubricants, and avoiding light exposure may prove useful, but further clinical study is needed. Hofstra et al25 reported that flunarizine, a selective calcium channel antagonist, has been used successfully to treat one patient diagnosed with visual-evoked potential abnormalities. Kwan et al4 reported a case of bilateral panretinal laser photocoagulation, but the therapy was ineffective because the best-corrected visual acuity remained unchanged 6 months later. Based on previous reports, nearly all PCIONs were irreversible, and the best-corrected visual acuity failed to improve significantly. Currently, there is no biomarker available to effectively predict these severe PCIONs.\n\nConclusion\nPTX- and CDDP-induced ocular toxicity is extremely rare and usually irreversible. The clinical manifestations mainly include abnormal vision, hemianopia, photopsia, visual disturbance, blindness, ocular pain, cystoid macular edema, and other similar symptoms. The possible mechanisms of PCION might be related to the ischemic and electrophysiological changes within ocular neural structures. There are no effective strategies for the early detection, treatment, and prediction of PCION, which is warranted for further investigation. Clinical oncologists should consider the risk of severe PCION prior to initiating anti-cancer treatment.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Color wash and dose-volume histogram.\n\nNote: The radiation dose distribution at the optic chiasm (red solid line), and the left (green solid line) and right (purple solid line) optic nerves are shown in a color wash (A) and dose-volume histogram (B).\n\nFigure 2 Flash visual-evoked potential and electroretinogram results.\n\nNotes: During flash visual-evoked potential (A and B), and electroretinogram (C), there was no waveform observed in the left eye (A and C), but a normal wave was found in the right (B and C). SYSN means the synchronic signal was used during the information acquisition. N75, P100 and N145 are three different waves in pattern visual-evoked potential.\n\nAbbreviations: L-frequency, low frequency; H-frequency, high frequency; SYSN, synchronous signal.\n\nFigure 3 Visual field test.\n\nNote: Temporal hemianopsia and a nasal peripheral visual field defect were diagnosed during the right eye visual field study.\n\nAbbreviations: O/O, 0%; POS, positive; NEG, negative; SITA-fast, Swedish Interactive Threshold Algorithms; RX, correction of refractive errors; DS, Diopter sphere; DC, Diopter cylinder; GHT, Glaucoma Hemifield Test; VFI, visual field index; MD, mean defect; PSD, pattern standard deviation.\n\nTable 1 Summarized paclitaxel- and/or cisplatin-induced ocular toxicity reported in prior and present studies\n\nAuthor(s)\tCase number\tToxicity\tDrug\tDiagnosis\t\nKwan et al4\t1\tHemianopia\tCDDP\tNonseminomatous germ cell testicular tumor\t\nBerman and Mann8\t1\tCortical blindness\tCDDP\tEmbryonic cell carcinoma of the testicle\t\nWilding et al9\t13\tBlurred vision\tCDDP\tOvarian carcinoma\t\nTan and Walsh10\t2\tPhotopsia\tCDDP, PTX\tLung cancer\t\nWang et al11\t1\tBilateral blindness\tCarmustine, CDDP\tBreast carcinoma\t\nWatanabe et al12\t1\tVisual disturbance\tCarboplatin\tGlioblastoma\t\nWu et al13\t1\tIntraorbital and intraocular pain\tCDDP\tGlioblastoma multiforme\t\nScaioli et al14\t1\tOptic neuropathy\tPTX, doxorubicin\tBreast cancer\t\nModi and Dubovy15\t1\tMaculopathy\tPTX\tBreast cancer\t\nJoshi and Garretson16\t1\tCystoid macular edema\tPTX\tBreast cancer\t\nLi et al (present study)\t1\tBilateral blindness\tCDDP, PTX\tNasopharyngeal cancer\t\nAbbreviations: PTX, paclitaxel; CDDP, cisplatin.\n==== Refs\nReferences\n1 Ziske CG Schöttker B Gorschlüter M Acute transient encephalopathy after paclitaxel infusion: report of three cases Ann Oncol 2002 13 4 629 631 12056715 \n2 Cavaletti G Bogliun G Marzorati L Peripheral neurotoxicity of taxol in patients previously treated with cisplatin Cancer 1995 75 5 1141 1150 7850713 \n3 Anand A Huberman M Peripheral neurotoxicity of taxol in patients previously treated with cisplatin Cancer 1995 76 5 916 917 8625200 \n4 Kwan AS Sahu A Palexes G Retinal ischemia with neovascularization in cisplatin related retinal toxicity Am J Ophthalmol 2006 141 1 196 197 16387001 \n5 Tan W Li Y Han G Target volume and position variations during intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma Onco Targets Ther 2013 6 1719 1728 24311943 \n6 National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 U.S. Department of Health and Human Services Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf Accessed July 11, 2014 \n7 Walsh TJ Clark AW Parhad IM Green WR Neurotoxic effects of cisplatin therapy Arch Neurol 1982 39 11 719 720 6889850 \n8 Berman IJ Mann MP Seizures and transient cortical blindness associated with cis-platinum (II) diamminedichloride (PDD) therapy in a thirty-year-old man Cancer 1980 45 4 764 766 7188878 \n9 Wilding G Caruso R Lawrence TS Retinal toxicity after high-dose cisplatin therapy J Clin Oncol 1985 3 12 1683 1689 4067616 \n10 Tan WW Walsh T Ocular toxicity secondary to paclitaxel in two lung cancer patients Med Pediatr Oncol 1998 31 3 177 9722903 \n11 Wang MY Arnold AC Vinters HV Glasgow BJ Bilateral blindness and lumbosacral myelopathy associated with high-dose carmustine and cisplatin therapy Am J Ophthalmol 2000 130 3 367 368 11020424 \n12 Watanabe W Kuwabara R Nakahara T Severe ocular and orbital toxicity after intracarotid injection of carboplatin for recurrent glioblastomas Graefes Arch Clin Exp Ophthalmol 2002 240 12 1033 1035 12483326 \n13 Wu HM Lee AG Lehane DE Chi TL Lewis RA Ocular and orbital complications of intraarterial cisplatin. A case report J Neuroophthalmol 1997 17 3 195 198 9304534 \n14 Scaioli V Caraceni A Martini C Visual evoked potentials findings in course of paclitaxel doxorubicin combination chemotherapy. Report of a case J Neurooncol 1995 25 3 221 225 8592172 \n15 Modi D Dubovy SR Non-leaking Cystoid Maculopathy Secondary to Systemic Paclitaxel Ophthalmic Surg Lasers Imaging Retina 2013 44 2 183 186 23429715 \n16 Joshi MM Garretson BR Paclitaxel maculopathy Arch Ophthalmol 2007 125 5 709 710 17502517 \n17 Agustoni F Platania M Vitali M Emerging toxicities in the treatment of non-small cell lung cancer: ocular disorders Cancer Treat Rev 2014 40 1 197 203 23850197 \n18 Katz BJ Ward JH Digre KB Creel DJ Mamalis N Persistent severe visual and electroretinographic abnormalities after intravenous Cisplatin therapy J Neuroophthalmol 2003 23 2 132 135 12782925 \n19 Capri G Munzone E Tarenzi E Optic nerve disturbances: a new form of paclitaxel neurotoxicity J Natl Cancer Inst 1994 86 14 1099 1101 7912737 \n20 Seidman AD Barrett S Canezo S Photopsia during 3-hour paclitaxel administration at doses ≥250 mg/m2 J Clinical Oncol 1994 12 8 1741 1742 7913722 \n21 Kuznetcova TI Cech P Herbort CP The mystery of angiographically silent macular oedema due to taxanes Int Ophthalmol 2012 32 3 299 304 22484725 \n22 Bakbak B Gedik S Koktekir BE Assessment of ocular neurotoxicity in patients treated with systemic cancer chemotherapeutics Cutan Ocul Toxicol 2014 33 1 7 10 23638802 \n23 Hagiwara H Sunada Y Mechanism of taxane neurotoxicity Breast Cancer 2004 11 1 82 85 14718798 \n24 Scaioli V Caraceni A Martini C Curzi S Capri G Luca G Electrophysiological evaluation of visual pathways in paclitaxel-treated patients J Neurooncol 2006 77 1 79 87 16132528 \n25 Hofstra LS de Vries EG Willemse PH Ophthalmic toxicity following paclitaxel infusion Ann Oncol 1997 8 10 1053 9402182\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "7()",
"journal": "OncoTargets and therapy",
"keywords": "CDDP; PTX; chemotherapy; cytotoxic drugs; oncology",
"medline_ta": "Onco Targets Ther",
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"nlm_unique_id": "101514322",
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"pages": "1361-6",
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"pmid": "25114574",
"pubdate": "2014",
"publication_types": "D002363:Case Reports",
"references": "6889850;17502517;11020424;16387001;23638802;9722903;7913722;9304534;23850197;7850713;4067616;7188878;8625200;8592172;16132528;12056715;12782925;7912737;23429715;12483326;14718798;9402182;24311943;22484725",
"title": "Paclitaxel- and/or cisplatin-induced ocular neurotoxicity: a case report and literature review.",
"title_normalized": "paclitaxel and or cisplatin induced ocular neurotoxicity a case report and literature review"
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"abstract": "Tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) are the standard treatment for lung cancer patients with activating EGFR mutation. The traditional direct polymerase chain reaction (PCR) has lower sensitivity in the detection of EGFR mutations in patient tissue samples. Whilst PCR amplification kits increase the sensitivity in detecting some types of EGFR mutations, not many types of rare mutations are found. Here, we report a patient who had lung adenocarcinoma harboring EGFR T751_I759delinsS mutation and had good response to afatinib initially and osimertinib after developing resistance to afatinib. This rare EGFR mutation was not detected by Scorpion and ARMS method but was found using the next-generation sequencing method. There are less prospective trials in the treatment of lung adenocarcinoma with very rare EGFR mutations. Our case report could therefore provide clinical experience to the clinicians in the management of their patients.",
"affiliations": "Department of Thoracic Medicine, Chang Gung Foundation, Chang Gung Memorial Hospital, Taoyuan, Taiwan.;Divison of Pulmonary, Critical Care, and Sleep Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.",
"authors": "Fang|Yueh-Fu|YF|https://orcid.org/0000-0003-2211-3076;Liu|Ping-Chi|PC|",
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"doi": "10.1111/1759-7714.14215",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n34729927\n10.1111/1759-7714.14215\nTCA14215\nCase Report\nCase Reports\nAfatinib and osimertinib in lung adenocarcinoma harbored EGFR T751_I759delinsS mutation: A case report\nFang and Liu\nFang Yueh‐Fu https://orcid.org/0000-0003-2211-3076\n1 2 dr.fang.yf@gmail.com\n\nLiu Ping‐Chi 3\n1 Department of Thoracic Medicine, Chang Gung Foundation Chang Gung Memorial Hospital Taoyuan Taiwan\n2 College of Medicine Chang Gung University Taoyuan Taiwan\n3 Divison of Pulmonary, Critical Care, and Sleep Medicine Chang Gung Memorial Hospital Keelung Taiwan\n* Correspondence\nYueh‐Fu Fang, Department of Thoracic Medicine, Chang Gung Memorial Hospital, 199 Tun‐Hwa N. Rd., Taipei, Taiwan.\nEmail: dr.fang.yf@gmail.com\n\n02 11 2021\n12 2021\n12 24 10.1111/tca.v12.24 34293432\n17 10 2021\n05 10 2021\n18 10 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nTyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) are the standard treatment for lung cancer patients with activating EGFR mutation. The traditional direct polymerase chain reaction (PCR) has lower sensitivity in the detection of EGFR mutations in patient tissue samples. Whilst PCR amplification kits increase the sensitivity in detecting some types of EGFR mutations, not many types of rare mutations are found. Here, we report a patient who had lung adenocarcinoma harboring EGFR T751_I759delinsS mutation and had good response to afatinib initially and osimertinib after developing resistance to afatinib. This rare EGFR mutation was not detected by Scorpion and ARMS method but was found using the next‐generation sequencing method. There are less prospective trials in the treatment of lung adenocarcinoma with very rare EGFR mutations. Our case report could therefore provide clinical experience to the clinicians in the management of their patients.\n\nThe patient received afatinib for recurrent lung cancer (a) with a partial response (b). The patient had progressed disease (c) and rebiopsy of lung tumor showed positive EGFR exon 20 p.T790M mutation. He had a partial response to osimertinib treatment (d)\n\nafatinib\nEGFR\nOsimertinib\nT751_I759insdelS\nsource-schema-version-number2.0\ncover-dateDecember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.7.0 mode:remove_FC converted:15.12.2021\nFang Y‐F , Liu P‐C . Afatinib and osimertinib in lung adenocarcinoma harbored EGFR T751_I759delinsS mutation: A case report. Thorac Cancer. 2021;12 :3429–3432. 10.1111/1759-7714.14215\n==== Body\npmcINTRODUCTION\n\nLung adenocarcinoma patients diagnosed with mutant EGFR usually have a good response to EGFR tyrosine kinase inhibitors (TKIs). Complex mutation patterns can be detected by traditional direct polymerase chain reaction (PCR). 1 Direct PCR showed a lower sensitivity in patient samples which had a lower proportion of cancer cells. Some EGFR PCR kits increase the sensitivity but can only detect some specific mutations. The Scorpion and amplification refractory mutation system (ARMS) can detect several types of point mutations (G719X, S768I, T790M, L858R, L861Q), three subtypes of exon 20 insertion and 25 subtypes of exon 19 deletions. Many subtypes of rare EGFR mutations cannot be detected by PCR kits. 2 In these patients, next‐generation sequencing (NGS) is a good method to find the rare EGFR mutations and other oncogenic mutations or amplifications.\n\nThere have been fewer prospective trials in the treatment of rare EGFR mutations. 3 , 4 Retrospective studies of real‐world data in lung cancer patients have reported the outcome of EGFR TKIs treatments in lung cancer patients. 5 , 6 Some case reports of vary rare EGFR mutations provide details of clinical experience and suggestions for clinicians for patient treatment. 1 , 7 , 8 Deletion in exon 19 of EGFR has been found in many lung adenocarcinomas, but insertion in exon 19 of EGFR is less commonly reported in lung cancer patients. Here, we report the case of a lung adenocarcinoma patient who was found to have EGFR exon 19 insertion and achieved a good response to EGFR TKIs.\n\nCASE REPORT\n\nIn March 2019, a 58‐year‐old male presented to our clinic with a cough and chest X‐ray revealed a mass in the right lung. Following biopsy, the pathology confirmed that the patient had pulmonary adenocarcinoma. Positron emission tomography (PET‐CT) showed a positive uptake in the right lung mass and bilateral mediastinal lymph nodes but there was no distal metastasis. Brain magnetic resonance imaging (MRI) with contrast showed no brain metastasis. The Scorpion and ARMS method showed no detectable EGFR mutation. Immunohistochemistry staining of anaplastic lymphoma kinase (ALK) was negative. Programmed‐death 1 ligand staining was 10%. He received concurrent chemoradiotherapy (CCRT) with docetaxel and cisplatin from April 9 to May 13 for stage III lung cancer. Chest computed tomography (CT) showed a partial response after CCRT. The patient received immunotherapy with durvalumab on June 19 and July 7 and had progressive dyspnea and grade 3 pneumonitis which was diagnosed on July 15. He was treated with steroids and had no further immunotherapy after his recovery from pneumonitis (Figure 1).\n\nFIGURE 1 The patient was diagnosed with adenocarcinoma stage III (a) and received concurrent chemoradiotherapy (CCRT). Regression of the tumor (b) was noted and the patient subsequently received durvalumab after CCRT. The patient had pneumonitis after two cycles of durvalumab (c) but his pneumonitis improved after steroid treatment (d)\n\nHowever, chest CT and brain MRI showed disease progression in the right lung with lymphangitic carcinomatosis and brain metastases in December 2019. Brain radiotherapy was performed for brain metastases. The NGS panel ACTDrug+ (ACT Genomics) showed EGFR T751_I759delinsS and EGFR amplification (copy number 23.5). The patient subsequently received afatinib on January 21, 2020 and brain MRI and chest CT showed a partial response. However, grade 1 skin rash and paronychia were reported. Chest CT showed progressed lymphangitic carcinomatosis of the right lung after treatment with afatinib for 9 months. The pathology of rebiopsy of the lung tumor confirmed a positive EGFR exon 20 p.T790M mutation by the Scorpion and ARMS method. We subsequently prescribed osimertinib for the patient commencing on October 5, 2020 and his chest CT and brain MRI have revealed a partial response. Our report showed EGFR T751_I759delinsS and EGFR amplification are sensitive to afatinib. Progression‐free survival was 9 months for the patient in our study. Osimertinib was effective for this rare mutation after the patient was found to be resistant to afatinib because of EGFR exon 20 p.T790M mutation (Figure 2).\n\nFIGURE 2 Next‐generation sequencing of the patient's tissue showed EGFR mutation with T751_I759delinsS and amplification (copy number 23.5)\n\nDISCUSSION\n\nHere, we present the report of a patient who was found to harbor EGFR T751_I759delinsS and amplification of EGFR and had a good response to afatinib and osimertinib. Deletion from E746 or L747 of exon 19 are common mutations of EGFR and have shown a good response to EGFR TKIs. A study of 195 patients with exon 19 deletion showed shorter progression‐free survival (PFS) 2.9 months of first‐generation EGFR TKIs in the patients who had deletion from T751 or S752. The lower detection rate (16.7%) of EGFR exon 20 p.T790M may have resulted in shorter PFS in a previously reported study. 9 A case report showed a patient had PFS 7.0 months to icotinib and had resistant mutation T751_I759delinsS after icotinib treatment. 10 The patient had no response to three combinations with chemotherapy, bevacizumab and erlotinib but had a good response to osimertinib for 16 months. The EGFR T751_I759delinsS should be sensitive osimertinib depended on our report (Figure 3).\n\nFIGURE 3 The patient received afatinib for recurrent lung cancer (a) and had a partial response (b). The patient had progressive disease (c) and rebiopsy of the lung tumor showed positive EGFR exon 20 p.T790M mutation. He had a partial response to osimertinib treatment (d)\n\nEGFR amplification has been reported as one resistant mechanism to EGFR TKIs. 11 , 12 Our patient had coexisting EGFR T751_I759delinsS mutation and EGFR amplification and received 9 months PFS following afatinib treatment. The 9‐months PFS was shorter than in those patients who receive first‐line treatment with afatinib for common EGFR exon 19 deletions. In patients with other uncommon EGFR mutations, PFS was less than 9 months and depended on retrospective analysis of clinical trial and real‐world evidence. 4\n\nThe T751_I759delinsS in EGFR exon 19 could not be detected by several commercial PCR kits. NGS should be a better method to detect complex variants of EGFR mutations. Half lung adenocarcinoma patients had common EGFR mutations or expression of ALK in Asia. For economic reasons, NGS is often only performed in patients who have been confirmed to ahve negative EGFR mutations by PCR kits and low expression of ALK in Asia. In a subgroup of patients who had a lower ratio of EGFR mutation, NGS was reported to be the better method of detecting driver genes. 13\n\nIn summary, we report a case of lung adenocarcinoma with T751_I759delinsS in EGFR exon 19 which may be a predictive factor of poor response to first generation TKIs as reported in a previous study. 14 Our case showed acceptable PFS to afatinib after CCRT and checkpoint immunotherapy. This rare mutation may indicate good PFS to osimertinib but more real‐world data is needed to support our findings.\n\nCONFLICT OF INTEREST\n\nThe authors do not report any conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Hsieh MH , Fang YF , Chang WC , Kuo HP , Lin SY , Liu HP , et al. Complex mutation patterns of epidermal growth factor receptor gene associated with variable responses to gefitinib treatment in patients with non‐small cell lung cancer. Lung Cancer. 2006;53 :311–22.16870303\n2 Qin L , Zhong W , Zhang L , Li LY , Wang MZ . Comparison of three methods for detecting epidermal growth factor receptor mutations in plasma DNA samples of Chinese patients with advanced non‐small cell lung cancer. Chin Med J (Engl). 2011;124 :887–91.21518597\n3 Cho JH , Lim SH , An HJ , Kim KH , Park KU , Kang EJ , et al. Osimertinib for patients with non‐small‐cell lung cancer harboring uncommon EGFR mutations: a multicenter, open‐label, phase II trial (KCSG‐LU15‐09). J Clin Oncol. 2020;38 :488–95.31825714\n4 Yang JC , Sequist LV , Geater SL , et al. Clinical activity of afatinib in patients with advanced non‐small‐cell lung cancer harbouring uncommon EGFR mutations: a combined post‐hoc analysis of LUX‐lung 2, LUX‐lung 3, and LUX‐lung 6. Lancet Oncol. 2015;16 :830–8.26051236\n5 Brindel A , Althakfi W , Barritault M , Watkin E , Maury JM , Bringuier PP , et al. Uncommon EGFR mutations in lung adenocarcinoma: features and response to tyrosine kinase inhibitors. J Thorac Dis. 2020;12 :4643–50.33145037\n6 Chantharasamee J , Poungvarin N , Danchaivijitr P , Techawatanawanna S . Clinical outcome of treatment of metastatic non‐small cell lung cancer in patients harboring uncommon EGFR mutation. BMC Cancer. 2019;19 :701.31315599\n7 Ibrahim U , Saqib A , Atallah JP . EGFR exon 18 delE709_T710insD mutated stage IV lung adenocarcinoma with response to afatinib. Lung Cancer. 2017;108 :45–7.28625646\n8 Xia P , Liu E , Li P , Li W , Jiang G . A case of primary resistance to Ge fi tinib due to novel deletion‐insertion mutation of EGFR exon 19 in NSCLC. J Thorac Oncol. 2019;14 :e117–e9.31122561\n9 Xu H , Li W , Yang G , Li J , Yang L , Xu F , et al. Heterogeneous response to first‐generation tyrosine kinase inhibitors in non‐small‐cell lung cancers with different EGFR exon 19 mutations. Target Oncol. 2020;15 :357–64.32418166\n10 Li H , Yu T , Lin Y , Xie Y , Feng J , Huang M , et al. Three novel EGFR mutations (750_758del, I759S, T751_I759delinsS) in one patient with metastatic non‐small cell lung cancer responding to Osimertinib: a case report. Onco Targets Ther. 2020;13 :7941–8.32982275\n11 Lin L , Lu Q , Cao R , Ou Q , Ma Y , Bao H , et al. Acquired rare recurrent EGFR mutations as mechanisms of resistance to Osimertinib in lung cancer and in silico structural modelling. Am J Cancer Res. 2020;10 :4005–15.33294282\n12 Lee PC , Fang YF , Yamaguchi H , Wang WJ , Chen TC , Hong X , et al. Targeting PKCdelta as a therapeutic strategy against heterogeneous mechanisms of EGFR inhibitor resistance in EGFR‐mutant lung cancer. Cancer Cell. 2018;34 :954–69. e4.30537515\n13 Guo G , Li G , Liu Y , Li H , Guo Q , Liu J , et al. Next‐generation sequencing reveals high uncommon EGFR mutations and tumour mutation burden in a subgroup of lung cancer patients. Front Oncol. 2021;11 :621422.33889543\n14 Xu CW , Lei L , Wang WX , Lin L , Zhu YC , Wang H , et al. Molecular characteristics and clinical outcomes of EGFR exon 19 C‐helix deletion in non‐small cell lung cancer and response to EGFR TKIs. Transl Oncol. 2020;13 :100791.32492620\n\n",
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"abstract": "BACKGROUND\nElderly patients, in particular, have been reported to develop psychiatric side effects from antibiotics. Clarithromycin, quinolones, sulfamethoxazole-trimethoprim, isoniazid, penicillin, and cephalosporins have been reported to cause psychosis. This case report bridges a void in the medical literature with regards to the psychiatric adverse effects of imipenem-cilastatin.\n\n\nMETHODS\nA 64-year-old Hispanic man in septic shock due to urinary tract infection was initiated on imipenem-cilastatin and mechanically ventilated, following admission to hospital. His mentation was normal for 72 hours after extubation and discontinuation of sedatives and opioids, following which he was noted to be in acute psychosis. Our patient's imipenem-cilastatin dose had been increased 24 hours prior to his violent visual and auditory hallucinations because his renal function had improved. The physical examination and laboratory tests did not reveal evidence of a new central nervous infection or endocrinopathy. His mentation improved after his antibiotic was switched to ceftriaxone, based on culture and sensitivity testing. Similar psychiatric symptoms developed 2 months later when he was treated with imipenem for a recurrent urinary tract infection. His symptoms again resolved with modification of his antibiotic regimen.\n\n\nCONCLUSIONS\nEndocrine dysfunctions (thyroid, adrenal, and pituitary disorders) and toxic ingestions are medical disorders known to cause brief psychotic episodes. Fluoroquinolones, penicillins, and trimethoprim-sulfamethoxazole are common antibiotics associated with this rare adverse effect. Several pharmacokinetic hypotheses have been proposed for this adverse effect: (1) N-methyl-D-aspartate receptor hypofunctioning, (2) sequential blockade of folic acid production, (3) inhibition of prostaglandin E2 and proinflammatory cytokine production, (4) increased central dopamine turnover, and (5) accumulation of toxic levels of the drug. Pre-existing psychopathology, relevant comorbidities, slow acetylation status, and increased permeability of the blood-brain barrier have been suggested to make patients more prone to developing psychosis. According to the literature, this psychiatric manifestation resolves within 2 weeks of discontinuing the offending agent. There appears to be underreporting of the psychiatric manifestations of imipenem-cilastatin, contrary to post-marketing surveillance data. It is imperative that physicians recognize these psychiatric side effects of antibiotics, because they are a fundamental treatment option.",
"affiliations": "Department of Hospital Medicine, Mayo Clinic Health Systems Franciscan Healthcare, La Crosse, WI, USA. ninan.jacob@mayo.edu.;Internal Medicine Residency Program, John H Stroger Hospital of Cook County, Chicago, IL, USA.",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 88310.1186/s13256-016-0883-xCase ReportImipenem-cilastatin-induced psychosis: a case report Ninan Jacob ninan.jacob@mayo.edu George Gemy Maria gemy.maria@gmail.com Department of Hospital Medicine, Mayo Clinic Health Systems Franciscan Healthcare, La Crosse, WI USA Internal Medicine Residency Program, John H Stroger Hospital of Cook County, Chicago, IL USA 27 4 2016 27 4 2016 2016 10 10715 12 2015 22 3 2016 © Ninan and George. 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nElderly patients, in particular, have been reported to develop psychiatric side effects from antibiotics. Clarithromycin, quinolones, sulfamethoxazole-trimethoprim, isoniazid, penicillin, and cephalosporins have been reported to cause psychosis. This case report bridges a void in the medical literature with regards to the psychiatric adverse effects of imipenem-cilastatin.\n\nCase presentation\nA 64-year-old Hispanic man in septic shock due to urinary tract infection was initiated on imipenem-cilastatin and mechanically ventilated, following admission to hospital. His mentation was normal for 72 hours after extubation and discontinuation of sedatives and opioids, following which he was noted to be in acute psychosis. Our patient’s imipenem-cilastatin dose had been increased 24 hours prior to his violent visual and auditory hallucinations because his renal function had improved. The physical examination and laboratory tests did not reveal evidence of a new central nervous infection or endocrinopathy. His mentation improved after his antibiotic was switched to ceftriaxone, based on culture and sensitivity testing. Similar psychiatric symptoms developed 2 months later when he was treated with imipenem for a recurrent urinary tract infection. His symptoms again resolved with modification of his antibiotic regimen.\n\nConclusions\nEndocrine dysfunctions (thyroid, adrenal, and pituitary disorders) and toxic ingestions are medical disorders known to cause brief psychotic episodes. Fluoroquinolones, penicillins, and trimethoprim-sulfamethoxazole are common antibiotics associated with this rare adverse effect. Several pharmacokinetic hypotheses have been proposed for this adverse effect: (1) N-methyl-D-aspartate receptor hypofunctioning, (2) sequential blockade of folic acid production, (3) inhibition of prostaglandin E2 and proinflammatory cytokine production, (4) increased central dopamine turnover, and (5) accumulation of toxic levels of the drug. Pre-existing psychopathology, relevant comorbidities, slow acetylation status, and increased permeability of the blood–brain barrier have been suggested to make patients more prone to developing psychosis. According to the literature, this psychiatric manifestation resolves within 2 weeks of discontinuing the offending agent. There appears to be underreporting of the psychiatric manifestations of imipenem-cilastatin, contrary to post-marketing surveillance data. It is imperative that physicians recognize these psychiatric side effects of antibiotics, because they are a fundamental treatment option.\n\nKeywords\nPsychosisAdverse drug reactionImipenem-cilastatinAntibioticsissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nAcute brain dysfunction has been proven to cause negative clinical outcomes, including increased mortality, length of hospital stay, and cost of care. Sedatives, opioid medications, dihydropyridines, and antihistamines are common classes of medications known to cause delirium [1]. It has been reported that 12–39 % of cases of delirium are caused by medication alone [2–4]. Antibiotics have also been associated with the development of delirium. There is a very thin line separating delirium from psychosis. Elderly patients, in particular, have been reported to develop psychiatric side effects from antibiotics. The antibiotics well known to cause psychosis are penicillins, cephalosporins, trimethoprim-sulfamethoxazole, fluoroquinolones, and antitubercular medications. This case report bridges a void in medical literature with regards to the psychiatric adverse effects of imipenem-cilastatin.\n\nCase presentation\nA 64-year-old Hispanic man with traumatic paraplegia presented with a urinary tract infection (UTI). He had a neurogenic bladder and a history of recurrent UTIs but no prior history of psychiatric diseases. On examination, he was noted to have a temperature of 100.7 °F (38.17 °C), blood pressure of 93/56 mm Hg, a pulse of 147 beats per minute, and a respiratory rate of 28 breaths per minute. He had labored breathing, suprapubic tenderness, and frank pus in his urine when a urinary catheter was placed. He was emergently intubated and mechanically ventilated because his cardiorespiratory status deteriorated. At the time of admission, our patient’s white blood cell (WBC) count was 16,500/μL (neutrophils 75 %, lymphocyte 12.5 %, and bands 8.4 %). His biochemical parameters were within physiological limits except for his serum creatinine at 2.4 mg/dL (estimated glomerular filtration rate [eGFR], 25 mL/min/1.73 m2) and blood urea nitrogen (BUN) at 52 mg/dL. Two sets of blood culture and a urine culture grew Klebsiella pneumoniae (a final report including the culture antibiotic sensitivity was reported on day 4 of his hospitalization). A renally adjusted dose of imipenem-cilastatin was initiated because of his prior history of extended-spectrum beta-lactamase (ESBL) Klebsiella UTIs. Sedatives were discontinued, and our patient was successfully extubated after he demonstrated clinical improvement. Our patient was oriented to place, person, time, and situation after extubation; an assessment using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) did not demonstrate any delirium. His family noted that he looked better and was conversing normally. The dose of imipenem-cilastatin was readjusted (increased) on his third day of hospitalization owing to the recovery of his renal function. On the fourth day of hospitalization, he was restless and agitated by paranoid thoughts (Fig. 1). He reported seeing and hearing people from his church planning to burn him at the stake.Fig. 1 Timeline of development and resolution of symptoms with relevant events during the patient’s course of admission and readmission\n\n\n\nThe differential diagnoses entertained at this time were ICU delirium, encephalitis, endocrine dysfunction, structural neurological lesions (possibly stroke), or toxic ingestion. Our patient was oriented to place, person, and time with no new neurological deficits except for the visual and auditory hallucinations. Despite having an acute change in his baseline mental status (Richmond Agitation Sedation Score [RASS] 0 to 1+), he did not demonstrate any inattention (as demonstrated by picking ‘2’s) and, therefore, CAM-ICU was not diagnostic for ICU delirium. When our patient’s laboratory tests were repeated at the time of the psychotic symptoms, his WBC count was 9400/μL (neutrophils 74.2 %, lymphocyte 14.2 %). His biochemistry panel revealed serum creatinine of 0.9 mg/dL (eGFR, 65 mL/min/1.73 m2), BUN of 15 mg/dL, serum sodium of 138 mEq/L, serum potassium of 4.1 mEq/L, serum chloride of 102 mEq/L, and serum bicarbonate of 22 mEq/L. His 8 a.m. cortisol level was 18 μg/dL and his thyroid function was within physiological limits (TSH 1.04 mIU/L, free T4 7.4 μg/dL, and free T3 83 ng/dL). Repeat urine and blood cultures performed while he was experiencing psychotic symptoms were later reported to have tested negative for any infection. Further neurological imaging or invasive neurological procedures were not performed because he did not have any new focal neurological deficits.\n\nBrief psychotic episode was diagnosed as per the fifth edition Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, and delirium was excluded because inattention could not be demonstrated. All reversible causes of psychosis were sought. The only change in the management of our patient was a change in the dose of imipenem-cilastatin; this was considered to be a possible etiology for psychosis. Objective evidence of a causal relationship between the drug and psychosis was assessed using the Naranjo Probability Scale. Our patient’s Naranjo adverse drug reaction (ADR) probability scale score was calculated to be +7; imipenem-cilastatin was the probable culprit [5]. Imipenem-cilastatin was discontinued, and he was switched to ceftriaxone according to susceptibilities from the blood and urine culture. His mood and behavior improved; all visual and auditory hallucinations resolved by his sixth day of hospitalization. He experienced similar psychiatric symptoms 2 months later when imipenem-cilastatin was initiated empirically for complicated UTI. On this readmission, the Naranjo ADR probability scale score was +9, definite, when he was rechallenged with imipenem-cilastatin. His hallucinations resolved within 48 hours of discontinuing imipenem-cilastatin, as in the first instance. Unfortunately, on both occasions, the levels of imipenem or cilastatin were not estimated owing to laboratory and logistic issues.\n\nDiscussion\nPrior to the third edition of the DSM, many terms existed to describe generalized brain dysfunction—acute confusional state, encephalopathy, acute brain failure, and ICU psychosis—causing terminological chaos. The American Psychiatric Association, since its third edition of the DSM, has worked diligently to update the definition to help clinicians identify delirium in patients of all ages. DSM-5 does not use the term “consciousness” but instead restrictively defines delirium in terms of attention, arousal, and cognition for the purpose of testability. Alterations in attention and awareness are core to the diagnosis of delirium. For example, despite an alteration in his level of consciousness (as evidenced by a change in RASS score), our patient did not demonstrate inattention, thereby excluding delirium. Brief psychotic disorder, as defined by DSM-5, is an episode of disturbance lasting at least a day but less than a month, characterized by one or more of the following: delusion, hallucination, disorganized speech, and grossly disorganized behavior. These symptoms should occur in the absence of a mood disorder or psychosis due to substance use/withdrawal or general medical condition. Our patient satisfied all the above criteria, with his symptoms occurring after his recovery from sepsis due to a UTI, when all his biochemical and microbiological tests were within normal limits.\n\nPsychotic symptoms in patients being treated with antibiotics with non-central nervous system (CNS) infections have been reported in the past. The first documented case of neuropsychiatric symptoms following administration of antibiotics was noted with the intramuscular administration of penicillin in 1959 [6]. This disorder was characterized by severe psychomotor agitation with confusion, sensations of depersonalization and derealization, visual and auditory hallucinations, panic-like anxiety, and seizures. The term Hoigne’s syndrome was coined for an acute nonallergic reaction with the above-mentioned acute psychiatric symptoms to procaine penicillin.\n\nThe exact incidence of antibiotic-associated psychosis is not well known because of underreporting and an unknown volume of distribution of the medications. The majority of the associations between psychosis and antibiotic treatment in the medical literature are case reports. The common antibiotics associated with the development of psychosis are penicillins, cephalosporins, trimethoprim-sulfamethoxazole, fluoroquinolones, macrolides, and antituberculosis medications (Table 1).Table 1 Common antibiotics causing psychosis\n\nClass of Antibiotic\tName of Antibiotic\t\nPenicillins\tAmoxicillin\t\n\tAugmentin\t\nCephalosporin\tCefalexin\t\nAminoglycosides\tGentamicin\t\nTetracycline\tMinocycline\t\nFluoroquinolones\tCiprofloxacin\t\n\tOfloxacin\t\n\tNorfloxacin\t\n\tTemofloxacin\t\n\tGatifloxacin\t\nSulfonamides\t Trimethoprim-sulfamethoxazole \t\nMetronidazole\t\t\nMacrolide\tClarithromycin\t\n\tErythromycin\t\nAntituberculosis medication\t Isoniazid \t\nAntivirals\tAcyclovir\t\n\tDidanosine\t\n\tZalcitabine\t\n\tIndinavir\t\nAntifungal medication\t Fluconazole \t\n\n\nInfections are well known to be associated with acute psychosis. UTIs, in particular, have been noted to cause acute psychosis in geriatric patients. Manepalli et al. noted that 20 % of their geriatric patients with acute psychiatric illness had concomitant UTIs [7]. In a systematic review by Mostafa and Miller, a causal relationship was demonstrated between antibiotic treatment and psychosis in 60 % of the reported cases [8]. The common culprits associated with acute psychosis during the treatment of UTI were penicillin, trimethoprim-sulfamethoxazole, and fluoroquinolones. Eight of the 15 patients in the systematic review had a prior history of psychiatric disorders. In a paper published by the World Health Organization (WHO), seven of 82 patients reported to have manic episodes with antibiotics use were concurrently on mood-stabilizing agents [7]. In the systematic review, 80 % of the patients developed psychiatric symptoms within 1 week of initiation of the antibiotics [8]. The mean duration of psychotic symptoms was 5.1 days, and seven of the 15 patients required treatment with antipsychotics. Three of the 15 patients had a recurrence of symptoms when challenged with the same antibiotics.\n\nThe US Food and Drug Administration (FDA)-approved package insert for imipenem-cilastatin warns against CNS adverse effects such as seizures, confusional states, and myoclonic activity. The European Medicines Agency-approved package insert reports the frequency of hallucinations due to imipenem-cilastatin to be between 0.1 % and 1 %. The WHO Collaborating Center for International Drug monitoring, Uppsala Monitoring Centre, has 412 reports demonstrating a causal relationship between psychiatric disorders and imipenem-cilastatin sodium. The most common psychiatric disorder associated with imipenem-cilastatin was delirium (including confusion) with 208 reports, followed by disturbance in thinking and perception (including visual, auditory, or mixed hallucinations) with 105 reports [9]. However, a PubMed search {(“imipenem”[MeSH Terms] OR “imipenem”[All Fields]) AND ((((“mental disorders”[MeSH Terms] OR (“mental”[All Fields] AND “disorders”[All Fields]) OR “mental disorders”[All Fields] OR (“psychiatric”[All Fields] AND “disorder”[All Fields]) OR “psychiatric disorder”[All Fields]) OR (“hallucinations”[MeSH Terms] OR “hallucinations”[All Fields] OR “hallucination”[All Fields])) OR (“psychotic disorders”[MeSH Terms] OR (“psychotic”[All Fields] AND “disorders”[All Fields]) OR “psychotic disorders”[All Fields] OR “psychosis”[All Fields])) OR (“delirium”[MeSH Terms] OR “delirium”[All Fields]))} for articles related to imipenem-cilastatin causing psychiatric disorders failed to yield any results. This demonstrates an underreporting of the psychiatric adverse effects of imipenem-cilastatin in medical literature, contrary to post-marketing surveillance data. The early identification of these remediable psychiatric adverse effects could shorten the length of hospitalization, prevent avoidable mortality, and prevent eventual dementia.\n\nThere are various pharmacokinetic properties of the antibiotics proposed as hypotheses for these psychiatric adverse effects. GABA-A receptors are competitively inhibited by fluoroquinolones, causing an up-regulation of glutamatergic up-regulation; the resulting deficit in prefrontal-mediated executive function might induce psychosis [10]. Antibiotics cause the destruction of intestinal bacterial flora that produces D–alanine, which is essential for the normal functioning of the N-methyl-D-aspartate (NMDA) receptor [11]. Hypofunctioning NMDA receptors could cause psychosis, again by the loss of prefrontal control. The sequential blockade of folic acid production in the CNS has been postulated to cause the development of psychiatric symptoms in patients on sulfamethoxazole-trimethoprim. Psychosis associated with indomethacin has been attributed to the inhibition of prostaglandin E2 and proinflammatory cytokines. It has been postulated that macrolide antibiotics may also have similar anti-inflammatory properties, increasing central dopamine turnover, leading to psychosis [12].\n\nConclusions\nThere is a very thin line between medication-induced delirium and medication-induced acute brief psychosis, but these conditions are reversible. Case reports record the resolution of psychiatric symptoms within 2 weeks of stopping the offending medication. Some patients may require neuroleptic medications. The treatment of this condition begins with identifying the culprit medication and suspension of the same. It is imperative that physicians recognize the psychiatric side effects of antibiotics because they are a fundamental treatment option.\n\nConsent\nWritten 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-in-Chief of this journal.\n\nAbbreviations\nADRAdverse drug reaction\n\nBUNBlood urea nitrogen\n\nCAM- ICUConfusion Assessment Method for Intensive Care Unit\n\nDSM-5Diagnostic and Statistical Manual of Mental Disorders, 5th Edition\n\neGFREstimated glomerular filtration rate\n\nESBLExtended spectrum beta-lactamase\n\nNMDAN-methyl-D-aspartate\n\nRASSRichmond Agitation Sedation Score\n\nUTIUrinary tract infection\n\nWBCWhite blood cell\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nJN drafted the initial manuscript. JN and GMG completed a review of the literature and revised it critically for important intellectual content. A collective final decision was made to submit the twelfth version for publishing after our thorough critical appraisal. We will be accountable for all aspects of the work. Both authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Rudberg MA Pompei P Foreman MD Ross RE Cassel CK The natural history of delirium in older hospitalized patients: a syndrome of heterogeneity Age Ageing. 1997 26 169 74 10.1093/ageing/26.3.169 9223710 \n2. Inouye SK The dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients Am J Med. 1994 97 278 88 10.1016/0002-9343(94)90011-6 8092177 \n3. Moore AR O’Keeffe ST Drug-induced cognitive impairment in the elderly Drugs Aging. 1999 15 15 28 10.2165/00002512-199915010-00002 10459729 \n4. Clegg A Young JB Which medications to avoid in people at risk of delirium: a systematic review Age Ageing. 2011 40 23 9 10.1093/ageing/afq140 21068014 \n5. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther. 1981 30 239 45 10.1038/clpt.1981.154 7249508 \n6. Hoigne R Schoch K [Anaphylactic shock and acute nonallergic reactions following procaine-penicillin] Schweiz Med Wochenschr 1959 89 1350 6 14402529 \n7. Manepalli J Grossberg GT Mueller C Prevalence of delirium and urinary tract infection in a psychogeriatric unit J Geriatr Psychiatry Neurol. 1990 3 198 202 10.1177/089198879000300404 2073307 \n8. Mostafa S Miller BJ Antibiotic-associated psychosis during treatment of urinary tract infections: a systematic review J Clin Psychopharmacol. 2014 34 483 90 10.1097/JCP.0000000000000150 24911441 \n9. WHO Collaborating Centre for International Drug Monitoring - Uppsala Monitoring Centre. VigiAccess. 1978. http://vigiaccess.org. Accessed on 5 February 2016.\n10. Koul S Bhan-Kotwal S Jenkins HS Carmaciu CD Organic psychosis induced by ofloxacin and metronidazole Br J Hosp Med (Lond). 2009 70 236 7 10.12968/hmed.2009.70.4.41632 19357607 \n11. Mehdi S Antibiotic-induced psychosis: a link to D-alanine? Med Hypotheses. 2010 75 676 7 10.1016/j.mehy.2010.07.021 20691544 \n12. Tamaoki J Kadota J Takizawa H Clinical implications of the immunomodulatory effects of macrolides Am J Med 2004 117 Suppl 9A 5S 11 15586558\n\n",
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"abstract": "We report a case of localized pustular eruption on the face in a patient with Hodgkin lymphoma treated with granulocyte colony-stimulating factor for the development of chemotherapy-induced neutropenia. The administration of granulocyte colony-stimulating factor and the level of neutrophils were closely associated with disease activity, and negative cultures ruled out the hypothesis of an infective etiology. Because of the role of colony-stimulating factor in mobilization of the neutrophils we considered this phenomenon a skin reaction caused by granulocyte colony-stimulating factor-driven neutrophil accumulation.",
"affiliations": "Unit of Dermatology, University of Padua, Padua, Italy.;Unit of Dermatology, University of Padua, Padua, Italy.;Unit of Hematology, University of Padua, Padua, Italy.;Unit of Dermatology, University of Padua, Padua, Italy - mauro.alaibac@unipd.it.",
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"journal": "Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia",
"keywords": null,
"medline_ta": "G Ital Dermatol Venereol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D003875:Drug Eruptions; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006689:Hodgkin Disease; D006801:Humans; D009503:Neutropenia",
"nlm_unique_id": "8102852",
"other_id": null,
"pages": "276-277",
"pmc": null,
"pmid": "27845511",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pustular eruption associated with granulocyte colony-stimulating factor treatment.",
"title_normalized": "pustular eruption associated with granulocyte colony stimulating factor treatment"
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"abstract": "BACKGROUND\nCerebral salt wasting syndrome (CSWS), characterized by natriuresis, polyuria, and hypovolemia, is a rare complication of central nervous system injury or disease.\n12-year-old girl was admitted with second attack of nephrotic syndrome (NS). On admission she presents with edema, blood pressure 110/60 mm Hg, proteinuria 145 mg/kg/24h, hypoalbuminemia (1.7 g/dL), GFR 94.4 mL/min/1.73m2, sodium 133 mmol/L. On 5th day the patient developed thrombosis of right subclavian and axillary vein and was treated with recombinant tissue plasminogen activator (0.3 mg/kg/h i.v.). 45 minutes after onset of the infusion severe headache appeared. Computed tomography revealed subarachnoid hemorrhage in a region of left occipital lobe and posterior 1/3 part of sickle of the brain. Control ultrasonography examination revealed resolution of the thrombus. No deficits were found on neurologic examination. Proteinuria subsided on 11th day of hospitalization. After the hemorrhage hypovolemia, hypotension (80/40 - 100/60 mm Hg, heart rate 100/min), polyuria, and pathologic natriuresis (up to 13.0 mmol/kg/24h) were observed. Cerebral salt wasting syndrome was recognized. The girl was supplemented with oral and intravenous sodium (up to 10 mmol/ kg/24h). In following days gradual decrease of diuresis and urinary sodium loss was observed. The patient was discharged home after 41 days with normal diuresis (1.5l/24h) and natriuresis (1.44 mmol/kg/24h).\n\n\nCONCLUSIONS\nTreatment of thromboembolic complications in children with NS poses a risk of central nervous system bleeding. Serum sodium concentration and diuresis must be strictly monitored in patients with central nervous system lesion, especially in the course of nephrotic syndrome.",
"affiliations": "Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland.;Student Scientific Group at the Department of Pediatrics and Nephrology. Medical University of Warsaw, Poland.;Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland.;Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland.;Department of Clinical and Experimental Neuropathology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.;Department of Pediatric Radiology, Medical University of Warsaw, Poland.;Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland.",
"authors": "Skrzypczyk|Piotr|P|;Tachasiuk|Klaudia|K|;Szymanik-Grzelak|Hanna|H|;Mizerska-Wasiak|Małgorzata|M|;Szymańska|Krystyna|K|;Brzewski|Michał|M|;Pańczyk-Tomaszewska|Małgorzata|M|",
"chemical_list": "D010959:Tissue Plasminogen Activator",
"country": "Poland",
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"issn_linking": "1426-9686",
"issue": "47(278)",
"journal": "Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego",
"keywords": "cerebral salt wasting syndrome; nephrotic syndrome; subarachnoid hemorrhage; thrombotic complications",
"medline_ta": "Pol Merkur Lekarski",
"mesh_terms": "D002648:Child; D005260:Female; D006801:Humans; D007010:Hyponatremia; D009318:Natriuresis; D009404:Nephrotic Syndrome; D013345:Subarachnoid Hemorrhage; D013577:Syndrome; D010959:Tissue Plasminogen Activator; D014882:Water-Electrolyte Balance",
"nlm_unique_id": "9705469",
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"pages": "72-75",
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"pmid": "31473757",
"pubdate": "2019-08-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebral salt wasting syndrome as a complication of subarachnoid hemorrhage in a girl with nephrotic syndrome - a case report.",
"title_normalized": "cerebral salt wasting syndrome as a complication of subarachnoid hemorrhage in a girl with nephrotic syndrome a case report"
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"abstract": "Lower extremity tendon injuries often occur in physically active individuals. Most ruptures not involving great force are diagnosed in patients presenting underlying tendon degenerations. This also applies to patients taking medications because of a disease. We have observed several cases of bilateral Achilles tendon ruptures in patients who have been taking cortisone for a long period. We treated a healthy colleague (neurologist) in our clinic who sustained ruptures of the Achilles tendon on the left side (2012) and the peroneus brevis tendon on left side (2015) and right side (2016) after minimal traumata. Aim of this report is to provide a systematic review of this case and a literature review of similar cases, as few such cases have been published.\nWe reviewed and analysed this patient's records containing the sport-specific anamnesis, pre-existing condition, anamnesis of medications and therapy. The three injuries were magnetic resonance imaging-proven. Furthermore, the tendon's condition was examined histologically in the context of the operative treatment through lace technique of the Achilles tendon and transfer of the peroneus brevis to the peroneus longus. We also researched the literature for bilateral ruptures of the peroneal tendons.\nThe anamnesis confirmed no underlying disease. The patient took a macrolide antibiotic about half a year prior to the first peroneal injury for an otitis media. He denied having taken any other antibiotics, especially no quinolone antibiotics. However, the patient reported cortisone intake for 2 days some months before the second peroneal injury to treat an allergic reaction. That involved no local cortisone infiltration in the lower extremity. He underwent surgery within the first 2 weeks after each trauma. Each time, postoperative follow-ups revealed a good healing process. Three months after each operation, the patient was free of complaints. Axibal and Anderson described a patient with bilateral peroneus longus and peroneus brevis ruptures, as well as an Achilles tendon rupture on the left side plus tendinopathy of the Achilles tendon on the right side of uncertain aetiology. We detected additional similar cases in patients who had taken medications, especially cortisone and levofloxacine. Further research should be conducted to clarify other risk factors to help prevent such injuries.",
"affiliations": "Altius Swiss Sportmed Center AG, Rheinfelden, Switzerland.;Altius Swiss Sportmed Center AG, Rheinfelden, Switzerland.;Altius Swiss Sportmed Center AG, Rheinfelden, Switzerland.",
"authors": "Scheidegger|Patric|P|;Weisskopf|Lukas|L|;Hirschmüller|Anja|A|",
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"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1774522510.1177_2050313X17745225Case ReportAtraumatic bilateral rupture of the peroneus brevis tendon in recreational sport: A case report Scheidegger Patric 1Weisskopf Lukas 1Hirschmüller Anja 121 Altius Swiss Sportmed Center AG, Rheinfelden, Switzerland2 Department of Orthopedics and Trauma Surgery, Medical Center – University of Freiburg, Freiburg, GermanyPatric Scheidegger, Altius Swiss Sportmed Center AG, Habich Dietschy-Strasse 5A, 4310 Rheinfelden, Switzerland. Email: patric.scheidegger@gmx.ch11 12 2017 2017 5 2050313X1774522510 7 2017 6 11 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page(https://us.sagepub.com/en-us/nam/open-access-at-sage).Issue:\nLower extremity tendon injuries often occur in physically active individuals. Most ruptures not involving great force are diagnosed in patients presenting underlying tendon degenerations. This also applies to patients taking medications because of a disease. We have observed several cases of bilateral Achilles tendon ruptures in patients who have been taking cortisone for a long period. We treated a healthy colleague (neurologist) in our clinic who sustained ruptures of the Achilles tendon on the left side (2012) and the peroneus brevis tendon on left side (2015) and right side (2016) after minimal traumata. Aim of this report is to provide a systematic review of this case and a literature review of similar cases, as few such cases have been published.\n\nMethods:\nWe reviewed and analysed this patient’s records containing the sport-specific anamnesis, pre-existing condition, anamnesis of medications and therapy. The three injuries were magnetic resonance imaging–proven. Furthermore, the tendon’s condition was examined histologically in the context of the operative treatment through lace technique of the Achilles tendon and transfer of the peroneus brevis to the peroneus longus. We also researched the literature for bilateral ruptures of the peroneal tendons.\n\nResults and conclusion:\nThe anamnesis confirmed no underlying disease. The patient took a macrolide antibiotic about half a year prior to the first peroneal injury for an otitis media. He denied having taken any other antibiotics, especially no quinolone antibiotics. However, the patient reported cortisone intake for 2 days some months before the second peroneal injury to treat an allergic reaction. That involved no local cortisone infiltration in the lower extremity. He underwent surgery within the first 2 weeks after each trauma. Each time, postoperative follow-ups revealed a good healing process. Three months after each operation, the patient was free of complaints. Axibal and Anderson described a patient with bilateral peroneus longus and peroneus brevis ruptures, as well as an Achilles tendon rupture on the left side plus tendinopathy of the Achilles tendon on the right side of uncertain aetiology. We detected additional similar cases in patients who had taken medications, especially cortisone and levofloxacine. Further research should be conducted to clarify other risk factors to help prevent such injuries.\n\nAchilles tendon rupturebilateral peroneus brevis rupturecover-dateJanuary-December 2017\n==== Body\nIntroduction\nMost ruptures not involving great force are diagnosed in patients presenting underlying tendon degeneration. This is often related to an underlying disease1 or the intake of medications.2,3 We thus describe several cases of bilateral Achilles tendon ruptures and concurrent ingestion of cortisone and/or antibiotics.4–7\n\nAnatomical anomalies are also possible risk factors for tendon injuries, that is, an os peroneum for a lesion of the peroneus longus tendon8 or a Haglund exostosis for Achilles tendinopathy.9 Furthermore, a sharp ridge on the dorsal distal fibula, luxated peroneal tendons10 and most notably ankle instability are potential risk factors for a rupture of the peroneus brevis tendon.11\n\nLower extremity tendon injuries occur very frequently in physically active people, and their incidence is rising.12 These injuries often involve the Achilles tendon, in some cases even bilaterally.13,14 This fact reveals missing knowledge about further risk factors. With this in mind, we treated a patient who suffered a threefold tendon injury caused by minimal traumata while presenting almost none of the known risk factors.\n\nPatient information\nWe report about a physician (a neurologist) born in 1963 from Switzerland. In November 2012, he presented the first time in our sportorthopaedic clinic after having carried out a magnetic resonance imaging (MRI) that revealed a total Achilles tendon rupture on the left side after stumbling over the ball during a tennis match.\n\nThe next consultation took place in June 2015 because of an ankle sprain again on the left side while playing golf. The patient heard an initial ‘knick’ and felt pain around the peroneal tendons. Note that he had already injured the left ankle ligaments in the past.\n\nIn October 2016, we consulted with the patient again after he slipped during a walk whereby he had to come to a stop suddenly and forcefully with his right foot. Again, he heard a ‘knick’ and felt pain on the lateral side of the affected ankle.\n\nApart from these foot problems, the patient is healthy. Because of an otitis media, he had taken a macrolide antibiotic during the spring 2015. He does not remember having taken any chinolone antibiotics. Additionally, in the summer of 2016, he took 20 mg of prednisolone twice a day and 10 mg the following day because of a probably allergic reaction involving oedematous swelling of the lips during and after a meal (Table 1).\n\nTable 1. Comparison of the known risk factors with the patient’s records.\n\nRisk factors\tAchilles tendon left\tPeroneus brevis left\tPeroneus brevis right\t\nSpecial anatomy\tNo\tNo luxation of peroneal tendons, no sharp ridge\tNo luxation of peroneal tendons, no sharp ridge\t\nAnkle instability\tNo\tYes, status post ankle sprains\tNo\t\nCortisone intake\tNo\tNo\tSystemic, 3 months pretraumatic\t\nAntibiotics intake\tNo\tMacrolide ½ year pretraumatic\tNo\t\nUnderlying disease\tNo\tNo\tNo\t\nClinical findings\nIn November 2012, we examined this patient presenting considerable swelling around the left ankle, a positive Thompson test15 as well as a dent in the left Achilles tendon. Active plantar flexion was attenuated.\n\nIn June 2015, he presented a haematoma and slight swelling of the distal lateral lower leg, insufficient peroneal tendons and pain during activation. Moreover, we noted a slight increase in the AP-translation of the talus.\n\nHis next examination was in October 2016. Arriving at our clinic, the patient was already wearing compression stockings and an ankle orthesis. Therefore, there was neither swelling nor a haematoma present. Nevertheless, he reported retromalleolar pressure pain, a palpable stump of a tendon and a considerable reduction in pronation force.\n\nTimeline\n08 November 2012 Left foot, total Achilles tendon rupture after stumbling;\n\n13 November 2012 Left foot, open reconstruction of the Achilles tendon in lace technique with reinforcement via plantaris tendon and soleus reconstruction;\n\n09 June 2015 Left foot, peroneus brevis rupture after ankle sprain;\n\n23 June 2015 Left foot, open reconstruction of the peroneus brevis through transfer on longus;\n\n30 October 2016 Right foot, peroneus brevis rupture after sidestep;\n\n08 November 2016 Right foot, open reconstruction of the peroneus brevis through transfer on longus.\n\nDiagnostics\nMRI of left Achilles tendon (November 2012)\nTotal Achilles tendon rupture is about 9 cm proximal to the calcanean insertion with a dehiscence of 22 mm; the plantaris tendon is intact (Figures 1–3).\n\nFigure 1. Total Achilles tendon rupture about 9 cm proximal to the calcanean insertion (MRI sagittal view).\n\nFigure 2. Achilles tendon rupture with dehiscence of 22 mm (MRI sagittal view).\n\nFigure 3. Para-Achilles liquid and intact plantaris tendon on the medial side (MRI axial view).\n\nSecondary findings are obvious effusion in the upper and lower ankle joints and liquid around the peroneal tendons with the peroneus brevis tendon revealing distal hypointensity. No subchondral cysts, and no further ligament lesions (Figures 4–6).\n\nFigure 4. Obvious effusion in the upper and lower ankle joints without subchondral cysts (MRI sagittal view).\n\nFigure 5. Liquid around the peroneal tendons (MRI oblique axial view).\n\nFigure 6. Distal hypointensity of the peroneus brevis tendon (MRI axial view).\n\nMRI of lower left leg and ankle (June 2015)\nExtensive partial rupture of the peroneus brevis tendon from the musculotendinous transition to the insertion. The most severely affected part is dorsal of the lateral malleolus with 90% of the tendon ruptured. Furthermore, fibre-tears in the mm. peroneus longus and brevis with haematomas along the fascias is visible (Figures 7 and 8).\n\nFigure 7. Rupture of the peroneus brevis tendon proximal to the lateral malleolus with haematomas along the fascia. Status post Achilles tendon suture without peritendinous changes (MRI axial view).\n\nFigure 8. Rupture of the peroneus brevis tendon distal to the lateral malleolus, subchondral cysts of the anteromedial upper ankle joint with bone bruise of the medial malleolus (MRI coronal view).\n\nSecondary findings are mid-portion tendinopathy of the Achilles tendon with a spindle-like distension and slight, longitudinal signal disorder (<10% of the tendon) status post Achilles tendon suture in 2012. No peritendinous changes. Furthermore, note the small cartilage defects anteromedial of the upper ankle joint (tibiotalar) with subchondral cysts. No lesions in the ligaments; even the ligamentum fibulotalare anterius is intact (Figures 9 and 10).\n\nFigure 9. Spindle-like distension and slight, longitudinal signal disorder of the Achilles tendon (MRI sagittal view).\n\nFigure 10. Cartilage defects and subchondral cysts anteromedial of the tibiotalar joint (MRI sagittal view).\n\nLaboratory findings from 22 June 2015\nLeucocytes, 4.0 G/L; haemoglobin, 158 g/L; haematocrit, 47.4%; thrombocytes, 195 G/L; international normalized ratio (INR), 1.0; C-reactive protein (CRP) < 5 mg/L; creatinine, 86 µmol/L; glucose, 6.0 mmol/L; urea, 6.02 mmol/L; potassium, 4.7 mmol/L; sodium, 142 mol/L; creatine kinase, 187 U/L; aspartate aminotransferase (ASAT), 22 U/L; and alanine aminotransferase (ALAT), 24 U/L.\n\nSonography of left peroneal tendons (July 2015)\nSuture material is intact. No signs of new rupture visible.\n\nSonography of right peroneal tendons (October 2016)\nSubtotal rupture of the peroneus brevis tendon with wavy image of the proximal stump of the tendon and a haematoma.\n\nMRI of lower right leg and ankle (October 2016)\nA subtotal rupture of the peroneus brevis tendon 4 cm proximal of the lateral malleolus to about 4 cm proximal of the insertion with a retracted proximal stump and haematoma around the musculotendinous transition. The syndesmosis is intact. No ligament lesions and no subchondral cysts (Figures 11–15).\n\nFigure 11. Rupture of the peroneus brevis tendon (MRI oblique axial view).\n\nFigure 12. Rupture of the peroneus brevis tendon (MRI oblique axial view).\n\nFigure 13. Rupture of the peroneus brevis tendon (MRI axial view).\n\nFigure 14. Retracted proximal stump of the peroneus brevis tendon (MRI oblique axial view).\n\nFigure 15. Distal stump of the peroneus brevis tendon (MRI sagittal view).\n\nTherapeutic interventions\nAll operations were done within 2 weeks after each trauma. We administered non-steroidal anti-inflammatory drug (NSAID), paracetamol and metamizole according to the World Health Organization (WHO) pain ladder.16 No invasive methods such as infiltration were administered (except thromboprophylaxis with 40 mg of subcutaneous enoxaparine).\n\nHis first surgery was open reconstruction of the left Achilles tendon via lace technique and reinforcement by the plantaris tendon, and a soleus reconstruction, all performed on 13 November 2012. Medial para-Achilles incisions were used. After the plantaris tendon was exposed and detached proximally, the distal insertion was maintained. The Achilles tendon was reconstructed with lace technique in a maximum plantar flexion. We also fixated the soleus. We made a quadruple frame-suture of the plantaris tendon entailing spreading of the remaining fibres to reconstruct a sliding layer. Finally, the Achilles tendon reveals a good preload.\n\nThe second operation was an open reconstruction of the left peroneus brevis through transfer on the peroneus longus on 23 June 2015. Liquid drained while opening the tendon sheath; we noted a total rupture of the peroneus brevis tendon with distracted stumps, which prevented us from doing an immediate reconstruction. Since the peroneus longus was intact, we decided on a tendon transfer. The patient exhibited a good preload here as well (Figures 16–18).\n\nFigure 16. Total rupture of the left peroneus brevis tendon with retracted stumps.\n\nFigure 17. Attached suture of the stumps. The peroneus longus tendon is retained.\n\nFigure 18. Open reconstruction of the left peroneus brevis tendon through transfer on the peroneus longus.\n\nThe third intervention was an open reconstruction of the right peroneus brevis through a transfer on the peroneus longus on 8 November 2016. We detected intraoperatively a small lesion on the peroneus longus retromalleolar which had to be resected. Finally, we observed that the tendons were very stable (Figures 19–21).\n\nFigure 19. Total rupture of the right peroneus brevis tendon with retracted stumps. The peroneus longus tendon is retained.\n\nFigure 20. Open reconstruction of the right peroneus brevis through transfer on the peroneus longus.\n\nFigure 21. Closed fascia and retinaculum.\n\nFollow-up and outcome\nAfter the Achilles tendon suture, the patient was immobilised in plantar flexion with a ventral splint for overnight and an Achilles tendon boot with 3 wedges for 6 weeks during daytime. After those 6 weeks, use of the wedges was slowly decreased. The patient underwent regular physiotherapy and was given crutches to use for 2 weeks to assure good wound healing.\n\nPostoperative medications consisted of enoxaparine (Clexane®) 40 mg/0.4 mL once daily administered subcutaneously, acemetacine (Tilur® ret.) 90 mg twice daily, pantoprazole (Pantozol®) 40 mg once daily, bromelain (Traumanase® forte) thrice daily and paracetamol (Dafalgan®) 1 g on demand maximum four times a day.\n\nAfter the left peroneus tendon transfer, we proposed partial weight-bearing of 15 kg in the VACOped17 with a subsequent increase in the load in a Künzli shoe.18 However, as this was not tolerated, the patient used the Airwalker19 with half of his body weight.\n\nHis clinical presentation revealed almost no irritation, little swelling and hardly any pain. Five weeks after surgery, the swelling increased after resumption of work. Nevertheless, the tendon continued to work well. Consequently, and thanks to the physiotherapy he received, the load was increased. Three months following surgery, the patient was free of complaints and exhibited good force development without swelling.\n\nAfter the right peroneus tendon transfer, the same follow-up treatment with the VACOped17 was conducted until wound healing was assured. The load was then increased in a Künzli shoe18.\n\nDiscussion\nResults and conclusion\nThe patient’s history revealed no underlying disease. He took a macrolide antibiotic once a half a year prior to the first peroneal injury because of an otitis media. He denied having taken any other antibiotics. Furthermore, the patient reported cortisone intake for 2 days a few months before the second peroneal injury because of an allergic reaction. He experienced no local infiltration of cortisone in the lower extremity.\n\nThe operative treatment took place within the first 2 weeks after the trauma. Each postoperative follow-up revealed a good healing process. Three months after each surgery, the patient was free of complaints.\n\nAxibal and Anderson20 described a patient with bilateral peroneus longus and peroneus brevis ruptures, as well as an Achilles tendon rupture on the left side plus a tendinopathy of the Achilles tendon on the right side of uncertain aetiology. We identified more similar cases of patients who had taken medications, especially cortisone and levofloxacine.2,3\n\nTendon injuries potentially triggered by the intake of macrolide antibiotics have not yet been reported in the literature. This patient’s 2-day cortisone intake prior to the right peroneal tendon’s rupture certainly did not favour tendon metabolism. A correlation with the systemic cortisone therapy cannot be entirely ruled out due to cortisone’s known and lengthy latency (>6 months).21\n\nTo prevent such injuries, further research should be conducted to determine other risk factors.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The article processing charge was funded by the German Research Foundation (DFG) and the University of Freiburg in the funding programme Open Access Publishing.\n\nInformed consent: Written informed consent was obtained from the patient for his anonymised information to be published in this article.\n==== Refs\nReferences\n1 \nVan Linthoudt D Gabay C Ott H \nMultiple tendon ruptures in a case of calcium pyrophosphate crystal deposit disease (chondrocalcinosis) . Schweiz Med Wochenschr \n1989 ; 119 (34 ): 1164 –1165 .2814411 \n2 \nKnobloch K \nDrug-induced tendon disorders . Adv Exp Med Biol \n2016 ; 920 : 229 –238 .27535265 \n3 \nBraun D Petitpain N Cosserat F et al \nRupture of multiple tendons after levofloxacin therapy . Joint Bone Spine \n2004 ; 71 (6 ): 586 –587 .15589446 \n4 \nRao SK Navadgi BC Vasdev A \nBilateral spontaneous rupture of Achilles tendons: a case report . J Orthop Surg \n2005 ; 13 (2 ): 178 –180 .\n5 \nWeinstabl R Hertz H \nSimultaneous bilateral Achilles tendon rupture following minor trauma on steroid treatment: a case report . Unfallchirurgie \n1990 ; 16 (1 ): 50 –54 .2180165 \n6 \nKhanzada Z \nBilateral spontaneous non-traumatic rupture of the Achilles tendon: a case report . J Med Case Rep \n2011 ; 5 : 263 .21718513 \n7 \nAttarzadeh AP Ryge C \nBilateral rupture of the Achilles tendons after treatment with ciprofloxacin . Ugeskr Laeger \n2013 ; 175 (39 ): 2264 –2265 .24063715 \n8 \nStockton KG Brodsky JW \nPeroneus longus tears associated with pathology of the os peroneum . Foot Ankle Int \n2014 ; 35 (4 ): 346 –352 .24505044 \n9 \nPorsch M Hackenbroch MH König DP \nAtypical Achilles tendon rupture in Haglund exostosis: a case report . Z Orthop Ihre Grenzgeb \n1998 ; 136 (6 ): 568 –570 .10036748 \n10 \nDombek M Orsini R Mendicino RW et al \nPeroneus brevis tendon tears . Clin Podiatr Med Surg \n2001 ; 18 (3 ): 409 –427 .11499171 \n11 \nBonnin M Tavernier T Bouysset M \nSplit lesions of the peroneus brevis tendon in chronic ankle laxity . Am J Sports Med \n1997 ; 25 (5 ): 699 –703 .9302480 \n12 \nGanestam A Kallemose T Troelsen A et al \nIncreasing incidence of acute Achilles tendon rupture and a noticeable decline in surgical treatment from 1994 to 2013. A nationwide registry study of 33,160 patients . Knee Surg Sports Traumatol Arthrosc \n2016 ; 24 (12 ): 3730 –3737 .25697284 \n13 \nKaraaslan F Yurdakul E Baloglu M et al \nBilateral spontaneous atraumatic rupture of the Achilles tendon in an athlete . Am J Emerg Med \n2016 ; 34 (1 ): 114e1 –114e2 .\n14 \nKapoor C Jhaveri M Golwala P et al \nAcute bilateral traumatic Achilles tendon rupture: a rare presentation . Cureus \n2016 ; 8 (7 ): e706 .27588227 \n15 \nThompson TC \nA test for rupture of the tendo achillis . Acta Orthop Scand \n1962 ; 32 : 461 –465 .13981206 \n16 \nWorld Health Organization . Cancer pain relief: with a guide to opioid availability . 2nd ed. \nGeneva : WHO , 1996 .\n17 http://fuss.oped.de/vacoped/ (accessed 28 May 2017 ).\n18 http://www.kuenzli-schuhe.ch/ortho/schuhe/standard-schuhe.html (accessed 28 May 2017 ).\n19 http://www.ottobock.at/orthetik/produkte-a-bis-z/infinity-air-walker/ (accessed 28 May 2017 ).\n20 \nAxibal DP Anderson JG \nMultiple tendon ruptures of unknown etiology . Foot Ankle Spec \n2013 ; 6 (5 ): 380 –383 .23966259 \n21 \nTurmo-Garuz A \nCan local corticosteroid injection in the retrocalcaneal bursa lead to rupture of the Achilles tendon and the medial head of the gastrocnemius muscle? \nMusculoskelet Surg \n2014 ; 98 (2 ): 121 –126 .24222527\n\n",
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"title": "Atraumatic bilateral rupture of the peroneus brevis tendon in recreational sport: A case report.",
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"abstract": "OBJECTIVE\nThe effectiveness of buprenorphine treatment of opioid dependence is limited by suboptimal medication adherence, abuse, and diversion.\n\n\nOBJECTIVE\nTo determine whether 6-month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients with stable abstinence.\n\n\nMETHODS\nOutpatient, randomized, active-controlled, 24-week, double-blind, double-dummy study conducted at 21 US sites from June 26, 2014, through May 18, 2015. Outpatients were prescribed daily sublingual buprenorphine for 6 months or more, were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer, and were determined to be clinically stable by their physician.\n\n\nMETHODS\nParticipants were randomized to receive sublingual buprenorphine plus 4 placebo implants or sublingual placebo plus four 80-mg buprenorphine hydrochloride implants (expected efficacy, 24 weeks).\n\n\nMETHODS\nThe primary end point was between-group difference in proportion of responders (≥4 of 6 months without opioid-positive urine test result [monthly and 4 times randomly] and self-report). The noninferiority established for the lower bound of the 95% confidence interval was greater than -0.20 (P < .025). Secondary end points included cumulative percentage of negative opioid urine results, abstinence, and time to first illicit opioid use. Safety was assessed by adverse event reporting.\n\n\nRESULTS\nOf 177 participants (mean age, 39 years; 40.9% female), 90 were randomized to sublingual buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo; 165 of 177 (93.2%) completed the trial. Eighty-one of 84 (96.4%) receiving buprenorphine implants and 78 of 89 (87.6%) receiving sublingual buprenorphine were responders, an 8.8% difference (1-sided 97.5% CI, 0.009 to ∞; P < .001 for noninferiority). Over 6 months, 72 of 84 (85.7%) receiving buprenorphine implants and 64 of 89 (71.9%) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio, 13.8; 95% CI, 0.018-0.258; P = .03). Non-implant-related and implant-related adverse events occurred in 48.3% and 23% of the buprenorphine implant group and in 52.8% and 13.5% of participants in the sublingual buprenorphine group, respectively.\n\n\nCONCLUSIONS\nAmong adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine, the use of buprenorphine implants compared with continued sublingual buprenorphine did not result in an inferior likelihood of remaining a responder. However, the study population had an exceptionally high response rate in the control group, and further studies are needed in broader populations to assess the efficacy in other settings.\n\n\nBACKGROUND\nclinicaltrials.gov Identifier: NCT02180659.",
"affiliations": "Center for Addictive Disorders, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.;University of Kentucky College of Medicine, Center on Drug and Alcohol Research, Lexington.;Braeburn Pharmaceuticals, Princeton, New Jersey.;TCM Groups Inc, Berkeley Heights, New Jersey.;Titan Pharmaceuticals, South San Francisco, California.;Friends Research Institute Inc, Baltimore, Maryland.",
"authors": "Rosenthal|Richard N|RN|;Lofwall|Michelle R|MR|;Kim|Sonnie|S|;Chen|Michael|M|;Beebe|Katherine L|KL|;Vocci|Frank J|FJ|;|||",
"chemical_list": "D000701:Analgesics, Opioid; D004343:Drug Implants; D009292:Narcotic Antagonists; D002047:Buprenorphine",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.2016.9382",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-7484",
"issue": "316(3)",
"journal": "JAMA",
"keywords": null,
"medline_ta": "JAMA",
"mesh_terms": "D000286:Administration, Sublingual; D000328:Adult; D000701:Analgesics, Opioid; D002047:Buprenorphine; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004343:Drug Implants; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists; D009293:Opioid-Related Disorders; D057566:Self Report",
"nlm_unique_id": "7501160",
"other_id": null,
"pages": "282-90",
"pmc": null,
"pmid": "27434441",
"pubdate": "2016-07-19",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of Buprenorphine Implants on Illicit Opioid Use Among Abstinent Adults With Opioid Dependence Treated With Sublingual Buprenorphine: A Randomized Clinical Trial.",
"title_normalized": "effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine a randomized clinical trial"
} | [
{
"companynumb": "US-INDIVIOR LIMITED-INDV-096774-2016",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
},
"drugadditional"... |
{
"abstract": "A 3-year-old girl with acute lymphocytic leukemia (ALL) in remission developed lower extremity paraparesis and areflexia 15 days after receiving intrathecal methotrexate, cytarabine, and hydrocortisone. Cerebrospinal fluid protein was 107 mg/dl. Compound muscle action potential amplitudes were reduced, F waves were absent, and sensory conduction studies were normal. Needle electromyography (EMG) revealed reduced motor unit potential recruitment. Magnetic resonance imaging (MRI) showed lumbosacral ventral root enhancement. She was treated with intravenous immunoglobulin and slowly recovered. Nerve conduction and EMG abnormalities correlated with MRI root enhancement, facilitated early diagnosis, and distinguished this from a myelopathy or distal polyneuropathy. These findings could represent selective ventral nerve root vulnerability to intrathecal chemotherapy. A selective autoimmune process cannot be excluded.",
"affiliations": "Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA. sanderso@massmed.org",
"authors": "Anderson|Stephen C|SC|;Baquis|George D|GD|;Jackson|Anthony|A|;Monteleone|Philip|P|;Kirkwood|J Robert|JR|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D006854:Hydrocortisone; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/mus.1219",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-639X",
"issue": "25(1)",
"journal": "Muscle & nerve",
"keywords": null,
"medline_ta": "Muscle Nerve",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D003561:Cytarabine; D004576:Electromyography; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007278:Injections, Spinal; D008279:Magnetic Resonance Imaging; D008727:Methotrexate; D011128:Polyradiculopathy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "7803146",
"other_id": null,
"pages": "106-10",
"pmc": null,
"pmid": "11754193",
"pubdate": "2002-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ventral polyradiculopathy with pediatric acute lymphocytic leukemia.",
"title_normalized": "ventral polyradiculopathy with pediatric acute lymphocytic leukemia"
} | [
{
"companynumb": "US-SA-2021SA387800",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
"d... |
{
"abstract": "Pain management guidelines for burn injury in pregnant women are scarce. Maternal and fetal morbidity and mortality in pregnant burn patients have been shown to be higher than that of the general population, especially in severe burns. Early intervention and interdisciplinary treatment are critical to optimize maternal and fetal outcomes. Proper pain management is central to wound treatment, as poor control of pain can contribute to delayed healing, re-epithelialization, as well as persistent neuropathic pain. We present this case of a 34-year-old female patient who suffered an 18% total body surface area burn during the third trimester of pregnancy to demonstrate that ketamine can be considered as an adjunct for procedural and background analgesia during the third trimester, as part of a multimodal strategy in a short-term, monitored setting after a thorough and complete analysis of risks and benefits and careful patient selection.",
"affiliations": "Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.;Rowan University School of Osteopathic Medicine, Stratford, New Jersey.;Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.;Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.;Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Surgery, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.;Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.",
"authors": "Roy|Akshay B|AB|;Hughes|Liam P|LP|;West|Lindsay A|LA|;Schwenk|Eric S|ES|;Elkhashab|Yasmin|Y|;Hughes|Michelle K|MK|;Hughes|William B|WB|;Viscusi|Eugene R|ER|",
"chemical_list": "D000700:Analgesics; D007649:Ketamine",
"country": "England",
"delete": false,
"doi": "10.1093/jbcr/iraa056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1559-047X",
"issue": "41(4)",
"journal": "Journal of burn care & research : official publication of the American Burn Association",
"keywords": null,
"medline_ta": "J Burn Care Res",
"mesh_terms": "D000328:Adult; D000700:Analgesics; D002056:Burns; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine; D010146:Pain; D011247:Pregnancy; D011263:Pregnancy Trimester, Third",
"nlm_unique_id": "101262774",
"other_id": null,
"pages": "913-917",
"pmc": null,
"pmid": "32266387",
"pubdate": "2020-07-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Meeting the Challenge of Analgesia in a Pregnant Woman With Burn Injury Using Subanesthetic Ketamine: A Case Report and Literature Review.",
"title_normalized": "meeting the challenge of analgesia in a pregnant woman with burn injury using subanesthetic ketamine a case report and literature review"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP014592",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nCase reports and poison center data have demonstrated that the second-generation antipsychotic quetiapine is being obtained and used for recreational abuse. The purpose of this study was to describe the relative rates of single-substance abuse for different atypical antipsychotics and compare their demographic and clinical features.\n\n\nMETHODS\nWe conducted a 10-year retrospective analysis of the National Poison Data System (NPDS) database (2003 - 2013). Trained nurses and pharmacists with specialty training in toxicology prospectively collect all NPDS data at poison control centers around the United States. We queried the NPDS for all cases of single-substance second-generation antipsychotic exposures coded as \"intentional abuse.\" The data provided by the NPDS regarding rates and clinical features of quetiapine abuse and the abuse of all other second-generation antipsychotics were compared and described descriptively.\n\n\nRESULTS\nDuring the study period, 2,118 cases of quetiapine abuse and 1,379 cases of other second-generation antipsychotic abuse were identified. Quetiapine abuse was more common than the abuse of other second-generation antipsychotics, compromising 60.6% of all abuse cases during the study period. After quetiapine, the next most frequently abused medications were risperidone (530 cases, 15.2%) and olanzapine (246 cases, 7.0%). For all second-generation antipsychotics including quetiapine, central nervous system clinical effects were most common, including drowsiness, confusion, and agitation. Other serious clinical effects observed with second-generation antipsychotic abuse included hypotension, respiratory depression, and seizures.\n\n\nCONCLUSIONS\nQuetiapine abuse is relatively common, and is abused far more often than any other second-generation antipsychotic. Emergency physicians should be aware of the clinical effects that may occur after second-generation antipsychotic abuse.",
"affiliations": "Hennepin County Medical Center, Department of Emergency Medicine, Minneapolis, Minnesota.;Minnesota Poison Control System, Minneapolis, Minnesota.;Hennepin County Medical Center, Department of Emergency Medicine, Minneapolis, Minnesota; Minnesota Poison Control System, Minneapolis, Minnesota.",
"authors": "Klein|Lauren|L|;Bangh|Stacey|S|;Cole|Jon B|JB|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.5811/westjem.2016.10.32322",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 10.5811/westjem.2016.10.32322wjem-18-243Behavioral HealthOriginal ResearchIntentional Recreational Abuse of Quetiapine Compared to Other Second-generation Antipsychotics Klein Lauren MD*Bangh Stacey PharmD†Cole Jon B. MD*†* Hennepin County Medical Center, Department of Emergency Medicine, Minneapolis, Minnesota† Minnesota Poison Control System, Minneapolis, MinnesotaAddress for Correspondence: Lauren Klein, MD, Hennepin County Medical Center, Department of Emergency Medicine, 701 Park Avenue, MC825, Minneapolis, MN 55415. Email: laurenruthklein@gmail.com.2 2017 06 12 2016 18 2 243 250 05 9 2016 30 9 2016 15 10 2016 Copyright: © 2017 Klein et al.2017This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Introduction\nCase reports and poison center data have demonstrated that the second-generation antipsychotic quetiapine is being obtained and used for recreational abuse. The purpose of this study was to describe the relative rates of single-substance abuse for different atypical antipsychotics and compare their demographic and clinical features.\n\nMethods\nWe conducted a 10-year retrospective analysis of the National Poison Data System (NPDS) database (2003 – 2013). Trained nurses and pharmacists with specialty training in toxicology prospectively collect all NPDS data at poison control centers around the United States. We queried the NPDS for all cases of single-substance second-generation antipsychotic exposures coded as “intentional abuse.” The data provided by the NPDS regarding rates and clinical features of quetiapine abuse and the abuse of all other second-generation antipsychotics were compared and described descriptively.\n\nResults\nDuring the study period, 2,118 cases of quetiapine abuse and 1,379 cases of other second-generation antipsychotic abuse were identified. Quetiapine abuse was more common than the abuse of other second-generation antipsychotics, compromising 60.6% of all abuse cases during the study period. After quetiapine, the next most frequently abused medications were risperidone (530 cases, 15.2%) and olanzapine (246 cases, 7.0%). For all second-generation antipsychotics including quetiapine, central nervous system clinical effects were most common, including drowsiness, confusion, and agitation. Other serious clinical effects observed with second-generation antipsychotic abuse included hypotension, respiratory depression, and seizures.\n\nConclusion\nQuetiapine abuse is relatively common, and is abused far more often than any other second-generation antipsychotic. Emergency physicians should be aware of the clinical effects that may occur after second-generation antipsychotic abuse.\n==== Body\nINTRODUCTION\nQuetiapine is a second-generation antipsychotic (SGA) approved for use in schizophrenia and bipolar disorder.1 It is also commonly prescribed for generalized anxiety disorder, major depression, and mood disorders.2,3 While the majority of quetiapine prescriptions are used for their intended purpose, some patients obtain quetiapine from both legitimate and illicit sources and use this medication as a drug of abuse.\n\nAlthough SGAs are not classically considered to have significant abuse potential, over the last decade case reports and poison center data have demonstrated that quetiapine abuse is a common phenomenon.4–15 The intentional abuse of quetiapine reportedly achieves a variety of desirable recreational alterations of sensorium, including anxiolysis, hypnosis, and euphoria.4,5,14,16,17 Quetiapine is also abused concomitantly with other illicit substances, such as cocaine or other sympathomimetics, to enhance their effects or to aid in self-treatment of withdrawal.8,16\n\nQuetiapine abuse is particularly concerning given the morbidity and mortality associated with its “non-prescribed” use. This has been demonstrated most extensively in the literature discussing quetiapine overdoses. Many studies have shown that patients who overdose on quetiapine are at risk for coma, hypotension, respiratory depression, seizure, and death.18–22 Additional literature demonstrates the need for advanced resuscitative measures after quetiapine overdose, including intravenous fat emulsion (Intralipid®) therapy and extracorporeal membrane oxygenation.23,24 Based on these observations, some have remarked that quetiapine ingestions may be more dangerous than comparable ingestions of other antipsychotics.18\n\nThe purpose of this study was to identify the relative incidence of intentional recreational single-substance abuse of quetiapine compared to other SGAs, and to compare their demographic and clinical features. This study question is of great importance because if quetiapine abuse is in fact as common as prior literature suggests, quetiapine abuse presenting to the emergency department (ED) should be better characterized to prepare emergency physicians for management of these patients.\n\nMETHODS\nStudy Setting\nThis study is a retrospective review evaluating the intentional recreational abuse of quetiapine compared to other SGAs reported to the National Poison Data System (NPDS) from September 1, 2003, to September 1, 2013. Approval for this study was obtained from the institutional review board human subjects research committee.\n\nThe NPDS is owned and managed by the American Association of Poison Control Centers (AAPCC); it contains over 62 million exposure cases on over 420,000 different products since 1983. Nurses and pharmacists with specialty training in toxicology collect all NPDS data in real time. These trained experts use a systematic tool to assign clinical effects, clinical outcomes, and reasons for exposure to each case in a prospective manner. The NPDS also obtains close follow up by communicating directly with the caregivers for each case.\n\nDefinitions\nThe definition of “intentional abuse” used by AAPC-accredited poison centers is “an exposure resulting from the intentional improper or incorrect use of a substance where the patient was likely attempting to gain a high, euphoric effect or some other psychotropic effect, including recreational use of a substance for any effect.”25 In terms of NPDS coding, intentional abuse is a distinct entity from “intentional misuse” (“an exposure resulting from the intentional improper or incorrect use of a substance for reasons other than the pursuit of a psychotropic effect”) and “intentional – suspected suicidal” (“an exposure resulting from the inappropriate use of a substance for self-harm or for self-destructive or manipulative reasons”).25\n\nThe AAPCC also designates clinical outcomes for each individual case. Again, these outcomes are determined using standardized criteria.26\nTable 1 defines criteria for each clinical outcome from the NPDS guidelines, and examples may be found in the NPDS coding manual.25\n\nStudy Protocol\nWe queried the NPDS for all SGA exposures coded as “intentional abuse.” Only single-substance exposures (those without co-ingestions of other substances) were included. We identified cases by the NPDS using all known product codes (generic and brand names for all formulations). The SGAs included in the query were quetiapine (Seroquel©), risperidone (Risperdal©), clozapine (Clozaril©), olanzapine (Zyprexa©), iloperidone (Fanapt©), arirpiprazole (Abilify©), paliperidone (Invega©), ziprasadone (Geodon©), asenapine (Saphris©), and lurasidone (Latuda©). We did not include combination formulations with drugs from other classes. Exclusion criteria were cases coded as “confirmed non-exposure,” as well as cases where the patient age was less than 10 years old, as these were unlikely to be intentional abuse.\n\nAfter acquisition of the electronic NPDS database, we divided cases into study cohorts. The primary study cohort included all cases of quetiapine abuse. Additional study cohorts for comparison included a group of all other SGA cases combined, in addition to cohorts of each individual SGA. If an individual SGA had fewer than 50 total cases reported to the NPDS over the 10-year period, it was excluded from comparative analysis as an individual cohort, but was still included in the cohort of all other antipsychotics combined.\n\nFor the first part of the investigation, we analyzed demographic data. The data points extracted included age, gender, route of exposure, chronicity of abuse, and patient disposition. This demographic analysis included cases with any medical outcome (no effect, minor effect, moderate effect, major effect, death, unable to follow, and not followed). The next part of the investigation sought to describe the clinical features of SGA abuse. This part of the analysis only included cases with known outcomes (no effect, minor effect, moderate effect, major effect, or death). This was done to improve the accuracy of the reported clinical data. The data collected regarding clinical features of SGA abuse included data on clinical effects (agitated/irritable, ataxia, coma, confusion, dizziness/vertigo, drowsy/lethargy, dystonia, hallucinations, seizure, slurred speech, conduction disturbance, dysrhythmia, electrocardiogram changes, hypotension, syncope, tachycardia, elevated creatine kinase/rhabdomyolysis, respiratory arrest, respiratory depression), therapies provided (alkalinization, benzodiazepines, cathartics, charcoal, CPR, intravenous fluids, intubation, lavage, naloxone, oxygen, physostigmine, sedation, vasopressors), and medical outcome (no effect, minor effect, moderate effect, major effect, or death).\n\nData Analysis\nAll data were obtained directly from the electronic NPDS database and analyzed with descriptive statistics. For all variables previously mentioned, we determined proportions for each cohort (quetiapine cohort, all other SGAs combined cohort, and each individual SGA cohort). All analyses were conducted using STATA (Version 12.1, StataCorp, College Station, TX).\n\nRESULTS\nDuring the study period there were 2,134 total cases of quetiapine exposures and 1,398 cases of SGA exposures coded as intentional abuse reported to the NPDS. In the quetiapine cohort, 16 cases were excluded (six due to age less than 10 years, 10 confirmed non-exposures), leaving 2,118 for analysis. In the other SGA cohort, we excluded 19 cases (17 due to age less than 10 years, two confirmed non-exposures), leaving 1,379 for analysis.\n\nQuetiapine was the most commonly abused SGA (n = 2118) during the study period, accounting for 60.6% of all cases. The next most frequently abused SGA was risperidone (530), followed by olanzapine (246), aripiprazole (229), ziprasadone (229), clozapine (101), paliperidone (34), asenapine (6), iloperidone (2), and lurasidone (2). Table 2 depicts demographic data. Table 3 depicts patient disposition.\n\nOf the 2,118 cases in the quetiapine cohort, there were 1,446 cases with known outcomes. Of the 1,379 cases in the cohort of all other SGAs, there were 919 with known outcomes. Table 4 demonstrates these medical outcomes for each cohort. Table 5 describes the clinical effects seen with SGA intentional abuse. Table 6 describes the therapies provided for each cohort.\n\nDISCUSSION\nEmergency physicians encounter substance abuse on a daily basis. Although quetiapine has not classically been considered a “drug of abuse,” in this last decade there have been many reports in the medical literature as well as in the media describing this phenomenon.4, 5, 7–9, 14, 15 Emergency medicine literature has previously been far more robust in describing the clinical features and adverse events associated with quetiapine overdoses;18–23 however, recreational abuse of quetiapine appears to be another significant public health problem that emergency physicians must be aware of.\n\nThis study corroborates that quetiapine is the most commonly abused SGA. Although perspectives from case reports4,14, and survey data16 suggested this was likely to be the case, this NPDS query confirmed that quetiapine abuse was identified and prospectively reported more frequently than any other SGA; in fact, quetiapine was abused more often than all other SGAs combined. In addition to our work, the most comprehensive publication thus far supporting this notion was a study using the Drug Abuse Warning Network (DAWN). 27 The DAWN is a public health surveillance system in the United States that uses medical record data from a representative group of hospitals in addition to population data to approximate prevalence. This differs from the NPDS dataset in that the data from the DAWN is estimated based on retrospective chart review, rather than prospectively identified cases called into national poison centers. Despite these different methods, the authors of this study found similar results; quetiapine-related ED visits increased by 90% from 2005 to 2011, including visits for misuse/abuse, suicide, and adverse events. Although they did combine visits for misuse and abuse, they identified 27,114 visits for these purposes during their study period, of which 6,780 were single-substance (quetiapine-only) visits. This number represented 52% of all SGA misuse/abuse visits, with the next most common being risperidone misuse/abuse (5,804, 11%) and olanzapine misuse/abuse (4,528 cases, 9%), all figures similar to ours. 27\n\nQuetiapine prescribing is common in the U.S. A 2013 IMS Health report showed that quetiapine was the most frequently prescribed SGA, with over 14 million dispensed prescriptions that year.28 Other studies support this, identifying a three-fold increase in prescribing over a decade,29 an observation likely driven by the increasing popularity of quetiapine use for “off-label” indications.2,3,16,29,30,31 These prescribing patterns may contribute to why quetiapine is the most commonly abused SGA in terms of absolute numbers of cases.\n\nAside from the public health concerns that emerge from these results, other outcomes of interest in this study were the medical consequences of quetiapine abuse. Clinical outcomes due to non-prescribed ingestions of quetiapine were recently described by a group of researchers who similarly used the NPDS, but in a smaller sample. Although their study combined cases characterized as “misuse” and “abuse,” the present study generally supports many of their findings regarding clinical outcomes. In this study, we confirmed that an ingestion of quetiapine for recreational purposes was likely to present symptomatic; 79.1% of cases with outcome data available described some degree of clinical effect, of which 26.6% were considered major or moderate effect. This finding is of particular importance to emergency physicians who will be caring for these patients.\n\nAccording to our data, central nervous system (CNS) clinical effects will hallmark the quetiapine abuse patient presentation, as well as the presentation of any SGA abuse. SGAs treat both positive and negative symptoms of schizophrenia, and pharmacologically antagonize dopamine (D2) and serotonin (5HT2a) receptors.32 Thus, as expected, sedation was often observed in this study. Interestingly, certain severe CNS effects were significantly more common in the clozapine and olanzapine cohorts. While quetiapine, clozapine, and olanzapine are unique among SGAs in that they all have antagonistic activity at muscarinic (M1) receptors, olanzapine and clozapine are much more potent than quetiapine, which may be responsible for the increased incidence of agitation, confusion, coma, and hallucinations. In addition, clozapine is a known GABA-A receptor antagonist,33 and in previous data has been known to cause seizures at higher rates than other antipsychotics.34 Thus, the increased incidence of seizures seen for this particular medication in our study is not surprising.\n\nOther than CNS effects, cardiovascular clinical effects were observed but were overall less common. Tachycardia was the most frequently observed cardiovascular clinical effect, followed by hypotension for most cohorts. While many SGAs cause adrenergic (α1) antagonism, which would typically lead to hypotension and reflex tachycardia, cardiovascular effects are often multi-factorial and in our data did not align with the varying degrees of α1-antagonism between drugs. The overall low rates of serious cardiovascular clinical effects suggest that hemodynamic instability is unlikely to be a key component of the presentation of SGA abuse, quetiapine or otherwise.\n\nThe intubation rate observed in this retrospective cohort of cases of quetiapine abuse was 1.4%, which represents a significant number of patients who may require airway management by emergency providers. The NPDS database does not specify reasons for intubation in each case but based on rates of clinical effects seen, CNS depression and/or severe agitation are the most likely indications. Studies characterizing quetiapine overdose identify much higher rates of intubation, suggesting a dose-dependent relationship regarding the need for intubation. One study found that 14 of 20 patients in their quetiapine overdose cohort of intensive care unit patients required mechanical ventilation.20 A larger retrospective review of 945 quetiapine overdose cases found an intubation rate of 16%.18 These findings should remind clinicians to have a high index of suspicion for acute respiratory failure in quetiapine abuse patients presenting after larger ingestions.\n\nThe rate of dystonia in the quetiapine abuse cohort was extremely low, with only 0.6% of cases manifesting this clinical effect. The pathophysiology of drug-induced dystonia is not wholly agreed upon. A commonly held theory is that a drug induces dystonia via dopamine (D2) antagonism in the nigrostriatal pathways of the basal ganglia, leading to excessive cholinergic input.35 This is supported by the presence of dystonic symptoms in patients with Parkinson’s disease as well as the observation that drugs with increased D2 antagonism cause dystonia that improves when antimuscarinic medications are administered. Considering the inherent antimuscarinic activity of quetiapine, olanzapine and clozapine, it is not surprising these three cohorts had the lowest rates of dystonia. This relative infrequency of dystonia in the quetiapine cohort could hypothetically contribute to quetiapine’s higher incidence of abuse, as dystonia is generally viewed as an undesirable side effect.\n\nLIMITATIONS\nThere are several limitations present in this study. The major limitation is its retrospective nature and the potential inaccuracy innate to the data available to the NPDS. Although highly trained poison center personnel collect NPDS data in real time, there was no means to verify data in this study, other than what was coded. NPDS data are at risk for certain misclassifications; however, this should be the same across all groups of SGAs and therefore mitigated. Cases can be incorrectly coded as single-substance ingestions when there were in fact co-ingestions, which could influence the reported clinical data. “Misuse” versus “abuse” could be interchangeably misclassified as well. Unfortunately, very limited data were collected regarding doses, which would have been helpful in understanding the clinical presentations of these cases. Prevalence of abuse is also likely underestimated in the present study due to the exclusion of co-ingestions and incomplete reporting to poison centers. (There is regional variability in poison center use as some poison centers charge hospitals for use and others preferentially use inpatient consulting toxicology services.) Again, these limitations however would hypothetically be similar for all medications included, so should not alter the conclusions regarding relative frequencies of SGA abuse.\n\nCONCLUSION\nThis study is a large retrospective cohort evaluating demographic features, clinical features, and the relative frequency of quetiapine abuse as it compares to other SGAs. According to these data, quetiapine is the most commonly abused SGA by a substantial margin. The findings of this study also confirm that most patients who present to the ED will be symptomatic and may require therapeutic interventions. It is important for emergency physicians to be aware of these findings, as they are likely to encounter this scenario in their clinical practice.\n\nSection Editor: Brandon Wills, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n\nTable 1 Clinical outcome definitions in the National Poison Data System26.\n\nMedical outcome\tDefinition\t\nMajor effect\tThe patient exhibited signs or symptoms as a result of the exposure that were life-threatening or resulted in significant residual disability or disfigurement\t\nModerate effect\tThe patient exhibited signs or symptoms as a result of the exposure that were more pronounced, more prolonged, or more systemic in nature than minor symptoms. Usually, some form of treatment is indicated. Symptoms were not life-threatening, and the patient had no residual disability or disfigurement.\t\nMinor effect\tThe patient developed some signs or symptoms as a result of the exposure, but they were minimally bothersome and generally resolved rapidly with no residual disability or disfigurement\t\nUnable to follow\tInsufficient follow up available\t\nNot followed\tInsufficient follow up available\t\nTable 2 Patient demographics.\n\nDemographics\tQuetiapine (n = 2118)\tAll other SGAs (n = 1379)\t\nMedian age (years) (IQR)\t17 (15 – 27)\t18 (15 – 25)\t\nGender, male (%)\t1313 (62.0%)\t915 (66.4%)\t\nChronicity\t\n Acute\t1685 (79.6%)\t1044 (75.7%)\t\n Acute on chronic\t335 (15.8%)\t260 (18.9%)\t\n Chronic\t32 (1.5%)\t20 (1.5%)\t\nRoute of exposure\t\n Ingestion\t1988 (93.8%)\t1307 (94.5%)\t\n Inhalation\t120 (5.7%)\t73 (5.3%)\t\n Parenteral\t16 (0.8%)\t5 (0.4%)\t\nAll data provided as n (%) unless otherwise specified.\n\nSGA, second-generation antipsychotics; IQR, inter-quartile range; if cases had multiple exposure routes coded, all were included.\n\nTable 3 Disposition of patients coded as having intentionally abused second-generation antipsychotics (SGA).\n\nPatient disposition\tQuetiapine\nn = 2118\tAll other SGAs\nn = 1379\tAripiprazole\nn = 229\tClozapine\nn = 101\tOlanzapine\nn = 246\tRisperidone\nn =530\tZiprasidone\nn = 229\t\nTreated and discharged\t40.8%\t39.4%\t38.4%\t23.4%\t28.9%\t44.3%\t47.6%\t\nCritical care admission\t10.3%\t9.3%\t6.5%\t22.8%\t18.3%\t5.8%\t5.2%\t\nPatient refused referral to hospital\t7.8%\t8.8%\t10.4%\t7.9%\t9.3%\t8.7%\t6.1%\t\nPsychiatric admission\t7.2%\t7.2%\t9.6%\t4.0%\t8.5%\t7.4%\t5.2%\t\nNon critical care admission\t6.5%\t6.6%\t5.2%\t14.8%\t8.2%\t6.2%\t3.5%\t\nAll cases not included in table did not have available disposition data.\n\nTable 4 Medical outcomes for each cohort.\n\nMedical outcomes\tQuetiapine\nn = 1446\tAll other SGAs\nn = 919\tAripiprazole\nn = 142\tClozapine\nn = 72\tOlanzapine\nn = 167\tRisperidone\nn = 361\tZiprasidone\nn = 149\t\nDeath\t0.1%\t0.1%\t0\t0\t0\t0.3%\t0\t\nMajor outcome\t2.0%\t2.5%\t0.7%\t8.3%\t5.4%\t1.4%\t1.3%\t\nModerate outcome\t24.6%\t37.6%\t25.4%\t50%\t35.9%\t44.0%\t32.9%\t\nMinor outcome + no effect\t73.4%\t76.8%\t73.9%\t41.3%\t63.8%\t54.1%\t65.7%\t\nSGA, second-generation antipsychotics\n\nTable 5 Clinical effects seen with intentional abuse of second-generation antipsychotics.\n\nClinical effects\tQuetiapine\nn = 1446\tAll other SGAs\nn = 919\tAripiprazole\nn = 142\tClozapine\nn = 72\tOlanzapine\nn = 167\tRisperidone\nn = 361\tZiprasidone\nn = 149\t\nCNS effects\t\n Drowsy/lethargy\t54.5%\t39.4%\t16.9%\t62.5%\t59.3%\t31.6%\t47.0%\t\n Slurred speech\t7.8%\t6.4%\t0.7%\t16.7%\t12.6%\t4.2%\t4.7%\t\n Agitated/Irritable\t5.5%\t8.1%\t3.5%\t23.6%\t16.2%\t5.3%\t3.4%\t\n Dizziness/vertigo\t5.0%\t4.9%\t4.9%\t0\t5.4%\t3.9%\t8.7%\t\n Ataxia\t4.4%\t2.7%\t0.7%\t4.2%\t7.2%\t1.7%\t2.0%\t\n Confusion\t4.2%\t6.2%\t3.5%\t26.4%\t11.4%\t3.3%\t0.7%\t\n Hallucinations\t1.6%\t2.8%\t0.7%\t9.7%\t4.8%\t2.5%\t0.7%\t\n Coma\t1.2%\t1.6%\t0\t9.7%\t3.0%\t0.3%\t1.3%\t\n Seizures\t0.8%\t1.0%\t1.4%\t4.2%\t1.8%\t0.3%\t0\t\n Dystonia\t0.6%\t12.5%\t12.0%\t0\t3.0%\t19.1%\t10.1%\t\nCardiovascular effects\t\n Tachycardia\t22.9%\t20.3%\t14.1%\t34.7%\t19.2%\t23.5%\t12.1%\t\n Hypotension\t5.9%\t3.0%\t0\t5.6%\t1.8%\t3.9%\t4.7%\t\n Syncope\t1.8%\t0.3%\t0.7%\t1.4%\t0\t0.3%\t0\t\n Conduction disturbance\t1.2%\t1.2%\t1.4%\t1.4%\t0.6%\t1.7%\t0.7%\t\n ECG changes\t0.9%\t0.5%\t0\t1.4%\t0\t0.3%\t1.3%\t\n Dysrhythmia\t0.1%\t0.1%\t0\t0\t0\t0.3%\t0\t\nOther effects\t\n Respiratory depression\t1.0%\t0.2%\t0\t0\t1.2%\t0\t0\t\n Elevated CK/rhabdomyolysis\t0.4%\t0.4%\t0.7%\t0\t0.6%\t0.6%\t0\t\n Respiratory arrest\t0.1%\t0.2%\t0\t0\t0.6%\t0.3%\t0\t\nSGA, second-generation antipsychotics; CNS, central nervous system; ECG, electrocardiogram; CK, creatine kinase\n\nTable 6 Therapies provided to patients who intentionally abused second-generation antipsychotics (SGA).\n\nTherapies\tQuetiapine\nn = 1446\tAll other SGAs\nn = 919\tAripiprazole n = 142\tClozapine\nn = 72\tOlanzapine\nn = 167\tRisperidone\nn = 361\tZiprasidone\nn = 149\t\nIntravenous fluids\t24.5%\t24.3%\t14.8%\t41.7%\t31.1%\t24.1%\t18.1%\t\nCharcoal\t15.1%\t15.2%\t16.2%\t11.1%\t25.1%\t12.7%\t14.1%\t\nCathartics\t4.6%\t5.1%\t5.6%\t4.2%\t9.0%\t3.9%\t4.7%\t\nOxygen\t3.9%\t3.0%\t0.7%\t8.3%\t6.0%\t2.2%\t2.0%\t\nBenzodiazepines\t3.3%\t6.0%\t5.6%\t12.5%\t9.0%\t4.4%\t2.0%\t\nNaloxone\t2.4%\t2.5%\t0\t8.3%\t6.6%\t0.8%\t2.0%\t\nSedation\t1.7%\t0.1%\t0\t4.2%\t3.6%\t0\t0\t\nIntubation\t1.4%\t1.5%\t0.7%\t5.6%\t4.2%\t0.6%\t0\t\nLavage\t1.0%\t1.1%\t1.4%\t0\t3.0%\t0.8%\t0\t\nAlkalinization\t0.5%\t0.2%\t0\t0\t0.6%\t0.8%\t0\t\nCPR\t0.1%\t0\t0\t0\t0\t0.3%\t0\t\nPhysostigmine\t0\t0\t0\t0\t0\t0\t0\t\nVasopressors\t0\t0\t0\t0\t0\t0.3%\t0\t\nCPR, cardiopulmonary resuscitation\n==== Refs\nREFERENCES\n1 Quetiapine fumarate (Seroquel©) (package insert) AstraZeneca Available at: http://www1.astrazeneca-us.com/pi/seroquel.pdf Accessed Jul 2015 \n2 Maglione M Maher AR Hu J Off-Label Use of Atypical Antipsychotics: An Update (Internet) Rockville (MD) Agency for Healthcare Research and Quality (US) 2011 \n3 Bandelow B Chouinard G Bobes J Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder. Data from a randomized, double-blind, placebo- and active-controlled study Int J Neuropsychopharmacol 2010 13 3 305 20 19691907 \n4 Pierre JM Shnayder I Wirshing DA Intranasal quetiapine abuse Am J Psychiatry 2004 161 9 1718 \n5 Hussain MZ Waheed W Hussain S Intravenous quetiapine abuse Am J Psychiatry 2005 162 9 1755 6 \n6 Morin AK Possible intranasal quetiapine misuse Am J Health Syst Pharm 2007 1 64 7 723 5 17384357 \n7 Pinta ER Taylor RE Quetiapine addiction? Am J Psychiatry 2007 164 1 174 5 17202569 \n8 Waters BM Joshi KG Intravenous quetiapine-cocaine use (“Q-ball”) Am J Psychiatry 2007 164 1 173 4 \n9 Reeves RR Brister JC Additional evidence of the abuse potential of quetiapine South Med J 2007 100 8 834 6 17713313 \n10 Murphy D Bailey K Stone M Addictive potential of quetiapine Am J Psychiatry 2008 165 7 918 \n11 Paparrigopoulos T Karaiskos D Liappas J Quetiapine: another drug with potential for misuse? A case report J Clin Psychiatry 2008 69 1 162 3 18312052 \n12 Fischer BA Boggs DL The role of antihistaminic effects in the misuse of quetiapine: a case report and review of the literature Neurosci Biobehav Rev 2010 34 4 555 8 19896973 \n13 George M Haasz M Coronado A Acute dyskinesia, myoclonus, and akathisa in an adolescent male abusing quetiapine via nasal insufflation: a case study BMC Pediatr 2013 16 13 187 \n14 Sansone RA Sansone LA Is seroquel developing an illicit reputation for misuse/abuse? Psychiatry 2010 7 1 13 6 \n15 Klein-Schwartz W Schwartz EK Anderson BD Evaluation of quetiapine abuse and misuse reported to poison centers J Addict Med 2014 8 3 195 8 24662370 \n16 Malekshahi T Tioleco N Ahmed N Misuse of atypical antipsychotics in conjunction with alcohol and other drugs of abuse J Subst Abuse Treat 2015 48 1 8 12 25216812 \n17 Tcheremissine OV Is quetiapine a drug of abuse? Reexamining the issue of addiction Expert Opin Drug Saf 2008 7 6 739 48 18983220 \n18 Ngo A Ciranni M Olson KR Acute quetiapine overdose in adults: a 5-year retrospective case series Ann Emerg Med 2008 52 5 541 7 18433934 \n19 Tan H Hoppe J Heard K A systematic review of cardiovascular effects after atypical antipsychotic medication overdose Am J Emerg Med 2009 27 5 607 16 19497468 \n20 Eyer F Pfab R Felgenhauer N Clinical and analytical features of severe suicidal quetiapine overdoses-a retrospective cohort study Clin Toxicol 2011 49 9 846 53 \n21 Balit CR Isbister GK Hackett LP Quetiapine poisoning: a case series Ann Emerg Med 2003 42 6 751 8 14634598 \n22 Langman LJ Kaliciak HA Carlyle S Fatal overdoses associated with quetiapine J Anal Toxicol 2004 28 6 520 5 15516308 \n23 Bartos M Knudsen K Use of intravenous lipid emulsion in the resuscitation of a patient with cardiovascular collapse after a severe overdose of quetiapine Clin Toxicol 2013 51 6 501 4 \n24 Lannemyr L Knudsen K Severe overdose of quetiapine treated successfully with extracorporeal life support Clin Toxicol 2012 50 4 258 61 \n25 American Association of Poison Control Centers National Poison Data System (NPDS) Coding Users’ Manual, Version 3.0. Approved May 7, 2014.\n\n\n26 Mowry JB Spyker DA Cantilena LR Jr 2013 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31th Annual Report Clin Toxicol (Phila) 2014 52 10 1032 283 25559822 \n27 Mattson ME Albright VA Yoon J Emergency Department Visits Involving Misuse and Abuse of the Antipsychotic Quetiapine: Results from the Drug Abuse Warning Network (DAWN) Subst Abuse 2015 24 9 39 46 \n28 IMS Institute Healthcare Reports Available at: http://www.drugstorenews.com/sites/drugstorenews.com/files/AnnualDiseaseStateReport_August2012.pdf Accessed Aug 2016 \n29 Pringsheim T Gardner D Dispensed prescriptions for quetiapine and other second-generation antipsychotics in Canada from 2005 to 2012: a descriptive study CMAJ Open 2014 2 4 E225 E232 \n30 Monnelly EP Ciraulo DA Knapp C Quetiapine for treatment of alcohol dependence J Clin Psychopharmacol 2004 24 5 532 5 15349010 \n31 Mariani JJ Pavlicova M Mamczur AK Open-label pilot study of quetiapine treatment for cannabis dependence Am J Drug Alcohol Abuse 2014 40 4 280 4 24963729 \n32 Juurlink DN Antipsychotics Goldfrank’s Toxicologic Emergencies Hoffman RS Howland MA Lewin NA 10th edition New York, NY McGraw-Hill 2015 960 71 \n33 Squires RF Saederup E Mono N-aryl ethylenediamine and piperazine derivatives are GABA-A receptor blockers: implications for psychiatry Neurochem Res 1993 18 7 787 93 8103578 \n34 Pisani F Oteri G Costa C Effects of psychotropic drugs on seizure threshold Drug Saf 2002 25 91 110 11888352 \n35 Marsden CD Jenner P The pathophysiology of extrapyramidal side-effects of neuroleptic drugs Psychol Med 1980 10 1 55 72 6104342\n\n",
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"issue": "18(2)",
"journal": "The western journal of emergency medicine",
"keywords": null,
"medline_ta": "West J Emerg Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D001007:Anxiety; D004636:Emergency Service, Hospital; D055416:Evidence-Based Emergency Medicine; D005260:Female; D006801:Humans; D008297:Male; D011039:Poison Control Centers; D017410:Practice Guidelines as Topic; D063487:Prescription Drug Misuse; D000069348:Quetiapine Fumarate; D012189:Retrospective Studies; D012559:Schizophrenia; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "101476450",
"other_id": null,
"pages": "243-250",
"pmc": null,
"pmid": "28210359",
"pubdate": "2017-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "24238149;18312052;8103578;26056465;15337673;22077248;23768031;17713313;25216812;19896973;19497468;17384357;16135642;19691907;25559822;17202569;11888352;24662370;24963729;6104342;17202567;15349010;18983220;14634598;18593794;20386631;18433934;22380463;15516308;25485247",
"title": "Intentional Recreational Abuse of Quetiapine Compared to Other Second-generation Antipsychotics.",
"title_normalized": "intentional recreational abuse of quetiapine compared to other second generation antipsychotics"
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"abstract": "Spontaneous non-traumatic renal haemorrhage, or Wunderlich's syndrome, is a rare but potentially life-threatening event. We present the case of a 63-year-old man on clopidogrel who became haemodynamically unstable as a result of this condition. Angioembolisation revealed the unusual finding of active bleeding from multiple distinct subsegmental renal vessels, for which haemostasis was successfully achieved by coil placement. The patient remains well and with near-normal renal function on follow-up.",
"affiliations": "Austin Hospital, Heidelberg, Victoria, Australia.;Austin Hospital, Heidelberg, Victoria, Australia.;Royal Adelaide Hospital, Adelaide, South Australia, Australia.;Austin Hospital, Heidelberg, Victoria, Australia.",
"authors": "Kinnear|Ned|N|;Hennessey|Derek Barrry|DB|;Douglass-Molloy|Hannah|H|;Jack|Greg|G|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-216171",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D001803:Blood Transfusion; D000077144:Clopidogrel; D004621:Embolization, Therapeutic; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D013577:Syndrome; D013988:Ticlopidine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27873745",
"pubdate": "2016-11-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2672096;11912370;21941463;18606339;26814780;1159905",
"title": "Life-threatening Wunderlich's syndrome with concurrent clopidogrel use.",
"title_normalized": "life threatening wunderlich s syndrome with concurrent clopidogrel use"
} | [
{
"companynumb": "AU-APOTEX-2016AP016235",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
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"activesubstancename": "ATENOLOL"
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{
"abstract": "Peripartum cardiomyopathy is an idiopathic reduction in left ventricular systolic function (ejection fraction <45%) toward the end of pregnancy or in the months after delivery. A multidisciplinary approach to management with shock team support is key to identifying and adequately treating patients with refractory heart failure and peripartum cardiomyopathy. (Level of Difficulty: Intermediate.).",
"affiliations": "Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.;Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.;Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.;Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.;Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.",
"authors": "Aldrugh|Summer|S|;Gracia|Ely|E|;Harrington|Colleen M|CM|;Meyer|Theo E|TE|;Kovell|Lara C|LC|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2020.01.020",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)30129-7\n10.1016/j.jaccas.2020.01.020\nCase Report\nClinical Case\nRecurrent and Life-Threatening Peripartum Cardiomyopathy\nDiagnosis, Delivery Considerations, and Management\nAldrugh Summer MD\nGracia Ely MD\nHarrington Colleen M. MD\nMeyer Theo E. MD, PhD\nKovell Lara C. MD Lara.Kovell@umassmemorial.org\n∗\nDivision of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts\n∗ Address for correspondence: Dr. Lara C. Kovell, University of Massachusetts Medical School, 55 North Lake Avenue, UMass Medical School Building, Worcester, Massachusetts 01650. Lara.Kovell@umassmemorial.org\n15 4 2020\n4 2020\n15 4 2020\n2 4 681684\n3 12 2019\n19 12 2019\n29 1 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPeripartum cardiomyopathy is an idiopathic reduction in left ventricular systolic function (ejection fraction <45%) toward the end of pregnancy or in the months after delivery. A multidisciplinary approach to management with shock team support is key to identifying and adequately treating patients with refractory heart failure and peripartum cardiomyopathy. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nPeripartum cardiomyopathy is an idiopathic reduction in left ventricular systolic function (ejection fraction, <45%) toward the end of pregnancy…\n\nKey Words\n\ncardiovascular disease in women\ndelivery considerations\nmechanical support\npregnancy\nperipartum cardiomyopathy\nAbbreviations and Acronyms\n\nCO, cardiac output\nEF, ejection fraction\nLV, left ventricle\nMR, mitral regurgitation\nPA, pulmonary artery\nPEC, pre-eclampsia\nPPCM, peripartum cardiomyopathy\nTTE, transthoracic echocardiogram\n==== Body\nHistory of Presentation\n\nA 38-year-old African-American woman, gravida 6 para 3, with a history of peripartum cardiomyopathy (PPCM) diagnosed 10 years earlier during her second pregnancy, severe mitral regurgitation (MR), and hypertension presented to the heart failure clinic at 23 weeks’ gestation. Since her last episode of PPCM, the patient was advised against further pregnancies but did not undergo permanent sterilization. In the clinic, she was asymptomatic and appeared euvolemic. A transthoracic echocardiogram (TTE) from 3 years earlier showed a dilated, hypokinetic left ventricle (LV) with an ejection fraction (EF) of 20% and severe MR. A repeat TTE was recommended but not completed. At 36 weeks, she presented with worsening orthopnea, dyspnea, weight gain, and bilateral lower extremity edema acutely over 2 weeks. Vital signs on presentation included blood pressure of 145/81 mm Hg, tachycardia, tachypnea, and hypoxia requiring 4 L of oxygen via nasal canula. Admission electrocardiogram showed sinus tachycardia, biatrial enlargement, and LV hypertrophy.Learning Objectives\n\n• To review the epidemiology, outcomes, and risk factors for recurrence of peripartum cardiomyopathy.\n\n• To provide a summary of the latest guidelines regarding the medical management, delivery considerations, and hemodynamic support of patients with PPCM.\n\nDifferential Diagnosis\n\nThe most likely diagnosis was decompensated systolic/diastolic heart failure due to PPCM. Other diagnoses included other forms of cardiomyopathy (viral, stress, and ischemic), pre-eclampsia (PEC) causing pulmonary edema, valvular heart disease, and myocardial infarction.\n\nInvestigations\n\nInitial laboratory test results showed troponin I level of 0.14 ng/ml, brain natriuretic peptide level of 379 pg/ml, and an elevated urine spot protein/creatinine ratio. Results of the remaining laboratory tests, including liver function test, were normal. Chest x-ray film showed cardiomegaly and pulmonary vascular congestion (Figure 1). TTE showed a severely dilated LV (LV internal dimension in diastole, 7.4 cm) with LVEF of 10%, dilated right ventricle, severe eccentric MR, estimated pulmonary artery systolic pressure of 73 mm Hg, and biatrial enlargement (Figure 2).Figure 1 Admission Chest X-Ray\n\nAdmission chest x-ray film showing pulmonary vascular congestion and cardiomegaly.\n\nFigure 2 Transthoracic Echocardiogram Images\n\nTransthoracic echocardiogram images showing dilated left ventricle.\n\nManagement\n\nThe patient was admitted to the cardiac critical care unit and diuresed. To aid in delivery planning, the heart failure team recommended placement of a pulmonary artery (PA) catheter, which showed right atrial pressure of 13 mm Hg, right ventricle pressure of 65/28 mm Hg, pulmonary capillary wedge pressure of 30 mm Hg, PA pressure of 60/28/39 mm Hg with PA saturation of 76%, systemic vascular resistance of 1300 dynes/s/cm–5, and Fick cardiac output (CO) and cardiac index of 5.23 l/min and 3.24 l/min/m2, respectively. After multidisciplinary discussions, the maternal-fetal medicine team recommended a cesarean birth as the mode of delivery, and the heart failure team advised pre-surgery shock prophylaxis. The patient proceeded with a cesarean and bilateral tubal ligation after placement of femoral sheaths to prepare for emergent extracorporeal membrane oxygenation. Intraoperatively, the patient became hypotensive, requiring intravenous vasopressor support with norepinephrine and epinephrine. Post-operatively, she became acutely hypertensive, with systolic blood pressure of 200 mm Hg. Vasopressors were weaned, and she was started on nitroprusside, furosemide, and epoprostenol with stabilization of her hemodynamics.\n\nDiscussion\n\nPPCM is an idiopathic reduction in LVEF (EF <45%) during pregnancy or in the postpartum period in the absence of other etiologies (1). The incidence of PPCM in the United States is estimated to be approximately 1 in 2,500 to 4,000 live births (1). PPCM has serious risks for both morbidity and mortality, with mortality rates ranging from 5% to 25% (1, 2, 3). In the IPAC (Investigations of Pregnancy-Associated Cardiomyopathy) study, 13% of women developed major events (i.e., death, mechanical support, heart transplant) or failed to recover their LVEF (2). Notably, 5% of heart transplants in women in the United States are due to PPCM (4). Additionally, LVEF recovery does not eliminate the risk of recurrence: 20% of women, despite EF recovery, will have a re-exacerbation in subsequent pregnancies compared with 54% of women with persistent LV dysfunction (3).\n\nThe demands of pregnancy lead to significant changes in cardiovascular physiology. Through pregnancy, coupled with a decrease in systemic vascular resistance, CO increases 30% to 50% above pre-pregnancy levels by the second trimester and rises further with contractions and postpartum autotransfusion (5). In women with LV dysfunction, abnormal contractility prevents adaptation to the increased preload and CO associated with pregnancy, leading to elevated filling pressures and pulmonary edema (6). The pathogenesis of PPCM remains largely unknown; however, multiple known risk factors exist, including PEC, increased maternal age (>30 years), African American race, multiple gestations, and maternal hypertension (1,7). There is also a strong association between PEC and PPCM, with a shared pathophysiology that includes upregulation of placental antivascular factors such as soluble vascular endothelial growth factor receptor (sFlt-1) (7).\n\nThe management of PPCM relies on a multidisciplinary team approach focused on the hemodynamic stability of mother and fetus (Figure 3). Multiple factors require added attention when caring for patients with PPCM, including optimal timing, mode of delivery, and availability of mechanical support. Many cardiac regimens require adjustments during pregnancy because of teratogenicity. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are both contraindicated during pregnancy because of teratogenic effects, and aldosterone antagonists are relatively contraindicated because of their anti-androgenic effect on male fetuses (5). Beta-blockers, especially metoprolol, are generally safe for use, and hydralazine and nitrates are utilized for afterload reduction during pregnancy (5). Diuretics are generally continued during pregnancy in the setting of acute or chronic heart failure, pulmonary edema, or cardiogenic shock (5). Bromocriptine has been proposed to have beneficial effects on LV recovery, although clinical use remains limited because of the small size of these studies (1,3).Figure 3 Peripartum Cardiomyopathy Management\n\nSummary of peripartum cardiomyopathy management. BNP = B-type natriuretic peptide; CRT-D = cardiac resynchronization therapy defibrillator; ECMO = extracorporeal membrane oxygenation.\n\nCurrently, there are limited and conflicting data regarding the long-term management of patients with PPCM and recovered LV function (3). One study showed no deterioration in LV function during a 2-year follow-up period in 15 PPCM patients after discontinuation of beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (8). Conversely, the recently published TRED-HF (Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy) trial showed that patients with dilated cardiomyopathy more frequently relapsed 6 months after discontinuing heart failure medications compared with those continuing treatment (44% vs. 0%, p = 0.0001) (9). Only 2 of the patients stopping treatment had PPCM, and 1 of the 2 relapsed (9). A suggested approach is to gradually discontinue heart failure medications in patients with PPCM after recovery, stabilization of LVEF, and normalization of LV size over several months, along with close serial echocardiographic monitoring during the discontinuation period (3).\n\nIn critically ill pregnant women, norepinephrine is a first-line agent for vasopressor support, although dopamine and dobutamine are alternatives in a low output state (5,10). In terms of mechanical support, intra-aortic balloon pump, LV assist devices, and extracorporeal membrane oxygenation have been used successfully in patients with low-output cardiogenic shock as a bridge to either recovery or transplant (2,3,10).\n\nDecisions regarding the timing and mode of delivery require a multidisciplinary approach with accurate hemodynamic measurements. Although cesarean delivery is not required in all patients with PPCM, approximately 43% PPCM deliveries are via cesarean section (10). Vaginal delivery is preferred unless there is an obstetric emergency or hemodynamic contraindications indicating cardiac inadequacy or instability when attempting to meet the increase in preload/CO (1,10).\n\nFollow-Up\n\nThe patient was successfully extubated and discharged on furosemide, lisinopril, and metoprolol succinate based on the recommendations of the heart failure team. She did not plan to breastfeed. TTE at 6 months postpartum showed a severely reduced LV systolic function (EF 20% to 25%), dilated LV (LV internal dimension in diastole, 8.1 cm), with a diffusely hypokinetic LV. Given the persistent LV dysfunction, she is being evaluated for a heart transplant.\n\nConclusions\n\nPPCM is a rare but serious condition associated with significant morbidity and mortality that remains poorly understood in terms of etiology and pathogenesis. A multidisciplinary approach is key to identifying and adequately treating patients with PPCM. Medical management should focus on controlling symptoms and preventing complications during pregnancy, with mechanical support reserved for patients with a low-output state and as additional support during pregnancy or the early postpartum period.\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, or patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n==== Refs\nReferences\n\n1 Sliwa K. Hilfiker-Kleiner D. Petrie M.C. Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy Eur J Heart Fail 12 2010 767 778 20675664\n2 McNamara D.M. Elkayam U. Alharethi R. Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (Investigations of Pregnancy-Associated Cardiomyopathy) J Am Coll Cardiol 66 2015 905 914 26293760\n3 Elkayam U. Risk of subsequent pregnancy in women with a history of peripartum cardiomyopathy J Am Coll Cardiol 64 2014 1629 1636 25301468\n4 Rasmusson K. Brunisholz K. Budge D. Peripartum cardiomyopathy: post-transplant outcomes from the United Network for Organ Sharing Database J Heart Lung Transplant 31 2012 180 186 22305380\n5 Halpern D.G. Weinberg C.R. Pinnelas R. Mehta-Lee S. Economy K.E. Valente A.M. Use of medication for cardiovascular disease during pregnancy: JACC state-of-the-art review J Am Coll Cardiol 73 2019 457 476 30704579\n6 Anthony J. Sliwa K. Decompensated heart failure in pregnancy Card Fail Rev 2 2016 20 26 28785449\n7 Bello N. Rendon I.S.H. Arany Z. The relationship between pre-eclampsia and peripartum cardiomyopathy: a systematic review and meta-analysis J Am Coll Cardiol 62 2013 1715 1723 24013055\n8 Amos A.M. Jaber W.A. Russell S.D. Improved outcomes in peripartum cardiomyopathy with contemporary Am Heart J 152 2006 509 513 16923422\n9 Halliday B.P. Wassall R. Lota A.S. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial Lancet 393 2019 61 73 30429050\n10 Stergiopoulos K. Lima F.V. Peripartum cardiomyopathy-diagnosis, management, and long term implications Trends Cardiovasc Med 29 2019 164 173 30111492\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "2(4)",
"journal": "JACC. Case reports",
"keywords": "CO, cardiac output; EF, ejection fraction; LV, left ventricle; MR, mitral regurgitation; PA, pulmonary artery; PEC, pre-eclampsia; PPCM, peripartum cardiomyopathy; TTE, transthoracic echocardiogram; cardiovascular disease in women; delivery considerations; mechanical support; peripartum cardiomyopathy; pregnancy",
"medline_ta": "JACC Case Rep",
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"pages": "681-684",
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"title": "Recurrent and Life-Threatening Peripartum Cardiomyopathy: Diagnosis, Delivery Considerations, and Management.",
"title_normalized": "recurrent and life threatening peripartum cardiomyopathy diagnosis delivery considerations and management"
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"abstract": "Meige syndrome is a relatively rare type of oral facial dystonia. The dominant symptoms involve involuntary eye blinking and chin thrusting. Some patients may experience excessive tongue protrusion, squinting, muddled speech, or uncontrollable contraction of the platysma muscle. A 44-year-old Japanese male was suffering from schizophrenia. The initial presentation of his psychosis consisted of auditory hallucinations, delusions of persecution, psychomotor excitement, loosening association, and restlessness. After being prescribed several antipsychotic drugs, risperidone was started and gradually increased to 4 mg/day. The above symptoms were relieved, particularly auditory hallucination and excitement were promptly improved. Persecutory delusion, however persisted, and deteriorated. At one year after the start of this risperidone regimen, he exhibited severe blepharospasm symptoms (increased rate of eye blinking, light sensitivity) and oromandibular symptoms (trismus, jaw pain, dysarthria). He was diagnosed with Meige syndrome. His antipsychotic drug was changed from risperidone to paliperidone. Two months after switching from risperidone to paliperidone, his eye blinking, light sensitivity, jaw pain, and trismus gradually improved, although the dysarthria persisted. Six months after starting paliperidone, his symptoms of Meige syndrome were completely remitted. He has been well without relapse at 12 mg/day of paliperidone. The case suggests that Meige syndrome is relieved by changing from risperidone to paliperidone. The precise mechanism of the relief remains, however, unknown.",
"affiliations": "Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Japan.",
"authors": "Yoshimura|Reiji|R|;Hori|Hikaru|H|;Katsuki|Asuka|A|;Atake|Kiyokazu|K|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone; D000068882:Paliperidone Palmitate",
"country": "Japan",
"delete": false,
"doi": "10.7888/juoeh.38.233",
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"keywords": null,
"medline_ta": "J UOEH",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D006801:Humans; D008297:Male; D008538:Meige Syndrome; D000068882:Paliperidone Palmitate; D018967:Risperidone; D012559:Schizophrenia; D016896:Treatment Outcome",
"nlm_unique_id": "7909645",
"other_id": null,
"pages": "233-6",
"pmc": null,
"pmid": "27627971",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Marked Improvement of Meige Syndrome in a Japanese Male Patient with Schizophrenia After Switching from Risperidone to Paliperidone: A Case Report.",
"title_normalized": "marked improvement of meige syndrome in a japanese male patient with schizophrenia after switching from risperidone to paliperidone a case report"
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"abstract": "Primary cutaneous T-cell lymphoma gamma-delta subtype is an extremely rare entity of all the cutaneous T-cell lymphomas. Our case provides an insight on clinical behavior and treatment response with feasible effective combination chemotherapy. We believe this will be of great interest to clinicians when facing this difficult clinical entity. We present a case of a 66-year-old Malay man with a threeweek history of rapidly growing skin nodules and plaques which spread throughout his body. He was commenced on combination chemotherapy gemcitabine, etoposide, and carboplatin with near complete remission on completion of second cycle but he defaulted. He relapsed within a month and he progressed despite treatment with the same regime. He was salvaged with fludarabine, cytarabine, and vinblastine combination chemotherapy but progressed with brain metastasis and died. However, more investigations and studies need to be done in this relatively unknown rare entity. A rare lymphoma registry might be of help to better understand and treat similar conditions.",
"affiliations": "Hospital Melaka, Department of Medicine, Jalan Mufti Haji Khalil, 75400 Melaka, Malaysia. drgancc85@hotmail.com.;Hospital Melaka, Department of Medicine, Jalan Mufti Haji Khalil, 75400 Melaka, Malaysia.",
"authors": "Guan|Y K|YK|;Gan|C C|CC|",
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"issn_linking": "0300-5283",
"issue": "71(5)",
"journal": "The Medical journal of Malaysia",
"keywords": null,
"medline_ta": "Med J Malaysia",
"mesh_terms": "D000368:Aged; D001932:Brain Neoplasms; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous; D008297:Male; D012878:Skin Neoplasms",
"nlm_unique_id": "0361547",
"other_id": null,
"pages": "296-297",
"pmc": null,
"pmid": "28064300",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary Cutaneous T Cell Lymphoma (Gamma Delta subtype).",
"title_normalized": "primary cutaneous t cell lymphoma gamma delta subtype"
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"companynumb": "MY-FRESENIUS KABI-FK201702391",
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"abstract": "Long-term radiotherapy-related complications in children with head and neck cancer have been frequently reported, especially facial growth disorders and dental abnormalities. We report on two male children (8 and 14 years old) with head and neck cancer, who were successfully treated with chemoradiotherapy and presented with growth deficiency of middle face and mandible hypoplasia, eight years and one year later, respectively. These severe growth complications attributed to chemoradiotherapy, while the patients survived primary malignancy. Patient age at irradiation was significantly correlated with the severity of disorders. We consider late sequelae in children with head and neck cancer due to chemoradiotherapy another era for pediatric oncologic pathology for prevention, if possible, or to manage them efficiently.",
"affiliations": "A'Propedeutic Department of Internal Medicine, AHEPA University Hospital.",
"authors": "Eleftheriadis|Nikolaos|N|;Papaloukas|Christos|C|;Eleftheriadis|Damianos|D|;Hatzitolios|Apostolos|A|;Ioannidou-Marathiotou|Ioulia|I|;Pistevou-Gompaki|Kiki|K|",
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"country": "New Zealand",
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"issue": "2()",
"journal": "International journal of general medicine",
"keywords": "growth disorders; head and neck cancer; radiotherapy",
"medline_ta": "Int J Gen Med",
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"nlm_unique_id": "101515487",
"other_id": null,
"pages": "63-6",
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"pmid": "20360888",
"pubdate": "2009-07-30",
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"references": "17973328;2473970;15609302;10066121;18515782;15234036;12729365;11121653;15641027;15108222;10491544;11166864",
"title": "Long-term radiotherapy related complications in children with head and neck cancer: Another era for pediatric oncologic pathology.",
"title_normalized": "long term radiotherapy related complications in children with head and neck cancer another era for pediatric oncologic pathology"
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"abstract": "Two phase 3 trials reported a prolonged survival in the third-line setting of colorectal cancer patients treated with regorafenib with the longest duration of treatment of 16 months. Herein, we reported a unique case of a patient refractory to conventional chemotherapy who showed a prolonged stable disease with regorafenib.",
"affiliations": "Medical Oncology Unit IRCCS Istituto Tumori \"Giovanni Paolo II\" Bari Italy.;Radiology Unit IRCCS Istituto Tumori \"Giovanni Paolo II\" Bari Italy.;Medical Oncology Unit IRCCS Istituto Tumori \"Giovanni Paolo II\" Bari Italy.;Medical Oncology Unit IRCCS Istituto Tumori \"Giovanni Paolo II\" Bari Italy.;Medical Oncology Unit IRCCS Istituto Tumori \"Giovanni Paolo II\" Bari Italy.",
"authors": "Brunetti|Oronzo|O|https://orcid.org/0000-0002-7014-6828;Calabrese|Angela|A|;Palermo|Loredana|L|;Solimando|Antonio Giovanni|AG|;Argentiero|Antonella|A|https://orcid.org/0000-0001-9187-3891",
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"country": "England",
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"doi": "10.1002/ccr3.2496",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2496CCR32496Case ReportCase ReportsLong‐term survival of an advanced colorectal cancer patient treated with Regorafenib: Case report and literature review BRUNETTI et al.Brunetti Oronzo https://orcid.org/0000-0002-7014-6828\n1\ndr.oronzo.brunetti@tiscali.it Calabrese Angela \n2\nPalermo Loredana \n1\nSolimando Antonio Giovanni \n1\n\n3\nArgentiero Antonella https://orcid.org/0000-0001-9187-3891\n1\n\n1 \nMedical Oncology Unit\nIRCCS Istituto Tumori \"Giovanni Paolo II\"\nBari\nItaly\n\n2 \nRadiology Unit\nIRCCS Istituto Tumori \"Giovanni Paolo II\"\nBari\nItaly\n\n3 \nDepartment of Biomedical Sciences and Human Oncology\nSection of Internal Medicine “G. Baccelli”\nUniversity of Bari Medical School\nBari\nItaly\n* Correspondence\n\nOronzo Brunetti, Medical Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, Viale Orazio Flacco, 65, 70124 Bari, Italy.\n\nEmail: dr.oronzo.brunetti@tiscali.it\n24 10 2019 12 2019 7 12 10.1002/ccr3.v7.122379 2383 01 8 2019 12 9 2019 26 9 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nTwo phase 3 trials reported a prolonged survival in the third‐line setting of colorectal cancer patients treated with regorafenib with the longest duration of treatment of 16 months. Herein, we reported a unique case of a patient refractory to conventional chemotherapy who showed a prolonged stable disease with regorafenib.\n\nTwo phase 3 trials reported a prolonged survival in the third‐line setting of colorectal cancer patients treated with regorafenib with the longest duration of treatment of 16 months. Herein, we reported a unique case of a patient refractory to conventional chemotherapy who showed a prolonged stable disease with regorafenib.\n\n\ncolorectal cancerlong‐term survivalregorafenibApulian Regional Project “Medicina di Precisione” source-schema-version-number2.0cover-dateDecember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.3 mode:remove_FC converted:29.12.2019\n\n\nBrunetti \nO \n, \nCalabrese \nA \n, \nPalermo \nL \n, \nSolimando \nAG \n, \nArgentiero \nA \n. Long‐term survival of an advanced colorectal cancer patient treated with Regorafenib: Case report and literature review . Clin Case Rep . 2019 ;7 :2379 –2383 . 10.1002/ccr3.2496\n==== Body\n1 INTRODUCTION\nRegorafenib (Stivarga®) is a tyrosin kinase inhibitor (TKI) impairing angiogenesis through the block of both vascular endothelial growth factor receptors (VEGFR) 1 and 3 (VEGFR3) and tyrosine kinase with immunoglobulin‐like and EGF‐like domains 2 (TIE2). Moreover, it targets tumor microenvironment through the inhibition of platelet‐derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).1, 2, 3\n\n\nActually, this drug represents a therapeutic option in the third‐line setting of metastatic colorectal cancer (mCRC) patients according to the results of two phase III randomized trials (CORRECT and CONCUR) which showed a significant improvement both in terms of progression‐free survival (PFS) and overall survival (OS) compared to best supportive care (BSC)4, 5 alone. Median overall survivals (mOS)s were 6.4 and 8.8 months, for Western4 and Asiatic trials,5 respectively, with the longest duration of treatment of 16 months in CORRECT trial.\n\nHerein, we report a unique case of a patient refractory to oxaliplatin‐based and irinotecan‐based chemotherapy combined with bevacizumab who showed a prolonged response (25 months) to regorafenib.\n\n2 CASE PRESENTATION\nA 57‐year‐old caucasian woman underwent right hemicolectomy for a poorly differentiated mucinous CRC. Presurgical radiological staging deemed negative for distant metastases. Pathological stage was pT3N2M0 (stage III). Subsequently, she received adjuvant systemic therapy with the combination of capecitabine plus oxaliplatin for eight cycles.\n\nA computed tomography (CT) scan carried out at the end of this treatment revealed a bulky left ovarian mass (70 × 67 mm) associated with high serum levels of CA19.9 (289 µ/mL) and CEA (48 ng/mL). Therefore, the patient underwent an exploratory laparotomy with evidence of multiple peritoneal nodules. Thus, debulking surgery was performed with left ovariectomy and excision of two peritoneal metastases. Histological examination revealed a localization of well‐differentiated mucinous CRC (CDX2 positive, CK7, and CK20 partially positive; KRAS‐codon 12 mutation and BRAF wild‐type) associated with peritoneal carcinosis. RAS and RAF determinations had been performed on metastatic site since it had been demonstrated the high concordance between RAS and RAF between primary and metastatic CRC.6\n\n\nThe CT scan performed 2 months after surgery showed controlateral ovaric mass (100 × 80 mm) and multiple peritoneal nodules (maximum diameter of 70 mm in recto‐uterine pouch). High levels of tumor markers (CA19.9 302 µ/mL, CEA 27 ng/mL) were observed.\n\nFirst‐line therapy according to FOLFIRI regimen in combination with bevacizumab was started. Nevertheless, 2 months after starting of therapy a CT scan showed an increase in ovaric mass (140 × 130 mm) and peritoneal involvement and the appearance of two hepatic lesions (largest diameters of 12 and 10 mm in V and II hepatic segments, respectively). She was enrolled in a clinical trial by another referral cancer center. Nonetheless, a CT scan documented an early progression with the appearance of right ovarian metastases (largest diameter of 30 cm) associated with omolateral hydroureteronephrosis and bowel subocclusion. A second debulking cytoreductive surgery was performed with histological confirmation of moderately differentiated mucinous metastases from CRC.\n\nSubsequently CT scan confirmed multiple peritoneal and omental implants up to 95 mm and liver metastases (Figure 1). Serum levels of CA19.9 and CEA were 434 ng/mL and 32 µ/mL, respectively.\n\nFigure 1 Abdominal CT scan at the beginning of therapy with regorafenib showed: (A) peritoneal mass localized in recto‐uterine pouch (largest diameter of 95 mm); (B) liver metastasis at segment VIII (largest diameter of 34 mm) (B). Abdominal CT scan performed 6 mo after the beginning of therapy (best response) showed the reduction of peritoneal and liver lesions (largest diameters: 81 and 25 mm, respectively) (C‐D)\n\nA third‐line treatment with regorafenib (160 mg po day for 3 weeks and 1‐week rest) was started. Remarkably, this therapeutic approach allowed to obtain a prolonged modest reduction of the dimensions of both peritoneal nodules and liver metastases associated with the decrease in serum levels of CA19.9 and CEA (up to 113 ng/mL and 13 µ/mL, respectively). (Figure 1) The most frequent observed regorafenib‐related grade 1‐2 adverse events were hypertension, hand‐foot syndrome, stomatitis, and hoarseness. Occasionally, grade 3 diarrhea and fatigue required dosage modulations.\n\nAfter 25 months of treatment with regorafenib, a CT scan revealed a peritoneal and liver metastases progression in combination with a performance status decline. After few weeks of BSC, the patient's exitus was registered.\n\n3 DISCUSSION\nRegorafenib improved mOS in patients with CRC who were pretreated with conventional chemotherapies. In particular, mOSs were 6.4 and 5 months in the regorafenib group and placebo group, respectively (hazard ratio 0.77; 95% CI 0.64‐0.94; one‐sided P = .0052), in CORRECT trial.4 This phase III trial randomized pretreated patients with CRC to receive regorafenib or placebo. Additionally, CONCUR phase III trial on pretreated Asian CRC patients investigated the same randomization.5 This trial demonstrated a mOS improvement with regorafenib than placebo (hazard ratio 0.55, 95% CI 0.40‐0.77, one‐sided P = .00016; 8.8 vs 6.3 months, respectively). The longest duration of regorafenib treatment was 16 months.\n\nOnly few reports described patients who received this molecule for a prolonged period (Table 1). Rosati et al reported an OS of 13 months after administration of regorafenib.7\n\n\nTable 1 Review of literature of long‐term survivor mCRC patient treated with regorafenib\n\nPatient's characteristics\tPretretments\tRegorafenib‐OS\tMonths of regorafenib treatment\tReferences\t\nCaucasian male, 67 y\t\nCetuximab plus irinotecan‐based bevacizumab plus oxaliplatin and 5‐FU\n\n\nRechallenge with panitumumab rechallenge of an oxaliplatin‐based CT\n\n\n\t13 mo\t13 mo\tRosati7\n\t\nCaucasian male, 59 y\t\nFolfox‐Bevacizumab\n\n\nFolfiri‐Bevacizumab\n\n\nFolfox‐Cetuximab\n\n\n\t24 mo\t17 mo\tCallebout8\n\t\nAsiatic male, 54 y\t\nFOLFIRI\n\n\nOral FU plus LV\n\n\nXELOX‐bevacizumab\n\n\nFOLFIRI‐panitumumab\n\n\nmFOLFOX6‐panitumumabmab\n\n\n\t24 mo+\t24 mo+\tYoshino9\n\t\nCaucasian male, 54 y\t\nFOLFOX‐4\n\n\nFOLFIRI‐aflibercept\n\n\n\t36 mo (interspersed by RT)\t36 mo+\tRoberto10\n\t\nCaucasian male, 54 y\t\nFOLFOX‐4\n\n\nFOLFIRI‐aflibercept\n\n\n\t30 mo (interspersed by RT)\t25 mo\tKorphaisarn11\n\t\nCaucasian male, 63 y\t\nFOLFOX\n\n\nFolfiri‐Bevacizumab\n\n\n\t25 mo\t25 mo\tAmram22\n\t\nCaucasian female, 57 y\t\nXelox\n\n\nFolfiri‐Bevacizumab\n\n\n\t25 mo\t25 mo\tPresent report\t\nAbbreviations: CT, chemotherapy; FU, fluorouracil; LV, leucovorin; OS, overall survival; RT, radiotherapy; ys, years.\n\nJohn Wiley & Sons, LtdOf note, Callebout et al reported an OS of 25 months.8 Nonetheless, in this report the therapeutic program was discontinuous due to radiotherapy combinatorial approach. Conversely, our case achieved the same OS with uninterrupt ed medical treatment. Intriguingly, the histology of Callebout and colleagues’ report was a mucinous colorectal cancer likewise our patient. As these authors reported, mucinous histology shows highly epithelial‐mesenchimal transition signature, which, given FGFR and PDGFR inhibition, could represent a regorafenib target. Also Yoshino et al described a case of a 2‐year survival with regorafenib treatment.9 These authors reported a case of a CRC patient with RAS‐RAF WT and a sustained OS of over 9 years. Roberto et al illustrated the case of a CRC patient with a regorafenib‐related OS of 36 months, even if his oligometastatic disease was controlled with stereotactic radiotherapy.10 Also in this report, the patient's OS resulted in about 6 years. Similarly, Korphaisarnet al. described the case of a chemo‐resistant rectal cancer with a prolonged response to regorafenib and locoregional progression which underwent a RT control.11\n\n\nThese patients shared common features, such as their prolonged response to previous lines of therapy. It is reasonable to speculate the presence of biological features of these tumors related to their chemo‐responsiveness.12, 13 Two peculiar aspects of our patient are represented by the prolonged response to regorafenib combined to the lack of response to oxaliplatin‐based and irinotecan‐based chemotherapy. Furthermore, our patient underwent two debulking surgeries before the beginning of therapy with regorafenib.\n\nIn order to better understand the predictive role and the clinical activity of regorafenib in CRC, a retrospective, exploratory analysis of circulating DNA and protein biomarkers had been carried out in patients enrolled in the CORRECT trial. Several biomarkers have been evaluated. In particular, it was demonstrated that regorafenib had a greater impact on OS of patients with high concentration of TIE‐1 than in those with a low concentration14 as emerges from the study a post hoc analysis. In fact, the great response to regorafenib should be improved to sensible activation of pathways conventionally inhibited by regorafenib,15 namely angiogenesis and vasculogenesis, which in mucinous mCRC result hyperactivated due to hypoxic microenvironment.16\n\n\nOur patient displayed several regorafenib‐related adverse events (ie, hand‐foot syndrome, stomatitis, hypertension, and hoarseness), even if only of grades 1‐2 with the exception of grade 3 diarrhea and fatigue which required temporary dose modifications according to summary of product characteristics. Also, this aspect is relevant in our case due to the frequent correlation between the length of treatment and the appearance of AE which sometimes could require hospitalization.17, 18\n\n\nHistopatological and clinical features of this tumor associated with its chemorefractory to previous lines of chemotherapy support its poor prognosis. Conversely, the prolonged stable disease to regorafenib in combination with its good toxicity profile supports the potential therapeutic role of this drug.\n\nConclusively, we believe that only the knowledge of the molecular aspects of primary tumor and of its metastases could have helped in the deeper comprehension of the unique history of this patient. In particular, the analysis of clinical, laboratoristic, and biological features s uch as for other anti‐angiogenic drug 19, 20, 21 might provide novel insights explaining the long‐term survival.\n\nCONFLICT OF INTEREST\nThe authors declare the absence of conflicts of interest.\n\nAUTHOR CONTRIBUTIONS\nOB, LP, and AGS: conceptualized the study. AC and AA: involved in methodology. OB, AC, and LP: formally analyzed the data. AA, OB, and AGS: investigated the study. OB: involved in data curation. AA and OB: involved in writing—original draft preparation. OB: involved in writing—review and editing; AA and OB: provided resources. OB and AGS: supervised the study; AGS: acquired funding.\n\nACKNOWLEDGMENTS\nThis research project was supported in part by the Apulian Regional Project “Medicina di Precisione”\n==== Refs\nREFERENCES\n1 \n\nStrumberg \nD \n, \nScheulen \nME \n, \nSchultheis \nB \n, et al. Regorafenib (BAY 73–4506) in advanced colorectal cancer: a phase I study . Br J Cancer . 2012 ;106 :1722 ‐1727 .22568966 \n2 \n\nMross \nK \n, \nFrost \nA \n, \nSteinbild \nS \n, et al. A phase I dose‐escalation study of regorafenib (BAY 73–4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors . Clin Cancer Res . 2012 ;18 :2658 ‐2667 .22421192 \n3 \n\nQuatrale \nAE \n, \nPorcelli \nL \n, \nSilvestris \nN \n, et al. GFR tyrosine kinases inhibitors in cancer treatment: In vitro and in vivo evidence . Front Biosci . 2011 ;16 :1962 ‐1972 .\n4 \n\nGrothey \nA \n, \nVan Cutsem \nE \n, \nSobrero \nA \n, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo‐controlled, phase 3 trial . Lancet . 2013 ;381 :303 ‐312 .23177514 \n5 \n\nLi \nJ \n, \nQin \nS \n, \nXu \nR \n, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, doubleblind, placebo‐controlled, phase 3 trial . Lancet Oncol . 2015 ;16 :619 ‐629 .25981818 \n6 \n\nSantini \nD \n, \nSpoto \nC \n, \nLoupakis \nF \n, et al. High concordance of BRAF status between primary colorectal tumours and related metastatic sites: implications for clinical practice . Ann Oncol . 2010 ;21 :1565 .20573852 \n7 \n\nRosati \nG \n, \nDel Gaudio \nN \n, \nScarano \nE \n, et al. Unexpected and durable response with regorafenib in a metastatic colorectal cancer patient without KDR mutation . Medicine . 2018 ;97 :e11178.29924031 \n8 \n\nCallebout \nE \n, \nRibeiro \nSM \n, \nLaurent \nS \n, et al. Long term response on regorafenib in non‐V600E BRAF mutated colon cancer: a case report . BMC Cancer . 2019 ;19 :567 .31185985 \n9 \n\nYoshino \nK \n, \nManaka \nD \n, \nKudo \nR \n, et al. Metastatic colorectal cancer responsive to regorafenib for 2 years: a case report . J Med Case Rep . 2017 ;11 :227 .28818109 \n10 \n\nRoberto \nM \n, \nFalcone \nR \n, \nMazzuca \nF \n, et al. The role of stereotactic body radiation therapy in oligometastatic colorectal cancer: clinical case report of a long‐responder patient treated with regorafenib beyond progression . Medicine . 2017 ;96 :e9023.29310420 \n11 \n\nKorphaisarn \nK \n, \nLoree \nJM \n, \nNguyen \nV \n, et al. Genomic analysis of exceptional responder to regorafenib intreatment‐refractory metastatic rectal cancer: a case report and review of the literature . Oncotarget . 2017 ;8 :57882 ‐57888 .28915719 \n12 \n\nNakayama \nI \n, \nShinozaki \nE \n, \nMatsushima \nT \n, et al. Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first‐line chemotherapy with bevacizumab in metastatic colorectal cancer patients . BMC Cancer . 2017 ;17 :38 .28068936 \n13 \n\nRusso \nA \n, \nRizzo \nS \n, \nBronte \nG \n, et al. The long and winding road to useful predictive factors for anti‐egfr therapy in metastatic colorectal carcinoma: the KRAS/BRAF pathway . Oncology . 2009 ;77 :57 ‐68 .20130433 \n14 \n\nTabernero \nJ \n, \nLenz \nHJ \n, \nSiena \nS \n, et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial . Lancet Oncol . 2015 ;16 :937 ‐948 .26184520 \n15 \n\nYan \nY \n, \nGrothey \nA \n. Molecular profiling in the treatment of colorectal cancer: focus on regorafenib . Onco Targets Ther . 2015 ;8 :2949 ‐2957 .26508880 \n16 \n\nMalfettone \nA \n, \nSilvestris \nN \n, \nParadiso \nA \n, et al. Overexpression of nuclear NHERF1 in advanced colorectal cancer: association with hypoxic microenvironment and tumor invasive phenotype . Exp Mol Pathol . 2012 ;92 :296 ‐303 .22440733 \n17 \n\nNumico \nG \n, \nLongo \nV \n, \nCourthod \nG \n, et al. Cancer survivorship: long‐term side‐effects of anticancer treatments of gastrointestinal cancer . Curr Opin Oncol . 2015 ;27 :351 ‐357 .26049277 \n18 \n\nNumico \nG \n, \nCristofano \nA \n, \nMozzicafreddo \nA \n, et al. Hospital admission of cancer patients: avoidable practice or necessary care? \nPLoS ONE . 2015 ;10 :e0120827.25812117 \n19 \n\nSilvestris \nN \n, \nScartozzi \nM \n, \nGraziano \nG \n, et al. Basal and bevacizumab‐based therapy‐induced changes of lactate dehydrogenases and fibrinogen levels and clinical outcome of previously untreated metastatic colorectal cancer patients: a multicentric retrospective analysis . Expert Opin Biol Ther . 2015 ;15 :155 ‐162 .25411089 \n20 \n\nAzzariti \nA \n, \nPorcelli \nL \n, \nBrunetti \nO \n, et al. Total and not bevacizumab‐bound vascular endothelial growth factor as potential predictive factors to bevacizumab‐based chemotherapy in colorectal cancer . World J Gastroenterol . 2016 ;22 :6287 ‐6295 .27468218 \n21 \n\nSilvestris \nN \n, \nMarech \nI \n, \nBrunetti \nAE \n, et al. Predictive factors to targeted treatment in gastrointestinal carcinomas . Cancer Biomark . 2014 ;14 :151 ‐162 .24878816 \n22 \n\nAmram \nML \n, \nMontet \nX \n, \nRoth \nAD \n. Long‐term survival with regorafenib in KRAS‐mutated metastatic rectal cancer . Case Rep Oncol . 2017 ;10 :1029 ‐1034 .29279709\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "7(12)",
"journal": "Clinical case reports",
"keywords": "colorectal cancer; long‐term survival; regorafenib",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2379-2383",
"pmc": null,
"pmid": "31893063",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "29310420;22568966;26508880;28818109;25411089;29279709;25981818;25812117;28915719;24878816;26184520;20573852;27468218;22440733;28068936;29924031;21196276;20130433;23177514;31185985;26049277;22421192",
"title": "Long-term survival of an advanced colorectal cancer patient treated with Regorafenib: Case report and literature review.",
"title_normalized": "long term survival of an advanced colorectal cancer patient treated with regorafenib case report and literature review"
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"abstract": "SLC6A1 is associated with an autosomal dominant early-onset seizure and epileptic encephalopathy associated with intellectual disability. We present a 2-yr-old girl with developmental delay and epilepsy, using a new computational filtering impact score to show the patient's variant ranks with other pathogenic variants. Genomic studies within the patient revealed a G443D variant of uncertain significance. Structural and evolutionary assessments establish this variant as a loss of function to the protein. Compiled metrics through our custom tools on sequence, structure, and protein dynamics combined with PolyPhen-2, PROVEAN, SIFT, and Align-GVGD reveal this variant to rank in the top functional outcome changes relative to gnomAD, TOPMed, and ClinVar variants known to date. The patient was resistant to multiple epileptic drugs, finally finding that valproic acid controls the seizures. This is consistent with additional groups studying SLC6A1 variants within patients.",
"affiliations": "Pediatric Neurology, Helen DeVos Children's Hospital, Grand Rapids, Michigan 49503, USA.;Pediatric Neurology, Helen DeVos Children's Hospital, Grand Rapids, Michigan 49503, USA.;Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503, USA.;Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503, USA.;Spectrum Health Division of Medical Genetics, Grand Rapids, Michigan 49503, USA.",
"authors": "Devries|Seth|S|;Mulder|Monica|M|;Charron|Jacob G|JG|;Prokop|Jeremy W|JW|;Mark|Paul R|PR|",
"chemical_list": "D050485:GABA Plasma Membrane Transport Proteins; C493413:SLC6A1 protein, human; D014635:Valproic Acid",
"country": "United States",
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"doi": "10.1101/mcs.a005371",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case Stud\nCold Spring Harb Mol Case Stud\ncshmcs\ncshmcs\ncshmcs\nCold Spring Harbor Molecular Case Studies\n2373-2873 Cold Spring Harbor Laboratory Press \n\n32660967\n10.1101/mcs.a005371\nMCS005371Dev\nRapid Communication\nSLC6A1 G443D associated with developmental delay and epilepsy\nSLC6A1 computational variant screenSLC6A1 computational variant screenDevries Seth 1 Mulder Monica 1 Charron Jacob G. 2 Prokop Jeremy W. 23 Mark Paul R. 4 1 Pediatric Neurology, Helen DeVos Children's Hospital, Grand Rapids, Michigan 49503, USA;\n2 Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503, USA;\n3 Department of Pharmacology and Toxicology, Michigan State University, East Lansing Michigan 48824, USA;\n4 Spectrum Health Division of Medical Genetics, Grand Rapids, Michigan 49503, USA\nCorresponding author: seth.devries@helendevoschildrens.org\n8 2020 \n6 4 a0053719 3 2020 29 6 2020 © 2020 Devries et al.; Published by Cold Spring Harbor Laboratory Press2020This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.SLC6A1 is associated with an autosomal dominant early-onset seizure and epileptic encephalopathy associated with intellectual disability. We present a 2-yr-old girl with developmental delay and epilepsy, using a new computational filtering impact score to show the patient's variant ranks with other pathogenic variants. Genomic studies within the patient revealed a G443D variant of uncertain significance. Structural and evolutionary assessments establish this variant as a loss of function to the protein. Compiled metrics through our custom tools on sequence, structure, and protein dynamics combined with PolyPhen-2, PROVEAN, SIFT, and Align-GVGD reveal this variant to rank in the top functional outcome changes relative to gnomAD, TOPMed, and ClinVar variants known to date. The patient was resistant to multiple epileptic drugs, finally finding that valproic acid controls the seizures. This is consistent with additional groups studying SLC6A1 variants within patients.\n\nabsence seizuresautismmoderate global developmental delayNational Institutes of Health (NIH) 10.13039/100000002National Institute of Environmental Health Sciences (NIEHS) 10.13039/100000066K01ES025435\n==== Body\nCASE PRESENTATION\nThe patient is a 2-yr-old Hispanic child with developmental delay and epilepsy. She did not walk until 20 mo of age. She has speech delays and has been diagnosed with autism spectrum disorder. She had previously been evaluated by physical therapy and speech therapy and was measured to be delayed by ∼3 mo. At ∼19 mo of age, her mother noted recurrent episodes of staring and unresponsiveness. During these events, she would display sudden behavioral arrest and staring, lasting 10–15 sec at a time. Upon resolution, she would immediately return to her baseline. An electroencephalogram (EEG) was obtained and confirmed the presence of absence seizures involving generalized 3-Hz spike-and-wave complexes lasting <10 sec. Clinically, she displayed brief behavioral arrest with upward eye deviation and eyelid flutter.\n\nIn light of the clinical presentation and EEG findings, the patient was started on ethosuximide. Her seizures continued despite escalating doses of ethosuximide. Over the next 3 mo, her mother also witnessed multiple falls with her seizures. The patient was transitioned from ethosuximide to zonisamide. Her seizures continued on zonisamide despite escalating doses. A 24-h EEG was obtained at 24 mo of age. This displayed generalized background slowing, rhythmic posterior δ activity, loosely organized generalized 3-Hz spike-and-wave discharges, and numerous absence seizures. This EEG was remarkable for worsening encephalopathy when compared to the tracing at 19 mo of age. Valproic acid was added to the patient's regimen after her long-term video-EEG monitoring study. Her seizure burden became significantly improved after starting valproic acid; however, she had occasional breakthrough seizures in the setting of fatigue and illness. Clobazam was added to her regimen, which provided further seizure control. She was diagnosed to be on the autism spectrum by 30 mo of age, after undergoing a full physical and psychological evaluation at the Autism Spectrum Disorders Assessment Clinic.\n\nTECHNICAL ANALYSIS\nThe patient was referred to Medical Genetics at 22 mo of age. Neither the maternal nor paternal family history shared her clinical findings (Table 1). A chromosomal microarray was obtained and found to be normal. A comprehensive epilepsy gene panel evaluating 181 known epilepsy-causing genes was obtained (Invitae), with follow-up performed on both parents. Variants were assessed through our previously published sequence-to-structure-to-function workflow (Prokop et al. 2017), comparing the patient variant to all gnomAD, TOPMed, and ClinVar missense variants for SLC6A1. These tools develop a high density conservation and evolutionary selection map of each amino acid and the additive conservation of motifs while also developing a quantitative map of biophysical insights of the protein structure. All variants were assessed with PolyPhen-2, PROVEAN, SIFT, and Align-GVGD. A total of 18 nsec of molecular dynamics simulations (mds) were run on a lipid membrane-embedded SLC6A1 protein model using the AMBER03 force field (Duan et al. 2003). Using mds is a way to track atomic movement based on biophysical parameters, allowing for taking 3D structure qualitative insights and translating them into quantitative assessments of protein folding.\n\nTable 1. Clinical findings\n\nFeature\tProband\tMother\tFather\t\nDevelopmental delay\tYes\tNo\tNo\t\nEpilepsy\tYes\tNo\tNo\t\nEpisodes of staring and unresponsiveness\tYes\tNo\tNo\t\nAutism\tYes\tNo\tNo\t\nVARIANT INTERPRETATION\nGenetic testing revealed six gene mutations as noted on Table 2. One de novo heterozygous variant of uncertain significance (VUS) was present in SLC6A1. Heterozygous variants for GRIN2B, KANSL1, and MBD5 were inherited from the unaffected father, changing their classification from VUS to likely benign. CERS1 and SLC25A22 also had one heterozygous variant each, but these are both autosomal recessive linked disorders, thus classifying the variants as noncausal.\n\nTable 2. Genomic findings\n\nGene\tChromosome\tHGVS DNA reference\tHGVS protein reference\tVariant type\tPredicted effect (substitution, deletion, etc.)\tdbSNP/dbVar ID\tGenotype (heterozygous/ homozygous)\tClinVar ID\tParent of origin\tComments\t\nSLC6A1\t3: 11031181 (GRCh38)\tc.1328G > A\tp.Gly443Asp\tSNV\tMissense\tN/A\tHeterozygous\tVCV000845407.1\tDe novo\tVUS\t\nGRIN2B\t12: 13865884 (GRCh38)\tc.325G > T\tp.Ala109Ser\tSNV\tMissense\trs772078838\tHeterozygous\tVCV000246440.3\tPaternal\tLikely benign\t\nKANSL1\t17: 46039111 (GRCh38)\tc.2308C > T\tp.Arg770Cys\tSNV\tMissense\tN/A\tHeterozygous\tVCV000833548.1\tPaternal\tLikely benign\t\nMBD5\t2: 148469427-148469429 (GRCh38)\tc.1484_1486CAA\tp.Thr496del\t3-bp microsatellite\tdeletion\tN/A\tHeterozygous\tVCV000833549.1\tPaternal\tLikely benign\t\nCERS1\t19: 18884102 (GRCh38)\tc.575C > T\tp.Ser192Phe\tSNV\tMissense\trs1009080328\tHeterozygous\tVCV000656194.2\tNot evaluated\tNoncausal (recessive gene)\t\nSLC25A22\t11: 792588 (GRCh38)\tc.552C > A\tp.Ala184=\tSNV\tSynonymous\trs368807589\tHeterozygous\tVCV000506576.2\tNot evaluated\tNoncausal (recessive gene)\t\n(HGVS) Human Genome Variation Society, (SNV) single-nucleotide variation, (N/A) not applicable, (VUS) variant of uncertain significance.\n\nOur top VUS was found within the SLC6A1 gene that codes for the sodium- and chloride-dependent GABA transporter one protein (GAT-1). GAT-1 is important in GABA concentration management in synapsis and has been associated with myoclonic–atonic epilepsy with some variability in epilepsy types, whereas most patients have an intellectual disability with autistic features similar to this patient (Carvill et al. 2015; Johannesen et al. 2018; Mattison et al. 2018). Johannesen et al. also report that the genetic etiology of childhood absence epilepsy can include SLC6A1. This is consistent with our patient's epilepsy phenotype. Similar to the findings from Johannesen et al., we find that valproic acid is an effective drug in seizure control, whereas clobazam has also provided some benefit. This may be related in part to the positive effects that both of these medications have on the GABA system. GAT-1 acts as a voltage-regulated transmembrane transporter that reuptakes GABA from the synaptic cleft by process of a Na+ and Cl− exchange for GABA, with mouse knockouts showing spike-wave discharges (Jin et al. 2011; Carvill et al. 2015). Modulation of GABA by various means has been shown to minimize the myoclonic–atonic seizures (Palmer et al. 2016).\n\nAs of early 2020, ClinGen annotates “sufficient” evidence for haploinsufficiency-linked disorder for SLC6A1 with 229 deposited cases of SLC6A1 variants in ClinVar. Of these, 29 missense variants are annotated as pathogenic or likely pathogenic. A total of 67 (29.3%) have been annotated as VUSs similar to the patient presented here, highlighting the need for additional insights of variant linked pathology outside of phenotype matching, linking VUSs to pathogenic variants using bioinformatics. Evolution and structural analysis of the SLC6A1 G443D variant suggests a loss of function to the protein. A protein model for SLC6A1 was generated and embedded into a lipid membrane (Fig. 1A), revealing the G413 site to be found at the base of an α-helix (Fig. 1B,C) that is well-packed within the structure based on mds (Fig. 1D). Alterations of the flexible Gly to a polar acidic residue at this position will disrupt helix formation, disrupting the transmembrane helix packing. A deep evolutionary analysis of 225 species’ open reading frames (ORFs) for SLC6A1 reveals amino acid 443 to fall in a highly conserved region (Fig. 1E) under very high selection (Fig. 1F). The conservation and selection confirm the critical need for the flexible Gly residue at this position. Integrating the conservation for each amino acid with a sliding window of conservation to map important motifs and functional predictions (PolyPhen-2, PROVEAN, SIFT, and Align-GVGD), we developed a numerical value for all known SLC6A1 variants. Variant impact for all gnomAD/TOPMed, ClinVar, and patient variants reveals the G443D to fall near several other ClinVar variants with high variant impact scores including several pathogenic variants (Fig. 1G). The G443D combined impact is one of the highest categorized annotations, ranking 14th out of 254 variants assessed (Fig. 1H) and falls three-dimensionally near L214 and S437 previously associated with disease (Fig. 1I). The mds data supports G443 to be critical in the folding of the protein, with movement far below the average of all other variant groups (Fig. 1J). The structural, evolutionary, and functional bioinformatics can confirm clustering of impactful variants between VUS and pathogenic. This data supports the G443D variant to be a loss-of-function site for SLC6A1, ranking as one of the most impactful VUSs within ClinVar annotations, clustering in score to pathogenic variants. We also noted that one variant annotated as likely benign for intellectual disability, I292T, scores very high with conservation in all species assessed and functional damaging call in all tools used. A second ClinVar inclusion for I292T linked to myoclonic–atonic epilepsy has the variant entered as a VUS.\n\nFigure 1. SLC6A1 variant analysis. (A,B) Structural model of SLC6A1 (gray) in a lipid membrane (A, multicolored) or alone (B). The top represents a view of the protein from the extracellular surface, whereas the bottom is from a cross section of the membrane. On B, the G443 position is marked and the zoom-in view is provided on the right. (C) 3D printed model of G443 (red) on SLC6A1 (gray) with a cutout of the membrane (cyan) available at www.shapeways.com/product/AAUK2K5JU/slc6a1?li=marketplace&optionId=150795805. (D) Molecular dynamic simulation of the SLC6A1 protein model in A shown for the carbon α root mean squared deviation (RMSD) for each amino acid averaged throughout 18 nsec of simulation. These values provide quantitative values for amino acids well packed (low RMSD) and those found within loops with no atomic hindrance in movement, with most values of SLC6A1 here low, suggestive of a well-folded protein. The bottom red box is a zoom-in view of amino acid 443 region showing high stability of the structure. (E) Deep evolutionary analysis using 225 species open reading frame sequences for SLC6A1. The plot shows a sliding window calculation for each site (plus 10 upstream and downstream), identifying the most selected and conserved linear motifs within the gene. Amino acid 443 is identified in red. (F) Zoom-in view of conservation for amino acid 443 (red) linear motif. The numbers above represent the percent of sequences with synonymous/nonsynonymous variants throughout evolution. (G) Variant impact scoring for all TOPMed/gnomAD (gray), ClinVar (benign or likely benign in green, pathogenic or likely pathogenic in orange, VUS in cyan), and patient (red) variants for SLC6A1. (H) Box and whisker plot for each group plotted in G, with colors consistent within G–J. This shows that the value clustering for each ClinVar annotation was likely pathogenic, pathogenic values are seen elevated over gnomAD/TOPMed and benign annotation, and only a few VUSs score high including G443D in red. (I) Clustered 3D variants on SLC6A1 relative to the patients with the same colors as those labeled in H. The lipid membrane is shown in magenta. (J) Root mean squared fluctuation (RMSF) of variant groups. The values show the average movement of each amino acid throughout biochemical simulations in which benign and gnomAD/TOPMed variants have higher movement and all other groups (excluding a few VUSs and pathogenic variants) are low, suggestive of well-packed amino acids including G443D.\n\nIn combination we show the variant is de novo in proband with confirmed lack of presence in parents and paternity confirmed through the presence of other rare variants (PS2) and is absent in controls of gnomAD/TOPMed (PM2), and we have multiple lines of computational evidence (PP3) ranking the variant as likely pathogenic using American College of Medical Genetics and Genomics (ACMG) standards (Richards et al. 2015). In addition, we show that pharmacogenomics aligns our likely pathogenic variant in SLC6A1 with known successful drug response.\n\nSUMMARY\nIn conclusion, we identify a variant in SLC6A1, G443D, that associates with seizures and developmental delay. Based on assessments to all known variants in SLC6A1, we show that G443 is a far outlier for functional impact and structural fold contribution, which indicates its critical loss-of-function role in SLC6A1. This represents a novel strategy for SLC6A1 assessments for VUSs that can be used in future screening projects.\n\nADDITIONAL INFORMATION\nData Deposition and Access\nAll variants have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) with accession numbers VCV000845407.1, VCV000246440.3, VXV000833548.1, VCV000833549.1, VCV000656194.2, and VCV000506576.2.\n\nEthics Statement\nSigned consent was obtained for research publication from the patient's parents. Spectrum Health IRB approval is not needed for a single care report.\n\nAcknowledgments\nWe thank the patient and family for consenting to share this story and providing all clinical samples.\n\nAuthor Contributions\nS.D. was lead clinician and oversaw all clinical care, M.M. managed patient care and extracted clinical information, J.G.C. and J.W.P. performed all bioinformatic variant interpretation work, and P.R.M. was lead geneticist on the project. All authors contributed to the writing of the manuscript.\n\nFunding\nFunding for variant characterization came from the National Institutes of Health (NIH) Office of the Director and National Institute of Environmental Health Sciences (NIEHS) grant K01ES025435 (J.W.P.).\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n==== Refs\nREFERENCES\nCarvill \nGL , McMahon \nJM , Schneider \nA , Zemel \nM , Myers \nCT , Saykally \nJ , Nguyen \nJ , Robbiano \nA , Zara \nF , Specchio \nN , \n2015 \nMutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic–atonic seizures\n. Am J Hum Genet \n96 : 808 –815\n. 10.1016/j.ajhg.2015.02.016 25865495 \nDuan \nY , Wu \nC , Chowdhury \nS , Lee \nMC , Xiong \nG , Zhang \nW , Yang \nR , Cieplak \nP , Luo \nR , Lee \nT , \n2003 \nA point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations\n. J Comput Chem \n24 : 1999 –2012\n. 10.1002/jcc.10349 14531054 \nJin \nX-T , Galvan \nA , Wichmann \nT , Smith \nY . 2011 \nLocalization and function of GABA transporters GAT-1 and GAT-3 in the basal ganglia\n. Front Syst Neurosci \n5 : 63 .21847373 \nJohannesen \nKM , Gardella \nE , Linnankivi \nT , Courage \nC , de Saint Martin \nA , Lehesjoki \nA-E , Mignot \nC , Afenjar \nA , Lesca \nG , Abi-Warde \nM-T , \n2018 \nDefining the phenotypic spectrum of SLC6A1 mutations\n. Epilepsia \n59 : 389 –402\n. 10.1111/epi.13986 29315614 \nMattison \nKA , Butler \nKM , Inglis \nGAS , Dayan \nO , Boussidan \nH , Bhambhani \nV , Philbrook \nB , da Silva \nC , Alexander \nJJ , Kanner \nBI , \n2018 \nSLC6A1 variants identified in epilepsy patients reduce γ-aminobutyric acid transport\n. Epilepsia \n59 : e135 –e141\n. 10.1111/epi.14531 30132828 \nPalmer \nS , Towne \nMC , Pearl \nPL , Pelletier \nRC , Genetti \nCA , Shi \nJ , Beggs \nAH , Agrawal \nPB , Brownstein \nCA . 2016 \nSLC6A1 mutation and ketogenic diet in epilepsy with myoclonic–atonic seizures\n. Pediatr Neurol \n64 : 77 –79\n. 10.1016/j.pediatrneurol.2016.07.012 27600546 \nProkop \nJW , Lazar \nJ , Crapitto \nG , Smith \nDC , Worthey \nEA , Jacob \nHJ . 2017 \nMolecular modeling in the age of clinical genomics, the enterprise of the next generation\n. J Mol Model \n23 : 75 \n10.1007/s00894-017-3258-3 28204942 \nRichards \nS , Aziz \nN , Bale \nS , Bick \nD , Das \nS , Gastier-Foster \nJ , Grody \nWW , Hegde \nM , Lyon \nE , Spector \nE , \n2015 \nStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology\n. Genet Med \n17 : 405 –424\n. 10.1038/gim.2015.30 25741868\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "6(4)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "absence seizures; autism; moderate global developmental delay",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D002675:Child, Preschool; D002658:Developmental Disabilities; D004827:Epilepsy; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability; D000073658:Loss of Function Mutation; D009154:Mutation; D010641:Phenotype; D012640:Seizures; D014635:Valproic Acid",
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"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "25865495;29315614;30132828;21847373;25741868;27600546;28204942;14531054",
"title": "SLC6A1 G443D associated with developmental delay and epilepsy.",
"title_normalized": "slc6a1 g443d associated with developmental delay and epilepsy"
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"abstract": "The clinical implications of cohesin gene complex mutation in acute myeloid leukemia (AML) are not well characterized. In the present study, a cohort of 152 de novo unselected adult AML patients underwent conventional and molecular cytogenetic analysis for chromosomal aberrations. Further, we examined the frequency and clinical implications of mutations in cohesin gene complex STAG1, STAG2, RAD21, SMC1, and SMC3 using whole exome sequencing as a pilot study in 10 de novo patients with AML-FAB M2. Among the 10 cases, we identified a functionally heterozygous mutation in exon16 of STAG1 in one patient (10%), however no mutation was observed in STAG2, RAD21, SMC1, and SMC3. Sanger sequencing analysis for exon 16 of STAG1 in the remaining 142 AML cases did not reveal any further mutations, which underlined the observation that mutations took place throughout the cohesin gene complex without presence of a mutational hot spot region. The present study identified a positive correlation between serum bilirubin, LDH, and hematological parameters such as Hb, WBC, and platelet count with STAG1 mutation. Our data suggest that the cohesin complex may represent an attractive therapeutic target for future preclinical and clinical studies. However, more studies with a larger number of patients should be performed prospectively to determine the pathogenic involvement of STAG 1 mutation in AML patients.",
"affiliations": "Laboratory of Cytogenetics and Molecular Diagnostics, Division of Cancer Research, Regional Cancer Centre, Medical College Post, Trivandrum, Kerala, India; Department of Biochemistry, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore, India.;Division of Medical Oncology, Regional Cancer Centre, Medical College Post, Trivandrum 695011, Kerala, India.;Laboratory of Cytogenetics and Molecular Diagnostics, Division of Cancer Research, Regional Cancer Centre, Medical College Post, Trivandrum, Kerala, India.;Laboratory of Cytogenetics and Molecular Diagnostics, Regional Cancer Centre, Medical College Post, Trivandrum 695011, Kerala, India.;Division of Cancer Epidemiology and Biostatistics, Regional Cancer Centre, Medical College Post, Trivandrum, Kerala, India.;Laboratory of Cytogenetics and Molecular Diagnostics, Division of Cancer Research, Regional Cancer Centre, Medical College Post, Trivandrum, Kerala, India.",
"authors": "Sakthivel|Kunnathur Murugesan|KM|;Geetha|Narayanan|N|;Raj|Thampirajan Vimaladevi Akhila|TVA|;Chandran|Ramachandran Krishna|RK|;Krishna|Kumarapillai Mohanan Nair Jagathnath|KMNJ|;Sreedharan|Hariharan|H|",
"chemical_list": "D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; C108522:STAG1 protein, human; C118077:cohesins",
"country": "United States",
"delete": false,
"doi": "10.1615/JEnvironPatholToxicolOncol.2020035890",
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"issue": "40(1)",
"journal": "Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer",
"keywords": null,
"medline_ta": "J Environ Pathol Toxicol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D015331:Cohort Studies; D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D007194:India; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D010865:Pilot Projects; D011379:Prognosis; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "8501420",
"other_id": null,
"pages": "51-64",
"pmc": null,
"pmid": "33639073",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Whole Exome Sequencing Identifies Cohesin Component STAG1 Mutation in de novo Acute Myeloid Leukemia (FAB M2): A Pilot Study with Cytogenetics, Clinical and Prognostic Implications.",
"title_normalized": "whole exome sequencing identifies cohesin component stag1 mutation in de novo acute myeloid leukemia fab m2 a pilot study with cytogenetics clinical and prognostic implications"
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"abstract": "A 63-year-old man underwent cardioversion of atrial fibrillation with intravenous amiodarone through an antecubital fossa cannula. Mid-infusion, the cannula tissued. He developed immediate pain and swelling. At 3 weeks, he continued to have significant pain and had developed a fixed flexion deformity. MRI demonstrated focal myositis of the biceps and brachialis muscles. Treatment included physiotherapy and plastic surgery but sadly in spite of this, the patient has had minimal symptomatic improvement at 1 year. Amiodarone extravasation is well recognised to cause local injection site reactions. Involvement of deeper tissues is rare. To our knowledge, this is only the second description of a consequent focal myositis in the literature.",
"affiliations": "Department of Neurology, James Cook University Hospital, Middlesbrough, UK.;Department of Neurophysiology, Liverpool Hospital, Sydney, New South Wales, Australia.",
"authors": "Ledingham|David|D|;Cordato|Dennis|D|",
"chemical_list": "D000638:Amiodarone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227725",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "12(1)",
"journal": "BMJ case reports",
"keywords": "cardiovascular system; contraindications and precautions; pain (neurology)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000638:Amiodarone; D001281:Atrial Fibrillation; D006328:Cardiac Catheterization; D004554:Electric Countershock; D006801:Humans; D000075662:Injection Site Reaction; D008297:Male; D008875:Middle Aged; D009220:Myositis; D026741:Physical Therapy Modalities; D013518:Surgery, Plastic; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30661048",
"pubdate": "2019-01-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24420913;28352402",
"title": "Focal myositis and contracture secondary to amiodarone extravasation from a peripheral cannula.",
"title_normalized": "focal myositis and contracture secondary to amiodarone extravasation from a peripheral cannula"
} | [
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"abstract": "A 66-year-old Caucasian male became unconscious 2 weeks after initiation of add-on therapy with empagliflozin for poorly controlled type 2 diabetes mellitus. The inpatient had recently suffered focal pontine stroke, rendering him bedridden and requiring increased nursing care, including assistance with drinking. The patient had received empagliflozin 10 mg once daily for glycaemic control. Investigations revealed hypernatraemia (164 mmol/l), a urine glucose level of 3935 mg/dl, and a creatinine level of 2.1 mg/dl. The patient was diagnosed with severe hypernatraemic dehydration due to iatrogenic glucosuria and prerenal kidney failure. Empagliflozin was discontinued and the patient received hypotonic fluids (including 5% dextrose and free water). Over the following 4 days, glucosuria subsided, blood sodium levels and kidney function normalized and the patient regained full consciousness. He was discharged for rehabilitation 40 days after admission. A Naranjo assessment score of 6 was obtained, indicating a probable relationship between the patient's hypernatraemic dehydration and administration of empagliflozin. In this care-dependent inpatient, who lost the ability to replace water loss autonomously because of a stroke, continuous administration of empagliflozin caused persistent glucosuria and contributed to progressive volume depletion. Excessive dehydration resulted from ignorance of both the populations that are susceptible to dehydration under sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy and the drug's mechanism of action. In patients who depend on support from others in daily tasks, including fluid intake, patients with an impaired sense of thirst and those who have lost the ability to communicate thirst, SGLT2 inhibitor therapy should not be initiated or might be (temporarily) discontinued.",
"affiliations": "Department of Emergency Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Internal Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Emergency Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Emergency Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. michael.schwameis@meduniwien.ac.at.",
"authors": "Gelbenegger|Georg|G|;Buchtele|Nina|N|;Schoergenhofer|Christian|C|;Roeggla|Martin|M|;Schwameis|Michael|M|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1007/s40800-017-0058-8",
"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 291015015810.1007/s40800-017-0058-8Case ReportSevere Hypernatraemic Dehydration and Unconsciousness in a Care-Dependent Inpatient Treated with Empagliflozin Gelbenegger Georg n01242124@students.meduniwien.ac.at 1Buchtele Nina nina.buchtele@meduniwien.ac.at 2Schoergenhofer Christian christian.schoergenhofer@meduniwien.ac.at 3Roeggla Martin martin.roeggla@meduniwien.ac.at 1Schwameis Michael +4314040019640michael.schwameis@meduniwien.ac.at 11 0000 0000 9259 8492grid.22937.3dDepartment of Emergency Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria 2 0000 0000 9259 8492grid.22937.3dDepartment of Internal Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria 3 0000 0000 9259 8492grid.22937.3dDepartment of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria 3 11 2017 3 11 2017 12 2017 4 17© The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.A 66-year-old Caucasian male became unconscious 2 weeks after initiation of add-on therapy with empagliflozin for poorly controlled type 2 diabetes mellitus. The inpatient had recently suffered focal pontine stroke, rendering him bedridden and requiring increased nursing care, including assistance with drinking. The patient had received empagliflozin 10 mg once daily for glycaemic control. Investigations revealed hypernatraemia (164 mmol/l), a urine glucose level of 3935 mg/dl, and a creatinine level of 2.1 mg/dl. The patient was diagnosed with severe hypernatraemic dehydration due to iatrogenic glucosuria and prerenal kidney failure. Empagliflozin was discontinued and the patient received hypotonic fluids (including 5% dextrose and free water). Over the following 4 days, glucosuria subsided, blood sodium levels and kidney function normalized and the patient regained full consciousness. He was discharged for rehabilitation 40 days after admission. A Naranjo assessment score of 6 was obtained, indicating a probable relationship between the patient’s hypernatraemic dehydration and administration of empagliflozin. In this care-dependent inpatient, who lost the ability to replace water loss autonomously because of a stroke, continuous administration of empagliflozin caused persistent glucosuria and contributed to progressive volume depletion. Excessive dehydration resulted from ignorance of both the populations that are susceptible to dehydration under sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy and the drug’s mechanism of action. In patients who depend on support from others in daily tasks, including fluid intake, patients with an impaired sense of thirst and those who have lost the ability to communicate thirst, SGLT2 inhibitor therapy should not be initiated or might be (temporarily) discontinued.\n\nissue-copyright-statement© The Author(s) 2017\n==== Body\nKey Points\n\nSustained glucosuria by sodium-glucose cotransporter 2 (SGLT2) inhibition may cause critical dehydration.\t\nPatients depending on others’ support in daily tasks, including drinking, may be at particular risk.\t\nAwareness of populations susceptible to dehydration upon SGLT2 inhibitor exposure needs to be increased.\t\nClose monitoring of volume status is vital in SGLT2 inhibitor recipients.\t\n\n\n\nBackground\nInhibitors of sodium-glucose cotransporter 2 (SGLT2) are increasingly used in adults with type 2 diabetes mellitus to improve glycaemic control. Inhibition of the SGLT2 in the proximal renal tubules lowers blood glucose levels via a decrease in the renal glucose threshold and an increase in urinary glucose excretion [1]. Furthermore, SGLT2 inhibitors are natriuretic and antihypertensive because SGLT2 reabsorbs filtered glucose together with sodium [1].\n\nCommon side effects include glucosuria-associated genital and urinary tract infections. However, glucosuria-induced free water loss may contribute to critical dehydration, particularly in patients who are care dependent and unable to autonomously regulate their fluid intake. Although the use of SGLT2 inhibitors is contraindicated in the presence of apparent dehydration, the risk and clinical significance of volume depletion in susceptible patient groups may not be sufficiently emphasized in recent literature.\n\nCase Presentation\nA 66-year-old Caucasian male inpatient was transferred from the neurological ward to the emergency department (critical care unit) of the same hospital because of decreased consciousness. His medical history included poorly controlled type 2 diabetes mellitus, atrial fibrillation and cardiovascular disease.\n\nThe patient had been admitted to the department of cardiology 17 days earlier because of a myocardial infarction. He underwent successful percutaneous coronary intervention and felt well during the first days of hospitalisation. The patient developed focal pontine stroke [National Institutes of Health Stroke Scale (NIHSS) 7] 12 days later and was subsequently transferred to the neurology ward for further care. The patient experienced moderate dysarthria, some degree of hemiparesis and limb ataxia but was otherwise alert and responsive. However, reduced general condition with moderately severe disability kept the patient bedridden and necessitated intensified nursing care, including assistance with drinking and personal care, including bodily functions (modified Rankin scale 4). The patient was transferred to the emergency department 5 days later because of progressive loss of consciousness. Figure 1 highlights the medically relevant events that occurred during hospitalisation.Fig. 1 Timeline of events from hospital admission to discharge. Three days after admission to the hospital (department of cardiology), empagliflozin treatment was initiated to improve glycaemic control. Pontine stroke occurred 9 days later (day 12), and the patient was transferred to the neurology ward. Because of progressive loss of consciousness during the following days, the patient was then transferred to the critical care unit of the hospital’s emergency department (day 17). Severe dehydration, along with excessive glucosuria prompted cessation of empagliflozin treatment and careful administration of hypotonic fluids. With this therapy, free water loss subsided, blood sodium levels decreased to normal and consciousness improved. The patient was discharged for rehabilitation therapy in good clinical condition 56 days after admission to the hospital. ED-CCU emergency department—critical care unit\n\n\n\n\nOn admission to the emergency department, the patient was stuporous (Glasgow coma scale 10; eye response 3, motor response 4, verbal response 3), had elevated body temperature (38.5 °C) and low blood pressure (95/50 mmHg) and appeared to be dehydrated. Laboratory findings included severe hypertonic hypernatraemia (164 mmol/l), hyperglycaemia (322 mg/dl), excessive glucosuria (3935 mg/dl) and impaired kidney function (creatinine 2.1 mg/dl). Chest X-ray (posterioranterior) showed patchy consolidations in upper lung fields. Table 1 gives a summary of laboratory test results, the patient’s medical history and a list of his medications.Table 1 Patient characteristics and laboratory findings at admission to the emergency department (critical care unit)\n\nGeneral condition\tStuporous, dehydrated\t\nVital signs\tTachycardia (180 bpm), tachypnoea (RR 26/min), oxygen saturation 94% (while receiving 2 litres of oxygen per minute via an oxygen mask), blood pressure 95/50, tympanic temperature 38.5 °C\t\nMedical history\tArterial hypertension, type 2 diabetes mellitus, obesity, hernia of the abdominal wall, coronary artery disease, unknown mass in the adrenal gland\t\nConcomitant medication\tMetformin, rapid-acting and long-acting insulin, acetylsalicylic acid, ticagrelor, amlodipine, valsartan, hydrochlorothiazide, carvedilol, rosuvastatin, ipratropium bromide, pantoprazole\t\nLaboratory findingsa\n\t\n Na\t164 (136–145) mmol/l\t\n K\t3.3 (3.4–4.5) mmol/l\t\n Ca\t1.24 (1.15–1.30) mmol/l\t\n Cl\t121 (95–106) mmol/l\t\n pH\t7.45 (7.35–7.45)\t\n \npCO2\n\t34 (35–45) mmHg\t\n \npO2\n\t89 (> 79) mmHg\t\n Glucose\t322 (70–120) mg/dl\t\n Lactate\t1.5 (< 1.8) mmol/l\t\n Creatinine\t2.1 (< 0.9) mg/dl\t\n Base excess\t0.0 (0 ± 2)\t\n Osmolality\t355 (280–296) mosmol/kg\t\n C-reactive protein\t2.34 (< 0.5) mg/dl\t\n WBC\t12 (4–10) × 109/l\t\n GFR (MDRD)\t34 (> 90) ml/min/1.73 m2\n\t\n HbA1c\n\t8.1 (< 6) %\t\nUrinalysis\t\n Osmolality\t758 mosmol/kg\t\n Glucose\t3935 mg/dl\t\n Ketone bodies\t50 mg/dl\t\n Sodium\t20 mmol/l\t\n Potassium\t57 mmol/l\t\n Erythrocytes\t250 per μl\t\n Protein\t75 mg/dl\t\n Nitrite\tPositive\t\n pH\t5\t\n Leucocytes\tNegative\t\nCranial computed tomography\tSubacute ischaemic pontine stroke (paramedian left)\t\nChest X-ray\tPatch consolidations in both lungs, otherwise normal\t\nTransthoracic echocardiogram\tSeverely reduced left ventricular function, septal akinesia\t\nElectrocardiogram\tLeft bundle branch block, atrial fibrillation\t\nUrinary dip stick, urinary cultures, blood cultures\tNo growth\t\n\nGFR glomerular filtration rate, HbA\n1c glycated haemoglobin, MDRD Modification of Diet in Renal Disease, RR respiratory rate, WBC white blood cell\n\n\naLaboratory data are given with reference range\n\n\n\n\nDiagnostic work-up primarily focused on the differential diagnosis of hypernatraemia as it was the predominant laboratory finding and considered the cause of impaired consciousness.\n\nCentral Diabetes Insipidus\nThe sensation of thirst is regulated by the hypothalamus, which senses electrolyte concentrations and fluid status and controls the release of vasopressin. Decreased or absent production of vasopressin inhibits the reabsorption of water in the renal collecting ducts, thereby increasing blood sodium levels and blood osmolality, referred to as diabetes insipidus.\n\nOur patient had recently suffered cerebral infarction, and diabetes insipidus following vertebrobasilar ischaemia has been described previously [2]. However, a diagnosis of diabetes insipidus was unlikely. Although ischaemia-associated swelling of the brain theoretically could have caused hypothalamic insufficiency, leading to central diabetes insipidus, this would not have been compatible with non-space occupying pontine stroke. Furthermore, severe hypernatraemia usually does not occur in central diabetes insipidus, as the thirst response is intact except when the thirst sensation is impaired concurrently. Likewise, the high urine osmolality (758 mosmol/kg) observed in our patient was not characteristic of diabetes insipidus, in which urine osmolality is usually low (< 200–300 mosmol/kg).\n\nMineralocorticoid Excess\nAldosterone plays a major role in electrolyte homeostasis and blood pressure regulation. Aldosterone increases reabsorption through implementation of epithelial sodium channels, whereas potassium is excreted over an aldosterone-sensitive potassium channel, resulting in hypernatraemia and hypokalaemia.\n\nThe patient’s past medical history included a mass in the adrenal glands, but blood aldosterone and renin levels were not assessed. The urine potassium level was 57 mmol/l, the blood potassium level was 3.3 mmol/l and the transtubular potassium gradient (TTPG) was 8.1. As the blood potassium level was low, TTPG should also have been low (< 4). Although an elevated TTPG of 8.1 in the presence of hypokalaemia would have been compatible with a diagnosis of hyperaldosteronism, it is not typically associated with excessive hypernatraemia but rather with slightly elevated blood sodium levels, resistant arterial hypertension, hypokalaemia and metabolic alkalosis.\n\nSodium Overload\nSodium overload is usually associated with the administration of hypertonic sodium solutions or excessive salt ingestion. Neither had occurred in this case.\n\nOn the neurology ward, treatment for suspected pneumonia was started with piperacillin/tazobactam (4.5 g three times daily), which—rarely—can be associated with hypernatraemia [3]. However, one would expect increased urinary sodium excretion (> 100 mmol/l) in sodium overload as the kidneys try to eliminate the excessive sodium. Although urinary sodium levels may be misleading in cases of concomitant dehydration, sodium overload was unlikely to be the main cause of hypernatraemia.\n\nAntidiabetic Therapy and Concomitant Medication\nConcomitant medication included antiplatelet drugs (aspirin and ticagrelor), antihypertensive agents (amlodipine, valsartan, hydrochlorothiazide and carvedilol), a bronchodilator (ipratropium bromide), a cholesterol-lowering agent (rosuvastatin) and a proton pump inhibitor (pantoprazole). None of these is usually associated with severe hypernatraemia.\n\nHowever, thorough anamnesis revealed that empagliflozin (10 mg once daily) had newly been added to the patient’s antidiabetic medications to improve glycaemic control 2 weeks before admission to the emergency department (Fig. 1).\n\nEmpagliflozin belongs to the gliflozin class of oral antidiabetics and inhibits renal SGLT2, which is localised in the proximal tubules of the kidneys and reabsorbs 97% of primarily filtered glucose. SGLT2 inhibitors decrease blood glucose levels by increasing the amount of urinary glucose that is eventually excreted from the kidneys. Glucosuria increases linearly with the tubular glucose load and induces osmotic diuresis [1]. Sustained diuresis due to persisting glucosuria may contribute to volume depletion and subsequent kidney failure, as seen in our patient. Furthermore, SGLT2 inhibitors have a mild natriuretic effect. However, in contrast to glucosuria, the natriuretic effect is balanced over time by declining plasma volume provoking equilibration between sodium excretion and intake [1]. SGLT2 inhibition may also increase urinary potassium excretion through increased distal tubular flow. Yet, in cases of dehydration, urinary potassium levels may be difficult to interpret.\n\nWe considered treatment with empagliflozin as a significant contributor to hypernatraemia in this case. Our hypothesis was supported by a Naranjo score of 6.\n\nTreatment\nTreatment with empagliflozin was stopped to limit glucosuria and free water loss. The primary goal was careful fluid replacement to reduce sodium levels by 10–12 mmol/l per day. Intravenous fluid repletion included 5% dextrose (100 ml/h), free water (50 ml/h) and balanced potassium solutions to correct concurrent hypokalaemia. During the first day of treatment, blood sodium levels were measured every 1–2 h to ensure an adequate rate of correction. Hyperglycaemia was treated with insulin. Atrial fibrillation converted into sinus rhythm with fluid and potassium substitution. Piperacillin/tazobactam was continued. No adverse events occurred.\n\nOutcome\nUpon cessation of empagliflozin and administration of hypotonic fluids, free water loss subsided and blood sodium levels decreased to 145 mmol/l over the following 4 days. Fever resolved, kidney function improved and the patient finally regained consciousness. The patient was subsequently transferred back to the neurology ward and began rehabilitative therapy. Antidiabetic therapy was continued with metformin and insulin. About 6 weeks after admission to the emergency department, sodium levels remained in the normal range and the patient was discharged for further rehabilitation in good clinical condition.\n\nDiscussion\nThis report describes a care-dependent patient with diabetes unable to manage his fluid intake after suffering pontine stroke who was treated with an SGLT2 inhibitor and subsequently developed severe dehydration manifesting as unconsciousness.\n\nSGLT2 inhibitors have an emerging role in the management of type 2 diabetes mellitus. These agents reduce blood glucose levels independent of insulin by inhibiting renal SGLT2, a novel and unique mechanism of action [4]. Despite glycaemic-lowering effects, they are considered to beneficially affect metabolics and cardiovascular risk [5]. Blood pressure reduction through natriuresis and plasma volume contraction with subsequent improvement of arterial wall stiffness is a potential mechanism underlying the drug’s cardio-protective effect [6]. In this context, empagliflozin has recently been demonstrated to reduce both the risk of cardiovascular death and overall mortality in high-risk diabetic patients [7].\n\nSGLT2 inhibitors have already been intensively studied and shown to be safe and well tolerated. Common side effects are related to increased renal glucose excretion and include mostly mycotic genital infections [8]. However, in susceptible patients, glucosuria may potentially result in severe dehydration [8, 9]. Yet, in our opinion, patient populations at risk of volume depletion upon exposure to SGLT2 inhibitor therapy are poorly emphasized by recent literature.\n\nThe risk of critical dehydration is admittedly negligible in individuals who are not dependent on care and have a normal daily fluid intake. As in diabetes insipidus, thirst response is preserved with SGLT2 inhibitor therapy, triggering appropriate fluid intake. Likewise, the initial plasma volume contraction by natriuresis stabilizes over time. In contrast, osmotic diuresis through glucosuria persists [1]. Volume depletion and dyselectrolytaemia may develop, particularly in patients who are unable to replace water loss by themselves, as highlighted in this report.\n\nIn our patient, progression of volume depletion resulted from the interplay of several factors, including the patient’s inability to drink autonomously because of dysarthria and bedriddenness following pontine stroke, the care provider’s failure to continuously monitor the patient’s clinical volume status and the ignorance of both at-risk populations susceptible to dehydration upon SGLT2 inhibitor exposure and the drug’s mechanism of action. Moreover, hypernatraemia—indicating dehydration—remained unnoticed. However, the continuous administration of empagliflozin resulting in sustained glucosuria, osmotic diuresis and free water loss was likely a further factor contributing to excessive volume depletion. Whether dehydration in turn contributed to the development of stroke in this patient can only be speculated. Yet, recent data suggest that patients with atrial fibrillation may have a significant risk of stroke in cases of concomitant dehydration [10]. On the other hand, the EMPA-REG OUTCOME trial, which assigned more than 7000 patients with diabetes to receive empagliflozin or placebo once daily over more than 3 years, found no difference between the groups in the rate of stroke across all patients (3 vs. 3.5%; p = 0.26) [7].\n\nThe patient presented here is admittedly not representative of the majority of patients with diabetes receiving therapy with an SGLT2 inhibitor. However, it should be kept in mind that inadequate thirst response to osmotic stimuli is not necessarily associated with a specific disease (such as stroke) but may also occur in elderly, otherwise healthy patients [11]. Individuals with inadequate thirst response, those who do not adequately communicate thirst, and those who depend on support of others for daily tasks, including fluid intake, may be at particular risk of dehydration under SGLT2 inhibitor therapy and need continuous monitoring by the prescribing physician and other care providers. Post-marketing surveillance studies may further characterize conditions in which initiation or continuation of SGLT2 inhibitor therapy should be avoided.\n\nConclusions\nThis report highlights that SGLT2 inhibition can contribute to critical dehydration in a susceptible patient. Populations that may (temporarily) not be suitable for initiation of antidiabetic treatment with an SGLT2 inhibitor need to be better emphasised. Sufficient hydration and close monitoring of clinical volume status is vital in SGLT2 inhibitor recipients.\n\n\nAbbreviations\nNIHSSNational Institutes of Health Stroke Scale\n\nSGLT2Sodium-glucose cotransporter 2\n\nTTPGTranstubular potassium gradient\n\nAcknowledgements\nThis case has been presented at the 5th European conference on clinical and medical case reports.\n\nAuthor Contributions\nAuthors certify that they have participated sufficiently in the work to take public responsibility for the entire content of the manuscript. GG, NB and CS collected data, conducted the chart review and performed the literature search. MS and MR cared for the study patient. MS obtained informed consent from the patient. MR served as scientific advisor. GG, NB and CS wrote the first draft of the report. MS and MR critically revised the report. All authors reviewed and approved the final submitted manuscript.\n\nCompliance with Ethical Standards\nConsent for publication\nWritten 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, upon request, from the corresponding author.\n\nEthics approval and consent to participate\nAt the Medical University of Vienna, the publication of case reports does not require ethics approval.\n\nConflict of interest\nGeorg Gelbenegger, Nina Buchtele, Christian Schoergenhofer, Martin Roeggla and Michael Schwameis have no conflicts of interest.\n\nFunding\nNo sources of funding were used for this work.\n==== Refs\nReferences\n1. Vallon V Thomson SC Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition Diabetologia. 2017 60 2 215 225 10.1007/s00125-016-4157-3 27878313 \n2. Kraus J Ondine’s curse in association with diabetes insipidus following transient vertebrobasilar ischemia Clin Neurol Neurosurg. 1999 101 3 196 198 10.1016/S0303-8467(99)00023-2 10536907 \n3. Hussain S Syed S Baloch K Electrolytes imbalance: a rare side effect of piperacillin/ tazobactam therapy J Coll Physicians Surg Pak. 2010 20 6 419 420 20642978 \n4. Monica Reddy RP Inzucchi SE SGLT2 inhibitors in the management of type 2 diabetes Endocrine. 2016 53 2 364 372 10.1007/s12020-016-0943-4 27270407 \n5. Kashiwagi A Maegawa H Metabolic and hemodynamic effects of sodium-dependent glucose co-transporter 2 inhibitors on cardio-renal protection in the treatment of patients with type 2 diabetes mellitus J Diabetes Investig. 2017 8 4 416 427 10.1111/jdi.12644 28178390 \n6. Heerspink HJ Sodium glucose cotransporter 2 Inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications Circulation. 2016 134 10 752 772 10.1161/CIRCULATIONAHA.116.021887 27470878 \n7. Zinman B Lachin JM Inzucchi SE Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes N Engl J Med. 2016 374 11 1094 10.1056/NEJMc1600140 26981940 \n8. Trujillo JM Nuffer WA Impact of sodium-glucose cotransporter 2 inhibitors on nonglycemic outcomes in patients with type 2 diabetes Pharmacotherapy. 2017 37 4 481 491 10.1002/phar.1903 28102030 \n9. Johnsson K Osmotic diuresis with SGLT2 inhibition: analysis of events related to volume reduction in dapagliflozin clinical trials Postgrad Med. 2016 128 4 346 355 10.1080/00325481.2016.1153941 26878357 \n10. Swerdel JN Association between dehydration and short-term risk of ischemic stroke in patients with atrial fibrillation Transl Stroke Res. 2017 8 2 122 130 10.1007/s12975-016-0471-9 27212039 \n11. Phillips PA Reduced osmotic thirst in healthy elderly men Am J Physiol 1991 261 1 Pt 2 R166 R171 1858944\n\n",
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"title": "Severe Hypernatraemic Dehydration and Unconsciousness in a Care-Dependent Inpatient Treated with Empagliflozin.",
"title_normalized": "severe hypernatraemic dehydration and unconsciousness in a care dependent inpatient treated with empagliflozin"
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"abstract": "A patient manifesting an acute psychosis after receiving an injection of procaine penicillin is reported. The psychosis began immediately after drug administration and gradually abated over a forty-eight-hour period. The clinical presentation was dominated by paranoid delusions and a Capgras-like syndrome. Sixty-six previously reported cases were identified and reviewed. Patients manifested combinations of fear, auditory hallucinations, somatic hallucinations, visual hallucinations, and paranoid or religious delusions. The syndrome may occur with inadvertent intravenous injection of procaine and most likely reflects the action of procaine on limbic system structures.",
"affiliations": null,
"authors": "Cummings|J L|JL|;Barritt|C F|CF|;Horan|M|M|",
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"mesh_terms": "D003702:Delusions; D006212:Hallucinations; D006801:Humans; D008297:Male; D008875:Middle Aged; D010400:Penicillin G; D010402:Penicillin G Procaine; D011605:Psychoses, Substance-Induced",
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"title": "Delusions induced by procaine penicillin: case report and review of the syndrome.",
"title_normalized": "delusions induced by procaine penicillin case report and review of the syndrome"
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"abstract": "The VEGF inhibitor pazopanib is a widely used first-line therapy for the treatment of advanced renal cell carcinoma. Potential drug-drug interactions and toxicities may be underrecognized.\nA 73-year-old woman with metastatic renal cell carcinoma on treatment with pazopanib presented with progressive inability to ambulate. The initial concern was for metastasis to the spine. However, MRI of the spine revealed diffuse muscle edema with no metastatic deposits or lytic lesions. Upon further evaluation, creatine kinase was significantly elevated and the diagnosis of rhabdomyolysis was made. With aggressive hydration and discontinuation of both pazopanib and rosuvastatin, the patient made a full recovery.\nThis case of drug-induced rhabdomyolysis demonstrates an unexpected toxicity resulting from concomitant pazopanib and rosuvastatin therapy. This combination is predicted to be safe due to different, nonoverlapping effects on the cytochrome p450 enzymes. Discontinuation of statin therapy in patients with metastatic cancer should be considered when the risk of cancer-related death exceeds the risk of cardiovascular-related death.",
"affiliations": "Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.;Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.;Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.",
"authors": "Logue|Jennifer M|JM|;Kiani|Bahram|B|;Bitting|Rhonda L|RL|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000481659cro-0010-0954Case ReportPazopanib and Statin-Induced Rhabdomyolysis Logue Jennifer M. abKiani Bahram acBitting Rhonda L. abd*aWake Forest School of Medicine, Winston-Salem, North Carolina, USAbDepartment of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USAcDepartment of Radiology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USAdWake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA*Rhonda L. Bitting, Section on Hematology and Oncology, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (USA), E-Mail rbitting@wakehealth.eduSep-Dec 2017 31 10 2017 31 10 2017 10 3 954 957 20 9 2017 20 9 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Background\nThe VEGF inhibitor pazopanib is a widely used first-line therapy for the treatment of advanced renal cell carcinoma. Potential drug-drug interactions and toxicities may be underrecognized.\n\nCase Presentation\nA 73-year-old woman with metastatic renal cell carcinoma on treatment with pazopanib presented with progressive inability to ambulate. The initial concern was for metastasis to the spine. However, MRI of the spine revealed diffuse muscle edema with no metastatic deposits or lytic lesions. Upon further evaluation, creatine kinase was significantly elevated and the diagnosis of rhabdomyolysis was made. With aggressive hydration and discontinuation of both pazopanib and rosuvastatin, the patient made a full recovery.\n\nConclusion\nThis case of drug-induced rhabdomyolysis demonstrates an unexpected toxicity resulting from concomitant pazopanib and rosuvastatin therapy. This combination is predicted to be safe due to different, nonoverlapping effects on the cytochrome p450 enzymes. Discontinuation of statin therapy in patients with metastatic cancer should be considered when the risk of cancer-related death exceeds the risk of cardiovascular-related death.\n\nKeywords\nPazopanibRosuvastatinRhabdomyolysisVEGF inhibitorStatinHyperlipidemiaRenal cell carcinomaCytochrome p450\n==== Body\nBackground\nThe VEGF tyrosine kinase inhibitor pazopanib is a widely used first-line therapy for the treatment of advanced renal cell carcinoma, on the basis of large studies which demonstrated efficacy and safety [1, 2]. With the increased use of any drug, rare side effects are expected to manifest. Here, we describe a patient with statin-induced rhabdomyolysis, most likely due to inhibition of the cytochrome p450 system by pazopanib.\n\nCase Presentation\nA 73-year-old woman presented with gross hematuria, and a large right renal mass was discovered. She underwent right radical nephrectomy, and pathology revealed clear cell renal cell carcinoma. Postoperative imaging showed nodularity in the nephrectomy bed, multiple hepatic lesions, bilateral pulmonary nodules, and mediastinal adenopathy, giving concern for residual metastatic disease. She started pazopanib 600 mg daily, initially 25% dose-reduced due to frailty. Due to hypertensive urgency, the dose was further decreased to 400 mg daily during the first month of treatment. Other early treatment side effects included elevated TSH with normal T3 and T4 and grade 1 thrombocytopenia. Follow-up imaging after 3 months of treatment showed a partial response, with tumor regression noted in all affected areas.\n\nAfter 6 months of treatment with pazopanib 400 mg, she presented to the clinic for routine follow-up and reported 9 days of progressive bilateral lower extremity weakness, ultimately requiring wheelchair use. She also reported worsening of her chronic lower back pain. She had intentionally decreased her fluid intake in order to decrease her urine output, as it had become too difficult to get to the bathroom at home. Physical examination revealed mildly decreased but symmetrical lower extremity strength and diffuse tenderness of the lumbar and sacral spine and paraspinal region. Initial laboratory findings were notable for a BUN level of 51 mg/dL and creatinine of 2.82 mg/dL, up from her baseline of 1.5 mg/dL. She also had a new transaminitis with AST of 172 IU/L (normal 5–40 IU/L) and ALT of 158 IU/L (normal 5–50 IU/L).\n\nShe was given intravenous fluids and admitted to the hospital for further workup. MRI of the lumbosacral spine revealed diffuse paraspinal muscle edema from L2 to the sacrum, without evidence of osseous metastasis to the spine (Fig. 1). Further evaluation revealed creatine kinase of 5,719 IU/L (normal 50–160 IU/L) and a fractional excretion of sodium of 2.42%, consistent with intrinsic renal injury caused by rhabdomyolysis. On review of her home medications, she had been taking rosuvastatin 40 mg daily for several years for hyperlipidemia. Her statin was stopped due to concern for statin-induced rhabdomyolysis. Pazopanib was also stopped. With continued fluid resuscitation, her creatine kinase normalized and her renal and hepatic function recovered to baseline. After several weeks of physical therapy, she returned to her baseline physical functioning and performance status.\n\nDiscussion\nThe prescribing information for pazopanib carries a warning with regard to the severe and fatal hepatotoxicity observed in clinical trials, though there are no absolute contraindications listed. Per Novartis, the most common adverse reactions when treating for advanced renal cell carcinoma are diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting [3]. In vitro studies suggest that pazopanib undergoes oxidative metabolism in human liver microsomes, primarily via CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Results from drug-drug interaction trials suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, and concomitant use of agents with narrow therapeutic windows that are metabolized by these enzymes is not recommended. Pazopanib has no known effect on CYP2C9. Concomitant use of pazopanib and simvastatin has been shown to increase the risk of ALT elevations, and providers are instructed to use this combination with caution and close monitoring. There is presently insufficient data, however, to assess the risk of alternative statins given in combination with pazopanib [3].\n\nUse of statins in the presence of known drug interactions has been extensively studied in the treatment of HIV due to the high prevalence of dyslipidemia in patients receiving highly active antiretroviral therapy (HAART) and the CYP3A4 inhibition commonly caused by HAART. As a result, nondrug therapies such as dietary and exercise interventions are first recommended and given a thorough trial. When there is an urgent need to intervene in the case of hyperlipidemia, pravastatin is recommended because it is predominantly metabolized outside of the liver. Simvastatin and lovastatin have major interactions with CYP3A4 and are generally avoided. Atorvastatin also interacts with CYP3A4 but to a lesser degree [4]. Rosuvastatin, in contrast, is metabolized predominantly through CYP2C9 [5]. Because current guidelines recommend high-intensity statin therapy for both primary and secondary prevention of atherosclerotic cardiovascular disease, side effects such as rhabdomyolysis are seen more commonly. The most important consideration to reduce such side effects is to limit concomitant use of CYP3A4 inhibitors or inducers [5]. In the case reported here, statin-induced rhabdomyolysis occurred with concomitant pazopanib and rosuvastatin use, despite the fact that rosuvastatin is predominantly metabolized by CYP2C9.\n\nConclusion\nThis case of statin-induced rhabdomyolysis demonstrates a severe effect of cytochrome P450 inhibition due to pazopanib. Though the drug-drug interaction studies suggest that pazopanib is a weak inhibitor only of CYP3A4, CYP2C8, and CYP2D6, this patient's experience would argue that the inhibition may be more potent than suspected and that CYP2C9 may also be affected. Discontinuation of statin therapy for patients with metastatic cancer should be considered when the risk of cancer-related death exceeds the risk of cardiovascular-related death.\n\nStatement of Ethics\nThe authors have no ethical conflicts to declare.\n\nDisclosure Statement\nThe authors have no relevant disclosures or conflicts of interest. JL and RB analyzed and interpreted the patient data in the context of the literature. BK provided the radiologic interpretation. All authors read and approved the final manuscript.\n\nFig. 1 MRI of the lumbosacral spine showing diffuse paraspinal muscle edema from L2 to the sacrum, without evidence of osseous metastasis to the spine.\n==== Refs\nReferences\n1 Sternberg CN Hawkins RE Wagstaff J A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update Eur J Cancer 2013 49 1287 1296 23321547 \n2 Motzer RJ Hutson TE Cella D Pazopanib versus sunitinib in metastatic renal-cell carcinoma N Engl J Med 2013 369 722 731 23964934 \n3 Novartis Pharmaceuticals Corporation Votrient (pazopanib) tablets: US prescribing information. 2017. https://www.pharma.us.novartis.com (accessed July 5, 2017).\n4 Mayer KH Dube MP Sprecher D Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with HIV and receiving antiretroviral therapy: recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group Clin Infect Dis 2000 31 1216 1224 11073755 \n5 Benes LB Bassi NS Davidson MH The risk of hepatotoxicity, new onset diabetes and rhabdomyolysis in the era of high-intensity statin therapy: does statin type matter? Prog Cardiovasc Dis 2016 59 145 152 27503844\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "10(3)",
"journal": "Case reports in oncology",
"keywords": "Cytochrome p450; Hyperlipidemia; Pazopanib; Renal cell carcinoma; Rhabdomyolysis; Rosuvastatin; Statin; VEGF inhibitor",
"medline_ta": "Case Rep Oncol",
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"pages": "954-957",
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"pmid": "29279698",
"pubdate": "2017",
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"title": "Pazopanib and Statin-Induced Rhabdomyolysis.",
"title_normalized": "pazopanib and statin induced rhabdomyolysis"
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"abstract": "OBJECTIVE\nTo describe outcomes of combined rituximab and bortezomib treatment for non-paraneoplastic autoimmune retinopathy.\n\n\nMETHODS\nA 37-year-old female developed photopsias and reduced vision. Electroretinography, optical coherence tomography, and positive serum anti-retinal antibodies were consistent with autoimmune retinopathy. A negative malignancy work-up specified her non-paraneoplastic presentation. Given absence of response to periocular steroids, azathioprine, and methotrexate, a combination of rituximab and bortezomib was initiated as fifth-line therapy.\n\n\nRESULTS\nThere was no significant improvement in the patient's symptoms or visual function following treatment. The full field electroretinogram amplitudes were reduced with progressive outer retinal degeneration evident on optical coherence tomography. Post-treatment anti-retinal antibody testing demonstrated the persistence of antibodies and revealed additional antibodies not previously detected.\n\n\nCONCLUSIONS\nCombined rituximab and bortezomib treatment did not result in significant clinical improvement and there was evidence of disease progression. Further prospective studies are required to assess the efficacy of immunotherapy in patients with autoimmune retinopathy.",
"affiliations": "Department of Ophthalmology and Visual Sciences, University of Alberta , Edmonton, Canada.;Department of Ophthalmology and Visual Sciences, University of Alberta , Edmonton, Canada.;Department of Medicine, University of Alberta , Edmonton, Canada.;Department of Medicine, University of Alberta , Edmonton, Canada.;Department of Ophthalmology and Visual Sciences, University of Alberta , Edmonton, Canada.;Department of Ophthalmology and Visual Sciences, University of Alberta , Edmonton, Canada.",
"authors": "Benson|Matthew D|MD|;Plemel|David J A|DJA|;Yacyshyn|Elaine|E|;Sandhu|Irwindeep|I|;MacDonald|Ian M|IM|https://orcid.org/0000-0001-7472-8385;Baker|Chad F|CF|",
"chemical_list": "D001323:Autoantibodies; D007155:Immunologic Factors; D000069283:Rituximab; D000069286:Bortezomib",
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"journal": "Ocular immunology and inflammation",
"keywords": "Anti-retinal antibodies; autoimmune retinopathy; bortezomib; non-paraneoplastic autoimmune retinopathy; rituximab",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D001327:Autoimmune Diseases; D000069286:Bortezomib; D004359:Drug Therapy, Combination; D004596:Electroretinography; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D010257:Paraneoplastic Syndromes; D011446:Prospective Studies; D012160:Retina; D012164:Retinal Diseases; D000069283:Rituximab; D041623:Tomography, Optical Coherence; D058609:Visual Field Tests; D014794:Visual Fields",
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"title": "Combination Treatment with Rituximab and Bortezomib in a Patient with Non-Paraneoplastic Autoimmune Retinopathy.",
"title_normalized": "combination treatment with rituximab and bortezomib in a patient with non paraneoplastic autoimmune retinopathy"
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"abstract": "Thirteen patients (7 male, 9 female) aged 22-71 years (means = 55 years) with acute non-lymphocytic leukemia and contraindications for anthracyclin therapy were treated with combined chemotherapy using m-amsacrine primarily or in relapse. The main reasons for avoiding cardiotoxic substances were overt cardiac insufficiency and former administration of daunorubicin with more than 540 mg/m2 body surface area. Amsacrine was combined with 6-thioguanine, VP 16-213 and cytosine arabinoside in conventional or high dosage. Eight out of 13 patients (62%) achieved complete remission after one or two courses of chemotherapy. One patient showed partial remission and could be brought into complete remission with another chemotherapy using high-dose ara-C and mitoxantrone. Three patients died in aplasia after chemotherapy and 1 other patient had to be regarded as a complete non-responder. Remission duration and survival time for the 8 successfully-treated patients so far is 1-12 months; however, medians have not yet been reached, since only one of the eight patients relapsed after 6 months of complete remission. These data indicate a high efficacy of m-amsacrine in combined chemotherapy for acute non-lymphocytic leukemia in high-risk patients with contraindications for anthracyclins.",
"affiliations": null,
"authors": "Maschmeyer|G|G|;Hiddemann|W|W|;Kreutzmann|H|H|;Wendt|F|F|",
"chemical_list": "D000677:Amsacrine; D003561:Cytarabine; D005047:Etoposide; D013866:Thioguanine",
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"issue": "10(1)",
"journal": "Onkologie",
"keywords": null,
"medline_ta": "Onkologie",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000677:Amsacrine; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D005047:Etoposide; D005500:Follow-Up Studies; D006801:Humans; D007938:Leukemia; D008875:Middle Aged; D013866:Thioguanine",
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"pages": "18-21",
"pmc": null,
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"pubdate": "1987-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combined chemotherapy with m-amsacrine in high-risk patients with acute non-lymphocytic leukemia.",
"title_normalized": "combined chemotherapy with m amsacrine in high risk patients with acute non lymphocytic leukemia"
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"abstract": "We report here the first case of life-threatening hypomagnesemia in a Zollinger-Ellison syndrome patient with multiple endocrine neoplasia type 1 (MEN1) syndrome. The severe symptomatic hypomagnesemia proved to be due to proton pump inhibitors (PPIs), but withdrawal of PPIs led to early severe peptic complications despite a substitution by histamine H2-receptor antagonist therapy. Simultaneous management of life-threatening hypomagnesemia, severe gastric acid hypersecretion and MEN1-associated gastrinomas was complex. A total gastrectomy was performed in order to definitely preclude the use of PPIs in this frail patient who was not eligible for curative pancreatoduodenal resection.",
"affiliations": "Department of Gastroenterology and Digestive Oncology, Reims University Hospital, Reims, France. Electronic address: mperrier@chu-reims.fr.;Department of Endocrinology, Diabetes and Nutrition, Reims University Hospital, Reims, France; Center for Research in Sciences and Technologies of Information and Communication (CReSTIC), University of Reims Champagne Ardennes (URCA), France.;Department of General and Digestive Surgery, Reims University Hospital, Reims, France.;Department of Intensive Care Medicine, Reims University Hospital, Reims, France.;Department of Gastroenterology and Digestive Oncology, Reims University Hospital, Reims, France.;Department of General and Digestive Surgery, Reims University Hospital, Reims, France.;Department of Gastroenterology and Digestive Oncology, Reims University Hospital, Reims, France.",
"authors": "Perrier|Marine|M|;Delemer|Brigitte|B|;Deguelte|Sophie|S|;Legros|Vincent|V|;Brixi|Hedia|H|;Kianmanesh|Reza|R|;Cadiot|Guillaume|G|",
"chemical_list": "D054328:Proton Pump Inhibitors",
"country": "Switzerland",
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"doi": "10.1016/j.pan.2020.12.002",
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"issn_linking": "1424-3903",
"issue": "21(1)",
"journal": "Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]",
"keywords": "Gastrinoma; Hypomagnesemia; Multiple endocrine neoplasia type 1 syndrome; Proton pump inhibitor; Total gastrectomy; Zollinger-Ellison syndrome",
"medline_ta": "Pancreatology",
"mesh_terms": "D000073496:Frailty; D005743:Gastrectomy; D006801:Humans; D008275:Magnesium Deficiency; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1; D010437:Peptic Ulcer; D054328:Proton Pump Inhibitors; D013270:Stomach; D016896:Treatment Outcome; D015043:Zollinger-Ellison Syndrome",
"nlm_unique_id": "100966936",
"other_id": null,
"pages": "236-239",
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"pmid": "33309626",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Total gastrectomy for severe proton pump inhibitor-induced hypomagnesemia in a MEN1/Zollinger Ellison syndrome patient.",
"title_normalized": "total gastrectomy for severe proton pump inhibitor induced hypomagnesemia in a men1 zollinger ellison syndrome patient"
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"abstract": "Eikenella corrodens has been noted as a causative organism in both neonatal and perinatal sepsis. Positivity of blood cultures at birth among preterm infants may be influenced by the maternal use of peripartum antimicrobials and a normal C-reactive protein result within the first 24 hours need not always reflect the absence of fetal invasion by the highly pathogenic organisms. For these reasons, supportive and adjunctive approaches such as appropriately collected placental swabs for culture would be of value in optimizing the antimicrobial choice for sick preterm infants during the early neonatal period. Fetal infection by E. corrodens detected by placental swab culture influencing antimicrobial management of an extremely premature infant with sepsis is described. Management of the youngest premature survivor with the lowest birthweight among the reported cases in English language of neonatal E. corrodens infection is summarized and literature is reviewed. The value of placental swab, which is often underused, is highlighted in this review.",
"affiliations": "University Maternity Hospital Limerick, Limerick, Ireland.;University Hospital Limerick, Limerick, Ireland.;University Hospital Limerick, Limerick, Ireland.;University Hospital Limerick, Limerick, Ireland.;University Maternity Hospital Limerick, Limerick, Ireland.;University Maternity Hospital Limerick, Limerick, Ireland.",
"authors": "Garvey|A|A|;Powell|J|J|;Murphy|B|B|;O'Connell|N|N|;Imcha|M|M|;Philip|R K|RK|",
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"doi": "10.1016/j.nmni.2017.10.012",
"fulltext": "\n==== Front\nNew Microbes New InfectNew Microbes New InfectNew Microbes and New Infections2052-2975Elsevier S2052-2975(17)30088-410.1016/j.nmni.2017.10.012Mini-ReviewYoungest survivor of perinatal infection by Eikenella corrodens: case analysis and literature review highlighting the merits of placental swab culture Garvey A. 1Powell J. 2Murphy B. 2O'Connell N. 2Imcha M. 1Philip R.K. roy.philip@hse.ie1∗1) University Maternity Hospital Limerick, Limerick, Ireland2) University Hospital Limerick, Limerick, Ireland∗ Corresponding author: R.K. Philip, Division of Neonatology, Department of Paediatrics, University Maternity Hospital Limerick, Limerick V94 C566, IrelandDivision of NeonatologyDepartment of PaediatricsUniversity Maternity Hospital LimerickLimerickV94 C566Ireland roy.philip@hse.ie07 11 2017 1 2018 07 11 2017 21 81 85 27 8 2017 23 10 2017 27 10 2017 © 2017 The Author(s)2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Eikenella corrodens has been noted as a causative organism in both neonatal and perinatal sepsis. Positivity of blood cultures at birth among preterm infants may be influenced by the maternal use of peripartum antimicrobials and a normal C-reactive protein result within the first 24 hours need not always reflect the absence of fetal invasion by the highly pathogenic organisms. For these reasons, supportive and adjunctive approaches such as appropriately collected placental swabs for culture would be of value in optimizing the antimicrobial choice for sick preterm infants during the early neonatal period. Fetal infection by E. corrodens detected by placental swab culture influencing antimicrobial management of an extremely premature infant with sepsis is described. Management of the youngest premature survivor with the lowest birthweight among the reported cases in English language of neonatal E. corrodens infection is summarized and literature is reviewed. The value of placental swab, which is often underused, is highlighted in this review.\n\nKeywords\nChorioamnionitisEikenella corrodensextremely low birthweightneonatal sepsisperinatal infectionsplacental swab\n==== Body\nIntroduction\nEikenella corrodens is a Gram-negative rod associated with human gastrointestinal (particularly oral cavity) or upper respiratory tracts. Less commonly, it has been known to be a contributing agent in meningitis, endocarditis, head and neck infections, intra-abdominal infections and gynaecological infections [1], [2], [3], [4]. Association of E. corrodens infection with preterm labour, chorioamnionitis and early neonatal mortality has been reported [5], [6], [7], [8], [9], [10], [11].\n\nWe describe a case of E. corrodens in utero fetal infection detected by a positive placental swab culture influencing antimicrobial management of an extremely-low-birthweight infant with clinical features of sepsis soon after birth. Value of placental swabs, which are often underused, is highlighted and we have reviewed all published reports of neonatal E. corrodens infections.\n\nCase\nA 36-year-old Irish Caucasian, G3 P0+2 attended our hospital for antenatal care. She had gestational diabetes mellitus which was diet controlled. Her past medical history was positive for hypertension, asthma, the drainage of a Bartholin's cyst 10 years ago and she had had a termination of pregnancy 16 years previously. In this pregnancy, her antenatal viral serology including human immunodeficiency virus and hepatitis B/C viruses was negative and immunity to rubella virus was demonstrated. She had also previously delivered a baby prematurely at 21/40 associated with acute, severe chorioamnionitis which merited maternal treatment with intravenous amoxicillin and metronidazole. She conceived approximately 1 month after the above described fetal loss. In the current pregnancy, she had a cervical suture placed at 14/40 gestation. She was admitted at 21+4/40 for bed rest due to shortening of the cervix with funnelling. A mid-stream urine at 22/40 grew group B streptococcus and she received a 5-day treatment course of an oral amoxicillin/clavulanic acid combination. Antenatal steroids (betamethasone) were given at 23+4 and she received a loading dose of magnesium sulphate before delivery.\n\nA baby girl was born by emergency lower segment caesarean section due to preterm breech in labour with bulging, intact membranes at 24+6 weeks of gestation. Birthweight was 570 g. Baby was intubated post-delivery and received one dose of surfactant (Beractant α®) in theatre. Apgar scores were 7, 7 and 8 at 1, 5 and 10 minutes, respectively. Umbilical vascular access was obtained and a septic work up, including a full blood count, C-reactive protein (CRP) and blood cultures, was performed. On the day after delivery, mother was febrile with a white blood cell count of 9.05 × 109/L and her CRP reached 310 mmol/L.\n\nThe baby was initiated on ventilatory support, specifically synchronized intermittent mandatory ventilation but she developed respiratory acidosis with CO2 retention soon after delivery, which improved with a second dose of surfactant. Tachycardia, tachypnoea, increased capillary refill time and desaturations (SaO2 of 75%) were also observed at this time and high-frequency ventilation was initiated. She remained hypoxaemic (PaO2 of 3 kPa) initially and point-of-care echocardiography at 3 h of age showed evidence of persistent pulmonary hypertension of newborn. However, following initiation of high-frequency ventilation and before introduction of inhaled nitric oxide (iNO) she improved with PaO2 reaching 8.2 kPa. Her systemic blood pressure remained stable at 28–34 mmHg and as her metabolic acidosis persisted she received two, 10 mL/kg boluses of 0.9% NaCl and maintenance acetate in her patient-specific total parenteral nutrition.\n\nShe was initially commenced on intravenous benzylpenicillin (standard dose 25 mg/kg) and intravenous gentamicin (5 mg/kg) at 2.5 h of life. She was also commenced on prophylactic fluconazole as a preventive strategy for invasive candidal infections among extremely-low-birthweight infants, which was the unit policy. Her initial CRP taken at 2.5 h of life was 25 mmol/L and full blood count showed white blood cell count 5.01 × 109/L with neutrophil count of 1.35 × 109/L. Following this result, her benzylpenicillin was changed to high-dose (50 mg/kg). Her CRP was repeated at 24 h of life and had increased to 87 mmol/L. A lumbar puncture was performed for cerebrospinal fluid (CSF) studies and intravenous cefotaxime (50 mg/kg) was added to her current antimicrobial regimen.\n\nAlthough her blood cultures were sterile at 36 and 48 h, antimicrobials were continued pending final results of blood and CSF cultures, as her clinical features were consistent with sepsis and secondary persistent pulmonary hypertension of newborn. Her CSF cultures were sterile with <5/μL leucocytes, glucose was 4.1 mmol/L and protein was 1.64 g/L. CSF showed negative PCR results for group B streptococcus and Escherichia coli.\n\nPlacental swab culture results became available on day 3 and both the maternal and fetal surfaces revealed 0–4/high-power field leucocytes and grew E. corrodens, which was sensitive to cephalosporins, penicillin and clindamycin. She received a total of 10 days of intravenous benzylpenicillin and 7 days cefotaxime. A repeat blood culture was performed on day 4 of life and was reported sterile. Maternal expressed breast milk was commenced on day 1 of life, which was continued along with donor expressed breast milk until maternal supply was established. She remained on synchronized intermittent mandatory ventilation with pressure support for 4 days, Nasal continuous positive airway pressure for 18 days and high/low-flow humidified oxygen for 11 days. Her cranial ultrasound scans were normal and she showed appropriate growth parameters during the neonatal course and during follow up for the given gestation.\n\nDiscussion\nEarly-onset neonatal sepsis is one of the most important causes of neonatal morbidity and mortality worldwide. Eikenella corrodens is a rare cause of early-onset neonatal sepsis with only seven case studies previously described in English literature [5], [6], [7], [8], [9], [10], [11].\n\nEikenella corrodens is a fastidious, facultative, anaerobic, Gram-negative organism that is part of the normal human oral flora. It has the peculiar characteristic of creating a depression or pit on the agar medium and hence is referred to as the corroding bacillus. Eikenella corrodens is oxidase positive, catalase negative, non-motile and non-spore forming and does not have a capsule. It grows slowly on both blood and chocolate agar and growth is enhanced in carbon dioxide conditions (3%–10% CO2). Culture typically requires longer than 2 days to recognize the pinpoint colonies, which are greyish and small with an almost greenish discoloration on blood agar. Colonies may have an odour resembling hypochlorite. Following growth of placental swabs on blood and chocolate agar, identification of the pitting organism is confirmed by Gram stain and matrix-assisted laser-desorption/ionization time of flight mass spectrometry [12], [13].\n\nIn the 12-year period from April 2004 to March 2016, a total of 1200 placental specimens were cultured in the Microbiology Laboratory from University Maternity Hospital Limerick. While offering clinical and microbiological benefits in high-risk perinatal contexts, the value of performing routine placental cultures for all pregnancies appears limited [14]. Placental swabs for all severely premature babies was also not the standard of care in our hospital until the end of 2015 due to their perceived low yield; however, placentas from all extremely-low-birthweight babies are now swabbed.\n\nThis is the first positive report of confirmed E. corrodens identified from placental, fetal, neonatal or peripartum maternal specimens. Perhaps the newer and more sensitive molecular methods, automation and culture techniques could be playing a role in the identification of uncommon, yet clinically significant organisms [13].\n\nOf late, interesting evidence is emerging to suggest that hematogenous spread of bacteria is colonizing the placenta [15], [16], [17]. Positive placental cultures may provide the clinician with valuable information on which to base therapy; however, it is confirmed only in a small number of placentas with histological evidence of chorioamnionitis and funisitis [14]. Correlation between the bacteriological and histopathological findings in placentas from women with suspected or proven chorioamnionitis has been established with concordance in about 70% of the examined placentas [18].\n\nThere are several ways to perform placental swabs. A suggested technique involves the careful cleansing of the placenta, before incision is made to reach and identify the interface between the chorion and amnion membranes and at this interface, a swab can be collected [19].\n\nPositive culture result from the maternal side of the placenta alone, especially in a vaginal delivery, would be of limited value, particularly if the isolated bacteria is from the normal vaginal flora. However, isolation of highly pathogenic bacteria from the fetal side offers higher correlation with chorioamnionitis [18]. The current method of placental swabbing and culture technique is highly specific but not sensitive [14].\n\nRecent studies have suggested that bacteria associated with the placenta, a ‘placental microbiome’, may be important in reproductive health and disease. However, a challenge in working with specimens with low bacterial biomass, such as placental samples, is that some or all of the bacterial DNA may also derive from contamination [20].\n\nIn this case, it is possible that the treatment of the mother with amoxicillin/clavulanic acid combination before delivery could have contributed to the sterile blood cultures in our patient. It is known that bacteraemia could resolve rapidly after the initiation of appropriate antibiotic therapy and source control [21]. Benzylpenicillin diffuses across the placenta into the fetal circulation at levels 10%–30% of those found in maternal plasma. High concentrations are also attained in the amniotic fluid [22]. The terminal half-life of benzylpenicillin in neonates <32 weeks has been estimated to be about 3.9 hours [23] so trace levels with the potential to inhibit positive growth on culture media may be present more than 24 h after cord clamping. Consideration should be given to adopting alternative diagnostic techniques as adjuncts such as cord-blood novel biomarkers and placental swab cultures for neonatal culture negative sepsis [14], [24], [25], [26], [27], [28], [29], [30], [31].\n\nEikenella corrodens cases documented in the literature to-date describe babies born at a mean age of 30 weeks of gestation [5], [6], [7], [8], [9], [10], [11]. Five of seven babies improved clinically with antimicrobial therapy and had a favourable outcome. Interestingly, these babies were all born with a birthweight >1000 g. The two reported cases of death occurred in infants of 24 and 23 weeks of gestation [8], [9]. All of the mothers except one had evidence of infection including raised inflammatory markers and presence of a fever, and risk factors including poor oral hygiene and history of oral sex during pregnancy were only reported in two women. Interestingly, in the case described by Sawyer et al., the mother was well with no risk factors identified. This baby subsequently had positive blood cultures and raised white blood cell count in CSF studies. Table 1 summarizes the reported feto–maternal and neonatal E. corrodens infections. Our patient was born at 24+6 weeks gestation, but in this case we had a high index of suspicion for infection causing preterm birth given the history of chorioamnionitis in a previous delivery and so treated empirically and promptly with antibiotics, which was likely a contributing factor in the good clinical outcome of our patient.Table 1 Summary of published literature on neonatal Eikenella corrodens infections\n\nCase\tMaternal risk factors\tMaternal signs and symptoms\tMaternal treatment\tGestational age\tBirthweight\tNewborn signs and symptoms\tNewborn treatment\tNewborn outcome\t\nHu et al. [6]\tNone\tWBC 19 000/mm3\tNone\t33 weeks\t1395 g\tPositive blood culture at 30 min of life. WBC 2990/mm3, ANC 388, respiratory distress\tAmpicillin 100 mg/kg IV every 12 h for 14 days; Gentamicin 4 mmg/kg IV every 36 h for 10 days; Cefotaxime 50 mg/kg every 12 h for 5 days\tInfant survived and improved clinically on antimicrobial therapy.\t\nAndres-Gomez et al. [11]\tNone reported\tTemperature 38°C, positive cervical and vaginal cultures\tNone\t28 weeks\t1035 g\tPositive cultures from blood, pharynx, nose, ear and umbilical cord. WBC 16 000/mm3 (80% neutrophils)\tAmpicillin 50 mg/kg IV every 8 hours for 2 weeks\tInfant survived and improved clinically on antimicrobial therapy.\t\nKostadinov & Pinar [8]\tBleeding gums\tPlacental histology showed acute necrotizing chorioamnionitis\tNone\t23 weeks\t590 g\tPositive blood and lung cultures post-mortem; bronchopneumonia and funisitis on autopsy\tNone\tInfant died shortly after birth\t\nSporken et al. [9]\tOral sex during pregnancy\tWBC 15 200/mm3, temperature 38.9°C, positive cervical and amnionic fluid cultures\tCephalothin 4 g per day and metronidazole 2 g per day started 18 h before delivery\t24 weeks\t570 g\tPositive cultures from blood, axilla, groin, mouth, throat, nose, ear and anus, intracerebral haemorrhage, bronchopneumonia and acute enteritis on autopsy\tNone\tInfant died shortly after birth\t\nGarnier et al. [5]\tNone\t38.9°C, premature labour, CRP 105, WBC 25 000/mm3\tNot documented\t32+6 weeks\t1830 g\tTachycardia, hepatomegaly, Positive gastric aspirates\tCefotaxime (8 days) and Gentamicin (3 days)\tFavourable\t\nGarnier et al. [5]\tNone\t37.8°C, premature labour, CRP 105, positive placental cultures\tNot documented\t30 weeks\t1800 g\tRDS, infectious alveolitis, hypotension, tachycardia, neonatal jaundice, positive gastric aspirates\tCefotaxime (10 days) and Gentamicin (2 days)\tFavourable\t\nSawyer et al. [10]\tNone\tPremature labour, mother otherwise well\tSingle dose ampicillin 1 h before delivery\t27 weeks\t1000 g\tRDS, WBC 4800/mm3, blood cultures positive, CSF WBC 990/mm3\tAmpicillin and gentamicin (7 days) and cefotaxime (21 days)\tInfant survived and improved clinically on antimicrobial therapy.\t\nThis study\tNone reported\tHx chorioamnionitis in previous pregnancy, WBC 9.05 × 109/L, CRP 310, preterm labour\tIV Benzylpenicillin 6 h before delivery\t24+6 weeks\t570 g\tRaised CRP 25, positive placental cultures\tBenzylpenicillin (7 days) and Cefotaxime (5 days)\tFavourable\t\nAbbreviations: ANC, absolute neutrophil count; CRP, C-reactive protein; IV, intravenous; RDS, respiratory distress syndrome; WBC, white blood cell count.\n\n\n\nConclusion\nEikenella corrodens has been noted as a causative organism in both neonatal and perinatal sepsis. As the positivity of blood cultures at birth among preterm infants could be influenced by the maternal use of peripartum antimicrobials and a normal CRP result within the first 24 hours need not always reflect the absence of fetal invasion by the highly pathogenic organisms, supportive and adjunctive approaches such as appropriately collected placental swabs for culture would be of value in optimizing the antimicrobial choice of sick preterm infants during the early neonatal period [14].\n\nOur patient, the youngest premature survivor of E. corrodens infection with the lowest birthweight documented in the literature to date, presented with culture-negative sepsis following preterm delivery at 24+6 weeks of gestation and her successful outcome was aided by placental swab cultures and appropriate antimicrobial use.\n\nTransparency declaration\nAll authors report no conflicts of interest relevant to this article.\n\nFinancial support\nNone reported.\n\nAcknowledgements\nThe authors would like to express their appreciation to the staff of the Microbiology Department of the University Hospital and Neonatal Unit of University Maternity Hospital, Limerick, Ireland.\n==== Refs\nReferences\n1 Paul K. Patel S.S. Eikenella corrodens infections in children and adolescents: case reports and review of the literature Clin Infect Dis 33 1 2001 54 61 11389495 \n2 Emmerson A. Mills F. Recurrent meningitis and brain abscess caused by Eikenella corrodens Postgrad Med J 54 631 1978 343 353768 \n3 Chhabra M.S. Motley W.W. Mortensen J.E. Eikenella corrodens as a causative agent for neonatal conjunctivitis J Am Assoc Pediatr Ophthalmol Strabis 12 5 2008 524 525 \n4 Yoshino Y. Inamo Y. Fuchigami T. Hashimoto K. Ishikawa T. Abe O. A pediatric patient with acute suppurative thyroiditis caused by Eikenella corrodens J Infect Chemother 16 5 2010 353 355 20424880 \n5 Garnier F. Masson G. Bedu A. Masson P. Decroisette E. Guigonis V. Maternofetal infections due to Eikenella corrodens J Med Microbiol 58 Pt 2 2009 273 275 19141750 \n6 Hu B.L. Crewalk J.-A.M. Ascher D.P. Congenital sepsis caused by Eikenella corrodens Open J Pediatr 2 02 2012 175 \n7 Jeppson K. Reimer L. Eikenella corrodens chorioamnionitis Obstet Gynecol 78 3 Pt 2 1991 503 505 1870808 \n8 Kostadinov S. Pinar H. Amniotic fluid infection syndrome and neonatal mortality caused by Eikenella corrodens Pediatr Dev Pathol 8 4 2005 489 492 16235131 \n9 Sporken J. Muytjens H. Vemer H. Intra-uterine infection due to Eikenella corrodens Acta Obstet Gynecol Scand 64 8 1985 683 684 3914181 \n10 Sawyer C. Angelis D. Bennett R. Eikenella corrodens sepsis with cerebrospinal fluid pleocytosis in a very low birth weight neonate Case Rep Pediatr 2015 2015 \n11 Andrés Gómez M.T. Martín M.C. Fierro Roza J.F. Méndez Silva F.J. Chorioamnionitis and neonatal septicaemia caused by Eikenella corrodens J Infect 44 2 2002 133 134 12076071 \n12 Sheng W.-S. Hsueh P.-R. Hung C.-C. Teng L.-J. Chen Y.-C. Luh K.-T. Clinical features of patients with invasive Eikenella corrodens infections and microbiological characteristics of the causative isolates Eur J Clin Microbiol Infect Dis 20 4 2001 231 236 11399011 \n13 O'Connor C. Fitzgibbon M. Powell J. Barron D. O'Mahony J. Power L. A commentary on the role of molecular technology and automation in clinical diagnostics Bioengineered 5 3 2014 155 160 24658184 \n14 Bhola K. Al-Kindi H. Fadia M. Kent A.L. Collignon P. Dahlstrom J.E. Placental cultures in the era of peripartum antibiotic use Aust N Z J Obstet Gynaecol 48 2 2008 179 184 18366492 \n15 Aagaard K. Ma J. Antony K.M. Ganu R. Petrosino J. Versalovic J. The placenta harbors a unique microbiome Sci Transl Med 6 237 2014 237ra65-ra65 \n16 Han Y.W. Ikegami A. Bissada N.F. Herbst M. Redline R.W. Ashmead G.G. Transmission of an uncultivated Bergeyella strain from the oral cavity to amniotic fluid in a case of preterm birth J Clin Microbiol. 44 4 2006 1475 1483 16597879 \n17 Fardini Y. Chung P. Dumm R. Joshi N. Han Y.W. Transmission of diverse oral bacteria to murine placenta: evidence for the oral microbiome as a potential source of intrauterine infection Infect Immun 78 4 2010 1789 1796 20123706 \n18 da Mota V.Q. Prodhom G. Yan P. Hohlfheld P. Greub G. Rouleau C. Correlation between placental bacterial culture results and histological chorioamnionitis: a prospective study on 376 placentas J Clin Pathol 66 3 2013 243 248 23268318 \n19 Aquino T.I. Zhang J. Kraus F.T. Knefel R. Taff T. Subchorionic fibrin cultures for bacteriologic study of the placenta Am J Clin Pathol 81 4 1984 482 486 6702749 \n20 Lauder A.P. Roche A.M. Sherrill-Mix S. Bailey A. Laughlin A.L. Bittinger K. Comparison of placenta samples with contamination controls does not provide evidence for a distinct placenta microbiota Microbiome 4 1 2016 29 27338728 \n21 Canzoneri C.N. Akhavan B.J. Tosur Z. Andrade P.E.A. Aisenberg G.M. Follow-up blood cultures in Gram-negative bacteremia: are they needed? Clin Infect Dis 2017 cix648 \n22 NZ M. Penicillin G Sodium 2017 [Available from: http://www.medsafe.govt.nz/SearchResults.asp?q=%22penicillin%20G%20Sodium%20Injection%22.\n23 Muller A.E. DeJongh J. Bult Y. Goessens W.H. Mouton J.W. Danhof M. Pharmacokinetics of penicillin G in infants with a gestational age of less than 32 weeks Antimicrob Agents Chemother 51 10 2007 3720 3725 17646418 \n24 Laforgia N. Coppola B. Carbone R. Grassi A. Mautone A. Iolascon A. Rapid detection of neonatal sepsis using polymerase chain reaction Acta Paediatr 86 10 1997 1097 1099 9350892 \n25 Clerc O. Prod'hom G. Senn L. Jaton K. Zanetti G. Calandra T. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry and PCR-based rapid diagnosis of Staphylococcus aureus bacteraemia Clin Microbiol Infect 20 4 2014 355 360 23991748 \n26 Mestan K. Yu Y. Thorsen P. Skogstrand K. Matoba N. Liu X. Cord blood biomarkers of the fetal inflammatory response J Matern Fetal Neonatal Med 22 5 2009 379 387 19529994 \n27 Romero R. Chaemsaithong P. Docheva N. Korzeniewski S.J. Tarca A.L. Bhatti G. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response J Perinat Med 44 1 2016 53 76 26360486 \n28 Matoba N. Yu Y. Mestan K. Pearson C. Ortiz K. Porta N. Differential patterns of 27 cord blood immune biomarkers across gestational age Pediatrics 123 5 2009 1320 1328 19403498 \n29 Kalathia M.B. Shingala P.A. Parmar P.N. Parikh Y.N. Kalathia I.M. Study of umbilical cord blood culture in diagnosis of early-onset sepsis among newborns with high-risk factors J Clin Neonatol 2 4 2013 169 24404528 \n30 Polin J.L. Knox I. Baumgart S. Campman E. Mennuti M.T. Polin R.A. Use of umbilical cord blood culture for detection of neonatal bacteremia Obstet Gynecol 57 2 1981 233 237 7465130 \n31 Meena J. Charles M.V.P. Ali A. Ramakrishnan S. Gosh S. Seetha K.S. Utility of cord blood culture in early onset neonatal sepsis Aust Med J 8 8 2015 263\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-2975",
"issue": "21()",
"journal": "New microbes and new infections",
"keywords": "Chorioamnionitis; Eikenella corrodens; extremely low birthweight; neonatal sepsis; perinatal infections; placental swab",
"medline_ta": "New Microbes New Infect",
"mesh_terms": null,
"nlm_unique_id": "101624750",
"other_id": null,
"pages": "81-85",
"pmc": null,
"pmid": "29263790",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "12076071;16597879;26392823;6702749;16235131;19403498;26635988;19529994;18562227;23268318;23991748;24848255;19141750;3914181;20123706;20424880;18366492;1870808;353768;17646418;27338728;9350892;26360486;29020307;11399011;24404528;11389495;24658184;7465130",
"title": "Youngest survivor of perinatal infection by Eikenella corrodens: case analysis and literature review highlighting the merits of placental swab culture.",
"title_normalized": "youngest survivor of perinatal infection by eikenella corrodens case analysis and literature review highlighting the merits of placental swab culture"
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"abstract": "Tacrolimus is a potent immunosuppressant that is frequently used in organ transplantation. However, adverse effects include cardiac toxicity. Herein we describe transient myocardial hypertrophy induced by tacrolimus after heart transplantation. The hypertrophy caused no clinical symptoms but was noted because of elevation of plasma brain natriuretic peptide concentration and confirmed at echocardiography. Initially, allograft rejection was feared; however, myocardial biopsy samples revealed only interstitial edema and mild myocardial hypertrophy; neither cellular nor humoral rejection was detected. The blood tacrolimus concentration was higher than usual at that time; thus, tacrolimus dosage was reduced. Myocardial hypertrophy completely resolved upon reducing the target concentration of tacrolimus and did not recur, as confirmed at echocardiography and myocardial biopsy. Thus, we conclude that tacrolimus induces reversible myocardial hypertrophy. In patients receiving tacrolimus therapy, blood concentration should be carefully controlled and extreme attention paid to cardiac involvement.",
"affiliations": "Department of Emergency and Critical Care Medicine, Tokushima University, Tokushima, Japan. akkmano1972@kve.biglobe.ne.jp",
"authors": "Mano|A|A|;Nakatani|T|T|;Yahata|Y|Y|;Kato|T|T|;Hashimoto|S|S|;Wada|K|K|;Ishibashi-Ueda|H|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2009.05.040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "41(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000293:Adolescent; D001706:Biopsy; D006332:Cardiomegaly; D002311:Cardiomyopathy, Dilated; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3831-4",
"pmc": null,
"pmid": "19917396",
"pubdate": "2009-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible myocardial hypertrophy induced by tacrolimus in a pediatric heart transplant recipient: case report.",
"title_normalized": "reversible myocardial hypertrophy induced by tacrolimus in a pediatric heart transplant recipient case report"
} | [
{
"companynumb": "JP-PFIZER INC-2016011787",
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIntraperitoneal chemotherapy has shown a survival advantage over intravenous chemotherapy for women with newly diagnosed optimally debulked epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. However, significant toxicity has limited its acceptance. In an effort to reduce toxicity, the Gynecologic Oncology Group conducted a Phase I study to evaluate the feasibility of day 1 intravenous (IV) paclitaxel and intraperitoneal (IP) cisplatin followed by day 8 IP paclitaxel on an every 21-day cycle.\n\n\nMETHODS\nPatients with Stage IIB-IV epithelial ovarian, fallopian tube, primary peritoneal carcinomas or carcinosarcoma received paclitaxel 135mg/m(2) IV over 3h followed by cisplatin 75mg/m(2) IP on day 1 and paclitaxel 60 mg/m(2) IP on day 8 of a 21 day cycle with 6 cycles planned. Dose-limiting toxicity (DLT) was defined as febrile neutropenia or dose-delay of greater than 2 weeks due to failure to recover counts, or Grade 3-5 non-hematologic toxicity occurring within the first 4 cycles of treatment.\n\n\nRESULTS\nTwenty of 23 patients enrolled were evaluable and nineteen (95%) completed all six cycles of therapy. Three patients experienced a DLT consisting of infection with normal absolute neutrophil count, grade 3 hyperglycemia, and grade 4 abdominal pain.\n\n\nCONCLUSIONS\nThis modified IP regimen which administers both IV paclitaxel and IP cisplatin on day one, followed by IP paclitaxel on day eight, of a twenty-one day cycle appears feasible and is an attractive alternative to the intraperitoneal treatment regimen administered in GOG-0172.",
"affiliations": "The Warren Alpert Medical School of Brown University, Providence, RI 02905, USA. ddizon@wihri.org",
"authors": "Dizon|Don S|DS|;Sill|Michael W|MW|;Gould|Natalie|N|;Rubin|Stephen C|SC|;Yamada|S Diane|SD|;Debernardo|Robert L|RL|;Mannel|Robert S|RS|;Eisenhauer|Eric L|EL|;Duska|Linda R|LR|;Fracasso|Paula M|PM|",
"chemical_list": "D017239:Paclitaxel; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2011.07.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "123(2)",
"journal": "Gynecologic oncology",
"keywords": null,
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D005185:Fallopian Tube Neoplasms; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D010534:Peritoneal Neoplasms",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "182-6",
"pmc": null,
"pmid": "21820161",
"pubdate": "2011-11",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "4038390;18303475;7082756;20610543;10655437;17264340;16312841;16394300;6682012;7907208;16368440;15026475;4709516;9164208;8960474;12401906;21277623;11181662",
"title": "Phase I feasibility study of intraperitoneal cisplatin and intravenous paclitaxel followed by intraperitoneal paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: a gynecologic oncology group study.",
"title_normalized": "phase i feasibility study of intraperitoneal cisplatin and intravenous paclitaxel followed by intraperitoneal paclitaxel in untreated ovarian fallopian tube and primary peritoneal carcinoma a gynecologic oncology group study"
} | [
{
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"actiondrug": "5",
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"activesubstancename": "PACLITAXEL"
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"drugadditional": "3",
... |
{
"abstract": "The spectrum of disorders associated with hyperinsulinemic hypoglycemia (HHI) has vastly increased over the past 20 years with identification of molecular, metabolic and cellular pathways involved in the regulation of insulin secretion and its actions. Hereditary tyrosinemia (HT1) is a rare metabolic disorder associated with accumulation of toxic metabolites of the tyrosine pathway due to a genetically mediated enzyme defect of fumarylacetoacetate hydrolase. Transient tyrosinemia of the newborn (TTN) is a benign condition with a maturational defect of the enzymes associated with tyrosine metabolism without any genetic abnormalities.\n\n\n\nWe describe two rare cases of HHI, one in a patient with HT1 and for the first time, in a patient with TTN. Each of our patients presented in the neonatal period with persistent hypoglycemia that on biochemical evaluation was consistent with HHI. Each patient received diazoxide therapy for 3.5 months and 17 months of life, respectively and HHI resolved thereafter.\n\n\n\nDespite the fact that HHI has been described in HT1 for several decades, no specific mechanism has been delineated. Although we considered the common embryonal origin of the liver and pancreas with the hepatotoxic effect in HT1 also impacting the latter, this was not a possible explanation for TTN. The commonality between our two patients is the accumulation of certain amino acids which are known to be insulinotropic. We therefore hypothesize that the excess of amino acids such as leucine, lysine, valine and isoleucine in our patients resulted in HHI, which was transient. Both patients responded to diazoxide. This novel presentation in TTN and the reassuring response in both HT1 and TTN to diazoxide will be useful to inform physicians about managing HHI in these patients. Further studies are required to delineate the mechanism of HHI in these infants.",
"affiliations": "Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1616, New York, NY, 10029, USA. swathi.s.ram@gmail.com.;Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1616, New York, NY, 10029, USA.;Division of Pediatric Endocrinology, Yale School of Medicine, New Haven, CT, USA.;Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1616, New York, NY, 10029, USA.",
"authors": "Sethuram|Swathi|S|0000-0002-7101-5045;Sperling|Mark A|MA|;Gujral|Jasmine|J|;Romero|Christopher J|CJ|",
"chemical_list": "D014443:Tyrosine; D003981:Diazoxide",
"country": "England",
"delete": false,
"doi": "10.1186/s13023-020-01642-y",
"fulltext": "\n==== Front\nOrphanet J Rare Dis\nOrphanet J Rare Dis\nOrphanet Journal of Rare Diseases\n1750-1172\nBioMed Central London\n\n1642\n10.1186/s13023-020-01642-y\nResearch\nNeonatal hyperinsulinism in transient and classical forms of tyrosinemia\nhttp://orcid.org/0000-0002-7101-5045\nSethuram Swathi swathi.s.ram@gmail.com\n\n1\nSperling Mark A. 1\nGujral Jasmine 2\nRomero Christopher J. 1\n1 grid.59734.3c 0000 0001 0670 2351 Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1616, New York, NY 10029 USA\n2 grid.47100.32 0000000419368710 Division of Pediatric Endocrinology, Yale School of Medicine, New Haven, CT USA\n28 4 2021\n28 4 2021\n2021\n16 1909 6 2020\n9 12 2020\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/. 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.\nBackground\n\nThe spectrum of disorders associated with hyperinsulinemic hypoglycemia (HHI) has vastly increased over the past 20 years with identification of molecular, metabolic and cellular pathways involved in the regulation of insulin secretion and its actions. Hereditary tyrosinemia (HT1) is a rare metabolic disorder associated with accumulation of toxic metabolites of the tyrosine pathway due to a genetically mediated enzyme defect of fumarylacetoacetate hydrolase. Transient tyrosinemia of the newborn (TTN) is a benign condition with a maturational defect of the enzymes associated with tyrosine metabolism without any genetic abnormalities.\n\nResults\n\nWe describe two rare cases of HHI, one in a patient with HT1 and for the first time, in a patient with TTN. Each of our patients presented in the neonatal period with persistent hypoglycemia that on biochemical evaluation was consistent with HHI. Each patient received diazoxide therapy for 3.5 months and 17 months of life, respectively and HHI resolved thereafter.\n\nConclusion\n\nDespite the fact that HHI has been described in HT1 for several decades, no specific mechanism has been delineated. Although we considered the common embryonal origin of the liver and pancreas with the hepatotoxic effect in HT1 also impacting the latter, this was not a possible explanation for TTN. The commonality between our two patients is the accumulation of certain amino acids which are known to be insulinotropic. We therefore hypothesize that the excess of amino acids such as leucine, lysine, valine and isoleucine in our patients resulted in HHI, which was transient. Both patients responded to diazoxide. This novel presentation in TTN and the reassuring response in both HT1 and TTN to diazoxide will be useful to inform physicians about managing HHI in these patients. Further studies are required to delineate the mechanism of HHI in these infants.\n\nKeywords\n\nHyperinsulinism\nHypoglycemia\nHyperinsulinism in hereditary tyrosinemia I\nTransient tyrosinemia of the newborn\nAmino acids and hyperinsulinism\nHyperinsulinemic hypoglycemia\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nOur knowledge of the metabolic and molecular basis of hyperinsulinemic hypoglycemia of infancy (HHI) has dramatically increased over the past 20 years [5, 6, 9, 18]. Monogenic forms of HHI have been identified with defects in the pancreatic ATP sensitive potassium (KATP) channels, transcription factors and enzymes of the insulin secretory pathway resulting in excessive production and secretion. Syndromic forms of HHI form a separate entity of genetic HHI disorders, which include Beckwith Wiedemann Syndrome, Kabuki Syndrome, Turner Syndrome and Hereditary Tyrosinemia Type I (de Leon and Stanley 2017) [10, 18].\n\nHereditary Tyrosinemia Type 1 (HT1, OMIM # 276700) is a rare autosomal recessive disorder with an estimated incidence of 1:100,000 [4]. HT1 results from an inability to metabolize the amino acid tyrosine due to deficiency of the enzyme fumarylacetoacetate hydrolase (FAH, EC number EC Number: 3.7.1.2) encoded by the FAH gene (Gene ID: 2184) on chromosome 15q25.1. This leads to the accumulation of succinylacetone, a toxic metabolite, resulting in damage to the liver, kidneys and peripheral nerves. HT1 has a broad spectrum of clinical presentations, which may be complicated by liver and kidney dysfunction if not appropriately treated [3, 15].\n\nIn contrast to HT1, transient tyrosinemia of the newborn (ORPHA:3402) is considered to be a benign condition caused by a maturational delay in the enzymatic action of the tyrosine catabolic process without any genetic mutation. This condition resolves spontaneously after several months of life and generally is without long-term sequelae [22].\n\nHHI has rarely been reported in infants with HT1, but to date no cases have been reported in patients with transient tyrosinemia of infancy [1, 3] .We describe two unrelated patients with HHI in infancy, one with genetic and the other with transient forms of tyrosinemia. To maintain euglycemia, both patients initially required diazoxide, which was eventually discontinued in each of them.\n\nWe hypothesize that the metabolic derangements associated with tyrosinemia place a patient at risk for hyperinsulinism that may require pharmacological treatment. With scarce literature available on the subject, we explore some possible mechanisms for the etiology of this presentation in both these forms of tyrosinemia. This report should alert clinicians to the possible risk for hypoglycemia and its resolution with diazoxide treatment in patients with tyrosinemia, and highlights the need for further mechanistic studies.\n\nCase presentations\n\nPatient 1\n\nThis is a female infant born appropriate for gestational age [birth weight: 2.6 kg (Z = − 0.71 SD), birth length: 50 cm (Z = 0.78 SD)] at 37 weeks to a healthy mother [Gravida (G) 5,Parity (P)2], with no significant prenatal history. Physical examination at birth was unremarkable. The patient developed hypoglycemia at 2.5 h of life, with a point of care (POC) glucose measurement of 0.72 mmol/L (13 mg/dL). The patient required a combined glucose infusion rate (GIR) of up to 12 mg/kg/min [intravenous (IV) dextrose plus oral feeds] to maintain euglycemia. A critical sample was drawn when the plasma glucose was 1.9 mmol/L (34 mg/dL) on day of life 5 to evaluate the corresponding insulin and counter-regulatory hormone response (Table 1). Hyperinsulinism was diagnosed based on the elevated serum insulin (30.6 pmol/L or 4.4uU/ml) and C-peptide level (0.004 nmol/L or 1.1 ng/mL) with undetectable serum ketone levels (Table 1). Normal growth hormone and cortisol levels ruled out pituitary or adrenal dysfunction. The newborn screening test (drawn on day of life 3 and 22) reported elevated tyrosine levels in blood, but urine succinylacetone was negative, indicating that this was not HT1. The consulting genetic-metabolic team considered this to be transient tyrosinemia of infancy. Despite being on ad lib oral feeds with fortified (24 kcal/30 mL) formula, the patient continued to have intermittent hypoglycemic episodes (less than 3.3 mmol/L or 60 mg/dL beyond day 3 of life). Hence, diazoxide was started at two weeks of life at a dose of 12 mg/kg/day along with hydrochlorothiazide at 1 mg/kg/day. Thereafter, no further hypoglycemia or treatment-induced hyperglycemia was recorded. Given consistently normal blood glucose, the same diazoxide dose was continued during subsequent follow up visits, resulting in a lower per kilogram body weight dosing. The parents discontinued her medications at 3.5 months of life, while continuing to monitor her glucose levels via a POC glucose meter. She has since remained euglycemic with appropriate growth and development for age. Her transient tyrosinemia resolved biochemically when tested at 6 months of life and she was subsequently discharged from the endocrine clinic at 7 months of life.Table 1 Patient profiles during hypoglycemia\n\n\tPatient 1\tPatient 2\t\nLaboratory samples (values consistent with hyperinsulinemic hypoglycemia) [7, 13]\tTransient tyrosinemia of infancy\tHereditary tyrosinemia type I\t\nPreserved plasma glucose < 3.3 mmol/L (< 60 mg/dL)\t1.9 (34)\t2.2 (39)\t\nBeta-hydroxy butyrate < 1.8 mmol/L\t < 0.2\t < 0.2\t\nC-peptide > 0.002 nmol/L (> 0.5 ng/dL)\t0.004 (1.1)\t0.007 (2.1)\t\nInsulin > 13.9 pmol/L (> 2 uU/mL)\t30.6 (4.4)\t20.8 (3)\t\nGrowth hormone > 7.5 ug/L (> 7.5 ng/mL)\t17 (17)\t7.5 (7.5)\t\nCortisol 496 nmol/L (> 18 mcg/dL)\t551.8 (20)\t689.7 (25)\t\n\nPatient 2\n\nThis is a male infant born appropriate for gestational age [birth weight: 3.68 kg (Z = 1.24 SD), birth length: 52.1 cm (Z = 1.24 SD]) at 38 weeks to a G1P1 mother who developed gestational diabetes requiring insulin therapy from the 8th month of pregnancy. At birth, physical examination was normal with no signs of dysmorphia. The patient was born at a regional hospital where he required IV fluids for hypoglycemia which was attributed to him being an infant of a diabetic mother. However, his hypoglycemia persisted with repeated POC glucose readings as low as 0.72 mmol/L (13 mg/dL). He received intravenous dextrose infusion in addition to oral feeds, requiring a combined GIR of up to 13.6 mg/kg/min to maintain euglycemia. His newborn screening test (drawn on day of life 2) was positive for elevated levels of succinylacetone, suggestive of HT1. The diagnosis of HT1 was confirmed by identifying a homozygous pathogenic mutation, c.192G > T, p.Q64H in the FAH gene. He was treated with nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione, NTBC) and a tyrosine-free formula from day 9 of life. His tyrosine levels did normalize with this therapy by day 12 of life. However, he continued to have recurrent hypoglycemic episodes after two weeks of life. To establish a diagnosis for his hypoglycemia, a critical sample was drawn when his plasma glucose level was 2.2 mmol/L (39 mg/dL). Undetectable β-OH butyrate (< 0.2 mmol/L) with elevated C-peptide (0.007 nmol/L or 2.1 ng/mL) and insulin levels (20.8 pmol/L or 3 uU/mL) in this sample (Table I1 led to the diagnosis of hyperinsulinism. Serum growth hormone and cortisol showed an appropriate response to the hypoglycemia indicative of normal pituitary and adrenal function (Table 1). He was started on treatment with diazoxide at 10 mg/kg/day at two weeks of life, which stabilized glycemic control without additional need for intravenous glucose. Following discharge from the neonatal intensive care unit, the baby had moderate control of his tyrosinemia with nitisinone and dietary management. He did not have any further hypoglycemic episodes while on diazoxide. The patient gained adequate weight in the first year of life with appropriate development for age. Diazoxide dose was gradually weaned to sub-therapeutic levels (1.5 mg/kg/day) and discontinued at 17 months of life. The patient had one episode of hypoglycemia during an upper respiratory tract illness after stopping therapy. Diazoxide has since then not been restarted and the baby remains euglycemic to date.\n\nDiscussion\n\nWe report two cases of neonatal hyperinsulinemic hypoglycemia in the setting of tyrosinemia; one case with hereditary tyrosinemia type I, which has been previously reported and another case with transient tyrosinemia of the newborn, which to our knowledge has not been described.\n\nDespite similar nomenclature, Hereditary Tyrosinemia Type I and transient tyrosinemia of infancy have very different pathophysiology and prognosis. While the former is a permanent, genetic condition with significant morbidity and mortality, the latter is a benign and transient immaturity of enzyme(s). The common factor in both conditions, however, is the accumulation of tyrosine.\n\nHypoglycemia may affect up to 10% of healthy term infants in the first 24–48 h of life, but typically resolves spontaneously by day three of life. Screening and treatment of hypoglycemia is important to prevent adverse neurological sequelae. There remains some debate over the definition of hypoglycemia in the neonatal period and the glucose levels at which neurological development may be affected. More recently, the Pediatric Endocrine Society recommended treatment in patients with plasma glucose < 2.8 mmol/L (< 50 mg/dL) in the first 48 h of life and < 3.3 mmol/L (< 60 mg/dL) beyond 48 h of life [19–21].\n\nBoth of our patients presented with significant hypoglycemia during their first few days of life that persisted up to 2 weeks of age. Hyperinsulinism was evident in each of these patients based on their biochemical evaluation during hypoglycemia. Mild liver dysfunction was documented in both patients which was not severe enough to account for such low glucose levels while receiving adequate alimentary nutrition.\n\nOur first patient was diagnosed with transient tyrosinemia of infancy based on her biochemical evaluation. Based on our review of the literature, there has been no previous report of hyperinsulinism in infants with transient tyrosinemia, and although hypoglycemia has been described in patients with HT1, the mechanism of this presentation is not well understood [1, 3].\n\nThere are various etiologies of congenital hyperinsulinism, which include eleven monogenic forms as well as milder episodes as seen in infants with transient perinatal stress and prematurity [18]. Different amino acids have been known to induce positive as well as negative effects on beta cell insulin secretion [12].\n\nLeucine is an amino acid whose well known insulinotropic effects are mediated by several different mechanisms, including the production of alpha ketoglutarate and allosteric activation of glutamate dehydrogenase (GDH) [12]. Patients with leucine sensitive hypoglycemia were described as early as in 1960, although the mechanism was only understood after several decades [11]. Animal studies in sheep have demonstrated a rise in insulin secretion with intravenous administration of amino acids such as leucine, glycine, alanine, lysine and serine. Similarly, phenylalanine, a precursor to tyrosine, has been shown to induce insulin secretion in sheep although no such effects have been demonstrated with tyrosine [14].\n\nHuman studies have also demonstrated this insulinotropic effect of amino acids, both individually and in amino acid mixtures [8]. In an experiment in healthy humans, Fajans et al. elicited insulin release following IV infusion of certain amino acids. Infusion with arginine, lysine, leucine, phenylalanine, valine, methionine and histidine all resulted in insulin production with arginine being maximally potent and histidine the least [8].\n\nOur first patient with transient tyrosinemia had transiently elevated levels of leucine, phenylalanine, isoleucine and valine (Table 2). The patient with HT1 had transient elevation of alanine, valine and lysine which normalized by two months of life. Both patients demonstrated elevated tyrosine levels (Table 2). We postulate that these elevated amino acids had transient insulinotropic effects, therefore manifesting as hypoglycemia in both patients.Table 2 Amino acid levels in both infants\n\nAmino acid levels μM (normal values)\tPatient I\tPatient II\t\nDay 19 of life\tDay 22 of life\tApproximately 2 months of life\tDay 7–8 of life\tDay 12 of life 3 days after starting Nitisinone\t17 months of life\t\nLeucine 47–155\t⇑ 164.1\t⇑ 166.7\t78.3\t126.1\t157.7\t103.1\t\nAlanine 131–710\t534.8\t526.6\t352.7\t⇑ 841.3\t628.6\t302.3\t\nIsoleucine 31–86\t⇑ 92.9\t⇑ 102\t51.0\t50.9\t81.1\t43.9\t\nValine 86–190\t⇑ 258.3\t⇑ 234\t147.2\t⇑ 265.7\t⇑ 290.5\t267.6\t\nLysine 52–196\t⇑ 200.9\t⇑ 242.7\t127.4\t⇑ 395.9\t⇑ 345.9\t69\t\nPhenylalanine 31–75\t⇑ 96.5\t⇑ 78.3\t41.3\t53.6\t12\t72.6\t\nTyrosine 22–108\t⇑ 904.3\t⇑ 660.5\t⇑ 211.8\n\n⊛ 79 (6 months of life)\n\n\t⇑ 506\t26.8\t⇑ 426.4\t\nValues with upward arrow and in italic indicate high levels of amino acids\n\nIn addition, reports have demonstrated that patients with HT1 have hyperplasia of the islet cells of the pancreas [16, 17]. This anatomical change, therefore, could reflect and be responsible for the hyperinsulinism causing significant hypoglycemia. In HT1, there is constant damage to hepatic tissue by toxic metabolites. This results in liver repair and nodule formation by activation of the stem cell compartment. There is evidence that stem cells and progenitor cells in the major duodenal papilla give rise to the biliary tree stem cells, which eventually lead to organogenesis of both the liver and the pancreas [2]. Given the common origin of liver and pancreatic cells, one could propose that inadvertent activation of stem cells could lead to hyperplasia of pancreatic islet cells in addition to hepatocytes, leading to hyperinsulinism (Figure 1). This theory, however, could not explain hyperinsulinism in transient tyrosinemia where toxic metabolites do not accumulate.Fig. 1 Common origin for the development of pancreatic β-cells form from bile duct epithelium. It could be postulated that abnormal development of liver cells or abnormalities within the biliary tree could affect the appropriate development and/or function of future pancreatic cells. The diagram is an adapted proposal illustrating a possible path to the development of pancreatic β-cells.\n\nAdapted from Cardinale et al. [12]\n\nWe found one reported case series of three children with hyperinsulinemic hypoglycemia in the setting of HT1 that responded to diazoxide therapy [1]. All three patients required this medication only transiently, for 9, 18 and 34 months respectively. Our patient with HT1 required therapy until 17 months of life with some transient hypoglycemia during illness following discontinuation of medication. It is yet to be determined if his hypoglycemia will recur and require diazoxide again. However, hyperinsulinism in our patient with transient tyrosinemia was transient with discontinuation of therapy by 3.5 months of life.\n\nConclusion\n\nIn conclusion, we report the first incidence hyperinsulinism in a patient with transient tyrosinemia of infancy. We also report a patient with HT1 diagnosed with hyperinsulinism requiring diazoxide therapy until 17 months of life. Both cases had transient, but prolonged hyperinsulinism that was diazoxide responsive. Although hyperinsulinemic hypoglycemia has been reported in patients with HT1, no clear mechanism for this has been delineated. We postulate that the elevation of certain amino acids such as leucine, glycine, valine, phenylalanine and isoleucine could lead to excess insulin production. This hypothesis has not been previously proposed. Although pancreatic hyperplasia has been described in HT1, its mechanism is not clear. It seems more likely that amino acids stimulating insulin production result in islet cell hyperplasia. The common origin of the liver and pancreas does not explain the etiology of hyperinsulinism in transient tyrosinemia of infancy and hence cannot be invoked in this scenario. Nevertheless, the major novelty of our report is that clinicians should be alert about potential hypoglycemia in a patient diagnosed with either transient or hereditary tyrosinemia type I. Fortunately, we show these patients to be diazoxide responsive, so that euglycemia can be achieved in a relatively safe and effective manner. This report provides evidence of the transient nature of the hypoglycemia along with guidance for treatment to the health care provider and reassurance to the parents. Our proposed theory of amino acid induced hyperinsulinism is a known entity but has not been previously described with these metabolic disorders. Further studies are necessary to delineate the precise mechanism in these infants.\n\nAcknowledgements\n\nWe would like to acknowledge the Pediatric Endocrinology Division at Icahn School of Medicine at Mount Sinai Hospital and the Neonatology unit for helping us care for these patients and collect required data to publish this article.\n\nAuthors’ contributions\n\nSS was involved in the conception, drafting and revision of all intellectual content of article. MAS was involved in conception and revising article critically for important intellectual content. JG was involved in revising article critically for important intellectual content. CR was involved in revising article critically for important intellectual content. All authors read and approved the final manuscript.\n\nFunding\n\nNo external funding sources were used for this article.\n\nAvailability of data and materials\n\nData presented in this article is available in each of the patient’s electronic medical record.\n\nEthics approval and consent to participate\n\nEthics approval and patient consents were not required for this study since no personal information was used and no human experiment conducted. All data have been deidentified for the purpose of this publication.\n\nConsent for publication\n\nNot applicable. Consent to publish was not required for this study since no personal information was used and no human experiment conducted.\n\nCompeting interests\n\nSS received a travel award to present this data as a poster in the Hyperinsulinism symposium conducted at Children’s Hospital of Philadelphia in September 2019. MAS is a consultant for the insulin advisory board for Novo Nordisk. JG has no competing interests. CR is a consultant for the Ascendis Advisory Board.\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. Baumann U Preece MA Green A Hyperinsulinism in tyrosinaemia type I J Inherit Metab Dis 2005 28 131 135 10.1007/s10545-005-5517-1 15877201\n2. Cardinale V Wang Y Carpino G The biliary tree—a reservoir of multipotent stem cells Nat Rev Gastroenterol Hepatol 2012 9 231 240 10.1038/nrgastro.2012.23 22371217\n3. Chinsky JM Singh R Ficicioglu C Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations Genet Med 2017 19 1380 10.1038/gim.2017.101\n4. de Laet C Dionisi-Vici C Leonard JV Recommendations for the management of tyrosinaemia type 1 Orphanet J Rare Dis 2013 8 8 10.1186/1750-1172-8-8 23311542\n5. de Leon DD, Stanley CA. Congenital hypoglycemia disorders: new aspects of etiology, diagnosis, treatment and outcomes: highlights of the proceedings of the congenital hypoglycemia disorders symposium, Philadelphia April 2016. Pediatr Diabetes. 2017;18(1):3–9.\n6. de Lonlay P Touati G Robert J-J Saudubray J-M Persistent hyperinsulinaemic hypoglycaemia Semin Neonatol SN 2002 7 95 100 10.1053/siny.2001.0090 12069542\n7. Ferrara C Patel P Becker S Biomarkers of insulin for the diagnosis of hyperinsulinemic hypoglycemia in infants and children J Pediatr 2016 168 212 219 10.1016/j.jpeds.2015.09.045 26490124\n8. Floyd JC Fajans SS Conn JW Stimulation of insulin secretion by amino acids J Clin Invest 1966 45 1487 1502 10.1172/JCI105456 5919350\n9. Galcheva S Demirbilek H Al-Khawaga S Hussain K The genetic and molecular mechanisms of congenital hyperinsulinism Front Endocrinol 2019 10 111 10.3389/fendo.2019.00111\n10. Ghosh A Banerjee I Morris AAM Recognition, assessment and management of hypoglycaemia in childhood Arch Dis Child 2016 101 575 580 10.1136/archdischild-2015-308337 26718813\n11. Grumbach MM Kaplan SL Amino acid and alpha-keto acid-induced hyperinsulinism in the leucine-sensitive type of infantile and childhood hypoglycemia J Pediatr 1960 57 346 362 10.1016/S0022-3476(60)80242-9 13829840\n12. Keane K, Newsholme P (2014) Metabolic Regulation of Insulin Secretion. In: Vitamins & Hormones. Elsevier, pp 1–33\n13. Kelly A Tang R Becker S Stanley CA Poor specificity of low growth hormone and cortisol levels during fasting hypoglycemia for the diagnoses of growth hormone deficiency and adrenal insufficiency Pediatrics 2008 122 e522 e528 10.1542/peds.2008-0806 18694902\n14. Kuhara T Ikeda S Ohneda A Sasaki Y Effects of intravenous infusion of 17 amino acids on the secretion of GH, glucagon, and insulin in sheep Am J Physiol-Endocrinol Metab 1991 260 E21 E26 10.1152/ajpendo.1991.260.1.E21\n15. Mudd SH Hypermethioninemias of genetic and non-genetic origin: A review Am J Med Genet C Semin Med Genet 2011 157 3 32 10.1002/ajmg.c.30293\n16. Perry TL Tyrosinemia associated with hypermethioninemia and islet cell hyperplasia Can Med Assoc J 1967 97 18 1067 1075 4862180\n17. Russo P O’Regant S Visceral pathology of hereditary tyrosinemia type I Am J Hum Genet 1990 47 2 317 324 2378357\n18. Stanley CA Perspective on the genetics and diagnosis of congenital hyperinsulinism disorders J Clin Endocrinol Metab 2016 101 815 826 10.1210/jc.2015-3651 26908106\n19. Stomnaroska-Damcevski O Petkovska E Jancevska S Danilovski D Neonatal hypoglycemia: a continuing debate in definition and management Pril Makedon Akad Na Nauk Umet Oddelenie Za Med Nauki 2015 36 91 97 10.1515/prilozi-2015-0083\n20. Thompson-Branch A Havranek T Neonatal hypoglycemia Pediatr Rev 2017 38 4 147 157 10.1542/pir.2016-0063 28364046\n21. Thornton PS Stanley CA De Leon DD Recommendations from the pediatric endocrine society for evaluation and management of persistent hypoglycemia in neonates, infants, and children J Pediatr 2015 167 238 245 10.1016/j.jpeds.2015.03.057 25957977\n22. Transient Tyrosinemia of the newborn. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=3402.\n\n",
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"title": "Neonatal hyperinsulinism in transient and classical forms of tyrosinemia.",
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"abstract": "Calciphylaxis is a rare disease that typically presents in patients with end-stage renal disease on dialysis or those who have received a renal transplant. Nonuremic calciphylaxis leads to ischemia and subsequent necrosis of subcutaneous tissue. Diseases associated with nonuremic calciphylaxis include primary hyperparathyroidism, connective tissue disease, malignancy, and alcoholic liver disease. Due to its high mortality, early identification and an aggressive multidisciplinary treatment approach is necessary to improve patient outcomes.",
"affiliations": "At the Mayo Clinic in Rochester, Minn., Amber Hesse practices in the Division of Hematology and Andrew Herber and Mike Breunig practice in the Division of Hospital Internal Medicine. The authors have disclosed no potential conflicts of interest, financial or otherwise.",
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"title": "Calciphylaxis in a patient without renal failure.",
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"abstract": "Alpha-Pyrrolidinopentiothiophenone (α-PVT) belongs to the drug class of pyrrolidinophenones, a subgroup of synthetic cathinones, which are among the most prevalent new psychoactive substances. The study describes a series of 44 authentic forensic cases with analytical confirmed intake of α-PVT. Plasma concentrations, determined by a validated LC-MS/MS method, ranged from ca. 0.9 to 306 µg/L (median 35.6; mean 66.6 µg/L). Comprehensive toxicological analysis proved excessive co-consumption in almost all cases, including other pyrovalerones and classic stimulants as well as central depressant drugs such as opiates/opioids, benzodiazepines, pregabalin and/or ethanol. Subjects were aged between 26 and 54 years (median 35 years, mean 36 years) and appeared to be mainly experienced intravenous drug consumers. A high incidence of aberrant behavior in terms of aggressive, combative behavior and psychotic changes could be observed, as also reflected in accused offences, which frequently presented violent crimes. In consideration of several confounding factors, the study suggests a relationship between frequency of such impairment and plasma concentrations of α-PVT, but individual cases without signs of behavioral changes and high plasma concentrations also occurred, which might be explained by developed tolerance and/or individual vulnerably for the psychotic effects of pyrovalerones.",
"affiliations": "Department of Forensic Toxicology, Institute of Legal Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany. Electronic address: liane.paul@med.uni-muenchen.de.;Department of Forensic Toxicology, Institute of Legal Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.;Department of Forensic Toxicology, Institute of Legal Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.;Department of Forensic Toxicology, Institute of Legal Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.;Institute of Legal Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.",
"authors": "Paul|Liane D|LD|;Welter-Luedeke|Jessica|J|;Penzel|Saskia|S|;Zangl|Anna|A|;Graw|Matthias|M|",
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"abstract": "Bile Salt Export Pump (BSEP) Deficiency disease, including Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2), is a rare disease, usually leading within the first ten years to portal hypertension, liver failure, hepatocellular carcinoma. Often liver transplantation is needed. Sodium 4-phenylbutyrate (4-PB) seems to be a potential therapeutic compound for PFIC2. Psychiatric side effects in the adolescent population are little known and little studied since the drug used to treat children and infants. So we described a case of Caucasian boy, suffering from a late onset PFIC2, listed for a liver transplant when he was sixteen and treated with 4-FB (200 mg per kilogram of body weight per day). The drug was discontinued for the onset of bipolar and related disorders. This case illustrates possible psychiatric side effects of the drug.",
"affiliations": "Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Mental Health, SPDC Unit, USL Local Health Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.",
"authors": "Vitale|Giovanni|G|;Simonetti|Giulia|G|;Pirillo|Martina|M|;Taruschio|Gianfranco|G|;Andreone|Pietro|P|",
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"fulltext": "\n==== Front\nPsychiatry InvestigPsychiatry InvestigPIPsychiatry Investigation1738-36841976-3026Korean Neuropsychiatric Association 10.4306/pi.2016.13.5.580Case ReportBipolar and Related Disorders Induced by Sodium 4-Phenylbutyrate in a Male Adolescent with Bile Salt Export Pump Deficiency Disease Vitale Giovanni 1Simonetti Giulia 1Pirillo Martina 1Taruschio Gianfranco 2Andreone Pietro 11 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.2 Department of Mental Health, SPDC Unit, USL Local Health Bologna, Bologna, Italy.Correspondence: Giulia Simonetti, PhD. Dipartimento di Science Mediche e Chirurgiche, Università di Bologna, Via Massarenti 9, 40138 Bologna, Italy. Tel: +39 0512144873, +39 0512143152, Fax: +39 051345806, simgiu@hotmail.it9 2016 30 9 2016 13 5 580 582 01 7 2015 18 12 2015 28 12 2015 Copyright © 2016 Korean Neuropsychiatric Association2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Bile Salt Export Pump (BSEP) Deficiency disease, including Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2), is a rare disease, usually leading within the first ten years to portal hypertension, liver failure, hepatocellular carcinoma. Often liver transplantation is needed. Sodium 4-phenylbutyrate (4-PB) seems to be a potential therapeutic compound for PFIC2. Psychiatric side effects in the adolescent population are little known and little studied since the drug used to treat children and infants. So we described a case of Caucasian boy, suffering from a late onset PFIC2, listed for a liver transplant when he was sixteen and treated with 4-FB (200 mg per kilogram of body weight per day). The drug was discontinued for the onset of bipolar and related disorders. This case illustrates possible psychiatric side effects of the drug.\n\nBipolar and related disordersSodium 4-phenylbutyrateProgressive Familial Intrahepatic Cholestasis type 2\n==== Body\nINTRODUCTION\nPFIC are an heterogeneous group of autosomal recessive disorders of childhood that present with intrahepatic cholestasis, characterized by defects in biliary proteins, involved in the synthesis and transport of bile1, leading to portal hypertension, liver failure and transplantation within first ten years of life. Up to now three different type of PFIC have been identified: type 1, 2 and 3. PFIC2, also known as BSEP deficiency disease, involves ABCB11 gene, encoding the bile salt export pump (BSEP), a liver-specific adenosine triphosphate binding cassette transporter that mediates the excretion of bile monovalent salts.2 Current treatments available are high-dose of ursodeoxycholic acid (25–30 mg/kg/die) in initial management, rifampicin for itching and fat-soluble vitamins (A, K, D, E) supplementation.2 Some patients with PFIC2 may also benefit from biliary diversion, and endoscopic nasobiliary drainage, maintained for a few weeks, may help to select potential responders to biliary surgery.2 If these medical and surgical therapies fail, liver transplantation remains the only alternative treatment.3 4-PB is an orphan drug (AMMONAPS; Swedish Orphan AB Inter, Stockolm, Sweden), routinely used to treat ornithine trans-carbamylase deficiency (OTC). In last years, reports in vitro and in vivo, emerged about the effective use of the 4-PB in PFIC, able to improve liver tests and itching by increasing the hepatocanalicolar expression of BSEP and the biliary excretion capacity of bile salts.45 Dosage was 500 mg per kilogram of body weight per day or total dose of 10 grams per day.67 Results of clinical trials have shown that 4-PB has few side effects and it is safe for patients: grade 3 neuro-cortical toxicity, consisting of excessive somnolence and confusion, was sudden, dose-dependent, accompanied by metabolic changes (hyponatremia and hypocalcemia) and reversible after discontinuation of the drug.8 Even when pilot studies were conducted in patients with cystic fibrosis or thalassemia, severe adverse events were not reported.910 There are limited information on side effects of long-term administration of drug to patients with OTC deficiency. In this case, the most common adverse event was amenorrhea in 23% of post-pubertal females treated; other problems included anorexia and vomiting.11 When 4-FB was used in patients with PFIC2, no severe side effects were observed during or after these studies.4612 Finally, the leaflet of the drug reported only two common psychiatric adverse effects, depression and irritability. Considering OTC deficiency provides per se to the development of neurological symptoms such as lethargy and irritability, related to hyperammonemia, the adverse events are to be analysed in this clinical setting.13\n\nCASE\nMr. N., a Caucasian boy of 18 years, suffering from a genetically diagnosed late onset PFIC2, dyslexia and dyschromia, was listed for a liver transplant in January 2013 without evidence of psychiatric contraindications or mental disorders, detected during a specialist evaluation, performed as part of the examinations for inclusion in the waiting list.\n\nFrom August 2014, he presented a recurrent jaundice with progressive increase in total bilirubin (until to 14.5 mg/dL) without liver failure. Ultrasounds and endoscopy excluded complications such as ascites, esophageal varices and portal vein thrombosis. An off-label treatment with 4-PB was started at the initial dose of 200 mg per kilogram of body weight per day, refracted in four times. Concomitant therapies were ursodeoxycholic acid (25 mg per kilogram of body weight per day), rifampin, taken for the itching (300 mg per day) and regular supplementation of fat-soluble vitamins (A, D, E, K). Systematically, after taking the drug, the patient complained dysphoria with uncontrolled irritability.\n\nLaboratory tests didn't show electrolyte or metabolic abnormalities and infections were excluded. These manifestations caused a significant negative impact on his quality of life and on interpersonal relationship. Furthermore the family referred that Mr N. appears very different and showed behaviors related to other-directed verbal aggressiveness, never occurred before taking the drug, repeated consistently after each 4-PB intake. In particular, the patient reported that after 30 minutes of the drug administration, he felt a sense of \"nervous tension\" that could not control nor to manage with coping activities. After these episodes, intense asthenia and fatigue were reported. Then, recurrent headache and nausea and, occasionally, feeling of retrosternal weight with features not suggestive of angina were also complained. After two weeks, the treatment was discontinued and a psychiatric consultation was requested. A comprehensive psychiatric evaluation was performed by administering the Toronto Alexitymia Scale (TAS-20)14 (cut off scores for psychopatology >50), the State Trait Anger Expression Inventory (STAXI-II)15 (range of normality between 25° and 75° percentile), the Disability Scale and the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II).16 For an initial analysis, the psychodiagnostic exam provided few relevant elements. In fact we excluded the alexitymic disease for TAS score <50 and 5/8 subscale of the STAXI-II presented subthreshold scores (<25° percentile). After careful analysis of the STAXI-II, we note very much subthreshold scores but out of the range for the subscale concerning the control of anger (Ax/Con >75° percentile). These results reported a picture of a boy who may use excessively psychological defenses such as negation and repression that prevent uncomfortable or unacceptable feelings of anger. Mr. N. tended to invest a lot of energy controlling and preventing the experience and expression of the anger. He referred an ego-dystonic perception of the behaviors acted out. Even if not confirmed by SCID II scores,16 the hypothesis of a passive-aggressive personality disorder emerged clearly and the psychiatric symptoms completely regressed immediately after drug discontinuation. The interview revealed that the study activities was strongly influenced by the disease, however considering the diagnosis of dyslexia, instead the social and family life have not been affected by the health problem. Despite these psychological analyses, were not present evident symptoms of psychopathology, so the psychiatric evaluation excluded the presence of mental disorders in progress. The absence of disturbance in attention and awareness, an additional disturbance in cognition, finally, psychomotor behavioral disturbances ruled out alternative diagnosis of delirium. Instead, according with the DSM-5 criteria,17 the psychiatric manifestations occurred in this boy were suggestive of bipolar and related disorders induced by 4-PB; the clinical features are: A) a significant and persistent altered mood that dominates the clinical situation, characterized by irritable mood; B) the symptoms developed immediately after drug exposure and this drug can produce psychiatric symptoms; C) the disturb is not explained by a bipolar disorder or related disorders not induced by drugs; D) the disturbance does not occur during a delirium; E) alteration causes clinically significant distress.\n\nDISCUSSION\n4-PB is a chaperone orphan drug that has been recently indicated for the treatment of BSEP deficiency disease67 because is able to improve the quality of life through the reduction of itching, the episodes of jaundice and the need for invasive treatment, including liver transplantation. Psychiatric side effects as depression and irritability have been reported but no cases of bipolar and related disorders have been described until now in patient with PFIC2. We do not know the influence of personality traits and psychological factors on the development of symptoms, but can hypothesize in this case the presence of a psychological predisposition to a dysfunctional functioning concerning the expression of anger. So it is possible that this drug has also amplified a silent psychological tendency. Moreover, the drug obviously has effects other than just being a substrate for an alternate pathway of ammonia excretion and because it penetrate well into cerebrospinal fluid.18 Also, 4-FB was been studied in many diseases affecting the CNS such as spinal muscular atrophy, multiple sclerosis and cerebral ischemia where it seems to have helped, being able to slow cell apoptosis.19\n\nEarly researches showed that bipolar disorder is accompanied by the activation of immune-inflammatory pathways as indicated by the increased levels of pro-inflammatory cytokines, positive acute-phase proteins, such as multiple changes in oxidative and nitrosative stress, tryptophan and tryptophan catabolites, neurotrophins, circadian dysregulation, hypothalamic pituitary adrenal, axis dysregulation activation markers.2021\n\nThe drug crosses the blood-brain barrier and influences the brain activity in different ways including tryptophan metabolism,222324 but the exact mechanisms of the 4-PB related CNS adverse effects, have not yet been identified.\n\nNew studies should investigate aspects of neuropharmacology and possible relationships with the psychological aspects of subjects taking this drug. This is the first report documenting other psychiatric manifestations related to 4-PB administration, recurring regularly after re-taking the drug, and reinforce the need of a careful psychiatric evaluation before starting the treatment in patients with PFIC.\n==== Refs\n1 Morotti RA Suchy FJ Magid MS Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings Semin Liver Dis 2011 31 3 10 21344347 \n2 Hori T Nguyen JH Uemoto S Progressive familial intrahepatic cholestasis Hepatobiliary Pancreat Dis Int 2010 6 570 578 \n3 Soubrane O Gauthier F DeVictor D Bernard O Valayer J Houssin D Orthotopic liver transplantation for Byler disease Transplantation 1990 50 804 806 2238055 \n4 Hayashi H Sugiyama Y 4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps Hepatology 2007 45 1506 1516 17538928 \n5 Hasegawa Y Hayashi H Naoi S Kondou H Bessho K Igarashi K Intractable itch relieved by 4-phenylbutyrate therapy in patients with progressive familial intrahepatic cholestasis type 1 Orphanet J Rare Dis 2014 9 89 25022842 \n6 Naoi S Hayashi H Inoue T Tanikawa K Igarashi K Nagasaka H Improved liver function and relieved pruritus after 4-phenylbutyrate therapy in a patient with progressive familial intrahepatic cholestasis type 2 J Pediatr 2014 5 1219 1227.e3 24530123 \n7 Gonzales E Grosse B Cassio D Davit-Spraul A Fabre M Jacquemin E Successful mutation specific chaperone therapy with 4-phenylbutyrate in a child with progressive familial intrahepatic cholestasis type 2 J Hepatol 2012 57 695 698 22609309 \n8 Carducci MA Gilbert J Bowling MK Noe D Eisenberger MA Sinibaldi V A phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule Clin Cancer Res 2001 7 3047 3055 11595694 \n9 Rubenstein RC Zeitlin PL A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in Delta F508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function Am J Respir Crit Care Med 1998 157 484 490 9476862 \n10 Olivieri NF Rees DC Ginder GD Thein SL Brittenham GM Way JS Treatment of thalassemia major with phenylbutyrate and hydroxyurea Lancet 1997 350 491 492 9274590 \n11 Burlina AB Ogier H Korall H Trefz FK Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients Mol Genet Metab 2001 72 351 355 11286510 \n12 Gonzales E Grosse B Schuller B Davit-Spraul A Conti F Guettier C Targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2: Evidence for improvement of cholestasis with 4-phenylbutyrate Hepatology 2015 62 558 566 25716872 \n13 European Medicine Agency European Public Assessment Report of Ammonaps Sep 11, 2009 publishing on http://www.ema.europa.eu/docs/it_IT/document_library/EPAR__Product_Information/human/000219/WC500024753.pdf4 \n14 Bressi C Taylor G Parker J Bressi S Brambilla V Aguglia E Cross validation of the -159-factor structure of the 20-item Toronto Alexithymia Scale: an Italian multicenter study J Psychosom Res 1996 41 551 559 9032718 \n15 Spielberger CD STAXI-2: State-Trait Anger Expression Inventory-2: Manual / Adaptation Italian, at Anna Laura Comunian Care Florence Special Organizations 2004 \n16 Mazzi F Morosini P De Girolamo G Guaraldi GP SCID-II. O.S. The Italian Version Florence Special Organizations 2003 \n17 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Arlington, VA American Psychiatric Publishing 2013 \n18 Berg S Serabe B Aleksic A Bomgaars L McGuffey L Dauser R Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate Cancer Chemother Pharmacol 2001 47 385 390 11391852 \n19 Qi X Hosoi T Okuma Y Kaneko M Nomura Y Sodium 4-Phenylbutyrate protects against cerebral ischemic injury Mol Pharmacol 2004 66 899 908 15226415 \n20 Anderson G Maes M Bipolar disorder: role of immune-inflammatory cytokines, oxidative and nitrosative stress and tryptophan catabolites Curr Psychiatry Rep 2015 17 8 25620790 \n21 Liu M Brusilow WS Needleman R Activity of the yeast Tat2p tryptophan permease is sensitive to the anti-tumor agent 4-phenylbutyrate Curr Genet 2004 46 256 268 15490173 \n22 Grzanowski A Needleman R Brusilow WS Immunosuppressant-like effects of phenylbutyrate on growth inhibition of Saccharomyces cerevisiae Curr Genet 2002 41 142 149 12111095 \n23 Cho JW Choi SR Hwang SG Pharmaceutical composition for prevention and treatment of drug or alcohol addiction or bipolar disorder using sodium phenylbutyrate U.S. Patent No 7,968,604 2011 \n24 Kulkarni NN Yi Z Huehnken C Agerberth B Gudmundsson GH Phenylbutyrate induces cathelicidin expression via the vitamin D receptor: Linkage to inflammatory and growth factor cytokines pathways Mol Immunol 2015 63 530 539 25458314\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-3684",
"issue": "13(5)",
"journal": "Psychiatry investigation",
"keywords": "Bipolar and related disorders; Progressive Familial Intrahepatic Cholestasis type 2; Sodium 4-phenylbutyrate",
"medline_ta": "Psychiatry Investig",
"mesh_terms": null,
"nlm_unique_id": "101242994",
"other_id": null,
"pages": "580-582",
"pmc": null,
"pmid": "27757140",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": "11286510;2238055;9476862;11595694;9274590;11391852;21344347;21134824;12111095;9032718;17538928;22609309;24530123;15226415;25458314;25716872;25620790;15490173;25022842",
"title": "Bipolar and Related Disorders Induced by Sodium 4-Phenylbutyrate in a Male Adolescent with Bile Salt Export Pump Deficiency Disease.",
"title_normalized": "bipolar and related disorders induced by sodium 4 phenylbutyrate in a male adolescent with bile salt export pump deficiency disease"
} | [
{
"companynumb": "IT-HORIZON-BUP-0109-2016",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": null,
... |
{
"abstract": "Phenytoin has been reported to have major interactions with warfarin. Phenytoin induces warfarin's metabolism. However, there are many case reports which provide conflicting conclusions. Here, we report a case of a 65-year-old man with mechanical heart valve on chronic warfarin therapy who experienced persistent fluctuations of INR and bleeding secondary to probable warfarin-phenytoin interactions. The patient's anticoagulation clinic visits prior to hospitalization were thoroughly evaluated and we continued to follow-up the case for 3 months post-hospitalization. The reported interaction could be reasonably explained from the chronology of events and the pattern of INR fluctuations whenever phenytoin was either added or discontinued from his drug regimen.",
"affiliations": "Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia. yahaya@usm.my",
"authors": "Hassan|Yahaya|Y|;Awaisu|Ahmed|A|;Aziz|Noorizan Abd|NA|;Ismail|Omar|O|",
"chemical_list": "D000925:Anticoagulants; D000927:Anticonvulsants; D014859:Warfarin; D010672:Phenytoin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s11096-004-5150-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0928-1231",
"issue": "27(1)",
"journal": "Pharmacy world & science : PWS",
"keywords": null,
"medline_ta": "Pharm World Sci",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D000927:Anticonvulsants; D004357:Drug Synergism; D006350:Heart Valve Prosthesis; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D010672:Phenytoin; D012640:Seizures; D014859:Warfarin",
"nlm_unique_id": "9307352",
"other_id": null,
"pages": "16-9",
"pmc": null,
"pmid": "15861930",
"pubdate": "2005-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11503010;6705425;7249508;7985894;15001972;11157641;7944078;9324181;15001971;7776988;15037485;8747411;11157640",
"title": "The complexity of achieving anticoagulation control in the face of warfarin-phenytoin interaction: an Asian case report.",
"title_normalized": "the complexity of achieving anticoagulation control in the face of warfarin phenytoin interaction an asian case report"
} | [
{
"companynumb": "US-VISTAPHARM, INC.-VER201711-001174",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": nu... |
{
"abstract": "The association between sodium-glucose cotransporter 2 inhibitors (SGLT2is) and cancer risk is unclear. The objective of this study was to analyze whether a disproportionate number of cases of bladder cancer are reported for SGLT2is in EudraVigilance. A case/noncase study was conducted to assess the association between bladder cancer and SGLT2is, calculating reporting odds ratios (RORs) from November 11, 2012 (approval date for the first SGLT2i, dapagliflozin) to May 19, 2020. First, cases involving SGLT2is were compared with those involving all other drugs; and similar analysis was performed for each SGLT2i. Second, to reduce the risk of confounding by indication, the RORs for SGLT2is compared with other antidiabetics were obtained. Besides, 2 measures were taken to evaluate a possible notoriety bias: a sensitivity analysis excluding pioglitazone was performed and the evolution of the ROR over time for SGLT2is was measured. There were 6602 cases of bladder cancer in the 4,213,637 reports during the study period. SGLT2is were involved in 155 cases. The ROR for pooled SGLT2is was 3.97 (95% confidence interval [CI], 3.39-4.66), disproportionality also being observed for each SGLT2i separately. The association was strongest for dapagliflozin (ROR, 7.02; 95%CI, 5.69-8.66). Nonetheless, this association disappeared when comparing SGLT2is with other antidiabetic drugs (ROR, 0.20; 95%CI, 0.17-0.24). But when excluding pioglitazone from the analysis, a safety signal for SGLT2is compared with other antidiabetics emerged (ROR, 6.84; 95%CI 5.41-8.65). Our study found a disproportionately high number of cases of bladder cancer among users of SGLT2is. However, observational analytical studies will be needed to confirm these results.",
"affiliations": "Biocruces Bizkaia Health Research Institute, Osakidetza Basque Health Service, Galdakao-Usansolo Hospital, Basque Country Pharmacovigilance Unit, Galdakao, Spain.;Osakidetza Basque Health Service, Primary Health Centre Lakua-Arriaga, Vitoria-Gasteiz, Spain.;Bioaraba Health Research Institute, Osakidetza Basque Health Service, Araba Mental Health Network, Araba Psychiatric Hospital, Pharmacy Service, Vitoria-Gasteiz, Spain.;Biocruces Bizkaia Health Research Institute, Osakidetza Basque Health Service, Galdakao-Usansolo Hospital, Basque Country Pharmacovigilance Unit, Galdakao, Spain.",
"authors": "García|Montserrat|M|;Arteche-Martinez|Unai|U|;Lertxundi|Unax|U|;Aguirre|Carmelo|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/jcph.1722",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2700",
"issue": "61(2)",
"journal": "Journal of clinical pharmacology",
"keywords": "EudraVigilance; SGLT2 inhibitors; bladder cancer; drug safety surveillance; spontaneous reporting system",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "0366372",
"other_id": null,
"pages": "187-192",
"pmc": null,
"pmid": "32827151",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "SGLT2 Inhibitors and Bladder Cancer: Analysis of Cases Reported in the European Pharmacovigilance Database.",
"title_normalized": "sglt2 inhibitors and bladder cancer analysis of cases reported in the european pharmacovigilance database"
} | [
{
"companynumb": "ES-JNJFOC-20181100327",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
},
"drugadditional": null,
... |
{
"abstract": "Sprue-like enteropathy associated with the angiotensin II receptor blocker (ARB) olmesartan was first described in 2012, and a number of cases have since been reported. This syndrome is characterized by severe diarrhea and sprue-like histopathologic findings in the intestine, often with increased subepithelial collagen. The incidence of this adverse drug reaction is not entirely clear, although it is thought to be rare. It is also not well established if other ARBs cause such a syndrome, although case reports suggest they can. The histopathologic features of olmesartan-related injury have only been described in a limited number of cases, and there are no guidelines regarding the histopathologic distinction of olmesartan-associated enteropathy from other causes of sprue (eg, celiac disease, tropical sprue). Herein, we review the histopathologic changes and clinical observations described in recent reports of olmesartan-associated sprue-like enteropathy comprising case series and isolated reports, other relevant literature, and our experience at a referral center specializing in small intestinal disorders. We will review recent literature suggesting other ARBs can be associated with a similar phenotype. Lastly, we will discuss the histopathologic differential diagnosis and provide clues to distinguish this entity from other entities which can cause sprue-like histopathology.",
"affiliations": "Tulane University School of Medicine, New Orleans, LA 70118.;Celiac Disease Center, Columbia University Medical Center, New York, NY 10032.;Celiac Disease Center, Columbia University Medical Center, New York, NY 10032.;Celiac Disease Center, Columbia University Medical Center, New York, NY 10032.;Department of Pathology and Cell Biology, New York Presbyterian Hospital-Columbia University Medical Center, New York, NY 10032.;Department of Pathology and Cell Biology, New York Presbyterian Hospital-Columbia University Medical Center, New York, NY 10032. Electronic address: sml2179@cumc.columbia.edu.",
"authors": "Burbure|Nina|N|;Lebwohl|Benjamin|B|;Arguelles-Grande|Carolina|C|;Green|Peter H R|PH|;Bhagat|Govind|G|;Lagana|Stephen|S|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0046-8177",
"issue": "50()",
"journal": "Human pathology",
"keywords": "Angiotensin receptor blockers; Diarrhea; Enteropathy; Olmesartan; Sprue",
"medline_ta": "Hum Pathol",
"mesh_terms": "D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001706:Biopsy; D003937:Diagnosis, Differential; D003967:Diarrhea; D006801:Humans; D007093:Imidazoles; D007422:Intestines; D008286:Malabsorption Syndromes; D011237:Predictive Value of Tests; D011379:Prognosis; D012307:Risk Factors; D013777:Tetrazoles",
"nlm_unique_id": "9421547",
"other_id": null,
"pages": "127-34",
"pmc": null,
"pmid": "26997446",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Olmesartan-associated sprue-like enteropathy: a systematic review with emphasis on histopathology.",
"title_normalized": "olmesartan associated sprue like enteropathy a systematic review with emphasis on histopathology"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-05898",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLMESARTAN"
},
"druga... |
{
"abstract": "Asymptomatic pulmonary infiltrates and eosinophilia developed in a patient with chronic ulcerative colitis 1 month after therapy with sulfasalazine had been instituted. The abnormalities resolved completely after use of the drug was discontinued. The sulfapyridine component of the sulfasalazine was the likely causative agent because 41 years earlier, the patient had experienced fever, myalgias, and eosinophilia after taking a sulfonamide. Ten previous cases of sulfasalazine pulmonary toxicity, including one fatality, have been reported.",
"affiliations": null,
"authors": "Wang|K K|KK|;Bowyer|B A|BA|;Fleming|C R|CR|;Schroeder|K W|KW|",
"chemical_list": "D012460:Sulfasalazine",
"country": "England",
"delete": false,
"doi": "10.1016/s0025-6196(12)61431-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "59(5)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000368:Aged; D001991:Bronchitis; D001999:Bronchoscopy; D002908:Chronic Disease; D003093:Colitis, Ulcerative; D006801:Humans; D008297:Male; D011657:Pulmonary Eosinophilia; D012460:Sulfasalazine",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "343-6",
"pmc": null,
"pmid": "6144819",
"pubdate": "1984-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pulmonary infiltrates and eosinophilia associated with sulfasalazine.",
"title_normalized": "pulmonary infiltrates and eosinophilia associated with sulfasalazine"
} | [
{
"companynumb": "US-PFIZER INC-2021791033",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": "3",
... |
{
"abstract": "The aim of this study was to build and validate five types of machine learning models that can predict the occurrence of BRONJ associated with dental extraction in patients taking bisphosphonates for the management of osteoporosis.\n\n\n\nA retrospective review of the medical records was conducted to obtain cases and controls for the study. Total 125 patients consisting of 41 cases and 84 controls were selected for the study. Five machine learning prediction algorithms including multivariable logistic regression model, decision tree, support vector machine, artificial neural network, and random forest were implemented. The outputs of these models were compared with each other and also with conventional methods, such as serum CTX level. Area under the receiver operating characteristic (ROC) curve (AUC) was used to compare the results.\n\n\n\nThe performance of machine learning models was significantly superior to conventional statistical methods and single predictors. The random forest model yielded the best performance (AUC = 0.973), followed by artificial neural network (AUC = 0.915), support vector machine (AUC = 0.882), logistic regression (AUC = 0.844), decision tree (AUC = 0.821), drug holiday alone (AUC = 0.810), and CTX level alone (AUC = 0.630).\n\n\n\nMachine learning methods showed superior performance in predicting BRONJ associated with dental extraction compared to conventional statistical methods using drug holiday and serum CTX level. Machine learning can thus be applied in a wide range of clinical studies.",
"affiliations": "Department of Oral & Maxillofacial Surgery, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: DWKIMOMFS@yuhs.ac.;Department of Radiological Science, Yonsei University College of Medicine, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: HYKIM82@yuhs.ac.;Department of Oral & Maxillofacial Surgery, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; Oral Cancer Research Institute, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: OMSNAM@yuhs.ac.;Department of Oral & Maxillofacial Surgery, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; Oral Cancer Research Institute, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: KIMOMS@yuhs.ac.;Department of Oral & Maxillofacial Surgery, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; Oral Cancer Research Institute, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: CHA8764@yuhs.ac.",
"authors": "Kim|Dong Wook|DW|;Kim|Hwiyoung|H|;Nam|Woong|W|;Kim|Hyung Jun|HJ|;Cha|In-Ho|IH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bone.2018.04.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-2763",
"issue": "116()",
"journal": "Bone",
"keywords": "Artificial intelligence; Bisphosphonate-associated osteonecrosis of the jaw; Machine learning; Osteonecrosis; Osteoporosis; Random Forest",
"medline_ta": "Bone",
"mesh_terms": "D000368:Aged; D019540:Area Under Curve; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D003663:Decision Trees; D005260:Female; D006801:Humans; D000069550:Machine Learning; D008297:Male; D016571:Neural Networks, Computer; D012372:ROC Curve; D060388:Support Vector Machine; D014081:Tooth Extraction",
"nlm_unique_id": "8504048",
"other_id": null,
"pages": "207-214",
"pmc": null,
"pmid": "29698784",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Machine learning to predict the occurrence of bisphosphonate-related osteonecrosis of the jaw associated with dental extraction: A preliminary report.",
"title_normalized": "machine learning to predict the occurrence of bisphosphonate related osteonecrosis of the jaw associated with dental extraction a preliminary report"
} | [
{
"companynumb": "PHHY2019KR093297",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "Porphyria cutanea tarda (PCT) is a rare dermatologic condition characterized by blistering of sun-exposed surfaces and elevated hepatic enzymes. It may infrequently occur as the primary presentation of underlying hemochromatosis. A 61-year-old female with anemia caused by chronic kidney disease and end-stage renal disease on hemodialysis presented with a bullous rash on her hands with associated pruritus. The rash worsened despite conservative treatment. An initial biopsy demonstrated a pauci-inflammatory cell-poor subepidermal cleft. Subsequent workup revealed elevated serum and urine porphyrins, confirming a diagnosis of PCT. Additionally, her skin was darkened and ferritin was elevated. MRI of the liver demonstrated iron overload with genetic testing negative for C282Y or H63D mutations, supporting a diagnosis of secondary hemochromatosis. Further genetic testing revealed that the patient had a rare heterozygous nonsense mutation of the uroporphyrinogen decarboxylase (UROD) gene, for a sequence variant designated c.616C>T, which is predicted to result in premature protein termination (p.Gln206*). PCT occurs due to decreased function of UROD, leading to accumulation of porphyrins causing dermatologic manifestations and liver injury. UROD is inactivated in an iron-dependent process, explaining the mechanistic link between hemochromatosis and PCT.",
"affiliations": "Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Grand Forks, USA.;Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Grand Forks, USA.;Internal Medicine, Sanford Health, Fargo, USA.;Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Grand Forks, USA.;Hospital Medicine, Sanford Health, Fargo, USA.",
"authors": "Anderson|Hallie B|HB|;Storandt|Michael H|MH|;Kallamadi|Rekha|R|;Bande|Dinesh|D|;Matta|Abhishek|A|",
"chemical_list": null,
"country": "United States",
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"doi": "10.7759/cureus.16215",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16215\nDermatology\nInternal Medicine\nHematology\nIatrogenic Iron Overload Causing Porphyria Cutanea Tarda in a Patient With a Rare Nonsense Heterozygous UROD Gene Mutation\nMuacevic Alexander\nAdler John R\nAnderson Hallie B 1\nStorandt Michael H 1\nKallamadi Rekha 2\nBande Dinesh 1\nMatta Abhishek 31\n1 Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Grand Forks, USA\n2 Internal Medicine, Sanford Health, Fargo, USA\n3 Hospital Medicine, Sanford Health, Fargo, USA\nRekha Kallamadi rekha.kallamadi@sanfordhealth.org\n6 7 2021\n7 2021\n13 7 e162156 7 2021\nCopyright © 2021, Anderson et al.\n2021\nAnderson et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/55536-iatrogenic-iron-overload-causing-porphyria-cutanea-tarda-in-a-patient-with-a-rare-nonsense-heterozygous-urod-gene-mutation\nPorphyria cutanea tarda (PCT) is a rare dermatologic condition characterized by blistering of sun-exposed surfaces and elevated hepatic enzymes. It may infrequently occur as the primary presentation of underlying hemochromatosis. A 61-year-old female with anemia caused by chronic kidney disease and end-stage renal disease on hemodialysis presented with a bullous rash on her hands with associated pruritus. The rash worsened despite conservative treatment. An initial biopsy demonstrated a pauci-inflammatory cell-poor subepidermal cleft. Subsequent workup revealed elevated serum and urine porphyrins, confirming a diagnosis of PCT. Additionally, her skin was darkened and ferritin was elevated. MRI of the liver demonstrated iron overload with genetic testing negative for C282Y or H63D mutations, supporting a diagnosis of secondary hemochromatosis. Further genetic testing revealed that the patient had a rare heterozygous nonsense mutation of the uroporphyrinogen decarboxylase (UROD) gene, for a sequence variant designated c.616C>T, which is predicted to result in premature protein termination (p.Gln206*). PCT occurs due to decreased function of UROD, leading to accumulation of porphyrins causing dermatologic manifestations and liver injury. UROD is inactivated in an iron-dependent process, explaining the mechanistic link between hemochromatosis and PCT.\n\nporphyria cutanea tarda\nhemochromatosis\nurod mutation\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nPorphyria cutanea tarda (PCT) is caused by a hepatic deficiency of uroporphyrinogen decarboxylase (UROD), an enzyme responsible for catalyzing the conversion of uropophyrinogen to coproporphyrinogen in the heme synthesis pathway. UROD deficiency leads to the accumulation of uroporphyrinogen, which is oxidized to form uroporphyrins. When exposed to sunlight, these uroporphyrins cause an immune-mediated reaction and the release of free radicals, causing the characteristic blistering lesions of PCT [1]. Most cases of PCT are classified as sporadic and are caused by viruses and substances that interfere with hepatic function, such as the hepatitis C virus, human immunodeficiency virus, high alcohol consumption, and iron overload [2]. Less commonly, familial mutations in the UROD gene can cause an increased risk of PCT in conjunction with substances that reduce UROD enzyme activity [1,2]. Here, we present a case of PCT caused by an iatrogenic iron overload due to frequent iron infusions for anemia caused by chronic kidney disease (CKD) in the setting of a rare heterozygous UROD mutation.\n\nCase presentation\n\nA 61-year-old female with a past medical history of anemia caused by CKD and end-stage renal disease (ESRD) on hemodialysis presented to the emergency room with acute-onset blisters on the dorsum of her hands, sparing her palms, with associated pruritus. Her pre-dialysis creatinine levels ranged from 5.99 to 8.62 mg/dL, and her red blood cell indices ranged from 2.42 to 2.62 M/uL in the month prior to the initial presentation. She was started on conservative treatment with prednisone, diphenhydramine, and triamcinolone cream. Three weeks later, the patient presented to the emergency department again for worsening of the rash (Figure 1) along with facial swelling. She was admitted, and clinical genetics and hematology-oncology were consulted.\n\nFigure 1 Image of the hand demonstrating multiple bullae with sparing of the palms.\n\nA punch biopsy was performed which demonstrated thick homogeneous deposition of immunoglobulin (Ig)G, IgA, and fibrinogen within the walls of superficial dermal vessels (Figure 2). As the biopsy results were concerning for PCT, further workup was ordered which revealed elevated total porphyrins and uroporphyrins (Table 1). On examination, the patient’s pigmentation was noted to be significantly darker compared to a photograph in her chart (Figure 3). Due to the patient’s history of anemia and regular iron infusions every two weeks, previous iron studies were reviewed which showed a high ferritin level and total iron-binding capacity (Table 2). MRI of the liver showed iron overload and steatosis with a calculated iron concentration at 148 µmol/g (Figure 4). Genetic testing failed to demonstrate C282Y and H63D mutations in the HFE gene, supporting a diagnosis of secondary hemochromatosis.\n\nFigure 2 Biopsy showing thick homogeneous deposition of IgG, IgA, and fibrinogen within the walls of superficial dermal vessels.\n\nIg: immunoglobulin\n\nTable 1 The patient’s porphyrin studies.\n\nLaboratory study\tValue\t\nSerum total porphyrins\t253 µg/dL (normal value <0.1 µg/dL)\t\nUroporphyrin\t34.6 µg/dL (normal value <0.1 µg/dL)\t\nHexacarboxyl porphyrins\t2.5 µg/dL (normal value <0.1 µg/dL)\t\nHepatacarboxyl porphyrins\t17 µg/dL (normal value <0.1 µg/dL)\t\nProtoporphyrin\t<0.1 µg/dL\t\nCoproporphyrin\t<0.1 µg/dL\t\n\nFigure 3 Image from the patient’s chart (left) compared to an image of the patient at presentation (right) demonstrating new darkening of pigmentation.\n\nTable 2 The patient’s iron studies.\n\nLaboratory study\tValue\t\nFerritin\t5029 ng/mL (H)\t\nPercentage iron saturation\t17% (L)\t\nTotal iron level\t28 µg/dL (L)\t\nTotal iron-binding capacity\t168 µg/dL (H)\t\n\nFigure 4 MRI of the abdomen showing iron overload in the liver and spleen. The calculated iron concentration in the liver measured 148 µmol/g (normal iron concentration in the liver is less than 36 µmol/g).\n\nMRI: magnetic resonance imaging\n\nA porphyria genome analysis revealed a rare heterozygous nonsense mutation of the UROD gene for a sequence variant designated c.616C>T, which is predicted to result in premature protein termination (p.Gln206*). The mutation itself does not necessarily cause PCT; however, any condition that causes liver damage or iron overload can trigger PCT in the setting of decreased enzyme activity [3]. The patient had received iron infusions with dialysis every two weeks in the 11 months before presentation, with ferritin levels peaking at 5,029 ng/mL two weeks before symptom onset. This provides strong support that iron overload caused by iron infusions for anemia of CKD, with the underlying heterozygous mutation, led to the development of PCT.\n\nThe patient was started on hydroxychloroquine 1,000 mg twice weekly. Phlebotomy was not recommended due to the patient’s average hemoglobin level of 8 mg/dL. Her erythropoietin dose was increased to 500 µg twice weekly, and she was started on deferoxamine for iron chelation with the plan to bring her ferritin level down to less than 1,000 ng/mL. Regular iron infusions with hemodialysis per treatment guidelines were discontinued to prevent further iron overload.\n\nDiscussion\n\nPCT is a dermatologic disease marked by skin blistering on sun-exposed areas of the skin (most notably on the dorsal aspects of the hands), skin hyperpigmentation, skin thickening, and facial hypertrichosis. Patients with PCT are also at an increased risk of developing hepatocellular carcinoma [4]. Most cases of PCT are sporadic and caused by viruses and other substances that decrease hepatic function, as described previously; however, 15-50% of PCT cases are caused by familial mutations in the UROD gene [5]. Familial PCT is inherited in an autosomal dominant manner, and most patients with familial PCT do not have an affected parent due to reduced penetrance of the gene [6]. The clinical manifestations of PCT in patients with deficient UROD enzyme activity occur when enzyme activity is below 20%. This decrease in enzyme activity occurs when an individual with familial PCT is exposed to other factors that decrease hepatic function such as alcohol, iron overload, and hepatitis C virus. This report highlights a case of familial PCT caused by an iron overload due to regular iron infusions for the treatment of anemia in the setting of CKD. This is the first known case of a patient with a rare heterozygous nonsense mutation of the UROD gene at a sequence variant designated c.616C>T.\n\nPatients with CKD are at an increased risk of developing iron-deficiency anemia due to increased levels of hepcidin, as it is a renally cleared peptide [7]. Iron may also be lost during dialysis. Current guidelines recommend regular intravenous iron infusions in ESRD with a maximum allowed ferritin level of 500 ng/mL [8]. Prior to the manifestation of PCT in this patient, she was receiving 4,000 mg of intravenous sodium ferric gluconate complex in sucrose with the dialysis every three months. One month prior to symptom onset, the patient’s ferritin level increased to 5,029 ng/mL. Iron overload alone decreases hepatic UROD enzyme levels, hence, the patient’s iatrogenic iron overload in conjunction with a familial UROD mutation likely led to the development of PCT. Interestingly, ESRD has also been shown to be associated with PCT in rare cases likely due to decreased porphyrin excretion [9].\n\nTreatment of PCT in patients with ESRD can be particularly challenging due to chronic anemia that is often associated with the condition. The first-line treatment of PCT traditionally involves phlebotomy with the removal of 450 mL of blood every two weeks and low-dose hydroxychloroquine [10]. However, phlebotomy may be contraindicated in severe cases of anemia, as was the case for this patient. The use of hydroxychloroquine in patients with ESRD may also not be effective due to inefficient porphyrin removal from the blood via dialysis. Hence, iron chelation medications such as deferoxamine have been used in cases of PCT in the setting of ESRD with a successful reduction in ferritin levels [11], as well as erythropoietin to increase hemoglobin level for subsequent phlebotomy. The patient in this case continues to take hydroxychloroquine 100 mg twice weekly and erythropoietin 500 µg every three weeks. Deferoxamine was discontinued due to improvement in ferritin levels and in preparation for therapeutic phlebotomy.\n\nConclusions\n\nThis case highlights the importance of recognizing the clinical manifestations of PCT, as well as factors, both environmental and iatrogenic, that may lead to its development. Particular care must be taken in patients with a family history of PCT. Treatment and management of PCT may be complicated by concomitant chronic conditions such as ESRD.\n\nHuman Ethics\n\nWe would like to acknowledge Dr. Erik Heitkamp, MD, and Dr. Mahendra Gupta, MD, for their assistance in preparing this case report.\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Porphyria cutanea tarda: recent update Mol Genet Metab Singal AK 271 281 128 2019 30683557\n2 Porphyria cutanea tarda: an intriguing genetic disease and marker Int J Dermatol Handler NS Handler MZ Stephany MP Handler GA Schwartz RA 0 17 56 2017\n3 Seven novel point mutations in the uroporphyrinogen decarboxylase (UROD) gene in patients with familial porphyria cutanea tarda (f-PCT) Hum Mutat Cappellini MD Martinez di Montemuros F Tavazzi D 350 17 2001\n4 Familial Porphyria Cutanea Tarda Liu LU Phillips J Bonkovsky H Seattle, WA University of Washington, Seattle 1993-2021 https://pubmed.ncbi.nlm.nih.gov/23741761/\n5 Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies Clin Chem Aarsand AK Boman H Sandberg S 795 803 55 2009 19233912\n6 Early presentation of adult-onset conditions: a dual diagnosis of hereditary hemochromatosis and porphyria cutanea tarda Mol Genet Metab Rep Strong A Keller K Merves J 100638 25 2020 32874917\n7 Iron deficiency anemia in chronic kidney disease Acta Haematol Gafter-Gvili A Schechter A Rozen-Zvi B 44 50 142 2019 30970355\n8 Notice Kidney Int Suppl (2011) 279 2 2012\n9 Desferrioxamine treatment of porphyria cutanea tarda in a patient with HIV and chronic renal failure Dermatol Ther Vasconcelos P Luz-Rodrigues H Santos C Filipe P 16 18 27 2014 24502304\n10 Erythropoietin for the treatment of porphyria cutanea tarda in a patient on long-term hemodialysis N Engl J Med Anderson KE Goeger DE Carson RW Lee SM Stead RB 315 317 322 1990 2104958\n11 Porphyria cutanea tarda in a patient with end-stage renal disease: a case of successful treatment with deferoxamine and ferric carboxymaltose Case Rep Nephrol Rodrigues N Caeiro F Santana A Mendes T Lopes L 4591871 2017 2017 28210512\n\n",
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"abstract": "BACKGROUND\nColorectal adenocarcinoma and Crohn's disease are known to be associated entities. However, a carcinoma arising within a chronic perianal fistulous tract in a patient with Crohn's disease is a rare complication.\n\n\nMETHODS\nWe present a case of a 40-year-old male patient with a long-standing perianal Crohn's disease who developed an anal mucinous adenocarcinoma within the fistulous tracts.\n\n\nCONCLUSIONS\nAlthough, Crohn's disease and colorectal carcinoma association is well established, few cases have been reported where the cancer has originated within a perianal fistula. Constant mucosal regeneration occurring within a fistula seems to be the predominant pathogenetic mechanism, while immunosuppressants and anti-TNF agents may also contribute to the malignant transformation. Unfortunately, the lack of suspicion and the inadequate physical examination or colonoscopy due to exacerbation of the perianal symptoms could lead to delayed diagnosis; and thus, a poor prognosis.\n\n\nCONCLUSIONS\nAlbeit a rare complication, clinicians should maintain a high degree of vigilance about the possible development of adenocarcinoma in patients with long-standing perianal Crohn's disease. Thus, these patients should be kept under regular surveillance with examination under anaesthesia and biopsies or curettage of the tracts.",
"affiliations": "2nd Department of Surgery, Aretaieion Hospital, Medical School, University of Athens, 76 V. Sofias Avenue, 11528, Athens, Greece. Electronic address: johnpapacon@hotmail.com.;2nd Department of Surgery, Aretaieion Hospital, Medical School, University of Athens, 76 V. Sofias Avenue, 11528, Athens, Greece. Electronic address: dionmantzos1@yahoo.gr.;Department of Pathology, Aretaieion Hospital, Medical School, University of Athens, 76 V. Sofias Avenue, 11528, Athens, Greece. Electronic address: akondi@med.uoa.gr.;Department of Gastroenterology, University Hospital of Heraklion, 71003 Heraklion, Crete, Greece. Electronic address: ikoutroubakis@gmail.com.",
"authors": "Papaconstantinou|Ioannis|I|;Mantzos|Dionysios S|DS|;Kondi-Pafiti|Agathi|A|;Koutroubakis|Ioannis E|IE|",
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"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(15)00193-510.1016/j.ijscr.2015.04.013Case ReportAnal adenocarcinoma complicating chronic Crohn’s disease Papaconstantinou Ioannis johnpapacon@hotmail.comaMantzos Dionysios S. dionmantzos1@yahoo.gra⁎Kondi-Pafiti Agathi akondi@med.uoa.grbKoutroubakis Ioannis E. ikoutroubakis@gmail.comca 2nd Department of Surgery, Aretaieion Hospital, Medical School, University of Athens, 76 V. Sofias Avenue, 11528, Athens, Greeceb Department of Pathology, Aretaieion Hospital, Medical School, University of Athens, 76 V. Sofias Avenue, 11528, Athens, Greecec Department of Gastroenterology, University Hospital of Heraklion, 71003 Heraklion, Crete, Greece⁎ Corresponding author. Tel.: +30 6945060768; fax: +30 2107286127. dionmantzos1@yahoo.gr08 4 2015 2015 08 4 2015 10 201 203 24 12 2014 17 3 2015 3 4 2015 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• We report a rare case of cancer arising within fistulae in a Crohn’s disease patient.\n\n• A deterioration of the fistulous disease may conceal a cancer development.\n\n• Examination under anaesthesia with biopsies or curettage of the fistulae is crucial.\n\n• Patients with fistulising Crohn’s disease should be kept under regular surveillance.\n\n\n\nIntroduction\nColorectal adenocarcinoma and Crohn’s disease are known to be associated entities. However, a carcinoma arising within a chronic perianal fistulous tract in a patient with Crohn’s disease is a rare complication.\n\nPresentation of case\nWe present a case of a 40-year-old male patient with a long-standing perianal Crohn’s disease who developed an anal mucinous adenocarcinoma within the fistulous tracts.\n\nDiscussion\nAlthough, Crohn’s disease and colorectal carcinoma association is well established, few cases have been reported where the cancer has originated within a perianal fistula. Constant mucosal regeneration occurring within a fistula seems to be the predominant pathogenetic mechanism, while immunosuppressants and anti-TNF agents may also contribute to the malignant transformation. Unfortunately, the lack of suspicion and the inadequate physical examination or colonoscopy due to exacerbation of the perianal symptoms could lead to delayed diagnosis; and thus, a poor prognosis.\n\nConclusion\nAlbeit a rare complication, clinicians should maintain a high degree of vigilance about the possible development of adenocarcinoma in patients with long-standing perianal Crohn’s disease. Thus, these patients should be kept under regular surveillance with examination under anaesthesia and biopsies or curettage of the tracts.\n\nAbbreviations\nCD, Crohn’s diseaseMRI, magnetic resonance imagingKeywords\nCrohn’s diseasePerianal fistulaAdenocarcinoma\n==== Body\n1 Introduction\nThe association between Crohn’s disease (CD) and colorectal cancer is well established. However, carcinoma associated with chronic fistulous CD is a rare complication. We report a case of a 40-year-old CD patient who developed an anal adenocarcinoma within a long-standing perianal fistulous tract and review the available literature.\n\n2 Presentation of case\nA 40-year-old male patient with ileocolonic CD and perianal fistulising lesions, diagnosed 23 years ago, was referred to our institution for a new finding of soft tissue within a perianal fistula. His past medical history included loop sigmoidostomy and seton insertion 3 years ago for control of his perianal disease. Three months later, due to ileus caused by terminal ileitis, he underwent emergency right colectomy. At the same time, the loop sigmoidostomy was converted to end colostomy with closure of the peripheral stump; since, the perianal disease was still uncontrollable. At this time, taking into account the benign nature of the disease, as well as patient’s age, it was decided to give to the patient a second chance to keep his sphincter mechanism rather than to perform an abdominoperineal resection. The patient had received in the past, either in conjunction or consequently, corticosteroids, antibiotics (metronidazole, ciprofloxacin), immunosuppressants (azathioprine, methotrexate) and anti-TNF agents (infliximab) for the control of the frequent flare-ups. On referral, he was on adalimumab and mercaptopurine. Physical examination revealed mild perianal inflammation with muco-purulent discharge from two sore-like fistulous orifices, located at 7 and 11 o’clock in supine position (Fig. 1). Pelvic magnetic resonance imaging (MRI) demonstrated pathological tissue development within one fistulous tract (Fig. 2) suggesting a mucinous cancer arising within the fistula. The rectosigmoidoscopy depicted mild lesions compatible with moderately active CD, without any other sign of obvious malignancy. Mucosal biopsies were obtained from the lesions and the underlying fistulous tracts; granulomatous tissue infiltrated by mucus-producing adenocarcinoma was found on pathology. Staging with computed tomography did not reveal any metastatic disease. Thus, the patient underwent abdominoperineal resection, where a 37 cm segment of colon with the mesorectum, anal canal of 7 cm and the corresponding overlying soft tissue of the perineum was resected. On histopathology, a T4N1 moderately/poorly differentiated mucinous adenocarcinoma was detected (Fig. 3). According to the referrer, his last physical examination, six months prior to admission, was unremarkable. Unfortunately, three months postoperatively the patient developed multiple bone metastases and he is currently receiving chemotherapy.\n\n3 Discussion\nUp to 43% of CD patients will develop perianal fistulising disease [1]. The development of carcinoma within a chronic perianal fistula is a rare complication of CD, first reported by Lightdale et al. in 1975 [2]. Iesalnieks et al. has reported 65 cases with anorectal cancer associated with perianal fistulae in patients with CD [3] with an estimated incidence of 0.3–0.7% [4].\n\nThe pathogenesis has not yet been fully elucidated; Traube at al. suggested that the environment of constant mucosal regeneration occurring within a fistula may cause dysplastic changes, which may ultimately lead to adenocarcinoma [5]. On the contrary, Church et al. supported that a fistula formation may be a result of the cancer itself [6]. In the present case, the pre-existence of long-standing fistulae renders the latter improbable. It has been suggested that immunosuppressants and anti-TNF agents may contribute to the malignant transformation [7]. In a recent article, Osterman et al. supported that patients treated with combination of adalimumab and immunomodulators were more likely to develop cancer compared both to general population and patients with adalimumab monotherapy [8]. This plausible pathogenetic mechanism may hold true in the present case, where the patient had been treated with anti-TNF and immunomodulators for approximately ten years prior to the diagnosis of cancer.\n\nPatients with long-standing CD, diagnosed before thirty years of age and with faecal diversion are at greater risk for the development of carcinoma arising in association with a perianal fistula [9]. Unfortunately, the majority of these patients have poor prognosis due to the advanced disease stage at diagnosis. Similarities between benign deterioration of the perianal symptoms and de novo development of cancer, as well as the lack of a high degree of suspicion for this rare complication may be responsible for the delay of diagnosis. Furthermore, the exacerbation of the symptoms makes physical examination or colonoscopy cumbersome to occur. A complex, long-standing fistula requires thorough examination of the rectum and the perianal area under anaesthesia followed by biopsies and/or curettage of the fistulous tracts. It follows, those patients with chronic perianal fistulising CD should be kept under a regular and careful surveillance. Ogawa et al. have suggested that a patient should undergo surveillance for carcinoma after seven years of perianal disease [4].\n\nThe gold standard treatment of fistulae-associated anal adenocarcinoma in patients with CD is abdominoperineal resection. In a recent article, Gaertner et al. reported that all patients with perianal adenocarcinoma who had undergone neoadjuvant chemoradiation therapy followed by abdominoperineal resection had a complete response [10]. The potential benefits of this kind of therapy have not yet been established; and therefore, in our patient we proceeded only to surgical treatment.\n\n4 Conclusion\nClinicians who manage patients with long-standing perianal CD should maintain high level of suspicion for adenocarcinoma development on the setting of perianal fistulising CD. A chronic, complex fistulous disease may conceal a tumour and the examination under anaesthesia with biopsies and/or curettage of the fistulous tracts may be warranted. Therefore, all patients suffering from chronic perianal CD should be kept under regular surveillance.\n\nConflict of interest\nAll authors declare that there is no financial arrangement or other relationship that could be construed as a conflict of interest.\n\nFunding\nThere was not involvement of study sponsors in this work.\n\nAuthors contribution\nPapaconstantinou I. conceived of the study, carried out its design and the critical revision for important intellectual content and had the overall responsibility of the manuscript.\n\nMantzos S.D. carried out the design, the collection, analysis and interpretation of the data and drafted the manuscript.\n\nKondi-Pafiti A. provided some of the data and participated in the critical revision.\n\nKoutroubakis I. conceived of the study, participated in the design and carried out the critical revision.\n\nAll authors read and approved the final manuscript.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAcknowledgements\nWe would like to express our very great appreciation to Mr Mylonas S.N. MD, of the Vascular Unit of Aretaieion Hospital, as well as Mr Elissaios Kontis MD and Mr Spyropoulos B.G. MD of the 2nd Department of Surgery of Aretaieion Hospital, for their valuable advice regarding to the final form of this manuscript.\n\nFig. 1 Fistulous orifices at 7 and 11 o’clock.\n\nFig. 2 MRI of adenocarcinoma developing within fistulous tracts (high signal intensity on T2-weighted image).\n\nFig. 3 Histological section of perianal fistulous tract infiltrated by moderately–poorly differentiated mucus – producing adenocarcinoma (haematoxylin − eosin × 100).\n==== Refs\nReferences\n1 Loftus E.V. Jr Cima R.R. Inflammatory bowel disease Yeo C.J. Matthews J.B. Mc Fadden D.W. Pemberton J.H. Peters J.H. Shackelford’s Surgery of the Alimentary Tract 7th edition 2013 Philadelphia: Elsevier 1966 1968 \n2 Lightdale C.J. Sternberg S.S. Posner G. Sherlock P. Carcinoma complicating Crohn’s disease. Report of seven cases and review of the literature Am. J. Med. 59 1975 262 268 1155482 \n3 Iesalnieks I. Gaertner W.B. Glass H. Strauch U. Hipp M. Agha A. Fistula-associated anal adenocarcinoma in Crohn’s disease Inflamm. Bowel Dis. 16 2010 1643 1648 20186945 \n4 Ogawa H. Haneda S. Shibata C. Miura K. Nagao M. Ohnuma S. Adenocarcinoma associated with perianal fistulas in Crohn’s disease Anticancer Res. 33 2013 685 689 23393368 \n5 Traube J. Simpson S. Riddell R.H. Levin B. Kirsner J.B. Crohn’s disease and adenocarcinoma of the bowel Digest. Dis. Sci. 25 1980 939 944 7449590 \n6 Church J.M. Weakley F.L. Fazio V.W. Sebek B.A. Achkar E. Carwell M. The relationship between fistulas in Crohn’s disease and associated carcinoma: report of four cases and a review of the literature Dis. Colon Rectum 28 1985 361 366 3158499 \n7 Ball C.S. Wujanto R. Haboubi N.Y. Schofield P.F. Carcinoma in anal Crohn’s disease: discussion paper J. R. Soc. Med. 81 1988 217 219 3373467 \n8 Osterman M.T. Sandborn W.J. Colombel J.F. Robinson A.M. Lau W. Huang B. Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn’s disease Gastroenterology 146 2014 941 949 24361468 \n9 Tokunaga Y. Sasaki H. Saito T. Carcinoma in anorectal fistulas of Crohn’s Disease with seton drainage case report and review of the literature Digestion 77 2008 20 21 18253046 \n10 Gaertner W.B. Hagerman G.F. Finne C.O. Alavi K. Jessurun J. Rothenberger D.A. Fistula-associated anal adenocarcinoma: good results with aggressive therapy Dis. Colon Rectum 51 2008 1061 1067 18418652\n\n",
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"abstract": "mRNA COVID-19 vaccine is more effective than traditional vaccines owing to superior immune activation. Nevertheless, the impact of mRNA COVID-19 vaccine on triggering de novo/relapsing glomerulonephritis (GN) is limited. We report a case series of patients who developed new or relapsing GN postvaccination.\nWe evaluated baseline characteristics, vaccine type, and clinical outcomes of 13 patients from our institution who had a new diagnosis or relapse of their GN post-mRNA COVID-19 vaccination.\nOf 13 patients, 8 patients were newly diagnosed with having GN and 5 patients had relapse. Median age was 62 years (range 19-83 years). Autoimmune disease (38%) was the most prevalent underlying disease followed by cancer (23%). Most patients were White males. IgA nephropathy (IgAN) was the most common GN in our series (5 patients, 38%) followed by membranous nephropathy (MN) (3 patients, 23%). There was 1 patient with IgAN who had evidence of IgA deposits before vaccination suggesting the immune activation after vaccination triggered a flare of the disease. Our case series also included the first case report of tip-variant focal segmental glomerulosclerosis (FSGS), NELL-1-associated MN, and atypical anti-glomerular basement membrane (GBM) nephritis. A total of 77% developed acute kidney injury (AKI) with most being Kidney Disease: Improving Global Outcomes stage 1 (67%). Outcomes are favorable with 80% responding to therapy.\nNew cases and relapse of GN can present shortly after mRNA COVID-19 vaccination. New cases of IgAN may result from unmasking of undiagnosed IgAN owing to robust immune activation rather than development of new deposits.",
"affiliations": "Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Nephrology and Hypertension, Essentia Health, Fargo, North Dakota, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Klomjit|Nattawat|N|;Alexander|Mariam Priya|MP|;Fervenza|Fernando C|FC|;Zoghby|Ziad|Z|;Garg|Arvind|A|;Hogan|Marie C|MC|;Nasr|Samih H|SH|;Minshar|Marwan Abu|MA|;Zand|Ladan|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ekir.2021.09.008",
"fulltext": "\n==== Front\nKidney Int Rep\nKidney Int Rep\nKidney International Reports\n2468-0249\nElsevier\n\nS2468-0249(21)01448-0\n10.1016/j.ekir.2021.09.008\nClinical Research\nCOVID-19 Vaccination and Glomerulonephritis\nKlomjit Nattawat 12\nAlexander Mariam Priya 3\nFervenza Fernando C. 1\nZoghby Ziad 1\nGarg Arvind 1\nHogan Marie C. 1\nNasr Samih H. 3\nMinshar Marwan Abu 4\nZand Ladan zand.ladan@mayo.edu\n1∗\n1 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA\n2 Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, Minnesota, USA\n3 Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota, USA\n4 Division of Nephrology and Hypertension, Essentia Health, Fargo, North Dakota, USA\n∗ Correspondence: Ladan Zand, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, 200 First Street Southwest, Rochester, Minnesota 55901, USA. zand.ladan@mayo.edu\n06 10 2021\n12 2021\n06 10 2021\n6 12 29692978\n9 8 2021\n6 9 2021\n13 9 2021\n© 2021 International Society of Nephrology. Published by Elsevier Inc.\n2021\nInternational Society of Nephrology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nmRNA COVID-19 vaccine is more effective than traditional vaccines owing to superior immune activation. Nevertheless, the impact of mRNA COVID-19 vaccine on triggering de novo/relapsing glomerulonephritis (GN) is limited. We report a case series of patients who developed new or relapsing GN postvaccination.\n\nMethods\n\nWe evaluated baseline characteristics, vaccine type, and clinical outcomes of 13 patients from our institution who had a new diagnosis or relapse of their GN post–mRNA COVID-19 vaccination.\n\nResults\n\nOf 13 patients, 8 patients were newly diagnosed with having GN and 5 patients had relapse. Median age was 62 years (range 19–83 years). Autoimmune disease (38%) was the most prevalent underlying disease followed by cancer (23%). Most patients were White males. IgA nephropathy (IgAN) was the most common GN in our series (5 patients, 38%) followed by membranous nephropathy (MN) (3 patients, 23%). There was 1 patient with IgAN who had evidence of IgA deposits before vaccination suggesting the immune activation after vaccination triggered a flare of the disease. Our case series also included the first case report of tip-variant focal segmental glomerulosclerosis (FSGS), NELL-1–associated MN, and atypical anti–glomerular basement membrane (GBM) nephritis. A total of 77% developed acute kidney injury (AKI) with most being Kidney Disease: Improving Global Outcomes stage 1 (67%). Outcomes are favorable with 80% responding to therapy.\n\nConclusion\n\nNew cases and relapse of GN can present shortly after mRNA COVID-19 vaccination. New cases of IgAN may result from unmasking of undiagnosed IgAN owing to robust immune activation rather than development of new deposits.\n\nKeywords\n\nCOVID-19\nglomerulonephritis\nIgA nephropathy\nminimal change disease\nmRNA vaccine\nSARS-CoV-2\n==== Body\npmcRapid and mass SARS-CoV-2 vaccination has been one of the pivotal strategies to curb the COVID-19 pandemic. The use of recently developed mRNA vaccine, such as BNT162b2 (Pfizer) and mRNA-1273 (Moderna), has provided effective protection against severe COVID-19 infection.1,2 mRNA vaccines use lipid nanoparticle as a vehicle to deliver genetically modified mRNA. Once injected, the mRNA is translated into target protein resulting in robust immune response.3 These vaccines thus far have been found to have excellent safety profile, and the most common immediate and short-term side effects for both mRNA vaccines have mostly involved injection site reaction. Severe reactions have been rare.1,2 Since mass-scale vaccination, however, several immune-mediated reactions, including cases of myocarditis and newly diagnosed or relapsed GN, have been reported.4,5 Most cases have been associated with mRNA vaccines (Pfizer and Moderna) and adenovirus vector deliveries.6, 7, 8, 9, 10, 11, 12, 13, 14 Nevertheless, rare cases of GN related to inactivated virus vaccine (CoronaVac from Sinovac) have also been reported.15 The most common reported GN thus far is IgAN. But whether COVID-19 vaccine results in an immune response that triggers IgA antibody (Ab) production and formation of new deposits in the kidneys or whether the immune response to the vaccine only unmasks the presence of previously formed deposits is unclear. In this case series, we report 13 cases of newly diagnosed or flares of GN post–COVID-19 mRNA vaccines and provide a literature review of all the reported GN cases thus far. We also provide evidence in 1 case of “new” IgAN wherein the deposits were present previously. We also report on 3 new diagnoses after COVID-19 vaccination, including a case of NELL-1–associated MN, a case of primary FSGS, and a case of atypical anti-GBM nephritis.\n\nMethod\n\nPatient Selection\n\nPatients who were either newly diagnosed or had a relapse of their GN after vaccination are reported in this case series. All patients had their kidney pathology results reviewed at the Mayo Clinic, Rochester, Minnesota. Clinical data and baseline characteristics, vaccine type, onset of symptoms, laboratories on presentation, treatments, and outcomes are based on review of medical records.\n\nLiterature Review\n\nWe searched all literature since the inception that reported newly diagnosed or relapse of GN after any type of COVID-19 vaccines through PubMed. We then extracted baseline characteristics, laboratories on presentation, treatments, and outcomes.\n\nStatistical Analysis\n\nWe report continuous data with median and range. Categorical data are found with number and percentage. We used descriptive statistics in this report as the sample size is quite small and no analytical statistics were implemented.\n\nResults\n\nBaseline Demographic and Clinical Characteristics of Newly Diagnosed and Relapsed GNs\n\nThere were 13 patients reported in this case series. Of these, 8 of 13 cases (62%) were newly diagnosed with having GN whereas 5 of 13 cases (38%) were relapses. The median age was 62 (19–83) years. Most patients were White (12 of 13, 92%) and male (9 of 13, 69%). Autoimmune disease (38%) was the most common comorbidity in our series followed by cancer (23%). The autoimmune diseases included diabetes mellitus type 1, Crohn’s disease, ulcerative colitis, primary sclerosing cholangitis, and psoriatic arthritis. IgAN was the most common GN in our case series (5 of 13, 38%). The second most common GNs were MN (3 of 13, 23%) and primary podocytopathy (2 cases of minimal change disease [MCD] and 1 case of primary FSGS) (3 of 13, 23%). In addition, 54% of our patients received mRNA-1273 (Moderna) and the other 46% received BNT162b2 (Pfizer) vaccine. Most patients presented after the second dose (10 of 13, 77%). The median time of onset varied. Median time of onset in those newly diagnosed with having GN was 1 week after the first dose and 4 weeks after the second dose. In contrast, all of our relapse cases occurred after the second dose with median onset of 3 weeks. AKI, edema, and macroscopic hematuria were common presentations. Median serum creatinine level was 1.6 (0.6–2.5) mg/dl. Baseline clinical characteristics of each patient are found in Table 1.Table 1 Characteristics of initial presentation of patients with newly diagnosed and relapsed glomerulonephritis post–COVID-19 vaccination\n\nCase\tAge\tSex\tRace\tDiagnosis\tVaccine\tOnset after which dose\tOnset time (wk)\tPresenting symptoms\tBaseline SCr (mg/dl)\tLaboratories during presentation\t\nSCr (g/dl)\tUrine RBC (/HPF)\tUrine protein (g/d)\tSAlb (g/dl)\t\nNew cases\t\n1\t38\tM\tW\tIgAN\tPfizer\t2nd\t2\tGross hematuria\t1.3\t1.6\t51–100\t0.32\tNA\t\n2\t44\tM\tW\tIgAN + acute interstitial nephritis\tModerna\t1st\t2\tAKI\t1.1\t2.5\t21–30\t14\t3.7\t\n3\t66\tM\tW\tIgAN\tModerna\t1st\t2\tGross hematuria\t1.1\t1.5a\t51–100\t1.2\t4.1\t\n4\t62\tM\tW\tIgAN\tPfizer\t2nd\t6\tAKI\t1\t2.2\t31–40\t0.9\t4.2\t\n5\t77\tM\tW\tAtypical anti-GBM nephritis\tPfizer\t1st\t1\tHypertension\t1\t1.8\t51–100\t1.6\tNA\t\n6\t83\tM\tW\tMCD + ATN\tModerna\t2nd\t4\tAKI\t1.19\t2.19\t<3\t18\t2.0\t\n7\t50\tF\tW\tNELL-1 MN\tPfizer\t2nd\t4\tJoint pain and proteinuria\t0.84\t0.7\t3–10\t6.5\t3.5\t\n8\t82\tF\tW\tMPO-ANCA\tModerna\t2nd\t4\tAKI, hematuria, proteinuria\t0.8\t2.5b\t3–10\t1.2\tNA\t\nRelapsed cases\t\n9\t67\tF\tW\tMCD\tModerna\t2nd\t3\tEdema\t1\t1.6\t<3\t19\t2.5\t\n10\t29\tF\tA\tFSGS (tip-variant)\tPfizer\t2nd\t3\tEdema\t0.6\t0.6\t<3\t10\t2.2\t\n11\t39\tM\tW\tPLA2R MN\tPfizer\t2nd\t1\tEdema\t0.91\t1.13\t3–10\t8.7\t2\t\n12\t70\tM\tW\tPLA2R MN\tModerna\t2nd\t4\tEdema\t1.7\t2.1\t<3\t16.6\t2.7\t\n13\t19\tM\tW\tIgAN\tModerna\t2nd\t1\tGross hematuria\t0.96\t0.76\t11–20\t0.61\t4.5\t\nA, Asian; AKI, acute kidney injury; ATN, acute tubular necrosis; F, female; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; HPF, high high-powered field; IgAN, IgA nephropathy; M, male; MCD, minimal change disease; MN, membranous nephropathy; MPO-ANCA, myeloperoxidase-antineutrophilic cytoplasmic antibody; NA, nonavailable; PLA2R: phospholipase A2 receptor; RBC, red blood cell; SAlb, serum albumin; SCr, serum creatinine; W, White.\n\na Serum creatinine peaked at 2.2 mg/dl.\n\nb Serum creatinine peaked at 3.1 mg/dl.\n\nClinical Characteristics of Patients With Newly Diagnosed GNs\n\nOf newly diagnosed cases (8 patients), there were 4 cases of IgAN, 1 case of MCD, 1 case of NELL-1–associated MN, 1 case of myeloperoxidase-antineutrophilic cytoplasmic Ab (ANCA) crescentic GN, and 1 case of atypical anti-GBM nephritis. The clinical characteristics of these patients are found in Table 1. There were 5 patients who presented after the second dose of the vaccine (range 2–6 weeks) and 3 patients who presented after the first dose (range 1–2 weeks). The main presenting symptom in patients with new diagnosis of IgAN included AKI and gross hematuria. Furthermore, 1 patient had a symptom of pericarditis in addition to gross hematuria at the time of presentation. There was also 1 patient who had a history of inflammatory bowel disease which raised possibility that he may have had IgA deposits in the kidney before undergoing vaccination and likely had asymptomatic IgAN. This patient also had history of renal cell carcinoma and had undergone partial nephrectomy 7 years before his vaccination. Results of his serum creatinine and urine studies had been normal at the time and in follow-up (last value from 1 year before vaccination). To evaluate for the presence of IgA deposits before vaccination, the nephrectomy sample was retrieved for further evaluation. Glomeruli were unremarkable on light microscopy. Immunofluorescence on pronase-digested, paraffin tissue was performed and revealed segmental mesangial staining of IgA, kappa, and lambda. Electron microscopy revealed presence of mesangial deposits. Therefore, the partial nephrectomy sample revealed evidence of subclinical IgAN. In addition, we had 1 case of atypical anti-GBM nephritis, characterized by bright diffuse linear GBM staining for IgG, kappa, and lambda on immunofluorescence and mesangial proliferation and basement membrane duplication on light microscopy, without the necrotizing and crescentic phenotype typically found in classic anti-GBM nephritis.16\n\nClinical Characteristics of Patients With Relapse of GN\n\nOf the 5 patients who had a relapse, 2 patients had underlying phospholipase A2 receptor (PLA2R)-associated MN, 1 patient had relapse of MCD, and 1 patient originally had diagnosis of MCD but underwent a repeat kidney biopsy on relapse which revealed tip-variant lesion of primary FSGS, and 1 patient had underlying IgAN. All cases of relapse occurred after the second dose with onset ranging from 1 to 4 weeks. Detailed clinical characteristics of each patient are found in Table 1.\n\nThere was 1 patient with PLA2R-associated MN who was in complete remission with negative PLA2R Ab titer result and on no immunosuppression for 18 months before relapse. On relapse, the patient developed sudden-onset nephrotic syndrome and PLA2R Ab was elevated at 28 IU/ml. Another patient with PLA2R-associated MN who was in remission for 8 months presented with nephrotic syndrome, and PLA2R Ab titer result was positive at 3 IU/ml on enzyme-linked immunosorbent assay and positive by indirect immunofluorescence (they were both previously negative). The patient with primary FSGS was in complete remission and off immunosuppression for 24 months before relapse and presented with nephrotic syndrome. The patient with MCD was originally diagnosed with having MCD 3 months before vaccination. She went into complete remission within 4 weeks of starting therapy with high-dose steroids with proteinuria down to 200 mg per 24 hours. As a result, prednisone was tapered to 5 mg daily at which point she received her first dose of the vaccine. Nevertheless, 3 weeks after her second dose, she presented with worsening edema and was noted to have 19 g of protein in 24 hours. The patient with IgAN on last evaluation (2 months before vaccination) had serum creatinine level of 0.96 mg/dl, and urinalysis results revealed 50 to 100 red blood cells per high-powered field with 431 mg of protein per 24 hours. The patient also developed gross hematuria 24 hours after the second dose of COVID-19 vaccination. He had a similar reaction after influenza vaccination a year before.\n\nTreatment and Clinical Follow-Up\n\nOf 13 patients, 9 (69%) received immunosuppression (5 of 8 [63%] had new diagnosis and 4 of 5 [80%] were recurrence). The other 4 patients were treated conservatively. There were 10 patients who have available follow-up data ranging from 1 to 5 months. Of these, 8 patients responded to the treatments (6 treated with immunosuppression and 2 treated conservatively with angiotensin-converting enzyme inhibitor). Patient number 3 who responded to therapy had developed symptoms after the first dose and had further elevation in creatinine after the second dose (peak creatinine 2.2 mg/dl) which then subsequently improved to 1.4 mg/dl. One patient with IgAN and acute interstitial nephritis and the patient with atypical anti-GBM nephritis were both treated with immunosuppressive therapy but have not yet responded and have had progression of their kidney disease. Both of these patients developed symptoms after the first dose of the vaccine but proceeded to receive the second dose. Additional treatment details and outcomes are outlined in Table 2.Table 2 Treatment and follow-up of patients with newly diagnosed and relapsed glomerulonephritis post–COVID-19 vaccination\n\nCase\tAge\tSex\tDiagnosis\tVaccine\tTreatment\tResponse\tF/U time (mo)\tLaboratories during last follow-up\tDuration of remission before relapse (m)\t\nSCr (g/dl)\tUrine RBC (/HPF)\tUrine protein (g/d)\tSAlb (g/dl)\t\nNew cases\t\n1\t38\tM\tIgAN\tPfizer\tConservative\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tNA\t\n2\t44\tM\tIgAN+ interstitial nephritis\tModerna\tHigh-dose steroid\tNR\t3\t3.6\t3–10\t5.6\t3.8\tNA\t\n3\t66\tM\tIgAN\tModerna\tPrednisonea\tR\t5\t1.4\t3–10\t0.3\tNA\tNA\t\n4\t62\tM\tIgAN\tPfizer\tConservative\tR\t1.5\t2.0\t<3\t0.2\tNA\tNA\t\n5\t77\tM\tAtypical anti-GBM\tPfizer\tPrednisone + mycophenolate\tNR\t1.5\t2.9\t51–100\t0.3\t4\tNA\t\n6\t83\tM\tMCD + ATN\tModerna\tHigh-dose steroid\tR\t1\t1.2\t<3\t2\t2.7\tNA\t\n7\t50\tF\tNELL-1 MN\tPfizer\tConservative\tR\t2\t0.7\t<3\t0.4\t4.3\tNA\t\n8\t82\tF\tMPO-ANCA\tModerna\tHigh-dose steroid + rituximab\tR\t1\t2.3\tNA\tNA\tNA\tNA\t\nRelapsed cases\t\n9\t67\tF\tMCD\tModerna\tHigh-dose steroid + rituximab\tR\t2\t1.5\t0–2\t0.07\t4.4\t1\t\n10\t29\tF\tPrimary FSGS\tPfizer\tHigh-dose steroid + tacrolimus\tR\t3.5\t0.7\t<3\t3.7\t3.2\t24\t\n11\t39\tM\tPLA2R MN\tPfizer\tTacrolimus\tR\t1\t1.1\t3–10\t5.7\t2.9\t18\t\n12\t70\tM\tPLA2R MN\tModerna\tObinutuzumab\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t8\t\n13\t19\tM\tIgAN\tModerna\tConservative\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t6\t\nATN, acute tubular necrosis; F, female; F/U, follow-up; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; HPF, high high-powered field; IgAN, IgA nephropathy; M, male; MCD, minimal change disease; MN, membranous nephropathy; NA, nonapplicable; NR, no response; PLA2R, phospholipase A2 receptor; R, response; RBC, red blood cell; SAlb, serum albumin; SCr, serum creatinine.\n\na Prednisone was initiated for treatment of pericarditis.\n\nClinical Characteristics of Patients From Published Literatures\n\nWe found a total of 20 articles related to COVID-19 vaccines and GN published since inception until July 25, 2021. There were 27 cases including 13 cases of newly diagnosed GNs (48%) and 14 cases of relapse (52%) (Table 3). IgAN was the most common pathology (11 cases [41%]: 4 new and 7 relapse) followed by MCD (10 cases [37%]: 4 new and 6 relapse). Other pathologies include 2 cases of anti-GBM (7%) (both new cases), 2 cases of ANCA vasculitis (7%) (both new cases, 1 case of myeloperoxidase-ANCA and 1 case of proteinase 3-ANCA), 1 case of ANCA-negative granulomatous vasculitis (4%) (relapse), and 1 case of PLA2R-associated MN (4%) (relapse). Median age was 41 years, and 48% were male. Nevertheless, patients tended to be younger in the relapse group (median age 38 years) compared with the newly diagnosed group (median age 56 years) (Table 4).Table 3 Summary of published cases of newly diagnosed and relapsed glomerulonephritis\n\nAuthors\tCase\tAge\tSex\tUnderlying disease\tVaccine\tSymptoms\tOnset after which dose\tOnset\tDiagnosis\tTreatments\tOutcomes\t\nNew cases\t\nLebedev et al.10\t1\t50\tM\tNo\tmRNA (Pfizer)\tNephrotic syndrome, AKI, HTN\t1st\tD 10\tMCD\tHigh-dose steroid\tProteinuria and AKI significantly improved at 2 wks\t\nD’Agati et al.6\t2\t77\tM\tDM type 2\tmRNA (Pfizer)\tNephrotic syndrome, AKI, HTN\t1st\t1 wk\tMCD\tHigh-dose steroid\tProteinuria and SCr not improved at 3 wks\t\nHolzworth et al.7\t3\t63\tF\tHTN, tobacco dependence\tmRNA (Moderna)\tNephrotic syndrome, uncontrolled HTN\t1st\t<1 wk\tMCD\tHigh-dose steroid\tNA\t\nMaas et al.35\t4\t80\tF\tNA\tmRNA (Pfizer)\tNephrotic syndrome, HTN\t1st\t1 wk\tMCD\tHigh-dose steroid\tProteinuria reduced from 15 g/d to >0.7 g/d at d 10\t\nSekar et al.12\t5\t52\tM\tHTN\tmRNA (Moderna)\tHeadache, AKI, hematuria\t2nd\t2 wks\tPR3-ANCA vasculitis\tRTX (side effects) and then i.v. CyC + steroid was started\tDialysis was started. 2nd dose of i.v. CyC was planned\t\nShakoor et al.36\t6\t78\tF\tHTN, DM type 2\tmRNA (Pfizer)\tAKI, hematuria, proteinuria\t1st\t2 wks\tMPO-ANCA vasculitis\tHigh-dose steroid and RTX\tSCr improved from 3.5 to 2.3 mg/dl\t\nGillion et al.13\t7\t77\tM\tNo\tAdenovirus vector (AstraZeneca)\tFever, night sweat, and AKI\t1st\t4 wks\tANCA-negative granulomatous vasculitis\tHigh-dose steroid\tSCr was normalized at 4 wks\t\nKudose et al.37\t8\t50\tF\tHTN, APS\tmRNA (Moderna)\tGross hematuria\t2nd\tD 2\tIgAN\tConservative\tHematuria resolved in 5 d\t\n9\t19\tM\tMicroscopic hematuria\tmRNA (Moderna)\tGross hematuria\t2nd\tD 2\tIgAN\tConservative\tHematuria resolved in 2 d\t\nTan et al.38\t10\t41\tF\tGDM\tmRNA (Pfizer)\tGross hematuria\t2nd\tD 1\tIgAN\tHigh-dose steroid + IV CyC\tNA\t\n11\t60\tM\tHyperlipidemia\tmRNA (Pfizer)\tGross hematuria\t2nd\tD 1\tAnti-GBM\tHigh-dose steroid + oral CyC + PLEX\tNA\t\nHanna et al.17\t12\t17\tM\tNo\tmRNA (Pfizer)\tGross hematuria, AKI, proteinuria\t2nd\t<24 h\tIgAN\tHigh-dose steroid\tSCr improved (duration not reported)\t\nSacker et al.39\t13\t—\tF\tNo\tmRNA (Moderna)\tAKI, hematuria, proteinuria\t2nd\t2 wks\tAnti-GBM\tHigh-dose steroid, CyC, PLEX\tRemained dialysis dependent\t\nRelapsed cases\t\nNegrea et al.18\t1\t38\tF\tIgAN in remission\tmRNA (Moderna)\tMacroscopic hematuria\t2nd\t8–24 h\tIgAN\tConservative\tSpontaneously resolved\t\n2\t38\tF\tIgAN in remission\tmRNA (Moderna)\tMacroscopic hematuria\t2nd\t8–24 h\tIgAN\tConservative\tSpontaneously resolved\t\nPerrin et al.11\t3\t22\tM\tIgA vasculitis\tmRNA (Moderna)\tMacroscopic hematuria\t1st\tD 2\tIgAN\tConservative\tSpontaneously resolved\t\n4\t41\tF\tKidney transplant\tmRNA (Pfizer)\tMacroscopic hematuria\t1st\tD 2\tIgAN\tConservative\tSpontaneously resolved\t\n5\t27\tF\tOn hemodialysis\tmRNA (Pfizer)\tMacroscopic hematuria\t2nd\tD 2\tIgAN\tConservative\tSpontaneously resolved\t\nHanna et al.17\t6\t13\tM\tDM type 1\tmRNA (Pfizer)\tGross hematuria, AKI\t2nd\t<24 h\tIgAN\tConservative\tHematuria and AKI resolved within 1 wk\t\nRahim et al.19\t7\t52\tF\tIgAN treated with ACEi\tmRNA (Pfizer)\tGross hematuria, worsening proteinuria\t2nd\t<24 h\tIgAN\tConservative\tHematuria resolved within 1 wk\t\nSchwotzer et al.40\t8\t22\tM\tSteroid-dependent MCD\tmRNA (Pfizer)\tNephrotic syndrome\t1st\tD 3\tMCD\tHigh-dose steroid + TAC\tRemission was achieved at d 17 after treatment\t\nKervella et al.8\t9\t34\tF\tSteroid-dependent MCD\tmRNA (Pfizer)\tNephrotic syndrome\t1st\tD 10\tMCD\tHigh-dose steroid\tRemission was achieved shortly after treatment\t\nKomaba et al.9\t10\t65\tM\tMCD in remission\tmRNA (Pfizer)\tNephrotic syndrome\t1st\tD 19\tMCD\tHigh-dose steroid + cyclosporine\tRemission was achieved at 2 wks\t\nMorlidge et al.14\t11\t30\tM\tMCD previously treated with RTX, TAC, and prednisone\tAdenovirus vector (AstraZeneca)\tFoamy urine\t1st\tD 2\tMCD\tHigh-dose steroid\tRemission was achieved at 10 d\t\n12\t40\tF\tMCD on prednisone and TAC maintenance\tAdenovirus vector (AstraZeneca)\tFoamy urine\t1st\tD 2\tMCD\tHigh-dose steroid\tRemission was achieved at 2 wks\t\nMancianti et al.41\t13\t39\tM\tMCD in remission for 37 yr\tmRNA (Pfizer)\tNephrotic syndrome\t1st\t1 wk\tMCD\tHigh-dose steroid\tRemission was achieved at 4 wks\t\nAydin et al.15\t14\t66\tF\tHTN; DM type 2; MN previously on cyclosporine and steroid but off 7 yr ago\tInactivated virus (Sinovac)\tNephrotic syndrome, AKI\t1st\t2 wks\tPLA2R-associated MN\tNA\tNA\t\nACEi, angiotensin angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ANCA, antineutrophil cytoplasmic antibodies; APS, antiphospholipid syndrome; CyC, cyclophosphamide; DM, diabetes mellitus; F, female; GBM, glomerular basement membrane; GDM, gestational diabetes; HTN, hypertension; IgAN, IgA nephropathy; M, male; MCD, minimal change disease; MN, membranous nephropathy; MPO, myeloperoxidase; NA, nonapplicable; PLA2R, phospholipase A2 receptor; PLEX, plasma exchange; PR3, proteinase 3; RTX, rituximab; SCr, serum creatinine; TAC, tacrolimus.\n\nTable 4 Clinical characteristics of patients with GN post–COVID-19 vaccine from previously published literatures and current case series\n\nCharacteristics\tCurrent case series (n = 13)\tLiteratures (n = 27)\tTotal (n = 40)\t\nAge (yr)\t62 (19–83)\t41 (13–80)\t50 (13–83)\t\nMale sex, n (%)\t9 (69)\t13 (48)\t22 (55)\t\nUnderlying disease, n (%)\t\t\t\t\n - Autoimmune disease\t5 (38)\tNA\tNA\t\n - Diabetes\t2 (15)\tNA\tNA\t\n - Cancer\t3 (23)\tNA\tNA\t\nNew vs. recurrent disease, n (%)\t\t\t\t\n - New\t8 (62)\t13 (48)\t21 (53)\t\n - Recurrent\t5 (38)\t14 (52)\t19 (47)\t\nDiagnosis, n (%)\t\t\t\t\n - IgA nephropathy\t5 (38)\t11 (41)\t16 (40)\t\n - Minimal change disease\t2 (15)\t10 (37)\t12 (30)\t\n - Membranous nephropathy\t3 (23)\t1 (4)\t4 (10)\t\n - Anti-GBM disease\t1 (8)\t2 (7)\t3 (7)\t\n - ANCA vasculitis\t1 (8)\t2 (7)\t3 (7)\t\n - Focal segmental glomerulosclerosis\t1 (8)\t—\t1 (3)\t\n - ANCA-negative granulomatous vasculitis\t—\t1 (4)\t1 (3)\t\nVaccine type, n (%)\t\t\t\t\n - BNT162b2 (Pfizer)\t6 (46)\t15 (55)\t21 (53)\t\n - mRNA-1273 (Moderna)\t7 (54)\t8 (30)\t15 (37)\t\n - Adenovirus vector (AstraZeneca)\t—\t3 (11)\t3 (7)\t\n - Inactivated vaccine (CoronaVac by Sinovac)\t—\t1 (4)\t1 (3)\t\nSymptoms occur after 1st or 2nd dose, n (%)\t\t\t\t\n - 1st dose\t3 (23)\t15 (56)\t18 (45)\t\n - 2nd dose\t10 (77)\t12 (44)\t22 (55)\t\nOnset\t\t\t\t\n - New case s/p 1st dose\t1 (1, 2)\t1 (1, 4)\t1 (1, 4)\t\n - New case s/p 2nd dose\t4 (2, 6)\t1 (1, 2)\t2 (1, 6)\t\n - Relapse case s/p 1st dose\t—\t1 (1, 2)\t1 (1, 2)\t\n - Relapse case s/p 2nd dose\t3 (1, 4)\t1 (1, 1)\t1 (1, 4)\t\nLaboratory on presentation\t\t\t\t\n - Serum creatinine (mg/dl)\t1.6 (0.6, 2.5)\t1.7 (0.7, 8.4)\t1.7 (0.6, 8.4)\t\n - Serum albumin (g/dl)\t3.1 (2, 4.5)\t2.7 (0.7, 4.7)\t2.9 (0.7, 4.7)\t\n - Hematuria, n (%)\t9 (75)\t15 (58)\t24 (63)\t\n - Urine protein (g/d)\t6.5 (0.3, 19)\t2.0 (0.3, 23.2)\t2.2 (0.3, 23.2)\t\nTreatment, n (%)\t\t\t\t\n - Conservative management\t4 (31)\t9 (33)\t13 (32)\t\n - Immunosuppression\t9 (69)\t18 (67)\t27 (68)\t\nOutcome,an (%)\t\t\t\t\n - Response\t8 (80)\t21 (91)\t29 (88)\t\n - Not response\t2 (20)\t2 (9)\t4 (12)\t\nANCA, antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane; GN, glomerulonephritis; NA, nonavailable; s/p, status post.\n\na There were only 10 patients in our case series and 23 patients from the literatures with follow-up outcome.\n\nBNT162b2 (Pfizer) vaccine was the most common vaccine administered (15 of 27 patients, 55%) followed by mRNA-1273 (Moderna) (8 of 27 patients, 30%). There were 3 patients who received AstraZeneca vaccine (11%), and only a single patient who received inactivated vaccine (4%) (CoronaVac by Sinovac) (Table 4).\n\nOf 27 patients, 15 patients (56%) developed symptoms after the first dose whereas the remaining (12 patients, 44%) developed symptoms after the second dose. Nevertheless, patients newly diagnosed with having GN tended to develop symptoms after the second dose (7 of 13 patients, 54%) and those with relapses tended to develop symptoms after the first dose (9 of 14 patients, 64%) (Table 4).\n\nClinical Characteristics and Follow-Up of Patients by Disease\n\nIgA Nephropathy\n\nIn our case series, there were 5 cases of IgAN (4 new and 1 relapse). In the literatures, there were 11 cases of IgAN reported (4 new and 7 relapse). Gross hematuria was the most common presentation followed by AKI. Nevertheless, in most patients, gross hematuria was often self-limited and seldom required immunosuppression. Of the total of 16 patients, only 3 patients received immunosuppression and 1 patient had superimposed acute interstitial nephritis as well. All cases of relapsed IgA improved spontaneously within 1 to 2 weeks.\n\nPrimary Podocytopathy\n\nIn our case series, there were 2 cases of MCD (1 new and 1 relapse) and 1 case that was previously MCD but on repeat biopsy revealed a tip-variant FSGS lesion. In the literatures, there were 10 cases (4 new and 6 relapse). All cases in our series developed symptoms after the second dose, whereas all MCD cases in the literature developed symptoms after the first dose. All patients received immunosuppression. One patient with new MCD responded rapidly to therapy. One patient with relapse of MCD did not respond to high-dose steroids and received rituximab to which the patient responded. The patient with primary FSGS had partial response to prednisone in combination with tacrolimus.\n\nMembranous Nephropathy\n\nIn our case series, there were 3 cases of MN in which 2 cases were associated with PLA2R (relapse) and 1 case with NELL-1 (new). The patient with NELL-1–associated MN had age-appropriate cancer screening completed with negative results. On the basis of literature review, there has been 1 case of PLA2R-associated MN after inactivated vaccine. All patients in our series developed nephrotic syndrome after the second dose. The patient with NELL-1–associated MN significantly improved after conservative management. Proteinuria improved from 6.5 g/d to 0.4 g/d within 3 months after angiotensin-converting enzyme inhibitor initiation. Of 2 patients with PLA2R-asociated MN, only 1 patient from our series has follow-up data. The patient was restarted on tacrolimus. At 1 month, proteinuria and serum albumin improved from 8.7 g/d to 5.7 g/d and 2.0 g/dl to 2.9 g/dl, respectively.\n\nAnti-GBM and ANCA–Associated Vasculitis\n\nIn our case series, there was 1 case of atypical anti-GBM nephritis. In the literatures, there have been 2 cases of classic anti-GBM nephritis. The patient from our series presented 1 week after the first dose with symptom of uncontrolled hypertension (systolic blood pressure level >200 mm Hg), whereas the other 2 cases from literatures presented within 2 weeks after the second dose. Outcome data were available in 2 patients (one from our series and another from the literature). Our patient did not respond to mycophenolate and high-dose steroid, and his serum creatinine level continued to rise. He has now been initiated on cyclophosphamide, but it is too early to know the response. Another patient received cyclophosphamide, plasmapheresis, and high-dose steroid, but the patient did not respond and has remained on dialysis.\n\nWe had 1 patient with myeloperoxidase-ANCA–associated vasculitis, and in the literature, there were 2 cases of ANCA–associated vasculitis, one associated with myeloperoxidase and another with proteinase 3. In addition, there was a single case report of ANCA-negative granulomatous vasculitis post adenoviral vector vaccine. Our patient presented with shortness of breath and fatigue 4 weeks after the second dose. The patient was found to have AKI, serum creatinine level of 2.5, with microscopic hematuria and subnephrotic range proteinuria. Subsequently, serum creatinine level increased to 3.1, and a kidney biopsy was done which revealed pauci-immune crescentic GN. The patient was treated with rituximab and high-dose prednisone, and serum creatinine level 1 month post-treatment improved at 2.3 mg/dl. From the literature, patients with myeloperoxidase-ANCA and ANCA-negative granulomatous vasculitis responded to therapy with improvement in serum creatinine. In contrast, the patient with proteinase 3-ANCA–associated vasculitis required initiation of dialysis.\n\nDiscussion\n\nOur case series is the largest series to report on both newly diagnosed and relapsed cases of GN post–COVID-19 vaccination. All patients in our series received mRNA vaccines. The BNT162b (Pfizer) and mRNA-1273 (Moderna) are the 2 most widely used vaccines in the United States after their use was approved under emergency use authorization by the US Food and Drug Administration. Most patients in our series developed kidney-related symptoms after the second dose, but the onset of symptoms varied from 1 week after the first dose to 6 weeks after the second dose. Taking into account cases reported in the literature, the onset of symptoms has been reported as early as few hours after the first dose.17, 18, 19 It is possible that some patients in our series may have had signs of kidney injury (e.g., elevated creatinine, proteinuria, or microscopic hematuria) between the first and second doses but had not been medically evaluated in that interim. In addition, the 3 patients who had developed symptoms after the first dose proceeded to receive the second dose as their presentations at the time were not attributed to the COVID-19 vaccine. Even though the median age was 62 years, the range varied from 19 to 83 years of age. This wide range of presentation has also been noted in the other recent reports in the literature ranging from 13 to 80 years of age (Table 4).\n\nThe mRNA vaccine has been developed and refined for nearly 2 decades, but it was not used clinically until only recently.20 The vaccine contains purified modified mRNA and a vehicle that helps deliver mRNA into host cells.20 After injection, mRNA will be translated into target protein which in turn results in immune system activation. Growing evidence from several large phase 3 randomized controlled trials and real-world data have revealed superiority of mRNA vaccine over inactivated vaccine.1,2,21,22 This may be partly due to their ability to induce robust cell-mediated and Ab-mediated immune responses.3 Indeed, they have been found to induce neutralizing Ab to the level far beyond convalescent serum.23 Moreover, the neutralizing Ab after mRNA vaccine seems to be higher than that of adenoviral vector COVID-19 vaccine.23 The cell-mediated response results from up-regulation of CD4+ and CD8+ T cells accompanied by increasing interferon γ secretion.3 The CD4+ T cell response from mRNA vaccine has been found to confer partial protection to nonancestral strain of SARS-CoV-2 and endemic coronavirus suggesting immune crossover.24 Similarly, another study was found to have cross-reactivity of Ab to SARS-CoV-2 spike protein and nucleocapsid to other self-human antigens, such as transglutaminase 3, extractable nuclear antigen, myelin basic protein, mitochondria, α-myosin, thyroid peroxidase, collagen, and claudin.25 Therefore, it is conceivable that this higher immunogenicity and cross-reactivity could lead to unexpected and perhaps nonspecific immune activation that may aggravate, unmask, or incite autoimmune processes. Similar to the cases of GN, this immune activation after mRNA COVID-19 vaccination has been associated with cases of myocarditis, particularly in young males.5 A detailed investigation in a single patient with myocarditis revealed up-regulated specific natural killer cells but absence of Th17 and certain cytokines that are often associated with myocarditis suggesting underlying host-related factors can play a role in development of autoimmunity.4 Indeed, we observed a high prevalence of autoimmune diseases in our series, and it is likely that this underlying immune dysregulation is a risk factor for development of GN or relapse of the disease.\n\nIt is noteworthy that many of the reported GNs in association with COVID-19 vaccination have also been noted with the COVID-19 infection itself. Podocytopathy and collapsing glomerulopathy in addition to cases of anti-GBM disease and ANCA–associated vasculitis have all been reported.26, 27, 28, 29 The pathophysiology of GNs in association with COVID-19 infection is complex and may include direct cytotoxicity to the podocytes in addition to immune dysregulation.27,28 It is possible that the immune response to COVID-19 vaccine mimics what happens in response to natural infection thus resulting in GN in susceptible patients.\n\nRelapse of GN after vaccination when there is up-regulation of both cell-mediated (e.g., in cases of relapse of MCD)30 and Ab-mediated immunity (e.g., relapse of PLA2R-associated MN) is conceivable. But why do some patients develop new GN? One possibility is that they have underlying immune dysregulation which in turn makes them predisposed to development of GN. As noted previously, 38% of the individuals in our series had altered autoimmunity at baseline. Another possibility is that the disease perhaps was present before the vaccination, but patient was clinically asymptomatic. This may be the case in patients with new IgAN. We were able to reveal for the first time that in at least 1 patient with “new” diagnosis of IgAN, the IgA deposits were indeed present before the vaccination. This patient had a previous partial nephrectomy sample available from 7 years before, and review of this sample confirmed IgA deposits. This case provides proof that in some individuals, the vaccine only results in a “flare” of the already present disease rather than development of new IgA antibodies that are deposited in the kidney. Although we cannot confirm this finding in other cases of IgAN owing to lack of prevaccination kidney specimen, it is likely that cases with earlier onset of symptoms postvaccination have already had IgA deposits. IgAN was the most often noted GN post–COVID-19 vaccination both in our series and based on review of the literature. This finding might be explained by the fact that IgA comprises the major Ab response early after mRNA COVID-19 vaccination.31\n\nThe development of GN (e.g., IgAN and MCD) after vaccination is not new and has been reported in humans and animal models.34, 33, 32 It is likely that the mRNA vaccine results in a more potent immune response and therefore associated with a higher rate of GN compared with other types of vaccine (inactivated virus). It is important to also note that this unwanted immune activation occurs in only a very small percentage of vaccinated patients. The exact incidence is unknown as some cases may not have been reported in the literature or may not have been recognized. The rarity of GNs post–COVID-19 vaccine may be similar to the cases of myocarditis in association with the mRNA vaccines, and thus far, the Centers for Disease Control and Prevention endorses continuation of COVID-19 vaccination owing to benefit over risk profile.5\n\nAt this point in time, outcome of newly diagnosed and relapsed GNs post–COVID-19 vaccine seems favorable in patients with nephrotic syndrome and IgAN. Most IgAN cases who presented with gross hematuria spontaneously remitted without specific intervention. Approximately 69% of the patients in our case series developed AKI, but most of them developed AKI stage 1. Of the 10 patients with available follow-up data, 8 have responded to therapy (conservative and immunosuppression). One case of IgAN has had a progressive course. This patient, however, also had features of acute interstitial nephritis on his kidney biopsy results which may have contributed to progression of the disease. In contrast, patients with anti-GBM and ANCA–associated vasculitis particularly seem to have fewer desirable outcomes. One patient with atypical anti-GBM nephritis has had progressive disease after treatment with high-dose steroids and mycophenolate mofetil. His treatment has been changed to cyclophosphamide, and additional follow-up at this point is not available. None of the patient from our case series required dialysis. Nevertheless, there were 2 patients from the literature including anti-GBM and proteinase 3-ANCA vasculitis who did not respond to therapy and thus required dialysis initiation. Taken together, of 40 reported cases, only 2 patients (5%) have been reported to require dialysis. Longer term follow-up is needed to better understand the trajectory and kidney outcome of these patients.\n\nOur case series has limitations. Even though it is the largest series reported thus far, the sample size is still limited. This is likely in part due to the fact that the incidence is low, but we cannot exclude the possibility that some cases may have been missed. Another limitation is lack of long-term data on these patients. Even though in short-term outcomes seem favorable we need longer term follow-up of these patients. Finally, we cannot prove with certainty that the vaccine resulted in development of new or relapse of the GN, but certainly the temporal association is compelling.\n\nIn summary, this case series in combination with cases published thus far in the literature provides data on 40 patients with new and relapsed GN post–mRNA COVID-19 vaccine. As mass vaccination efforts continue, and recognizing the overwhelming benefits of vaccination for individuals with chronic kidney disease who are at increased risk of devastating COVID-19 complications (including death, dialysis, long COVID-19 infection), nephrologists and other physicians should be aware of this association and remain vigilant when evaluating patients postvaccination especially when there are symptoms of kidney-related injury present.\n\nDisclosure\n\nAll the authors declared no competing interests.\n==== Refs\nReferences\n\n1 Polack F.P. Thomas S.J. Kitchin N. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine N Engl J Med 383 2020 2603 2615 10.1056/NEJMoa2034577 33301246\n2 Baden L.R. El Sahly H.M. Essink B. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine N Engl J Med 384 2021 403 416 10.1056/NEJMoa2035389 33378609\n3 Sahin U, Muik A, Vogler I, et al. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans. medRxiv. 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Prevention and attenuation of COVID-19 with the BNT162b2 and mRNA-1273 vaccines N Engl J Med 385 2021 320 329 10.1056/NEJMoa2107058 34192428\n23 Tada T, Zhou H, Samanovic MI, et al. Comparison of neutralizing antibody titers elicited by mRNA and adenoviral vector vaccine against SARS-CoV-2 variants. bioRxiv. Published August 6, 2021. Accessed July 23, 2021. https://www.biorxiv.org/content/10.1101/2021.07.19.452771v3.full.pdf\n24 Woldemeskel B.A. Garliss C.C. Blankson J.N. SARS-CoV-2 mRNA vaccines induce broad CD4+ T cell responses that recognize SARS-CoV-2 variants and HCoV-NL63 J Clin Invest 131 2021 e149335 10.1172/JCI149335\n25 Vojdani A. Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases Clin Immunol 217 2020 108480 10.1016/j.clim.2020.108480 32461193\n26 Gupta R.K. Bhargava R. Shaukat A.A. Spectrum of podocytopathies in new-onset nephrotic syndrome following COVID-19 disease: a report of 2 cases BMC Nephrol 21 2020 326 10.1186/s12882-020-01970-y 32753052\n27 Prendecki M. Clarke C. Cairns T. Anti-glomerular basement membrane disease during the COVID-19 pandemic Kidney Int 98 2020 780 781 10.1016/j.kint.2020.06.009 32599088\n28 Shetty A.A. Tawhari I. Safar-Boueri L. COVID-19-associated glomerular disease J Am Soc Nephrol 32 2021 33 40 10.1681/ASN.2020060804 33214201\n29 Uppal N.N. Kello N. Shah H.H. De novo ANCA-associated vasculitis with glomerulonephritis in COVID-19 Kidney Int Rep 5 2020 2079 2083 10.1016/j.ekir.2020.08.012 32839744\n30 Ishimoto T. Shimada M. Araya C.E. Minimal change disease: a CD80 podocytopathy? Semin Nephrol 31 2011 320 325 10.1016/j.semnephrol.2011.06.002 21839364\n31 Wisnewski A.V. Campillo Luna J. Redlich C.A. Human IgG and IgA responses to COVID-19 mRNA vaccines PLoS One 16 2021 e0249499 10.1371/journal.pone.0249499\n32 Kavukçu S. Soylu A. Sarioğlu S. IgA nephropathy in mice following repeated administration of conjugated Haemophilus influenzae type B vaccine (PRP-T) Tokai J Exp Clin Med 22 1997 167 174 9777007\n33 Kielstein J.T. Termühlen L. Sohn J. Kliem V. Minimal change nephrotic syndrome in a 65-year-old patient following influenza vaccination Clin Nephrol 54 2000 246 248 11020024\n34 Gutiérrez S. Dotto B. Petiti J.P. Minimal change disease following influenza vaccination and acute renal failure: just a coincidence? Nefrologia 32 2012 414 415 10.3265/Nefrologia.pre2012.Feb.11370 22592437\n35 Maas R.J. Gianotten S. van der Meijden W.A.G. An additional case of minimal change disease following the Pfizer-BioNTech COVID-19 vaccine Am J Kidney Dis 78 2021 312 10.1053/j.ajkd.2021.05.003\n36 Shakoor M.T. Birkenbach M.P. Lynch M. ANCA-associated vasculitis following the Pfizer-BioNTech COVID-19 vaccine Am J Kidney Dis 78 2021 611 613 10.1053/j.ajkd.2021.06.016 34280507\n37 Kudose S. Friedmann P. Albajrami O. D’Agati V.D. Histologic correlates of gross hematuria following Moderna COVID-19 vaccine in patients with IgA nephropathy Kidney Int 100 2021 468 469 10.1016/j.kint.2021.06.011 34146600\n38 Tan H.Z. Tan R.Y. Choo J.C.J. Is COVID-19 vaccination unmasking glomerulonephritis? Kidney Int 100 2021 469 471 10.1016/j.kint.2021.05.009 34033857\n39 Sacker A. Kung V. Andeen N. Anti-GBM nephritis with mesangial IgA deposits after SARS-CoV-2 mRNA vaccination Kidney Int 100 2021 471 472 10.1016/j.kint.2021.06.006 34119511\n40 Schwotzer N. Kissling S. Fakhouri F. Letter regarding “Minimal change disease relapse following SARS-CoV-2 mRNA vaccine” Kidney Int 100 2021 458 459 10.1016/j.kint.2021.05.006 34052236\n41 Mancianti N. Guarnieri A. Tripodi S. Minimal change disease following vaccination for SARS-CoV-2 J Nephrol 34 2021 1039 1040 10.1007/s40620-021-01091-1 34143368\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-0249",
"issue": "6(12)",
"journal": "Kidney international reports",
"keywords": "COVID-19; IgA nephropathy; SARS-CoV-2; glomerulonephritis; mRNA vaccine; minimal change disease",
"medline_ta": "Kidney Int Rep",
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"title": "COVID-19 Vaccination and Glomerulonephritis.",
"title_normalized": "covid 19 vaccination and glomerulonephritis"
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"abstract": "A 52 year-old man with Erdheim-Chester Disease (ECD) (a non-Langerhans polyostotic sclerosing histiocytosis) had next-generation sequencing (NGS) performed as part of his diagnostic workup. In addition to the tissue BRAF V600E mutation that is found in over 50% of ECD cases, he was also found to have a JAK2 V617F alteration in cell-free circulating tumor DNA (ctDNA) (liquid biopsy). The latter was thought to be an \"incidental\" finding, perhaps due to clonal hematopoiesis (though this usually occurs in older individuals), as his blood counts were normal and he had no splenomegaly. Approximately 13 months after the ctDNA test showing JAK2 V617F, he developed anemia, thrombocytopenia, and splenomegaly. Marrow biopsy then showed megakaryocytic atypia and markedly increased marrow fibrosis, consistent with WHO grade 2 of 3 myelofibrosis. Therefore, the patient was determined to have ECD with a typical BRAF V600E mutation, as well as primary myelofibrosis, with the latter diagnosis manifesting clinically over one year after the JAK2 V617F was first detected in ctDNA. He recently was started on the JAK2 inhibitor ruxolitinib. This case demonstrates that genomic alterations detected by liquid biopsy for evaluation of specific malignancies already present may serve as an early harbinger of hematological disease.",
"affiliations": "a Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine , University of California San Diego Moores Cancer Center , La Jolla , CA , USA.;a Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine , University of California San Diego Moores Cancer Center , La Jolla , CA , USA.;b Department of Pathology , University of California San Diego , La Jolla , CA , USA.;b Department of Pathology , University of California San Diego , La Jolla , CA , USA.;c Guardant Health , Redwood City , CA , USA.;a Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine , University of California San Diego Moores Cancer Center , La Jolla , CA , USA.",
"authors": "Choi|Michael Y|MY|;Kato|Shumei|S|;Wang|Huan-You|HY|;Lin|Jonathan H|JH|;Lanman|Richard B|RB|;Kurzrock|Razelle|R|",
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"doi": "10.1080/15384047.2018.1450120",
"fulltext": "\n==== Front\nCancer Biol TherCancer Biol. TherKCBTkcbt20Cancer Biology & Therapy1538-40471555-8576Taylor & Francis 29565699145012010.1080/15384047.2018.1450120Bedside to Bench ReportJAK2 V617F mutation in plasma cell-free DNA preceding clinically overt myelofibrosis: Implications for early diagnosis M. Y. CHOI ET AL.CANCER BIOLOGY & THERAPYChoi Michael Y. aKato Shumei aWang Huan-You bLin Jonathan H. bLanman Richard B. cKurzrock Razelle aa Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USAb Department of Pathology, University of California San Diego, La Jolla, CA, USAc Guardant Health, Redwood City, CA, USACONTACT Michael Y Choi, MD, mychoi@ucsd.eduUniversity of California San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC #0820, La Jolla, California, 92093-08202018 22 3 2018 22 3 2018 19 8 664 668 21 11 2017 30 1 2018 3 3 2018 © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC2018The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.ABSTRACT\nA 52 year-old man with Erdheim-Chester Disease (ECD) (a non-Langerhans polyostotic sclerosing histiocytosis) had next-generation sequencing (NGS) performed as part of his diagnostic workup. In addition to the tissue BRAF V600E mutation that is found in over 50% of ECD cases, he was also found to have a JAK2 V617F alteration in cell-free circulating tumor DNA (ctDNA) (liquid biopsy). The latter was thought to be an “incidental” finding, perhaps due to clonal hematopoiesis (though this usually occurs in older individuals), as his blood counts were normal and he had no splenomegaly. Approximately 13 months after the ctDNA test showing JAK2 V617F, he developed anemia, thrombocytopenia, and splenomegaly. Marrow biopsy then showed megakaryocytic atypia and markedly increased marrow fibrosis, consistent with WHO grade 2 of 3 myelofibrosis. Therefore, the patient was determined to have ECD with a typical BRAF V600E mutation, as well as primary myelofibrosis, with the latter diagnosis manifesting clinically over one year after the JAK2 V617F was first detected in ctDNA. He recently was started on the JAK2 inhibitor ruxolitinib. This case demonstrates that genomic alterations detected by liquid biopsy for evaluation of specific malignancies already present may serve as an early harbinger of hematological disease.\n\nKEYWORDS\nctDNAerdheim chester diseasepre-PMFNational Cancer InstituteP30 CA016672Funded in part by the Joan and Irwin Jacobs fund and by National Cancer Institute grant P30 CA016672 (RK).\n==== Body\nIntroduction\nNext-generation sequencing (NGS) is being incorporated into the management of patients with cancer. In some rare tumors, such as Erdheim-Chester Disease (ECD) (a non-Langerhans histiocytosis), NGS can assist in confirming the diagnosis, as a majority cases have a mutation of BRAF V600E.1,2 However, in some cases, NGS testing will report mutations that may be unexpected or appear to be irrelevant. When NGS testing is performed on blood-derived circulating tumor DNA (ctDNA), mutations in TP53, IDH2, DNMT3A, TET2, ASXL1 and JAK2 may be found; these alterations are common in myelodysplastic syndrome or other myeloid disorders.3 However, a subset of elderly individuals can harbor these alterations and be without any clinical signs of a hematologic disease, a condition now called clonal hematopoesis of indeterminate potential (CHIP).4 CHIP is found in over 10% of patients that are 80 years old or more, but at much lesser frequencies in patients that are younger.5 While CHIP is associated with a subsequent diagnosis of hematologic malignancy (or cardiovascular disease), the overall incidence is only about 0.5% to 1.0% per year for hematologic cancer.6 Therefore, the clinical context can help in the assessment of NGS findings. Here we present a case in which a seemingly incidental mutation of JAK2 was found on NGS of ctDNA, with development of clinically overt myelofibrosis (a disease classically associated with the the JAK2 V617F alteration) about 13 months after the blood test. The implications for early diagnosis and monitoring of hematologic and other malignancies are discussed.\n\nCase presentation\nA 52 year-old Caucasian gentleman presented initially with eye swelling and a retro-orbital mass histologically consisting of CD68-positive foamy histiocytes (Fig. 1A and B) in the background of chronic inflammation. He was also found to have sclerotic lesions of long bones, including tibia, fibula, and femur, with epiphyseal sparing. Collectively these findings were most consistent with a diagnosis of Erdheim-Chester disease (ECD), as reviewed by our ophthalmic pathologist (JHL).7\nFigure 1. Microphotography of Erdheim Chester disease (ECD) and bone marrow fibrosis. A-B: There are numerous bland foamy histiocytes with abundant pale to clear cytoplasm (A) with immunoreactivity for CD68 (B) (original magnifications for A and B are 200x and 200x, respectively); C: The bone marrow core biopsy shows megakaryocytic hyperplasia, atypia and cellular streaming, indicative of fibrosis (original magnification 200x). D-E: Reticulin (D) and Trichrome (E) special stains show markedly increased reticulin fibrosis (D) and rare bundle of collagen (blue, E) (original magnifications of D and E are 200x and 200x, respectively).\n\n\n\n\nTo further evaluate the nature of the foamy histiocytes, the orbital mass tissue was assessed by targeted NGS, using the clinical-grade Foundation One panel (315 genes) (https://www.foundationmedicine.com). The NGS showed a BRAF V600E that is commonly associated with ECD, and further supported the diagnosis.2 Sequencing of the orbital mass also demonstrated ASXL1 R693* and U2AF1 Q157P mutations, which were felt to be incidental and, at the time, not clinically relevant (Table 1).\nTable 1. Summary of molecular alterations and clinical findings.\n\nDate of Assessment:\tMay 2014\tDecember 2015\tApril 2017\t\nSource for NGS:\tOrbital mass1\tBlood (ctDNA)2\tBlood (ctDNA)2\t\nNGS results:\tASXL1 R693* U2AF1 Q157P\tJAK2 V617F (2.9%)\tRIT1 M90V (4.0%)\t\n \tBRAF V600E\t \tJAK2 V617F (3.2%)\t\n \t \t \tBRAF V600E (0.06%)\t\n \t \t \tKRAS A59T (2.9 %)\t\nIntervention at the time of NGS assessment:\tNone\tVemurafenib followed by trametinib, starting in November 2014\tInterferon alfa-2b, starting January 2016\t\nStatus of ECD\t \tStable disease\tStable disease\t\nStatus of myelofibrosis\tNot clinically apparent: No anemia or thrombocytopenia\tNot clinically apparent\tWHO grade 2 myelofibrosis. Hgb 7.5, Platelet count 70\t\nBold: Associated with myelofibrosis. Other genomic alterations are potentially associated with ECD.\n\n1 315 gene NGS Foundation One.\n\n2 73 gene panel; Guardant.\n\n\n\n\nThe patient was initially treated with vemurafenib and achieved disease stability. However, vemurafenib was poorly tolerated due to arthralgias, rash, and visual changes, despite dose reduction. He was then treated with trametinib, but similarly had difficulty tolerating it due to conjunctival swelling and uveitis.\n\nAt that time, plasma was sent for assessment of ctDNA both as a biomarker of response and to identify other potential actionable alterations. We used the Guardant360 test (Guardant Health, Inc., http://www.guardanthealth.com/) (digital sequencing (73 genes) in a Clinical Laboratory Improvement Amendments (CLIA)-licensed, College of American Pathologist (CAP)-accredited, New York State Department of Health-approved clinical laboratory).8 The BRAF V600E mutation was no longer detected, consistent with the fact that he had stabilized on BRAF and MEK inhibitors, which slow cell growth and turnover, leading to decreased shedding of abnormal ctDNA in the blood.9,10 However, a mutation of JAK2 V617F was identified with a variant allele frequency (VAF) of 2.9%. In the absence of hematologic abnormalities, this anomaly was also interpreted as an incidental finding without clinical relevance.\n\nHe was then treated with pegylated interferon alfa-2b, with stability of ECD based on symptoms and radiographic findings. However, approximately 13 months after detection of the JAK2 alteration in ctDNA, he developed transfusion-dependent anemia (hemoglobin, 7 g/dL), thrombocytopenia (platelets 70–903/uL), and splenomegaly. A marrow core biopsy was performed and showed megakaryocytic atypia (Fig. 1C) and markedly increased marrow fibrosis by reticulin (Fig. 1D) and trichrome (Fig. 1E) stains, consistent with WHO grade 2 out of 3 myelofibrosis. There was no increase or aberrancy of myeloid blasts (not shown). Plasma was reassessed at this time by NGS of ctDNA and showed the following mutations: RIT1 M90V (VAF 4.0%), JAK2 V617F (3.2%), KRAS A59T (2.9%), and BRAF V600E (0.06%). (Table 1) Although KRAS and RIT1 have been associated with other malignancies, such as lung cancer, workup including a PET/CT scan did not reveal other malignancy.\n\nCollectively, therefore, the patient is assessed to have ECD with a typical BRAF V600E mutation, as well as primary myelofibrosis, with a typical JAK2 V617F. The myelofibrosis was not clinically apparent when first detected. He recently started ruxolitinib therapy. A repeat marrow biopsy has not yet been assessed; however, he has had a clinical response, with a decrease in splenomegaly, from 16.1 cm craniocaudal dimension (4.1 cm greater than upper range of normal) to 13.9 cm (2.9 cm). He still remains dependent on packed red blood cell transfusions approximately monthly.\n\nDiscussion\nThis case illustrates an increasingly common scenario in which genomic evaluation of malignancy reveals unexpected findings, and it may be difficult to determine their significance or make sense of seemingly discrepant results. In this case, with the appropriate clinical context, JAK2 V617F is very supportive of a diagnosis of a myeloproliferative neoplasm.11 Similarly, mutations of U2AF1, ASXL1, and RIT1 have been shown to occur commonly in myeloid neoplasms (Table 1).12–15 The U2AF1 and ASXL1 genes found in tissue would not have been found in the ctDNA NGS targeted 73-gene panel because those genes are not covered. Why the RIT1 M90V mutation was found in plasma but not tissue may reflect a tissue false negative due to spatial heterogeneity (present in a different location than the biopsied location) or temporal heterogeneity (mutation acquired after the tissue biopsy).\n\nSeemingly incidental gene mutations may therefore represent very early stages of malignancy. The presence of asymptomatic premalignant states in hematologic cancers is well established. Monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis very commonly precede the diagnoses of multiple myeloma and chronic lymphocytic leukemia, respectively. Similarly, in our patient, blood counts were normal and there was no splenomegaly at the time of initial ctDNA positivity for JAK2 V617F. Indeed, it was recently reported that JAK2 V617F mutated clones may be present at very low levels sometimes years prior to diagnosis.16\n\nFor those reasons, NGS may facilitate the detection of premalignant clones, and aid in determining prognosis. Indeed, the genes most commonly found to be mutated in healthy individuals include DNMT3A, TET2, and ASXL1, which have been shown to be early driver mutations that may result in a pre-leukemic state.17,18 Similarly, TP53 mutations have been identified at low levels several years before diagnosis of therapy-related acute myeloid leukemia (AML) and secondary myelodysplastic syndrome (MDS).19 Monitoring for such mutations may be helpful in individuals at increased risk for developing secondary AML or MDS. Of relevance to our case is the recent finding that there is a high prevalence (approximately 10%) of myeloid neoplasms in adults with ECD.20\n\nOn the other hand, clonal hematopoiesis may also be a benign condition, and this can confound the interpretation of NGS results. Blood cells of a proportion of healthy individuals without any clinically apparent hematologic abnormality can also be found to have such mutations, a condition called clonal hematopoiesis of indeterminate potential (CHIP).21,22 This appears to be an aspect of aging, and such mutations can be found in greater than 10% of individuals over the age of 80; however, at age 52 (our patient's age), such mutations are uncommon.6 Interestingly, CHIP is associated with a nearly two-fold risk of coronary heart disease, possibly due to increased inflammation.22 CHIP is also associated with an increased relative risk for subsequent diagnosis of hematologic cancer, approximately ten times higher than the general population, though the absolute risk of hematologic cancer remains low, approximately 0.5-1% per year in persons with an incidental mutation.4,6 Therefore, diagnosis of a hematologic malignancy is largely dependent on morphologic changes and clinical signs and symptoms.23,24 As in this case, knowledge of mutations and their association with specific conditions may allow for a more streamlined diagnostic workup should blood count abnormalities develop in the future.\n\nThis case also illustrates the potential utility of monitoring ctDNA for genomic aberrations and early diagnosis. ctDNA is released to the circulation from cells undergoing cell death, and has been useful in aiding with the diagnosis of ECD, as well as other cancers, as an alternative or an adjunct to tissue biopsy.8,25–31 The amount of mutant DNA may also correlate with disease burden or prognosis.25–28,32 In this case, it appears that the variant allele fraction (VAF) of BRAF V600E correlated well with response to BRAF inhibitor treatment, becoming undetectable when on therapy, and then expanding at the most recent assessment to a low but detectable level when off vemurafenib and on interferon.\n\nThe clinician should be aware that genomic testing for established tumors may reveal CHIP mutations of hematopoietic origin. There are several relatively simple means of distinguishing a CHIP mutation from a somatic mutation due to a solid tumor or a disorder such as ECD. First of all, some of the genes that drive many hematologic malignancies are relatively uncommon in solid tumor malignancies and in conditions such as ECD.33 Although one can find case reports of JAK2 mutations associated with cancers such as lung cancer, these may be related to tissue biopsies heavily infiltrated with lymphocytes. Notably drivers of lung cancer such as EGFR and ROS1 are not reported as drivers of hematologic conditions (although KRAS mutations may play a role in myelodysplastic syndromes).34 Secondly, the VAF of the CHIP mutation is unlikely to change when the established malignancy is treated, unless the treatment would also be expected to impact the hematological disorder. For example, in this case, the JAK2 V617F VAF in the liquid biopsy does not change over time (3.2% then 2.9%). A third potential differentiator is when the other somatic mutations cluster around one level of allele fraction, while the CHIP occurs at a much higher or lower VAF. This case was illustrated recently in a report by Zhang et al. where an IDH2 R140Q mutation was found at 19.6% VAF while the other somatic mutations clustered at VAFs two orders of magnitude lower, at 0.1%-0.2% VAF.35\n\nMost importantly, our results suggest potential clinical utility of ctDNA analysis in early detection of malignant states. Indeed, our patient showed the JAK2 V617F, a hallmark of myelofibrosis, in his ctDNA 13 months before any signs or symptoms suggestive of myelofibrosis. ctDNA may also be useful because dynamic changes in levels may indicate response to therapy, as seen in our patient and reported in the literature.25 However, confounders to the interpretation of ctDNA for use as an early diagnostic tool exist, including the fact that benign lesions may harbor mutations often associated with malignancy36 and that clonal hematopoiesis occurs in the elderly and does not always progress to malignancy.5,6 Even so, as illustrated by the individual presented herein, ctDNA alterations can be a very early harbinger of cancer, indicating that further exploration of this modality for early diagnosis or prevention of hematological malignancy is needed, particular in high-risk individuals.\n\nDeclarations\nRichard Lanman is an employee of Guardant. Razelle Kurzrock receives consultant fees from X-biotech, Loxo Actuate Therapeutics, as well as speaker fees from Roche, and research funds from Incyte, Genentech, Pfizer, Sequenom, Guardant, Foundation Medicine and Merck Serono, and has an ownership interest in CureMatch Inc.\n==== Refs\nReferences\n1. Blombery P , Wong SQ , Lade S , Prince HM \nErdheim-Chester disease harboring the BRAF V600E mutation . J Clin Oncol. \n2012 ;30 (32 ):e331 –32 . doi:10.1200/JCO.2012.43.2260 . PMID:23008323.23008323 \n2. Haroche J , Charlotte F , Arnaud L , von Deimling A , Helias-Rodzewicz Z , Hervier B , Cohen-Aubart F , Launay D , Lesot A , Mokhtari K , et al. \nHigh prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses . Blood. \n2012 ;120 (13 ):2700 –703 . doi:10.1182/blood-2012-05-430140 . PMID:22879539.22879539 \n3. 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Gomez-Segui I , Makishima H , Jerez A , Yoshida K , Przychodzen B , Miyano S , Shiraishi Y , Husseinzadeh HD , Guinta K , Clemente M , et al. \nNovel recurrent mutations in the RAS-like GTP-binding gene RIT1 in myeloid malignancies . Leukemia. \n2013 ;27 (9 ):1943 –946 . doi:10.1038/leu.2013.179 . PMID:23765226.23765226 \n14. Tefferi A. \nNovel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1 . Leukemia. \n2010 ;24 (6 ):1128 –138 . doi:10.1038/leu.2010.69 . PMID:20428194.20428194 \n15. Tefferi A , Finke CM , Lasho TL , Wassie EA , Knudson R , Ketterling RP , Hanson CA , Pardanani A \nU2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype . Leukemia. \n2014 ;28 (2 ):431 –33 . doi:10.1038/leu.2013.286 . PMID:24097336.24097336 \n16. McKerrell TPN , Chi J. , Collord G. , Moreno T. , Ponstingl H. , Dias J. , Gerasimou P. , Melanthiou K. , Prokopiou C. , Antoniades M. , et al. \nJAK2 V617F hematopoietic clones are present several years prior to MPN diagnosis and follow different expansion kinetics . Blood Advances. \n2017 ;1 (14 ):968 –71 . doi:10.1182/bloodadvances.2017007047 . PMID:29296738.29296738 \n17. Jan M , Snyder TM , Corces-Zimmerman MR , Vyas P , Weissman IL , Quake SR , Majeti R \nClonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia . Sci Transl Med. \n2012 ;4 (149 ):149ra118 . doi:10.1126/scitranslmed.3004315 . PMID:22932223.22932223 \n18. Shlush LI , Zandi S , Mitchell A , Chen WC , Brandwein JM , Gupta V , Kennedy JA , Schimmer AD , Schuh AC , Yee KW , et al. \nIdentification of pre-leukaemic haematopoietic stem cells in acute leukaemia . Nature. \n2014 ;506 (7488 ):328 –33 . doi:10.1038/nature13038 . PMID:24522528.24522528 \n19. Wong TN , Ramsingh G , Young AL , Miller CA , Touma W , Welch JS , Lamprecht TL , Shen D , Hundal J , Fulton RS , et al. \nRole of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia . Nature. \n2015 ;518 (7540 ):552 –55 . doi:10.1038/nature13968 . PMID:25487151.25487151 \n20. Papo M , Diamond EL , Cohen-Aubart F , Emile JF , Roos-Weil D , Gupta N , Durham BH , Ozkaya N , Dogan A , Ulaner GA , et al. \nHigh prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis . Blood. \n2017 ;130 (8 ):1007 –013 . doi:10.1182/blood-2017-01-761718 . PMID:28679734.28679734 \n21. Genovese G , Kahler AK , Handsaker RE , Lindberg J , Rose SA , Bakhoum SF , Chambert K , Mick E , Neale BM , Fromer M , et al. \nClonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence . N Engl J Med. \n2014 ;371 (26 ):2477 –487 . doi:10.1056/NEJMoa1409405 . PMID:25426838.25426838 \n22. Jaiswal S , Natarajan P , Silver AJ , Gibson CJ , Bick AG , Shvartz E , McConkey M , Gupta N , Gabriel S , Ardissino D , et al. \nClonal hematopoiesis and risk of atherosclerotic cardiovascular disease . N Engl J Med. \n2017 ;377 (2 ):111 –21 . doi:10.1056/NEJMoa1701719 . PMID:28636844.28636844 \n23. Arber DA , Orazi A , Hasserjian R , Thiele J , Borowitz MJ , Le Beau MM Bloomfield CD , Cazzola M , Vardiman JW \nThe 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia . Blood. \n2016 ;127 (20 ):2391 –405 . doi:10.1182/blood-2016-03-643544 . PMID:27069254.27069254 \n24. Tefferi A , Noel P , Hanson CA \nUses and abuses of JAK2 and MPL mutation tests in myeloproliferative neoplasms a paper from the 2010 William Beaumont hospital symposium on molecular pathology . J Mol Diagn. \n2011 ;13 (5 ):461 –66 . doi:10.1016/j.jmoldx.2011.05.007 . PMID:21723416.21723416 \n25. Husain H , Melnikova VO , Kosco K , Woodward B , More S , Pingle SC , Weihe E , Park BH , Tewari M , Erlander MG , et al. \nMonitoring daily dynamics of early tumor response to targeted therapy by detecting circulating tumor DNA in urine . Clin Cancer Res. \n2017 ;23 (16 ):4716 –723 . doi:10.1158/1078-0432.CCR-17-0454 .28420725 \n26. Husain H , Nykin D , Bui N , Quan D , Gomez G , Woodward B , Venkatapathy S , Duttagupta R , Fung E , Lippman SM , et al. \nCell-Free DNA from ascites and pleural effusions: Molecular insights into genomic aberrations and disease biology . Mol Cancer Ther. \n2017 ;16 (5 ):948 –55 . doi:10.1158/1535-7163.MCT-16-0436 . PMID:28468865.28468865 \n27. Janku F , Kurzrock R \nBringing blood-based molecular testing to the clinic . Clin Cancer Res. \n2016 ;22 (22 ):5400 –402 . doi:10.1158/1078-0432.CCR-16-1769 . PMID:27663595.27663595 \n28. Schwaederle M , Husain H , Fanta PT , Piccioni DE , Kesari S , Schwab RB , Patel SP , Harismendy O , Ikeda M , Parker BA , et al. \nUse of liquid biopsies in clinical oncology: Pilot experience in 168 Patients . Clin Cancer Res. \n2016 ;22 (22 ):5497 –505 . doi:10.1158/1078-0432.CCR-16-0318 . PMID:27185373.27185373 \n29. Schwaederle M , Patel SP , Husain H , Ikeda M , Lanman R , Banks KC , Talasaz A , Bazhenova L , Kurzrock R \nUtility of genomic assessment of blood-derived circulating tumor DNA (ctDNA) in patients with advanced lung adenocarcinoma . Clin Cancer Res. \n2017 ;23 (17 ):5101 –111 . doi:10.1158/1078-0432.CCR-16-2497 . PMID:28539465.28539465 \n30. Kato S , Krishnamurthy N , Banks KC , De P Williams K , Williams C , Leyland-Jones B , Lippman SM , Lanman RB , Kurzrock R \nUtility of genomic analysis in circulating tumor DNA from patients with carcinoma of unknown primary . Cancer Res. \n2017 ;77 (16 ):4238 –246 . doi:10.1158/0008-5472.CAN-17-0628 . PMID:28642281.28642281 \n31. Schwaederle M , Chattopadhyay R , Kato S , Fanta PT , Banks KC , Choi IS , Piccioni DE , Ikeda S , Talasaz A , Lanman RB , et al. \nGenomic alterations in circulating tumor DNA from diverse cancer patients identified by next-generation sequencing . Cancer Res. \n2017 ;77 (19 ):5419 –427 . doi:10.1158/0008-5472.CAN-17-0885 . PMID:28807936.28807936 \n32. Oxnard GR , Paweletz CP , Kuang Y , Mach SL , O'Connell A , Messineo MM , Luke JJ , Butaney M , Kirschmeier P , Jackman DM , et al. \nNoninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA . Clin Cancer Res. \n2014 ;20 (6 ):1698 –705 . doi:10.1158/1078-0432.CCR-13-2482 . PMID:24429876.24429876 \n33. Govindan R , Ding L , Griffith M , Subramanian J , Dees ND , Kanchi KL , Maher CA , Fulton R , Fulton L , Wallis J , et al. \nGenomic landscape of non-small cell lung cancer in smokers and never-smokers . Cell. \n2012 ;150 (6 ):1121 –134 . doi:10.1016/j.cell.2012.08.024 . PMID:22980976.22980976 \n34. Makishima H , Yoshizato T , Yoshida K , Sekeres MA , Radivoyevitch T , Suzuki H , Przychodzen B , Nagata Y , Meggendorfer M , Sanada M , et al. \nDynamics of clonal evolution in myelodysplastic syndromes . Nat Genet. \n2017 ;49 (2 ):204 –12 . doi:10.1038/ng.3742 . PMID:27992414.27992414 \n35. Zhang BM , Aleshin A , Lin CY , Ford J , Zehnder JL , Suarez CJ \nIDH2 mutation in a patient with metastatic colon cancer . N Engl J Med. \n2017 ;376 (20 ):1991 –992 . doi:10.1056/NEJMc1701072 . PMID:28514606.28514606 \n36. Kato S , Lippman SM , Flaherty KT , Kurzrock R \nThe conundrum of genetic \"drivers\" in benign conditions . J Natl Cancer Inst. \n2016 ;108 (8 ). doi:10.1093/jnci/djw036 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1538-4047",
"issue": "19(8)",
"journal": "Cancer biology & therapy",
"keywords": "ctDNA; erdheim chester disease; pre-PMF",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D019943:Amino Acid Substitution; D015415:Biomarkers; D001706:Biopsy; D001853:Bone Marrow; D000073888:Cell-Free Nucleic Acids; D003062:Codon; D042241:Early Diagnosis; D006801:Humans; D053614:Janus Kinase 2; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055728:Primary Myelofibrosis",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "664-668",
"pmc": null,
"pmid": "29565699",
"pubdate": "2018-08-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27185373;21723416;27059373;25426838;25931582;23765226;28807936;28642281;19609284;28420725;28551613;27069254;28636844;24429876;27663595;27384348;24097336;22879539;22932223;28600478;20428194;25003820;27992414;25487151;29296738;16603627;25326804;28679734;28468865;25426837;28514606;27215596;22980976;23008323;24522528;28539465",
"title": "JAK2 V617F mutation in plasma cell-free DNA preceding clinically overt myelofibrosis: Implications for early diagnosis.",
"title_normalized": "jak2 v617f mutation in plasma cell free dna preceding clinically overt myelofibrosis implications for early diagnosis"
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"abstract": "BACKGROUND\nLithium can cause not only acute neurotoxicity but also chronic and persistent neurotoxicity known as syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). The combined use of lithium and antipsychotics increases the possibility of SILENT. Neuroleptic malignant syndrome (NMS) is a reversible, idiosyncratic, and potentially life-threatening reaction, which is usually caused by antipsychotics and other agents, such as mood stabilizers (eg, lithium and metoclopramide). Neuroleptic malignant syndrome is characterized by hyperpyrexia, muscle rigidity, and altered mental status. We describe a case of SILENT combined with NMS in this case report.\n\n\nMETHODS\nA 46-year-old man who had been treated with lithium for bipolar II disorder since 2008 was prescribed lorazepam, lithium, and aripiprazole at his last outpatient visit. The patient experienced financial difficulties (bankruptcy) and suffered severe emotional stress. Subsequently, he overused lorazepam, lithium, and aripiprazole. Two days after the overdose, he experienced a high fever, confused mental status, and rhabdomyolysis and was diagnosed with NMS. However, even after resolution of NMS-related symptoms, quadriplegia, visual field defects, ataxia, and severe dysarthria persisted. A positron emission tomography-computed tomography brain scan showed decreased 15F-fludeoxyglucose uptake in bilateral primary motor cortices and in the thalamus, midbrain, and cerebellum. Brain magnetic resonance imaging diffusion tensor imaging and diffusion tensor tractography of the subcortical tracts revealed structural disruptions, especially in the corticospinal tract, dentatorubrothalamic tract, and optic radiation, which seemed to be correlated with the clinical symptoms of the patient.\n\n\nCONCLUSIONS\nThis case suggests that the clinical use of diffusion tensor tractography could be helpful to explain the clinical features in the case of SILENT combined with NMS.",
"affiliations": "Department of Physical Medicine and Rehabilitation, National Health Insurance Service Ilsan Hospital, Ilsan, Republic of Korea.",
"authors": "Rhee|Seung Yeon|SY|;Kim|Hyoung Seop|HS|",
"chemical_list": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D008094:Lithium",
"country": "United States",
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"doi": "10.1097/WNF.0000000000000439",
"fulltext": "\n==== Front\nClin Neuropharmacol\nClin Neuropharmacol\nCNP\nClinical Neuropharmacology\n0362-5664\n1537-162X\nLippincott Williams & Wilkins\n\n33560007\nCNP_200010\n10.1097/WNF.0000000000000439\n00005\nCase Reports\nSubcortical Structure Disruption in Diffusion Tensor Tractography of the Patient With the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity Combined With Neuroleptic Malignant Syndrome: A Case Report\nRhee Seung Yeon MD rp0113@yuhs.ac\n\nKim Hyoung Seop MD\nDepartment of Physical Medicine and Rehabilitation, National Health Insurance Service Ilsan Hospital, Ilsan, Republic of Korea.\nAddress correspondence and reprint requests to Hyoung Seop Kim, MD, Department of Physical Medicine and Rehabilitation, National Health Insurance Service Ilsan Hospital, 100 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi Province 10444, Republic of Korea; E-mail: rehappydoc@gmail.com\nMar-Apr 2021\n09 2 2021\n44 2 6267\nCopyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nWolters Kluwer Health, Inc. All rights reserved.\nThis is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nBackground\n\nLithium can cause not only acute neurotoxicity but also chronic and persistent neurotoxicity known as syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). The combined use of lithium and antipsychotics increases the possibility of SILENT. Neuroleptic malignant syndrome (NMS) is a reversible, idiosyncratic, and potentially life-threatening reaction, which is usually caused by antipsychotics and other agents, such as mood stabilizers (eg, lithium and metoclopramide). Neuroleptic malignant syndrome is characterized by hyperpyrexia, muscle rigidity, and altered mental status. We describe a case of SILENT combined with NMS in this case report.\n\nCase Report\n\nA 46-year-old man who had been treated with lithium for bipolar II disorder since 2008 was prescribed lorazepam, lithium, and aripiprazole at his last outpatient visit. The patient experienced financial difficulties (bankruptcy) and suffered severe emotional stress. Subsequently, he overused lorazepam, lithium, and aripiprazole. Two days after the overdose, he experienced a high fever, confused mental status, and rhabdomyolysis and was diagnosed with NMS. However, even after resolution of NMS-related symptoms, quadriplegia, visual field defects, ataxia, and severe dysarthria persisted. A positron emission tomography-computed tomography brain scan showed decreased 15F-fludeoxyglucose uptake in bilateral primary motor cortices and in the thalamus, midbrain, and cerebellum. Brain magnetic resonance imaging diffusion tensor imaging and diffusion tensor tractography of the subcortical tracts revealed structural disruptions, especially in the corticospinal tract, dentatorubrothalamic tract, and optic radiation, which seemed to be correlated with the clinical symptoms of the patient.\n\nConclusion\n\nThis case suggests that the clinical use of diffusion tensor tractography could be helpful to explain the clinical features in the case of SILENT combined with NMS.\n\nKey Words\n\nlithium\nneuroleptic malignant syndrome\nneurotoxic disorder\nOPEN-ACCESSTRUE\n==== Body\nThe use of lithium as a treatment for bipolar disorder has increased recently. Because of its narrow therapeutic window, it is important to check the serum dose. Since lithium was first introduced in the field of psychiatry in 1949, a number of cases of lithium neurotoxicity and potentially life-threatening complications have been reported.1–3 Among neurotoxic complications of lithium, there are reported cases of acute and reversible neurotoxicity.4,5 Adityanjee6 reported 55 cases of chronic and persistent neurotoxicity and sequelae associated with the use of lithium. In these cases, the main sequelae of the patients were persistent cerebellar symptoms. Adityanjee7 was the first to propose the name syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) to represent persistent neurotoxic sequelae of lithium. Lithium intoxication is associated with several neurological symptoms, such as tremor, ataxia, encephalopathy, comatous mental change, and dysarthria.8 Also, SILENT mostly induces cerebellar and extrapyramidal symptoms.8\n\nNeuroleptic malignant syndrome (NMS) is an idiosyncratic and potentially life-threatening reaction, characterized by hyperpyrexia, muscle rigidity, autonomic dysfunction, mental status change, tremors, leukocytosis, and creatinine kinase (CK) elevation.9–11 Although the reported incidence of NMS is reported to be just 0.01% to 0.02%, it is responsible for a significant portion of morbidity and mortality in patients who use antipsychotics.11–13 In terms of pathophysiological aspects, NMS is thought to be a subcortical motor syndrome caused by dopaminergic dysregulation.14 Neuroleptic malignant syndrome is associated with the use of conventional, old-generation antipsychotics. Recently, the development of newer generation antipsychotic agents has decreased the incidence of NMS.\n\nCatatonia, which refers to cortical psychomotor immobility and abnormal behavior, shares similar features with NMS, but it is the result of GABAergic dysregulation.14 In some previous cases, the initial presentation of NMS was catatonia.10,14,15\n\nWe describe the case of a 46-year-old man with bipolar disorder who was diagnosed with SILENT and NMS by the clinical symptoms after drug intoxication, such as persistent catatonia and quadriplegia, tremor, ataxia, and dysarthria. Moreover, imaging analysis by using diffusion tensor tractography (DTT) in this case was also performed.\n\nCASE REPORT\n\nA 46-year-old man had received treatment for bipolar II disorder since 2008. In September 2018, he suffered severe emotional stress due to bankruptcy. In October 2018, he visited the outpatient clinic of a university hospital and was prescribed lorazepam, lithium, and aripiprazole. The same day, he took a massive overdose of the medication. He became delirious 1 day later and exhibited abnormal behaviors, including confusion. He developed a high fever (40°C) 2 days later, with concomitant aggravation of his mental status. A laboratory study showed CK elevation (over 40,000 IU/L; reference value = 44–245 IU/L) and metabolic acidosis. At that time, his serum lithium level was 1.63 mmol/L (reference value = 0.6–1.2 mmol/L). Subsequently, oliguria with azotemia due to acute kidney injury after rhabdomyolysis and hemodynamic instability developed. Continuous renal replacement therapy was administered, with intensive care unit management for 8 days. Blood, sputum, and urine culture, in addition to abdomen and pelvic computed tomography (CT), cerebrospinal fluid tapping, and brain imaging, including magnetic resonance imaging (MRI) (Fig. 1) and CT, were performed, none of which revealed any significant findings. Due to the suspicion of NMS, the patient was treated with dantrolene via the intravenous route. Seven days after the administration of dantrolene, the patient's CK level began to decrease.\n\nFIGURE 1 Brain MRI T2 Axial and T2 FLAIR Sagittal (2019.1.18). There was no remarkable finding.\n\nHowever, even after resolution of rhabdomyolysis and acute kidney injury, catatonia, limb and trunk ataxia, visual field defects, and severe dysarthria remained. To rule out possible organic problems, electroencephalography and brain positron emission tomography (PET) were performed. The electroencephalography showed sharply formed diffuse theta and delta and theta dominant waves, which suggested mild nonspecific diffuse cerebral dysfunction. A PET brain scan taken in May 2019 revealed decreased 15F-fludeoxyglucose (FDG) uptake in bilateral primary motor cortices and the thalamus, midbrain, and cerebellum (Fig. 2).\n\nFIGURE 2 PET-CT brain scan (2019.5.15). Decreased FDG uptake in bilateral primary motor cortices (red arrow), thalamus (white arrow), midbrain (red arrowhead), and cerebellum (white arrowhead) was shown.\n\nIn June 2019, the patient was admitted to our hospital. In a neurological examination at that time, his Mini-Mental Status Examination score was 28 points, with slight time disorientation and attention deficit detected. In the manual muscle test using the Medical Research Council (MRC) scale, the patient was grade III to IV for both the upper and lower extremities. Brain MRI was performed twice. Both times, structural brain MRI sequences, including T1WI, T2WI, T2 FLAIR, SWI, MPR, and DWI, showed no abnormalities (lesions) (Fig. 3).\n\nFIGURE 3 Brain MRI T2 FLAIR Axial and T1 Sagittal (2019.6.14). There was no remarkable finding. Compared with a previous study (2019.1.8), no interval change was observed.\n\nDiffusion tensor imaging (DTI) was performed using a 3.0 T system (Philips Achieva TX, Best, Netherlands). The DTI sequence parameters were as follows: repetition time = 7,958.5 ms and echo time = 71 ms. After this DTI sequence, a DTI diffusion scheme was used, and 32 diffusion sampling directions were acquired. The b-value was 600 s/mm2. The in-plane resolution was 1.91071 mm. The slice thickness was 2 mm. The b-table was checked using an automatic quality control routine to ensure its accuracy.16 To obtain the spin distribution function,17 the diffusion data were reconstructed in the Montreal Neurological Institute space using q-space diffeomorphic reconstruction.18 A diffusion sampling length ratio of 1.25 was used, with isotropic output resolution of 2 mm. The restricted diffusion was quantified using restricted diffusion imaging.19\n\nThen, the DSI Studio software (http://dsi-studio.labsolver.org/) was used to visualize the subcortical tracts. The DSI Studio software has auto-tracking tools for most subcortical tracts, including the corticospinal tract (CST), rubrospinal tract, and spinothalamic tract. However, some tracts, such as the dentatorubrothalamic tract (DRTT), which is associated with motor planning and initiation of movement, motor coordination, verbal fluency, and working memory,20,21 could not be obtained using the auto-tracking tools. Anatomically, DRTT arises from deep cerebellar nuclei, mainly the dentate nucleus, passing through the superior cerebellar peduncle, and then decussates to the contralateral red nucleus to ascend to the thalamus and brain cortex.22 In this case, DRTT fiber tracking was conducted using deterministic fiber-tracking algorithm based on Human Connectome Project (Q1–Q3 release, WU-Minn HCP consortium).20,23\n\nWe obtained DTT of each subcortical tracts, including the CST, arcuate fasciculus, rubrospinal tract, corpus callosum, optic radiation, and DRTT. Diffusion tensor tractography of the subcortical tracts revealed subtle impairment of the bilateral CST (Figs. 4A, B, C) and substantial structural impairment of left optic radiation compared with the right side (Fig. 4D). In addition, DRTT showed severe subcortical disruption (Figs. 4E, F) that seemed to be correlated with the quadriplegic, ataxic, catatonic symptoms, and dysarthria of the patient.\n\nFIGURE 4 DTT of CST (A, B, C), optic radiation (d), and DRTT (E, F) (June 14, 2019). Subcortical disruptions were observed. (Arrows and arrowheads: suspected disruption of each tracts) (red: left, blue: right).\n\nThe patient received intensive rehabilitation, including physiotherapy (30 min/session, 2 sessions/d, 5 times/wk), occupational therapy (30 min/session, 2 sessions/d, 5 times/wk), and speech therapy (40 min/session, 2–3 three times/wk) until July 2019. In the manual muscle test, his muscle power increased from MRC grade I in November 2018 to MRC grade III to IV in July 2019. In terms of hand function, pinch and grasp power of both hands improved, but fine motor function of his left hand showed no improvement (Table 1). The patient’s Functional Independence Measure score improved from 38 in January 2019 to 71 in July 2019. Correspondingly, his modified Barthel Index score improved from 0 in January 2019 to 49 in July 2019. In a speech evaluation, articulation and pronunciation improved slightly, but his speech remained very slow (Table 2). Ataxia-related features also improved, with the CARS score declining from 72 in June 2019 to 60 in July 2019 (Table 3).\n\nTABLE 1 Hand Function Test\n\n\tJanuary 2019\tJuly 2019\t\nPinch power (kg)\t\nTip pinch\t\n Rt.\t1.6\t5.5\t\n Lt.\tNT\tNT\t\nLateral pinch\t\n Rt.\t3.8\t9\t\n Lt.\t1\t3.5\t\nPalmar pinch\t\n Rt.\t2.5\t8.5\t\n Lt.\tNT\tNT\t\nBox and block (/min)\t\n Rt.\t14\t13\t\n Lt.\tNT\t6\t\nGrip power (kg)\t\n Rt.\t4\t26\t\n Lt.\tNT\t9\t\nNT indicates not testable; Rt., right; Lt., left.\n\nTABLE 2 Speech Test (Paradise K-WAB)\n\n\tJanuary 2019\tMay 2019\tJune 2019\t\nAQ\t92.4\t94.5\t96.2\t\nLQ\t—\t92.5\t94.6\t\nMPT\t2.45 s\t20.83 s\t10.44 s\t\nDDK\t\n AMR\n“/pa/”\t\t8 times/5 s\t13 times/5 s\t\n AMR\n“/ta/”\t\t6 times/5 s\t13.7times/5 s\t\n AMR\n“/ka/”\t\t5 times/5 s\t12 times/5 s\t\n SMR\n“/pataka/”\t\t2 times/5 s\t4 times/5 s\t\nK-WAB indicates Korean version—the Western Aphasia Battery; AQ, aphasia quotient; LQ, language quotient; MPT, maximum phonation time; DDK, diadochokinetic rate; AMR, alterate motion rate; SMR, sequencing motion rate.\n\nTABLE 3 International Cooperative Ataxia Rating Scale (ICARS)\n\n\tJune 2019\tJuly 2019\t\nPosture and gait disturbances\t\n Walking capacities\t8\t8\t\n Gait speed\t4\t4\t\n Standing capacities, eyes open\t5\t5\t\nSpread of feet in natural position/s support, eyes open\t4\t2\t\n Body sway with feet together, eyes open\t4\t3\t\n Body sway with feet together, eyes closed\t4\t4\t\n Quality of sitting position\t1\t0\t\nKinetic functions\t\n Knee-tibia test (decomposition of movement and intention tremor)\t3/4\t3/3\t\n Action tremor in the heel to knee test\t3/3\t2/2\t\n Finger to nose test: decomposition and dysmetria\t2/3\t2/3\t\n Finger to nose test: intention tremor of finger\t2/3\t2/2\t\nFinger-finger test (action tremor and/or instability)\t2/3\t2/2\t\n Pronation supination alternating movements\t2/3\t1/2\t\n Drawing of Archimedes' spiral on a predrawn pattern\t2\t1\t\nSpeech disorders\t\n Dysarthria: fluency of speech\t3\t3\t\n Dysarthria: clarity of speech\t2\t2\t\nOculomotor disorders\t\n Gaze-evoked nystagmus\t1\t1\t\n Abnormalities of ocular pursuit\t1\t1\t\nDysmetria of saccade\t0\t0\t\nTotal\t72/100\t60/100\t\n\nDISCUSSION\n\nNeuroleptic malignant syndrome is a rare but potentially life-threatening complication associated with the use of antipsychotics.12 The characteristic symptom triad of NMS includes hyperpyrexia, rigidity, and altered mental status.24 Other clinical features include tremor, urinary incontinence, dysphagia, elevated CK, and leukocytosis.24\n\nOver 75% of patients with long-term use of lithium experience some kind of toxicity because of its narrow therapeutic dose.25 Lithium toxicity is associated with confusion, lethargy, slurred speech, tremor, and gait difficulties.26 Before 1987, the majority of reported lithium toxicity cases involved acute neurotoxicity, which was reversible.4,5 In 1987, the first case report of SILENT, which represents persistent and irreversible neurotoxic sequelae of lithium, was described.6–8 In a literature review, SILENT was mostly associated with extrapyramidal features and cerebellar symptoms.8,27\n\nIn the present case, the persistent catatonic features of the patient raised the suspicion of NMS. However, other than in the acute phase of his illness, the patient did not exhibit abrupt onset of mutism, negativism, immobility, or rigidity, all of which are part of the clinical presentation of catatonia. A number of studies have reported chronic neurological sequelae (SILENT) resulting from lithium intoxication.6–8 In the present case, we assumed that the chronic neurological sequelae were attributed to SILENT rather than persistent catatonia after NMS.\n\nOur patient made some recovery, although extrapyramidal features, cerebellar ataxia, severe dysarthria, and autonomic instability remained. Thus, in this case of lithium toxicity, the patient appeared to exhibit not only NMS-related features in the acute stage but also SILENT-type features in the chronic stage. This case emphasizes the need to consider the possibility of SILENT, especially in cases of combined use of lithium and antipsychotics.8,28 Furthermore, we propose the possibility that SILENT might be a chronic subtype of NMS.10,15\n\nIn this case, after the diagnosis of SILENT combined with NMS, we performed imaging studies in an effort to identify possible causes of the patient’s symptoms. Among the imaging studies performed, a PET brain scan showed decreased FDG uptake in bilateral primary motor cortices and in the thalamus, midbrain, and cerebellum. Routine brain structural MRI revealed no lesions that could explain the patient's symptoms. As a PET CT brain scan provides only biochemical evidence, we performed DTI to assess the subcortical structure.\n\nTo acquire DTI, in addition to the three-dimensional gradient magnetic field, which is already used in the diffusion-weighted image sequence, an extra magnetic field is used to measure the motion of water molecules. If the water molecules in a specific space take same probability of diffusion in any direction, this is called Brownian motion, and it is defined as “isotropic diffusion.” On the other hand, if the diffusion of water molecules shows a specific direction, such as in a white matter tract, this is called as “anisotropic diffusion.” Therefore, DTI is helpful to analyze the white matter structure and injury of this structure.29,30 Practically, there are 2 methods to detect injury of white matter tracts. One is to analyze the diffusion tensor parameters of the region of interest, and the other is to reconstruct the region of interest of each tract using DTT.31–33 In contrast to DTI analysis and diffusion tensor parameter, DTT provides visual information of each tracts. Diffusion tensor tractography can be considered an objective, reproducible, and reliable method to ascertain the structural integrity of white matter tracts.34–39\n\nThe DTT analysis revealed structural disruptions of the CST and optic radiation, which were, respectively, correlated with quadriplegia and visual field defects. In particular, DTT showed severe structural disruption of the DRTT, which is associated with motor planning and initiation of movement. This disruption was not visible on routine brain MRI.\n\nCONCLUSIONS\n\nIn the present case, although brain MRI sequences revealed no specific abnormal findings, DTT derived from the DTI sequence revealed severe subcortical disruption of the CST, optic radiation and DRTT, all of which seemed to be correlated with the patient's clinical symptoms. Therefore, the DTI sequence and DTT appear to be useful in evaluating and correlating neurological symptoms of patients with SILENT combined with NMS.\n\nConflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare.\n==== Refs\nREFERENCES\n\n1 Corcoran AC Taylor RD Page IH . Lithium poisoning from the use of salt substitutes. J Am Med Assoc 1949;139 (11 ):685–688.18110875\n2 Hanlon LW Romaine M 3rd , . Lithium chloride as a substitute for sodium chloride in the diet; observations on its toxicity. JAMA 1949;139 (11 ):688–692.\n3 Stern RL . Severe lithium chloride poisoning with complete recovery; report of case. JAMA 1949;139 (11 ):710.\n4 Glesinger B . Evaluation of lithium in treatment of psychotic excitement. Med J Aust 1954;41 (1 8 ):277–283.13153553\n5 Noack CH Trautner EM . The lithium treatment of maniacal psychosis. Med J Aust 1951;2 (7 ):219–222.14881840\n6 Adityanjee. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). Pharmacopsychiatry 1989;22 (2 ):81–83.2717661\n7 Adityanjee. The syndrome of irreversible lithium effectuated neurotoxicity. J Neurol Neurosurg Psychiatry 1987;50 (9 ):1246–1247.3668585\n8 Adityanjee, Munshi KR Thampy A . The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol 2005;28 (1 ):38–49.15714160\n9 Agrawal A Bajaj D Bajaj S , . Aripiprazole induced late neuroleptic malignant syndrome. Am J Ther 2019;26 :e772–e773.30730330\n10 Reilly TJ Cross S Taylor DM , . Neuroleptic malignant syndrome following catatonia: vigilance is the price of antipsychotic prescription. SAGE Open Med Case Rep 2017;5 :2050313x17695999.\n11 Chung YJ Lee SJ . Case report of neuroleptic malignant syndrome with prolonged mental changes and severe dyskinesia. Asia Pac Psychiatry 2018;10 (1 ).\n12 Stübner S Rustenbeck E Grohmann R , . Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry 2004;37 (Suppl 1 ):S54–S64.15052515\n13 Pileggi DJ Cook AM . Neuroleptic malignant syndrome. Ann Pharmacother 2016;50 (11 ):973–981.27423483\n14 Northoff G . Catatonia and neuroleptic malignant syndrome: psychopathology and pathophysiology. J Neural Transm (Vienna) 2002;109 (12 ):1453–1467.12486486\n15 Ihara M Kohara N Urano F , . Neuroleptic malignant syndrome with prolonged catatonia in a dopa-responsive dystonia patient. Neurology 2002;59 (7 ):1102–1104.12370475\n16 Nath V Schilling KG Parvathaneni P , . Deep learning reveals untapped information for local white-matter fiber reconstruction in diffusion-weighted MRI. Magn Reson Imaging 2019;62 :220–227.31323317\n17 Yeh FC Wedeen VJ Tseng WY . Generalized q-sampling imaging. IEEE Trans Med Imaging 2010;29 (9 ):1626–1635.20304721\n18 Yeh FC Tseng WY . NTU-90: a high angular resolution brain atlas constructed by q-space diffeomorphic reconstruction. NeuroImage 2011;58 (1 ):91–99.21704171\n19 Yeh FC Liu L Hitchens TK , . Mapping immune cell infiltration using restricted diffusion MRI. Magn Reson Med 2017;77 (2 ):603–612.26843524\n20 Meola A Comert A Yeh FC , . The nondecussating pathway of the dentatorubrothalamic tract in humans: human connectome-based tractographic study and microdissection validation. J Neurosurg 2016;124 (5 ):1406–1412.26452117\n21 Javalkar V Khan M Davis DE . Clinical manifestations of cerebellar disease. Neurol Clin 2014;32 (4 ):871–879.25439285\n22 Kwon HG Hong JH Hong CP , . Dentatorubrothalamic tract in human brain: diffusion tensor tractography study. Neuroradiology 2011;53 (10 ):787–791.21547376\n23 Yeh FC Verstynen TD Wang Y , . Deterministic diffusion fiber tracking improved by quantitative anisotropy. PLoS One 2013;8 (11 ):e80713.24348913\n24 Berman BD . Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist 2011;1 (1 ):41–47.23983836\n25 Groleau G . Lithium toxicity. Emerg Med Clin North Am 1994;12 (2 ):511–531.8187694\n26 Edokpolo O Fyyaz M . Lithium toxicity and neurologic effects: probable neuroleptic malignant syndrome resulting from lithium toxicity. Case Rep Psychiatry 2012;2012 :271858.22953147\n27 Schou M . Long-lasting neurological sequelae after lithium intoxication. Acta Psychiatr Scand 1984;70 (6 ):594–602.6524425\n28 Silva AL Ourique C Martins F , . Syndrome of irreversible lithium-effectuated neurotoxicity. Acta Medica Port 2017;30 (2 ):151–153.\n29 Neil J Miller J Mukherjee P , . Diffusion tensor imaging of normal and injured developing human brain—a technical review. NMR Biomed 2002;15 (7–8 ):543–552.12489100\n30 Pierpaoli C Basser PJ . Toward a quantitative assessment of diffusion anisotropy. Magn Reson Med 1996;36 (6 ):893–906.8946355\n31 Brandstack N Kurki T Tenovuo O . Quantitative diffusion-tensor tractography of long association tracts in patients with traumatic brain injury without associated findings at routine MR imaging. Radiology 2013;267 (1 ):231–239.23297328\n32 Kim N Branch CA Kim M , . Whole brain approaches for identification of microstructural abnormalities in individual patients: comparison of techniques applied to mild traumatic brain injury. PLoS One 2013;8 (3 ):e59382.23555665\n33 Shenton ME Hamoda HM Schneiderman JS , . A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury. Brain Imaging Behav 2012;6 (2 ):137–192.22438191\n34 Brandstack N Kurki T Laalo J , . Reproducibility of tract-based and region-of-interest DTI analysis of long association tracts. Clin Neuroradiol 2016;26 (2 ):199–208.25283182\n35 Danielian LE Iwata NK Thomasson DM , . Reliability of fiber tracking measurements in diffusion tensor imaging for longitudinal study. NeuroImage 2010;49 (2 ):1572–1580.19744567\n36 Hasan KM Kamali A Abid H , . Quantification of the spatiotemporal microstructural organization of the human brain association, projection and commissural pathways across the lifespan using diffusion tensor tractography. Brain Struct Funct 2010;214 (4 ):361–373.20127357\n37 Lee HD Jang SH . Injury of the corticoreticular pathway in patients with mild traumatic brain injury: a diffusion tensor tractography study. Brain Inj 2015;29 (10 ):1219–1222.26204321\n38 Malykhin N Concha L Seres P , . Diffusion tensor imaging tractography and reliability analysis for limbic and paralimbic white matter tracts. Psychiatry Res 2008;164 (2 ):132–142.18945599\n39 Wang JY Abdi H Bakhadirov K , . A comprehensive reliability assessment of quantitative diffusion tensor tractography. NeuroImage 2012;60 (2 ):1127–1138.22227883\n\n",
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"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D056324:Diffusion Tensor Imaging; D006801:Humans; D008094:Lithium; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome",
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"title": "Subcortical Structure Disruption in Diffusion Tensor Tractography of the Patient With the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity Combined With Neuroleptic Malignant Syndrome: A Case Report.",
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"abstract": "BACKGROUND\nRecent studies support the use of gemcitabine and nab-paclitaxel in adults with locally advanced unresectable or metastatic pancreatic adenocarcinoma although insufficient data are available on prognostic and predictive markers of response to treatment.\n\n\nOBJECTIVE\nThe objective of this study is to identify treatment response markers in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma.\n\n\nMETHODS\nThis is an observational, retrospective, and multicenter study. Sociodemographic, clinical, and therapeutic data were collected. Cox regression models were applied to determine associations.\n\n\nRESULTS\nIn total, 39 patients were included; 23.1% presented locally advanced pancreatic cancer and 76.9% metastatic disease. They received a mean of 6 ± 3 treatment cycles; 59% required dose reduction, 59% treatment delay, and 20.5% switched to a biweekly regimen. The overall response rate was 23% and the disease control rate was 81%. Median progression-free survival was 9 months and median overall survival (OS) was 15 months. A higher neutrophil/lymphocyte ratio (NLR) was significantly associated with lower OS. We reported Grades 1-4 nonhematological and hematological toxicities.\n\n\nCONCLUSIONS\nNLR is a useful prognostic factor for OS in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with gemcitabine and nab-paclitaxel. Moreover, we suggest that a biweekly regimen is an option for certain groups of patients.",
"affiliations": "Departament of Medical Oncology, Complexo Hospitalario Universitario de Ourense, Ourense, Spain.;Departament of Medical Oncology, Complexo Hospitalario Universitario de Vigo, Pontevedra, Spain.;Departament of Medical Oncology, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain.;Departament of Medical Oncology, Complexo Hospitalario Universitario de Ferrol, Ferrol, A Coruña, Spain.;Departament of Medical Oncology, Hospital Lucus Augusti, Lugo, Spain.;Departament of Medical Oncology, Hospital de Pontevedra, Pontevedra, Spain.;Departament of Medical Oncology, Complexo Hospitalario Universitario de Ourense, Ourense, Spain.;Departament of Medical Oncology, Complexo Hospitalario Universitario de Vigo, Pontevedra, Spain.",
"authors": "Montes|Ana Fernández|AF|;Villarroel|Paula González|PG|;Ayerbes|Manuel Valladares|MV|;Gómez|Juan De la Cámara|JC|;Aldana|Guillermo Quintero|GQ|;Tuñas|Lidia Vázquez|LV|;Fernández|Mercedes Salgado|MS|;Fernández|Mónica Jorge|MJ|",
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"title": "Prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nab-paclitaxel: Results of a retrospective analysis.",
"title_normalized": "prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine nab paclitaxel results of a retrospective analysis"
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"abstract": "The impact of basal ganglia stroke on mental health is better described in adults than in children. We report 2 children with significant mental health issues after basal ganglia stroke.\nPatient 1, an 8-year-old boy, had mild anxiety before his left basal ganglia stroke. Post-stroke, he developed severe anxiety, obsessions, depression, and attention deficit hyperactivity disorder, in addition to a right hemiplegia and some mild chorea. He gradually improved over 3 years with psychiatric care and medication but continued to have residual symptoms. Patient 2, a 10-year-old boy, had no history of mental health issues before his right basal ganglia stroke. Post-stroke, he developed significant anxiety and mild depression, along with a left hemiplegia. He improved over 9 months and returned to his mental health baseline.\nMental health issues after basal ganglia stroke in children can be significant, and recovery can take months to years.",
"affiliations": "Division of Pediatric Neurology, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.;Division of Pediatric Neuroradiology, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.;Division of Pediatric Neurology, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.",
"authors": "Badar|Sidrah A|SA|;Radhakrishnan|Rupa|R|;Golomb|Meredith R|MR|https://orcid.org/0000-0002-9707-6735",
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"fulltext": "\n==== Front\nChild Neurol Open\nChild Neurol Open\nCNO\nspcno\nChild Neurology Open\n2329-048X SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2329048X20979248\n10.1177_2329048X20979248\nOriginal Article\nThe Impact of Pediatric Basal Ganglia Stroke on Mental Health in Children: Report of 2 Cases\nBadar Sidrah A. 1 Radhakrishnan Rupa MD2 https://orcid.org/0000-0002-9707-6735Golomb Meredith R. MD, MSc1 \n1 Division of Pediatric Neurology, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA\n\n2 Division of Pediatric Neuroradiology, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA\nMeredith Golomb, MD, MSc, Division of Child Neurology, 575 Riley Hospital Dr. RI 1340, Indianapolis, IN 46202, USA. Email: mgolomb@iupui.edu\n15 12 2020 \nJan-Dec 2020 \n7 2329048X2097924820 8 2020 05 10 2020 07 11 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background:\nThe impact of basal ganglia stroke on mental health is better described in adults than in children. We report 2 children with significant mental health issues after basal ganglia stroke.\n\nCase Reports:\nPatient 1, an 8-year-old boy, had mild anxiety before his left basal ganglia stroke. Post-stroke, he developed severe anxiety, obsessions, depression, and attention deficit hyperactivity disorder, in addition to a right hemiplegia and some mild chorea. He gradually improved over 3 years with psychiatric care and medication but continued to have residual symptoms. Patient 2, a 10-year-old boy, had no history of mental health issues before his right basal ganglia stroke. Post-stroke, he developed significant anxiety and mild depression, along with a left hemiplegia. He improved over 9 months and returned to his mental health baseline.\n\nConclusions:\nMental health issues after basal ganglia stroke in children can be significant, and recovery can take months to years.\n\nbasal gangliamental healthpediatric strokechildrenanxietydepressioncover-dateJanuary-December 2020typesetterts3\n==== Body\nIntroduction\nBasal ganglia stroke can affect mental health. This has been most studied in adults. Many adult stroke patients suffer from generalized anxiety, major depressive disorder, phobias, and/or obsessive-compulsive disorder following a stroke in which the basal ganglia was involved.1-9 However, there are few studies describing mood disorders after pediatric basal ganglia stroke, and little data on how mental health issues in children after stroke affect the whole family, or how long recovery takes. This report presents 2 children with mental health issues after basal ganglia stroke and reviews the literature on the effects of basal ganglia stroke on mental health in adults and children. Possible mechanisms leading to mental health issues after basal ganglia stroke are described.\n\nCase Reports\nCase I\nAn 8-year-old boy was referred to our hospital for subacute stroke. Three days prior, he fell and hit the right side of his head on a coffee table. He seemed fine immediately after, but the following 2 days, he had right facial weakness, difficulty concentrating, and was doing and saying things that did not make sense. His mother brought him to the pediatrician, who ordered magnetic resonance imaging (MRI) which revealed new large infarction of the left caudate and putamen. He was started on aspirin 81 mg daily and admitted to our hospital. On exam, he had significant executive function and concentration errors, while constructions were intact. He had some choreiform movements on the right with mild hyperreflexia distally in the right leg and positive right Babinski. Computed tomography angiogram was negative for dissection; repeat MRI (Figure 1) with MR angiography (MRA) and MR venography (MRV) demonstrated restricted diffusion within the left caudate, anterior lentiform nucleus, anterior limb of the internal capsule, and deep white matter of the frontal lobe consistent with acute infarct, but no evidence of dissection or venous thrombosis. His past medical history was remarkable only for mild anxiety and an itchy rash 1 month earlier that did not look like varicella. His family history was remakable for a pulmonary embolism in his mother following cardiac ablation for Wolff-Parkinson-White and a maternal grandfather with multiple strokes starting at age 56; there was no known family history of mental health issues. Echocardiogram and electrocardiogram were unremarkable. His prothrombotic workup was remarkable only for mild anemia with mean cell volume of 78 fL and hemoglobin of 11.8 GM/dL; heterozygosity for the PAI 14G gene variant, and homozygosity for the MTHFR 1298C gene variant, with normal homocysteine. His alertness and concentration improved during his 3-day hospitalization, and he was discharged home on aspirin, iron, and folate with outpatient rehabilitation.\n\nFigure 1. Legend MRI of Cases I and II. Figure 1a and 1b. are axial diffusion weighted images (DWI) at the level of the caudate body and the thalamus in patient 1 showing bright diffusion signal (diffusion restriction; corresponding dark signal on ADC map not shown) centered in the left anterior caudate body (solid arrow), head of the left caudate nucleus (arrowheads) and anterior aspect of the left putamen (dashed arrow). Adjacent portions of the anterior limb of the internal capsule, the globus pallidus and external capsule are also involved. Figure 1c. and 1d are axial diffusion weighted images (DWI) at the level of the caudate body and the thalamus in patient 2 showing bright diffusion signal (diffusion restriction; corresponding dark signal on ADC map not shown) centered in the right posterior caudate body (solid arrow) and posterior aspect of the putamen (dashed arrow).\n\nHowever, after discharge home, his family noted severe anxiety, depression, impulsivity, aggression, hyperactivity, trouble with concentration, mouthing objects, restlessness, and no remorse for his actions. He was fighting, biting, kicking, punching, and spitting at family members. He lost interest in toys and only wanted to watch television. He was unable to return to school and was started on homebound instruction. He was started on cyproheptadine for decreased appetite, guanfacine for poor attention, and as-needed hydroxyzine for anxiety by his pediatrician. He returned to the hospital a month and a half post discharge with chest pain, but was discharged the next day when no cardiac pathology was found. At his follow up stroke clinic exam 2 months post discharge, he was uncooperative, and his insight and judgment appeared poor. He was referred urgently to psychiatry clinic, where he was diagnosed with a personality change due to cerebrovascular accident and combined type attention-deficit/hyperactivity disorder, specifically disinhibited and aggressive features. The mother quit her job to stay home and care for him.\n\nOver the next year, multiple medications were tried and discontinued by the pediatrician and psychiatry clinic. Cyproheptadine was stopped because it did not help. The initial guanfacine did not help. Amphetamine sulfate caused headaches. He became suicidal on atomoxetine. His aggression worsened on extended-release guanfacine. Atomoxetine was retried at a lower dose, but he became aggressive on that, and security was called to psychiatry clinic. Risperidone helped behavior, particularly rage outbursts, but caused weight gain and was sedating, so the dose was readjusted multiple times. Low dose methylphenidate was added approximately 16 months post discharge, and that helped impulsivity and inattention. In addition to medication, he received individual counseling and family counseling. The family was noticing definite improvements by 1 ½ years post discharge; then, he developed worsening anxiety and depression and an eye-blinking tic. Counseling, which had been stopped when he improved, was restarted. He was switched from short-acting to extended-release methylphenidate. Clonidine was added to help the tic and anxiety. He was weaned off risperidone, then it was restarted, and fluoxetine was added when he became anxious in school. At his last follow up, 3 years post stroke, he was doing well on aspirin, clonidine, dexmethylphenidate, and fluoxetine and was feeling back to his old self. However, he still got anxious in large crowds, and his family reported he acted like a younger child in the mornings until he got his morning medications.\n\nThe behavior symptoms had a significant impact on the child’s family due to the disruption of the behavioral symptoms. His motor symptoms had resolved much faster than the psychiatric symptoms and were barely noticeable after a few months. The mother finally returned to work 3 ½ years after his stroke.\n\nCase II\nA 10-year-old boy presented to his local hospital with left-sided numbness, along with weakness of the left side of his face and left arm and leg. There was history of head trauma; about 2 months prior, he had hit his head on the bathroom sink, but did not lose consciousness. MRI demonstrated acute infarction in the right basal ganglia involving the caudate and lentiform nucleus and extending to the corona radiata, and MRA was normal. He had a left hemiparesis with distal flaccidity in the left upper and lower extremities, but some preserved shoulder abduction and hip flexion. His past medical history was unremarkable. His family history was negative for early stroke and clotting disorders, but positive for anxiety and depression in several family members. Transthoracic echo with bubble study, prothrombotic workup, and infectious workup were all unremarkable. He was treated with aspirin 162 mg daily and heparin, which was transitioned to enoxaparin for about 2 weeks. He was referred to our hospital for rehabilitation 3 weeks post stroke. Both psychiatry and neuropsychology were consulted during rehabilitation, but no major problems with depression or anxiety were noted, though he did have some mood swings. He made significant motor improvements in the early weeks post stroke. He was discharged on aspirin. He was referred to outpatient counseling.\n\nAt neurology clinic follow up 2 months post stroke, he was making some slow improvement and was in physical therapy. He had some persistent left sided weakness and a hemiplegic gait, was struggling with post-stroke fatigue, headaches, concentration, anxiety, and mood changes, describing feeling “down” for a while. He had not started counseling yet. He became visibly distraught and anxious when blood work was mentioned. He was put on a vitamin D supplement for a slightly low vitamin D level.\n\nAt the next stroke clinic follow up, 5 months post stroke, his fatigue had improved slightly, and his left motor strength had improved significantly, with minimal residual weakness. He continued to have mood issues. He admitted to feeling depressed and anxious. He had an episode of whole body shaking, thought to be due to a panic attack at the thought of more blood work at an upcoming visit to neurology. His trouble with concentration and coordination had improved, but he had continued to have issues with feeling depressed and anxious. He was put on an increased dose of melatonin to help him sleep and was encouraged to see a counselor.\n\nAt stroke follow up 9 months post stroke, his depression had resolved, and he had only mild residual anxiety. His fatigue had improved, and he had stayed in physical therapy. He still had mild weakness on his left side, but his neurologic examination was unremarkable otherwise. He remained on the aspirin, and his melatonin was decreased from 3 mg to 2 mg.\n\nHis family had struggled with the notable change in behavior post stroke, which was not immediately evident after discharge from rehabilitation. They had described him as a “happy go lucky kid” prior to his stroke. They were encouraged by the gradual improvement in mood without additional therapy or medication.\n\nDiscussion\nMany adult patients suffer from major depressive disorder, along with several other mood disorders, post-stroke.1 Damage to the basal ganglia in particular has been associated with many mood disorders. Murakami et al.4 found that out of 149 adult stroke patients, 83 patients (55.7%) had affective and/or apathetic post-stroke depression (PSD) that was related to lesions involving the basal ganglia, brain stem, and frontal cortex. More recent work has reported an association between basal ganglia infarctions and the development of obsessive-compulsive disorder (OCD).7-9 Akaho et al.9 conducted a literature review which demonstrated that out of 21 cases of OCD following stroke, the most frequent site of lesion was the basal ganglia, with 12 cases.\n\nLiterature describing the impact of basal ganglia stroke on pediatric mental health is far smaller; a PUBMED search identified 4 studies (Table 1). In a study of 44 children with stroke involving the basal ganglia (n = 32) or thalamus (n = 12), Westmacott et al.10 found that diagnoses of attention deficit hyperactivity disorder (ADHD) and anxiety disorder were more prevalent after basal ganglia stroke. Similarly, Max et al.11 determined that ADHD or traits of the disorder were more prevalent among children with putamen lesions (6 out of 7 children) than among those without (2 out of 6 children). Kwak and Jankovic12 described 2 children who exhibited ADHD and OCD after suffering from stroke involving the basal ganglia. Ledochowski et al.13 studied 75 children with stroke involving the basal ganglia and/or thalamus and reported that a higher degree of anxiety and depression was present in those with post-stroke dystonia versus those with no dystonia. Both of our patients struggled with anxiety, depression, and attention after basal ganglia stroke, which is consistent with these previously described cases of children with basal ganglia stroke. Neither had post-stroke dystonia, though the first patient did have mild chorea.\n\nTable 1. Previously Reported Cases of Mental Health Issues After Basal Ganglia Stroke in Children.\n\n\nAuthor\n\t\nYear\n\t\nNo. of Patients\n\t\nGender\n\t\nAge at Stroke\n\t\nLesion Laterality\n\t\nSeizure History\n\t\nMood Disorders\n\t\n\nMax et al.11,a\n\n\t2002\tPutamen: 6/7\nPatient 1\nPatient 2\nPatient 3\nPatient 4\nPatient 5\nPatient 6\t\n\nM\nF\nM\nF\nF\nM\t\n\n5 years\n4 years\nUnclear b\n\nPrenatal\nPrenatal\n8 years\t\n\nR\nR\nR\nL\nL\nR\t\n\nYes\nNo\nNo\nYes\nNo\nNo\t\n\nADHD/ADHD traits\nADHD/ADHD traits\nADHD/ADHD traits\nADHD/ADHD traits\nADHD/ADHD traits\nADHD/ADHD traits\t\n\nKwak & Jancovic12\n\t2002\t2\tM\t8 years\tR\tNo\tADHD\nOCD\t\n\nWestmacott et al.10,c\n\t2018\t16\tUnclear\tUnclear\tUnclear\tUnclear\t\nd\n\nADHD: 7\nDepression: 6\nAnxiety: 5\t\n\nLedochowski et al.13,e\n\t2020\tUnclear\tUnclear\tUnclear\tUnclear\tUnclear\t\nd\n\n\nDystonia:\n\nDepression\n\nMild-Moderate = 8\nSevere = 6\n\nAnxiety\n\nMild-Moderate = 7\nSevere = 7\n\nNo dystonia:\n\nDepression\n\nMild-Moderate = 7\n\nAnxiety\n\nMild-Moderate = 10\nSevere = 2\t\nAbbreviations: M, male; F, female; m, months; R, right; L, left.\n\n\na This study looked for the presence of ADHD/traits, no other mood disorders. Only 1 out of the 7 patients with putamen lesions did not exhibit ADHD/traits.\n\n\nb Age was listed as 3:05, but it is unclear if it means at 3 minutes or hours of life.\n\n\nc 32 patients who had childhood basal ganglia stroke were studied, and 16 were diagnosed with mood disorders. The genders, ages, lesion laterality, and seizure history were unspecified for those 16. Of the 32, M = 21 and F = 11; the age range was between 5 months and 13 years; R = 15, L = 13, bilateral = 3; and 1 patient had a seizure disorder.\n\n\nd Some patients may have had multiple diagnoses of mood disorders, but the overlap was unspecified.\n\n\ne 75 children were studied (dystonia n = 24, no dystonia n = 51). 21 showed concerns for depression, and 26 for anxiety. They were considered individually, and the overlap was unspecified, so it is unclear how many patients out of the 75 showed concern for at least 1. The genders, ages, lesion laterality, and seizure history were also unspecified for those patients. Of the 24 with dystonia, M = 10, F = 14; the mean age was 3.13 years; R = 13, L = 11; and 2 had seizure disorders. Of the 51 with no dystonia, M = 39, F = 12; the mean age was 3.72 years; R = 20, L = 31; and 7 had seizure disorders.\n\nAnimal models and functional imaging have helped clarify the motor functions of the basal ganglia, but the neurobiological mechanisms leading to mood disorders after basal ganglia stroke are less clear. The basal ganglia are a group of subcortical nuclei that are strongly interconnected with several brain areas, including, but not limited to, the cerebral cortex and the thalamus.10,14 Parallel frontal to subcortical neuronal circuits that connect specific regions of the frontal cortex to the striatum, globus pallidus and the thalamus are implicated in neuropsychiatric disorders.15 Although the main anatomical structures that are involved are similar, the anatomical positions of the circuits are segregated in the caudate, putamen, and other deep gray structures.15 Therefore, injury to different regions may be associated with potentially differential impact on motor function, mood and behavior.16 Specifically, decreased volume in the caudate nucleus has been associated with depression,17 and caudate nucleus stroke has been implicated in transient psychosis.18 Basal ganglia involvement in neuronal pathways connected with the prefrontal cortex may contribute to the pathogenesis of several disorders affecting mood regulation, such as depression, anxiety, OCD, and attention.10,13,14 Murakami et al.4 proposed that post-stroke apathetic depression might be associated with the intracranial dopamine pathway since it includes projections to the bilateral striatum. The cortico-striatal-thalamic-cortical circuit is heavily involved in the development of Tourette syndrome, and it has been reported that dysfunction in this pathway is linked to OCD.12 Popa et al.7 also observed that abnormal hyperactivity within the mesio-prefrontal-cingulo-striatal circuit was linked to OCD. Additionally, dysfunction of the prefrontal cortical-striatal-pallidal pathways is thought to be involved with ADHD.11 Further research is needed to clarify specific mechanisms within this complex system that contribute to mood disorders after basal ganglia stroke. It is not clear which mechanisms caused our first patient to have a far more severe mental health course than the second, though we speculate that stroke size and pre-existing anxiety may have both played a role.\n\nMental health issues can be significant after pediatric basal ganglia stroke, as our patients demonstrate. These issues can be exacerbated by the presence of barriers to psychiatric care. While both of our patients received psychiatric care, many patients are not so fortunate. In the United States, approximately only one third (36.2%) of adolescents with mental health disorders accessed mental health services.19 Through an intensive literature review regarding the barriers to psychiatric care as perceived by parents, Reardon et al.20 found those barriers to center around issues with the mental health system, stigma associated with mental health services and treatment, understanding the mental health problem and possible solutions, and familial circumstances. Many states, including Indiana, have suboptimal access to mental health care for adults and children.21 Mental Health America released its 2020 rankings of how the states performed in mental health care in several categories, and Indiana was among the lowest-ranked states in almost every single one—it was ranked 33rd in prevalence of mental illness, 19th in prevalence and care for youth, 26th in access to care, and was ranked 33rd overall.21\n\n\nThis study has limitations. This is a small series, with only 2 cases described, limiting the ability to draw generalizable conclusions. In the second case, it is possible that the anxiety was related to post-traumatic stress after his hospitalization, rather than the stroke itself; post-traumatic stress after hospitalization in children has been well-described.22-24 To fully understand the complete relationship between the basal ganglia and mood disorders in children, how these mood disorders impact the family, and the time to recovery, larger studies are necessary.\n\nAnxiety, depression, and difficulty with attention can follow pediatric basal ganglia stroke.10-13 We describe 2 children with basal ganglia strokes who had all of these issues; both families were impacted by these issues, and the first child took several years to have significant recovery, while the second recovered over months. Further research is still needed to clarify the neurobiological mechanisms leading to mood disorders after basal ganglia stroke in both children and adults.\n\nDeclaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We have no conflicts of interest to report, this study did not receive funding support. This study was approved by the Indiana University School of Medicine Institutional Review Board.\n\nORCID iD: Meredith R. Golomb, MD, MSc \nhttps://orcid.org/0000-0002-9707-6735\n==== Refs\nReferences\n1 \nRobinson RG \nMood disorders secondary to stroke\n. Semin Clin Neuropsychiatry . 1997 ;2 (4 ):244 –251\n.10320468 \n2 \nAnnoni J-M Staub F Bruggimann L Gramigna S Bogousslavsky J \nEmotional disturbances after stroke\n. Clin Exp Hypertens . 2006 ;28 (3-4 ):243 –249\n.16833030 \n3 \nHama S Yamashita H Shigenobu M , et al.\nPost-stroke affective or apathetic depression and lesion location: left frontal lobe and bilateral basal ganglia\n. Eur Arch Psychiatry Clin Neurosci . 2007 ;257 (3 ):149 –152\n.17131217 \n4 \nMurakami T Hama S Yamashita H , et al.\nNeuroanatomic pathways associated with poststroke affective and apathetic depression\n. Am J Geriatr Psychiatry . 2013 ;21 (9 ):840 –847\n.23567364 \n5 \nKadojic D Vladetic M Candrlic M Kadojic M Dikanovic M Trkanjec Z \nFrequency and characteristics of emotional disorders in patients after ischemic stroke\n. Eur J Psychiatry . 2005 ;19 (2 ):88 –95\n.\n6 \nSyed MJ Farooq S Siddiqui S Awan S Wasay M \nDepression and the use of selective serotonin reuptake inhibitors in patients with acute intracerebral hemorrhage\n. Cureus . 2019 ;11 (10 ):e5975 .31803557 \n7 \nPopa T Morris LS Hunt R , et al.\nModulation of resting connectivity between the mesial frontal cortex and basal ganglia\n. Front Neurol . 2019 ;10 :587 .31275221 \n8 \nRicketts EJ Wu MS Leman T Piacentini J \nA review of tics presenting subsequent to traumatic brain injury\n. Curr Dev Disord Rep . 2019 ;6 :145 –158\n.31984203 \n9 \nAkaho R Deguchi I Kigawa H Nishimura K \nObsessive-compulsive disorder following cerebrovascular accident: a case report and literature review\n. J Stroke Cerebrovasc Dis . 2019 ;28 (4 ):e17 –e21\n.30638936 \n10 \nWestmacott R McDonald KP Roberts SD , et al.\nPredictors of cognitive and academic outcome following childhood subcortical stroke\n. Dev Neuropsychol . 2018 ;43 (8 ):708 –728\n.30321060 \n11 \nMax JE Fox PT Lancaster JL , et al.\nPutamen lesions and the development of attention-deficit/hyperactivity symptomatology\n. J Am Acad Child Adolesc Psychiatry . 2002 ;41 (5 ):563 –571\n.12014789 \n12 \nKwak CH Jankovic J \nTourettism and dystonia after subcortical stroke\n. Movement Disorders . 2002 ;17 (4 ):821 –825\n.12210884 \n13 \nLedochowski J Desrocher M Williams T Dlamini N Westmacott R \nMental health outcomes in children with acquired dystonia after basal ganglia stroke and associations with cognitive and motor outcomes\n. Child Neuropsychol . 2020 ;26 (5 ):691 –710\n.31996083 \n14 \nLi CX Kempf DJ Tong FC , et al.\nLongitudinal MRI evaluation of ischemic stroke in the basal ganglia of a rhesus macaque (Macaca mulatta) with seizures\n. Comp Med . 2018 ;68 (6 ):496 –502\n.30486918 \n15 \nTekin S Cummings JL \nFrontal-subcortical neuronal circuits and clinical neuropsychiatry: an update\n. J Psychosom Res . 2002 ;53 (2 ):647 –654\n.12169339 \n16 \nMendez MF Adams NL Lewandowski KS \nNeurobehavioral changes associated with caudate lesions\n. Neurology . 1989 ;39 (3 ):349 –354\n.2927642 \n17 \nKrishnan KR McDonald WM Escalona PR , et al.\nMagnetic resonance imaging of the caudate nuclei in depression. preliminary observations\n. Arch Gen Psychiatry . 1992 ;49 (7 ):553 –557\n.1627046 \n18 \nCheng Y-C Liu H-C \nPsychotic symptoms associated with left caudate infarction\n. Int J Gerontol . 2015 ;9 (3 ):180 –182\n.\n19 \nMerikangas KR He J Burstein ME , et al.\nService utilization for lifetime mental disorders in U.S. adolescents: results of the national comorbidity survey adolescent supplement (NCS-A)\n. J Am Acad Child Adolesc Psychiatry . 2011 ;50 (1 ):32 –45\n.21156268 \n20 \nReardon T Harvey K Baranowska M O’Brien D Smith L Creswell C \nWhat do parents perceive are the barriers and facilitators to accessing psychological treatment for mental health problems in children and adolescents? A systematic review of qualitative and quantitative studies\n. Eur Child Adolesc Psychiatry . 2017 ;26 (6 ):623 –647\n.28054223 \n21 \nOverall Ranking. Mental Health America . 2020 \nAccessed November 28, 2020 \nhttps://www.mhanational.org/issues/ranking-states#overall-ranking\n\n22 \nDaviss WB Mooney D Racusin R Ford JD Fleischer A McHugo GJ \nPredicting posttraumatic stress after hospitalization for pediatric injury\n. J Am Acad Child Adolesc Psychiatry . 2000 ;39 (5 ):576 –583\n.10802975 \n23 \nCoyne I \nChildren’s experiences of hospitalization\n. J Child Health Care . 2006 ;10 (4 ):326 –336\n.17101624 \n24 \nTriantafyllou C Matziou V \nAggravating factors and assessment tools for posttraumatic stress disorder in children after hospitalization\n. Psychiatriki . 2019 ;30 (3 ):264 –270\n.31685457\n\n",
"fulltext_license": "CC BY-NC",
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"journal": "Child neurology open",
"keywords": "anxiety; basal ganglia; children; depression; mental health; pediatric stroke",
"medline_ta": "Child Neurol Open",
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"title": "The Impact of Pediatric Basal Ganglia Stroke on Mental Health in Children: Report of 2 Cases.",
"title_normalized": "the impact of pediatric basal ganglia stroke on mental health in children report of 2 cases"
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"abstract": "Biological agents targeting inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) have emerged in recent years as effective medications for a variety of inflammatory arthropathies. Although the relationship between the use of anti-TNF drugs and an increase in the rate of infections is well established, the role of these drugs in the development of different types of cancer is unclear. Randomized clinical trials and national registries have not demonstrated a significant increase in the risk of cancer in patients treated with anti-TNF drugs, but numerous cases of the appearance of malignant tumors in patients receiving these drugs have been reported. We describe the case of a 73-year-old man, ex-smoker, who developed a lung cancer during treatment with infliximab further complicated by perforation of a metastasis in the sigmoid colon, which is a very infrequent event in the course of this malignancy. A few similar cases previously reported in the literature are reviewed.",
"affiliations": null,
"authors": "Sifuentes Giraldo|W A|WA|;González García|A|A|;Chamorro Tojeiro|S|S|;Sánchez Sánchez|O|O|;Pian|H|H|;Vázquez Díaz|M|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
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"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000911:Antibodies, Monoclonal; D003110:Colonic Neoplasms; D006801:Humans; D000069285:Infliximab; D007410:Intestinal Diseases; D007416:Intestinal Perforation; D008175:Lung Neoplasms; D008297:Male; D013167:Spondylitis, Ankylosing; D014409:Tumor Necrosis Factor-alpha",
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"title": "Colonic perforation secondary to metastatic lung adenocarcinoma during anti-TNF treatment for ankylosing spondylitis.",
"title_normalized": "colonic perforation secondary to metastatic lung adenocarcinoma during anti tnf treatment for ankylosing spondylitis"
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"abstract": "Melanoma is a potentially aggressive disease, and patients with metastatic melanoma have a poor prognosis, with a median survival of only 6-9 months. There is no effective standard treatment for liver metastasis of malignant melanoma. Primary ovarian malignant melanoma is extremely rare and is usually associated with teratoma. We report a case of malignant melanoma arising in a mature ovarian cystic teratoma that had metastasized to the liver. Six courses of systemic chemotherapy were administered. However, as the liver metastases became enlarged, we performed transarterial chemoembolization(TACE). Following repeated TACE using drug-eluting microspheres for the liver metastasis, the patient survived 80 months from the initial diagnosis.",
"affiliations": "Gate Tower Institute for Image Guided Therapy.",
"authors": "Yuki|Takeo|T|;Hori|Shinich|S|;Yamashiro|Keita|K|;Ohira|Ryosuke|R|;Hori|Atsushi|A|",
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"mesh_terms": "D016461:Chemoembolization, Therapeutic; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008545:Melanoma; D010051:Ovarian Neoplasms; D013997:Time Factors; D016896:Treatment Outcome",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transarterial Chemoembolization for Liver Metastasis of Ovarian Malignant Melanoma Resulting in Long-Term Survival.",
"title_normalized": "transarterial chemoembolization for liver metastasis of ovarian malignant melanoma resulting in long term survival"
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"abstract": "Spontaneous intracranial hypotension (SIH) is an uncommon headache etiology, typically attributable to an unprovoked occult spinal CSF leak. Although frequently benign, serious complications may occur, including cerebral venous thrombosis (CVT). The objective of this study was to examine a highly complicated case of CVT attributable to SIH as a lens for understanding the heterogeneous literature on this rare complication, and to provide useful, evidence-based, preliminary clinical recommendations. A 43-year-old man presented with 1 week of headache, dizziness, and nausea, which precipitously evolved to hemiplegia. CT venography confirmed CVT, and therapeutic heparin was initiated. He suffered a generalized seizure due to left parietal hemorrhage, which subsequently expanded. He developed signs of mass effect and herniation, heparin was discontinued, and he was taken to the operating room for clot evacuation and external ventricular drain placement. Intraoperatively, the dura was deflated, suggesting underlying SIH. Ventral T-1 CSF leak was identified, which failed multiple epidural blood patches and required primary repair. The patient ultimately made a complete recovery. Systematic review identified 29 publications describing 36 cases of SIH-associated CVT. Among 31 patients for whom long-term neurological outcome was reported, 25 (81%) recovered completely. Underlying coagulopathy/risk factors were identified in 11 patients (31%). CVT is a rare and potentially lethal sequela occurring in 2% of SIH cases. Awareness of the condition is poor, risking morbid complications. Evaluation and treatment should be directed toward identification and treatment of occult CSF leaks. Encouragingly, good neurological outcomes can be achieved through vigilant multidisciplinary neurosurgical and neurocritical care.",
"affiliations": "Departments of1Neurologic Surgery.;Departments of1Neurologic Surgery.;2Radiology-Diagnostic.;3Division of Neurosurgery, Department of Surgery, Tenwek Hospital, Bomet, Kenya.;4Neurology, and.;Departments of1Neurologic Surgery.",
"authors": "Perry|Avital|A|;Graffeo|Christopher S|CS|;Brinjikji|Waleed|W|;Copeland|William R|WR|;Rabinstein|Alejandro A|AA|;Link|Michael J|MJ|",
"chemical_list": null,
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"issn_linking": "1547-5646",
"issue": "28(6)",
"journal": "Journal of neurosurgery. Spine",
"keywords": "CTJ = cervicothoracic junction; CVT = cerebral venous thrombosis; EBP = epidural blood patch; EVD = external ventricular drain; SDH = subdural hematoma; SIH = spontaneous intracranial hypotension; cerebral venous thrombosis; cerebrospinal fluid leak; epidural blood patch; neurocritical care; spontaneous intracranial hypotension",
"medline_ta": "J Neurosurg Spine",
"mesh_terms": "D000328:Adult; D003422:Critical Care; D003937:Diagnosis, Differential; D006801:Humans; D019585:Intracranial Hypotension; D008297:Male; D020246:Venous Thrombosis",
"nlm_unique_id": "101223545",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
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"title": "Spontaneous occult intracranial hypotension precipitating life-threatening cerebral venous thrombosis: case report.",
"title_normalized": "spontaneous occult intracranial hypotension precipitating life threatening cerebral venous thrombosis case report"
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"activesubstancename": "MANNITOL"
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"dr... |
{
"abstract": "Interactions between enzyme-inducing anti-seizure medications (EI-ASMs) and antiretroviral drugs (ARVs) can lead to decreased ARV levels and may increase the likelihood of viral resistance. We conducted a study to determine if co-usage of ARVs and EI-ASMs is associated with ARV-resistant human immunodeficiency virus (HIV) among people living with HIV in Zambia.\n\n\n\nEligible participants were ≥18 years of age and concurrently taking ASMs and ARVs for at least 1 month of the prior 6-month period. Data were obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVLs), and HIV genotype and resistance profile in participants with a pVL >1000 copies/mL were obtained. Pearson's test of independence was used to determine whether treatment with EI-ASM was associated with pVL >1000/mL copies.\n\n\n\nOf 50 participants, 41 (82%) were taking carbamazepine (37 on monotherapy), and all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a tenofovir/lamivudine backbone. The majority (94%) were on a stable ARV regimen for >6 months. Median CD4 nadir was 205 cells/mm3 (interquartile range [IQR] 88-389), and 60% of participants had commenced ARV treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm3 (SD 226.3). Seven participants (14%) had a CD4 count <200 cells/mm3 . Four (8%) had a pVL >1000 copies/mL; all were on carbamazepine. Three participants with elevated pVL had a CD4 count <200 cells/mm3 . None had documented adherence concerns by providers; however, two had events concerning for clinical failure. HIV genotype testing showed mutations in three participants. Carbamazepine was not found to correlate with elevated pVL (P = .58).\n\n\n\nEI-ASMs are commonly used in sub-Saharan Africa. Despite concurrent use of EI-ASMs and ARVs, the majority of participants showed CD4 counts >200 cells/mm3 and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV-resistant HIV.",
"affiliations": "Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Neurology, University of Rochester, Rochester, NY, USA.;Chikankata Epilepsy Care Team, Mazabuka, Zambia.;University Teaching Hospitals Children's Hospital, Lusaka, Zambia.;Global Neurology Program, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.;Greater Lawrence Family Health Center, Lawrence, MA, USA.;Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Departments of Neurology, Pediatrics, Neuroscience and Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.;National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.;Infectious Disease Service, Brooke Army Medical Center, Joint Base San Antonio-Ft Sam Houston, Houston, TX, USA.;Department of Biostatistics, Center for AIDS Research, University of Rochester, Rochester, NY, USA.;Center for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia.;Department of Neurology, University of Rochester, Rochester, NY, USA.;Department of Neurology, University of Rochester, Rochester, NY, USA.",
"authors": "Navis|Allison|A|0000-0002-4353-3849;Dallah|Ifunanya|I|;Mabeta|Charles|C|;Musukuma|Kalo|K|;Siddiqi|Omar K|OK|;Bositis|Christopher M|CM|;Koralnik|Igor J|IJ|;Gelbard|Harris A|HA|;Theodore|William H|WH|0000-0002-4669-5747;Okulicz|Jason F|JF|;Johnson|Brent A|BA|;Sikazwe|Izukanji|I|;Bearden|David R|DR|;Birbeck|Gretchen L|GL|",
"chemical_list": "D019380:Anti-HIV Agents; D000927:Anticonvulsants; D002220:Carbamazepine",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.16723",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "61(12)",
"journal": "Epilepsia",
"keywords": "HIV resistance; carbamazepine; enzyme-inducing anti-seizure medications; virological failure",
"medline_ta": "Epilepsia",
"mesh_terms": "D000328:Adult; D000554:Ambulatory Care Facilities; D019380:Anti-HIV Agents; D000927:Anticonvulsants; D018791:CD4 Lymphocyte Count; D002220:Carbamazepine; D004347:Drug Interactions; D024882:Drug Resistance, Viral; D004827:Epilepsy; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D016896:Treatment Outcome; D019562:Viral Load; D015024:Zambia",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "2705-2711",
"pmc": null,
"pmid": "33084053",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "26200721;19487182;19438397;20810822;28931491;17635568;25101529;17706551;12045487;22433846;21358975;31356613;21575228;28003499;25868090;17627506;31661487;17032686;22218281;25659108;20585262;19929796;15535422;16945074",
"title": "Evaluating the impact of antiretroviral and antiseizure medication interactions on treatment effectiveness among outpatient clinic attendees with HIV in Zambia.",
"title_normalized": "evaluating the impact of antiretroviral and antiseizure medication interactions on treatment effectiveness among outpatient clinic attendees with hiv in zambia"
} | [
{
"companynumb": "ZM-CIPLA LTD.-2020ZM08731",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZM",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Our aim was to retrospectively assess the role of golimumab as a treatment choice in patients with Behçet's disease (BD). Seventeen patients diagnosed with BD according to the international criteria were consecutively enrolled; the BD Current Activity Form (BDCAF) was used to evaluate disease activity. After having collected clinical data from patients, statistical analysis was performed to identify differences between the start of therapy and last visit; significance was defined as p < 0.05. The mean duration of golimumab treatment was 18.47 ± 20.8 months. At the time of data enrollment, 12/17 (70.6%) patients were still on golimumab therapy. The mean time required to obtained clinical response was 4.9 ± 5.7 weeks. At 3 months evaluation, golimumab was able to control BD-related manifestations in 16/17 (94.1%) cases; the BDCAF values were significantly decreased at the last follow-up compared to those assessed at the start of golimumab (p = 0.002). The BDCAF improvement was significantly higher among patients co-administered with DMARDs than those undergoing golimumab as monotherapy (p = 0.048). At the last follow-up visit, corticosteroids had been discontinued in 10 (58.8%) patients, while the corticosteroid dosage was significantly lower at the last follow-up visit compared to the start of therapy in those patients already on corticosteroids at the end of the study (p = 0.001). Golimumab is a promising and safe treatment opportunity in BD patients with different systemic involvement, inducing a prompt resolution of clinical manifestations, a meaningful improvement of BDCAF score, and a significant corticosteroid-sparing effect. However, golimumab co-administered with DMARDs has provided better results than in patients undergoing monotherapy.",
"affiliations": "Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.;Interdisciplinary Department of Medicine, Rheumatology Unit, University of Bari, Bari, Italy.;Department of Ophthalmology, Humanitas Clinical and Research Center, via Manzoni 56, 20089, Rozzano, Milan, Italy. claudia.fabiani@gmail.com.;Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.;Interdisciplinary Department of Medicine, Rheumatology Unit, University of Bari, Bari, Italy.;Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Interdisciplinary Department of Medicine, Rheumatology Unit, University of Bari, Bari, Italy.;Institute of Pediatrics, Fondazione Policlinico Universitario \"A. Gemelli\", Università Cattolica Sacro Cuore, Rome, Italy.;Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy. cantariniluca@hotmail.com.",
"authors": "Vitale|Antonio|A|;Emmi|Giacomo|G|;Lopalco|Giuseppe|G|;Fabiani|Claudia|C|;Gentileschi|Stefano|S|;Silvestri|Elena|E|;Gerardo|Di Scala|DS|;Iannone|Florenzo|F|;Frediani|Bruno|B|;Galeazzi|Mauro|M|;Lapadula|Giovanni|G|;Rigante|Donato|D|;Cantarini|Luca|L|http://orcid.org/0000-0002-7352-1275",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; C529000:golimumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-017-3627-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "36(9)",
"journal": "Clinical rheumatology",
"keywords": "Autoinflammatory disease; Behçet’s disease; Biologics; Disease activity; Golimumab; TNF-α",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001528:Behcet Syndrome; D018450:Disease Progression; D005260:Female; D006801:Humans; D007558:Italy; D007826:Laryngismus; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012720:Severity of Illness Index",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "2063-2069",
"pmc": null,
"pmid": "28401434",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": "1970380;18245110;27679471;15630733;26185360;26156661;27163156;17180637;26463246;27981463;21168186;25245624;23441863;26162757;27054359;21968237;27822185;27853889;19505410;24622940;24549921;27310969;24976689;23252659;24996907;27228652;24733249;17174468;26487500;24305945;24844789;27075942;24642905",
"title": "Long-term efficacy and safety of golimumab in the treatment of multirefractory Behçet's disease.",
"title_normalized": "long term efficacy and safety of golimumab in the treatment of multirefractory beh et s disease"
} | [
{
"companynumb": "IT-JNJFOC-20170503687",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": null,
... |
{
"abstract": "Jarisch-Herxheimer reaction (JHR) is an acute and self-limited condition, which commonly occurs after treatment for spirochetal infections. Probably, it corresponds to a transient immunological reaction to endotoxin-like products released from the microorganism during the therapy. For this reason, JHR may be associated with many other infectious diseases besides syphilis. Here, we report a case of a patient affected by extended cutaneous candidiasis diagnosed by culture examination; a JHR occurred after an accidental overdose of oral fluconazole.",
"affiliations": "Department of Dermatology, La Sapienza University, Rome, Italy.;Department of Dermatology, La Sapienza University, Rome, Italy.;Independent Contractor, Rome, Italy.;Department of Dermatology, La Sapienza University, Rome, Italy.",
"authors": "Muscianese|Marta|M|;Magri|Francesca|F|0000-0002-6365-7291;Pranteda|Giulia|G|;Pranteda|Guglielmo|G|0000-0001-7122-3218",
"chemical_list": "D000900:Anti-Bacterial Agents; D015725:Fluconazole",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.13244",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "33(2)",
"journal": "Dermatologic therapy",
"keywords": "Jarisch-Herxheimer reaction; candidiasis; fluconazole",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002177:Candidiasis; D015725:Fluconazole; D006801:Humans; D007249:Inflammation; D013587:Syphilis",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e13244",
"pmc": null,
"pmid": "32020750",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of Jarisch-Herxheimer reaction in candidiasis treated with systemic fluconazole.",
"title_normalized": "a case of jarisch herxheimer reaction in candidiasis treated with systemic fluconazole"
} | [
{
"companynumb": "IT-PFIZER INC-2020084029",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAcetaminophen administration for more than 4 days causes aminotransferase elevation in some subjects. The objective of this randomized, placebo-controlled trial is to describe the course of alanine aminotransferase (ALT) elevation in subjects administered 4 g/day of acetaminophen for at least 16 days.\n\n\nMETHODS\nA randomized, placebo controlled trial of acetaminophen (4 g/day) vs placebo. Subjects were healthy volunteers with normal liver enzymes. The primary outcome was the course of ALT during acetaminophen administration. All subjects were treated for a minimum of 16 days. Subjects with ALT elevation at day 16 were continued on treatment until these elevations resolved up to a maximum of 40 days. Subjects were also evaluated for elevation of INR or serum bilirubin as evidence of hepatic dysfunction.\n\n\nRESULTS\n157/205 (77%) completed acetaminophen subjects had no ALT elevation or transient elevations that resolved by day 16. Of the 48 subjects who had ALT elevations at study day 16, 47 continued on acetaminophen and had resolution by study day 40. One acetaminophen subject did not have resolution by study day 40, and the course of aminotransferase elevation suggests an alternative cause. One placebo subject had an ALT elevation at day 16 that resolved by day 22. The highest observed ALT among all acetaminophen subjects was 191 IU/L. The mean ALT at day 16 was 4.4 IU/L higher for the acetaminophen than for the placebo group. No subject developed liver dysfunction.\n\n\nCONCLUSIONS\nA minority of subjects treated with 4 g/day of acetaminophen for 16 days will have low-grade aminotransferase elevations that are not accompanied by liver dysfunction and resolve if administration is continued.\n\n\nBACKGROUND\nClintrials.gov NCT00743093 registered August 26, 2008.",
"affiliations": "Rocky Mountain Poison and Drug Center, Denver Health, Denver, CO, USA. Kennon.Heard@rmpdc.org.",
"authors": "Heard|Kennon|K|;Green|Jody L|JL|;Anderson|Victoria|V|;Bucher-Bartelson|Becki|B|;Dart|Richard C|RC|",
"chemical_list": "D010919:Placebos; D000082:Acetaminophen; D000410:Alanine Transaminase",
"country": "England",
"delete": false,
"doi": "10.1186/2050-6511-15-39",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central 2050-6511-15-392504709010.1186/2050-6511-15-39Research ArticleA randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration Heard Kennon 12Kennon.Heard@rmpdc.orgGreen Jody L 13Jody.Green@rmpdc.orgAnderson Victoria 1Victoria.Anderson@rmpdc.orgBucher-Bartelson Becki 14Becki.Bucher-Bartelson@rmpdc.orgDart Richard C 12Richard.Dart@rmpdc.org1 Rocky Mountain Poison and Drug Center, Denver Health, Denver, CO, USA2 University of Colorado Department of Emergency Medicine, Aurora, CO, USA3 Vanderbilt School of Nursing, Nashville, TN, USA4 Colorado School of Public Health, Aurora, CO, USA2014 22 7 2014 15 39 39 16 3 2014 8 7 2014 Copyright © 2014 Heard et al.; licensee BioMed Central Ltd.2014Heard 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/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAcetaminophen administration for more than 4 days causes aminotransferase elevation in some subjects. The objective of this randomized, placebo-controlled trial is to describe the course of alanine aminotransferase (ALT) elevation in subjects administered 4 g/day of acetaminophen for at least 16 days.\n\nMethods\nA randomized, placebo controlled trial of acetaminophen (4 g/day) vs placebo. Subjects were healthy volunteers with normal liver enzymes. The primary outcome was the course of ALT during acetaminophen administration. All subjects were treated for a minimum of 16 days. Subjects with ALT elevation at day 16 were continued on treatment until these elevations resolved up to a maximum of 40 days. Subjects were also evaluated for elevation of INR or serum bilirubin as evidence of hepatic dysfunction.\n\nResults\n157/205 (77%) completed acetaminophen subjects had no ALT elevation or transient elevations that resolved by day 16. Of the 48 subjects who had ALT elevations at study day 16, 47 continued on acetaminophen and had resolution by study day 40. One acetaminophen subject did not have resolution by study day 40, and the course of aminotransferase elevation suggests an alternative cause. One placebo subject had an ALT elevation at day 16 that resolved by day 22. The highest observed ALT among all acetaminophen subjects was 191 IU/L. The mean ALT at day 16 was 4.4 IU/L higher for the acetaminophen than for the placebo group. No subject developed liver dysfunction.\n\nConclusions\nA minority of subjects treated with 4 g/day of acetaminophen for 16 days will have low-grade aminotransferase elevations that are not accompanied by liver dysfunction and resolve if administration is continued.\n\nTrials registration\nClintrials.gov\nNCT00743093 registered August 26, 2008\n\nAlanine aminotransferaseDrug-induced liver injuryHepatotoxicity\n==== Body\nBackground\nAcetaminophen (paracetamol) is a commonly used analgesic and antipyretic that has an excellent safety profile when taken in doses of 4 g/day or less\n[1]. However, several studies have found that a significant percentage of subjects who ingest 2–4 g of acetaminophen per day for more than 4 consecutive days develop asymptomatic elevation of serum alanine aminotransferase (ALT) activity\n[2-6]. These studies generally stopped dosing before the ALT elevations resolved. Multiple clinical studies have not identified any cases of liver failure with long-term acetaminophen use\n[7-11]. In contrast to prospective studies that found no cases of liver failure, there are anecdotal reports of patients who develop liver failure while allegedly taking therapeutic doses\n[12]. Given the widespread use of acetaminophen, if asymptomatic elevations of aminotransferase activity with therapeutic doses can progress to liver failure, even rarely, there is a substantial risk to public health.\n\nThe course of these aminotransferase activity elevations when acetaminophen is administered longer than 4 consecutive days is not well characterized. Anecdotally, patients take acetaminophen for years (as single ingredient and in combination with opioids) without symptomatic liver injury. In a small, placebo controlled 4-week study measuring the effect of acetaminophen on warfarin-induced anticoagulation, Parra reported a dose-dependent elevation in mean serum aminotransferase activity in subjects at two weeks during treatment with 2 or 4 g/day of acetaminophen\n[5]. Unlike other studies, acetaminophen was continued despite the mild increases in aminotransferase activity. These elevations resolved by week 4 of treatment and no subject had evidence of liver dysfunction. However, this study only included 15 acetaminophen-treated subjects and serum aminotransferase activity was only measured at baseline, 2 and 4 weeks. While this study suggests that the aminotransferase elevations resolve if therapy is continued, the course is not fully characterized.\n\nThe objective of this study is to describe the changes in serum aminotransferase activity in healthy subjects taking 4 g/day of acetaminophen for a minimum of 16 days and continued until any observed ALT elevations resolve. Our secondary aims were to determine if subjects who had aminotransferase elevations developed liver dysfunction and finally to determine if subjects who develop these elevations share any obvious demographic or clinical characteristics.\n\nMethods\nTrial design\nThis was a randomized, placebo controlled trial. Subjects were randomized 4:1 acetaminophen to placebo. This randomization plan was intended to increase the power of the study to detect infrequent adverse events in the acetaminophen group. This study was registered with clinicaltrials.gov (NCT00743093) and approved by The Colorado Multiple Institutional Review Board.\n\nParticipants\nThis was an outpatient study; subjects were evaluated at one of two clinical research sites. Subjects were recruited from a research listserv, posters, classified advertisement website (Craigslist) postings and media advertising. All subjects provided informed consent.\n\nWe included male and female subjects who were age 18 years or older and who did not have any of the following exclusion criteria: History of acetaminophen ingestion on any of the four days preceding study enrollment or a measurable serum acetaminophen concentration at time of enrollment; laboratory testing suggesting active viral hepatitis A,B or C infection; any of the following tests greater than the upper limit of normal at screening: serum aminotransferase or total bilirubin, International Normalized Ratio (INR) or alkaline phosphatase activity; platelet count less than 125,000/mL; positive pregnancy test; history of cholelithiasis (without cholecystectomy); history of heavy ethanol use defined as consuming more than an average of 3 alcohol containing drinks daily or 3 or more alcohol containing drinks on any given day over the preceding 2 weeks prior to study enrollment\n[13]; new prescription medication started within the previous 30 days; taking isoniazid or warfarin; currently has anorexia nervosa or reports a fasting type diet; clinically intoxicated, psychiatrically impaired or unable to give informed consent for any reason; known hypersensitivity or allergy to acetaminophen.\n\nInterventions\nSubjects were administered acetaminophen 4 g/day or placebo. Subjects were instructed to take 2 × 500 mg tablets every 4 hours for 4 doses each day (the exact timing varied but subjects were asked to take the doses every 4 hours after the first dose each day). The subjects noted the time of ingestion for each dose in a study diary. They also recorded other medications and alcohol consumption. Compliance was verified by study diary and pill counts at each study visit.\n\nWe included a placebo group for two reasons. First we recognized that there is day-to-day variation in aminotransferase activity and we felt it was important to be able to account for this variation as we quantified the effect of acetaminophen. Second, we have planned secondary studies to identify potential characteristics and biomarkers that may suggest a mechanism for these elevations.\n\nThe following tests were performed at each visit: serum aminotransferase (alanine aminotransferase-ALT and aspartate aminotransferase-AST), total bilirubin (TBL) and International Normalized Ratio (INR). Additional testing at the screening visit (study day -7 to -1) included a complete blood count, hepatitis A and C antibodies, hepatitis B antigen, serum acetaminophen and serum pregnancy (females only). Serum acetaminophen concentrations were also measured at day 10 and 16 for safety purposes but were not reported to study personnel unless they were above the critical concentration for our laboratory (>40 mcg/mL or 264 micromol/L) to maintain blinding. Adverse events were recorded using a structured interview at each visit. Subjects were specifically asked if they had nausea, vomiting, abdominal pain or jaundice and asked if they had any other symptoms.Patients were evaluated (including laboratory testing as described above) on study days 0 (baseline), 4, 7, 10, 13 and 16. At day 16, subjects were assessed for resolution (as defined in the outcome section below). Subjects who did not meet resolution criteria by day 16 went into the extended dosing period. In the extended study period, subjects continued treatment as assigned and continued to be evaluated every 3 days until study day 40. If the subject did not have resolution by study day 40, the study drug administration was stopped and the subject was monitored every 3 days until day 49. If the subject did not have resolution by that point, they were referred to a hepatologist for further evaluation and monitoring (Figure \n1).\n\nFigure 1 Subject flow and study decision points.\n\nOutcomes\nAs ALT is considered a more specific biomarker for the liver than AST, the primary outcome of this study was resolution of ALT elevation. Resolution criteria were defined at day 16 as an ALT that was less than 47 IU/L (the upper limit of the reference range for our laboratory) and within 10 IU/L of the subject’s baseline value. Subjects who did not meet resolution criteria were continued on the study protocol.\n\nThe resolution criteria after day 16 were dependent on the day 16 ALT values.\n\nIf the subject had a day 16 ALT >47 IU/L, we required 2 consecutive ALT values less than or equal to 47 IU/L for resolution. If the day 16 ALT was <47 IU/L but >10 IU/L above baseline, resolution occurred when they had 2 consecutive non-increasing ALT measurements less than or equal to 47 IU/L (however they could have a final ALT more than 10 IU/L above their baseline, Figure \n1). Our secondary outcome was the proportion of subjects who developed liver dysfunction defined by elevation of the INR above 1.4 or serum bilirubin >2× baseline\n[14].\n\nAs the primary study objective was to document the course of ALT while taking 4 gram per day of acetaminophen, our a-priori analysis plan was to restrict outcome analysis to subjects who completed the full protocol (i.e. met resolution criteria or reached study day 40). For safety reasons, subjects who withdrew from the study were required to have at least one measurement of ALT off study drug.\n\nTo assure subject safety, subjects were withdrawn if they developed drug induced liver injury as defined by the United States Food and Drug Administration Drug-Induced Liver Injury Premarketing Clinical Evaluation Guidelines\n[14]: ALT or AST >8× the upper limit of normal (ULN); ALT or AST >5× ULN for more than 2 weeks, ALT or AST >3× ULN and (total bilirubin >2× ULN or INR >1.5); ALT or AST >3× ULN with the appearance of worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia.\n\nSample size\nAs our primary purpose was to describe the course of ALT changes there was no obvious endpoint to use for power calculations. Therefore, we elected to power our study to measure the proportion of patients who did not meet resolution criteria by study day 40. We selected 40 days as a small previous study had suggested that many patients resolve by day 28\n[5]. We determined that a sample size of 300 completed subjects (240 acetaminophen: 60 placebo) was appropriate for our endpoint. This assumes that no subjects in the acetaminophen group would have ALT elevations that did not resolve by day 40. Zero out of 240 subjects would result in an upper 95% confidence limit for probability that the true incidence of non-resolution would be less than 0.015 (less than 1.5% of subjects would not resolve by day 40). We assumed a 15% screen failure and a 15% dropout rate.\n\nRandomization\nSequence generation was performed using pre-numbered packages dispensed according to a computer generated randomization list. We used block randomization within the following strata: Hispanic females, Hispanic males, non-Hispanic females, and non-Hispanic males. A separate randomized list of assignments was created for each site based on these strata. We stratified by Hispanic ethnicity as a previous study has suggested that the response to acetaminophen differs between Hispanic and non-Hispanic subjects\n[6].\n\nAllocation concealment mechanism\nPlacebo and acetaminophen tablets were provided by McNeil Consumer Healthcare and were identical in appearance. Study medications were packaged into 1-week supplies by a researcher not involved in subject management or data collection.\n\nImplementation\nTablets were dispensed during a study visit as a 1-week supply and the doses for each day were provided in a labeled packet.\n\nBlinding\nParticipants, investigators and statisticians were all blinded to the treatment groups during the main treatment period (days 0–16). We did not assess the success of blinding. When a subject met the criteria to stop at day 16, the treatment group assignment was unblinded to allow recruitment of acetaminophen-treated subjects into a follow-up study. This occurred after completion of the final study visit (including adverse event recording). The physician assessing relatedness of adverse events and the statistician performing the analysis remained blinded to subject treatment group until the study database was locked.\n\nStatistical methods\nDemographic characteristics are presented as medians and interquartile ranges for continuous variables and proportions for categorical variables.\n\nFor our primary outcome analysis, we calculated a 95% confidence interval on the proportion of subjects in the active treatment arm with unresolved, persistent elevation of ALT. To determine if ALT elevations were accompanied by changes in liver function (secondary analysis), we calculated a 95% confidence interval on the proportion of subjects in the active treatment arm with elevations of bilirubin or INR.\n\nIn a pre-planned exploratory analysis, we analyzed potential associations between aminotransferase elevations and demographic and clinical characteristics. We used logistic regression (PROC LOGISTIC) to determine if any of the following characteristics were associated with our 3 secondary outcomes: age, sex, race/ethnicity (Caucasian, Black, Hispanic, other), baseline ALT, body mass index (BMI) and average daily alcohol consumption (number of 14 gm servings of ethanol per day averaged over the study duration). The 3 outcomes of interest (defined above) were having an ALT elevation more than 1.5 times baseline, having an ALT elevation more than 10 IU/L above baseline, or meeting extension criteria at study day 16.\n\nResults\nA total of 398 subjects were screened for the study, 122 were excluded at baseline, 276 were randomized and 252 completed the study. Of the 122 excluded patients, 109 (89.3%) did not meet eligibility criteria at screening and baseline and 13 withdrew participation prior to confirming full eligibility (5 withdrew consent, 5 did not return for baseline eligibility assessments, and 3 withdrew because they could not tolerate the venipuncture). The most common reasons for screen failure (subjects could fail more than 1 criteria) were elevated bilirubin (n = 47), elevated INR (n = 22), elevated ALT or AST (n = 28), elevated alkaline phosphatase (n = 4), positive viral hepatitis markers (n = 17), history of excessive alcohol consumption (n = 9), starting a new prescription in the preceding month (n = 4) and history of acetaminophen ingestion in the 3 days prior to enrollment (n = 3). The study was started on August 20, 2008 and stopped on August 16, 2011 at less than the planned number of subjects due to a higher than expected (31%) screen failure rate. Figure \n2 is a CONSORT diagram showing the disposition of study subjects. Placebo and acetaminophen-treated subjects had similar baseline characteristics (Table \n1).The median ALT in the acetaminophen group (Figure \n3 panels A-D) was unchanged from baseline at study day 4, but increased by 6 IU/L to 26 IU/L on study day 7. The highest median ALT was observed on study day 10 (26.5 IU/L) and the median ALT decreased to 23.5 IU/L by study day 16. Changes in AST followed a slightly more accelerated course of elevation with the median increasing from 21 IU/L at baseline to 27 IU/L on day 7 and decreasing back to 23 IU/L on day 16 (Figure \n4 panels A-D). While there was some day-to-day variation in subject measurements, the median ALT and AST in the placebo group was stable throughout the study period (Figures \n3 and\n4 panel E). The changes in ALT over time in the acetaminophen group were significant (p < 0.001 repeated measure ANOVA) and the day 16 ALT was higher for the acetaminophen than the placebo group (p < 0.001).\n\nFigure 2 Consort diagram for study subjects.\n\nTable 1 Baseline characeteristics of study patients\n\n \tPlacebo (n = 47)\tAcetaminophen (n = 205)\t\nAge (years)\t32 (19.0, 64.0)\t34 (18.0 to 74.0)\t\nMale\t12 (25.5%)\t57 (27.8%)\t\nRace\t \t \t\n White\t35 (74.5%)\t142 (69.3%)\t\n Hispanic\t4 (8.5%)\t33 (16.1%)\t\n Black\t4 (8.5%)\t13 (6.3%)\t\n Other/Mixed\t4 (8.5%)\t17 (8.3%)\t\nBody Mass Index\t23.8 (17.3, 48.8)\t25.8 (16.5, 53.5)\t\nSelf-reported ethanol use\t35 (74.5%)\t167 (81.5%)\t\nBaseline ALT\t17.0 (11.0, 47.0)\t19.0(9.0, 44.0)\t\nNote: median (range) were provided for Age, BMI and Baseline ALT.\n\nFigure 3 Course of ALT for subjects administered acetaminophen (Panels A-D) and placebo (Panel E). Acetaminophen subjects were split into 4 groups to allow better resolution of subject values.\n\nFigure 4 Course of AST for subjects administered acetaminophen (Panels A-D) and placebo (Panel E). Acetaminophen subjects were split into 4 groups to allow better resolution of subject values.\n\nOf the 205 acetaminophen subjects who completed the study, 157 (77%) did not have ALT elevations or had transient elevations that met resolution criteria by study day 16. Forty-eight completed subjects (23%) in the acetaminophen group and 1 subject (2%) in the placebo group had ALT elevation that met criteria at day 16 to enter the extended treatment phase. Of these 49 subjects, the majority (n = 31) entered the extended treatment phase because they had an ALT greater than10 IU/L above their baseline but less than or equal to the upper resolution criteria limit of 47 IU/L (including the one placebo subject) at study day 16. One subject had an ALT less than10 IU/L above their baseline but greater than 47 IU/L while 17 subjects had an ALT that was both greater than10 IU/L above their baseline and greater than 47 IU/L. Among the 49 subjects who entered the extended treatment period, 19 had a final ALT value at least 10 IU above the baseline ALT value.\n\nOverall, 204/205 (99.5%; 95% confidence interval 97.0 to 99.9%) acetaminophen subjects and 47/47 (100%, 95% confidence interval 91.0 to 100%) placebo subjects met criteria for resolution of ALT elevation by study day 40 or less while on continued study dosing regimen (acetaminophen or placebo). The median INR was 1.0 for the acetaminophen group at all time points through study day 36. The two subjects who had an INR measured at study day 40 had a median INR of 1.1. No patient in either group had liver dysfunction defined as elevation in INR above 1.4 or bilirubin greater than 2 times their baseline measurement. No subject had a serum acetaminophen concentration greater than 40 mcg/mL (264 micromol/L).The subject in the acetaminophen group who had an ALT elevation that did not resolve by day 40 was monitored for an additional three weeks after ending acetaminophen administration. After stopping study medication, her ALT continued to trend upward to a maximum of 105 IU/L on study Day 63 (Figure \n5) and her INR and bilirubin remained normal. She had no symptoms of liver injury. She was referred for evaluation by a hepatologist but did not follow-up.\n\nFigure 5 Course of ALT for the one subject who did not have resolution of ALT elevation by study day 40. Acetaminophen was stopped at study day 40 and ALT continued to elevate.\n\nAmong the completed subjects, 110 (54%) of acetaminophen subjects and 40 placebo subjects (85%) had a peak ALT less than 1.5 times their baseline while 95 acetaminophen subjects (46%) and 7 placebo subjects (15%) had an ALT greater than 1.5 times their baseline. Among the completed subjects, 115 (56%) acetaminophen subjects and 40 (85%) placebo subjects had a peak ALT < 10 U/L above baseline while 90 acetaminophen subjects (44%) and 7 placebo subjects (15%) had an ALT > 10 IU/L above their baseline. For each of these outcomes a logistic model was constructed to identify clinical or demographic characteristics associated with the outcome in the acetaminophen group. The independent factors in the model included demographics and baseline variables (age, sex ethnicity, baseline ALT, alcohol user, BMI) and study group. Age, sex, baseline ALT, alcohol use and BMI were not related to any outcome (Table \n2). Ethnicity was not associated with entering the extended dosing outcome group. African American subjects were at increased risk for having an ALT increase more than 10 IU/L and there was an overall trend that non-Caucasian subjects had higher rates of all outcomes.\n\nTable 2 Adjusted risk for secondary outcomes for subjects treated with 4 g/acetaminiophen/day\n\n \tExtended dosing\tALT increase > 10 IU/L\tALT increase >50% above baseline\t\nVariable\tOdds ratio\t95% Confidence interval\tOdds ratio\t95% Confidence interval\tOdds ratio\t95% Confidence interval\t\nFemale (vs Male)\t1.47\t0.64 to 3.73\t1.03\t0.53 to 2.03\t1.21\t0.61 to 2.39\t\nRace\t \t \t \t \t \t \t\n Caucasian\t1.0\tRef\t1.0\tRef\t1.0\tRef\t\n Black\t1.71\t0.47 to 6.26\t3.56\t1.02 to 12.45\t1.80\t0.54 to 5.99\t\n Hispanic\t1.86\t0.79 to 4.40\t1.45\t0.66 to 3.2\t1.67\t0.75 to 3.69\t\n Other\t1.85\t0.58 to 5.91\t1.40\t0.50 to 3.96\t1.81\t0.63 to 5.24\t\nAge (per yr)\t1.01\t0.98 to 1.04\t1.02\t0.99 to 1.04\t1.02\t1.00 to 1.05\t\nBaseline ALT (Per IU/L)\t1.03\t0.98 to 1.08\t1.01\t0.97 to 1.05\t0.96\t0.92 to1.00\t\nBMI\t0.98\t0.93 to 1.04\t0.98\t0.93 to 1.03\t0.99\t0.94 to 1.04\t\nNo ethanol use\t1.81\t0.81 to 4.1\t0.90\t0.42 to 1.92\t0.89\t0.42 to 1.88\t\nA total of 19 acetaminophen subjects and 5 placebo subjects were withdrawn from the study after receiving at least one dose of study medication. Reasons for withdrawal included non-compliance (5 acetaminophen, 2 placebo), adverse event other than stopping criteria (4 acetaminophen, 1 placebo), day 0 ALT > 47 IU/L (4 acetaminophen) and subject request (6 acetaminophen, 2 placebo). The reasons subjects gave for requesting to be removed from the trial were: inconvenience/too much time required to participate (4 acetaminophen); no transportation (1 acetaminophen, 1 placebo); moved out of state (1 acetaminophen); and no reason given (1 placebo). No subject who requested withdrawal had any symptoms of liver injury. At the time of withdrawal, the median (range) ALT for acetaminophen subjects was 19.5 IU/L (17.0, 26.0 IU/L) for those withdrawn for non-compliance, 19 IU/L (15.0 to 28.0 IU/L) for those withdrawn after adverse events and 40.0 IU/L (13 to 120 IU/L) for those requesting withdrawal. Two subjects requesting withdrawal had an ALT above the reference range. One subject had a peak ALT of 120 on study day 10 that had decreased to 67 IU/L on day 28 when the subject stopped taking acetaminophen and withdrew. A follow-up ALT off medication on study day 30 was 54 IU/L. A second subject had an ALT of 36 on study day 16, stopped taking study medication on study day 18 and had an ALT of 119 IU/L on study day 21. His ALT decreased to 46 IU/L on study day 24 while not taking acetaminophen. For the placebo subjects requesting withdrawal, the ALT values at withdrawal were both 15 IU/L, for those removed for non-compliance the ALTs at the time of withdrawal were 11 and 21 IU/L and the subject removed for an adverse event had an ALT of 15 IU/L at the time of withdrawal. All subjects withdrawn had decreasing ALT documented on follow-up testing.\n\nSelf-reported medication compliance, as measured by the diary was similar for both groups. The median (interquartile range) percent of days where subjects took all 4 doses was 100% (86.7 to 100%) for the acetaminophen group and 86.5% (81.1 to 100%) for the placebo group.\n\nAdverse events\nThe overall proportion of subjects reporting any adverse event was 62.3%; 65.6% of the acetaminophen subjects and 48.1% of the placebo subjects. The characteristics of the adverse events are listed in the online supplement (Additional file\n1: Table S3.pdf Adverse Events). The most commonly reported adverse events were gastrointestinal. The majority of adverse events were rated as unrelated or possibly related to study drug. Nausea was the most frequent adverse event rated as probably related or related to study drug. No serious adverse events were reported. The proportion of acetaminophen-treated subjects suffering adverse events was similar for those who had an ALT elevation >10 IU/L: nausea 15/90 (16.7%) in those with elevation and 19/115 (16.5%) in those without; vomiting 2/90 (2.2%) in those with elevation and 2/115 (1.7%) in those without and abdominal pain 6/90 (6.7%) in those with elevation and 6/115 (5.2%) in those without.\n\nDiscussion\nWe found that ingestion of 4 grams per day of acetaminophen for a minimum of 16 days caused no significant change in ALT in approximately half of subjects, and a transient elevation that resolved by day 16 in approximately a quarter of patients. The remaining quarter of patients had modest ALT elevations that resolved when administration was continued over the next 24 days in all but one subject. The maximum observed ALT was 191 IU/L. No patient experienced drug-induced liver injury as defined by a Food and Drug Administration guideline despite continued therapy with acetaminophen while their aminotransferase activity was elevated. The proportion of acetaminophen subjects experiencing gastrointestinal symptoms was similar for those with and without ALT elevations.\n\nOnly one patient’s ALT elevation failed to resolve during continued administration of acetaminophen. The subject had no changes in INR or bilirubin, suggesting there was no liver dysfunction. Furthermore, this subject’s aminotransferase elevation continued to increase for 3 weeks after acetaminophen was stopped. As with any single case observation, it is not possible to determine causality, even within a clinical trial. However, this pattern of slowly progressive ALT elevation weeks after exposure is not consistent with acetaminophen-induced liver injury\n[15] and data from other randomized trials suggests that ALT elevations suspected to be related to acetaminophen resolve once acetaminophen is stopped\n[2,4,6,8]. This pattern of ALT increase suggests an alternative cause of aminotransferase elevation such as infection\n[16] or a change in diet\n[17]. Unfortunately, the subject declined a comprehensive hepatology evaluation (as planned in the study protocol). This limited our ability to identify potential causes for her ALT elevation.\n\nAs noted in previous studies\n[3,6], we found no association between aminotransferase elevation (using either of two definitions) and age or gender. While a previous study suggested an increased risk of elevation for Hispanic subjects\n[6], our study found no difference between Hispanic and Caucasian subjects. We also found no association between ethanol use and aminotransferase elevation. While there have been no previous trials that directly compare the effect of acetaminophen between drinkers and non-drinkers, separate studies have reported the effect sizes in these two groups. A study of moderate ethanol users administered 4 g/day of acetaminophen for 10 days reported a median ALT elevation of 8 IU/L\n[3] while a similar study in non-drinkers (using a more frequent sampling pattern) reported a median ALT elevation of 15 IU/L\n[4]. The current study suggests that the aminotransferase elevations do not differ between drinkers and non-drinkers and suggests that the differences in the previous trials are due to different sampling methods.\n\nThe degree of aminotransferase elevation caused by repeated therapeutic doses of acetaminophen has varied greatly among prior studies. Studies of ambulatory subjects have consistently reported that the highest observed elevation is less than 3 times the upper limit of normal\n[3-5,18], while studies of subjects confined to a clinical research facility reported elevations more than 8 times the upper limit of normal\n[2,6]. While the exact reason for these differences is not clear, there is meta-analytic evidence that subjects on a clinical research unit may increase their aminotransferase activity independent of treatment\n[19]. This meta-analysis compared the change in ALT for the placebo groups in studies where subjects were admitted to a clinical research unit to the change in ALT for the placebo group in studies where subjects were ambulatory. They noted that almost 10% of placebo treated patients on a clinical research unit had an increase in ALT that was at least 50% of the reference range width, while no outpatient subjects had elevations of this degree. It is possible that the marked increases observed in the acetaminophen group within studies using a clinical research unit are due to a potentiation of the acetaminophen effect by confinement. The clinical implications of an interaction between hospitalization and suggested acetaminophen-induced ALT elevations warrant further investigation. In a small observational study of inpatients (surgical and medical patients), acetaminophen users had an increased risk of developing an elevation of ALT compared to non-acetaminophen users\n[20]. While the elevations observed in this study were minimal, it is possible that acetaminophen-induced ALT elevations could progress to clinical liver injury if potentiated by other factors such as CYP 2E1 induction, malnutrition or oxidative stress. However, analysis of prospective trials that treated adult or pediatric patients with the therapeutic doses for a variety of medical conditions found no cases of acute liver failure\n[1,21].\n\nAcetaminophen is frequently used in both combination and single ingredient products for prolonged periods. The rarity of alleged cases of hepatic injury from therapeutic doses is strong evidence that these doses are safe even though ALT elevations occur. Until recently, ALT elevations alone during pre-clinical studies were considered a signal that would often lead a company to stop seeking approval for candidate drugs. However, the recent guidelines emphasize the importance of changes in hepatic function (INR and bilirubin) in addition to elevations of aminotransferase activity\n[22]. These guidelines recognize that a large number of medications cause self-limited ALT elevations that are not a precursor to clinical liver injury and are not an indication to stop therapy.\n\nOther medications that cause self-limited aminotransferase elevations include amiodarone, tacrine, heparin, isoniazid and the statins\n[23-27]. While liver failure has rarely been linked to isoniazid and amiodarone, there are no cases definitively caused by tacrine or heparin and the cases linked to the statins have been questioned\n[28]. These observations have led some to postulate that these transient elevations of the serum transaminase reflect hepatic adaptation\n[22]. While the mechanism is not clear hepatic adaptation may also occur with repeated acetaminophen dosing.\n\nOur study population was limited to healthy volunteers, so it is possible that subjects with underlying liver disease or other medical conditions may have a different course of ALT activity during prolonged acetaminophen dosing. Our internal validity is limited by the loss of several subjects prior to completing the protocol. It is possible that these subjects would not have resolved prior to completing the study. This would lead us to underestimate the proportion of subjects who did not resolve. We were also limited by not reaching our planned sample size, and this decreased our overall study power. Our study is also limited by the use of two biomarkers (ALT and AST). It is possible that other biomarkers may produce different patterns of change.\n\nConclusions\nIt is now clear that therapeutic doses of acetaminophen when administered for consecutive days may cause mild to moderate ALT elevations. These aminotransferase elevations are relatively common, usually less than 10 IU/L, not accompanied by liver dysfunction and resolve even when acetaminophen therapy is continued.\n\nAbbreviations\nAST: Aspartate aminotransferase; ALT: Alanine aminotransferase; BMI: Body mass index; CI: Confidence interval; INR: International Normalized Ratiol; ULN: Upper limit of normal.\n\nCompeting interests\nThis work was funded by an investigator-initiated award from McNeil Consumer Healthcare to Denver Health. The funding sponsor had no role in the conduct or analysis of the research. The manuscript was reviewed by the funding sponsor for proprietary information prior to publication, but the authors had the final decisions on all content. All authors were employees of Denver Health at the time of this study. Denver Health has research, consulting and clinical contracts with McNeil Consumer Healthcare. All authors received only their salary for work on this project. Dr. Heard was supported in part by Award Number K08DA020573 from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.\n\nAuthors’ contributions\nKH, JLG, RCD designed the study, KH, VA and JLG performed the research, BBB analyzed the data, KH drafted the manuscript and all authors contributed substantially to the revisions. KH had full access to the data and assumes responsibility for 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/2050-6511/15/39/prepub\n\nSupplementary Material\nAdditional file 1: Table S3\nAdverse Events by class for all randomized subjects. Subjects were treated with acetaminophen (4 g/day) or placebo).\n\nClick here for file\n\n Acknowledgements\nThe authors would like to thank the research staff at the Rocky Mountain Poison Center for their work on this project.\n==== Refs\nDart RC Bailey E Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy 2007 27 1219 1230 17723075 \nHarrill AH Watkins PB Su S Ross PK Harbourt DE Stylianou IM Boorman GA Russo MW Sackler RS Harris SC Smith PC Tennant R Bogue M Paigen K Harris C Contractor T Wiltshire T Rusyn I Threadgill DW Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans Genome Res 2009 19 1507 1515 19416960 \nHeard K Green JL Bailey JE Bogdan GM Dart RC A randomized trial to determine the change in alanine aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol Aliment Pharmacol Ther 2007 26 283 290 17593074 \nHeard KJ Green JL Dart RC Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers Pharmacotherapy 2010 30 818 822 20653358 \nParra D Beckey NP Stevens GR The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy Pharmacotherapy 2007 27 675 683 17461702 \nWatkins PB Kaplowitz N Slattery JT Colonese CR Colucci SV Stewart PW Harris SC Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial JAMA 2006 296 87 93 16820551 \nBradley JD Brandt KD Katz BP Kalasinski LA Ryan SI Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee N Engl J Med 1991 325 87 91 2052056 \nKuffner EK Temple AR Cooper KM Baggish JS Parenti DL Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials Curr Med Res Opin 2006 22 2137 2148 17076974 \nPincus T Koch GG Sokka T Lefkowith J Wolfe F Jordan JM Luta G Callahan LF Wang X Schwartz T Abramson SB Caldwell JR Harrell RA Kremer JM Lautzenheiser RL Markenson JA Schnitzer TJ Weaver A Cummins P Wilson A Morant S Fort J A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee Arthritis Rheum 2001 44 1587 1598 11465710 \nTemple AR Benson GD Zinsenheim JR Schweinle JE Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6–12 months) safety of acetaminophen in adult patients with osteoarthritis Clin Ther 2006 28 222 235 16678643 \nAltman RD Zinsenheim JR Temple AR Schweinle JE Three-month efficacy and safety of acetaminophen extended-release for osteoarthritis pain of the hip or knee: a randomized, double-blind, placebo-controlled study Osteoarthritis Cartilage 2007 15 454 461 17142063 \nPrescott LF Therapeutic misadventure with paracetamol: fact or fiction? Am J Ther 2000 7 99 114 11319578 \nGronbaek M Becker U Johansen D Gottschau A Schnohr P Hein HO Jensen G Sorensen TI Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer Ann Intern Med 2000 133 411 419 10975958 \nGuidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf \nSinger AJ Carracio TR Mofenson HC The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction Ann Emerg Med 1995 26 49 53 7793720 \nMaheshwari A Ray S Thuluvath PJ Acute hepatitis C Lancet 2008 372 321 332 18657711 \nKechagias S Ernersson A Dahlqvist O Lundberg P Lindstrom T Nystrom FH Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects Gut 2008 57 649 654 18276725 \nSudano I Flammer AJ Periat D Enseleit F Hermann M Wolfrum M Hirt A Kaiser P Hurlimann D Neidhart M Gay S Holzmeister J Nussberger J Mocharla P Landmesser U Haile SR Corti R Vanhoutte PM Lüscher TF Noll G Ruschitzka F Acetaminophen increases blood pressure in patients with coronary artery disease Circulation 2010 122 1789 1796 20956208 \nNarjes H Nehmiz G Effect of hospitalisation on liver enzymes in healthy subjects Eur J Clin Pharmacol 2000 56 329 333 10954348 \nMitchell SJ Hilmer SN Murnion BP Matthews S Hepatotoxicity of therapeutic short-course paracetamol in hospital inpatients: impact of ageing and frailty J Clin Pharm Ther 2011 36 327 335 21545612 \nLavonas EJ Reynolds KM Dart RC Therapeutic acetaminophen is not associated with liver injury in children: a systematic review Pediatrics 2010 126 e1430 e1444 21098156 \nSenior JR Monitoring for hepatotoxicity: what is the predictive value of liver \"function\" tests? Clin Pharmacol Ther 2009 85 331 334 19129750 \nChalasani N Aljadhey H Kesterson J Murray MD Hall SD Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity Gastroenterology 2004 126 1287 1292 15131789 \nNolan CM Goldberg SV Buskin SE Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic JAMA 1999 281 1014 1018 10086436 \nPollak PT Shafer SL Use of population modeling to define rational monitoring of amiodarone hepatic effects Clin Pharmacol Ther 2004 75 342 351 15060512 \nWatkins PB Zimmerman HJ Knapp MJ Gracon SI Lewis KW Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease JAMA 1994 271 992 998 8139084 \nOlsson R Korsan-Bengtsen BM Korsan-Bengtsen K Lennartsson J Waldenstrom J Serum aminotransferases after low-dose heparin treatment. Short communication Acta Med Scand 1978 204 229 230 696422 \nTolman KG The liver and lovastatin Am J Cardiol 2002 89 1374 1380 12062731\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-6511",
"issue": "15()",
"journal": "BMC pharmacology & toxicology",
"keywords": null,
"medline_ta": "BMC Pharmacol Toxicol",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D000410:Alanine Transaminase; D005260:Female; D006801:Humans; D008297:Male; D010919:Placebos; D055815:Young Adult",
"nlm_unique_id": "101590449",
"other_id": null,
"pages": "39",
"pmc": null,
"pmid": "25047090",
"pubdate": "2014-07-22",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "8139084;10954348;17142063;11465710;19129750;18657711;21545612;17593074;10975958;2052056;20956208;18276725;17076974;7793720;17461702;16820551;17723075;20653358;19416960;15131789;11319578;696422;16678643;12062731;21098156;10086436;15060512",
"title": "A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration.",
"title_normalized": "a randomized placebo controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration"
} | [
{
"companynumb": "US-JNJFOC-20140717263",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "OBJECTIVE\nA case of supratherapeutic International Normalized Ratio (INR) values and hematomas subsequent to concomitant administration of warfarin and intravesical gemcitabine is reported.\n\n\nCONCLUSIONS\nA 90-year-old man with bladder cancer refractory to bacillius Calmette-Guérin was diagnosed with deep vein thrombosis (DVT) and started on warfarin one month before starting treatment with intravesical gemcitabine 2 g (one dose per week for six weeks). Before intravesical gemcitabine was started, the patient reached consecutive therapeutic INR values. During the first five cycles of intravesical gemcitabine, the patient began to experience critically elevated INRs, which resulted in hospitalization and led to the discovery of hematomas. At hospital discharge, the decision was made to discontinue warfarin permanently given the patient's history of critically elevated INRs. Instead, enoxaparin was initiated due to the patient's history of DVT and active malignancy. Enoxaparin was started at a therapeutic, renally adjusted dosage of 60 mg subcutaneously once daily after the patient's hematomas resolved and hemoglobin level stabilized. The patient was cleared for discharge to his home after 17 days of hospitalization. He was scheduled to follow up with both urology and hematology departments regarding any further treatment for bladder cancer. A week after discharge, the patient's family decided that he would not receive the last (sixth) cycle of intravesical gemcitabine. To our knowledge, this is the first reported case of an interaction between intravesical gemcitabine and warfarin.\n\n\nCONCLUSIONS\nA 90-year-old man on a stable dose of warfarin experienced an increase in INR values after receiving intravesical gemcitabine for the treatment of bladder cancer.",
"affiliations": "Veterans Affairs Western New York Healthcare System, Buffalo, NY. kari.kurtzhalts@va.gov.;Veterans Affairs Western New York Healthcare System, Buffalo, NY.;Buffalo General Medical Center, Buffalo, NY.;Veterans Affairs Western New York Healthcare System, Buffalo, NY.",
"authors": "Kurtzhalts|Kari|K|;Gee|Megan E|ME|;Feuz|Lindsey|L|;Krajewski|Kristin C|KC|",
"chemical_list": "D000925:Anticoagulants; D000964:Antimetabolites, Antineoplastic; D001500:BCG Vaccine; D017984:Enoxaparin; D003841:Deoxycytidine; D014859:Warfarin; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp150425",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "73(19)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000283:Administration, Intravesical; D000369:Aged, 80 and over; D000925:Anticoagulants; D000964:Antimetabolites, Antineoplastic; D001500:BCG Vaccine; D002295:Carcinoma, Transitional Cell; D003841:Deoxycytidine; D004347:Drug Interactions; D017984:Enoxaparin; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D001749:Urinary Bladder Neoplasms; D020246:Venous Thrombosis; D014859:Warfarin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1508-11",
"pmc": null,
"pmid": "27646812",
"pubdate": "2016-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Evidence of a clinically significant interaction between warfarin and intravesical gemcitabine.",
"title_normalized": "evidence of a clinically significant interaction between warfarin and intravesical gemcitabine"
} | [
{
"companynumb": "US-TEVA-709632USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded-access treatment (T-IND) program. A post hoc analysis of nontransplant-associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented.\n\n\n\nPatients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended).\n\n\n\nOf the 1,154 patients in the T-IND, 137 had nontransplant-associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan-Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan-Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment-related adverse events occurred in 26.8%.\n\n\n\nIn this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan-Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies.",
"affiliations": "Pediatric Bone Marrow Transplantation Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, USA.;Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.;Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.;Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Stem Cell/Bone Marrow Transplantation Program, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Center for Stem Cell Transplantation, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.;Cancer and Blood Disorders Program, Children's Minnesota, Minneapolis, Minnesota, USA.;Jazz Pharmaceuticals, Palo Alto, California, USA.;Jazz Pharmaceuticals, Palo Alto, California, USA.;Jazz Pharmaceuticals, Palo Alto, California, USA.;Stem Cell/Bone Marrow Transplantation Program, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Pediatric Oncology, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.",
"authors": "Kernan|Nancy A|NA|;Richardson|Paul G|PG|;Smith|Angela R|AR|;Triplett|Brandon M|BM|0000-0001-8220-9980;Antin|Joseph H|JH|;Lehmann|Leslie|L|;Messinger|Yoav|Y|0000-0001-7990-1802;Liang|Wei|W|;Hume|Robin|R|;Tappe|William|W|;Soiffer|Robert J|RJ|;Grupp|Stephan A|SA|",
"chemical_list": "D000970:Antineoplastic Agents; D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "65(10)",
"journal": "Pediatric blood & cancer",
"keywords": "HSCT; VOD/SOS; defibrotide; nontransplant-associated chemotherapy",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D005343:Fibrinolytic Agents; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011089:Polydeoxyribonucleotides; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27269",
"pmc": null,
"pmid": "29873895",
"pubdate": "2018-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "12738663;12933575;14998849;19672975;19766729;20124218;20167278;22364685;22766981;23228043;24102514;24276042;2438942;25068424;25755580;25798682;26825712;27183098;27397724;28687420;28754544;28759025;28842141;28859028;29051993;29767845;3321587;6957419;7756636;8420443;8940735",
"title": "Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following nontransplant-associated chemotherapy: Final results from a post hoc analysis of data from an expanded-access program.",
"title_normalized": "defibrotide for the treatment of hepatic veno occlusive disease sinusoidal obstruction syndrome following nontransplant associated chemotherapy final results from a post hoc analysis of data from an expanded access program"
} | [
{
"companynumb": "US-JNJFOC-20180915154",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Çakan M, Aktay-Ayaz N, Gemici H, Annayev A, Çıtak A, Akçay A, Öztürk G. Sustained hyperferritinemia in a child with macrophage activation syndrome secondary to systemic juvenile idiopathic arthritis - perforinopathy: case based review. Turk J Pediatr 2018; 60: 598-603. Systemic juvenile idiopathic arthritis is a subtype of juvenile idiopathic arthritis and characterized by arthritis and many systemic features like fever, rash, hepatosplenomegaly, lymphadenopathy and serositis. Macrophage activation syndrome is the most dreadful complication of systemic juvenile idiopathic arthritis and can cause mortality and morbidity if not recognized and treated early and aggressively. Hemophagocytic lymphohistiocytosis (HLH) is characterized by diminished or absent activities of natural killer cells and cytotoxic T lymphocytes leading to cytokine storm and uncontrolled activation of T cells and macrophages. Primary (familial) HLH is a group of autosomal recessive disorders caused by mutations in the perforin and other related genes and distinctive for onset during early infancy and high rate of mortality. Secondary HLH may be caused by infectious, oncologic and rheumatologic disorders. The term Perforinopathy is used to describe cases with classical familial HLH and also for cases with familial HLH gene mutations but not following a classical familial HLH course. Herein we report a case of chronic perforinopathy in which clinical symptoms started with systemic juvenile idiopathic arthritis and severe macrophage activation syndrome that needed plasma exchange and extracorporeal membrane oxygenation during acute period and ongoing interleukin-1 blockage for sustained hyperferritinemia.",
"affiliations": "Clinics of Pediatric Rheumatology, Kanuni Sultan Süleyman Research and Training Hospital.;Clinics of Pediatric Rheumatology, Kanuni Sultan Süleyman Research and Training Hospital.;Clinics of Pediatrics, Kanuni Sultan Süleyman Research and Training Hospital, Kanuni Sultan Süleyman Research and Training Hospital.;Department of Pediatrics, Acıbadem University Atakent Hospital, Istanbul, Turkey.;Department of Pediatrics, Acıbadem University Atakent Hospital, Istanbul, Turkey.;Department of Pediatric Hematology and Oncology, Acıbadem University Atakent Hospital, Istanbul, Turkey.;Department of Pediatric Hematology and Oncology, Acıbadem University Atakent Hospital, Istanbul, Turkey.",
"authors": "Çakan|Mustafa|M|;Aktay-Ayaz|Nuray|N|;Gemici|Hakan|H|;Annayev|Agageldi|A|;Çıtak|Agop|A|;Akçay|Arzu|A|;Öztürk|Gülyüz|G|",
"chemical_list": "D016207:Cytokines; D007166:Immunosuppressive Agents; D005293:Ferritins",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "60(5)",
"journal": "The Turkish journal of pediatrics",
"keywords": "hyperferritinemia; macrophage activation syndrome; perforin A91V; perforinopathy; systemic juvenile idiopathic arthritis",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D001171:Arthritis, Juvenile; D002648:Child; D016207:Cytokines; D015199:Extracorporeal Membrane Oxygenation; D005293:Ferritins; D006801:Humans; D007166:Immunosuppressive Agents; D051359:Lymphohistiocytosis, Hemophagocytic; D055501:Macrophage Activation Syndrome; D008297:Male; D010951:Plasma Exchange",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "598-603",
"pmc": null,
"pmid": "30968645",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sustained hyperferritinemia in a child with macrophage activation syndrome secondary to systemic juvenile idiopathic arthritis - perforinopathy: case based review.",
"title_normalized": "sustained hyperferritinemia in a child with macrophage activation syndrome secondary to systemic juvenile idiopathic arthritis perforinopathy case based review"
} | [
{
"companynumb": "PHHY2019TR091165",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Cannabis is increasingly used by persons at end of life to ameliorate symptoms such as pain, spasticity, anorexia, or anxiety. Cannabis hyperemesis is a distressing adverse effect of chronic use and may cause significant morbidity. Unfortunately, the clinical presentation of this syndrome may be subtle in a person with complex medical issues or disability. Providers must remain vigilant for possible variations in presentation in these populations. To assess literature on cannabis hyperemesis and present unique considerations for clinical assessment and treatment for patients at end of life. Initial literature scoping yielded limited evidence on the subject in the setting of chronic disease and disability. A case of cannabis hyperemesis in a person with advanced amyotrophic lateral sclerosis is presented to illustrate challenges in diagnosis and management in this setting. A narrative synthesis of current literature on assessment and management and special considerations for evaluation and treatment for patients under palliative care was performed. Several unique considerations for the diagnosis and management of cannabis hyperemesis in palliative care patients are highlighted in the case presented, including: (1) Symptoms may possibly be abolished through decrease rather than complete abstinence from cannabis, (2) Frequent hot baths may not be present in patients with physical impairments in activities of daily living, and (3) Management of primary symptoms (pain, spasticity, nausea, and anxiety) in the end-of-life care patient must be considered to maximize comfort. The presentation of cannabis hyperemesis may be atypical in palliative care patients due to disability. More work is needed to improve risk stratification for patients using cannabis for palliative care.",
"affiliations": "Department of Rehabilitation Medicine, University of Washington, Seattle, Washington.",
"authors": "Howard|Ileana|I|",
"chemical_list": "D064086:Medical Marijuana",
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2018.0531",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1557-7740",
"issue": "22(10)",
"journal": "Journal of palliative medicine",
"keywords": "amyotrophic lateral sclerosis; cannabis; medical marijuana; nausea; palliative care; vomiting",
"medline_ta": "J Palliat Med",
"mesh_terms": "D000328:Adult; D000690:Amyotrophic Lateral Sclerosis; D006801:Humans; D008297:Male; D064086:Medical Marijuana; D010166:Palliative Care; D013577:Syndrome; D014839:Vomiting",
"nlm_unique_id": "9808462",
"other_id": null,
"pages": "1227-1231",
"pmc": null,
"pmid": "31084461",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cannabis Hyperemesis Syndrome in Palliative Care: A Case Study and Narrative Review.",
"title_normalized": "cannabis hyperemesis syndrome in palliative care a case study and narrative review"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2020-09965",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TIZANIDINE"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nPost-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach.\n\n\nMETHODS\nA single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence.\n\n\nRESULTS\nThe median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16).\n\n\nCONCLUSIONS\nSingle-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.",
"affiliations": "Department of Pharmacy, Barnes-Jewish Hospital, Washington University School of Medicine, Saint Louis, Mo., USA.",
"authors": "Spinner|Michael L|ML|;Bowman|Lyndsey J|LJ|;Horwedel|Timothy A|TA|;Delos Santos|Rowena B|RB|;Klein|Christina L|CL|;Brennan|Daniel C|DC|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000371587",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-8095",
"issue": "41(1)",
"journal": "American journal of nephrology",
"keywords": null,
"medline_ta": "Am J Nephrol",
"mesh_terms": "D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D005260:Female; D005919:Glomerular Filtration Rate; D015433:Glomerulonephritis, Membranous; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007155:Immunologic Factors; D007239:Infections; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8109361",
"other_id": null,
"pages": "37-47",
"pmc": null,
"pmid": "25634230",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Single-dose rituximab for recurrent glomerulonephritis post-renal transplant.",
"title_normalized": "single dose rituximab for recurrent glomerulonephritis post renal transplant"
} | [
{
"companynumb": "US-ROCHE-1227422",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL.\n\n\n\nPRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up.\n\n\n\nBetween June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment.\n\n\n\nR-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation.\n\n\n\nThe Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.",
"affiliations": "Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: kshimada@med.nagoya-u.ac.jp.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.;Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.;Division of Hematology/Oncology, Internal Medicine, Kameda Medical Center, Kamogawa, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan.;Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan.;Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.;Department of Hematology, Oita Prefectural Hospital, Oita, Japan.;Department of Hematology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Hematology, Oami Municipal Hospital, Oamishirasato, Japan.;Department of Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.;Department of Clinical Oncology, Nagoya Memorial Hospital, Nagoya, Japan.;Department of Hematology, Toranomon Hospital Kajigaya, Kawasaki, Japan.;Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.;Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan.;Division of Hematology, Tochigi Cancer Center, Utsunomiya, Japan.;Department of Hematology, Daini Osaka Police Hospital, Osaka, Japan.;Department of Hematology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan.;Division of Hematology, Ichinomiya Municipal Hospital, Ichinomiya, Japan.;Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.;Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.;Department of Hematology and Immunology, Kanazawa Medical University, Uchinada, Japan.;International Medical Center, Saitama Medical University, Hidaka, Japan.;Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of HSCT Data Management and Biostatistics, Nagoya University School of Medicine, Nagoya, Japan.;Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.;Division of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan.",
"authors": "Shimada|Kazuyuki|K|;Yamaguchi|Motoko|M|;Atsuta|Yoshiko|Y|;Matsue|Kosei|K|;Sato|Keijiro|K|;Kusumoto|Shigeru|S|;Nagai|Hirokazu|H|;Takizawa|Jun|J|;Fukuhara|Noriko|N|;Nagafuji|Koji|K|;Miyazaki|Kana|K|;Ohtsuka|Eiichi|E|;Okamoto|Masataka|M|;Sugita|Yasumasa|Y|;Uchida|Toshiki|T|;Kayukawa|Satoshi|S|;Wake|Atsushi|A|;Ennishi|Daisuke|D|;Kondo|Yukio|Y|;Izumi|Tohru|T|;Kin|Yoshihiro|Y|;Tsukasaki|Kunihiro|K|;Hashimoto|Daigo|D|;Yuge|Masaaki|M|;Yanagisawa|Atsumi|A|;Kuwatsuka|Yachiyo|Y|;Shimada|Satoko|S|;Masaki|Yasufumi|Y|;Niitsu|Nozomi|N|;Kiyoi|Hitoshi|H|;Suzuki|Ritsuro|R|;Tokunaga|Takashi|T|;Nakamura|Shigeo|S|;Kinoshita|Tomohiro|T|",
"chemical_list": "D000970:Antineoplastic Agents; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(20)30059-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "21(4)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011241:Prednisone; D011446:Prospective Studies; D000069283:Rituximab; D019043:Vascular Neoplasms; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "593-602",
"pmc": null,
"pmid": "32171071",
"pubdate": "2020-04",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial.",
"title_normalized": "rituximab cyclophosphamide doxorubicin vincristine and prednisolone combined with high dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large b cell lymphoma primeur ivl a multicentre single arm phase 2 trial"
} | [
{
"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2020EDE000011",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
... |
{
"abstract": "Severe gastrointestinal tract involvement is a rare manifestation of Stevens-Johnson syndrome (SJS). The case is described of a 17 year old man who developed SJS secondary to phenytoin. In addition to the cutaneous, ocular, and oral mucosal lesions typical of SJS, he also developed persistent, bloody diarrhoea associated with life threatening malnutrition. Serial colonoscopy showed severe and progressive colitis. He was treated with a combination of long term nutritional support, probiotic therapy, and supportive measures. He was eventually discharged from hospital six months after admission when the diarrhoea improved and he began to gain weight.",
"affiliations": "Department of Gastroenterology, Queen Elizabeth Hospital, London, UK. nick.powell@nhs.net",
"authors": "Powell|N|N|;Munro|J M|JM|;Rowbotham|D|D|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "England",
"delete": false,
"doi": "10.1136/pgmj.2005.042952",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-5473",
"issue": "82(968)",
"journal": "Postgraduate medical journal",
"keywords": null,
"medline_ta": "Postgrad Med J",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D003092:Colitis; D003967:Diarrhea; D004830:Epilepsy, Tonic-Clonic; D006801:Humans; D008297:Male; D044342:Malnutrition; D010672:Phenytoin; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "0234135",
"other_id": null,
"pages": "e10",
"pmc": null,
"pmid": "16754699",
"pubdate": "2006-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10791111;11437052;11713940;11964703;12164739;14654625;15790356;3873374;3721130;8168998;9721172;9774279;15647189;159145",
"title": "Colonic involvement in Stevens-Johnson syndrome.",
"title_normalized": "colonic involvement in stevens johnson syndrome"
} | [
{
"companynumb": "GB-VISTAPHARM, INC.-VER202010-001859",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": "1... |
{
"abstract": "We describe the use of ustekinumab for 4 patients with pediatric Crohn disease treated at the Seattle Children's Hospital Inflammatory Bowel Disease Center.\n\n\n\nA retrospective chart review was done to identify patients' clinical data, disease phenotype, treatment history, and laboratory and growth parameters before treatment with ustekinumab and at last follow-up. Adverse events while on ustekinumab were also recorded.\n\n\n\nFour adolescent patients with Crohn disease at our center received ustekinumab. All had previously received corticosteroids, methotrexate, azathioprine/6-mercaptopurine, and both infliximab and adalimumab. Patients had varying disease phenotypes. Ages at ustekinumab initiation were 12, 13, 16, and 17 years. Weight ranged from 40.5 to 57.8 kg, mean 49.5 kg. Two patients showed clinical response and remain on ustekinumab. Two patients discontinued therapy because of continued symptoms and disease complications and required multiple hospitalizations.\n\n\n\nUstekinumab was used in 4 children with pediatric Crohn disease with 2 of 4 patients showing clinical response (1 with persistently elevated C-reactive protein). A prospective study is needed to define its efficacy, safety, and placement in managing pediatric Crohn disease in the future.",
"affiliations": "*University of Rochester, Rochester, NY †University of Iowa, Iowa City ‡Inflammatory Bowel Disease Center, Seattle Children's Hospital, Seattle, WA.",
"authors": "Bishop|Casey|C|;Simon|Hayley|H|;Suskind|David|D|;Lee|Dale|D|;Wahbeh|Ghassan|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D002097:C-Reactive Protein; D000069549:Ustekinumab",
"country": "United States",
"delete": false,
"doi": "10.1097/MPG.0000000000001146",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-2116",
"issue": "63(3)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D000293:Adolescent; D000911:Antibodies, Monoclonal; D002097:C-Reactive Protein; D002648:Child; D003424:Crohn Disease; D006801:Humans; D010641:Phenotype; D012189:Retrospective Studies; D012720:Severity of Illness Index; D000069549:Ustekinumab",
"nlm_unique_id": "8211545",
"other_id": null,
"pages": "348-51",
"pmc": null,
"pmid": "26854655",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ustekinumab in Pediatric Crohn Disease Patients.",
"title_normalized": "ustekinumab in pediatric crohn disease patients"
} | [
{
"companynumb": "US-JNJFOC-20160903291",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": null,
... |
{
"abstract": "A young male presented in refractory shock from amlodipine poisoning despite vasopressors, insulin-normoglycemia therapy, calcium gluconate and glucagon. He needed venoarterial ECMO for hemodynamic support and TPE to remove protein-bound amlodipine. The use of extracorporeal membrane oxygenation (ECMO) for cardiotoxic poisoning and Total Plasma Exchange (TPE) in removing drugs has been described in the literature. We report a rare case where both lifesaving extracorporeal therapies were used in a patient with a severe drug overdose. Stabilizing hemodynamics with ECMO combined with TPE for drug removal is a feasible strategy in unstable patients with amlodipine overdose.",
"affiliations": "Department of Cardiothoracic and Vascular Surgery, National University Heart Centre, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore, Singapore. ram_ramanathan@nuhs.edu.sg.;Department of Cardiothoracic and Vascular Surgery, National University Heart Centre, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore, Singapore.;Department of Pharmacy, National University Hospital, Singapore, Singapore.;Department of Cardiothoracic and Vascular Surgery, National University Heart Centre, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore, Singapore.",
"authors": "Ramanathan|Kollengode|K|http://orcid.org/0000-0003-1822-9455;Mohanty|Bishwabikash|B|;Tang|Simeon|S|;MacLaren|Graeme|G|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10047-019-01132-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1434-7229",
"issue": "23(2)",
"journal": "Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs",
"keywords": "Amlodipine; Extracorporeal mebrane oxygenation; Poisoning",
"medline_ta": "J Artif Organs",
"mesh_terms": "D000328:Adult; D017311:Amlodipine; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D015199:Extracorporeal Membrane Oxygenation; D006439:Hemodynamics; D006801:Humans; D008297:Male; D010951:Plasma Exchange; D012121:Respiration, Artificial; D016896:Treatment Outcome",
"nlm_unique_id": "9815648",
"other_id": null,
"pages": "183-186",
"pmc": null,
"pmid": "31552515",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extracorporeal therapy for amlodipine poisoning.",
"title_normalized": "extracorporeal therapy for amlodipine poisoning"
} | [
{
"companynumb": "SG-STRIDES ARCOLAB LIMITED-2019SP009846",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nParalepistopsis acromelalga, formerly known as Clitocybe acromelalga, is a rare poisonous mushroom. The mycotoxins in this mushroom cause symptoms resembling those of erythromelalgia; however, its pathogenesis remains unclear. In this report, a patient who received nicotinic acid treatment for P. acromelalga poisoning and radiological evaluation for erythromelalgia has been presented. Case detail: A 59-year-old woman was hospitalized for redness, swelling, and burning pain in her extremities that rendered difficulty in walking, and a diagnosis of P. acromelalga poisoning was made by detailed interview and mushroom identification. She was treated with intravenous nicotinic acid for 17 days followed by oral nicotinic acid amide for 2 months. She exhibited rapid symptomatic improvement and walked independently after 11 days of initial treatment. Initial MRI of her feet revealed toe-dominated subcutaneous thickening. After nicotinic acid treatment, those radiological findings improved dramatically.\n\n\nCONCLUSIONS\nThe subcutaneous thickening evident on MRI indicated P. acromelalga poisoning-induced erythromelalgia involved subcutaneous inflammatory edema. The typical duration of edema without treatment is more than a month. The improvement on MRI after nicotinic acid treatment indicated that the adequate vasodilation induced by nicotinic acid contributed to resolution of the symptoms. Nicotinic acid was associated with the improvement of the edematous changes caused by the P. acromelalga intoxication.",
"affiliations": "a Department of Neurology , Kitamurayama Hospital , Yamagata , Japan ;;b Department of Neurology and Stroke Medicine , Tokyo Metropolitan Tama Medical Center , Tokyo , Japan.",
"authors": "Nakajima|Nobuhito|N|;Ueda|Masayuki|M|",
"chemical_list": "D009183:Mycotoxins; D009525:Niacin",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2016.1188205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "54(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Erythromelalgia; magnetic resonance imaging; mushroom poisoning",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D061605:Administration, Intravenous; D000363:Agaricales; D004305:Dose-Response Relationship, Drug; D004916:Erythromelalgia; D005260:Female; D006760:Hospitalization; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009145:Mushroom Poisoning; D009183:Mycotoxins; D009525:Niacin",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "597-600",
"pmc": null,
"pmid": "27219910",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nicotinic acid treatment for Paralepistopsis acromelalga intoxication: assessment using magnetic resonance imaging.",
"title_normalized": "nicotinic acid treatment for paralepistopsis acromelalga intoxication assessment using magnetic resonance imaging"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2016-04238",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NIACIN"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nWe describe a case of alemtuzumab (Campath®) hypersensitivity requiring desensitization within the medical intensive care unit (MICU) in a patient with T-cell prolymphocytic leukemia.\n\n\nMETHODS\nWe adopted a desensitization protocol from Gutierrez-Fernandez et al., which included three aliquots (0.15 mg intravenously (IV), 1.5 mg IV, and 28.5 mg IV) given approximately 1 h apart on day 1 followed by a full 30 mg dose IV on day 3. Unlike prior attempts to administer alemtuzumab to this patient, she tolerated the medication well and did not require any rescue medications.\nSuccessful plan development required a significant amount of strategic communication between hematology/oncology and MICU-related physicians, pharmacists, and nurses to ensure a safe and effective desensitization. The first step of planning required creation of a desensitization order set with directions for medication preparation and administration, premedications, and available medications in the event of an adverse reaction or anaphylaxis. Anaphylactoid-related medications were prepared at bedside and ready for administration prior to beginning the desensitization. Alemtuzumab was compounded in a chemotherapy-certified hood and verified by at least two chemotherapy-certified pharmacists. Foreword planning was also necessary to ensure multiple people were available or present at bedside for the desensitization, including a chemotherapy-certified nurse, a second chemotherapy-certified nurse for verification, a critical care-certified pharmacist, a pulmonary/critical care attending physician, and hematology attending physician.\n\n\nCONCLUSIONS\nThis case exemplifies the importance of clear and coordinated communication between different healthcare fields to safely and effectively complete extensive protocols such as desensitization strategies.",
"affiliations": "Department of Pharmacy Practice, University of Kentucky Medical Center, Lexington, KY, USA.;Department of Pharmacy Practice, University of Kentucky Medical Center, Lexington, KY, USA.;Department of Pulmonary Critical Care and Sleep Medicine, University of Kentucky Medical Center, Lexington, KY, USA.;Department of Hematology and Bone & Marrow Transplantation, University of Kentucky Medical Center, Lexington, KY, USA.;Department of Pharmacy Practice, University of Kentucky Medical Center, Lexington, KY, USA.",
"authors": "McKenzie|Matt G|MG|https://orcid.org/0000-0003-1945-9471;Bissell|Brittany D|BD|;Disselkamp|Margaret A|MA|;Hildebrandt|Gerhard C|GC|;Cox|Jessica N|JN|",
"chemical_list": "D000074323:Alemtuzumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219865313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Desensitization; alemtuzumab; hypersensitivity; intensive care unit; prolymphocytic leukemia",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000074323:Alemtuzumab; D000707:Anaphylaxis; D003142:Communication; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008875:Middle Aged; D010595:Pharmacists; D010820:Physicians",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "742-746",
"pmc": null,
"pmid": "31390960",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sensitizing the interdisciplinary team to desensitizations: An alemtuzumab case report.",
"title_normalized": "sensitizing the interdisciplinary team to desensitizations an alemtuzumab case report"
} | [
{
"companynumb": "US-TEVA-2020-US-1833043",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
... |
{
"abstract": "We describe seven women who developed acute polyarthritis after prolonged treatment with minocycline for acne. Arthritis persisted until minocycline was withdrawn, then recovered rapidly. A mild elevation of alanine or aspartate transaminase was noted in 4 patients, while pulmonary infiltrates were found in 2 patients. Antinuclear antibodies (ANA) were persistently present throughout treatment in 4 patients, but were only present on one occasion in 2 women and were absent in one. This syndrome has been described as \"drug-induced lupus\" although, as described with other drugs, many patients do not fulfil the diagnostic criteria for lupus. The proposed criteria for the diagnosis of \"drug-induced lupus\", which require only one clinical feature of SLE, also require a positive ANA test and therefore might exclude these patients. This could result in failure to recognise minocycline as the cause of the arthritis, and hence lead to prolonged illness and unnecessary investigations and treatment.",
"affiliations": "Lupus Research Unit, Rayne Institute, St Thomas' Hospital, UK.",
"authors": "Knights|S E|SE|;Leandro|M J|MJ|;Khamashta|M A|MA|;Hughes|G R|GR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000974:Antibodies, Antinuclear; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008911:Minocycline",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "16(5)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000152:Acne Vulgaris; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase; D000900:Anti-Bacterial Agents; D000974:Antibodies, Antinuclear; D001168:Arthritis; D001219:Aspartate Aminotransferases; D005260:Female; D006801:Humans; D008875:Middle Aged; D008911:Minocycline",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "587-90",
"pmc": null,
"pmid": "9779309",
"pubdate": "1998",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Minocycline-induced arthritis.",
"title_normalized": "minocycline induced arthritis"
} | [
{
"companynumb": "GB-BAUSCH-BL-2019-013307",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nBecause of the limitations of randomized controlled trials (RCTs) and observational studies, a prospective, randomized, open-label, blinded endpoint (PROBE) study may be an appropriate alternative, as the design allows the assessment of clinical outcomes in clinical practice settings. The Gastrointestinal (GI) Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug (NSAID) Study (GI-REASONS) was designed to reflect standard clinical practice while including endpoints rigorously evaluated by a blinded adjudication committee. The objective of this study was to assess if celecoxib is associated with a lower incidence of clinically significant upper and/or lower GI events than nonselective NSAIDs (nsNSAIDs) in standard clinical practice.\n\n\nMETHODS\nThis was a PROBE study carried out at 783 centers in the United States, where a total of 8,067 individuals aged ≥ 55 years, requiring daily NSAIDs to treat osteoarthritis, participated. The participants were randomized to celecoxib or nsNSAIDs (1:1) for 6 months and stratified by Helicobacter pylori status. Treatment doses could be adjusted as per the United States prescribing information; patients randomized to nsNSAIDs could switch between nsNSAIDs; crossover between treatment arms was not allowed, and patients requiring aspirin at baseline were excluded. The primary outcome was the incidence of clinically significant upper and/or lower GI events.\n\n\nRESULTS\nSignificantly more nsNSAID users met the primary endpoint (2.4% (98/4,032) nsNSAID patients and 1.3% (54/4,035) celecoxib patients; odds ratio, 1.82 (95% confidence interval, 1.31-2.55); P = 0.0003). Moderate to severe abdominal symptoms were experienced by 94 (2.3%) celecoxib and 138 (3.4%) nsNSAID patients (P=0.0035). Other non-GI adverse events were similar between treatment groups. One limitation is the open-label design, which presents the possibility of interpretive bias.\n\n\nCONCLUSIONS\nCelecoxib was associated with a lower risk of clinically significant upper and/or lower GI events than nsNSAIDs. Furthermore, this trial represents a successful execution of a PROBE study, where therapeutic options and management strategies available in clinical practice were incorporated into the rigor of a prospective RCT.",
"affiliations": "University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. Byron.Cryer@UTSouthwestern.edu",
"authors": "Cryer|Byron|B|;Li|Chunming|C|;Simon|Lee S|LS|;Singh|Gurkirpal|G|;Stillman|Martin J|MJ|;Berger|Manuela F|MF|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib",
"country": "United States",
"delete": false,
"doi": "10.1038/ajg.2012.467",
"fulltext": "\n==== Front\nAm J GastroenterolAm. J. GastroenterolThe American Journal of Gastroenterology0002-92701572-0241Nature Publishing Group ajg201246710.1038/ajg.2012.467StomachGI-REASONS: A Novel 6-Month, Prospective, Randomized, Open-Label, Blinded Endpoint (PROBE) Trial GI REASONS: A PROBE TrialCryer Byron MD1*Li Chunming PhD2Simon Lee S MD3Singh Gurkirpal MD4Stillman Martin J MD, JD5Berger Manuela F MD21 University of Texas Southwestern Medical Center, Dallas, Texas, USA2 Pfizer Inc, New York, New York, USA3 SDG, LLC, Cambridge, Massachusettes, USA4 Stanford University, Palo Alto, California, USA5 Hennepin County Medical Center, Minneapolis, Minnesota, USA* University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. E-mail: Byron.Cryer@UTSouthwestern.edu03 2013 12 02 2013 108 3 392 400 12 07 2012 14 12 2012 Copyright © 2013 American College of Gastroenterology2013American College of GastroenterologyThis work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/OBJECTIVES:\nBecause of the limitations of randomized controlled trials (RCTs) and observational studies, a prospective, randomized, open-label, blinded endpoint (PROBE) study may be an appropriate alternative, as the design allows the assessment of clinical outcomes in clinical practice settings. The Gastrointestinal (GI) Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug (NSAID) Study (GI-REASONS) was designed to reflect standard clinical practice while including endpoints rigorously evaluated by a blinded adjudication committee. The objective of this study was to assess if celecoxib is associated with a lower incidence of clinically significant upper and/or lower GI events than nonselective NSAIDs (nsNSAIDs) in standard clinical practice.\n\nMETHODS:\nThis was a PROBE study carried out at 783 centers in the United States, where a total of 8,067 individuals aged ≥55 years, requiring daily NSAIDs to treat osteoarthritis, participated. The participants were randomized to celecoxib or nsNSAIDs (1:1) for 6 months and stratified by Helicobacter pylori status. Treatment doses could be adjusted as per the United States prescribing information; patients randomized to nsNSAIDs could switch between nsNSAIDs; crossover between treatment arms was not allowed, and patients requiring aspirin at baseline were excluded. The primary outcome was the incidence of clinically significant upper and/or lower GI events.\n\nRESULTS:\nSignificantly more nsNSAID users met the primary endpoint (2.4% (98/4,032) nsNSAID patients and 1.3% (54/4,035) celecoxib patients; odds ratio, 1.82 (95% confidence interval, 1.31–2.55); P=0.0003). Moderate to severe abdominal symptoms were experienced by 94 (2.3%) celecoxib and 138 (3.4%) nsNSAID patients (P=0.0035). Other non-GI adverse events were similar between treatment groups. One limitation is the open-label design, which presents the possibility of interpretive bias.\n\nCONCLUSIONS:\nCelecoxib was associated with a lower risk of clinically significant upper and/or lower GI events than nsNSAIDs. Furthermore, this trial represents a successful execution of a PROBE study, where therapeutic options and management strategies available in clinical practice were incorporated into the rigor of a prospective RCT.\n==== Body\nINTRODUCTION\nNonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for the relief of arthritis pain; however, they have been shown to increase the risk of gastrointestinal (GI) ulcer bleeding (1,2,3,4,5). Previous blinded, prospective randomized controlled trials (RCTs) have provided evidence of NSAID-induced GI toxicities and have suggested a lower rate of upper GI complications with cyclooxygenase (COX)-2–selective NSAIDs compared with nonselective NSAIDs (nsNSAIDs) (6,7,8,9); however, the majority of these trials have focused on damage to the upper GI tract only (6,7,9,10,11,12). In addition, because of the relative inflexibility of management options in their protocols, prior RCTs of NSAIDs have not captured the common characteristics of NSAID utilization in clinical practice, such as switching among NSAIDs (13), modifications of dosing, drug holidays, and concomitant therapies used to potentially reduce GI symptoms and complications. Additional safety information that considers the potential for NSAID damage in both the upper and lower GI tract and better reflects standard clinical practice, could help clinicians make improved treatment decisions.\n\nBlinded RCTs are often regarded as the “gold standard” for assessing treatment effects of medications (14). However, when attempting to extrapolate findings from RCTs to clinical practice, the ability to generalize these results is commonly limited by factors, such as strict inclusion and exclusion criteria, inability to switch among comparator medications, restriction of dose adjustment, or the inability to institute a drug holiday as would happen in routine clinical practice. Furthermore, the protocol-driven study requirements of RCTs may lead to informative censoring of patient participation because of perceptions of medication adverse effects, which may lead to patient discontinuation from the study. Informative censoring may result in an imbalance of exposure time and a compromised ability to accrue clinically relevant or valid information regarding the primary clinical study outcomes (15).\n\nNoninterventional observational studies, compared with RCTs, may allow a better assessment of medication effects in typical clinical situations. However, as there is no randomization in these studies, it is difficult to draw firm conclusions about causation. Channeling, selection, and other biases inherent in nonrandomized studies may confound outcomes. Therefore, these types of studies often generate hypothesis rather than evidence of causality.\n\nProspective, randomized, open-label, blinded endpoint (PROBE) studies are designed to address some of the potential limitations of RCTs and observational studies. A PROBE trial design assesses clinical outcomes in large simple studies that allow a broad patient population, in this case patients who require the long-term use of NSAIDs owing to chronic pain, which better reflects clinical practice but with the advantage of randomization and a rigorous evaluation of endpoints by blinded expert adjudication committees (16).\n\nThe GI Randomized Event and Safety Open-Label NSAID Study (GI-REASONS; NCT00373685) is a novel PROBE study conducted in the United States, which measured clinical outcomes throughout the GI tract using blinded adjudication (17). Designed to address many of the potential limitations of RCTs and observational studies, the GI-REASONS tested the hypothesis that celecoxib use in patients with osteoarthritis of at least moderate GI risk (aged ≥55 years) would be associated with a lower incidence of clinically significant upper and/or lower GI events than nsNSAIDs in standard clinical practice. A prior double-blind RCT of celecoxib vs. diclofenac slow release plus omeprazole in patients with osteoarthritis and rheumatoid arthritis, the Celecoxib vs. Omeprazole and Diclofenac in Patients With Osteoarthritis and Rheumatoid Arthritis (CONDOR) trial, used a predefined primary endpoint of clinically significant upper and/or lower GI events to capture the spectrum of NSAID-associated GI damage throughout the entire GI tract (18). Although a similar endpoint is used in GI-REASONS, the novel aspect of this study is its PROBE design, which allowed for the possibility of switching among multiple nsNSAID comparators, dose adjustment, and the discretionary use of concomitant proton-pump inhibitors (PPIs) in both arms. Inclusion and exclusion criteria in the GI-REASONS were simple compared with conventional RCTs, providing a patient population more reflective of those encountered in typical clinical practice.\n\nMETHODS\nStudy design\nGI outcomes were evaluated in patients with osteoarthritis in need of daily NSAIDs (i.e., using celecoxib or nsNSAIDs) as a result of chronic pain, at moderate GI risk (defined as aged ≥55 years (12)), who were treated in a manner typical of US clinical patient care in 783 primary care and specialty practices. We hypothesized celecoxib would be associated with lower incidences of clinically significant upper and/or lower GI events compared with nsNSAIDs, with or without PPIs. Aspirin users were excluded to select a population with lower cardiovascular risk and to determine whether celecoxib has a greater GI benefit than nsNSAIDs, without the confounding use of aspirin. It has been reported that in patients taking COX-2 selective NSAIDs and low-dose aspirin, the GI advantages of COX-2 selective NSAIDs were reduced (19).\n\nWe estimated that 6,400 patients (3,200 per group) were needed to provide 90% power to detect a 56% reduction in the primary endpoint (from 1.6% for nsNSAIDs to 0.7% for celecoxib, observed in a similar population), (9) based on a χ2-test with a two-sided α=0.05. Assuming a 25% discontinuation rate, the target enrollment was 8,000. Eligible patients were randomized via an interactive voice response system (1:1) in block sizes of 4 to either open-label celecoxib or an nsNSAID for 6 months. The nsNSAID in the comparator group was any nsNSAID of the investigator's choice, prescribed within the dosages allowed in the US package insert. Patients with osteoarthritis, who previously had been taking an NSAID, were switched to their assigned study medication after randomization without a washout period. Patients were provided a pharmacy card that allowed each patient to fill prescriptions for their allocated treatment only. This pharmacy card was also used to capture study medication utilization behavior, such as dose adjustment and switching among nsNSAIDs. Patients were stratified at baseline by Helicobacter pylori status (assessed by serological testing at a central laboratory). H. pylori-positive patients were not treated for their infection during the trial. During the 6-month study, patients were evaluated every 2 months and at end of study in office visits that included assessment of hemoglobin. Celecoxib or nsNSAID dosage could be adjusted within the US prescribing guidelines. Patients randomized to the nsNSAID arm could switch between nsNSAIDs, but crossover between the nsNSAID and celecoxib treatment arms was not allowed. PPIs and histamine-2 receptor antagonists (H2-RA) were allowed in either arm at the provider's discretion. This study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and local regulatory requirements. The protocol was modified twice after study initiation: first to clarify the inclusion/exclusion criteria regarding estimation of cardiovascular risk, and second to include additional prespecified sensitivity analyses. These modifications did not result in any change in study conduct.\n\nStudy eligibility\nPatients aged ≥55 years with a clinical diagnosis of osteoarthritis, who required daily NSAID therapy for the management of osteoarthritis symptoms, were eligible. Key exclusions were active GI ulcer hemorrhage or gastroduodenal ulceration within 90 days of screening, known established cardiovascular disease, any patient who, in the opinion of the investigator, was at sufficiently high cardiovascular risk to require low-dose aspirin, or positive fecal occult blood test at screening. Acetaminophen for occasional treatment of nonarthritis pain (up to 4 g per day for no more than 2 consecutive days), narcotic analgesics, and gastroprotective agents were allowed.\n\nStudy endpoints\nThe primary endpoint was the incidence of clinically significant upper and/or lower GI events over 6 months, individual components of which are shown in the Results section (\nTable 1). Potential GI endpoint events were adjudicated by an independent, blinded, expert GI events adjudication committee that evaluated whether the suspected GI event met predefined criteria for a component of the composite GI endpoint. The primary endpoint component, clinically significant anemia of presumed occult GI origin, was defined as a hemoglobin decrease of more than 2 mg/dl from baseline, which had no apparent non-GI cause to explain the decrease. Patients could have only one primary endpoint. Secondary endpoints included moderate to severe abdominal symptoms, withdrawal owing to GI adverse events, changes in hemoglobin and hematocrit from baseline, study and nonstudy drug utilization, gastroprotective drug use, and fecal occult blood test results. Patient satisfaction was measured with a validated instrument (20) as a secondary endpoint to assess potential treatment benefit. Cardiovascular events were also assessed and adjudicated by an independent, blinded, expert cardiovascular adjudication committee.\n\nStatistical analysis\nThe primary and secondary endpoint analyses were based on the intent-to-treat population, defined as all randomized subjects. Statistical tests were significant at the 0.05 level. The primary endpoint was analyzed by comparing the incidence proportions between the treatment arms using a life-table (actuarial) extension of the Mantel–Haenszel method, stratified by H. pylori status at screening. As a secondary analysis to confirm robustness, the primary endpoint was analyzed using the Kaplan–Meier method and the log-rank test. Two sensitivity analyses were planned: a worst-case analysis, in which all patients who were lost to follow-up were conservatively assumed to have had a GI event meeting the criteria for a primary endpoint, and an analysis limited to patients with no protocol deviation. Incidences of hemoglobin and hematocrit drops were compared using a Cochran–Mantel–Haenszel test adjusted for H. pylori status at screening. Analysis of covariance was used to analyze continuous secondary endpoint variables, such as patient satisfaction. Secondary endpoint analyses were performed using the last observation carried forward, and were not adjusted for multiple comparisons. Safety data, physical examination, vital signs, laboratory data, and treatment-emergent adverse events were summarized. During the study, 36 patients were inadvertently randomized more than once. These patients were evenly distributed between groups and were excluded from analysis.\n\nStudy governance\nThe data and safety monitoring committee met regularly during the study to review the safety outcomes. An interim futility analysis was performed to re-estimate sample size after 50% of patients completed, and no adjustment to sample size or alpha was needed. An executive committee (BC, LSS, MJS, and GS) oversaw study conduct, analysis of outcomes, and interpretation of results.\n\nRESULTS\nPatient disposition\nBetween October 2006 and November 2010, a total of 4,035 celecoxib and of 4,032 nsNSAID patients were randomized and included in the intent-to-treat analyses (Figure 1). Baseline demographics were similar between treatment arms. Mean age (s.d.) was 63 (6) years, 76% were female, 259 patients (3.2%) had a history of GI ulcer or ulcer bleeding, 34% were H. pylori positive, and 15 patients (0.19%) had a history of coronary artery disease or myocardial infarction (\nTable 2).\n\nIn celecoxib-treated patients, 90% were initially prescribed celecoxib 200 mg daily. In nsNSAID-treated patients, the most common initially prescribed comparator nsNSAIDs were meloxicam (38%), naproxen (17%), nabumetone (11%), diclofenac (15%), ibuprofen (5%), and etodolac (5%). Because of switching, the number of patients who took these nsNSAIDs increased during the study, and the most common nsNSAIDs taken were as follows: meloxicam (42%, average total daily dose 13.0 mg); naproxen (21%, average total daily dose 819.8 mg); diclofenac (20%, average total daily dose 124.4 mg); nabumetone (14%, average total daily dose 1089.0 mg); ibuprofen (7%, average total daily dose 1453.2 mg); and etodolac (7%, average total daily dose 709.2 mg); and, as with celecoxib, the nsNSAIDs were taken at the usual US Food and Drug Administration-recommended dosages for management of osteoarthritis.\n\nSimilar percentages of celecoxib and nsNSAID patients completed the study (2,596 (64.3%) and 2,611 (64.8%), respectively). Overall, 1,376 (34.5%) and 1,340 (33.9%) patients discontinued treatment in the celecoxib and nsNSAID treatment groups, respectively. Reasons for discontinuations were similar between the two treatment arms, and patients discontinued because of adverse events were 7.0 % and 6.4% of the celecoxib- and nsNSAID-treated patients, respectively. Approximately, 2.8% and 3.0% of the celecoxib and nsNSAID treated patients, respectively, withdrew from the study owing to GI adverse events. Discontinued patients were not censored from the analysis; 186 patients were lost to follow-up (2.1% celecoxib and 2.6% nsNSAID).\n\nPrimary endpoint\nSignificantly more nsNSAID users met the primary endpoint (2.4% (98/4,032) nsNSAID patients and 1.3% (54/4,035) celecoxib patients; odds ratio, 1.82 (95% confidence interval (CI), 1.31–2.55); P=0.0003; Table 1 and Figure 2). Of the patients who were H. pylori positive, 1.8% met the primary endpoint in the celecoxib group and 2.5% in the nsNSAID group; of the patients who were H. pylori negative, 1.1% met the primary endpoint in the celecoxib group and 2.4% in the nsNSAID group. In a sensitivity analysis, attributing the primary endpoint to all patients lost to follow-up (worst case; 2.1% of celecoxib and 2.6% of nsNSAID patients), the difference between treatment arms remained significant (odds ratio, 1.46; 95% CI, 1.18–1.82; P=0.0006). In another sensitivity analysis, excluding patients with protocol deviations, the difference between treatment arms also remained significant (odds ratio, 2.51; 95% CI, 1.35–4.65; P=0.0025).\n\nSecondary endpoints\nA smaller proportion of patients receiving celecoxib (94 (2.3%)) experienced moderate to severe abdominal symptoms than those receiving nsNSAIDs (138 (3.4%); P=0.0035). However, withdrawals owing to GI adverse events were similar between groups (112 (2.8%) and 120 (3.0%), respectively; P=not significant).\n\nAt baseline, mean hemoglobin levels were similar between treatment groups (13.6 g/dl in each group). At study completion, the hemoglobin decrease from baseline was significantly greater in those taking nsNSAIDs (treatment difference, 0.132; 95% CI, 0.10–0.16; P<0.0001). Over the course of the 6-month study, 1.8% of celecoxib patients compared with 2.9% of nsNSAID patients had a ≥2-g decrease in hemoglobin or 10% or greater decrease in hematocrit (relative risk, 1.6; 95% CI, 1.2–2.2; P=0.0023).\n\nThe proportion of patients taking gastroprotective agents (PPI or H2-RA) for ≥75% of the time under study was 22.4% in the celecoxib group and 23.8% in the nsNSAID group. The proportion of patients with clinically significant upper and/or lower GI events among those who took a PPI was approximately 1.4% in the celecoxib group and 3.0% in the nsNSAID group, and among those who did not take a PPI, the proportion was 1.3% and 2.3%, respectively. Furthermore, among patients who took a PPI, the proportion of patients with clinically significant anemia (defined as either clinically significant anemia of defined GI origin or clinically significant anemia of presumed occult GI origin, including possible small-bowel blood loss) was approximately 1.3% in the celecoxib group and 2.4% in the nsNSAID group. This rate changed to 1.2% and 1.9%, respectively, for those who did not use a PPI.\n\nThe proportion of patients taking nonstudy analgesics for ≥75% of the time was comparable between treatment groups: 13.8% of patients in the celecoxib group (6.8% acetaminophen, 12.8% over-the-counter NSAID, 14.2% opioid) and 14.9% of patients in the nsNSAID group (6.5% acetaminophen, 13.3% over-the-counter NSAID, 15.6% opioid). Approximately 3.5% of celecoxib and 3.0% of nsNSAID patients used aspirin, which was noted as a protocol deviation.\n\nThe most commonly used nsNSAIDs were meloxicam (42%), naproxen (21%), diclofenac (20%), and nabumetone (14%), but comparison of celecoxib with any of the individual nsNSAIDs was not conducted, as the study was neither designed nor powered for such comparisons. About one quarter (24.4%) of nsNSAID patients modified their drug regimen (dose changes, switching to another NSAID); 5.4% of celecoxib patients changed their dose. Treatment satisfaction improved from baseline in both groups. However, patients taking celecoxib reported greater treatment satisfaction than patients taking nsNSAIDs (P<0.0001).\n\nOverall and cardiovascular safety evaluation\nOverall, adverse events and serious adverse events were similar between groups (Table 3). Adjudicated cardiovascular events were similar in both groups (celecoxib 0.4% vs. nsNSAID 0.3%). These included both Antiplatelet Trialists' Collaboration Combined Endpoint events (acute myocardial infarction, stroke, or cardiovascular death; eight celecoxib and six nsNSAID events) and cardiovascular events of special interest (unstable angina, coronary revascularization, transient ischemic attacks, venous and peripheral arterial vascular thrombotic events, and congestive heart failure; nine celecoxib and seven nsNSAID events; see Table 4 for more detail). There were seven deaths in total, five in the celecoxib group (three adjudicated as cardiovascular-related) and two in the nsNSAID group (none adjudicated as cardiovascular-related).\n\nDISCUSSION\nIn this study, designed to reflect the GI consequences of NSAIDs in a typical clinical practice setting, celecoxib was associated with an approximately twofold lower incidence of clinically significant upper and/or lower GI events than nsNSAIDs. Even in the “worst-case” sensitivity analysis, the treatment effect of COX-2-selective inhibition remained significant. The GI-REASONS had proportionally fewer upper GI ulcer complications than historical comparator studies (6,8,9), and changes in hemoglobin and/or hematocrit had a greater influence on the primary composite GI endpoint. A decline in clinically significant upper GI events and an increase in lower GI events have also been identified in some observational studies (21,22). This phenomenon of suspected lower GI events taking on a greater proportion of the total GI tract events seen in the GI-REASONS is an important contribution that adds to our current understanding of the proposed burden of the effects of NSAIDs throughout the entire GI tract. In addition, the concomitant allowance of GI-protective therapies in both arms may have decreased the observed incidence of upper GI ulcers, contributing to the relative finding of increased suspected lower GI events.\n\nWe have provided the data on the total number of adjudicated events based on individual NSAIDs, even though the authors do not believe that these data can be analyzed in any scientifically valid fashion, for the following reasons. To begin, the study was designed and powered to detect potential differences between celecoxib and nsNSAIDs as a collective group. The study was not designed to examine potential outcome differences among nsNSAIDs or between any single nsNSAID and celecoxib, and is therefore insufficiently powered to conduct valid subgroup analysis of any isolated nsNSAID comparator. Equally important, such analyses would be significantly biased. The major strengths of the GI-REASONS are (a) randomization and (b) the open-label PROBE design, which allows physicians to select any NSAID they want in the usual care arm, thus mimicking clinical practice. However, these strengths also make it uniquely ill-advised to conduct subgroup analyses of individual NSAIDs, because the selection of any individual nsNSAID in the usual care arm is not randomized. In fact, the decision of what nsNSAID to prescribe is made after randomization, in an open-label fashion. This introduces a strong channeling bias, similar to that often seen in observational studies. It is entirely possible that patients perceived to be at higher risk for GI complications in the usual-care arm will be selectively prescribed specific nsNSAIDs, which the physicians believe are “safer,” based on prior perceptions or marketing (e.g., meloxicam). No such channeling will occur in the celecoxib arm. The channeling bias would then result in a significantly higher complication rate in those receiving the channeled “presumed safer” NSAID (e.g., meloxicam) compared with the non-channeled arm (in this case, celecoxib). Therefore, the authors believe that it is not possible to compare specific nsNSAIDs with celecoxib, or with each other in a quantitative and scientifically valid fashion. Not only are these analyses not prespecified, the authors had agreed during the conduct of the study that subgroup analyses would not be conducted because of their questionable scientific validity. Therefore, although the authors feel that no conclusions can be drawn from the following data, it is provided at the editor's request.\n\nThe proportion of patients with clinically significant upper and/or lower GI events in the individual nsNSAID group (based on first prescription only) with ≥1 event was 9.1% (1/11 patients) in diflunisal-, 6.7% (7/105 patients) in oxaprozin-, 6.7% (1/15 patients) in indomethacin-, 3.3% (20/609) in diclofenac-, 2.8% (5/181 patients) in etodolac-, 2.7% (18/679 patients) in naproxen-, 2.7% (3/112) in piroxicam-, 2.2% (34/1514 patients) in meloxicam-, 1.4% (6/418 patients) in nabumetone-, and 1.4% (3/211 patients) in ibuprofen-treated patients.\n\nRecognizing the limitations of both RCTs and observational studies, recent discussions of the US Food and Drug Administration on the use of COX-2-selective NSAIDs and nsNSAIDs have proposed alternative clinical trial strategies, including the PROBE design as a novel method to be pursued for assessing the comparative effectiveness of these medications (23). The strengths of the PROBE design are randomization, prospective follow-up, and a rigorous evaluation of study endpoints by a blinded, independent, expert adjudication committee (16). Using a PROBE design, the GI-REASONS used simple inclusion and exclusion criteria to enroll a broad osteoarthritis patient population of moderate GI and low cardiovascular risk. Switching among nsNSAIDs, allowing dose adjustments, and drug holidays, along with use of PPIs and H2-RA as needed, more closely reflected daily clinical practice. Another strength of this study was providing pharmacy cards to each patient; this allowed tracking of prescriptions, evaluation of medication compliance, and monitoring of drug utilization and drug switching behavior, while preventing treatment crossover.\n\nThe relative merits of the various methods used to assess NSAID-induced GI damage (e.g., endoscopy of the upper GI tract, a composite endpoint evaluation of the entire GI tract, or assessment of ulcer complications) have been the focus of the recent US regulatory discussions (24). NSAID toxicity in GI-REASONS was assessed by a composite primary endpoint of clinically significant upper and/or lower GI events (17). Historically, the most commonly employed investigational method in the study of NSAID-related GI damage is endoscopy. Although upper endoscopy is useful to assess the upper GI tract, it is not appropriate for the entire small intestine. In the small intestine, capsule endoscopy studies have shown differences in mucosal damage between COX-2-selective and nonselective NSAIDs (25,26); however, the clinical relevance of these endoscopic findings is still unclear. In addition, a common gastroprotective strategy, PPI use, is not anticipated to have pharmacological effects extending beyond the duodenum. We believe a primary endpoint that assesses damage through the entire GI tract provides valuable safety data to guide management of arthritis patients, as well as methodological and regulatory discussions.\n\nPrior data indicate that the GI advantage of COX-2-selective NSAIDs may be compromised in patients taking concomitant aspirin (19). Aspirin use was an exclusion criterion in this study. Although we avoided the potential confounding of the GI endpoint, this exclusion criterion means that our observations may not be generalizable to patients on prophylactic aspirin therapy.\n\nThe largest proportion of the composite GI endpoint can be attributed to decreases in hemoglobin ≥2 g/dl and/or ≥10% hematocrit, and the clinical relevance of a 2-g/dl drop in hemoglobin is currently the subject of active debate. We believe that the difference reflects those taking nsNSAIDs, even with concomitant PPI use, are at increased risk of mucosal damage throughout the entire GI tract compared with the relative GI mucosa protection offered by COX-2 inhibition via celecoxib. On a large scale, such as that examined in this study, it is possible that this difference of protection between nsNSAIDs and celecoxib is likely enough to expose the smaller, nonscoped bleeding changes that can occur throughout the entire GI tract with nsNSAID use. These smaller bleeding changes would then be reflected in the hemoglobin differences seen in the two arms.\n\nWe recognize the challenge of determining the significance of hemoglobin drops, which counted as a primary outcome but did not render a participant anemic by laboratory definition (e.g., a hemoglobin drop from 15.5 to 13.5 g/dl). Although the relative merits of using reference ranges to define anemia rather than relative change from baseline is not yet settled, we believe that drops in hemoglobin ≥2 g/dl represent a change from the patient's usual baseline that is clinically informative and may warrant further clinical examination.\n\nTwo major risk factors for GI mucosal damage are H. pylori and NSAID use (27). Historically, H. pylori has been the major cause of peptic ulcer disease. Many previous studies of NSAID GI injury excluded H. pylori-positive patients. By stratifying for H. pylori status in the current study, we believe that our analysis provides clinically relevant information on the use of NSAIDs in a patient population of mixed H. pylori status as found in typical clinical practice.\n\nIn this study we did see a numeric but nonstatistically significant imbalance in rates of cardiovascular events between the two study groups. As the GI-REASONS trial is designed as a trial to evaluate GI endpoints, this study was not sufficiently powered to assess rates of cardiovascular events between celecoxib and NSAIDs. A larger trial is currently ongoing to evaluate cardiovascular events between celecoxib and NSAIDs (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen [PRECISION]) (28).\n\nPROBE-designed studies have several limitations (29). The open-label design presents the possibility of bias. That is, patients or investigators may add concomitant treatments to address lack of efficacy, or manage symptoms or risk based on their knowledge and beliefs of treatment allocation. However, although medications were open label, determination of endpoints was blinded and conducted by expert committees. In addition to these previously recognized limitations, our experience identified hurdles in the execution of a PROBE-designed study. Although assumed to be simple by design, in practice, incorporating the variety of therapeutic options and management strategies that are available in clinical practice, compared with the limited possibilities in an RCT, was challenging. However, greater investigator flexibility allowed outcomes reflective of actual clinical practice, and we believe that GI-REASONS has proven that clinically relevant comparative treatment data can be captured through a trial of PROBE design.\n\nIn summary, the GI-REASONS provides valuable GI safety data relevant to clinical practice. A greater understanding of NSAID risk throughout the entire GI tract should lead to more effective patient management and identification of improved risk-reduction strategies. Finally, we think this trial will be historically important with respect to clinical trial design in NSAID-related GI bleeding, as it represents the successful execution of a PROBE study, incorporating the variety of therapeutic options and management strategies that are available in clinical practice, with the rigor of a prospective RCT (Supplementary Information).\n\nSTUDY HIGHLIGHTS\n\n\nWe thank Dr Ha Nguyen (Pfizer) for many helpful and insightful comments on the manuscript. This trial was registered withclinicaltrials.gov identifier: NCT00373685.\n\nSUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg\n\nGuarantor of the article: Byron Cryer, MD.\n\nSpecific author contributions: B.C., L.S.S., G.S., and M.J.S. constituted the Executive Committee overseeing the study. M.F.B. designed the study with contributions from the other authors. C.L. performed the statistical analysis, and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors participated in drafting and revising the manuscript.\n\nFinancial support: This study was sponsored by Pfizer. Editorial support was provided by William Watkins, of PAREXEL, and was funded by Pfizer.\n\nPotential competing interests: Byron Cryer has served as a consultant for Pfizer, Astra-Zeneca, PLx Pharma, McNeil Consumer Products, and Ritter Pharmaceuticals, and has received consulting fees, honorarium, and travel support from Pfizer. Chunming Li and Manuela Berger are full-time employees of Pfizer and own stocks and shares in Pfizer. Lee S. Simon has served as a consultant for Pfizer, Astra-Zeneca, PLx Pharma, Logical Therapeutics, Bayer Healthcare, Horizon Pharmaceuticals, Takeda, and Posen, and has received consulting fees and travel support from these companies. Gurkirpal Singh has received consulting fees and honorarium from Pfizer and has received grants from Pfizer, Novartis, Pozen, and Astra-Zeneca. Martin Stillman has served as a consultant for Pfizer, Alpharma, and NicOx S.A., and has received consulting fees and honorarium from Pfizer.\n\nSupplementary Material\nSupplementary Information Click here for additional data file.\n\n Figure 1 Patient disposition. nsNSAID, nonselective nonsteroidal anti-inflammatory drug.\n\nFigure 2 Cumulative incidence of clinically significant upper and/or lower gastrointestinal events. CMH, Cochran–Mantel–Haenszel; nsNSAID, nonselective, nonsteroidal anti-inflammatory drug. Note: any potential event occurring during the 180 days of treatment plus 28 days after last dose would have been reviewed and adjudicated by design. Hence, the Kaplan–Meier (KM) plot is presented up to 210 days here. The KM estimate beyond that duration became unreliable owing to censoring.\n\nTable 1 Primary endpoint analysis\n \tCelecoxib (n=4,035)\tnsNSAID (n=4,032)\t\n \tPatients with events, no. (%)\tPatients with events, no. (%)\t\nClinically significant upper and/or lower GI events\t54 (1.3)\t98 (2.4)\t\n Gastroduodenal hemorrhagea\t0\t2 (<0.1)\t\n Gastric outlet obstructionb\t1 (<0.1)\t0\t\n Gastroduodenal, small bowel or large bowel perforationc\t1 (<0.1)\t1 (<0.1)\t\n Small bowel hemorrhaged\t0\t0\t\n Large bowel hemorrhagee\t3 (<0.1)\t6 (0.1)\t\n Clinically significant anemia of defined GI originf\t4 (0.1)\t6 (0.1)\t\n Symptomatic ulcersg\t0\t5 (0.1)\t\n Small bowel obstructionh\t0\t0\t\n Acute GI hemorrhage of unknown origin, including presumed small bowel hemorrhagei\t1 (<0.1)\t3 (<0.1)\t\n Clinically significant anemia of presumed occult GI origin including possible small bowel blood lossj\t44 (1.1)\t75 (1.9)\t\nOdds ratio (95% CI)\t1.82 (1.31–2.55)\t\nHypothesis testing\tP=0.0003\t\nHelicobacter pylori status\t\n Positive\t25/1,401 (1.8)\t34/1,386 (2.5)\t\n Negative\t29/2,634 (1.1)\t64/2,646 (2.4)\t\nCI, confidence interval; EGD, esophagogastroduodenoscopy; GI, gastrointestinal; nsNSAID, nonselective, nonsteroidal anti-inflammatory drug.\n\nDefinitions of endpoint components\n\na Endoscopic evidence of gastroduodenal ulceration (mucosal break with definite depth) or erosion (mucosal break without depth), or other likely causative lesion and clinical evidence of hemorrhage (hematemesis or melena, or evidence of recent hemorrhage on EGD—e.g., clot, blood in stomach, or visible vessel).\n\nb Clinical, surgical, endoscopic, or radiographic evidence with symptoms consistent with gastric outlet obstruction.\n\nc Clinical, surgical, or radiographic confirmation associated with symptoms consistent with perforation.\n\nd Melena or hematochezia with likely causative lesion on small bowel investigation.\n\ne Melena or hematochezia with no evidence of source on EGD and likely causative lesion on colonoscopy.\n\nf No overt clinical evidence of acute GI hemorrhage, but with fall in hematocrit ≥10% points and/or hemoglobin ≥2 g/dl from baseline, with likely causative lesion on upper GI or lower GI endoscopic investigation, and with no non-GI source of anemia identified.\n\ng Ulcers without complications, which present with dyspepsia and have endoscopic or X-ray evidence of a gastric and/or duodenal ulcer.\n\nh Clinical, surgical, endoscopic or radiographic evidence with symptoms consistent with small bowel obstruction.\n\ni Hematemesis, melena, or hematochezia with no evidence of likely causative lesion on endoscopic investigation.\n\nj No overt clinical evidence of acute GI hemorrhage, but with fall in hematocrit ≥10% points and/or hemoglobin of ≥2 g/dl without a GI lesion endoscopically identified and no non-GI source of anemia.\n\nTable 2 Demographic characteristics\n \tCelecoxib (n=4,035)\tnsNSAID (n=4,032)\t\nFemale, no. (%)\t3,049 (75.6)\t3,064 (76.0)\t\nAge, mean (s.d.)\t63.3 (6.3)\t63.3 (6.4)\t\nWeight (kg), mean (s.d.)\t83.5 (20.1)\t83.5 (19.9)\t\nDuration of OA (years), mean (s.d.)\t8.0 (7.7)\t8.0 (7.6)\t\nH. pylori positive, no. (%)\t1,365 (33.8)\t1,350 (33.5)\t\nHistory of coronary artery disease or myocardial infarction, no. (%)\t7 (0.2)\t8 (0.2)\t\nnsNSAID, nonselective, nonsteroidal anti-inflammatory drug; OA, osteoarthritis.\n\nTable 3 Treatment-emergent adverse events\n \tCelecoxib (n=4,035) no. (%)\tnsNSAID (n=4,032) no. (%)\t\nTotal number of patients evaluable for AEs\t4,018 (99.6)\t4,022 (99.8)\t\nPatients with AEs\t1,663 (41.4)\t1,869 (46.5)\t\nPatients with serious AEs\t100 (2.5)\t96 (2.4)\t\nPatients with dose reduction or temporary discontinuation due to AEs\t144 (3.6)\t202 (5.0)\t\nAEs, adverse events; nsNSAID, nonselective, nonsteroidal anti-inflammatory drug.\n\nTable 4 Adjudicated cardiovascular events\n \tCelecoxib (n=4,035) no. (%)\tnsNSAID (n=4,032) no. (%)\t\nTotal CV events\t17 (0.4)a\t13 (0.3)\t\nAPTC-like events\t8 (0.2)\t6 (0.1)\t\nAcute myocardial infarction\t2 (<0.1)\t3 (0.1)\t\nStroke\t3 (0.1)\t3 (0.1)\t\nCardiovascular death\t3 (0.1)\t0\t\nCV events of special interest\t9 (0.2)\t7 (0.2)\t\nUnstable angina\t2 (<0.1)\t1 (<0.1)\t\nCoronary revascularization\t4 (0.1)\t0\t\nTransient ischemic attack\t2 (<0.1)\t2 (<0.1)\t\nVenous and peripheral arterial thrombotic event\t1 (<0.1)\t3 (0.1)\t\nCongestive heart failure\t0\t1 (<0.1)\t\nAPTC, Antiplatelet Trialists' Collaboration Combined Endpoint; CV, cardiovascular; nsNSAID, nonselective, nonsteroidal anti-inflammatory drug.\n\na One patient in the celecoxib group had an acute myocardial infarction and coronary revascularization.\n==== Refs\nGarcía Rodríguez L Williams R Derby LE Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors Arch Intern Med 1994 154 311 316 8297198 \nLaine L Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient Gastroenterology 2001 120 594 606 11179238 \nLaine L Curtis SP Cryer B Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison Lancet 2007 369 465 473 17292766 \nSingh G Ramey DR Morfeld D Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study Arch Intern Med 1996 156 1530 1536 8687261 \nWolfe MM Lichtenstein DR Singh G Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs N Engl J Med 1999 340 1888 1899 10369853 \nBombardier C Laine L Reicin A Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis N Engl J Med 2000 343 1520 1528 11087881 \nCannon CP Curtis SP FitzGerald GA Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison Lancet 2006 368 1771 1781 17113426 \nSchnitzer TJ Burmester GR Mysler E Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial Lancet 2004 364 665 674 15325831 \nSilverstein FE Faich G Goldstein JL Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial JAMA 2000 284 1247 1255 10979111 \nSilverstein FE Graham DY Senior JR Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial Ann Intern Med 1995 123 241 249 7611589 \nSingh G Fort JG Goldstein JL Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study Am J Med 2006 119 255 266 16490472 \nGutthann SP Garcia Rodriguez LA Raiford DS Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation Epidemiology 1997 8 18 24 9116088 \nLangman M Kahler KH Kong SX Drug switching patterns among patients taking non-steroidal anti-inflammatory drugs: a retrospective cohort study of a general practitioners database in the United Kingdom Pharmacoepidemiol Drug Saf 2001 10 517 524 11828834 \nU.S.Preventive Services Task Force U.S. Preventive Services Task Force Procedure Manual 2008 U.S.Preventive Services Task Force AHRQ Publication No. 08-05118-EF, Rockville, MD.\nHernán MA Hernández-Diaz S Robins JM A structural approach to selection bias Epidemiology 2004 15 615 625 15308962 \nHansson L Hedner T Dahlöf B Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials Blood Press 1992 1 113 119 1366259 \nChan FK Cryer B Goldstein JL A novel composite endpoint to evaluate the gastrointestinal (GI) effects of nonsteroidal antiinflammatory drugs through the entire GI tract J Rheumatol 2010 37 167 174 19884267 \nChan FK Lanas A Scheiman J Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial Lancet 2010 376 173 179 20638563 \nLanas A García-Rodríguez LA Arroyo MT Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin, and combinations Gut 2006 55 1731 1738 16687434 \nEvans CJ Trudeau E Mertzanis P Development and validation of the Pain Treatment Satisfaction Scale (PTSS): a patient satisfaction questionnaire for use in patients with chronic or acute pain Pain 2004 112 254 266 15561380 \nLanas A García-Rodríguez LA Polo-Tomás M Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice Am J Gastroenterol 2009 104 1633 1641 19574968 \nZhao Y Encinosa W Hospitalizations for Gastrointestinal Bleeding in 1998 and 2006 HCUP Statistical Brief #652008 Agency for Healthcare Research and Quality: Rockville, MD Available at: \n:\nhttp://www.hcup-us.ahrq.gov/reports/statbriefs/sb65.pdf\n.\nAccessed 15 August 2011.\nUS Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research Proceedings of the Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee 2005 US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research FDA Web site: Rockville, MD. Available at: \n:\nhttp://www.fda.gov/ohrms/dockets/ac/cder05.html\n.\nAccessed 23 April 2011.\nFood and Drug Administration Gastrointestinal Drug Advisory Committee Meeting: Outcome Measures for Claims to Reduce NSAID-Associated Upper Gastrointestinal (UGI) Toxicity Food and Drug Administration. Gastrointestinal Drug Advisory Committee Meeting 2010 FDA Web site: Rockville, MD. Available at: \n:\nhttp://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM231990.pdf\n.\nAccessed 21 March 2011.\nGoldstein JL Eisen GM Lewis B Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo Clin Gastroenterol Hepatol 2005 3 133 141 15704047 \nGoldstein JL Eisen GM Lewis B Small bowel mucosal injury is reduced in healthy subjects treated with celecoxib compared with ibuprofen plus omeprazole, as assessed by video capsule endoscopy Aliment Pharmacol Ther 2007 25 1211 1222 17451567 \nJi K-Y Hu F-L Interaction or relationship between Helicobacter pylori and non-steroidal anti-inflammatory drugs in upper gastrointestinal diseases World J Gastroenterol 2006 12 3789 3792 16804960 \nBecker MC Wang TH Wisniewski L Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal antiinflammatory agents in patients with arthritis Am Heart J 2009 157 606 612 19332185 \nKohro T Yamazaki T Cardiovascular clinical trials in Japan and controversies regarding prospective randomized open-label blinded end-point design Hypertens Res 2009 32 109 114 19262468\n\n",
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"title": "GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial.",
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"abstract": "Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course represent a diagnostic and therapeutic challenge for neurologists. Herein, we describe a 50-year-old woman presenting with subacute onset of left hemiparesis, memory difficulties and headache. Brain MRI revealed a tumefactive right frontal-parietal lesion with perilesional edema, mass effect and homogenous post-contrast enhancement, along with other small atypical lesions in the white-matter. Brain biopsy of cerebral lesion ruled out lymphoma or any other neoplastic process and patient placed on corticosteroids with complete clinical/radiological remission. Two years after disease initiation, there was disease exacerbation with reappearance of the tumor-like mass. The patient initially responded to high doses of corticosteroids but soon became resistant. Plasma-exchange sessions were not able to limit disease burden. Resistance to therapeutic efforts led to a second biopsy that showed perivascular demyelination, predominantly consisting of macrophages, with a small number of T and B lymphocytes, and the presence of reactive astrocytes, typical of Creutzfeldt-Peters cells. The patient received high doses of cyclophosphamide with substantial clinical/radiological response but relapsed after 7-intensive cycles. She received 4-weekly doses of rituximab with disease exacerbation and brainstem involvement. She eventually died with complicated pneumonia. We present a very rare case of recurrent tumefactive demyelinating lesions, with atypical tumor-like characteristics, with initial response to corticosteroids and cyclophosphamide, but subsequent development of drug-resistance and unexpected exacerbation upon rituximab administration. Our clinical case raises therapeutic dilemmas and points to the need for immediate and appropriate immunosuppression in difficult to treat tumefactive CNS lesions with Marburg-like features.",
"affiliations": "Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Department of Pathology, Evaggelismos Hospital, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Research Unit of Radiology, 2nd Department of Radiology, National and Kapodistrian University of Athens, Athens, Greece.;Research Unit of Radiology, 2nd Department of Radiology, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Vakrakou|Aigli G|AG|;Tzanetakos|Dimitrios|D|;Argyrakos|Theodore|T|;Koutsis|Georgios|G|;Evangelopoulos|Maria-Eleptheria|ME|;Andreadou|Elisabeth|E|;Anagnostouli|Maria|M|;Breza|Marianthi|M|;Tzartos|John S|JS|;Gialafos|Elias|E|;Dimitrakopoulos|Antonios N|AN|;Velonakis|Georgios|G|;Toulas|Panagiotis|P|;Stefanis|Leonidas|L|;Kilidireas|Constantinos|C|",
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"doi": "10.3389/fneur.2020.00536",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.00536\nNeurology\nBrief Research Report\nRecurrent Fulminant Tumefactive Demyelination With Marburg-Like Features and Atypical Presentation: Therapeutic Dilemmas and Review of Literature\nVakrakou Aigli G. 1* Tzanetakos Dimitrios 1 Argyrakos Theodore 2 Koutsis Georgios 1 Evangelopoulos Maria-Eleptheria 1 Andreadou Elisabeth 1 Anagnostouli Maria 1 Breza Marianthi 1 Tzartos John S. 1 Gialafos Elias 1 Dimitrakopoulos Antonios N. 1 Velonakis Georgios 3 Toulas Panagiotis 3 Stefanis Leonidas 1 Kilidireas Constantinos 1 1Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece\n2Department of Pathology, Evaggelismos Hospital, Athens, Greece\n3Research Unit of Radiology, 2nd Department of Radiology, National and Kapodistrian University of Athens, Athens, Greece\nEdited by: Maria Pia Amato, University of Florence, Italy\n\nReviewed by: Rocco Totaro, San Salvatore Hospital, Italy; Mattia Fonderico, University of Florence, Italy\n\n*Correspondence: Aigli G. Vakrakou avakrakou@med.uoa.grThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n\n30 6 2020 \n2020 \n11 53602 3 2020 14 5 2020 Copyright © 2020 Vakrakou, Tzanetakos, Argyrakos, Koutsis, Evangelopoulos, Andreadou, Anagnostouli, Breza, Tzartos, Gialafos, Dimitrakopoulos, Velonakis, Toulas, Stefanis and Kilidireas.2020Vakrakou, Tzanetakos, Argyrakos, Koutsis, Evangelopoulos, Andreadou, Anagnostouli, Breza, Tzartos, Gialafos, Dimitrakopoulos, Velonakis, Toulas, Stefanis and KilidireasThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course represent a diagnostic and therapeutic challenge for neurologists. Herein, we describe a 50-year-old woman presenting with subacute onset of left hemiparesis, memory difficulties and headache. Brain MRI revealed a tumefactive right frontal-parietal lesion with perilesional edema, mass effect and homogenous post-contrast enhancement, along with other small atypical lesions in the white-matter. Brain biopsy of cerebral lesion ruled out lymphoma or any other neoplastic process and patient placed on corticosteroids with complete clinical/radiological remission. Two years after disease initiation, there was disease exacerbation with reappearance of the tumor-like mass. The patient initially responded to high doses of corticosteroids but soon became resistant. Plasma-exchange sessions were not able to limit disease burden. Resistance to therapeutic efforts led to a second biopsy that showed perivascular demyelination, predominantly consisting of macrophages, with a small number of T and B lymphocytes, and the presence of reactive astrocytes, typical of Creutzfeldt-Peters cells. The patient received high doses of cyclophosphamide with substantial clinical/radiological response but relapsed after 7-intensive cycles. She received 4-weekly doses of rituximab with disease exacerbation and brainstem involvement. She eventually died with complicated pneumonia. We present a very rare case of recurrent tumefactive demyelinating lesions, with atypical tumor-like characteristics, with initial response to corticosteroids and cyclophosphamide, but subsequent development of drug-resistance and unexpected exacerbation upon rituximab administration. Our clinical case raises therapeutic dilemmas and points to the need for immediate and appropriate immunosuppression in difficult to treat tumefactive CNS lesions with Marburg-like features.\n\ntumefactive multiple sclerosisbrain biopsyrituximabcyclophosphamidemarburg-variant\n==== Body\nIntroduction\nTumefactive demyelinating lesions (TDL), characterized by the presence of large (>2 cm), tumor-like lesions in CNS with perilesional edema, mass effect and/or broken ring-enhancement on MRI imaging, require a careful differential diagnosis, mainly ruling out an underlying tumor-mimicker (1, 2). The prevalence of TDLs has been reported to be 1–2 per 1000 cases of Multiple Sclerosis (3). Nevertheless, this prevalence has not been replicated in all studies due to disease heterogenicity and to the lack of appropriate registries in all countries, with studies showing a range of prevalence between 1.4–8.2% of Multiple Sclerosis patients (4). The demographics of patients with tumefactive demyelinating lesions show a slight preference of the disease to women than in men, and seems to mostly affect patients in the third and fourth decade (4). TDL may emerge during the disease course of Multiple Sclerosis (MS) or even be its first clinical presentation (Tumefactive MS) (2, 5). Interestingly, specific disease modifying drugs (e.g., fingolimod) used in MS have been associated with the appearance of TDL lesions, especially after drug-initiation or cessation (6–8). Nevertheless, TDL could represent a unique form of isolated atypical demyelinating disease, without classical radiological MS features, presenting either as monophasic disease (Monophasic TDL) or as recurrent TDL (Recurrent TDL). Studies examining the pathology of TDL lesions have shown tissue similarities with prototypical MS lesions, albeit with the unique appearance of Creutzfeldt– Peters cells and dystrophic astrocytes (9). A rare atypical demyelinating disease, that shares radiological and pathological similarities with TDL and MS, is the Marburg variant of MS (10). Marburg's disease course is considered to be monophasic, with poor response to conventional acute treatments, leading soon to death. The hallmark of Marburg's pathology are highly destructive lesions with extensive macrophage infiltration, massive demyelination, and axonal injury with overt necrosis and cavitation (9).\n\nCase Presentation\nWe describe a 50-year-old woman, with an unremarkable past medical history, who presented with irritability, memory difficulties, severe headache and mild difficulty in gait, 1-month prior to her admission to hospital (hospitalization in another Neurology Department). Her physical examination showed left pyramidal tract signs, with a Babinski reflex on the left and motor deficit of the left upper (4+/5 MRC) and lower limb (5-/5 MRC). Magnetic resonance imaging (MRI) of the brain revealed a tumefactive right frontal-parietal lesion (T2/FLAIR hyperintense lesion), with perilesional edema, mass effect and with homogenous post-contrast enhancement, along with other small atypical lesions in the white matter (Figure 1). One of the white matter lesions in the left fronto-parietal junction displayed a ring-like appearance after gadolinium administration, whereas multiple other lesions exhibited a patchy enhancement pattern (Figure 1). Search for a primary neoplasm was negative (chest and abdominal CT scan). An extensive serological workup performed to exclude common infectious (including HIV) and autoimmune factors resulted negative. CSF analysis showed only increased IgG index (0.617), the absence of oligoclonal bands, and was negative for the detection of various common pathogens among which JC virus (PCR). Brain biopsy of cerebral lesion was performed and indicated the presence of foamy CD68-positive macrophages (macrophage rich lesion, with absence of expression of CD1a, Langerin, CD143, BRAFV600E, and S-100 markers by the macrophage histiocytes), along with dense perivascular presence of a variable numbers of T lymphocytes and a small number of B cells (images not available). No reaction with the antibody SV-40 that detects polyoma virus such as SV-40, JK, BK etc. was observed. There was no histological evidence of lymphoma or any other neoplastic process. The patient was treated with high doses of dexamethasone and levetiracetam (1,000 mg per day, initiated after brain biopsy by neurosurgeons), with gradual substantial clinical (EDSS = 0), and radiological remission (TDL lesion was not evident and only some T2-hyperintense areas persisted). A follow up brain MRI, 1 year after, also revealed resolution of the intraparenchymal mass lesion.\n\nFigure 1 Brain MRI's in chronological order showing the effect of various treatment modalities.\n\nTwo years after disease initiation, the patient experienced memory deficits, mild disorientation in time and space, gait instability and left upper extremity weakness, 15 days before her admission to our hospital. Neurological examination showed left hemiparesis. Brain MRI imaging revealed reappearance of a tumor-like mass, in the same site as the initial presentation, with a greater mass effect and strong contrast enhancement (almost homogeneous) (Figure 1). Spine MRI was normal. Evaluation of serological parameters, including AQ4 (Euroimmun, Lübeck, Germany) and MOG abs (live cell-based assay), was negative, except for the presence of serum monoclonal IgA (k) type paraprotein (11). Bone marrow examination revealed findings compatible with MGUS (less that ~5% were CD138+ plasma cells).\n\nThe patient was placed initially on dexamethasone (12 mg/days) treatment due to the mass effect of lesion and then was initiated on intravenously administered pulses of Methylprednisolone (total 10.5 gr), followed by tapering with oral methylprednisolone. The patient exhibited significant clinical improvement along with partial radiological remission of the tumefactive lesion, that showed significant reduction in contrast enhancement. We considered that our patient suffered an aggressive form of tumefactive demyelination, with Marburg -like characteristics and decided to start her on a cyclophosphamide protocol. Nevertheless, during routine laboratory evaluation, we observed an asymptomatic elevation of liver enzymes (AST, ALT). The patient was evaluated by a gastroenterologist, underwent ultrasound imaging and placed on ursodeoxycholic acid, considering that liver dysfunction was associated with high doses of corticosteroids. Due to recurrence of left hemiparesis, 3 months after the second clinical attack, our patent received 750 mg Methylprednisolone and a low dose of cyclophosphamide (500 mg), that led to further deterioration of liver enzymes and no clinical response. At that time point a magnetic resonance spectroscopy (MRS) study of the frontal lobe lesion was performed, and was consistent with a demyelinating central nervous disease {high choline (Cho)/creatine (Cr) = 6.4, high Cho / N-acetylaspartate (NAA) = 2.57, high NAA/Cr = 1.4 ratio within the center of the lesion, presence of glutamic acid, lactate, and lipids}. We decided to switch to less hepatotoxic treatments, and therefore placed our patient on PLEX (plasma exchange) sessions (n = 6). PLEX was unable to control the disease burden and a new brain imaging showed an expansion of the tumefactive lesion that involved more white matter areas, with more pronounced insult of the centrum semiovale, expansion to the left hemisphere, extensive invasion of the cortex and more Gd (gadolinium)-enhancing areas (Figure 1). Taking into consideration the published therapeutic effect of Rituximab on TDL, we decided to continue our therapeutic efforts with cycles of Rituximab (12–14). Our patient received 4 cycles of Rituximab (600 mg every week for 1 month) and remained clinically stable up till the third cycle. Disease exacerbation was observed following the 4th dose of Rituximab with worsening of hemiparesis and signs of intracranial hypertension (Figure 1). Interestingly, our patient relapsed while the total number of peripheral CD20 cells were 0. She received rescue therapy with mannitol and 6 gr of Methylprednisolone with modest clinical improvement.\n\nThe extremely aggressive nature of the disease and the resistance to intense therapeutic options prompted us to reconsider the diagnosis and perform a second brain biopsy (1 month after the 4th dose of Rituximab). Histopathologic analysis revealed inflammatory demyelination particularly in areas of perivascular cuffing, predominantly consisting of CD68 macrophages (Figure 2). Parenchymal and to lesser extent perivascular infiltrates composed of small number of T lymphocytes, with relatively fewer B cells (Figure 2). Moreover, we observed the presence of reactive astrocytes with concomitant presence of nuclei with 'granular mitosis', typical of Creutzfeldt-Peters cells, frequently seen in tumefactive demyelinating lesions. Again, both lymphoma and Progressive multifocal leukoencephalopathy (PML) were excluded (Figure 2). The possibility of “ghost lymphoma” (i.e., vanishing of primary central nervous system diffuse large B cell lymphoma after steroid treatment) could not be excluded totally, but did not seem plausible, especially since it was not observed in two different biopsies of the patient (Figure 2).\n\nFigure 2 Histopathological study of the tumefactive lesion showing active demyelination (second biopsy). Immunohistochemical (IHC) findings of parenchymal inflammatory infiltrates were invariably present and mainly consisted of macrophage rich lesions (A), accompanied by foamy macrophages with perivascular cuffing (B, black arrow) and astrocytes with granular mitosis, also known as Creutzfeldt-Peters cells (C, black arrow: Creutzfeldt cell with fragmented micronuclei) (hematoxylin and eosin stain). Tissue section with extensive macrophage infiltration (D, IHC for CD68/clone PGM1), with mainly perivascular location (E, black arrow). Relative axonal preservation (IHC stain for neurofilaments) (F). Demyelination was observed as a loss of Luxol fast blue staining (Kluver-Barrera stain), and was most obvious in perivascular areas (G, black arrow, region of pallor, indicating myelin loss). Presence of granules of myelin inside the cytoplasm of macrophages, in contrast to elongated structures forming the classical myelin sheaths (H, black arrows, granules of myelin). Perivascular demyelination was also evident by loss of Myelin Basic Protein (MBP), in perivascular spaces (I, black arrow, IHC stain for MBP). Only few B cells were observed in tissue sections (J: IHC for CD20). Progressive multifocal leukoencephalopathy was excluded by the absence of staining with antibodies against Simian Virus-40 and p53 (K,L, respectively).\n\nGiven that the patient's liver enzymes returned to normal values and the scenario of a CNS lymphoma seemed remote, we placed our patient on high doses of cyclophosphamide (1 gr/m,2 every 21 days), for the ensuing consecutive 7 months, along with prophylactic antibiotics. Our patient responded in a dramatic fashion to cyclophosphamide infusions, with initial improvement of her clinical condition, and without manifesting progression of the disease. Her residual deficits included mild left sided disability with an EDSS of 2. Brain MRI showed a reduction in the mass effect, as well as a reduction of contrast enhancement of prior lesions (Figure 1). Nevertheless, a new relapse (3 years after the first clinical attack) occurred after the seventh dose of cyclophosphamide, with expansion of lesions to the brainstem. She was placed on Rituximab with no clinical response. She deteriorated clinically, and finally died from complicated pneumonia after a long hospitalization period (5-months) (Figure 1). Post-mortem brain tissue examination was indicative of demyelinating lesions of the CNS without evidence of a neoplastic process.\n\nDiscussion\nFulminant demyelinating diseases represent a diagnostic challenge for clinicians and include acute disseminated encephalomyelitis, multiple sclerosis variants (Marburg variant, Tumefactive MS, Balo's concentric sclerosis) and neuromyelitis optica spectrum disorders (15). Herein we presented an extremely rare case with recurrent TDL appearance on brain imaging, with atypical tumor-like features (mass effect, homogenous enhancement, recurrence in the same anatomical site and expansion), with initial response to high doses of steroids and cyclophosmamide but subsequent resistance, with exacerbation after rituximab administration, and finally with fatal outcome. Tumefactive demyelination is considered to be not a distinct disease entity but rather a type of lesions encountered in different disease settings with Multiple Sclerosis and its variants to be the most prevalent (5). Nevertheless, TDL might occur in patients with other atypical demyelinating syndromes such as Acute Disseminated Encephalomyelitis (ADEM), AQ4 IgG seropositive or MOG-seropositive Neuromyelitis Optica Spectrum Disorders (NMOSD), as well as other neuroinflammatory disorders, such as Neurosarcoidosis or Behçet's disease (4). Of note, the spectrum of MOG antibody-associated encephalomyelitis the last years has expanded to involve cases with TDL and ADEM-like presentation, clinical presentations that could fit to our patient history (11, 16). Nevertheless, our patient was negative for both MOG and AQ4 autoantibodies. Another question regarding the differential diagnosis of our case is whether the observed demyelinating lesions could be encountered as part of a paraneoplastic syndrome or as part of an autoimmune encephalitis (17, 18). Screening for an underlying malignancy with whole body computed tomography and onconeural antibodies was negative. Particularly anti-NMDAR encephalitis has been recently associated with demyelinating events as concurrent or independent episodes (19–21). Whether the radiological and pathological differences between above disorders are sufficient to define them as separate diseases remain unclear. Till today a limited number of specific biomarkers exist to distinguish between the various demyelinating syndrome subtypes. The emergence of NMDAR, AQ4, and MOG IgG autoantibodies changed our diagnostic and treatment strategies, but more research is needed to expand our knowledge about these disease entities. An extended assessment for underlying infection, auto-immune and oncological disorders was performed in our case to rule out the various differential diagnosis, which is presented in Table 1 (15, 17, 22–26). The main differential diagnosis that remained was among tumefactive MS and the Marburg variant of MS.\n\nTable 1 Differential diagnosis of pseudotumoral lesions in brain MRI (tumors excluded).\n\nDifferential diagnosis of pseudotumoral lesions in brain MRI (tumors excluded)\tDisease entities\t\nCATEGORY\t\nMultiple sclerosis\tDuring disease course\t\n\tUpon drug initiation (fingolimod)\t\n\tUpon drug cessation (fingolimod, tysabri)\t\nAtypical MS\tBalo's concentric sclerosis\t\n\tSchilder's sclerosis (myelinoclastic diffuse sclerosis)\t\n\tMarburg varinat\t\n\tAcute hemorrhagic leukoencephalitis (AHL)\t\nIdiopathic demyalinting syndromes\tADEM\t\n\tNMO spectrum disorders\t\n\tMOG-encephalomyelitis\t\n\tMonophasic TDL\t\n\tRecurrent TDL\t\nNeuroinflammatory disorders\tSarcoidosis\t\n\tBehcet's disease\t\n\tIgG4 disease\t\n\tSystemic Lupus Erythematosus\t\n\tSjogren's Syndrome\t\n\tCerebral vasculitis (primary or secondary)\t\nParaneoplastic\tGerm cell tumor\t\n\tRenal cell carcinoma\t\n\tLymphoma\t\nInfectious\tHIV\t\n\tAbscess—bacterial, fungal\t\n\tTuberculoma\t\n\tToxoplasmosis\t\n\tCryptococcoma\t\n\tProgressive multifocal leukoencephalopathy (PML)\t\n\tLyme disease\t\n\tSyphilis\t\nGenetic disorders/ leuko-vasculopathies\tGenetic—retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations\n (RVCL-S)\t\n\tCADASIL\t\n\tCerebral amyloid angiopathy\t\nInherited leukodystrophy/\nleukoencephalopathy\tAdult-onset leukoencephalopathy with axonal spheroids\n and pigmented glia (ALSP) related to CSF1R gene\n mutations\t\n\tX-linked adrenoleukodystrophy (ALD)\t\nOthers\tOsmotic myelinolysis\t\n\tRadiation Leukoencephalopathy\t\n\tPosterior reversible encephalopathy syndrome (PRES)\t\n\tTacrolimus\t\n\tBevacizumab\t\nAHL, acute hemorrhagic leucoencephalitis; ADEM, acute disseminated encephalomyelitis; NMO, neuromyelitis optica; MOG, myelin oligodendrocyte glycoprotein; TDL, tumefactive demyelinating lesion; PML, progressive multifocal leukoencephalopathy; RVCL-S, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; ALSP, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; CSF1R, colony stimulating factor 1 receptor; ALD, adrenoleukodystrophy; PRES, posterior reversible encephalopathy syndrome.\n\nAn atypical and fulminant form of MS is the Marburg variant of disease. It was firstly described in 1906, and the classical form of the disease is characterized by a monophasic, highly aggressive course with rapid disease progression leading to death within weeks to months (27). The major histomorphological features of the disease involve intense macrophage infiltration, widespread demyelination (not only restricted to the perivascular areas), with further evidence of necrosis and cavitation, hypertrophic astrocytes and severe axonal injury (28). The fatal outcome of Marburg is mainly attributed to brainstem involvement and to the highly intense inflammatory process that involves tumefactive lesions with mass effect, usually not responding to acute treatments (high doses of corticosteroids). The role of plasma exchange is controversial, with past reports showing improvement in some patients; however, recent data support the inefficiency or even worsening of the disease (29, 30). Regarding the highly inflammatory nature of the disease, more aggressive immunosuppression is warranted, and treatment decisions are based on prior case reports. There are some reports showing encouraging results with the use of high dose cyclophosphamide, others with mitoxantrone and a more recently published case with alemtuzumab (31–33). Nevertheless, previously reported cases were unsuccessfully treated with cyclophosphamide with death within weeks to months after treatment (34, 35). A possible explanation for the heterogeneity in cyclophosphamide response could be the different treatment protocols (dose, frequency, time to treatment) applied to patients.\n\nTumefactive MS is one of the rare variants of MS. There are no therapeutic guidelines, but acute treatment involves high doses of corticosteroids and if needed plasma exchange therapy (25). Long term therapy, based on case reports, involves disease-modifying treatments classically used in typical MS (36, 37). Recent evidence supports that fingolimod and natalizumab should be avoided in MS patient with tumefactive lesions due to TDL exacerbation (25). Aggressive cases have been treated with Rituximab and/or cyclophosphamide (14). Pathological features are somewhat similar to those seen in prototypical MS, but with prominent Creutzfeldt– Peters cells and dystrophic astrocytes (9).\n\nOur patient presented both features of Marburg variant of MS (aggressive and finally fatal disease outcome, diffuse infiltrative lesions on MRI unlike typical MS lesions) and tumefactive MS (typical histopathology, recurrent TDL appearance). Nevertheless, there are atypical features for both diagnoses. In particular, regarding the diagnosis of Marburg, atypical features include the recurrent nature of disease, and the absence of overt necrosis, as well as of axonal degeneration on biopsy. Regarding tumefactive MS, an atypical feature is the eventual resistance to all conventional therapies (corticosteroids, plex cyclophosphamide, rituximab). We consider our case unique, due to its distinct neuropathological findings and the ultimately poor response to high dose immunosuppressive treatment. The main histopathological finding (from two tissue biopsies during disease evolution and postmortem biopsy) was the perivascular demyelination and the accumulation of macrophage-rich lesions in inflamed tissue specimens. B and T cells were present to a lesser extent. Interestingly, our patient suffered disease exacerbation twice after 4 cycles of rituximab without the presence of B cells in the periphery.\n\nVarious hypothesis can be made to delineate the post-rituximab relapses. Studies in mice in models of experimental autoimmune encephalomyelitis (EAE) and in human diseases such as Sjögren's syndrome or rheumatoid arthritis have shown that anti-CD20 treatment may not eliminate a fraction of memory antigen-experienced B cells, presumably in organs other than the blood (lymphoid tissues). In individuals with increased constitutive levels of the cytokine BAFF (tumor necrosis factor ligand superfamily member 13B), BAFF, a potent B cell stimulator, may promote a fast-clonal expansion of insufficiently depleted remaining B-cells. Nevertheless, peripheral blood immunophenotyping in our case, after rituximab treatment, did not reveal reemergence of B cells upon clinical relapse, indicating that other possible mechanisms independent of memory B cells may account for disease exarbetation. An alternative explanation could be the reactivation of autoreactive long-lived plasma cells, which are not targeted by rituximab. This observation is consistent with other reports of an increase in disease activity shortly after rituximab treatment in MS and NMO (38, 39). Finally, there is a cross-talk among specific subsets of regulatory B cells and cells of the myeloid lineage, resulting in a suppressive effect of B cells (IL-10 producing B cells) over the activation status and proinflammatory differentiation of monocytes (40, 41). This is highlighted in a recently published case report showing vast CNS infiltration of monocytes after administration of alemtuzumab in an NMO patient (42). Overall, these findings suggest that the therapeutic use of rituximab or other B-cell depleting therapies in various demyelinating diseases, including our case, requires high clinical vigilance, since post-rituximab effects could be variable, depending on the inflammatory milieu and the interaction with cells of myeloid lineages.\n\nThe largest case series of biopsy-proven tumefactive demyelination with 168 cases by Luchinetti et al., has shown that 14% of patients exhibited a monophasic course, and 70% of patients eventually developed definite multiple sclerosis, with the median time to relapse to be 4.8 years (43). Regarding the severity of the overall clinical course of TDLs, Staley A Brod et al., showed that patients with Tumefactive MS exhibit a benign disease course and are successfully treated with classical MS disease-modifying therapy (44). Till today there are no clear clinical/serological and/or radiographical biomarkers assessing the risk for disease evolution and conversion to clinically definite MS. This information is critically important because determines our further therapeutic strategies after the first TDL appearance. There is no consensus regarding the use of disease modifying therapies (DMT) to decrease the risk of a second clinical attack. Many clinicians suggest using DMTs only in patients with a higher risk of conversion or in patients fulfilling MS diagnostic criteria. Potential suggested risk factors described the literature, include age at disease onset, a particularly disabling first attack, the type of enhancement pattern, and the concomitant with TDL presence of other typical MS lesions (1). Regarding our case, during the initial clinical attack of TDL (hospitalization in another hospital), we postulate that there was insufficient evidence that time point for starting MS disease modifying therapy (DMT). OCBs were tested negative, brain MRI revealed white matter lesions not typical for classical MS lesions and there was almost complete clinical and radiological response to corticosteroids. Nevertheless, the natural history of the disease stresses the need for future studies assessing better the risk for disease recurrence (new serum or CSF biomarkers, IgG index).\n\nDiagnosis of TDL does not usually involve brain tissue biopsy, since emerging neuroimaging data contribute to proper diagnosis. The employment of various techniques, such as magnetic resonance spectroscopy (MRS), Positron emission tomography–computed tomography (PET-CT) and 8F-fluoroethyl-L-tyrosine (FET) PET can differentiate between tumor or tumefactive demyelinating (45–48). Nevertheless, the accuracy of this discrimination is not always optimal and there are limitations and gray zones. In one of the largest cohorts of biopsy-proven TDLs, about 30% of biopsies were initially misdiagnosed (43). Close monitoring of disease evolution with neurologic examination, repeated MRI scans and exclusion of other etiologies with appropriate work-up, aid the proper diagnosis. Atypical MRI characteristics (pattern of contrast enhancement, mass effect, oedema), inconclusive results of MRS, inappropriate response to immunotherapy render brain biopsy necessary.\n\nConclusions\nHerein, we report a case of late-onset recurrent Tumefactive Demyelinating lesion (TDL) mimicking a brain tumor. The demyelinating nature of the lesion was confirmed by brain biopsy and post-portem tissue examination as well. In our extremely rare case of fulminant tumefactive demyelination, only high doses of cyclophosphamide were able to control disease for a limited time period (7-months), indicating that alternative high-dose immunosuppressive therapies (e.g., hematopoietic stem cell transplantation) could possibly exhibit a therapeutic benefit. Of note, plasmapheresis did not control the highly aggressive tumefactive demyelination. The lack of therapeutic response despite a strenuous immunosuppressive attempt points out the need for future research in this area. Our clinical case is of great importance, as it raises therapeutic dilemmas, and points to the need for immediate and appropriate immunosuppression in difficult to treat tumefactive CNS lesions. It also highlights the need for better assessment of risk factors favoring disease relapse after the first TDL attack, in order to better determine optimal therapeutic strategies. Moreover, it underlines the value of neuropathological analysis of tumefactive lesions, not only for exclusion of other alternative diagnosis, but also for revealing the type of tissue inflammation in a attempt to better define the appropriate treatment options.\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nWritten informed consent was obtained from the next of kin of the patient for the publication of any potentially identifiable images or data included in this article.\n\nAuthor's Note\nThis case submission met all of the requirements for publication under the approval of the ethics committee of Eginition Hospital (12360/2.12.2019).\n\nAuthor Contributions\nAV wrote, edited manuscript, and designed figure. DT, GK, M-EE, EA, MA, MB, JT, EG, and AD collected clinical data and treated patients in the hospital. GV and PT analyzed MRI data. TA analyzed tissue biopsies by immunochemistry and critically revised manuscript. LS and CK contributed to drafting of the work and revising it critically for important intellectual content. All authors provided approval for publication of the content of the paper and agreed to be accountable for all aspects of the work.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Abdoli M Freedman MS \nNeuro-oncology dilemma: tumour or tumefactive demyelinating lesion\n. Mult Scler Relat Disord . (2015 ) 4 :555 –66\n. 10.1016/j.msard.2015.07.013 26590662 \n2. Frederick MC Cameron MH . Tumefactive demyelinating lesions in multiple sclerosis and associated disorders\n. Curr Neurol Neurosci Rep . (2016 ) 16 :26 . 10.1007/s11910-016-0626-9 26847090 \n3. Poser S Luer W Bruhn H Frahm J Bruck Y Felgenhauer K . 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"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "11()",
"journal": "Frontiers in neurology",
"keywords": "brain biopsy; cyclophosphamide; marburg-variant; rituximab; tumefactive multiple sclerosis",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "536",
"pmc": null,
"pmid": "32714265",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "24347182;31245023;29673573;21932127;21442242;23804236;1481644;22027448;30844860;22475882;28991707;21565508;14748210;29709955;2266377;19172322;19779719;10589540;26590662;20461429;25340086;12223381;26869529;17296993;24700511;27037180;30588483;32217464;28619436;8687186;18677644;25738163;23334629;31954354;27478954;29055482;18535080;12244307;30153143;25824955;30933712;8170550;26847090;25815356;30056362;29708466;26088612;30925320",
"title": "Recurrent Fulminant Tumefactive Demyelination With Marburg-Like Features and Atypical Presentation: Therapeutic Dilemmas and Review of Literature.",
"title_normalized": "recurrent fulminant tumefactive demyelination with marburg like features and atypical presentation therapeutic dilemmas and review of literature"
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"companynumb": "GR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-256748",
"fulfillexpeditecriteria": "1",
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"abstract": "BACKGROUND\nCardiovascular disease is a major cause of mortality in solid organ allograft recipients. Hand transplantation is not a lifesaving procedure, thus the effect of long-term immunosuppression on the cardiovascular system in these patients should be monitored. The aim of this study was to evaluate the morphology and function of heart and blood vessels in patients after hand transplantation.\n\n\nMETHODS\nThe study included 5 patients at ages 32 to 58 years, mean 39 years, who underwent hand transplantation between 2006 and 2010. Immunosuppressive treatment included basiliximab in induction and tacrolimus, mycophenolate mofetil, and prednisone. Cardiac status was assessed by echocardiography (according to the American Society of Echocardiography) and cardiac biomarkers. Blood vessels were estimated by carotid intima-media thickness, pulse wave velocity, and brachial artery flow-mediated dilatation (FMD). The examinations were performed at 28 to 79 (mean 43) months after transplantation.\n\n\nRESULTS\nCardiovascular risk factors were observed in all patients after transplantation: 2 had insulin-dependent diabetes, 3 developed dyslipidemia and hypertension, 2 had chronic kidney disease stage 3. Concentric left ventricular hypertrophy was found in 1 and ventricular concentric remodeling in 4 patients. Impaired diastolic function (E/e' > 8) was observed in 2 patients. The index volume of the left atrium was higher in all patients. The cardiac biomarkers N-terminal pro-brain natriuretic peptide, C-reactive protein, and troponins were within normal range. Carotid intima-media thickness was higher in 1 patient and normal in 4 patients. Arterial stiffness measured by pulse wave velocity was not increased in all patients. Native brachial artery FMD response, an index of endothelium-dependent function, was abnormal in 2 patients, but in the transplanted extremity FMD was abnormal in 4 patients.\n\n\nCONCLUSIONS\nPathologic changes in cardiac structures were found in all patients, but the arterial wall changes and endothelial dysfunction were observed in some patients. Patients after hand transplantation are at higher risk for cardiovascular disease.",
"affiliations": "Department of Nephrology and Transplant Medicine, Wrocław Medical University, Wrocław, Poland. Electronic address: maria.boratynska@op.pl.;Department of Cardiac Surgery, Wrocław Medical University, Wrocław, Poland.;Department of Angiology and Hypertension, Wrocław Medical University, Wrocław, Poland.;Department of Angiology and Hypertension, Wrocław Medical University, Wrocław, Poland.;Department of Nephrology and Transplant Medicine, Wrocław Medical University, Wrocław, Poland.;Department of Nephrology and Transplant Medicine, Wrocław Medical University, Wrocław, Poland.;Department of Nephrology and Transplant Medicine, Wrocław Medical University, Wrocław, Poland.;Department of Nephrology and Transplant Medicine, Wrocław Medical University, Wrocław, Poland.;Subdepartment of Limb Replantation, St. Hedvig Hospital, Trzebnica, Poland.;Subdepartment of Limb Replantation, St. Hedvig Hospital, Trzebnica, Poland.;Department of Nephrology and Transplant Medicine, Wrocław Medical University, Wrocław, Poland.",
"authors": "Boratyńska|M|M|;Obremska|M|M|;Małecki|R|R|;Gacka|M|M|;Magott|M|M|;Kamińska|D|D|;Banasik|M|M|;Kusztal|M|M|;Chełmoński|A|A|;Jablecki|J|J|;Klinger|M|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D002318:Cardiovascular Diseases; D059168:Carotid Intima-Media Thickness; D064595:Composite Tissue Allografts; D005260:Female; D063987:Hand Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D063986:Vascularized Composite Allotransplantation; D020257:Ventricular Remodeling",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2890-3",
"pmc": null,
"pmid": "25380944",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of immunosuppressive treatment on the cardiovascular system in patients after hand transplantation.",
"title_normalized": "impact of immunosuppressive treatment on the cardiovascular system in patients after hand transplantation"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-296220",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "A report of three cases of spontaneous rectus sheath haematoma within a 1-month period in a single hospital. The common feature was the recent treatment with low molecular weight heparin. In contrast to the perceived benign nature of the classically-described haematoma, the cases described were life-threatening and required aggressive intervention.",
"affiliations": "Centre for Academic Surgery, Royal London Hospital, London, UK.",
"authors": "Donaldson|J|J|;Knowles|C H|CH|;Clark|S K|SK|;Renfrew|I|I|;Lobo|M D|MD|",
"chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight",
"country": "England",
"delete": false,
"doi": "10.1308/003588407X179152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-8843",
"issue": "89(3)",
"journal": "Annals of the Royal College of Surgeons of England",
"keywords": null,
"medline_ta": "Ann R Coll Surg Engl",
"mesh_terms": "D015746:Abdominal Pain; D000368:Aged; D000925:Anticoagulants; D005260:Female; D006406:Hematoma; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008875:Middle Aged; D017568:Rectus Abdominis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7506860",
"other_id": null,
"pages": "309-12",
"pmc": null,
"pmid": "17394721",
"pubdate": "2007-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11694962;4261328;9313718;2972238;6450521",
"title": "Rectus sheath haematoma associated with low molecular weight heparin: a case series.",
"title_normalized": "rectus sheath haematoma associated with low molecular weight heparin a case series"
} | [
{
"companynumb": "GB-SA-2020SA157577",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "The safety and efficacy of the new 5HT-3 antagonist granisetron as an antiemetic in children with cancer was evaluated in 40 children at a single dose of 40 micrograms/kg. No adverse affects attributable to the granisetron were noted. The overall major and complete response rate was 82.5% and this was highest in the younger children. Only 2 patients showed no response. Pharmacokinetic studies showed associations between some pharmacokinetic parameters and age which were no longer apparent after normalisation for body weight. Granisetron is an effective and very well-tolerated antiemetic and appears to be an important addition to the supportive care available for children with cancer.",
"affiliations": "Children's Cancer Unit, University of Newcastle upon Tyne, United Kingdom.",
"authors": "Craft|A W|AW|;Price|L|L|;Eden|O B|OB|;Shaw|P|P|;Campbell|R|R|;Pierce|D M|DM|;Murdoch|R|R|;Upward|J|J|",
"chemical_list": "D000970:Antineoplastic Agents; D017829:Granisetron",
"country": "United States",
"delete": false,
"doi": "10.1002/mpo.2950250107",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-1532",
"issue": "25(1)",
"journal": "Medical and pediatric oncology",
"keywords": null,
"medline_ta": "Med Pediatr Oncol",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D017829:Granisetron; D006801:Humans; D008297:Male; D014839:Vomiting",
"nlm_unique_id": "7506654",
"other_id": null,
"pages": "28-32",
"pmc": null,
"pmid": "7752999",
"pubdate": "1995-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Granisetron as antiemetic therapy in children with cancer.",
"title_normalized": "granisetron as antiemetic therapy in children with cancer"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1099506",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GRANISETRON"
},
"drugadditional": "3",
... |
{
"abstract": "The cause of prolonged or recurrent symptoms following the cessation of long-term benzodiazepine use is proposed to be related to downregulation and allosteric decoupling of the γ-aminobutyric acid/benzodiazepine receptor complex. This case series describes 2 patients with prolonged (>2 weeks) recurrent complications during attempted tapering of benzodiazepine doses after long-term treatment. Excited catatonia developed in a 90-year-old woman, and prolonged delirium developed in a 69-year-old woman. Both patients showed improvement of symptoms after resumption of higher doses of benzodiazepine treatment and recurrence of symptoms when the dose was again lowered. Caution should be exercised regarding the long-term use of benzodiazepines in older adults (aged ≥65 years). Tapering of benzodiazepines in older patients after long-term treatment may require slow decreases in dose over long periods. Psychotherapeutic interventions, such as brief cognitive therapy with psychoeducation and motivational enhancement, and osteopathic manipulative treatment to decrease paravertebral muscle tension may be beneficial during the tapering process.",
"affiliations": null,
"authors": "Reeves|Roy R|RR|;Kamal|Arif|A|",
"chemical_list": "D001569:Benzodiazepines; D008140:Lorazepam; D003975:Diazepam",
"country": "United States",
"delete": false,
"doi": "10.7556/jaoa.2019.055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-6151",
"issue": "119(5)",
"journal": "The Journal of the American Osteopathic Association",
"keywords": null,
"medline_ta": "J Am Osteopath Assoc",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001569:Benzodiazepines; D015928:Cognitive Behavioral Therapy; D003975:Diazepam; D005260:Female; D006801:Humans; D008140:Lorazepam; D026301:Manipulation, Osteopathic; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "7503065",
"other_id": null,
"pages": "327-331",
"pmc": null,
"pmid": "31034071",
"pubdate": "2019-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complicated Withdrawal Phenomena During Benzodiazepine Cessation in Older Adults.",
"title_normalized": "complicated withdrawal phenomena during benzodiazepine cessation in older adults"
} | [
{
"companynumb": "US-MYLANLABS-2020M1049911",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nUsing national Danish registers, we estimated rates of clozapine-associated cardiac adverse events. Rates of undiagnosed myocarditis were estimated by exploring causes of death after clozapine initiation.\n\n\nMETHODS\nThrough nationwide health registers, we identified all out-patients initiating antipsychotic treatment (January 1, 1996-January 1, 2015). Rates of clozapine-associated myocarditis and pericarditis within 2 months from clozapine initiation and rates of cardiomyopathy within 1-2 years from clozapine initiation were compared to rates for other antipsychotics. Mortality within 2 months from clozapine initiation was extracted.\n\n\nRESULTS\nThree thousand two hundred and sixty-two patients of a total 7932 patients initiated clozapine as out-patients (41.12%). One patient (0.03%) developed myocarditis, and no patients developed pericarditis within 2 months from clozapine initiation. Two (0.06%) and four patients (0.12%) developed cardiomyopathy within 1 and 2 years respectively. Rates were similar for other antipsychotics. Twenty-six patients died within 2 months from clozapine initiation. Pneumonia (23.08%) and stroke (11.54%) were the main causes of death. We estimated the maximum rate of clozapine-associated fatal myocarditis to 0.28%.\n\n\nCONCLUSIONS\nCardiac adverse effects in Danish out-patients initiating clozapine treatment are extremely rare and these rates appear to be comparable to those observed for other antipsychotic drugs.",
"affiliations": "Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark.;Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.;Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.;Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark.;Metro South Addiction and Mental Health Service, Brisbane, QLD, Australia.;Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark.",
"authors": "Rohde|C|C|http://orcid.org/0000-0001-9458-506X;Polcwiartek|C|C|;Kragholm|K|K|;Ebdrup|B H|BH|http://orcid.org/0000-0002-2590-5055;Siskind|D|D|http://orcid.org/0000-0002-2072-9216;Nielsen|J|J|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.1111/acps.12827",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-690X",
"issue": "137(1)",
"journal": "Acta psychiatrica Scandinavica",
"keywords": "Danish nationwide registers; antipsychotics; cardiomyopathy; clozapine; mortality; myocarditis; pericarditis",
"medline_ta": "Acta Psychiatr Scand",
"mesh_terms": "D000328:Adult; D000368:Aged; D000553:Ambulatory Care; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D009202:Cardiomyopathies; D003024:Clozapine; D003718:Denmark; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009205:Myocarditis; D010493:Pericarditis; D011618:Psychotic Disorders; D012042:Registries; D012559:Schizophrenia",
"nlm_unique_id": "0370364",
"other_id": null,
"pages": "47-53",
"pmc": null,
"pmid": "29064084",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adverse cardiac events in out-patients initiating clozapine treatment: a nationwide register-based study.",
"title_normalized": "adverse cardiac events in out patients initiating clozapine treatment a nationwide register based study"
} | [
{
"companynumb": "DK-JNJFOC-20180105681",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "We discuss the current understanding of COVID-19's neurological implications, their basis, and the evolving clinical consensus with a focus on cerebrovascular stroke. We further illustrate the potential significance of these implications with the aid of an accompanying case report outlining the disease course and treatment of a COVID-19 patient suffering from ischemic stroke and pulmonary embolism. The ever-growing strain on the global healthcare system due to the spread of the novel coronavirus SARS-CoV-2 requires focused attention on urgent care of independent, coexisting, and associated comorbidities, including cerebrovascular accidents. For illustration purposes, we outline the case of a 68-year-old female presenting with COVID-19 subsequently complicated by bilateral pulmonary embolism and a right-sided cerebrovascular accident. The patient was successfully managed pharmacologically and discharged without significant neurological deficit. The evidence for a hypercoagulable state in this patient along with discussion of mechanistic bases, corroborative evidence from the literature, along with relevant guidance on screening, treatment, and prophylaxis is offered. Greater study of the pathogenesis of COVID-19-related cerebrovascular complications and revisiting current guidelines on their management including potentially heightened levels of thromboprophylaxis are warranted.",
"affiliations": "University of Toronto, Toronto, Ontario Canada.;Department of Neurology and Internal Medicine, Yale University, New Haven, CT USA.",
"authors": "Yeganegi|Masoud|M|0000-0002-5053-8517;Fattahi|Pooia|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s42399-021-00744-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2523-8973",
"issue": null,
"journal": "SN comprehensive clinical medicine",
"keywords": "Acute ischemic stroke (AIS); Anticoagulation; COVID-19; Case report; Cerebrovascular accident (CVA); Fibrinolysis; Hypercoagulation; Low-molecular-weight heparin (LMWH); Neurological; Pulmonary embolism; SARS-CoV-2; Stroke; Thrombolytics; Thromboprophylaxis; Tissue plasminogen activator (tPA)",
"medline_ta": "SN Compr Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101740833",
"other_id": null,
"pages": "1-12",
"pmc": null,
"pmid": "33490876",
"pubdate": "2021-01-16",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "32104915;32178975;32302448;32073213;32246317;32172226;32654680;32275288;32302445;32294289;32294295;15272286;32329796;32503883;32443166;33125542;33187638;32219356;33009426;32320008;31423111;32689588;32320003;32171076;32302462;32614385;32281766;31376606;32293910;32125452;32912525;32300051;31573350;32432996;32338827;32593341;32330277;32289789;32334918;32247329;32367170;32838109;32087114;32353746;32113704;32267998;32310017;32253352;32350134;31986264;32586968;32301553;16268470;32787707;32757751;32291094;32330276;27452769;32912598;14736283;32220112;32302438;20171552;32192578;32268022;32242738;32233980",
"title": "Management and Prevention of Cerebrovascular Accidents in SARS-CoV-2-Positive Patients Recovering from COVID-19: a Case Report and Review of Literature.",
"title_normalized": "management and prevention of cerebrovascular accidents in sars cov 2 positive patients recovering from covid 19 a case report and review of literature"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/21/0133013",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": nul... |
{
"abstract": "Severe cutaneous adverse drug reactions (SCAR) such as the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DIHS) can be induced by a plethora of medications. The field of pharmacogenomics aims to prevent severe adverse drug reactions by using our knowledge of the inherited or acquired genetic risk of drug metabolizing enzymes, drug targets, or the human leukocyte antigen (HLA) genotype. Dermatologists are experts in the diagnosis and management of severe cutaneous adverse drug reactions (SCAR) in both the inpatient and outpatient setting. However, most dermatologists in the US have not focused on the prevention of SCAR. Therefore, this paper presents a case series and review of the literature highlighting salient examples of how dermatologists can apply pharmacogenomics in the diagnosis and especially in the prevention of SCAR induced by allopurinol and sulfamethoxazole/trimethoprim, two commonly prescribed medications.",
"affiliations": "Department of Dermatology, University of California, San Diego, CA 92093, USA.;Department of Dermatology, University of California, San Diego, CA 92093, USA.",
"authors": "Ikediobi|Ogechi|O|;Schneider|Jeremy A|JA|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jpm11020071",
"fulltext": "\n==== Front\nJ Pers Med\nJ Pers Med\njpm\nJournal of Personalized Medicine\n2075-4426\nMDPI\n\n33530463\n10.3390/jpm11020071\njpm-11-00071\nCase Report\nPharmacogenomics of Allopurinol and Sulfamethoxazole/Trimethoprim: Case Series and Review of the Literature\nIkediobi Ogechi *\nSchneider Jeremy A.\nLee Su-Jun Academic Editor\nDepartment of Dermatology, University of California, San Diego, CA 92093, USA; j3schneider@health.ucsd.edu\n* Correspondence: oikediobi@health.ucsd.edu\n26 1 2021\n2 2021\n11 2 7105 1 2021\n23 1 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nSevere cutaneous adverse drug reactions (SCAR) such as the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DIHS) can be induced by a plethora of medications. The field of pharmacogenomics aims to prevent severe adverse drug reactions by using our knowledge of the inherited or acquired genetic risk of drug metabolizing enzymes, drug targets, or the human leukocyte antigen (HLA) genotype. Dermatologists are experts in the diagnosis and management of severe cutaneous adverse drug reactions (SCAR) in both the inpatient and outpatient setting. However, most dermatologists in the US have not focused on the prevention of SCAR. Therefore, this paper presents a case series and review of the literature highlighting salient examples of how dermatologists can apply pharmacogenomics in the diagnosis and especially in the prevention of SCAR induced by allopurinol and sulfamethoxazole/trimethoprim, two commonly prescribed medications.\n\npharmacogenomics\ndermatology\ndrug-induced hypersensitivity syndrome\nStevens–Johnson syndrome\ntoxic epidermal necrolysis\nsevere cutaneous adverse drug reaction\n==== Body\n1. Introduction\n\nSevere cutaneous adverse drug reactions (SCAR) such as the epidermal necrolysis characteristic of the Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and the morbilliform exanthematous rash with the systemic involvement characteristic of drug-induced hypersensitivity syndrome (DIHS) are classified as delayed type (type-IV) hypersensitivity reactions [1]. Type IV hypersensitivity reactions are characterized by the activation of CD4 and CD8 lymphocytes and often develop 7 days to several weeks after drug exposure [1]. Many studies have elucidated an interaction between human leukocyte antigen (HLA) and drugs in inducing T-cell receptor (TCR) signaling and subsequent lymphocyte activation. There are several examples of specific HLA alleles associated with SCAR. Notably, carbamazepine and lamotrigine, commonly used anticonvulsant drugs, are associated with SCAR in patients of Asian ethnicity and the HLA-B*15:02 allele and in patients of European ancestry and the HLA-A*31:01 allele [1]. Similarly, the presence of the HLA-B*57:01 allele is associated with abacavir DIHS [1]. In all these examples, pre-emptive screening has been shown to reduce the incidence of SCAR [1].\n\nAllopurinol-induced SCAR is associated with the presence of the HLA-B*58:01 allele [1]. Pre-emptive screening for the HLA-B*58:01 allele has been shown to reduce the incidence of SCAR in new users of allopurinol in Europe, Asia and the US [2]. However, screening for the HLA-B*5801 allele is not as widespread in the US compared to Taiwan and other Asian countries [1,2].\n\nThere are two main reasons for the difference in the clinical implementation of pre-emptive screening between Asian countries and the US. First, Taiwan and China have a relatively homogeneous population with very little admixture, therefore genetic screening is much easier. Second, the reimbursement of testing is supported by national health insurance in Taiwan, China and Korea [1]. In the US, Medicare does reimburse for pharmacogenetic testing. However, there are no transparent policies with regards to pharmacogenetic testing from other health insurance agencies. However, the cost of testing nowadays is negligible and can often be justified with supporting medical literature from medical journals or the FDA drug label [1]. In the case of allopurinol, although there is no FDA label warning of the association between SCAR and the presence of HLA-B*58:01, the American College of Rheumatology (ACR) guidelines recommend pre-emptive testing in select Asian populations.\n\nInherited differences in the metabolism of drugs have also been shown to be associated with the development of SCAR. N-acetyl transferase 2 (NAT2) is an enzyme expressed in the human liver and intestines that acetylates arylamine carcinogens and many medications including: dapsone, isoniazid, hydralazine and sulfonamides [3]. The NAT2 slow acetylator phenotype is associated with isoniazid-induced hepatitis, sulfamethoxazole-induced cutaneous hypersensitivity and the increased frequency of certain cancers [3,4]. The US FDA label for sulfamethoxazole states that patients with a slow acetylator status are at increased risk of hypersensitivity reactions. In spite of this knowledge, it is not common practice to perform pre-emptive screening for NAT2 acetylator status prior to treatment with isoniazid or sulfamethoxazole. In fact, to our knowledge, there are no published studies demonstrating the implementation of NAT2 genetic testing to diagnose sulfamethoxazole-induced SCAR or pre-emptive NAT2 genetic testing to prevent sulfamethoxazole-induced SCAR.\n\n2. Patients and Methods\n\nHere, we present a case series at a single US institution describing the clinical management of SCAR induced by allopurinol and sulfamethoxazole/trimethoprim (Bactrim), emphasizing the role of inherited genetic risk and how dermatologists can play a larger role in preventing SCAR. The cases were treated at the University of California, San Diego (UCSD) in 2016 and 2020, respectively. The HLA-B*58:01 genetic test was performed at the UCSD Center for Advanced Laboratory Medicine (San Diego, CA, USA). The N-acetyltransferase 2 (NAT2) genetic test was performed at the Mayo Clinic Laboratory (Rochester, MN, USA). Informed consent was obtained from patients for the NAT2 genetic test as well as for the publication of the accompanying images.\n\n3. Case 1: Allopurinol Drug-Induced Hypersensitivity Syndrome with Toxic Epidermal Necrolysis-Like Phenotype\n\nMr. J, a 42-year-old man with a past medical history of type 2 diabetes mellitus, hypertension and gout presented to the Emergency Department in August 2016 with a three-day history of facial swelling and a morbilliform rash on his face and torso. He was initially diagnosed as having an allergic reaction and was prescribed antihistamines and prednisone and sent home. He presented a few days later with a notable progression of the rash that developed into bullae on his face, neck, trunk, extremities and involved his oral and genital mucosa. His serum chemistries were notable for an elevated creatinine 2.04 mg/dL (baseline creatinine 2.06 mg/dL) and elevated liver enzymes AST 135 units/L and ALT 270 units/L. There was no eosinophilia. On review of his medication history, he had been prescribed allopurinol, 300 mg daily, eight weeks prior for the management of gout. Given the severity of his rash and concern for DIHS, an HLA-B*58:01 test was ordered and he was positive for the risk allele (Table 1). Over the next week, his morbilliform exanthem progressed, taking on a dusky appearance, followed by extensive denudation; clinical history and repeat histologic sampling confirmed a diagnosis of DIHS with a TEN-like phenotype (sometimes classified as an “overlap” syndrome). He was transferred to the Burn ICU as per protocol and received treatment with Intravenous immunoglobulin (IVIG) IVIG and methylprednisolone. By October 2016, he developed septic shock and was treated appropriately with antibiotics. However, given the 80% body surface area (BSA) involvement of the epidermal necrosis (Figure 1) as well as his persistently elevated troponins, he developed unstable supraventricular tachycardia and died.\n\nIn 2016, the American College of Rheumatology (ACR) guidelines for the management of gout recommended the HLA-B*58:01 test for patients of Han Chinese, Thai or Korean descent. That recommendation was based on the initial studies that elucidated the relationship between HLA-B*58:01 and allopurinol hypersensitivity syndrome which were performed in Asia [2]. In 2017, a large cohort study of US patients initiated on allopurinol showed that among all ethnicities represented in the cohort, Native Hawaiian/Pacific Islanders, Asians and African Americans/Blacks had a higher risk of SCARs compared with Caucasians and Hispanics [5]. The findings of the study reflect the now known population frequency of HLA-B*58:01: 5.8–22% in Pacific Islanders, 7–20% in Asians, 2.6–6.4% of US Blacks, 1% in Hispanics/Mexicans and 1–2.9% in Caucasians [5]. A strength of this US-based study was the elucidation of other associated risk factors for allopurinol DIHS: female gender, age over 60 years, baseline chronic kidney disease (CKD) and an initial allopurinol dose greater than 100 mg daily [5]. Mr. J, in addition to being positive for the HLA-B*58:01 allele, had baseline CKD and was initiated on an allopurinol dose greater than 100 mg daily. All those factors combined put him at an increased risk of experiencing allopurinol DIHS but because he was not of Asian ethnicity, per 2012 ACR guidelines, he was not considered at high risk.\n\nA cost-effectiveness analysis of HLA-B*58:01 screening to guide allopurinol use in the treatment of gout found that HLA-B*58:01 testing was cost-effective for African Americans and Asians but not Caucasians and Hispanics [6]. However, the study also found that compared to no testing, universal testing cost more and was more effective for all ethnicities [6]. This is because regardless of ethnicity, if a patient carries the HLA-B*58:01 allele and has other risk factors such as CKD or age over 60 years, they are at increased risk of allopurinol DIHS [2].\n\nIn light of the recent findings, the revised 2020 ACR guidelines now recommend testing for HLA-B*58:01 in patients of South East Asian ancestry (e.g., Han Chinese, Thai or Korean descent) and African Americans [7]. The 2020 ACR guidelines also conditionally recommend against universal HLA-B*58:01 testing [7].\n\n4. Case 2: Allopurinol Drug-Induced Hypersensitivity Syndrome in a Hispanic Patient\n\nMs. M, an 81-year-old woman with a past medical history of CKD, hypertension and hyperlipidemia was transferred to UCSD hospital in March 2020 with a 2-week history of a morbilliform rash and worsening kidney function. The rash was preceded by prodrome of fever T100.4F and malaise. Two days after rash onset, the patient presented to her nephrologist who noted that her serum creatinine was elevated at 3.62 mg/dL (baseline 1.38 mg/dL). Her urinalysis was notable for proteinuria and hematuria. Upon review of her medication history, it was noted that the only recent change was that the patient was prescribed allopurinol 100 mg daily for hyperuricemia 5 weeks prior to the rash onset. Allopurinol was discontinued and the patient was prescribed a 4-day course of oral prednisone. Her rash improved while on prednisone, however, upon the discontinuation of prednisone, the rash recurred with an associated tingling sensation in her mouth and dizziness. She presented to the emergency department at her local hospital and her serum chemistries were notable for eosinophilia and elevated serum creatinine 4.32 mg/dL (baseline 1.38 mg/dL). Due to concerns of DIHS, the patient was transferred to the UCSD hospital. On presentation, the patient had a morbilliform rash on her torso and her serum chemistries were notable for an elevated absolute eosinophil count of 5000/mm3, elevated serum creatinine of 3.47 mg/dL and urinalysis with evidence of proteinuria but normal liver function tests. An HLA-B*58:01 test showed that the patient was positive for the risk allele (Table 1). She started on prednisone 1 mg/kg daily with a long taper and serum chemistries normalized within 1 month.\n\nThis case further illustrates the knowledge gap inherent in the current 2020 ACR guidelines that only recommend HLA-B*58:01 testing in patients of certain ethnicities. This patient, although not South East Asian or African American, carries the HLA-B*58:01 risk allele, is over the age of 60, has CKD and was prescribed allopurinol 100 mg daily. Therefore, she was at increased risk for allopurinol DIHS but based on current guidelines would not be pre-screened for the HLA-B*58:01 allele.\n\nIt is well established that ethnicity describes a person’s recent geographic ancestry and this is often used as a proxy for predicted genetics [8]. However, in genetically diverse and admixed populations such as Hispanics with varying degrees of European, Native American and African ancestry, it would be faulty to assume a person’s genetics based on their phenotypic appearance. For example, Puerto Ricans have more African and European ancestry vs. Native American ancestry compared to Mexicans who have more Native American and less African and European ancestry [8]. Therefore, it may be that Hispanics from Puerto Rico may have a higher likelihood of carrying the HLA-B*58:01 allele compared to Mexicans. Thus far, pharmacogenomic knowledge of the frequency of the HLA-B*58:01 allele in Hispanic populations is sparce and further studies are warranted.\n\nThe updated ACR guidelines are a step in the right direction and will likely be closely adhered to by practicing rheumatologists. However, allopurinol is also prescribed by primary care physicians and other specialists who may or may not follow the ACR guidelines recommendation to test for an HLA-B*58:01 allele in specific populations prior to initiating allopurinol. Therefore, we posit that a larger governing body such as the FDA would be more appropriate to provide guidance to all practicing physicians that may prescribe allopurinol. However, the US FDA, unlike the Taiwanese FDA and the Japanese FDA, has not required a warning on the allopurinol drug label alerting physicians and patients to the association between the presence of the HLA-B*58:01 allele and DIHS, a life-threatening condition [8].\n\nWe posit that in order to prevent allopurinol DIHS, the following steps must be taken. First, the US FDA should require labelling for allopurinol, alerting physicians to the association between HLA-B*58:01 and allopurinol DIHS [8]. Second, because self-identified ethnicity is not predictive of genetics, health systems and individual physicians should be justified in screening all patients for the HLA-B*58:01 allele before prescribing allopurinol [8].\n\nTherefore, at our institution, the Department of Dermatology is working to implement a system-change in our electronic health record to alert prescribers of allopurinol to screen for the HLA-B*58:01 allele in all patients. We recently published an algorithm to help guide physicians to safely prescribe allopurinol [8]. The algorithm will be embedded into the alert which serves to educate physicians about the risk of DIHS in carriers of the HLA-B*58:01 allele but also in those with other associated risk factors, especially CKD. It has been shown that oxypurinol, an active metabolite of allopurinol, binds to the HLA-B*58:01 peptide binding groove with higher affinity and is excreted renally [5]. Therefore, patients with baseline CKD that are prescribed allopurinol, especially at doses greater than 100 mg daily, can experience DIHS secondary to oxypurinol accumulation even in the absence of HLA-B*58:01 allele [5].\n\n5. Case 3: Sulfamethoxazole/Trimethoprim (Bactrim) Drug-Induced Hypersensitivity Syndrome\n\nMr. L, a 66-year-old man with a history of hypertension and a remote history of bladder cancer, presented to the Emergency Department in November 2020 with a two-day history of a morbilliform rash that began on his torso and spread to his extremities (Figure 2). His serum chemistries were notable for elevated serum creatinine 2.24 mg/dL (baseline 1.2 mg/dL), normal liver enzymes and no eosinophilia. A review of his medication history revealed that he was prescribed sulfamethoxazole/trimethoprim (Bactrim) 7 days prior for the treatment of small intestinal bacterial overgrowth. The patient denied ever having had a similar rash in the past. He denied a prodrome of viral illness such as fever, malaise, arthralgias. Virologic serologies for cytomegalovirus (CMV), Epstein–Barr virus (EBV), human herpes virus 6 (HHV6) and coronavirus 19 (COVID-19) were negative. Bactrim was discontinued and the patient was started on prednisone 1 mg/kg daily. Within two days, his serum creatinine began to normalize, his rash began to resolve and he was discharged home on a 6-week course of a prednisone taper. During his outpatient follow up with dermatology, we ordered for genetic testing for N-acetyl transferase 2 (NAT2) and the results showed that Mr. L harbored several NAT2 haplotypes *5B/*6B, *5C/*6E, *5E/*12C associated with the slow acetylator phenotype (Table 2).\n\nThere is marked inter-individual and inter-ethnic variability in NAT2 acetylation. For example, 56% of US Whites are slow NAT2 acetylators compared to 44% of US Blacks [9]. This variation has been shown to be associated with an increased frequency of transitional cell bladder cancer in US Whites compared to Blacks [9]. Similar rates of NAT2 slow acetylator phenotype have been reported in other populations of European descent: 55.1% of Germans, and 65.4% of Spaniards [10]. In contrast, the NAT2 slow acetylator phenotype occurs in only 9% of Serbians [10]. Considering people of African descent, compared to 44% of US Blacks with a NAT2 slow acetylator genotype [9], 68% of Nigerians are NAT2 slow acetylators [11]. Similarly, in Asian populations, the frequency of NAT2 slow acetylator phenotype is higher in Thai populations (50%) compared to a frequency of 5–20% in other Asian populations (Japan, Korea, China) [12].\n\nThe US FDA label for Bactrim warns that hemolysis may occur in patients deficient in G6PD enzyme [13]. It also states that patients who are slow acetylators may be at higher risk for idiosyncratic adverse drug reactions. However, the label never mentions that the acetylator status can be ascertained by sequencing the NAT2 gene [14]. Similarly, the US FDA label for other commonly used medications metabolized by NAT2 (isoniazid, procainamide and sulfasalazine) only mentions that slow acetylators may be at increased risk of adverse drug reactions but never mentions the NAT2 gene [14]. Amifampridine, used in the treatment of Lambert–Eaton myasthenic syndrome, is the only medication for which there is a US FDA label warning of the association between NAT2 acetylator status and adverse drug reaction [13,14]. The label goes on to recommend a dose reduction of amifampridine in patients with reduced NAT2 enzyme activity [13,14].\n\nBactrim is widely used for the treatment of bacterial infections and prophylaxis against pneumocystis pneumonia (PCP) in immunocompromised and immunosuppressed patients [3]. In the US in 2018 alone, 8,448,278 prescriptions for Bactrim were written [15]. It is known that NAT2 slow acetylators are at increased risk of Bactrim-induced SCARs [3]. Given that 56% of US Whites, 44% of US Blacks and 5–20% of Asians are NAT2 slow acetylators [9,12], the US FDA Bactrim drug label should clearly emphasize the preventative role of NAT2 genetic testing. In the absence of such clear guidance, clinicians and health systems cannot make adequate changes to reduce the frequency of Bactrim-induced SCARs. To address the knowledge gap of the clinical application of pharmacogenomics in the prevention of Bactrim-induced SCARs, the Department of Dermatology at UCSD is beginning to utilize pre-emptive NAT2 genetic testing.\n\n6. Case 4: Pre-emptive NAT2 Genetic Testing\n\nMs. D is a 72-year-old woman with a history of pemphigus vulgaris, previously treated with rituximab. She presented to the UCSD dermatology clinic in September 2020 with several weeks of mucosal and cutaneous erosions, representing a flare of her pemphigus vulgaris. A month prior, she was started on mycophenolate mofetil and prednisone. Given the extent of mucosal and skin involvement of her pemphigus vulgaris, she would likely require a long course of prednisone therapy and therefore a consideration of PCP prophylaxis with Bactrim. Prior to prescribing Bactrim, a NAT2 genetic test was ordered and the results showed that the patient was homozygous for the NAT2*5B genotype associated with slow NAT2 acetylator status (Table 3). The risk of Bactrim-induced SCARs was discussed with the patient and she declined treatment with Bactrim opting instead for a safer alternative.\n\nThis case vignette illustrates the manner in which pre-emptive genetic testing can be performed. By performing NAT2 genetic testing before initiating Bactrim, a careful and thoughtful discussion of the risks and benefits allowed the patient to be involved in the care of her complex disease. In so doing, we likely prevented the patient, a NAT2 slow acetylator, from developing Bactrim-induced SCAR.\n\nTo our knowledge, this is the first reported case of NAT2 genetic testing to prevent Bactrim associated SCAR in a US dermatology clinic. Although this is not currently the standard of care in the US, it has the potential to dramatically improve patient care and reduce health care costs by preventing potentially life-threatening adverse drug reactions.\n\n7. Conclusions\n\nAlthough there are several examples of the utility of pharmacogenomics in preventing adverse drug reactions, in the US there is not yet the widespread adoption of pre-emptive testing [14] except for screening for the presence of the HLA-B*57:01 allele prior to prescribing abacavir which is routinely performed in the US [1]. There are many reasons for which pre-emptive pharmacogenomics is not widely practiced in the US: (1) a lack of coherent guidance from FDA drug labels; (2) the absence of clinical expertise; (3) diverse populations with many unknown pharmacogenomic markers of drug response due to being understudied; and (4) the lack of a knowledge base to facilitate clinical implementation models within health systems [14]. Presenting this case series, we demonstrated how Dermatologists and other physicians will play a role in implementing pharmacogenomics testing in the clinical setting. First, dermatologists can demonstrate how HLA-B*58:01 testing will aid in the diagnosis of allopurinol-induced SCAR by ordering the test when allopurinol is suspected as the culprit medication in a patient diagnosed with SCAR. Dermatologists and other physicians can also advocate for changes within health systems toward implementing pre-emptive HLA-B*58:01 testing prior to prescribing allopurinol to prevent future SCAR. The third case demonstrates how the NAT2 slow acetylator phenotype predisposes to Bactrim-induced SCAR. In the fourth case, we show how physicians can implement pre-emptive NAT2 genetic testing within their own practice to prevent Bactrim-induced SCAR. This serves as an example of the utility of NAT2 genetic testing to prevent Bactrim-induced SCAR for prescribing physicians of any specialty. In our experience, insurance companies have covered the cost of testing because it was associated with clinical care.\n\nIn the broader context, this case series serves as a template for how to advocate for more widespread pharmacogenetic testing to prevent SCAR induced by other culprit medications such as lamotrigine, carbamazepine and phenytoin and the associated risk alleles HLA-B*15:02 and HLA-A*31:01.\n\nAcknowledgments\n\nSincere gratitude to Taraneh Paravar for her involvement in clinical care and Anna Di Nardo for her involvement in the clinical care, review and editing of the manuscript.\n\nAuthor Contributions\n\nO.I. conceptualized the work, proposed the idea for the clinical implementation of NAT2 genetic testing in routine dermatologic care, was involved in clinical care and wrote the manuscript. J.A.S. provided the allopurinol and HLA-B*58:01 patient case 1, was involved in clinical care and reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nEthical review and approval were waived for this study, due to the fact that all patients were treated within scope of practice, in routine clinical care and did not receive experimental diagnostics or treatments. Informed consent was obtained from individual patients for genetic testing in the course of clinical care.\n\nInformed Consent Statement\n\nInformed consent for genetic testing was obtained from all subjects in the course of clinical care.\n\nData Availability Statement\n\nData is contained within the article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Patient with allopurinol drug-induced hypersensitivity syndrome (DIHS). Erythroderma and epidermal necrolysis with over 80% body surface area (BSA) involvement.\n\nFigure 2 Patient with Bactrim DIHS. Morbilliform rash with 50% body surface area (BSA) involvement.\n\njpm-11-00071-t001_Table 1 Table 1 Case series of allopurinol DIHS. M—male, F—female.\n\nSex\tAge (Years)\tRace/Ethnicity (Self-Identified)\tHLA-B*58:01\tAllopurinol Dose (Daily)\tBaseline Serum Creatinine (mg/dL)\t\nM\t42\tBlack\tPositive\t300 mg\t2.06\t\nF\t81\tHispanic\tPositive\t100 mg\t1.38\t\n\njpm-11-00071-t002_Table 2 Table 2 Case of Bactrim DIHS. M—male.\n\nSex\tAge (Years)\tRace/Ethnicity (Self-Identified)\tNAT2 Genotype\tMedication\tBaseline Serum Creatinine (mg/dL)\t\nM\t66\tWhite\t*5B/*6B, *5C/*6E, *5E/*12C\tBactrim\t1.2\t\n\njpm-11-00071-t003_Table 3 Table 3 Pre-emptive NAT2 genetic testing prior to prescribing Bactrim. F—female.\n\nSex\tAge (Years)\tRace/Ethnicity (Self-Identified)\tNAT2 Genotype\tMedication\tBaseline Serum Creatinine (mg/dL)\t\nF\t72\tWhite\t*5B/*5B\tBactrim\t0.66\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Chang C.-J. Chen C.-B. Hung S.-I. Ji C. Chung W. Pharmacogenetic Testing for Prevention of Severe Cutaneous Adverse Drug Reactions Front. Pharmacol. 2020 11 969 10.3389/fphar.2020.00969 32714190\n2. Yu K.-H. Yu C.-Y. Fang Y.-F. Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: An updated systematic review and meta-analysis Int. J. Rheum. Dis. 2017 20 1057 1071 10.1111/1756-185X.13143 28857441\n3. Sim E. Abuhammad A. Ryan A. Arylamine N-acetyltransferases: From drug metabolism and pharmacogenetics to drug discovery Br. J. Pharmacol. 2014 171 2705 2725 10.1111/bph.12598 24467436\n4. Wang D. Para M.F. Koletar S.L. Sadee W. Human N-acetyltransferase 1 (NAT1) *10 and *11 alleles increase protein expression via distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity Pharm. Genom. 2011 21 652 664 10.1097/FPC.0b013e3283498ee9 21878835\n5. Keller S.F. Lu N. Blumenthal K.G. Rai S.K. Yokose C. Choi J.W.J. Kim S.C. Zhang Y. Choi H.K. Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: A cohort study Ann. Rheum. Dis. 2018 77 1187 1193 10.1136/annrheumdis-2017-212905 29653927\n6. Jutkowitz E. Dubreuil M. Lu N. Kuntz K.M. Choi H.K. The cost-effectiveness of HLA-B*5801 screening to guide initial urate-lowering therapy for gout in the united states Semin. Arthritis Rheum. 2017 46 594 600 10.1016/j.semarthrit.2016.10.009 27916277\n7. FitzGerald J.D. Dalbeth N. Mikuls T.R. Brignardello-Petersen R. Guyatt G. Abeles A.M. Gelber A.C. Harrold L.R. Khanna D. King C. 2020 American College of Rheumatology Guideline for the Management of Gout Arthritis Rheumatol. 2020 72 879 895 10.1002/art.41247 32390306\n8. Ikediobi O. A Personalized Medicine Approach to Guide Allopurinol Use and Prevent Serious Adverse Events: Ethnicity Is Not a Proxy for Genetics Clin. Pharmacol. Ther. 2020 10.1002/cpt.2124 33330976\n9. Muscat J.E. Pittman B. Kleinman W. Lazarus P. Stellman S.D. Richie J.P. Comparison of CYP1A2 and NAT2 phenotypes between black and white smokers Biochem. Pharmacol. 2008 76 929 937 10.1016/j.bcp.2008.07.024 18703023\n10. Djordjevic N. Carrillo J.A. Ueda N. Gervasini G. Fukasawa T. Suda A. Jankovic S. Aklillu E. N-acetyltransferase-2 (NAT2) gene polymorphisms and enzyme activity in Serbs: Unprecedented high prevalence of rapid acetylators in a white population J. Clin. Pharmacol. 2011 51 994 1003 10.1177/0091270010377630 20801937\n11. Kotila O.A. Fawole O.I. Olopade O.I. Ayede A.I. Falusi A.G. Babalola C.P. N-acetyltransferase 2 enzyme genotype–phenotype discordances in both HIV-negative and HIV-positive Nigerians Pharm. Genom. 2019 29 106 113 10.1097/FPC.0000000000000373 30882558\n12. Sabbagh A. Langaney A. Darlu P. Gérard N. Krishnamoorthy R. Poloni E.S. Worldwide distribution of NAT2 diversity: Implications for NAT2 evolutionary history BMC Genet. 2008 9 21 10.1186/1471-2156-9-21 18304320\n13. Food and Drug Administration Table of Pharmacogenomic Biomarkers in Drug Labeling Available online: http://www.fda.gov (accessed on 2 December 2020)\n14. Whirl-Carrillo M. McDonagh E.M. Hebert J.M. Gong L. Sangkuhl K. Thorn C.F. Altman R.B. Klein T.E. Pharmacogenomics Knowledge for Personalized Medicine Clin. Pharmacol. Ther. 2012 92 414 417 10.1038/clpt.2012.96 22992668\n15. U.S. Outpatient Drug Usage Statistics ClinCalc DrugStats Database Version 21.1. Prescription Data Source: Medical Expenditure Panel Survey (MEPS) 2008–2018 Available online: www.clincalc.com/DrugStats/ (accessed on 26 December 2020)\n\n",
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"journal": "Journal of personalized medicine",
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"title": "Pharmacogenomics of Allopurinol and Sulfamethoxazole/Trimethoprim: Case Series and Review of the Literature.",
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"abstract": "A 59-year-old man with a history of coarctation repair, mechanical aortic valve, and warfarin therapy presented with right flank pain. Computed tomography showed a large hematoma encircling an intact descending thoracic aorta. Computed tomography angiography demonstrated multiple areas of intercostal artery extravasation. An interventional radiologist performed angiography and embolization. The patient's course was complicated by an effusion and hypoxia, but no further bleeding was noted. We hypothesize that coarctation associated aneurysms and potential vessel wall weakness are the causes of hematoma in our case. We present this case with history of repaired coarctation with multiple spontaneous intercostal artery aneurysmal rupture.",
"affiliations": "Department of Cardiothoracic Surgery, Stanford University Hospitals and Clinics, Stanford, California.;Department of Cardiothoracic Surgery, Stanford University Hospitals and Clinics, Stanford, California.;Department of Radiology, Stanford University Hospitals and Clinics, Stanford, California.;Department of Cardiothoracic Surgery, Stanford University Hospitals and Clinics, Stanford, California.;Department of Radiology, Stanford University Hospitals and Clinics, Stanford, California.;Department of Cardiothoracic Surgery, Stanford University Hospitals and Clinics, Stanford, California.;Department of Cardiothoracic Surgery, Stanford University Hospitals and Clinics, Stanford, California. Electronic address: natalielui@stanford.edu.",
"authors": "Wightman|Sean C|SC|;Wang|Yoyo|Y|;Rohr|Aaron M|AM|;Greene|Christina L|CL|;Hwang|Gloria L|GL|;Watkins|A Claire|AC|;Lui|Natalie S|NS|",
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"mesh_terms": "D017542:Aneurysm, Ruptured; D001017:Aortic Coarctation; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D012272:Ribs; D013895:Thoracic Arteries",
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"title": "Spontaneous Bleeding From Multiple Intercostal Arteries in a Patient With Coarctation of the Aorta.",
"title_normalized": "spontaneous bleeding from multiple intercostal arteries in a patient with coarctation of the aorta"
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"abstract": "Allergic reactions due to drug intake are responsible from an important amount of emergency admissions. Patients mostly complain of urticarial lesions. But clinical picture may sometimes include a large scale of signs and symptoms ranging from a simple confusion to serious conditions like coma and even cardiopulmonary arrest. In this article, a case of anaphylactic shock and respiratory arrest after lansoprazole intake is presented. Delays in reaching basic and advanced life support decrease chance of positive results of life support in anaphylactic shock victims. It is important to remember that any medication we usually prescribe in our daily practice for treatment of any disease has a potential to kill the patient.",
"affiliations": "Department of Emergency Medicine, Duzce University School of Medicine, Duzce, Turkey.;Department of Emergency Medicine, Duzce University School of Medicine, Duzce, Turkey.;Department of Emergency Medicine, Duzce University School of Medicine, Duzce, Turkey.;Department of Emergency Medicine, Duzce University School of Medicine, Duzce, Turkey.;Department of Anesthesiology and Reanimation, Duzce University School of Medicine, Duzce, Turkey.;Department of Emergency Medicine, Duzce University School of Medicine, Duzce, Turkey. Electronic address: a_saritas_@hotmail.com.",
"authors": "Candar|Melik|M|;Gunes|Harun|H|;Boz|Behic Volkan|BV|;Kandis|Hayati|H|;Kutlucan|Leyla|L|;Saritas|Ayhan|A|",
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"title": "Asystole after the first dose of lansoprazole.",
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"abstract": "Introduction.Vibrio species are curved, motile Gram-negative bacilli found in estuarine and marine environments, and are known to cause to gastroenteritis, skin and soft tissue infections, and septicaemia. While not responsible for cholera epidemics, non-O1/O139 Vibrio cholerae (NOVC) is increasingly reported as a cause of gastroenteritis. Case presentation. A 66-year-old man presented to an emergency department with a 1 week history of epigastric pain, emesis and fever. Blood cultures drawn on admission initially demonstrated Gram-negative bacilli, and ultimately grew NOVC, which was later confirmed by matrix-assisted laser desorption ionization-time of flight MS. Subsequent history revealed that the patient had eaten fish and seafood prior to falling ill. He was treated with intravenous ceftriaxone and oral doxycycline while admitted, and oral ciprofloxacin and doxycycline upon discharge. His bacteraemia was believed to be secondary to altered gut anatomy from prior surgery and proton-pump inhibitor use. Conclusion. Risk factors for NOVC bacteraemia include cirrhosis, immunosuppression and other forms of liver disease. Cases are often linked to a history of seafood ingestion when water temperatures rise, enabling Vibrio species to proliferate. While the optimal management of NOVC bacteraemia is unclear, a combination of a third-generation cephalosporin with a tetracycline has been suggested. Physicians should maintain a high index of suspicion for this pathogen when evaluating ill patients with a history of liver disease and seafood ingestion.",
"affiliations": "Faculty of Medicine, McGill University, Montreal, QC, Canada.;Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, ON, Canada.;Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, ON, Canada.",
"authors": "Billick|Maxime J|MJ|;Lam|Philip W|PW|;Bogoch|Isaac I|II|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1099/jmmcr.0.005103",
"fulltext": "\n==== Front\nJMM Case RepJMM Case RepJMMCRJMM Case Reports2053-3721Microbiology Society jmmcr00510310.1099/jmmcr.0.005103Case ReportGastrointestinalSinister seafood: bacteraemia secondary to non-O1/O139 Vibrio cholerae infection http://jmmcr.microbiologyresearch.orgBillick Maxime J. \n1\nLam Philip W. \n2\nBogoch Isaac I. \n2\n\n1\n \nFaculty of Medicine, McGill University, Montreal, QC, Canada\n\n2\n \nDepartment of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, ON, Canada\n*Correspondence: Isaac I. Bogoch, isaac.bogoch@uhn.ca7 2017 5 7 2017 4 7 e00510307 3 2017 13 6 2017 © 2017 The Authors2017This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.\nIntroduction.\nVibrio species are curved, motile Gram-negative bacilli found in estuarine and marine environments, and are known to cause to gastroenteritis, skin and soft tissue infections, and septicaemia. While not responsible for cholera epidemics, non-O1/O139 Vibrio cholerae (NOVC) is increasingly reported as a cause of gastroenteritis.\n\n\nCase presentation. A 66-year-old man presented to an emergency department with a 1 week history of epigastric pain, emesis and fever. Blood cultures drawn on admission initially demonstrated Gram-negative bacilli, and ultimately grew NOVC, which was later confirmed by matrix-assisted laser desorption ionization-time of flight MS. Subsequent history revealed that the patient had eaten fish and seafood prior to falling ill. He was treated with intravenous ceftriaxone and oral doxycycline while admitted, and oral ciprofloxacin and doxycycline upon discharge. His bacteraemia was believed to be secondary to altered gut anatomy from prior surgery and proton-pump inhibitor use.\n\n\nConclusion. Risk factors for NOVC bacteraemia include cirrhosis, immunosuppression and other forms of liver disease. Cases are often linked to a history of seafood ingestion when water temperatures rise, enabling Vibrio species to proliferate. While the optimal management of NOVC bacteraemia is unclear, a combination of a third-generation cephalosporin with a tetracycline has been suggested. Physicians should maintain a high index of suspicion for this pathogen when evaluating ill patients with a history of liver disease and seafood ingestion.\n\nVibriocholerabacteraemiaVibrio choleraegastroenteritisOpenAccessEmbargo0\n==== Body\nAbbreviation\nNOVC, non-O1/O139 Vibrio cholerae.\n\nIntroduction\n\nVibrio species are curved, motile Gram-negative bacilli found in estuarine and marine environments [1]. The three most common Vibrio species implicated in human illness are Vibrio parahaemolyticus, Vibrio vulnificus and Vibrio cholerae.\n\nThe United States Centers for Disease Control and Prevention estimate that 80 000 cases of vibriosis occur yearly in the USA, resulting in 500 hospitalizations and 100 deaths [2]. Vibriosis cases are associated with syndromes of gastroenteritis, skin and soft tissue infections, and septicaemia [2].\n\n\nV. cholerae is classified based on the O-antigen polysaccharide type, with over 200 serogroups described. Historically, only toxigenic serogroups O1 and O139 have been associated with widespread cholera epidemics [3]. Although other serogroups may cause smaller outbreaks, they are collectively termed non-O1/O139 Vibrio cholerae (NOVC). Severe illness with NOVC bacteraemia is a rare event; however, there have been numerous documented case reports of severe wound infections, gastroenteritis and sepsis [1]. Due to its rare presentation and potential for poor clinical outcomes, it is important to recognize NOVC bacteraemia in the clinical setting.\n\nCase report\nA 66-year-old man presented to an emergency room with a 1 week history of epigastric pain, emesis and fever. His medical history was significant for a benign pancreatic tumour causing biliary obstruction managed with a biliary stent, cholecystectomy, choledochojejunostomy and roux-en-Y reconstruction years before his presentation. His medications included pancrealipase, rabeprazole and insulin. With regards to social history, the patient had emigrated from Hong Kong 30 years previously and had no recent travel history or sick contacts. He was febrile (38.2 °C) but otherwise haemodynamically stable, and the remainder of his exam was only notable for mild epigastric and right upper quadrant tenderness, audible bowel sounds and no peritoneal signs.\n\nInvestigations\nLaboratory findings demonstrated a mild leukocytosis (13.3×109 cells l−1 white blood cell count) and mildly elevated liver enzymes (aspartate aminotransferase, 71 U l−1; alanine aminotransferase, 62 U l−1) with a normal blood glucose level of 6.6 mmol l−1. The remainder of his initial laboratory findings were normal. Two sets of blood cultures drawn on admission demonstrated Gram-negative bacilli on Gram stain, and were positive for NOVC via culture and confirmed by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS. The bacteria were plated on blood agar, chocolate agar, MacConkey agar and fastidious anaerobic agar, and grew on all four plates within 24 h. The organism was found to be susceptible to ampicillin, azithromycin, trimethoprim/sulfamethoxazole and tetracycline. A subsequent history that was taken revealed that the patient consumed home-prepared seafood hot pot and fish at a restaurant 3 and 5 days before symptom onset, respectively; thus, indicating a potential infectious source.\n\nTreatment\nThe patient was treated empirically with oral doxycycline (100 mg, twice daily) and intravenous ceftriaxone (1 g, daily) prior to V. cholerae speciation. He rapidly defervesced and was discharged home on a 7 day course of oral ciprofloxacin (500 mg) and doxycycline (100 mg), both taken twice daily.\n\nOutcome and follow-up\nThe patient was at his baseline level of function with a normalized complete blood count and liver enzyme testing at a follow up appointment 1 month after discharge.\n\nDiscussion\n\nVibrio species are curved, motile Gram-negative bacilli found in estuarine and marine environments [1]. The three most common Vibrio species implicated in human illness are V. parahaemolyticus, V. vulnificus and V. cholerae. The United States Centers for Disease Control and Prevention estimates 80 000 cases of vibriosis occur yearly in the USA, resulting in 500 hospitalizations and 100 deaths [2]. Vibrio may cause gastroenteritis if ingested, aggressive wound infections from percutaneous injuries and septicaemia [2].\n\nAlthough severe illness with NOVC bacteraemia is uncommon, case reports of wound infections, gastroenteritis and sepsis have been documented [1]. Risk factors for NOVC bacteraemia include cirrhosis, immunosuppression and other forms of liver disease [1, 2]. Additionally, cases are often linked to a history of seafood ingestion [1] in summer months when water temperatures rise, resulting in prime conditions for Vibrio species to proliferate [2]. We suspect the history of seafood ingestion, combined with altered gastrointestinal anatomy and proton pump inhibitor use, contributed to the pathogenesis of infection in our case. [4]. No family members, close contacts or others who shared meals with our patient had clinical illness, and we did not screen them for infection.\n\nThe optimal management of NOVC bacteraemia is unclear. A combination of a third-generation cephalosporin with a tetracycline have been suggested, based on in vivo evidence demonstrating synergy and the theoretical benefits of protein synthesis inhibition and reduced toxin production [1]. Furthermore, empiric dual antibiotic coverage may be warranted in light of increasing antimicrobial resistance.\n\nAlthough NOVC infections have not been linked to epidemics, these bacteria are associated with severe wound infections, gastroenteritis and sepsis in vulnerable hosts. As sea surface temperatures continue to rise globally [5], there is the risk of increased vibrio proliferation. Physicians should maintain a high index of suspicion for this pathogen when evaluating ill patients with a history of liver disease, seafood ingestion or marine exposure.\n\nFunding information\nThe authors received no specific grant from any funding agency.\n\nConflicts of interest\nThe authors declare that there are no conflicts of interest.\n==== Refs\nReferences\n1 Deshayes S Daurel C Cattoir V Parienti JJ Quilici ML Non-O1, non-O130 Vibrio cholerae bacteraemia: case report and literature review Springerplus 2015 4 575 10.1186/s40064-015-1346-3 26543710 \n2 Centers for Disease Control and Prevention. 2016 \nVibrio species causing vibriosis: information for health professionals and laboratorians www.cdc.gov/vibrio/healthcare.html [accessed 10 October 2016] \n3 Nair GB Ramamurthy T Bhattacharya SK Mukhopadhyay AK Garg S Spread of Vibrio cholerae O139 Bengal in India J Infect Dis 1994 169 1029 1034 10.1093/infdis/169.5.1029 8169387 \n4 Bavishi C Dupont HL Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection Aliment Pharmacol Ther 2011 34 1269 1281 10.1111/j.1365-2036.2011.04874.x 21999643 \n5 United States Environmental Protection Agency 2016 Climate change indicators: sea surface temperature www.epa.gov/climate-indicators/climate-change-indicators-sea-surface-temperature [accessed 28 Feb 2017]\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2053-3721",
"issue": "4(7)",
"journal": "JMM case reports",
"keywords": "Vibrio; Vibrio cholerae; bacteraemia; cholera; gastroenteritis",
"medline_ta": "JMM Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101639133",
"other_id": null,
"pages": "e005103",
"pmc": null,
"pmid": "29026630",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports",
"references": "21999643;26543710;8169387",
"title": "Sinister seafood: bacteraemia secondary to non-O1/O139 Vibrio cholerae infection.",
"title_normalized": "sinister seafood bacteraemia secondary to non o1 o139 vibrio cholerae infection"
} | [
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"companynumb": "CA-EISAI MEDICAL RESEARCH-EC-2017-030752",
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"activesubstancename": "INSULIN NOS"
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"abstract": "OBJECTIVE\nHepatic veno-occlusive disease (VOD) is well recognized potentially serious regimen-related toxicity seen after stem cell transplantation. Severe VOD is associated with poor long-term outcomes with very high mortality. Besides supportive care, only defibrotide has been found to be effective in the management of VOD. The recommended dose of defibrotide is 25mg/kg/d but there has been no classical dose finding study done for this drug. A higher dose of defibrotide is associated with increased risk of bleeding and this drug is prohibitively expensive. We report our experience of using fixed low dose of defibrotide in patients with VOD.\n\n\nMETHODS\nWe retrospectively evaluated 511 patients who underwent stem cell transplant at our center from November 2007 and December 2015. All patients received ursodeoxycholic acid as VOD prophylaxis. Modified Seattle criterion was used for diagnosis and severity grading of VOD. Patients developing VOD were initially treated with furosemide and adequate analgesia. Defibrotide was started within 12 to 24 hours of diagnosis of VOD. All adult patients received defibrotide at a fixed dose of 200mg twice daily while two children were given dose of 100mg and 50mg twice daily.\n\n\nRESULTS\nNine (1.7%) of our patients developed VOD. Daily dose of defibrotide ranged from 5mg/kg/d to 20mg/kg/d till resolution of VOD. All patients had complete resolution of VOD. None of our patients required ventilator support or dialysis. No episodes of bleeding were observed. No dose response relationship was observed between defibrotide dose and time to resolution of VOD.\n\n\nCONCLUSIONS\nLow fixed dose defibrotide initiated early seems to be effective and safe in treatment of VOD. This is relevant in a resource limited setting and warrants prospective evaluation.",
"affiliations": "Department of Medical Oncology, Tata Memorial Center, Mumbai, India. Electronic address: bagalbp@gmail.com.;Department of Medical Oncology, Tata Memorial Center, Mumbai, India.;Department of Nursing, Tata Memorial Center, Mumbai, India.;Department of Medical Oncology, Tata Memorial Center, Mumbai, India.",
"authors": "Bagal|Bhausaheb|B|;Chandrasekharan|Arun|A|;Chougle|Aliya|A|;Khattry|Navin|N|",
"chemical_list": "D011089:Polydeoxyribonucleotides; C036901:defibrotide",
"country": "England",
"delete": false,
"doi": "10.1016/j.hemonc.2017.02.005",
"fulltext": null,
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"issn_linking": null,
"issue": "11(1)",
"journal": "Hematology/oncology and stem cell therapy",
"keywords": "Defibrotide; Stem cell transplantation; Veno-occlusive disease",
"medline_ta": "Hematol Oncol Stem Cell Ther",
"mesh_terms": "D000328:Adult; D064591:Allografts; D002675:Child, Preschool; D005260:Female; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011089:Polydeoxyribonucleotides; D033581:Stem Cell Transplantation",
"nlm_unique_id": "101468532",
"other_id": null,
"pages": "47-51",
"pmc": null,
"pmid": "28460209",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Low, fixed dose defibrotide in management of hepatic veno-occlusive disease post stem cell transplantation.",
"title_normalized": "low fixed dose defibrotide in management of hepatic veno occlusive disease post stem cell transplantation"
} | [
{
"companynumb": "IN-MYLANLABS-2018M1018221",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "URSODIOL"
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"abstract": "Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas.Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20-400 mg twice a day, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort.Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2 Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response.Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702 Clin Cancer Res; 23(15); 4119-26. ©2017 AACR.",
"affiliations": "Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York. soumeraj@mskcc.org.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.;Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.;Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.;Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.;Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland.;Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland.;Memorial Sloan Kettering Cancer Center, New York, New York.;Memorial Sloan Kettering Cancer Center, New York, New York.;Memorial Sloan Kettering Cancer Center, New York, New York.;Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Soumerai|Jacob D|JD|;Zelenetz|Andrew D|AD|;Moskowitz|Craig H|CH|;Palomba|M Lia|ML|;Hamlin|Paul A|PA|;Noy|Ariela|A|;Straus|David J|DJ|;Moskowitz|Alison J|AJ|;Younes|Anas|A|;Matasar|Matthew J|MJ|;Horwitz|Steven M|SM|;Portlock|Carol S|CS|;Konner|Jason A|JA|;Gounder|Mrinal M|MM|;Hyman|David M|DM|;Voss|Martin H|MH|;Fury|Matthew G|MG|;Gajria|Devika|D|;Carvajal|Richard D|RD|;Ho|Alan L|AL|;Beumer|Jan H|JH|;Kiesel|Brian|B|;Zhang|Zhigang|Z|;Chen|Alice|A|;Little|Richard F|RF|;Jarjies|Christine|C|;Dang|Thu O|TO|;France|Fallon|F|;Mishra|Nishant|N|;Gerecitano|John F|JF|",
"chemical_list": "D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-16-3068",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "23(15)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D001562:Benzimidazoles; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D020714:Maximum Tolerated Dose; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000069283:Rituximab",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "4119-4126",
"pmc": null,
"pmid": "28314788",
"pubdate": "2017-08-01",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "26655425;17872900;9860292;17242396;19745592;18692448;18182663;23248254;18626004;20626754;26411584;19890959;17473206;23955074;11339428;16154860;16402269;19097774;17599772;15908650;12181253;25783753;24452810;16855634;11370553;11593053;6277470;26156122;1907096;23650408",
"title": "The PARP Inhibitor Veliparib Can Be Safely Added to Bendamustine and Rituximab and Has Preliminary Evidence of Activity in B-Cell Lymphoma.",
"title_normalized": "the parp inhibitor veliparib can be safely added to bendamustine and rituximab and has preliminary evidence of activity in b cell lymphoma"
} | [
{
"companynumb": "NVSC2020US035911",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ONDANSETRON"
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"drugadditional": "3",
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"abstract": "Patients with coronavirus disease 2019 (COVID-19) from novel coronavirus (SARS-CoV-2) infection may present with immune thrombocytopenia (ITP). Multisystem inflammatory syndrome in children (MIS-C) is a serious complication of SARS-CoV-2 causing systemic organ dysfunction. This case series presents the first reported cases of patients who developed ITP following MIS-C, while completing corticosteroid tapers. These patients responded to standard of care therapies for ITP and had appropriate platelet count recovery. We emphasize the importance of careful monitoring of those recovering from COVID-19 or MIS-C, to proactively identify clinical and laboratory abnormalities, in addition to long-term cardiovascular sequelae.",
"affiliations": "Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.",
"authors": "Kok|Eric Y|EY|;Srivaths|Lakshmi|L|;Grimes|Amanda B|AB|;Vogel|Tiphanie P|TP|;Sexson Tejtel|S Kristen|SK|;Muscal|Eyal|E|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D011239:Prednisolone; D001241:Aspirin; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2021.1917737",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "38(7)",
"journal": "Pediatric hematology and oncology",
"keywords": "COVID-19; ITP; MIS-C; SARS-CoV-2; novel coronavirus",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D000086382:COVID-19; D002648:Child; D019468:Disease Management; D005938:Glucocorticoids; D006801:Humans; D007223:Infant; D008297:Male; D008775:Methylprednisolone; D010976:Platelet Count; D011239:Prednisolone; D016553:Purpura, Thrombocytopenic, Idiopathic; D018746:Systemic Inflammatory Response Syndrome",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "663-668",
"pmc": null,
"pmid": "33949910",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Immune thrombocytopenia following multisystem inflammatory syndrome in children (MIS-C) - a case series.",
"title_normalized": "immune thrombocytopenia following multisystem inflammatory syndrome in children mis c a case series"
} | [
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"companynumb": null,
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"actiondrug": "5",
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"activesubstancename": "PREDNISOLONE"
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{
"abstract": "To explore contraceptive decision making among recently pregnant patients with a history of opioid use disorder.\n\n\n\nWe conducted semi-structured qualitative interviews, based on principles of the Ottawa Decision Support Framework, with 20 recently pregnant individuals diagnosed with opioid use disorder at a tertiary care medical center in Massachusetts. We audio-recorded the interviews and they were transcribed verbatim. We analyzed our interview data using inductive and deductive coding.\n\n\n\nParticipants value the availability of barrier methods as a means of preventing both sexually transmitted infections and pregnancy. For some participants, housing instability makes storing contraceptive methods and managing personal hygiene related to bleeding patterns difficult. For others, housing instability impacts their overall fertility goals. Side effects including weight gain, interactions with mood stabilizing medications, concern regarding post-operative opioids, or intrinsic aspects of a method that serve as reminders of opioid use may be unacceptable given the risk of relapse. The relapsing and remitting arc of recovery make remembering important aspects of both short- and long-acting contraceptive method use difficult, yet participants offer strategies to aid in doing so.\n\n\n\nWhen choosing a contraceptive method participants in our study exhibit similarities to individuals with other chronic medical conditions as well as motivations specific to opioid use disorder. Their contraceptive decisions are grounded in integrating a method into a chaotic life, preventing relapse, and protecting future fertility.\n\n\n\nOur data highlight how lived experiences at the intersection of active opioid use disorder and recovery fundamentally shape the lens through which pregnancy-capable individuals with opioid use disorder view their contraceptive decisions.",
"affiliations": "Department of Obstetrics, Gynecology, Boston Medical Center, Boston, MA. Electronic address: lauren.e.sobel@gmail.com.;Department of Obstetrics, Gynecology, Boston Medical Center, Boston, MA.;Department of Obstetrics, Gynecology, Boston Medical Center, Boston, MA.;Department of Obstetrics, Gynecology, Boston Medical Center, Boston, MA.;Department of Obstetrics, Gynecology, Boston Medical Center, Boston, MA.",
"authors": "Sobel|Lauren|L|;Lee|Yeon Woo|YW|;White|Katharine O'Connell|KO|;Woodhams|Elisabeth|E|;Patton|Elizabeth|E|",
"chemical_list": "D003270:Contraceptive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.contraception.2021.06.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-7824",
"issue": "104(4)",
"journal": "Contraception",
"keywords": "Contraceptive counseling; Decisional needs; Opioid use disorder; Patient-led care; Qualitative",
"medline_ta": "Contraception",
"mesh_terms": "D003267:Contraception; D003270:Contraceptive Agents; D003273:Contraceptive Devices; D003657:Decision Making; D005260:Female; D006801:Humans; D009293:Opioid-Related Disorders; D011247:Pregnancy; D062606:Tertiary Care Centers",
"nlm_unique_id": "0234361",
"other_id": null,
"pages": "355-360",
"pmc": null,
"pmid": "34118268",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Contraceptive decision making among pregnancy-capable individuals with opioid use disorder at a tertiary care center in Massachusetts.",
"title_normalized": "contraceptive decision making among pregnancy capable individuals with opioid use disorder at a tertiary care center in massachusetts"
} | [
{
"companynumb": "US-SPECGX-T202200557",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
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"drugadditional": "3",... |
{
"abstract": "The experience of supernumerary phantom limbs (SPLs) is a rare phenomenon known to occur following a variety of neurological ailments. This case report details visualized supernumerary phantom arms and legs in a polytrauma patient with suspicion of seizure as the primary contributing factor. Fewer than 30 cases of SPLs have been previously described. SPLs are usually confined to the phantom proprioception/sensation of the limb, with only 6 prior cases reporting visualized SPLs, all of which occurred in the setting of isolated stroke. This case presentation is notable because it is the first to describe visualized SPLs in a polytrauma patient.\n\n\nMETHODS\nV.",
"affiliations": "Department of Physical Medicine and Rehabilitation, University of Minnesota, MMC 297, 420 Delaware Street SE, 500 Boynton Health Services Bridge, Minneapolis, MN 55455(∗). Electronic address: lambx231@umn.edu.",
"authors": "Lamb|S Courtney-Kay|SC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.pmrj.2017.01.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1934-1482",
"issue": "9(9)",
"journal": "PM & R : the journal of injury, function, and rehabilitation",
"keywords": null,
"medline_ta": "PM R",
"mesh_terms": "D000328:Adult; D000070642:Brain Injuries, Traumatic; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009104:Multiple Trauma; D010591:Phantom Limb; D011434:Proprioception; D011782:Quadriplegia; D035583:Rare Diseases; D012640:Seizures; D013119:Spinal Cord Injuries",
"nlm_unique_id": "101491319",
"other_id": null,
"pages": "943-945",
"pmc": null,
"pmid": "28111302",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Post-traumatic Visualized Supernumerary Phantom Limbs: A Case Presentation.",
"title_normalized": "post traumatic visualized supernumerary phantom limbs a case presentation"
} | [
{
"companynumb": "US-UCBSA-2017041673",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSeroprevlence of chronic hepatitis C viral infection in correctional facilities ranges from 16% to 49%. However, there are only very limited data available on the course of hepatitis C viral infection and outcomes oftreatment with pegylated interferon plus ribavirin in correctional settings. The aim ofthis study was to assess the feasibility and effectiveness of use of pegylated interferon plus ribavirin treatment in the Serbian correctional setting.\n\n\nMETHODS\nThe study sample consisted of the patients with hepatitis C hospitalized in the Special Hospital for Prisoners in Belgrade (Serbia) during 2007-2013. Health authorities approved treatment for 32 patients out of 76 treatment-naive patients referred to this institution. The patients (N=32) received 180 mcg pegylated interferon alfa-2a once a week plus oral ribavirin in dosage of 800 mg or 1000/1200 mg/day for 24 or 48-week treatment. All patients who completed therapy were assessed at the end of an additional 24-week treatment-free period for a sustained virological response.\n\n\nRESULTS\nSustained virological response was achieved in 53.8% of hepatitis C viral infection genotype I patients and in 73.3% and 66.6% of patients with hepatitis C viral infection genotype 3 and 4, respectively. One patient with mixed genotype (1, 2) did not achieve sustained virological response. The overall safety profile of the treatment regimen was very good. The incidence of influenza-like symptoms and depression were low A serious adverse event was recorded only in 6.4% of patients.\n\n\nCONCLUSIONS\nThe results showed that pegylated interferon alfa-2a plus ribavirin given once a week was well tolerated among prisoners and the regimen had the same adherence and effectiveness as in general population.",
"affiliations": null,
"authors": "Simonović Babić|Jasmina|J|;Bojović|Ksenija|K|;Delić|Dragan|D|;Katanić|Nataga|N|;Mitrović|Nikola|N|;Malinić|Jovan|J|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a",
"country": "Serbia",
"delete": false,
"doi": "10.2298/mpns1604085s",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-8105",
"issue": "69(3-4)",
"journal": "Medicinski pregled",
"keywords": null,
"medline_ta": "Med Pregl",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D008297:Male; D055118:Medication Adherence; D011092:Polyethylene Glycols; D011330:Prisons; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D055771:Serbia; D015819:Substance Abuse, Intravenous; D016896:Treatment Outcome",
"nlm_unique_id": "2985249R",
"other_id": null,
"pages": "85-91",
"pmc": null,
"pmid": "27506095",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ANTIVIRAL TREATMENT OF HEPATITIS C IN SERBIAN PRISON SETTING: MEDICAL TREATMENT OUTCOMES AND PATIENTS' ADHERENCE.",
"title_normalized": "antiviral treatment of hepatitis c in serbian prison setting medical treatment outcomes and patients adherence"
} | [
{
"companynumb": "RS-ROCHE-1747156",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2A"
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"drugadditional": null,
... |
{
"abstract": "Renal cell carcinoma comprises 80%-85% of kidney malignancies. For early presentations, nephrectomy provides a high cure rate, but patients usually present at advanced stages, leading to poor outcomes. Even for patients without metastatic spread who undergo nephrectomy, metastatic recurrence is frequent. We report the case of a patient who underwent nephrectomy for stage iii renal cell carcinoma and who presented 20 months later with respiratory symptoms consistent with pneumonia, influenza, or (less likely) congestive heart failure or a cardiac event. Persistent right pleural effusion on serial chest radiographs despite treatment prompted computed tomography evaluation, which revealed lymphangitic carcinomatosis, a very rare form of renal cell carcinoma metastasis to the lung. This preliminary finding was confirmed by right middle lobe tissue biopsy through bronchoscopy and cytopathology examination.",
"affiliations": "Mount Sinai-Elmhurst Hospital Center, Elmhurst, NY, U.S.A.",
"authors": "Wallach|J B|JB|;McGarry|T|T|;Torres|J|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3747/co.v18i1.647",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-0052",
"issue": "18(1)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Renal cell carcinoma; lung metastasis; lymphangitic carcinomatosis; recurrence",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "e35-7",
"pmc": null,
"pmid": "21331270",
"pubdate": "2011-01",
"publication_types": "D016428:Journal Article",
"references": "10468753;15967255;10091742;7776446;19474385;9030784;2082848;8930034;10235157;12440625;9507823;18218137;15201737;10072620;10737472;8778606;831936;9146581;959551;10492179",
"title": "Lymphangitic metastasis of recurrent renal cell carcinoma to the contralateral lung causing lymphangitic carcinomatosis and respiratory symptoms.",
"title_normalized": "lymphangitic metastasis of recurrent renal cell carcinoma to the contralateral lung causing lymphangitic carcinomatosis and respiratory symptoms"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-325160",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SUNITINIB"
},
"druga... |
{
"abstract": "Natalizumab (NTZ) is an effective drug for the treatment of relapsing-remitting multiple sclerosis. In some patients discontinuation is mandatory due to the risk of progressive multifocal leukoencephalopathy. However, severe clinical and radiological worsening has been described after drug cessation. Our aim was to describe the clinical and radiological features of the rebound phenomenon.\n\n\n\nPatients switched from NTZ to Fingolimod (FTY) who had presented a rebound after discontinuation were selected. Clinical and magnetic resonance imaging (MRI) data were collected.\n\n\n\nFour JC virus positive patients were included. The mean disease duration was 9.5 years (SD: 4.12) with a mean time of 3.1 years on NTZ. All patients started FTY within 3-4 months. Neurological deterioration started in a mean time of 3.5 months (SD: 2.08) with multifocal involvement: 75% motor disturbances, 50% cognitive impairment, 25% seizures. The average worsening in Expanded Disability Status Scale [EDSS] was of 3.25 points (SD: 2.33). The MRI showed a very large increase in T2 and gadolinium-enhanced lesions (mean: 23.67, SD: 18.58). All patients received 5 days of IV methylprednisolone, one patient required plasma exchange. All the patients presented neurological deterioration with an EDSS worsening of 1.13 points (SD: 0.48). After the rebound three patients continued treatment with FTY, only one patient restarted NTZ.\n\n\n\nDiscontinuation of NTZ treatment may trigger a severe rebound with marked clinical and radiological worsening. A very careful evaluation of benefit-risk should be considered before NTZ withdrawal, and a close monitoring and a short washout period is recommended after drug withdrawal.",
"affiliations": "Neurology Department Multiple Sclerosis Center IdiSSC Hospital Clinico San Carlos Madrid Spain.;Neurology Department Hospital Universitario de Fuenlabrada Madrid Spain.;Neurology Department Multiple Sclerosis Center IdiSSC Hospital Clinico San Carlos Madrid Spain.;Demyelinating Disease Unit Neurology Department Hospital Universitario 12 de Octubre Madrid Spain.;Demyelinating Disease Unit Neurology Department Hospital Universitario 12 de Octubre Madrid Spain.;Neurology Department Multiple Sclerosis Center IdiSSC Hospital Clinico San Carlos Madrid Spain.;Neurology Department Multiple Sclerosis Center IdiSSC Hospital Clinico San Carlos Madrid Spain.;Radiology Department IdiSSC Hospital Clinico San Carlos Madrid Spain.;Neurology Department Multiple Sclerosis Center IdiSSC Hospital Clinico San Carlos Madrid Spain.",
"authors": "González-Suarez|Inés|I|0000-0002-9897-0771;Rodríguez de Antonio|Luis|L|;Orviz|Aida|A|;Moreno-García|Sara|S|;Valle-Arcos|María D|MD|;Matias-Guiu|Jordi A|JA|;Valencia|Cristina|C|;Jorquera Moya|Manuela|M|;Oreja-Guevara|Celia|C|",
"chemical_list": "D007155:Immunologic Factors; D000069442:Natalizumab; D000068876:Fingolimod Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1002/brb3.671",
"fulltext": "\n==== Front\nBrain BehavBrain Behav10.1002/(ISSN)2157-9032BRB3Brain and Behavior2162-3279John Wiley and Sons Inc. Hoboken 10.1002/brb3.671BRB3671Original ResearchOriginal ResearchCatastrophic outcome of patients with a rebound after Natalizumab treatment discontinuation González‐Suarez Inés http://orcid.org/0000-0002-9897-0771igonsua@gmail.com \n1\nRodríguez de Antonio Luis \n2\nOrviz Aida \n1\nMoreno‐García Sara \n3\nValle‐Arcos María D. \n3\nMatias‐Guiu Jordi A. \n1\nValencia Cristina \n1\nJorquera Moya Manuela \n4\nOreja‐Guevara Celia \n1\n1 Neurology DepartmentMultiple Sclerosis CenterIdiSSCHospital Clinico San CarlosMadridSpain2 Neurology DepartmentHospital Universitario de FuenlabradaMadridSpain3 Demyelinating Disease UnitNeurology DepartmentHospital Universitario 12 de OctubreMadridSpain4 Radiology DepartmentIdiSSCHospital Clinico San CarlosMadridSpain* Correspondence\n\nInés González‐Suarez, Neurology Department, Multiple Sclerosis Center, IdiSSC, Hospital Clinico San Carlos, Madrid, Spain.\n\nEmail: igonsua@gmail.com\n14 3 2017 4 2017 7 4 10.1002/brb3.2017.7.issue-4e0067103 1 2017 30 1 2017 © 2017 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nIntroduction\nNatalizumab (NTZ) is an effective drug for the treatment of relapsing‐remitting multiple sclerosis. In some patients discontinuation is mandatory due to the risk of progressive multifocal leukoencephalopathy. However, severe clinical and radiological worsening has been described after drug cessation. Our aim was to describe the clinical and radiological features of the rebound phenomenon.\n\nMaterial and Methods\nPatients switched from NTZ to Fingolimod (FTY) who had presented a rebound after discontinuation were selected. Clinical and magnetic resonance imaging (MRI) data were collected.\n\nResults\nFour JC virus positive patients were included. The mean disease duration was 9.5 years (SD: 4.12) with a mean time of 3.1 years on NTZ. All patients started FTY within 3–4 months. Neurological deterioration started in a mean time of 3.5 months (SD: 2.08) with multifocal involvement: 75% motor disturbances, 50% cognitive impairment, 25% seizures. The average worsening in Expanded Disability Status Scale [EDSS] was of 3.25 points (SD: 2.33). The MRI showed a very large increase in T2 and gadolinium‐enhanced lesions (mean: 23.67, SD: 18.58). All patients received 5 days of IV methylprednisolone, one patient required plasma exchange. All the patients presented neurological deterioration with an EDSS worsening of 1.13 points (SD: 0.48). After the rebound three patients continued treatment with FTY, only one patient restarted NTZ.\n\nConclusion\nDiscontinuation of NTZ treatment may trigger a severe rebound with marked clinical and radiological worsening. A very careful evaluation of benefit‐risk should be considered before NTZ withdrawal, and a close monitoring and a short washout period is recommended after drug withdrawal.\n\nimmune reconstitution inflammatoryNatalizumab withdrawalreboundsyndrome source-schema-version-number2.0component-idbrb3671cover-dateApril 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:13.04.2017\n\n\nGonzález‐Suarez \nI \n, \nRodríguez de Antonio \nL \n, \nOrviz \nA \n, et al. Catastrophic outcome of patients with a rebound after Natalizumab treatment discontinuation . Brain Behav . 2017 ;7 :e00671\nhttps://doi.org/10.1002/brb3.671\n==== Body\n1 Introduction\nNatalizumab (NTZ) is a human monoclonal antibody against α4 integrin, its mechanism of action blocks this protein and inhibits the entry of inflammatory cells into the brain (Engelhardt & Kappos, 2008). It is considered a very effective drug as it reduces the relapse rate and the disease activity on MRI dramatically and also moderately reduces the progression of disability; it is the treatment of choice for patients with aggressive multiple sclerosis (MS) or poor response to the first‐line therapy (Goodman et al., 2009; Miller et al., 2003; Polman et al., 2006). However, its use has been limited due to the risk of opportunistic infections, highlighting the progressive multifocal leukoencephalopathy (PML) secondary to JC virus reactivation. PML is a demyelinating disease of the CNS with frequent fatal consequences and with an incidence of approximately 1:1,000 in the treated patients (Yousry et al., 2006). The risk increases with longer treatment duration, the presence of anti‐JCV antibodies and the prior use of immunosuppression (Fernandez et al., 2015; Yousry et al., 2006). 638 PML cases have been reported with an incidence of 4.15/1,000 in treated patients (Biogen Idec data, March 2016, website http://www.biogenidec-international.com/tysabri.aspx?). Therefore, in some cases, the risk is not acceptable and the discontinuation of NTZ is mandatory; the European Medicines Agency and US Food and Drug Administration have established a risk management plan, and a re‐consent of all patients treated for longer than 2 years is recommended (2016; Fernandez et al., 2015).\n\nFrequently, after NTZ cessation the activity of the disease returns to pretreatment levels (Fox et al., 2014; O'Connor et al., 2011); however, some cases with severe clinical and radiological worsening have been described (Beume et al., 2015; Daelman et al., 2012; Gueguen et al., 2014; Jander et al., 2012; Kerbrat et al., 2011; Lenhard et al., 2010; Miravalle et al., 2011; Papeix et al., 2011; Rigau et al., 2012; Rinaldi et al., 2012; Salhofer‐Polanyi et al., 2014; Sorensen et al., 2014; Vellinga et al., 2008; West & Cree, 2010) probably related to immune reconstitution inflammatory syndrome (IRIS; Lenhard et al., 2010; Miravalle et al., 2011).\n\n2 Patients and Methods\nFrom a cohort of NTZ‐treated patients from three hospitals in Madrid, Spain, between 2012–2013; those switched to Fingolimod (FTY) who had presented a rebound after discontinuation were reported. Clinical and magnetic resonance imaging (MRI) data were collected.\n\n2.1 Case report 1\nA 29‐year‐old male was diagnosed with relapsing‐remitting MS (RRMS) in 1999. He was treated with interferon beta until 2010. He started NTZ due to two relapses in previous year (no gadolinium [Gd] enhanced lesions in MRI). In February 2012 NTZ was discontinued due to the presence of 2 risk factors for PML (26 NTZ infusions and anti‐JCV+). At this time, he had mild left hemiparesis and needed a cane for ambulation (Expanded Disability Status Scale [EDSS]: 6) but he was fully independent. In June 2012 FTY was started after a washout period of 3 months without adverse effects. One day later the patient was admitted to the emergency room due to drowsiness, disorientation, inattention, bradypsychia, and behavioral changes. 15 days' prior the patient had had a worsening in his left hemiparesis. On admission, neurological examination revealed a moderate encephalopathy with disorientation, severe inattention and bradyspsychia; Language was less fluent without dysphasia, he comprehended simple commands but not complex ones. He presented a worsening of his left hemiparesis with strength of 4/5 in left upper limb and 3/5 in left lower limb with generalized hyperreflexia and severe dysmetria, the patient was unable to stand up with aid (EDSS: 7). The MRI showed confluent bilateral white matter T2 hyperintensities with enhancement of multiple lesions (Figure 1a,b), also a Vth and VIIth nerve enhancement bilaterally. This enhancement was prolonged further. Spinal fluid examination was normal with absence of JCV by PCR. High‐dose methylprednisolone (MTP) for 5 days was started with progressive improvement. Fingolimod was restarted without new relapses but with a marked deterioration in comparison to his prior situation (EDSS:7).\n\nFigure 1 Axial T1 weighted magnetic resonance imaging (MRI) images after gadolinium (Gd) administration. The images demonstrated a high inflammation activity with elevated load of Gd‐enhancing lesions. (a) and (b) Patient 1; (c) and (d) patient 2; (e) and (f) patient 3; (g) and (h) patient 4\n\n2.2 Case report 2\nA 28‐year‐old female was diagnosed with RRMS in 2006. She was treated with interferon, Glatiramer Acetate and since September 2009 (a severe motor relapse the previous year) with NTZ. She presented no evidence of clinical and radiological activity in 2 years. In September 2012 NTZ was stopped due to a positive serology for VJC (EDSS: 1). Within the first month after the discontinuation the patient showed progressive worsening with paresthesia, instability, dizziness, and occasional diplopia. She was treated with several IV steroid pulses (MTP 13gr in total); in January 2013 FTY was started without response (EDSS: 6.5). An MRI revealed multiple T2 hyperintensities, of which at least 11 showed enhancement after Gd administration (Figure 1c,d). Due to the progressive worsening despite the treatment, the patient was admitted for plasma exchange (PLEX) with progressive clinical and radiological improvement. She was discharged and FTY was continued with a partial recovery (EDSS: 2.5).\n\n2.3 Case report 3\nA 38‐year‐old female diagnosed with RRMS in 1999. She was treated with Interferon B 1b with unsatisfactory control (two relapses in 2007), so in January 2008 the patient switched to NTZ. In September 2011, she presented an optic neuritis and was treated with high doses of MTP. In 2012 due to a high risk for PML a change to FTY was proposed. She received the last dose of NTZ in June 2012 (EDSS: 2.0). After a 3‐month washout period she started FTY with no secondary effect. In the last week of December 2012, she presented two partial seizures separated by 6 days and she was treated with levetiracetam. In the MRI of January 2013 multiple new lesions were observed in T2, 15 of them presented enhancement post Gd administration (Figure 1e,f). There were no signs of PML on MRI. Two weeks later she presented a marked worsening with severe paraparesis with moderate dysmetria in upper limbs. She needed a wheel chair for ambulation (EDSS: 7). The patient started treatment with two 5 day cycles of iv steroid pulses; NTZ was restarted 2 months later with progressive improvement (EDSS: 3.5) and no new relapses.\n\n2.4 Case report 4\nA 32‐year‐old female was diagnosed of MS in 2007 after myelitis. She started treatment with AG but she was switched to NTZ in July 2008 due to persistence of clinical activity (severe relapse with myelitis) and disability progression. In November 2011 NTZ was stopped because of the presence of two risk factors for PML (>2 years and JCV+) she was included in a clinical trial. During the first 4 months, she received placebo, starting FTY in March 2012, no bridging therapy was initiated (EDSS: 3.5). In March, she complained of cognitive worsening and weakness in lower limbs, she was unable to read, presented a severe inattention and behavioral changes (EDSS: 5); a neuropsychological study was conducted, with normal processing speed, verbal fluency and abstract reasoning. A moderate impairment of visuospatial processing information and visual‐constructional execution with dysgraphia was present. Also, Difficulty encoding and retrieval in verbal memory with conservation of such processes in visual memory implying bilateral hemispheric lesion. A MRI was performed showing multiple T2 lesions; 45 lesions presented post contrast‐enhancement (Figure 1g,h), JCV in CSF was negative. The treatment with IV MTP was started with progressive improvement. Five months later the patient was able to walk without aid although behavioral alteration and cognitive decline have not been recovered, EDSS: 4.\n\n3 Results\nFour patients with a mean disease duration of 9.5 years (SD: 4.12) were switched from NTZ to FTY due to PML risk (mean time on NTZ of 3.1 years, all patients anti‐ JCV+, at that time the JCV‐index status was not available). The patients presented a mean of 1.5 relapses prior to NTZ therapy. FTY was started in the 3–4 following months after discontinuation. Despite the treatment, the patients presented neurological deterioration (mean: 3.5 months, SD: 2.08) with multifocal involvement: 75% presented motor disturbances, 50% cognitive impairment, and 25% seizures. Mean EDSS worsening was of 3.25 points (SD: 2.33). The MRI showed a huge increase in T2 lesions and Gd enhanced lesions (mean: 23.67, SD: 18.58; Figure 1). All patients received 5 days of IV MTP, one patient required PLEX. After the rebound all the patients presented neurological deterioration (mean: EDSS 1.125; SD: 0.478). Three patients continued treatment with FTY with a positive outcome, only one patient restarted NTZ.\n\n4 Discussion\nThe existence of a rebound phenomenon after NTZ withdrawal is controversial. Several open studies and case reports have reported an increased clinic radiological activity after NTZ suspension beyond pretreatment levels (Beume et al., 2015; Daelman et al., 2012; Gueguen et al., 2014; Jander et al., 2012; Kerbrat et al., 2011; Lenhard et al., 2010; Miravalle et al., 2011; Papeix et al., 2011; Rigau et al., 2012; Rinaldi et al., 2012; Salhofer‐Polanyi et al., 2014; Sorensen et al., 2014; Vellinga et al., 2008; West & Cree, 2010). In a Danish cohort, 83/375 (22.1%) of patients presented a rebound after stopping the treatment (Sorensen et al., 2014). Another analysis of 200 patients who discontinued NTZ, 11.9% present a rebound activity (Salhofer‐Polanyi et al., 2014). Recently, an analysis of 47 NTZ withdrawals found a significant clinical worsening (defined as a two‐step EDSS increase) in 19% of patients (Vidal‐Jordana et al., 2015). Nevertheless, other studies pointed to a restoration of the inflammatory levels to pretreatment levels not exceeding the prior activity. A post hoc analysis from the AFFIRM, SENTINEL, and GLANCE studies showed a return of disease activity independently of receiving alternative treatment or not (O'Connor et al., 2011). The RESTORE study, a randomized 24‐week NTZ treatment interruption study, observed that up to 29% of patients after NTZ discontinuation showed an MRI disease recurrence and 15% had a clinical relapse (Fox et al., 2014). The TY‐STOP, an observational study, revealed that in the first year after NTZ cessation, up to 35% of patients had a relapse (Clerico et al., 2014). None of these studies described a rebound phenomenon.\n\nThese differences should come from the different study settings. The studies revised by O'Connor et al. (2011) were prior to the description of PML when NTZ was not restricted to groups of patients with more aggressive disease; Moreover, the RESTORE study, clinical (defined as a relapse the prior year) or radiological (defined as Gadolinium‐enhancing lesions on screening) activity were considered exclusion criteria so only stable patients were analyzed.\n\nThe return of disease activity probably reflects an accelerated influx of these immune cells and cytokines into the brain through the endothelial membranes (O'Connor et al., 2011). The mechanism of action of NTZ is not clearly understood; inhibitions of the adhesion to the VCAM at the endothelium with the consequent decreasing in the extravasations to adjacent tissues play an important role. Recently, patients in long‐term treatments with NTZ showed a reduction in CD4 and CD8 lymphocytes, CD19 B‐cells and CD138 plasma cells in the CSF (Stuve et al., 2006) with increased percentage of activated CD4 and CD8 cells expressing proinflammatory cytokines in peripheral blood. This may be due to the diminished extravasation to the CNS (Kivisakk et al., 2009). Also, increased IL‐17, IL‐2, and IL‐1βafter 1 year of treatment have been demonstrated (Oreja‐Guevara et al., 2012; Ramos‐Cejudo et al., 2011). The cessation of the NTZ may lead to an increased permeability of the blood‐brain barrier with the consequent massive transfer of activated lymphocytes form peripheral blood to CNS. Stuve et al. (2006) reported a clinical MS relapse in a patient with the highest total CSF CD4 and CD8 T‐cell count after cessation of NTZ therapy, suggesting that a more rapid return of immune surveillance and function may be associated with IRIS in patients with MS.There are few data about the neuropathological findings; in previous case reports a severe demyelinating immunopathologic pattern I lesions were described (Beume et al., 2015; Daelman et al., 2012; Lenhard et al., 2010) with a dense T‐cell infiltrate dominated by CD8 although cases with CD4 predominance have been described (Rigau et al., 2012) indicating probably a reactivation of the disease. Thus, debate continues among neurologists as to whether some of the clinical worsening in patients after NTZ withdrawal is caused by CNS‐IRIS or worsening of their MS.\n\nThe rebound rate varies among studies between 10% and 30% of patients (Gueguen et al., 2014; Havla et al., 2011; Kerbrat et al., 2011; Miravalle et al., 2011; Rinaldi et al., 2012; Salhofer‐Polanyi et al., 2014; Sorensen et al., 2014; Vidal‐Jordana et al., 2015). The reactivation of the disease activity occurs frequently within the 3‐6 months after NTZ cessation, in relation with the drug pharmacodynamics features (Kerbrat et al., 2011; O'Connor et al., 2011). Cree et al. (2013) evaluated biomarkers of NTZ treatment (lymphocyte counts, alpha4‐integrin saturation, sVCAM, and CD49d expression) and demonstrated that 4 months after discontinuation all the biomarkers returned to the same levels as in untreated patients.\n\nFast reintroduction of alternative treatment after NTZ cessation is recommended to reduce the risk of recurrence. However, there is no consensus on the appropriate management. Some studies have assessed the usefulness of different strategies, nonetheless, a bridging therapy with pulsed IV MTP or switching to disease‐modifying treatment have not proved to be effective enough in controlling the disease (Havla, Keliter, & Kümpfel, 2013). Up to 50% of patients switched to FTY, a second‐line treatment for RRMS, presented a relapse, preferably during the firsts weeks (Cohen et al., 2014; Havla, Keliter, et al., 2013; Havla, Tackenberg, et al., 2013; Rinaldi et al., 2012; Vidal‐Jordana et al., 2015); besides, rebound cases after FTY initiation have been described (Jander et al., 2012; Papeix et al., 2011).\n\nThere are controversial data on factors predisposing to recurrence, however some studies suggest that pretreatment activity, longer MS duration (Havla, Tackenberg, et al., 2013; Lenhard et al., 2010; Miravalle et al., 2011), increased activity in the prior months to cessation (Jokubaitis et al., 2014) and longer washout periods are the main predisposing factors. Classically, a 3‐ to 6‐month washout period has been recommended for FTY switching (Fazekas et al., 2013; Jeffery et al., 2011). Nevertheless, recent evidence suggests the need for shorter washout periods. O'Connor et al. (2011) pointed out that NTZ was cleared from peripheral blood by 2 months from the last infusion (O'Connor et al., 2011). The TOFINGO study (Disease control and safety in RRMS patients switching from NTZ to FTY: a 32‐week, rater‐ and patient‐blind, randomized, parallel‐group study) demonstrated that the 8‐week over the 12‐week washout group had least activity over 8 weeks of FTY treatment and over 24 weeks since the last NTZ dose, the lowest change in T2 lesion volume from baseline to week 24 and the highest proportion of patients free from Gd‐enhancing lesions at week 24 (Kappos et al., 2013). Moreover, other series supports that initiating FTY within the first 3 months is associated with a significantly lower risk of relapse (Cohen et al., 2014; Havla et al., 2011; O'Connor et al., 2011). In our series, all the patients started FTY after 3 months, classically recommended as washout period.\n\nThere are no randomized controlled trials or established guidelines about the correct treatment in a rebound. The most frequent treatment is pulsed IV MTP for 5 days. The usefulness of PLEX is controversial with some reports of worsening maybe due to a rapid NTZ clearance in peripheral blood and an increased flux of lymphocytes into the brain (Lenhard et al., 2010). Our patients had severe deterioration during the rebound; however, despite a mild improvement after the rebound treatment, significant disabilities (exceeding pre‐NTZ treatment) were maintained over time.\n\n5 Conclusion\nAfter stopping NTZ, disease activity may return to pretreatment levels or a severe rebound with a marked clinical and radiological worsening could be seen. Prior to NTZ withdraw, a risk benefit balance should be evaluated and, if cessation is mandatory, a close monitoring and an early initiation of alternative treatment are recommended after drug withdrawal.\n\nConflict of Interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n\n\nBeume , L. A. \n, \nDersch , R. \n, \nFuhrer , H. \n, \nStich , O. \n, \nRauer , S. \n, & \nNiesen , W. D. \n (2015 ). Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with Natalizumab . Journal of Clinical Neuroscience , 22 , 400 –401 .25150761 \n\n\nClerico , M. \n, \nSchiavetti , I. \n, \nDe Mercanti , S. F. \n, \nPiazza , F. \n, \nGned , D. \n, \nBrescia Morra , V. \n, … \nDurelli , L. \n (2014 ). Treatment of relapsing remitting multiple sclerosis after 24 doses of Natalizumab: Evidence from an Italian spontaneous, prospective, and observational study (the TY‐STOP study) . JAMA Neurology , 71 , 954 –960 .24977406 \n\n\nCohen , M. \n, \nMaillart , E. \n, \nTourbah , A. \n, \nDe Sèze , J. \n, \nVukusic , S. \n, \nBrassat , D. \n, … \nLebrun , C. \n (2014 ). Switching from Natalizumab to Fingolimod in multiple sclerosis: A French prospective study . JAMA Neurology , 71 , 436 –441 .24566807 \n\n\nCree , B. \n, \nDe Seze , J. \n, \nFox , R. \n, \nGold , R. \n, \nHartung , H. \n, \nJeffery , D. \n, & \nWoodworth , J. \n (2013 ). Natalizumab effects during a 6‐month dose interruption: Relationship of pharmacokinetic (PK), pharmacodynamic (PD), and MRI measurements . Neurology , 80 , Supplement: S41.003.\n\n\nDaelman , L. \n, \nMaitrot , A. \n, \nMaarouf , A. \n, \nChaunu , M. P. \n, \nPapeix , C. \n, & \nTourbah , A. \n (2012 ). Severe multiple sclerosis reactivation under Fingolimod 3 months after Natalizumab withdrawal . Multiple Sclerosis Journal , 18 , 1647 .22907938 \n\n\nEngelhardt , B. \n, & \nKappos , L. \n (2008 ). 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Journal of Neurology, Neurosurgery and Psychiatry , 85 , 1038 –1040 .\n\n\nHavla , J. \n, \nGerdes , L. A. \n, \nMeinl , I. \n, \nKrumbholz , M. \n, \nFaber , H. \n, \nWeber , F. \n, … \nKümpfel , T. \n (2011 ). De‐escalation from natalizumab in multiple sclerosis: Recurrence of disease activity despite switching to glatiramer acetate . Journal of Neurology , 258 , 1665 –1669 .21431380 \n\n\nHavla , J. \n, \nKeliter , I. \n, & \nKümpfel , T. \n (2013 ). Bridging, switching or drug holidays‐how to treat a patient who stops Natalizumab? \nTherapeutics and Clinical Risk Management , 9 , 361 –369 .24124371 \n\n\nHavla , J. \n, \nTackenberg , B. \n, \nHellwig , K. \n, \nMeinl , I. \n, \nKrumbholz , M. \n, \nSeitz , F. \n, … \nKümpfel , T. \n (2013 ). Fingolimod reduces recurrence of disease activity after Natalizumab withdrawal in multiple sclerosis . Journal of Neurology , 260 , 1382 –1387 .23266894 \n\n\nJander , S. \n, \nTurowski , B. \n, \nKieseier , B. C. \n, & \nHartung , H. P. \n ( 2012 ). Emerging tumefactive multiple sclerosis after switching therapy from Natalizumab to Fingolimod . Multiple Sclerosis Journal , 18 , 1650 –1652 .23100527 \n\n\nJeffery , D. R. \n, \nMarkowitz , C. E. \n, \nReder , A. T. \n, \nWeinstock‐Guttman , B. \n, & \nTobias , K. \n (2011 ). Fingolimod for the treatment of relapsing multiple sclerosis . Expert Review of Neurotherapeutics , 11 , 165 –183 .21158700 \n\n\nJokubaitis , V. G. \n, \nLi , V. \n, \nKalincik , T. \n, \nIzquierdo , G. \n, \nHodgkinson , S. \n, \nAlroughani , R. \n, … \nButzkueven , H. \n (2014 ). Fingolimod after Natalizumab and the risk of short‐term relapse . Neurology , 82 , 1204 –1211 .24610329 \n\n\nKappos , L. \n, \nMueller‐Lenke , N. \n, \nDahlke , F. \n, \nGottschalk , R. \n, \nVon Rosenstiel , P. \n, & \nZhang , Y. \n (2013 ). Disease control and safety in RRMS patients switching from natalizumab to fingolimod: a 32‐week, rater‐ and patient‐blind, randomized, parallel‐group study (TOFINGO). 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis . Multiple Sclerosis Journal, 19, 74 –558 .\n\n\nKerbrat , A. \n, \nLe Page , E. \n, \nLeray , E. \n, \nAnani , T. \n, \nCoustans , M. \n, \nDesormeaux , C. \n, … \nEdan , G. \n (2011 ). Natalizumab and drug holiday in clinical practice: An observational study in very active relapsing remitting multiple sclerosis patients . Journal of the Neurological Sciences , 308 , 98 –102 .21665227 \n\n\nKivisakk , P. \n, \nHealy , B. C. \n, \nViglietta , V. \n, \nQuintana , F. J. \n, \nHootstein , M. A. \n, \nWeiner , H. L. \n, & \nKhoury , S. J. \n (2009 ). Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells . Neurology , 72 , 1922 –1930 .19487650 \n\n\nLenhard , T. \n, \nBiller , A. \n, \nMueller , W. \n, \nMetz , I. \n, \nSchönberger , J. \n, & \nWildemann , B. \n (2010 ). Immune reconstitution inflammatory syndrome after withdrawal of Natalizumab? \nNeurology , 75 , 831 –833 .20805529 \n\n\nMiller , D. H. \n, \nKhan , O. A. \n, \nSheremata , W. A. \n, \nBlumhardt , L. D. \n, \nRice , G. P. \n, \nLibonati , M. A. \n, … \nO'Connor , P. W. \n (2003 ). International natalizumab multiple sclerosis trial group. A controlled trial of Natalizumab for relapsing remitting multiple sclerosis . New England Journal of Medicine , 348 , 15 –23 .12510038 \n\n\nMiravalle , A. \n, \nJensen , R. \n, & \nKinkel , R. P. \n (2011 ). Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of Natalizumab therapy . Archives of Neurology , 68 , 186 –191 .20937940 \n\n\nO'Connor , P. W. \n, \nGoodman , A. \n, \nKappos , L. \n, \nLublin , F. D. \n, \nMiller , D. H. \n, \nPolman , C. \n, … \nLucas , N. \n (2011 ). Disease activity return during Natalizumab treatment interruption in patients with multiple sclerosis . Neurology , 76 , 1858 –1865 .21543733 \n\n\nOreja‐Guevara , C. \n, \nRamos‐Cejudo , J. \n, \nAroeira , L. S. \n, \nChamorro , B. \n, & \nDiez‐Tejedor , E. \n (2012 ). TH1/TH2 Cytokine profile in relapsing‐remitting multiple sclerosis patients treated with Glatiramer Acetate or Natalizumab . BMC Neurology , 12 , 95 .22989378 \n\n\nPapeix , C. \n, \nDepaz , R. \n, \nTourbah , A. \n, \nStankoff , B. \n, & \nLubetzki , C. \n (2011 ). Dramatic worsening following plasma exchange in severe post‐Natalizumab withdrawal multiple sclerosis relapse . Multiple Sclerosis Journal , 17 , 1520 –1522 .21669937 \n\n\nPolman , C. H. \n, \nO'Connor , P. W. \n, \nHavrdova , E. \n, \nHutchinson , M. \n, \nKappos , L. \n, \nMiller , D. H. \n, … \nSandrock , A. W. \n (2006 ). AFFIRM Investigators: A randomized, placebo‐controlled trial of Natalizumab for relapsing remitting multiple sclerosis , New England Journal of Medicine , 354 , 899 –910 .16510744 \n\n\nRamos‐Cejudo , J. \n, \nOreja‐Guevara , C. \n, \nStark , A. L. \n, \nRodriguez de Antonio , L. \n, \nChamorro , B. \n, & \nDiez‐Tejedor , E. \n (2011 ). Treatment with Natalizumab in relapsing‐remitting multiple sclerosis patients induces changes in inflammatory mechanism . Journal of Clinical Immunology , 31 , 623 –631 .21491095 \n\n\nRigau , V. \n, \nMania , A. \n, \nBefort , P. \n, \nCarlander , B. \n, \nJonquet , O. \n, \nLassmann , H. \n, & \nThouvenot , E. \n (2012 ). Lethal multiple sclerosis relapse after Natalizumab withdrawal . Neurology , 79 , 2214 –2216 .23100404 \n\n\nRinaldi , F. \n, \nSeppi , D. \n, \nCalabrese , M. \n, \nPerini , P. \n, & \nGallo , P. \n (2012 ). Switching therapy from Natalizumab to Fingolimod in relapsing remitting multiple sclerosis: Clinical and magnetic resonance imaging findings . Multiple Sclerosis Journal , 18 , 1640 –1643 .23100526 \n\n\nSalhofer‐Polanyi , S. \n, \nBaumgartner , A. \n, \nKraus , J. \n, \nMaida , E. \n, \nSchmied , M. \n, & \nLeutmezer , F. \n (2014 ). The Austrian Tysabri Registry Group. What to expect after Natalizumab cessation in a real‐life setting? \nActa Neurologica Scandinavica , 130 , 97 –102 .24720783 \n\n\nSorensen , P. S. \n, \nKoch‐Henriken , N. \n, \nPetersen , T. \n, \nRavnborg , M. \n, \nOturai , A. \n, & \nSellebjerg , F. \n (2014 ). Recurrence or rebound of clinical relapses after discontinuation of Natalizumab therapy in highly active MS patients . Journal of Neurology , 262 , 1170 –1177 .\n\n\nStuve , O. \n, \nMarra , C. M. \n, \nJerome , K. R. \n, \nCook , L. \n, \nCravens , P. D. \n, \nCepok , S. \n, … \nRacke , M. K. \n (2006 ). Immune surveillance in multiple sclerosis patients treated with Natalizumab . Annals of Neurology , 59 , 743 –747 .16634029 \n\n\nVellinga , M. M. \n, \nCastelijns , J. A. \n, \nBarkhof , F. \n, \nUitdehaag , B. M. \n, & \nPolman , C. H. \n (2008 ). Post‐withdrawal rebound increase in T2 lesional activity in Natalizumab‐treated MS patients . Neurology , 70 , 1150 –1151 .17872364 \n\n\nVidal‐Jordana , A. \n, \nTintoré , M. \n, \nTur , C. \n, \nPérez‐Miralles , F. \n, \nAuger , C. \n, \nRío , J. \n, … \nMontalban , X. \n (2015 ). Significant clinical worsening after natalizumab withdrawal: Predictive factors . Multiple Sclerosis Journal , 21 , 780 –785 .25392320 \n\n\nWest , T. W. \n, & \nCree , B. A. \n (2010 ). Natalizumab dosage suspension: Are we helping or hurting? \nAnnals of Neurology , 68 , 395 –399 .20818793 \n\n\nYousry , T. A. \n, \nMajor , E. O. \n, \nRyschkewitsch , C. \n, \nFahle , G. \n, \nFischer , S. \n, \nHou , J. \n, … \nClifford , D. B. \n (2006 ). Evaluation of patients treated with Natalizumab for progressive multifocal leukoencephalopathy . New England Journal of Medicine , 354 , 924 –933 .16510746\n\n",
"fulltext_license": "CC BY",
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"issue": "7(4)",
"journal": "Brain and behavior",
"keywords": "Natalizumab withdrawal; immune reconstitution inflammatory; rebound; syndrome",
"medline_ta": "Brain Behav",
"mesh_terms": "D000328:Adult; D001921:Brain; D015331:Cohort Studies; D004185:Disability Evaluation; D057915:Drug Substitution; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007155:Immunologic Factors; D008279:Magnetic Resonance Imaging; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D017211:Treatment Failure",
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"pages": "e00671",
"pmc": null,
"pmid": "28413713",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22989378;17872364;19255407;25150761;24124371;20805529;20818793;21491095;21431380;24977406;28413713;22907938;23100404;20937940;24682966;24566807;16634029;23641231;16510746;12510038;21543733;24360652;23100526;18075270;21669937;16510744;21665227;24728334;23266894;25392320;24876183;24720783;23100527;24610329;21158700;19487650",
"title": "Catastrophic outcome of patients with a rebound after Natalizumab treatment discontinuation.",
"title_normalized": "catastrophic outcome of patients with a rebound after natalizumab treatment discontinuation"
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"abstract": "A 68-year-old woman with acute ischemic stroke presented for mechanical thrombectomy, after failed thrombolysis with intravenous recombinant tissue plasminogen activator. The procedure was completed successfully with dexmedetomidine infusion. However, she developed acute angioedema toward the end of the procedure requiring emergent fiberoptic-guided endotracheal intubation. Angioedema has been reported to occur after administering intravenous recombinant tissue plasminogen activator with an incidence of 1.3%-5.1% in patients with acute stroke.",
"affiliations": "General Anesthesiology and Department of Outcomes Research, Cleveland Clinic, Cleveland, OH. Electronic address: sonnya@ccf.org.;General Anesthesiology, Cleveland Clinic, Cleveland, OH. Electronic address: avitsir@ccf.org.;Vascular Neurology and Endovascular Surgical Neuroradiology, Cleveland Clinic, Cleveland, OH. Electronic address: hussais4@ccf.org.;General Anesthesiology and Department of Outcomes Research, Cleveland Clinic, Cleveland, OH. Electronic address: elsharh@ccf.org.",
"authors": "Sonny|Abraham|A|;Avitsian|Rafi|R|;Hussain|M Shazam|MS|;Elsharkawy|Hesham|H|",
"chemical_list": "D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator",
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"issue": "27(2)",
"journal": "Journal of clinical anesthesia",
"keywords": "Angioedema; Neurointerventional suite; Recombinant tissue plasminogen activator; Sedation; Stroke",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000368:Aged; D000799:Angioedema; D005260:Female; D006801:Humans; D007431:Intraoperative Complications; D011994:Recombinant Proteins; D020521:Stroke; D017131:Thrombectomy; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure",
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"other_id": null,
"pages": "170-4",
"pmc": null,
"pmid": "25434502",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Angioedema in the neurointerventional suite.",
"title_normalized": "angioedema in the neurointerventional suite"
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"companynumb": "US-ROCHE-1521778",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "ALTEPLASE"
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"abstract": "The West German Study Group PlanB trial evaluated an anthracycline-free chemotherapy standard (six cycles of docetaxel and cyclophosphamide [TC]) in the routine treatment of human epidermal growth factor receptor 2-negative early breast cancer (EBC).\n\n\n\nPatients with pT1 to pT4c, all pN+, and pN0/high-risk EBC were eligible. High-risk pN0 was defined by one or more of the following: pT greater than 2, grade 2 to 3, high urokinase-type plasminogen activator/plasminogen activator inhibitor-1, hormone receptor (HR) negativity, and less than 35 years of age. After an early amendment, all HR-positive tumors underwent recurrence score (RS) testing, with chemotherapy omission recommended in RS less than or equal to 11 pN0 to pN1 disease. Patients were randomly assigned to four cycles of epirubicin (E)90/cyclophoshamide (C)600 followed by four cycles of docetaxel (T)100 or six cycles of T75C600 (administered once every 3 weeks). The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The protocol specified P = .05 for a noninferiority margin of 4.4% for all patients combined.\n\n\n\nOf the 3,198 registered patients, 348 (RS ≤ 11) omitted chemotherapy, and 401 were not randomly assigned. The intention-to-treat population included 2,449 patients (1,227 EC-T v 1,222 TC: postmenopausal, 62.2% v 60.8%; pN0, 58.2% v 59.5%; pT1, 57.6% v 52.3%; HR positive, 81.4% v 82.2%; RS greater than 25 [in HR-positive patients], 26.2% v 27.5%). Within the safety population (1,167 v 1,178 patients), 87.5% v 93.0% completed therapy. After a 60-month median follow-up, 5-year outcomes were similar in the EC-T and TC arms (DFS, 89.6% [95% CI, 87.9% to 91.5%] v 89.9% [95% CI, 88.1% to 91.8%]; OS, 94.5% [95% CI, 93.1% to 95.9%] v 94.7% [95% CI, 93.3% to 96.1%]). The DFS difference was within the noninferiority margin of the original trial design. Five treatment-related deaths were reported for TC (one for EC-T), despite a trend toward more-severe adverse events in the latter. Interaction analysis revealed no predictive trends with respect to key factors, including triple-negative, luminal A/B-like, pN, age, and RS status.\n\n\n\nIn the West German Study Group PlanB trial, 5-year outcomes for TC and EC-T were equally excellent. Six cycles of TC is an effective/safe option in human epidermal growth factor receptor 2-negative EBC with pN0 high genomic risk or pN1 EBC with genomically intermediate- to high-risk disease.",
"affiliations": "1 West German Study Group, Mönchengladbach, Germany.;1 West German Study Group, Mönchengladbach, Germany.;4 Mutterhaus der Borromäerinnen, Trier, Germany.;3 University of Cologne, Cologne, Germany.;5 Clinics Suedstadt, Rostock, Germany.;6 Evangelical Hospital Bergisch Gladbach, Bergisch Gladbach, Germany.;7 University Clinics Essen, Essen, Germany.;9 Johanniter-Krankenhaus Genthin-Stendal Hospitals, Stendal, Germany.;10 Protestant Hospital Oberhausen, Oberhausen, Germany.;11 Horst-Schmidt-Kliniken, Wiesbaden, Germany.;12 Gynecological-Oncological Practice, Hildesheim, Germany.;13 City Hospital, Chemnitz, Germany.;14 Clinics Essen-Mitte, Essen, Germany.;1 West German Study Group, Mönchengladbach, Germany.;16 Genomic Health, Redwood City, CA.;1 West German Study Group, Mönchengladbach, Germany.;18 Hannover Medical School, Hanover, Germany.;1 West German Study Group, Mönchengladbach, Germany.;18 Hannover Medical School, Hanover, Germany.;1 West German Study Group, Mönchengladbach, Germany.",
"authors": "Nitz|Ulrike|U|;Gluz|Oleg|O|;Clemens|Michael|M|;Malter|Wolfram|W|;Reimer|Toralf|T|;Nuding|Benno|B|;Aktas|Bahriye|B|;Stefek|Andrea|A|;Pollmanns|Anke|A|;Lorenz-Salehi|Fatemeh|F|;Uleer|Christoph|C|;Krabisch|Petra|P|;Kuemmel|Sherko|S|;Liedtke|Cornelia|C|;Shak|Steven|S|;Wuerstlein|Rachel|R|;Christgen|Matthias|M|;Kates|Ronald E|RE|;Kreipe|Hans H|HH|;Harbeck|Nadia|N|;|||",
"chemical_list": "D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D018719:Receptor, ErbB-2",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.18.00028",
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"issue": "37(10)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D000077143:Docetaxel; D004334:Drug Administration Schedule; D015251:Epirubicin; D005260:Female; D005858:Germany; D006801:Humans; D053208:Kaplan-Meier Estimate; D007970:Leukopenia; D008875:Middle Aged; D009503:Neutropenia; D011446:Prospective Studies; D018719:Receptor, ErbB-2; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "799-808",
"pmc": null,
"pmid": "30785826",
"pubdate": "2019-04-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer.",
"title_normalized": "west german study planb trial adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in her2 negative early breast cancer"
} | [
{
"companynumb": "DE-PFIZER INC-2017428866",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPIRUBICIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Hairy tongue is a benign and mostly asymptomatic disorder characterized by elongation of papillae with typical hairy-like appearance on the dorsal surface of the tongue. Many medical conditions, antibiotics, and drugs inducing xerostomia are associated with hairy tongue. In this article, we report a female patient with polymyalgia rheumatica who developed hairy tongue following treatment with prednisolone. Clinicians should be aware of the predisposing factors and drugs that may have a role in the development of hairy tongue.",
"affiliations": "Department of Rheumatology, Balıkesir Atatürk City Hospital, Balıkesir, Turkey.;Department of Rheumatology, Akdeniz University Faculty of Medicine, Antalya, Turkey.",
"authors": "Uğur|Sevcan|S|;Kaçar|Cahit|C|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5606/ArchRheumatol.2019.7239",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2148-5046",
"issue": "34(3)",
"journal": "Archives of rheumatology",
"keywords": "Hairy tongue; polymyalgia rheumatica; prednisolone",
"medline_ta": "Arch Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101639000",
"other_id": null,
"pages": "348-351",
"pmc": null,
"pmid": "31598603",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "15447700;7249508;28247090;21168745;27343960;18136183;25152586;18501207;18476933;18331301;27011938;8348734;1451290;19088002;25671958",
"title": "Prednisolone-Induced Hairy Tongue: A Case Report.",
"title_normalized": "prednisolone induced hairy tongue a case report"
} | [
{
"companynumb": "TR-BAUSCH-BL-2019-059798",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "Traumatic brain injury (TBI) has had increased notoriety in light of chronic traumatic encephalopathy in professional sports. However, despite the increased rate at which mood disorders affect this population, there remains little information on management of these disorders. TBI has also been implicated in the development of Parkinson disease, increasing the likelihood that patients may be treated with dopaminergic agents. Management of coexisting pathologies can become challenging, especially when confounded by medication side effects. A case is presented of a 58-year-old man who was admitted to the hospital in a manic state 15 years after having suffered a closed head injury. Several psychiatric admissions during the past 2 years were noted, with various diagnoses including different iterations of bipolar disorder. Among his medications, levodopa-carbidopa was present for an unsubstantiated Parkinson disease diagnosis. His mania resolved after discontinuation of the agent. This case is presented with a review of the relevant literature pertaining to the use of levodopa-carbidopa in this context, the use of other dopaminergic agents, and a biological hypothesis for the potential increased likelihood of manic symptoms in TBI patients who receive levodopa-carbidopa. Currently, there is a lack of research in this area, which emphasizes a need to review treatment guidelines for Parkinson disease patients with TBI.",
"affiliations": "Department of Psychiatry, Henry Ford Hospital, 1 Ford Pl, 1C, Detroit, MI 48202. isablab1@hfhs.org.;Department of Psychiatry, Henry Ford Hospital, Detroit, Michigan, USA.",
"authors": "Sablaban|Ibrahim M|IM|;Sivananthan|Mauran|M|",
"chemical_list": "D018491:Dopamine Agonists; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2155-7780",
"issue": "21(1)",
"journal": "The primary care companion for CNS disorders",
"keywords": null,
"medline_ta": "Prim Care Companion CNS Disord",
"mesh_terms": "D001714:Bipolar Disorder; D000070642:Brain Injuries, Traumatic; D002230:Carbidopa; D018491:Dopamine Agonists; D004338:Drug Combinations; D006801:Humans; D007980:Levodopa; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101547532",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30677265",
"pubdate": "2019-01-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Man Made Manic: Levodopa-Carbidopa-Induced Mania in Traumatic Brain Injury.",
"title_normalized": "a man made manic levodopa carbidopa induced mania in traumatic brain injury"
} | [
{
"companynumb": "US-ACCORD-106467",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nFarletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha, over-expressed in epithelial ovarian cancer (EOC) but largely absent in normal tissue. Previously, carboplatin plus pegylated liposomal doxorubicin showed superior progression-free survival and an improved therapeutic index compared with carboplatin/paclitaxel in relapsed platinum-sensitive EOC. This study assessed safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive recurrent EOC.\n\n\nMETHODS\nThis multicenter, single-arm study enrolled patients with platinum-sensitive EOC in first or second relapse for treatment with weekly farletuzumab 2.5mg/kg plus carboplatin AUC5-6 and pegylated liposomal doxorubicin 30mg/m(2) every 4weeks for 6cycles. Subsequently, maintenance with single-agent farletuzumab 2.5mg/kg once weekly or farletuzumab 7.5mg/kg once every three weeks continued until progression. The primary objective was to assess the safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin.\n\n\nRESULTS\nFifteen patients received a median of 12.0cycles (range, 3-26) of farletuzumab as combination therapy or maintenance, for a median of 45.0weeks (range 9-95). Farletuzumab/carboplatin/pegylated liposomal doxorubicin was generally well tolerated, with no farletuzumab-related grades 3-4 adverse events. The most commonly reported adverse events were associated with combination chemotherapy: fatigue (73.3%), nausea (46.7%), and neutropenia (40%). Ten patients had grade ≥3 adverse events, most frequently neutropenia and fatigue. No cardiac toxicity was seen. Best overall responses (RECIST) were a complete response for one patient, partial responses for 10 patients, and stable disease for four patients.\n\n\nCONCLUSIONS\nFarletuzumab plus carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive EOC demonstrated a safety profile consistent with that of carboplatin plus pegylated liposomal doxorubicin.",
"affiliations": "University of North Carolina Health Care, Division of Gynecology Oncology, Chapel Hill, NC, United States.;Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States.;Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States.;Island Gynecologic Oncology, PLLC, Brightwaters, NY, United States.;Morphotek, Inc., Exton, PA, United States.;Morphotek, Inc., Exton, PA, United States.;University of Alabama at Birmingham, AL, United States. Electronic address: ralvarez@uabmc.edu.",
"authors": "Kim|Kenneth H|KH|;Jelovac|Danijela|D|;Armstrong|Deborah K|DK|;Schwartz|Benjamin|B|;Weil|Susan C|SC|;Schweizer|Charles|C|;Alvarez|Ronald D|RD|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C506643:liposomal doxorubicin; C527484:farletuzumab; D011092:Polyethylene Glycols; D004317:Doxorubicin; D016190:Carboplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\n03653043932Gynecol OncolGynecol. Oncol.Gynecologic oncology0090-82581095-68592664426310.1016/j.ygyno.2015.11.031nihpa751273ArticlePhase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer☆,☆☆,★ Kim Kenneth H. aJelovac Danijela bArmstrong Deborah K. bSchwartz Benjamin cWeil Susan C. dSchweizer Charles dAlvarez Ronald D. e*a University of North Carolina Health Care, Division of Gynecology Oncology, Chapel Hill, NC, United Statesb Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United Statesc Island Gynecologic Oncology, PLLC, Brightwaters, NY, United Statesd Morphotek, Inc., Exton, PA, United Statese University of Alabama at Birmingham, AL, United States* Corresponding author at: University of Alabama at Birmingham, 1700 6th Avenue South, Birmingham, AL 35233, United States, ralvarez@uabmc.edu (R.D. Alvarez)15 1 2016 28 11 2015 2 2016 01 2 2016 140 2 210 214 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objective\nFarletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha, over-expressed in epithelial ovarian cancer (EOC) but largely absent in normal tissue. Previously, carboplatin plus pegylated liposomal doxorubicin showed superior progression-free survival and an improved therapeutic index compared with carboplatin/paclitaxel in relapsed platinum-sensitive EOC. This study assessed safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive recurrent EOC.\n\nMethods\nThis multicenter, single-arm study enrolled patients with platinum-sensitive EOC in first or second relapse for treatment with weekly farletuzumab 2.5 mg/kg plus carboplatin AUC5–6 and pegylated liposomal doxorubicin 30 mg/m2 every 4 weeks for 6 cycles. Subsequently, maintenance with single-agent farletuzumab 2.5 mg/kg once weekly or farletuzumab 7.5 mg/kg once every three weeks continued until progression. The primary objective was to assess the safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin.\n\nResults\nFifteen patients received a median of 12.0 cycles (range, 3–26) of farletuzumab as combination therapy or maintenance, for a median of 45.0 weeks (range 9–95). Farletuzumab/carboplatin/pegylated liposomal doxorubicin was generally well tolerated, with no farletuzumab-related grades 3–4 adverse events. The most commonly reported adverse events were associated with combination chemotherapy: fatigue (73.3%), nausea (46.7%), and neutropenia (40%). Ten patients had grade ≥3 adverse events, most frequently neutropenia and fatigue. No cardiac toxicity was seen. Best overall responses (RECIST) were a complete response for one patient, partial responses for 10 patients, and stable disease for four patients.\n\nConclusions\nFarletuzumab plus carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive EOC demonstrated a safety profile consistent with that of carboplatin plus pegylated liposomal doxorubicin.\n\nOvarian cancerPlatinum-sensitive relapsePegylated liposomal doxorubicinFarletuzumabMonoclonal antibody therapy\n==== Body\n1. Introduction\nFarletuzumab (FAR) is a humanized monoclonal antibody that binds to folate receptor alpha, known to be overexpressed in epithelial ovarian cancer (EOC) but largely absent in normal tissue [1–4]. In preclinical studies, FAR has exhibited immune-effector mediated effects via antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity, and single-agent anti-tumor activity in xenograft models of ovarian cancer, as well as synergistic effects with chemotherapeutic agents [5,6]. The combination of carboplatin and paclitaxel has long been utilized as a preferred treatment regimen for platinum-sensitive EOC. This regimen was used in a Phase 2 study of FAR in patients with EOC who had experienced first relapse, with the combination of carboplatin/paclitaxel/FAR found to be active as well as well tolerated [7]. Recent studies have shown that FAR enhances type 2 cell death in tumor cells and that the combination of combination of these immune-effector cellular signaling pathway most likely result in tumor growth suppression and toxicity [8].\n\nRecent studies have suggested that the combination of carboplatin and pegylated liposomal doxorubicin (PLD) may be the preferred regimen than carboplatin/paclitaxel for platinum-sensitive recurrent EOC [9–11]. In a randomized Phase 3 noninferiority study [9] of carboplatin plus PLD versus carboplatin plus paclitaxel in relapsed platinum-sensitive ovarian cancer, the carboplatin/PLD combination demonstrated noninferiority with the comparator in terms of progression-free survival (PFS) (11.3 months versus 9.4 months; P = 0.005) and lower rates of severe and long-lasting neuropathy. The benefit of carboplatin/PLD over carboplatin/paclitaxel was noted to persist in analysis of patients who relapsed between 6 and 12 and 6–24 months [11,12]. Toxicities were more common with carboplatin/paclitaxel and included neutropenia, neuropathy, and hypersensitivity reactions. Interestingly, carboplatin/PLD was associated with a substantially reduced incidence of platinum-associated hypersensitivity reactions in this study. It should be noted that the safety profile of FAR consists of infrequent and mild drug hypersensitivity adverse events (AEs) and rare interstitial pulmonary changes. No adverse interaction with chemotherapy was expected.\n\nIn view of a recent increase in the use of carboplatin plus PLD in patients with platinum-sensitive EOC, a Phase 1b study of FAR plus carboplatin and PLD was undertaken to assess the safety of this triple-agent combination in this disease context.\n\n2. Methods\n2.1. Study population\nEach participant provided written informed consent before initiating study procedures. All enrolled patients were greater than 18 years old and had histologically- or cytologically-confirmed, platinum-sensitive EOC (including primary peritoneal or fallopian tube malignancies) with relapse as defined by Gynecologic Cancer InterGroup (GCIG) CA-125 criteria or protocol-specific modified (to reflect current practices in the medical oncology community and nuances specific to ovarian cancer) Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 for 6 months or longer after completion of first- or second-line platinum chemotherapy. All had a Karnofsky Performance Status at least 70%. Patients were required to have the following laboratory and clinical results within two weeks prior to study day 1: absolute neutrophil count (ANC) ≥1.5 × 109 cells/L; platelet count ≥100 × 109 cells/L; hemoglobin ≥9 g/dL; creatinine ≤1.5 × upper limit of normal (ULN); bilirubin ≤ 1.5 × ULN; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALK-P) <2.5 × ULN.\n\nWomen with known central nervous system (CNS) tumor involvement, other active malignancy, clinically significant cardiac disease, active serious systemic disease or infection, evidence of immune or allergic reaction or documented antidrug antibodies (ADAs) after prior monoclonal antibody therapy were excluded from participation.\n\n2.2. Study design and treatment\nThis was a multicenter, open-label Phase 1b study with 2.5 mg/kg intravenous (IV) FAR in combination with carboplatin and PLD to assess the safety of this drug regimen in patients with platinum-sensitive EOC. The primary objective of this study was to assess the safety of FAR/carboplatin/PLD in this patient population. Hematology, clinical chemistries, urine, and left ventricular ejection fraction (LVEF) were monitored on Day 1, Week 1 of every 4-week cycle. Tumor assessment (using RECIST v.1.0) was performed every other cycle. Secondary objectives included assessment of response and PFS and the pharmacokinetic effect of FAR on chemotherapy (not reported here).\n\nStudy patients received carboplatin AUC5–6 IV and PLD 30 mg/m2 IV on Day 1 of an every 4-week combination treatment cycle. An ANC of 1.5 × 109 cells/L was required for retreatment with chemotherapy. If toxicity due to carboplatin or PLD occurred, doses could be reduced or delayed according to institutional guidelines. If chemotherapy was discontinued without disease progression, the investigator could elect to continue the patient on single-agent FAR until disease progression. Following completion of approximately 6 cycles with FAR/carboplatin/PLD therapy, patients who had not progressed began maintenance treatment with single-agent FAR 2.5 mg/kg once weekly in 4-week cycles until disease progression. A protocol amendment based on new pharmacokinetic data subsequently changed the maintenance therapy administration to single-agent FAR 7.5 mg/kg once every three weeks. Disease response and progression free survival was assessed utilizing modified RECIST v1.0 based upon computed tomography (CT) scan or magnetic resonance imaging (MRI) findings and by CA-125 levels (i.e., CA-125 ≥ 2 × upper limit of normal documented on 2 occasions).\n\nAll patients were premedicated prior to FAR infusion with acetaminophen 650 mg by mouth and, optionally, diphenhydramine 25 mg to 50 mg IV or equivalent per clinic routine. In the event of a drug hypersensitivity reaction believed to be associated with FAR, patients were premedicated for subsequent infusions with antipyretic and histamine receptor blocking medications per clinic routine. Prophylactic antiemetics were used for carboplatin and PLD according to usual practice at each site.\n\nAll documents pertaining to study design, informed consent, and patient information received Institutional Review Board approval in accordance with the Declaration of Helsinki before the study began.\n\n2.3. Safety and efficacy evaluations\nSafety assessments consisted of monitoring and recording all AEs and serious AEs; performance of history and physical examinations; regular monitoring of hematology, blood chemistry, and urine laboratory values (prior to treatment on Day 1, Week 1 of cycle 1); and monitoring with ECHO or MUGA at baseline and every third cycle during combination therapy, then every fourth cycle during maintenance therapy.\n\nEfficacy evaluations by modified RECIST v1.0 were performed at screening, every second cycle during combination treatment, every third cycle during maintenance, and at the study exit visit. Patients who discontinued prior to disease progression for any other reason (e.g., intolerable AE) were followed radiographically until documented disease progression or initiation of a new anticancer treatment occurred. As feasible, follow-up scans were obtained every 3 months; CT or MRI scans were read locally.\n\n2.4. Anti-drug antibodies\nPatients were monitored for the presence of ADA at screening, Day 1 of each combination treatment cycle, Day 1 of every third once-weekly maintenance cycle (or every other maintenance cycle during FAR dosing every 3 weeks), study exit visit, and 30 days post final dose. Associated FAR serum concentration and occurrence of a drug hypersensitivity AE at the time of a positive ADA were identified. The validated assay used for ADA analysis was estimated at 0.5 ng/mL based on detection of a FAR-specific monoclonal IgG positive control used as a surrogate ADA; the sensitivity was well below the FDA minimum expected concentration of 250–500 ng/mL [13].\n\n2.5. Statistical analysis\nThe target sample size for this study was 15 patients. The sample size for this study, 15 patients, was determined to be sufficient to adequately address the primary objective. No statistical comparisons were performed that would require a minimum sample size for the study.\n\nSafety analyses were performed on all patients who received at least one dose of combination treatment. Safety data were summarized using descriptive statistics. For overall response and CA-125 response, the number (percentage) of patients who responded was obtained and an exact 2-sided 95% confidence interval (CI) was constructed based on Clopper-Pearson methodology [14]. For PFS, duration of response, and time to response, the median was estimated using Kaplan-Meier methodology [15]. The 2-sided 95% CI for the median was constructed using the methodology of Brookmeyer and Crowley [16]. Two-sided 95% CIs for estimates of these endpoints at selected time points were calculated using the log-log transformation [17].\n\n3. Results\n3.1. Patient disposition\nThis study was conducted at three centers in the United States between 18 May 2010 and 14 Aug. 2012. Fifteen patients were enrolled and received at least one dose of FAR (Fig. 1). Carboplatin was dosed at AUC5 in 8 patients and AUC6 in 7 patients. Patient demographics and baseline characteristics are presented in Table 1. The median age was 62.0 years (range 47–82). All patients were Caucasian. All but one patient (with fallopian tube cancer) had a primary diagnosis of ovarian cancer.\n\n3.2. Safety\nFifteen patients received a median of 12.0 cycles (range, 3–6) of FAR as a component of combination therapy or as maintenance monotherapy, 6 cycles (range, 3–9) during combination therapy and 6 cycles (range, 3–26) during maintenance. The median length of exposure to FAR was 45 weeks (range 9–95 weeks). Table 2 presents all related AEs that occurred in more than one patient. During combination treatment, the most common AEs were fatigue (73.3%), nausea (46.7%), and neutropenia (40%). For single-agent maintenance (once weekly), the most common AEs were peripheral edema (16.7%) and cough (16.7%). During single-agent maintenance (once every three weeks), the most common AE was urinary tract infection (25%). Ten patients on combination treatment reported Grade 3 or higher AEs, the most common being neutropenia (5 patients) and fatigue (2 patients). One patient experienced Grade 3 palmar-plantar erythrodysesthesia (PPE). Six patients (40%) experienced AEs that interrupted or delayed the administration of chemotherapy. The most frequent AEs that delayed or interrupted chemotherapy were neutropenia and PPE.\n\nAll 15 patients who received combination treatment reported 103 chemotherapy-related AEs. The most frequently reported chemotherapy-related AEs were fatigue (66.7%), neutropenia (40%), nausea (33.3%), PPE (33.3%), rash (33.3%), and alopecia (26.7%). These percentages were comparable to those seen with carboplatin/PLD only. Two patients (13.3%) experienced 2 drug hypersensitivity AEs, hyperhidrosis and pruritus. Because of the development of ADAs, these were considered FAR related. Both events occurred during combination treatment. Three of the 15 patients (20%) receiving FAR/carboplatin/PLD reported 11 AEs that were considered (investigator judgment) related to FAR, the most frequent being constipation and fatigue (2 patients each [13.3%]); during maintenance, there were no AEs considered at least possibly related to FAR.\n\nFour patients reported serious AEs during combination treatment, two with small bowel obstructions and one each with febrile neutropenia and venous thrombosis. One patient experienced 3 serious AEs of small bowel obstruction that were considered per investigator judgment to be related to chemotherapy. None of the reported serious events was related to FAR. Four of 15 patients (26.7%) tested positive for ADA at least once while on study. Potential immunogenic reactions to FAR occurred in two patients, one with grade 2 hyperdyrosis and one with grade 1 pruritus. Seven patients (46.7%) experienced Grade 3 laboratory abnormalities while receiving FAR/carboplatin/PLD: 6 patients with decreased neutrophils, one with increased alanine aminotransferase, and one with decreased white blood cell count. One patient experienced a Grade 3 increase in glucose while receiving maintenance treatment. No drug-induced liver events were identified. No cardiac toxicity, defined as a ≥ 15% decrease in LVEF from baseline or ≥5% from institutional lower limit of normal, was observed during chemotherapy or during FAR maintenance. All but 3 patients had the same LVEF at last study assessment as they had at screening. Three clinically not significant decreases were noted (14%, 10%, 27%); overall, the lowest value noted remained above the upper limit of normal for the site.\n\nNo patient discontinued treatment during the study for any reason other than disease progression, and no on-study deaths were reported.\n\n3.3. Antitumor activity\nMedian radiologic PFS was 10.4 months (range 9.3–15.5); median CA-125 PFS was 17.7 months (range 11.1–20.3). Best overall responses by RECIST were a complete response for one patient, partial responses for 10 patients, and stable disease for four patients. Median duration of radiologic response was 8.4 months (range 6.9–13.6). Overall CA-125 response occurred in 12 patients (80.0%) with 50% response, 8 patients (53.3%) with 75% response, and 10 patients (66.7%) with complete normalization of CA-125. and no patient had a study remission length longer than the prior remission.\n\n4. Discussion\nWhile the standard treatment of platinum-sensitive EOC continues to be debulking surgery followed by paclitaxel/carboplatin, adding a third cytotoxic agent provided no improvement in either PFS or OS when investigated in a Phase 3 study of 4312 women with advanced stage EOC [18]. Recently, the combination of FAR plus carboplatin/taxane (paclitaxel or docetaxel) was associated with high response rates in patients with platinum-sensitive EOC at first relapse, based on results of a Phase 2 trial [7] and in a subset of patients in a subsequent placebo-controlled Phase 3 trial [19]. The Phase 2 study of the efficacy of FAR plus carboplatin/taxane found normalization of CA-125 in 80.9% of patients, an objective response rate of 75%, as well as increased duration of the progression-free interval (relative to the first response interval) in 21% of evaluable patients [7].\n\nThough for many years carboplatin/paclitaxel has been regarded as the treatment of choice at time of relapse for patients with platinum-sensitive disease, recent clinical trial data have emerged to support the use of carboplatin/gemcitabine or carboplatin/PLD as an alternative to carboplatin/paclitaxel in this setting [9–11,20]. Carboplatin/PLD appears to be better tolerated and includes the benefit of a slight improvement in PFS [9]. Additionally, there are some aspects of this regimen that may be preferred by patients, including the lack of propensity for alopecia and psychological implications of receiving a new regimen (rather than retreatment with the original regimen, which ultimately resulted in recurrence). The use of carboplatin/PLD has increased since the aforementioned trials of FAR plus carboplatin/paclitaxel. In Europe, as well as in major academic centers in the US, a preference for carboplatin/PLD has evolved. However, in the US in general, a preference for carboplatin/paclitaxel remains. Accordingly, to assess the feasibility of adding FAR to the carboplatin/PLD combination, we undertook the Phase 1b safety study reported here in women with platinum-sensitive EOC. In this study, FAR in combination with carboplatin/PLD appeared to be generally well tolerated, with a safety profile consistent with that seen previously for FAR alone and in combination with the carboplatin/PLD regimen, where no additive toxicity was found [7]. The majority of AEs were those expected with the carboplatin/PLD combination chemotherapy backbone, including neutropenia and PPE. Compared with 103 chemotherapy-related AEs, there were 11 AEs that were considered by the investigators to be at least possibly FAR-related, the most common being constipation and fatigue at 2 reports each; however high-dose (10 mg/kg weekly) single-agent FAR did not show similar effects [21]. Although farletuzumab may be associated with fatigue, the incidence of fatigue in this study was low compared with the ~40% reported in other carboplatin/PLD studies [9,11]. No clinical safety concerns were noted after the maintenance dose was modified, from FAR 2.5 mg/kg every 4 weeks to 7.5 mg/kg every 3 weeks, per the protocol amendment. Although the efficacy data reported here are preliminary, given that this was a Phase 1b safety study, the CA-125 normalization rate of 67% and objective response rate of 73% (11 of 15) are encouraging for this study patient, which included patients in second as well as first platinum-sensitive relapse.\n\nThis Phase 1b study assessed the safety and tolerability of FAR plus carboplatin/PLD as a first step toward the pursuit of this triple-agent regimen in future studies of EOC. Use of PLD as a replacement for paclitaxel, specifically in the context of FAR, is also of interest, given observations of immunosuppressive effects for paclitaxel in an ovarian cell line (stemming from an observed interference with interleukin-2-mediated immune system activation) [22], which could potentially interfere with the immune-mediated mechanism of actions of FAR; however, the clinical relevance of these preclinical findings is uncertain. Nonetheless, in view of increased use of carboplatin/PLD in the platinum-sensitive EOC population, additional investigation of this combination plus a third agent appears warranted. Formal assessment of efficacy was not feasible given the study limitation of sample size in this Phase 1 study. As supported by the favorable safety data described here, a randomized, placebo-controlled Phase 2 study is planned (MORAb-003-011 [NCT02289950]) to assess the efficacy of FAR in combination with carboplatin/PLD or carboplatin/paclitaxel (per investigator choice) in patients with platinum-sensitive EOC (low CA-125 at ≤3× upper limit of normal) at first relapse, with PFS as the primary endpoint.\n\nIn conclusion, we found that when FAR was combined with carboplatin/PLD for the treatment of platinum-sensitive EOC, the safety profile was consistent with that of the doublet of carboplatin/PLD. Further evaluation of FAR/carboplatin/PLD is underway.\n\nMedical writing assistance was provided by J.R. Foehl, PhD, Sr. Medical Writer, Morphotek, Inc. and Laurie Orloski, PharmD, Sr. Medical Writer, Pharmite, and funding by Morphotek, Inc.\n\n☆ Financial support: Funding for this study was provided by Morphotek, Inc., Exton, PA.\n\n☆☆ Neither this manuscript nor any similar manuscript, in whole or in part, other than the abstract listed below, is under consideration, in press, published, or reported elsewhere.\n\n★ The results presented in this manuscript were previously presented at the ASCO 2011 Annual Meeting: Jelovac D. et al. Phase 1 safety study of Farletuzumab, Carboplatin and Pegylated Liposomal Doxorubicin (PLD) in subjects with platinum-sensitive epithelial ovarian cancer (EOC). J Clin Oncol 2011;29(suppl):abstr 5056.\n\nConflict of interest statements\n\nKenneth H. Kim: No conflicts to report.\n\nDanijela Jelovac: No conflicts to report.\n\nDeborah K. Armstrong: My institution received grant funding for this trial. Part of that funding included salary support for me.\n\nBenjamin Schwartz: No conflicts to report.\n\nSusan C. Weil: Employee of Morphotek.\n\nCharles Schweizer: Employee of Morphotek.\n\nRonald D. Alvarez: Received grant support from Morphotek for this study.\n\nFig. 1 Disposition of subjects across combination and maintenance treatment periods.\n\nTable 1 Patient demographics and baseline disease characteristics.\n\n\tAll subjects\n\t\n(N = 15)\t\nAge, median (range), years\t62.0 (47–82)\t\nAge group, n (%)\t\n 18–< 65 years\t10 (66.7)\t\n ≥65 years\t5 (33.3)\t\nRace white, n (%)\t15 (100)\t\nEthnicity not Hispanic or Latino, n (%)\t15 (100)\t\nKarnofsky performance status, n (%)\t\n 100%\t3 (20.0)\t\n 90%\t12 (80.0)\t\nStage of disease, n (%)\t\n IIC\t3 (20.0)\t\n IIIA\t1 (6.7)\t\n IIIC\t8 (53.3)\t\n IV\t3 (20.0)\t\nHistologic subtype, n (%)\t\n Serous\t10 (66.7)\t\n Adenocarcinoma NOS\t5 (33.3)\t\nPrimary site, n (%)\t\n Fallopian tube\t1 (6.7)\t\n Ovary\t14 (93.3)\t\nRelapse, n (%)\t\n First relapse\t12 (80)\t\n Second relapse\t3 (20)\t\nLength of first remission, a mean (SD), months\t21.6 (13.47)\t\nLength of first remission, a n (%), months\t\n 6 to <12\t6 (40.0)\t\n 12 to <18\t1 (6.7)\t\n 18 to 24\t3 (20.0)\t\n >24\t5 (33.3)\t\na Length of first remission is based on the platinum-based chemotherapy used prior to study entry and is defined as the period of time (in months) from the date of last dose of platinum-based chemotherapy until date of first relapse by RECIST or GCIG.\n\nTable 2 Treatment-related adverse events that occurred in more than one subject.\n\nMedDRA system organ class/preferred terma\tFAR/carboplatin/PLD (N = 15)\n\t\nFAR-related n (%)b\tChemotherapy-related n (%)b\t\nBlood and lymphatic system disorders\t\n Neutropenia\t\t6 (40.0)\t\n Anemia\t\t2 (13.3)\t\nGastrointestinal disorders\t\n Nausea\t\t5 (33.3)\t\n Diarrhea\t\t3 (20.0)\t\n Vomiting\t\t3 (20.0)\t\n Constipation\t2 (13.3)\t2 (13.3)\t\nGeneral disorders and administration site conditions\t\t\t\n Fatigue\t2 (13.3)\t10 (66.7)\t\n Mucosal inflammation\t\t3 (20.0)\t\nMetabolism and nutrition disorders\t\n Decreased appetite\t\t3 (20.0)\t\nMusculoskeletal and connective tissue disorders\t\t\t\n Pain in extremity\t\t2 (13.3)\t\nNervous system disorders\t\n Hypoesthesia\t\t3 (20.0)\t\n Dysgeusia\t\t2 (13.3)\t\n Neuropathy peripheral\t\t2 (13.3)\t\nSkin and subcutaneous tissue disorders\t\n Palmar-plantar erythrodysesthesia syndrome\t\t5 (33.3)\t\n Rash\t\t5 (33.3)\t\n Alopecia\t\t4 (26.7)\t\nFAR = farletuzumab, PLD = pegylated liposomal doxorubicin.\n\na Subjects may have more than one Preferred Term within a given System Organ Class.\n\nb For each Preferred Term: n = number of subjects; % = percentages are based on the number of subjects who received FAR/carboplatin/PLD.\n\nHIGHLIGHTS\nFarletuzumab (FAR), a monoclonal antibody to folate receptor alpha, which is expressed in epithelial ovarian cancer (EOC).\n\nFAR has shown activity against EOC in platinum-sensitive relapse when combined with carboplatin and a taxane.\n\nCarboplatin in combination with pegylated liposomal doxorubicin (PLD) is a frequently used alterative regimen.\n\nThis safety study assessed the addition of FAR to carboplatin/PLD, with a view toward future larger studies.\n\nThis combination was generally well tolerated; adverse event profile was similar to that of carboplatin/PLD alone.\n==== Refs\n1 Dainty LA Risinger JI Morrison C Overexpression of folate binding protein and mesothelin are associated with uterine serous carcinoma Gynecol Oncol 105 2007 563 570 http://dx.doi.org/10.1016/j.ygyno.2006.10.063 17400285 \n2 Weitman SD Lark RH Coney LR Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues Cancer Res 52 1992 3396 3401 1596899 \n3 Toffoli G Cenigoi C Russo A Overexpression of folate binding protein in ovarian cancers Int J Cancer 74 1997 193 198 9133455 \n4 Chen YL Chang MC Huang CY Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response Mol Oncol 6 2012 360 369 http://dx.doi.org/10.1016/j.molonc.2011.11.010 22265591 \n5 Ebel W Routhier EL Foley B Preclinical evaluation of MORAb-003, a humanized monoclonal antibody antagonizing folate receptor-alpha Cancer Immun 7 2007 6 13 17346028 \n6 Lin J Spidel JL Maddage CJ The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity Cancer Biol Ther 14 2013 1032 1038 http://dx.doi.org/10.4161/cbt.26106 24025360 \n7 Armstrong DK White AJ Weil SC Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer Gynecol Oncol 129 2013 452 458 http://dx.doi.org/10.1016/j.ygyno.2013.03.002 23474348 \n8 Wen Y Graybill WS Previs RA Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer Clin Cancer Res 21 2015 448 459 http://dx.doi.org/10.1158/1078-0432.CCR-14-1578 25416196 \n9 Pujade-Lauraine E Wagner U Aavall-Lundqvist E Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse J Clin Oncol 28 2010 3323 3329 http://dx.doi.org/10.1200/JCO.2009.25.7519 20498395 \n10 Power P Stuart G Oza A Efficacy of pegylated liposomal doxorubicin (PLD) plus carboplatin in ovarian cancer patients who recur within six to twelve months: a phase II study Gynecol Oncol 114 2009 410 414 http://dx.doi.org/10.1016/j.ygyno.2009.04.037 19520420 \n11 Gladieff L Ferraro A De Rauglaudre G Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial Ann Oncol 23 2012 1185 1189 http://dx.doi.org/10.1093/annonc/mdr441 21976386 \n12 Markman M Moon J Wilczynski S Single agent carboplatin versus carboplatin plus pegylated liposomal doxorubicin in recurrent ovarian cancer: Final survival results of a SWOG (S0200) phase 3 Gynecol Oncol 116 2010 323 325 http://dx.doi.org/10.1016/j.ygyno.2009.11.026 20044128 \n13 Human and Murine, ADA Isotyping Multiplexes for Immunogenicity Testing of Protein Therapeutics Using the MT-ADA™ Assay, Genalyte, Inc San Diego, CA 2013 \n14 Clopper CJ Pearson ES The use of confidence or fiducial limits illustrated in the case of the binomial Biometrika 26 1934 404 413 \n15 Kaplan EL Meier P Nonparametric estimation from incomplete observations J Am Stat Assoc 53 1958 457 481 \n16 Brookmeyer R Crowley J A confidence interval for the median survival time Biometrics 38 1982 29 41 \n17 Kalbfleisch JD Prentice RL The Statistical Analysis of Failure Time Data John Wiley & Sons, Inc 1980 \n18 Bookman MA Brady MF Maguire WP Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the gynecologic cancer InterGroup J Clin Oncol 27 2009 1419 1425 http://dx.doi.org/10.1200/JCO.2008.19.1684 19224846 \n19 Vergote I Armstrong D Scambia G Phase 3 double-blind, placebo controlled study of weekly farletuzumab with carboplatin/taxane in subjects with platinum-sensitive ovarian cancer in first relapse Oral Presentation at the 18th International Meeting of the European Society of Gynaecological Oncology October 19–22, 2013 Liverpool, UK \n20 Pfisterer J Plante M Vergote I Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG J Clin Oncol 24 2006 4699 4707 http://dx.doi.org/10.1200/JCO.2006.06.0913 16966687 \n21 Konner JA Bell-McGuinn KM Sabbatini P Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a phase I study Clin Cancer Res 16 2010 5288 5295 http://dx.doi.org/10.1158/1078-0432.CCR-10-0700 20855460 \n22 Javeed A Ashraf M Riaz A Paclitaxel and immune system Eur J Pharm Sci 38 2009 283 290 http://dx.doi.org/10.1016/j.ejps.2009.08.009 19733657\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0090-8258",
"issue": "140(2)",
"journal": "Gynecologic oncology",
"keywords": "Farletuzumab; Monoclonal antibody therapy; Ovarian cancer; Pegylated liposomal doxorubicin; Platinum-sensitive relapse",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D000077216:Carcinoma, Ovarian Epithelial; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D011092:Polyethylene Glycols",
"nlm_unique_id": "0365304",
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"pages": "210-4",
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"pubdate": "2016-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
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"title": "Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer.",
"title_normalized": "phase 1b safety study of farletuzumab carboplatin and pegylated liposomal doxorubicin in patients with platinum sensitive epithelial ovarian cancer"
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"abstract": "Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and overlap SJS/TEN are life-threatening diseases that are most frequently caused by drugs. Much debate remains about the role of systemic corticosteroids (SCs) in their treatment. Our aim to determine the incidence, causative drugs, the role and side effects of SCs in severe cutaneous adverse reactions (SCARs), in Assiut University Hospital (AUH). Patients This study was conducted in Department of Dermatology at AUH, from 2012 to 2017. All patients with SJS, overlap SJS/TEN and TEN admitted during this period were included in the study. Eighty-three patients with SCARs were included in this study. The most common type was SJS (67.5%). The incidence ranged from 1.7% in 2012 to 7.7% in 2017. Carbamazepine, valproic acid, lamotrigine, diclofenac sodium, and flucloxacillin-amoxicillin were the most common causative drugs. The most common side effects of SCs were peptic ulcer (55.5%) and hypertension (51.8%). The mortality rate in patients treated with SCs was 100% in TEN, 33.3% in overlap SJS/TEN and 16.3% in SJS. The patients of SCARs must be aware of the causative drugs and must never be re-administered. SCs in treatment of SCARs may increase the complications and the mortality rate.",
"affiliations": "Faculty of Medicine, Department of Dermatology, Venereology, and Andrology, Assiut University, Assiut, Egypt.;Faculty of Pharmacy, Department of Pharmaceutics, Assiut University, Assiut, Egypt.;Ministry of Health, Sana's, Yemen.;Faculty of Pharmacy, Department of Clinical Pharmacy, Assiut University, Assiut, Egypt.",
"authors": "Abou-Taleb|Doaa A E|DAE|0000-0002-9642-8233;El-Sayed|Ahmed M|AM|;Ghabesha|Ayad A|AA|;Hassan|Sahar B|SB|",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "United States",
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"doi": "10.1111/dth.14176",
"fulltext": null,
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"issn_linking": "1396-0296",
"issue": "33(6)",
"journal": "Dermatologic therapy",
"keywords": "Stevens-Johnson syndrome; severe cutaneous adverse reactions; systemic corticosteroids; toxic epidermal necrolysis",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D004534:Egypt; D006761:Hospitals; D006801:Humans; D015994:Incidence; D004364:Pharmaceutical Preparations; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9700070",
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"pages": "e14176",
"pmc": null,
"pmid": "32779328",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe cutaneous adverse drug reactions: Incidence, clinical patterns, causative drugs and modalities of treatment in Assiut University Hospital, Upper Egypt.",
"title_normalized": "severe cutaneous adverse drug reactions incidence clinical patterns causative drugs and modalities of treatment in assiut university hospital upper egypt"
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"abstract": "Monoclonal antibodies (mAb) targeting plasma cells are malignant gammopathy designed and approved therapies. In recent years, these antibodies have also been increasingly introduced for non-malignant conditions such as autoimmune-mediated diseases. The Anti-Phospholipid Syndrome (APS) is an immune-mediated disorder in which autoantibodies against phospholipid associated proteins could elicit the activation of the coagulation cascade in specific situations. Therefore, the mainstream treatment for APS patients is the use of anticoagulant therapy. However, there are refractory patients who would benefit from targeting the antibodies rather than their effects. Rituximab, a B-cell depleting mAb, and intravenous immunoglobulins (IVIG) have been used in APS patients without showing a clear beneficial effect or a significant drop in anti-phospholipid antibody (aPL) levels.\n\n\n\nWe present our first APS case treated with daratumumab, an anti-CD38 mAb, in a 21-year-old patient with APS who presented with recurrent venous thromboembolic events despite adequate anticoagulant therapy. She tested positive for lupus anticoagulant, anti-cardiolipin IgG, anti-beta-2-glycoprotein-I IgG and anti-phosphatidylserine/prothrombin IgG and IgM. She was administered one dose weekly of daratumumab for 4 weeks. The treatment showed an adequate safety profile and was well tolerated. The patient was discharged after undergoing a clinically significant improvement. After the therapy, her levels of positive aPL declined significantly and most continued to decrease during the next three months. The patient experienced a new thrombotic episode two years after the therapy associated with poor adherence to antithrombotic therapy.\n\n\n\nThe treatment with daratumumab showed an adequate safety profile, was well tolerated and led to a significant clinical improvement. Levels of aPL lowered on therapy and the next three months and then rose again during follow-up. Further investigation is needed to better elucidate the role and optimal timing and doses of daratumumab in treatment of refractory APS.",
"affiliations": "Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.;Department of Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain.;Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.;Department of Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain.;Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.;Department of Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain.;Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.",
"authors": "Pleguezuelo|Daniel E|DE|;Díaz-Simón|Raquel|R|;Cabrera-Marante|Oscar|O|;Lalueza|Antonio|A|;Paz-Artal|Estela|E|;Lumbreras|Carlos|C|;Serrano Hernández|Antonio|A|",
"chemical_list": "D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D015415:Biomarkers; D007155:Immunologic Factors; C556306:daratumumab",
"country": "Switzerland",
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"doi": "10.3389/fimmu.2021.667515",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.667515\nImmunology\nCase Report\nCase Report: Resetting the Humoral Immune Response by Targeting Plasma Cells With Daratumumab in Anti-Phospholipid Syndrome\nPleguezuelo Daniel E. 1 *\n\nDíaz-Simón Raquel 2\nCabrera-Marante Oscar 1\n\nLalueza Antonio 2\nPaz-Artal Estela 1\n\nLumbreras Carlos 2\nSerrano Hernández Antonio 1\n\n1 Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain\n2 Department of Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain\nEdited by: Pier Luigi Meroni, Istituto Auxologico Italiano (IRCCS), Italy\n\nReviewed by: Falk Hiepe, Charité-Universitätsmedizin Berlin, Germany; Elisabet Svenungsson, Karolinska Institutet (KI), Sweden\n\n*Correspondence: Daniel E. Pleguezuelo, dpleguezuelo@salud.madrid.org\nThis article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology\n\n12 4 2021\n2021\n12 66751513 2 2021\n22 3 2021\nCopyright © 2021 Pleguezuelo, Díaz-Simón, Cabrera-Marante, Lalueza, Paz-Artal, Lumbreras and Serrano Hernández\n2021\nPleguezuelo, Díaz-Simón, Cabrera-Marante, Lalueza, Paz-Artal, Lumbreras and Serrano Hernández\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nIntroduction\n\nMonoclonal antibodies (mAb) targeting plasma cells are malignant gammopathy designed and approved therapies. In recent years, these antibodies have also been increasingly introduced for non-malignant conditions such as autoimmune-mediated diseases. The Anti-Phospholipid Syndrome (APS) is an immune-mediated disorder in which autoantibodies against phospholipid associated proteins could elicit the activation of the coagulation cascade in specific situations. Therefore, the mainstream treatment for APS patients is the use of anticoagulant therapy. However, there are refractory patients who would benefit from targeting the antibodies rather than their effects. Rituximab, a B-cell depleting mAb, and intravenous immunoglobulins (IVIG) have been used in APS patients without showing a clear beneficial effect or a significant drop in anti-phospholipid antibody (aPL) levels.\n\nClinical case\n\nWe present our first APS case treated with daratumumab, an anti-CD38 mAb, in a 21-year-old patient with APS who presented with recurrent venous thromboembolic events despite adequate anticoagulant therapy. She tested positive for lupus anticoagulant, anti-cardiolipin IgG, anti-beta-2-glycoprotein-I IgG and anti-phosphatidylserine/prothrombin IgG and IgM. She was administered one dose weekly of daratumumab for 4 weeks. The treatment showed an adequate safety profile and was well tolerated. The patient was discharged after undergoing a clinically significant improvement. After the therapy, her levels of positive aPL declined significantly and most continued to decrease during the next three months. The patient experienced a new thrombotic episode two years after the therapy associated with poor adherence to antithrombotic therapy.\n\nConclusions\n\nThe treatment with daratumumab showed an adequate safety profile, was well tolerated and led to a significant clinical improvement. Levels of aPL lowered on therapy and the next three months and then rose again during follow-up. Further investigation is needed to better elucidate the role and optimal timing and doses of daratumumab in treatment of refractory APS.\n\nanti-phospholipid\nrefractory\ntreatment\ndaratumumab\nanti-CD38\n==== Body\nIntroduction\n\nAntiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL) (1). Antibodies against beta-2-glycoprotein I (aB2GPI) and Cardiolipin (aCL), together with the functional assay lupus anticoagulant (LA), are the three laboratory tests considered for classification of this Syndrome in the revised Sydney criteria (1).\n\nSince thrombosis is the most relevant clinical manifestation of this disorder, its treatment relies almost exclusively on anticoagulant therapy with warfarin, acenocoumarol and heparin-based regimens. EULAR recommendations from 2019 suggest assessing the anticoagulation range using International Normalized Ratio (INR)) (2). If the INR is found to be lower than the target, the patient would need the anticoagulant therapy to be adjusted to maintain the INR within the therapeutic ranges (INR: 2–3) (3). If the INR is within the therapeutic ranges at the time of a thrombotic episode, it is recommended to increase the intensity of anticoagulation to INR: 3–4 (2, 3). In patients with arterial events, another option would be to add low-dose acetylsalicylic acid (LDASA) to the anticoagulant treatment. However, it should be noted that this combination is burdened by a higher bleeding risk (4). Long-term low molecular weight heparin (LMWH) may also be considered as a safe and effective alternative to warfarin, according to the guidelines from the 13th International Congress on Anti-Phospholipid Antibodies (5–9). However, despite anti-thrombotic therapy, 3 to 24% of APS patients still develop recurrent thrombotic events (10–13).\n\nPatients with proven refractoriness to the anticoagulant therapy would benefit from etiological targeted therapies, as aPL are both diagnostic markers and pathogenic drivers of APS (14). Consequently, the 15th International Congress on Anti-Phospholipid Antibodies Task Force on Treatment Trends suggested that immunomodulatory therapy, in addition to or as an alternative to oral anticoagulation, could represent a valuable option for refractory cases (15).\n\nMuch of the accumulated experience on the use of immunomodulatory treatments in APS comes from the need to treat refractory patients. Some of them suffer from the catastrophic form of APS but most are carriers of conventional APS with persistent additional symptoms such as migraine, livedo reticularis, and fatigue, which are not included in the latest classification criteria. Most immunomodulatory agents used in APS usually target several steps in B-cell differentiation pathway and their activity. For example, corticosteroids difficult B-cell proliferation and maturation by inhibiting NFkB pathway (16). Other drugs, like hydroxychloroquine, show anti-inflammatory and anti-thrombotic effects (17) by detaching aPL from B2GPI on phospholipid-bound endothelial membranes and protecting annexin V (12). Plasmapheresis removes pathogenic mediators from blood such as autoantibodies and cytokines (18). Intravenous immunoglobulin (IVIG) helps blocking autoantibodies and autoreactive B-cell activation and expansion (19). Among them, hydroxychloroquine is one of the most largely prescribed. It has shown beneficial effects for secondary thromboprophylaxis, especially in SLE patients (20, 21). The combination of glucocorticoids, plasmapheresis or Intravenous immunoglobulins (IVIG) have also shown to be effective in preventing recurrent thrombosis in catastrophic (22) and non-catastrophic APS patients (23). While IVIG is preferred in APS patients with immune thrombocytopenia, plasmapheresis is recommended in microangiopathic hemolytic anemia. Eculizumab, a monoclonal antibody (mAb) blocking complement C5a, has been used for secondary thromboprophylaxis in kidney transplant patients with APS (24). Rituximab, a chimeric mAb targeting CD20 on the surface of B cells, was studied in an open-label phase IIa descriptive pilot study (RITAPS) carried out in 20 patients with non-criteria APS manifestations refractory to conventional treatments (25). The drug proved to be effective in controlling some of symptoms, but levels of aPL remained unchanged (25).\n\nMost of the above-mentioned drugs target B-cell activation, proliferation and/or lower the concentration of circulating antibodies for a short period of time, but they are not directed against the main sources for antibody secretion, which are known to be bone marrow-resident plasma cells (26, 27). These cells express the surface marker CD38 and have the ability to continuously secrete antibodies without further stimulation by their cognate antigen for years or decades. In autoimmunity, as autoreactive B-cells were supposed to be persistently activated by contact with self-antigens, short-lived plasma cells or plasmablasts, which are proliferating cells with a life span of 3 to 5 days (28), were thought to be the most relevant source for autoantibody production. Nonetheless, the clinical experience has proved this hypothesis to be wrong. Treatment with dexamethasone or cyclophosphamide causes a significant reduction in the presence of plasma cells in inflamed tissues, but not in bone marrow niches (27). These untargeted cells continue producing pathogenic autoantibodies that could form immune complexes and reactivate the disease via induction of inflammatory pathways in antigen presenting cells or motivate a direct activation of autoreactive memory B-cells (27). Our group previously described the association of thrombosis (29, 30) and non-criteria manifestations (31) in patients with APS and circulating immune complexes with B2GPI.\n\nAs the CD38 molecule is expressed on the surface of plasmablasts and plasma cells, although not exclusively (e.g.: on NK cells), they are targeted by daratumumab, an anti-CD38 IgG1-kappa human mAb. The binding of daratumumab to CD38 molecules on the surface of cells raises antibody-dependent cellular cytotoxicity and the depletion of the cells (32). Daratumumab was approved in 2016 in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of multiple myeloma patients as a second line therapy (33). However, some off-label uses have been reported in the literature for autoimmune hemolytic anemia (34–37), Evans’ Syndrome (38, 39), cold agglutinin disease (40, 41), pure red cell aplasia (42), immune thrombocytopenia (43), systemic lupus erythematosus (44), and anti-CASPR2 encephalitis (45).\n\nWe present the case of a young woman diagnosed of Primary APS with recurrent venous thromboembolic events, in whom the failure of conventional treatment and plasmapheresis led to off-label use of daratumumab.\n\nMethods\n\nPatient Consent and Approval of Off-Label Use of Daratumumab\n\nOff-label use of daratumumab was approved by the Medical Direction and the Pharmacy Department of our center. The patient was informed about the goals and possible side effects of the proposed treatment with daratumumab and signed the informed consent. The treatment was funded by our center.\n\nBlood Samples\n\nFresh blood samples were drawn from the patient whenever she came to the Hospital and before/after a relevant time point regarding the administered therapy.\n\nDetermination of Anti-Phospholipid Antibodies\n\nThe presence of aCL and aB2GPI IgG/IgM was evaluated using a Phadia 250 (ThermoFischer Scientific, MA, USA) with cutoffs established by the manufacturer and validated in our laboratory (99th percentile). LA was measured using HemosIL dRVVT (cutoff ratio 1.2) and HemosIL Silica Clotting Time (cutoff ratio 1.3) assays (Instrumentation Laboratory SpA, Milano, Italy). aPS/PT IgG/IgM antibodies were evaluated using QUANTA Lite ELISA (INOVA DIAGNOSTICS, San Diego, CA, USA) with cutoffs established by the 99th percentile of our local healthy population (IgG: 30 U/mL and IgM 40 U/mL).\n\nTotal Serum Immunoglobulin Quantification\n\nTotal serum IgG, IgA, and IgM were evaluated using an Immage 800 nephelometer (Beckman Coulter Fullerton, CA, USA).\n\nLymphocyte Subpopulations Study\n\nLymphocytes were labeled using whole blood (50 µL) and 20 µL of BD multitest 6-color TBNK reagent in Trucount tubes for 15 min. Red blood cells were lysed using fluorescence activated cell sorting lysing solution. Plasmablasts were assessed by a combination of monoclonal antibodies as CD45+CD19+CD38+++IgM− lymphocytes. Determination of lymphocyte subpopulations was performed with a FACSCanto II flow cytometer, and data analyzed by FACSCanto clinical software (BD Biosciences, San Jose, CA, USA).\n\nResults\n\nCase Description and Follow-Up\n\nA previously healthy 19-year-old woman taking oral contraceptives was diagnosed of right pulmonary thromoembolism (PTE). As other risk factors such as obesity, smoking or inherited thrombophilia were ruled out, she was investigated for aPL and resulted in positive titers of LA, aCL IgG, aB2GPI IgG and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM. Anti-nuclear antibodies (ANA), complement C3 or C4 consumption or other clinical signs associated to SLE were absent. She was diagnosed of Primary. APS and discharged with acenocoumarol and hydroxychloroquine. Two years later, she developed a new PTE despite adequate INR target. Acenocoumarol was discontinued, and treatment with Low Molecular Weight Heparin (LMWH) and low doses of aspirin were initiated. Four weeks later she was admitted again because of severe left iliofemoral vein thrombosis (VT).\n\nOn admission, we switched LMWH to parenteral sodium heparin with well-documented therapeutic anticoagulant activity. On day 1 she began with dyspnea and desaturation. A pulmonary angioCT scan demonstrated the presence of PTE. On day 2, she worsened clinically, and a new angioCT scan demonstrated the growth of the pulmonary thrombus.\n\nTo address this worsening clinical picture, we planned a sequential treatment regimen based on two-dose plasmaphereses (days −9 & −8 before the start of treatment with daratumumab) with albumin as reposition, 20 g IVIG (day −4) as a single replacement therapy after plasmapheresis and 4 doses of anti-CD38 daratumumab on days 0, + 7, +14 & +20. The first dose of daratumumab consisted of 8 mg/kg. In the second, third and fourth infusions, 16 mg/kg were administered. The patient experienced a clear improvement of symptoms and signs of VT and PTE from day +1 and could be discharged later on with a therapeutic regimen of subcutaneous enoxaparin (day +8). The overall tolerability of the treatment was adequate. She only developed mild diarrhea with the infusions and one upper respiratory tract infection.\n\nShe showed a partial response in her blood analyses from the start of the anti-CD38 therapy with all positive aPL slowly declining. Positive aPL reached their lowest values on day 108 after the first infusion of the drug and 84 days after the end of treatment. Since then, aCL IgG, aB2GPI IgG and aPS/PT IgG began a smooth increase until the time of this report, with aPL values surpassing those from baseline ( Figure 1 ). However, aPS/PT IgM values have remained stable on a plateau at half the titer of baseline values.\n\nFigure 1 Change in aPL levels before and after therapy. An extreme drop in aPL levels lasting for 4 days was observed after two sessions of plasmapheresis. aPS/PT IgM values even rose to higher levels than in baseline after plasmapheresis. One week after the first dose of daratumumab was administered, aCL IgG and aB2GPI IgG started a decline, this decline lasting until day +108. After day +108, a significant climb began. Levels of aPS/PT IgG lowered until day +248 and then went up again. Levels of aPS/PT IgM showed an intermittent up and down profile, but they have remained stable at half the titer of baseline from day +189 and onwards. PE, plasmapheresis; DARA, daratumumab.\n\nAlmost two years later, and coinciding with the rise of aB2GPI and aCL of IgG isotype, the patient unintentionally missed 6 doses of enoxaparin and was admitted to Hospital with a new VT. Since that episode, she has remained asymptomatic in the follow-ups with an adjusted dose of subcutaneous enoxaparin every 12 hours.\n\nBesides aPL, changes in the total serum immunoglobulins were noted, with a slow decline in total IgG until 4.58 g/L. To avoid susceptibility to infections, the patient was administered a single dose of 60 g polyclonal IVIG on day +79 and has remained within normal levels during the follow-up. Lymphocyte counts did not change significantly but a decline and absence of circulating NK cells was noted after the first infusion. NK count was restored two months after the end of the therapy. As expected by their surface expression of CD38, plasmablasts were removed from peripheral blood and did not show signs of restoration until eight months after the end of therapy. Other B-cell subpopulations did not change significantly ( Table 1 ).\n\nTable 1 Levels of aPL, serum immunoglobulins, d-dimer and lymphocyte subpopulations.\n\nTime Point\taPS/PT IgG\taPS/PT IgM\taB2GPI IgG\taB2GPI IgM\taCL IgG\taCL IgM\tTotal Serum IgG\tTotal Serum IgA\tTotal Serum IgM\tD-Dimer\tTotal Lymphocyte Count\tNK%\tNK\tCD19%\tCD19\tPlasma-blasts%\t\nDay −11. Baseline\t155\t125\t66\t2.1\t85\t8.5\t8.8\t0.9\t2.1\t\t\t\t\t\t\t\t\nDay −7. After Plasmapheresis\t77.1\t69.9\t11\t1.4\t11\t8.4\t3.2\t0.5\t0.6\t\t1418\t6.1\t87\t27.4\t389\t\t\nDay −3. After IVIG\t144\t210\t36\t1.4\t34\t8.9\t10.5\t0.8\t1\t2028\t\t\t\t\t\t\t\nDay +4. Right after 1st dose of 8 mg/kg\t149\t283\t48\t0.1\t62\t4.1\t10.1\t1.1\t1.5\t3497\t1631\t0.3\t5\t35.2\t575\t0.3\t\nDay +10. Before 2nd dose of 16 mg/kg\t113\t179\t33\t0.1\t44\t4.3\t7.8\t0.5\t0.9\t878\t1656\t1.7\t28\t26.9\t446\t\t\nDay +17. Before 3rd dose of 16 mg/kg\t131\t102\t29\t0.1\t30\t4.1\t6.8\t0.3\t0.8\t397\t1728\t0.7\t12\t27.2\t470\t\t\nDay +24. Before 4th dose of 16 mg/kg\t122\t102\t32\t0.1\t33\t4.3\t6.1\t0.2\t0.6\t178\t1660\t0.3\t4\t30\t498\t\t\nDay +31. After 7 days of the end of therapy\t120\t164\t26\t0.1\t26\t3.4\t6.9\t0.2\t0.8\t320\t1628\t1.2\t20\t29.1\t473\t\t\nDay +37.\t106\t121\t27\t0.1\t19\t3.3\t6.2\t0.1\t0.7\t340\t1606\t0.8\t12\t24\t386\t0\t\nDay +79. Before 60 g IVIG\t74.2\t134\t25\t1.5\t22\t5.4\t4.5\t0.1\t0.7\t264\t3116\t3.4\t108\t15.2\t475\t0\t\nDay +108. 29 days after IVIG\t82.2\t204\t22\t1.6\t18\t5\t11.5\t0.1\t1.1\t610\t2189\t2.6\t58\t20.1\t439\t0.1\t\nDay +135\t79.6\t112\t33\t1.8\t26\t8\t8.5\t0.1\t1.1\t1280\t3069\t3.8\t117\t15.4\t475\t\t\nDay +189\t105\t65.5\t36\t1.1\t28\t5\t6.6\t0.2\t1.2\t201\t2500\t3.9\t98\t14.4\t362\t\t\nDay +248\t56.1\t63.1\t55\t0.1\t53\t8.1\t6.8\t0.3\t1.5\t563\t2003\t4.7\t95\t16\t320\t0.6\t\nDay +398\t146\t69.7\t54\t0.1\t71\t8\t5.9\t0.4\t1.9\t1855\t2330\t4.4\t101\t19\t442\t\t\nDay +593\t169\t58.1\t83\t0.1\t70\t8.5\t5.7\t0.4\t1.4\t2348\t2541\t2.9\t74\t27.7\t704\t\t\nBold values represent the lowest levels achieved for every parameter. Besides aPL levels variation, which is described in Figure 1 , all serum immunoglobulins were affected after treatment with daratumumab, with IgG showcasing the most relevant decline. D-dimer also lowered after treatment and then went up again from day +79 until today. Total lymphocyte count did not change. NK cells and plasmablasts were practically removed from peripheral blood since the first infusion of daratumumab until day +79. aPL are expressed in U/mL. Total serum Immunoglobulins are expressed in g/L and D-dimer in mg/dL. Lymphocyte subpopulations are expressed as % of total lymphocytes or in counts/mL.\n\nDiscussion\n\nAs far as we know, this is the first reported use of anti-CD38 therapy in a patient with APS. This treatment was aimed at target plasma cells under the hypothesis that aPL are not only produced by memory B cells but also by bone marrow resident plasma cells. The decision of whether to give rituximab or daratumumab, both off-label uses, for this young lady with repeated PTE and VT despite right anticoagulant therapy, balanced in favor of daratumumab after a careful reading of the evidence. All the studies we found in the literature showed no clear changes in aPL levels after rituximab therapy. Targeting plasma cells also made sense as these cells play an important role in the pathogenesis of autoimmune diseases such as SLE (44, 46), systemic sclerosis (47), Sjögren syndrome (47), ANCA-vasculitis (47), autoimmune cytopenia (34), and rheumatoid arthritis (46).\n\nIn our patient, we used a conservative treatment scheme with one dose of 8 mg/kg and three of 16 mg/kg separated by 1 week, with a total duration of the cycle of 1 month. As anti-CD38 mAb therapy was initially developed to kill malignant plasma cells, at the time of administration, we did not have the experience to suggest that a shorter or longer cycle would be effective. At the time of writing of this manuscript, off-label use of daratumumab for autoimmune diseases has increased and some cases have been reported in the literature. In the most recent cases, the authors chose longer cycles with more doses than we proposed for our patient (41).\n\nClinically, the patient improved from a previously dramatic scenario in which continuous heparin infusion was administered without successful control of the thromboembolic disease.\n\nAs a result of the combined interventions made which included two consecutive sessions of plasmapheresis and daratumumab infusions, the patient experienced a remarkable improvement in dyspnea, pleuritic right pain, and the swelling of a leg, so that she could be discharged on day +7 after the start of anti-CD38 therapy. Although we saw an impressive change on the patient’s symptoms right after the first daratumumab infusion, we could not overlook the effect of the combined measures on this initial good outcome.\n\nHowever, we believe that the beneficial effects observed for two years, with absence of the continuous thrombotic episodes that the patient suffered before the intervention, could be explained by the decrease in aPL titers. Despite we did not achieve a total negativization of aPL, the clinical improvement might be explained by the random depletion of the plasma cell clones producing the more pathogenic antibodies.\n\nOn the follow-up, the patient acknowledged incomplete adherence to the treatment with missing of some doses of anticoagulant therapy at multiple time points. One of them led to a new VT two years later, coinciding with the increase in aPL levels, which reached or surpassed baseline levels. This behavior is understandable as we did not target circulating naïve and memory B cells, which would be responsible for the long-term repopulation of aPL. In a recent review on emerging B-cell therapies in SLE by Ayse Bag-Ozbek and Joyce S Hui-Yuen (48), they commented on further treatments employed in two patients with SLE who received four weekly doses of 16 mg/kg daratumumab as part of a clinical trial (44). These two patients were treated with belimumab starting four weeks after the end of therapy with daratumumab to prevent the activation and proliferation of autoreactive B cells.\n\nConclusion\n\nThe treatment with daratumumab showed an adequate safety profile, was well tolerated, and was associated with clinical improvement, although levels of aPL only showed a partial response. Based on our experience and on data now available in the literature, we suggest that anti-CD38 therapy could be a valuable tool to consider for APS patients who are refractory to the anticoagulant therapy, alone or in combination with B-cell depleting mAbs. Further investigation is needed to better elucidate the role and optimal timing and doses of daratumumab in the treatment of refractory APS.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Hospital Universitario 12 de Octubre, Avenida de Córdoba SN. Madrid, SPAIN. The patient provided her written informed consent to participate in this study.\n\nAuthor Contributions\n\nDP and RD-S equally contributed in patient evaluation, therapy administration, follow-up and preparation of this case report. DP and AS designed the strategy of therapy. OC-M, AL, EP-A, CL and AS wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis study was supported by grant PI17/00147 from “Fondo de Investigaciones Sanitarias” (Institute of Health Carlos III, Spanish Ministry of Economy and Competitiveness), and co-funded with European Regional Development Fund.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\n\nWe thank Barbara Shapiro for her excellent work of translation and English revision of this manuscript.\n==== Refs\nReferences\n\n1 Miyakis S Lockshin MD Atsumi T Branch DW Brey RL Cervera R . International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). 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"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "12()",
"journal": "Frontiers in immunology",
"keywords": "anti-CD38; anti-phospholipid; daratumumab; refractory; treatment",
"medline_ta": "Front Immunol",
"mesh_terms": "D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D016736:Antiphospholipid Syndrome; D015415:Biomarkers; D005260:Female; D006801:Humans; D056724:Immunity, Humoral; D007155:Immunologic Factors; D056687:Off-Label Use; D010950:Plasma Cells; D012008:Recurrence; D016896:Treatment Outcome; D054556:Venous Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "667515",
"pmc": null,
"pmid": "33912194",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
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"title": "Case Report: Resetting the Humoral Immune Response by Targeting Plasma Cells With Daratumumab in Anti-Phospholipid Syndrome.",
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"abstract": "Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, but little is known about rivaroxaban-related bleeding complications in daily care. Using data from a prospective, noninterventional oral anticoagulation registry of daily care patients (Dresden NOAC registry), we analyzed rates, management, and outcome of rivaroxaban-related bleeding. Between October 1, 2011, and December 31, 2013, 1776 rivaroxaban patients were enrolled. So far, 762 patients (42.9%) reported 1082 bleeding events during/within 3 days after last intake of rivaroxaban (58.9% minor, 35.0% of nonmajor clinically relevant, and 6.1% major bleeding according to International Society on Thrombosis and Haemostasis definition). In case of major bleeding, surgical or interventional treatment was needed in 37.8% and prothrombin complex concentrate in 9.1%. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1 (95% confidence interval 2.2-4.3) for stroke prevention in atrial fibrillation and 4.1 (95% confidence interval 2.5-6.4) for venous thromboembolism patients, respectively. In the as-treated analysis, case fatality rates of bleeding leading to hospitalizations were 5.1% and 6.3% at days 30 and 90 after bleeding, respectively. Our data indicate that, in real life, rates of rivaroxaban-related major bleeding may be lower and that the outcome may at least not be worse than that of major vitamin K antagonist bleeding, and probably better. This trial was registered at www.clinicaltrials.gov as identifier #NCT01588119.",
"affiliations": "Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Department of Medicine I, Division of Gastroenterology, University Hospital \"Carl Gustav Carus\" Dresden, Dresden, Germany; and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;ClinStat GmbH, Institute for Clinical Research and Statistics, Cologne, Germany.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.;Center for Vascular Medicine and Department of Medicine III, Division of Angiology, and.",
"authors": "Beyer-Westendorf|Jan|J|;Förster|Kati|K|;Pannach|Sven|S|;Ebertz|Franziska|F|;Gelbricht|Vera|V|;Thieme|Christoph|C|;Michalski|Franziska|F|;Köhler|Christina|C|;Werth|Sebastian|S|;Sahin|Kurtulus|K|;Tittl|Luise|L|;Hänsel|Ulrike|U|;Weiss|Norbert|N|",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D015331:Cohort Studies; D065427:Factor Xa Inhibitors; D005260:Female; D005858:Germany; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D011446:Prospective Studies; D012042:Registries; D000069552:Rivaroxaban; D013876:Thiophenes; D016896:Treatment Outcome; D014812:Vitamin K",
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"title": "Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry.",
"title_normalized": "rates management and outcome of rivaroxaban bleeding in daily care results from the dresden noac registry"
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"abstract": "Methicillin-sensitive Staphylococcus aureus (MSSA) meningitis is a rare disease when not related to neurosurgery: there are only few reported cases in the literature to date. We describe a case that highlights not only meningeal but also diffuse and rapidly progressive systemic involvement with multi-organ failure. A 64-year-old male presented to our hospital with a chief complaint of acute worsening of his usual chronic lower back pain, progressive weakness in lower extremities and subjective fevers at home. Hospital course demonstrated MSSA bacteremia, of questionable source, that resulted in endocarditis affecting right and left heart in a patient with no history of intravenous drug use. The case was complicated by septic emboli to systemic circulation involving the kidneys, vertebral spine, lungs and brain with consequent meningitis and stroke, even when treated empirically with vancomycin and then switched to nafcillin as indicated. Even though MSSA infections are well known, there are very few case reports describing such an acute-simultaneous-manifestation of multi-end-organ failure, including meningitis and stroke. Our case, also presented with an uncommon manifestation of persistent infection dissemination despite adequate antibiotic treatment.",
"affiliations": "Department of Internal Medicine, UF Health Jacksonville , FL, USA.;Department of Internal Medicine, UF Health Jacksonville , FL, USA.;Department of Internal Medicine, UF Health Jacksonville , FL, USA.;Department of Internal Medicine, UF Health Jacksonville , FL, USA.",
"authors": "Torres-Miranda|Daisy|D|;Al-Saffar|Farah|F|;Ibrahim|Saif|S|;Diaz-Font|Stephanie|S|",
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"fulltext": "\n==== Front\nInfect Dis RepInfect Dis RepIDRInfectious Disease Reports2036-74302036-7449PAGEPress Publications, Pavia, Italy 10.4081/idr.2015.5849Case ReportRapid Progressive Seeding of a Community Acquired Pathogen in an Immune-Competent Host: End Organ Damage from Head to Bone Torres-Miranda Daisy Al-Saffar Farah Ibrahim Saif Diaz-Font Stephanie Department of Internal Medicine, UF Health Jacksonville, FL, USADepartment of Internal Medicine, UF Health Jacksonville, 655 N 8th Street, Jacksonville, FL 32209, USA. +1.787.402.9550. daisy.torres-miranda@jax.ufl.eduContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n09 6 2015 15 4 2015 7 2 584904 2 2015 24 3 2015 26 3 2015 ©Copyright D. Torres-Miranda et al.2015Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Methicillin-sensitive Staphylococcus aureus (MSSA) meningitis is a rare disease when not related to neurosurgery: there are only few reported cases in the literature to date. We describe a case that highlights not only meningeal but also diffuse and rapidly progressive systemic involvement with multi-organ failure. A 64-year-old male presented to our hospital with a chief complaint of acute worsening of his usual chronic lower back pain, progressive weakness in lower extremities and subjective fevers at home. Hospital course demonstrated MSSA bacteremia, of questionable source, that resulted in endocarditis affecting right and left heart in a patient with no history of intravenous drug use. The case was complicated by septic emboli to systemic circulation involving the kidneys, vertebral spine, lungs and brain with consequent meningitis and stroke, even when treated empirically with vancomycin and then switched to nafcillin as indicated. Even though MSSA infections are well known, there are very few case reports describing such an acute-simultaneous-manifestation of multi-end-organ failure, including meningitis and stroke. Our case, also presented with an uncommon manifestation of persistent infection dissemination despite adequate antibiotic treatment.\n\nKey words\nBacteremiaseptic emboliMethicillin sensitive Staphylococcus aureus.\n==== Body\nIntroduction\nMethicillin-sensitive Staphylococcus aureus is a gram-positive cocci in clusters. It is carried in anterior nares by 20-30% of population. Higher carriage rates are seen in diabetics, intravenous drug users (IVDU), HIV and dialysis patients.1,2 All patients with S. aureus bacteremia should undergo transthoracic echocardiography (TTE), since S. aureus bacteremia is associated with heart valve involvement in 25% of the cases.3 Nevertheless, TEE has been shown to be superior to TTE for the diagnosis of infective endocarditis (IE), identifying small vegetations and abscesses.3,4 All infective foci must be identified and removed as soon as possible; however, foci are not always obvious and long-term antimicrobial therapy might be necessary. Mortality associated with S. aureus bacteremia is 20-40%.5 Nafcillin is a well-established agent for serious systemic non methicillin-resistant S. aureus (MRSA) infections and has been reported as superior over vancomycin.6-9 We present a very interesting case of a rapidly progressive methicillin-sensitive Staphylococcus aureus infection, for which empirical treatment with vancomycin and initial treatment with nafcillin did not stop further dissemination despite adequate MIC, taking longer than usual to respond to adequate treatment.\n\nCase Report\nA 64-year-old male patient with a past medical history of hypertension, hiatal hernia and osteoarthritis presented to the emergency department with a chief complaint of acute worsening of his chronic lower back pain for two weeks and progressive weakness in lower extremities. He used to ambulate with a cane and later used a walker for several days, but recently he felt non-ambulant. He also described subjective fevers at home. Physical examination was significant for temperature of 100.1°F. Blood pressure, respiratory and heart rate were within normal limits. He appeared in no distress, cachectic and disheveled with poor dentition. Cardiac examination showed a regular rate and rhythm with normal S1 and S2 and no murmurs. Lungs were clear to auscultation with bilateral air entry. He had crepitus in both knees and a limping gait. Kernig’s sign and Brudzinski’s sign were obscured by back pain. On further review of systems he reported having chronic bilateral knee pain related with osteoarthritis and a congenital deformation of his right knee. He was a smoker of 40 pack-years, occasional user of alcohol and marijuana, but denied ever using intravenous drugs and toxicology was positive only for oxycodone, which he used for chronic lumbar pain for several years.\n\nLaboratory exams displayed a leukocytosis of 25,500 with 89% neutrophils, no bands, sedimentation rate of 44, lactic acid 1.6, anion gap 18. Thoracic and lumbar spine computed tomography (CT) scan showed multilevel central canal and bilateral neural foraminal compromise, but did not show evidence of abscess. Partially visualized lungs showed a cavitary lesion in the superior segment of the left lower lobe, measuring 1.4 cm with circumferential thick wall, suggestive of septic emboli versus tuberculosis, and left inferior renal pole abnormalities suggestive of multiple infarctions. Blood cultures grew S. aureus.\n\nThe patient was started empirically on vancomycin 15 mg/kg IV q 12h, while waiting for sensitivities. The TTE performed after bacteremia diagnosis showed an ejection fraction of 65% with normal valves and no vegetations. On day two of hospitalization the clinical picture worsened as the patient suddenly developed an altered mental status and nuchal rigidity. Lumbar puncture confirmed meningitis with a cerebrospinal fluid leukocytosis of 1157 (neutrophil 95%) and culture positive for S. aureus. Testing for HIV, Herpes Simplex Virus (HSV) and Tuberculin skin test (PPD) were all negative. Spine magnetic resonance imaging (MRI) showed osteomyelitis at T12-L1 and previously seen (in CT scan) renal infarcts. The patient continued to be febrile despite pathogen susceptible to vancomycin with MIC <2 mg/mL, trough previous to 4th dose 11, repeated trough 18.4, repeat blood cultures at 48 and 96 hours remained negative. Six days later he had clinical deterioration with tachypnea, hypoxia, new systolic 2/6 murmur, louder over cardiac apex area, and bilateral respiratory crackles. He also developed new right hemiparesis with upgoing babinski reflex of the right side. At this point, the patient was switched to nafcillin 2 g IV q 4h when blood culture results confirmed methicillin susceptibility on day 3 of admission. Head MRI showed multiple infarcts in a non-vascular pattern secondary to septic embolisms (Figure 1). The TEE showed severe mitral and tricuspid regurgitations, with 1.5 cm mobile vegetation on the posterior leaflet of the mitral valve. The patient was transferred to the intensive care unit due to the complicated picture of MSSA bacteremia, IE, osteomyelitis, meningitis, ischemic stroke, renal and pulmonary infarcts secondary to septic emboli. Nafcillin was continued with appropriate resolution of leukocytosis and fever. Patient’s mental status slowly improved and returned to baseline. There were indications for emergent mitral valve replacement, however given his recent finding of embolic stroke; this was not feasible due to high mortality risk. Follow up TTE showed worsening mitral and tricuspid valve involvement, therefore mitral and tricuspid valve replacements were performed, four weeks from IE diagnosis. He completed 8 weeks of nafcillin (given his vertebral involvement and unknown source). After 2 months of hospitalization, patient was discharged home with a dual-chamber pacemaker due to persistent 3rd degree atrio-ventricular block, post surgery.\n\nDiscussion\nStaphylococcus aureus is one of the leading agents of infection among adult patients. When S. aureus invades deep structures it often metastasize hematogenously to other areas and organs with significant morbidity.10 Infection caused by community acquired MSSA strains are characterized by severe clinical course with increased incidence of endocarditis and organ failure. A bacterial origin is not always obvious. Two important questions should be asked to the patient with the intention to identify focal source and consider additional necessary diagnostic test. Those are: use of intravenous drugs and presence of painful joints. IVDU related infection can manifest as an initially insidious presentation that later complicates to be an aggressive metastatic disease.11\n\nWe presented a unique case since our patient was not an IVDU nor an initial focus of infection was identified. Additionally, the progression from negative to positive echocardiogram findings of valvular vegetations highlights the high virulence of this community-acquired pathogen, since severe valvular regurgitation or insufficiency should be equally observed on both types of echocardiograms. Altered mental status in such patients should alert the physicians to the possibility of brain emboli causing multifocal ischemia. A MRI is crucial to confirm the diagnosis with the visualization of a non-vascular pattern.12,13 Meningitis due to S. aureus is uncommon, when not related to neurosurgery. MSSA meningitis is a serious infection, which can occurs in patients without risk factors or immunosuppression. Like meningitis, stroke secondary CA-MSSA is rarely seen, regardless of the severity of infection. High level of clinical suspicion is needed in such patients, as back pain could be the only reliable predictor of an added spine infection.14,15\n\nWhen treating for gram-positive cocci bacteremia, empirical antibiotic therapy should provide coverage against staphylococci, usually with vancomycin to cover MRSA.15 Nafcillin/oxacillin remains the antibiotic of choice for treating infections caused by MSSA once culture and sensitivity results confirm it, because nafcillin is superior to vancomycin in preventing persistent or relapsing MSSA bacteremia.10 In the case of endocarditis, studies have demonstrated that vancomycin (versus nafcillin) is significantly associated with relapse given its slow bactericidal activity.5,6 For our case, the reasons why empirical treatment with vancomycin and initial treatment with nafcillin, did not stop further dissemination remained unknown. Nevertheless, continued treatment with nafcillin eventually did resolve the infection. We have to consider that, even though the MIC remains the only satisfactory in vitro measurement of the intrinsic activity of antimicrobials, the test has always been open for criticism since it is performed with the use of artificial media and fixed concentrations, under conditions that may be very different from those in the actual site of infection.16 There is evidence that support the concept of the principal determinant of efficacy of beta lactams to be the time for which the drug levels exceed the MIC at the site of infection, not just and MIC <2 mg/mL by itself. Also, bacterial strains have been detected to have a MBC (minimum bactericidal concentration) many times higher than the MIC, (known as phenotypic tolerance), isolated in vitro gram-positive bacteria causing slower clinical response.16-18 Another speculative answer would be the inoculum effect. The inoculum effect may be clinically relevant since the number of bacteria at the site of infection may much higher that the traditionally used for susceptibility testing.16,19 Unfortunately, molecular genotyping or DNA techniques were not performed.\n\nIn our case, specific nafcillin concentrations were not targeted. Although the benefit of such concentration is questionable since our patient’s infection was multifocal. Our laboratory was not able to analyze serum nafcillin concentrations; hence, samples would have to send to a referral laboratory.\n\nConclusions\nA community acquired pathogen, even when part of the normal flora could be virulent enough to cause end organ damage from head to toe. The use of head MRI as a pre evaluation tool for IE-related urgent valve surgery is imperative, to investigate whether such preoperative findings affect postoperative outcomes. The presence of characteristic cranial MRI lesions may prompt early diagnosis of infective source and lead to the adequate management. Beyond the MIC, the time the drug level exceeds the MIC, the phenotypic tolerance and the inoculum effects may be reasons why empirical treatment with vancomycin and initial treatment with nafcillin did not stop further dissemination, but, eventually, clearing the infection.\n\nFigure 1. A) Axial diffusion weighted image shows multifocal intra-parenchymal hyper-intensities in a non-vascular pattern with (B) corresponding hypo-intense apparent diffusion coefficient findings. C) and D) right occipital restricted diffusion. Findings are compatible with acute multifocal ischemia secondary to septic embolisms.\n==== Refs\nReferences\n1. von Eiff C Becker K Machka K \nNasal carriage as a source of Staphylococcus aureus bacteremia . Study Group. N Engl J Med \n2001 ;344 :11 -6 .\n2. Simor AE. \nStaphylococcal decolonisation: an effective strategy for prevention of infection? \nLancet Infect Dis \n2011 ;11 :952 -62 .22115070 \n3. Baddour LM Wilson WR Bayer AS \nInfective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America . Circulation \n2005 ;111 :394 -434 .15687125 \n4. Fowler VG JrLi J Boley J \nRole of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients . J Am Coll Cardiol \n1997 ;30 :1072 -8 .9316542 \n5. Thwaites GE Edgeworth JD Gkrania-Klotsas E \nClinical management of Staphylococcus aureus bacteraemia . Lancet Infect Dis \n2011 ;208 -22 .21371655 \n6. Valour F Bouaziz A Arsenty J \nDeterminants of methicillin-susceptible Staphylococcus aureus native bone and joint infection treatment failure: a retrospective cohort study . BMC Infect Dis \n2014 ;14 :443 .25128919 \n7. Chang FY Peacock JE Musher DM \nStaphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study . Medicine (Baltimore) \n2003 ;82 :333 -9 .14530782 \n8. Sung-Han K Kye-Hyug K Hong-Bin K \nOutcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia . Antimicrob Agents Chemother \n2008 ;52 :192 -7 .17984229 \n9. Leonard S. \nSynergy between vancomycin and nafcillin against Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic . Plos One \n2012 ;7 : e42103 .22848719 \n10. Chang WN Lu CH Wu JJ \nStaphylococcus aureus meningitis in adults: a clinical comparison of infections caused by methicillin-resistant and methicillin-sensitive strains . Infection \n2001 ;29 :245 -50 .11688900 \n11. Ji Y Kujtan L Kershner D. \nAcute endocarditis in intravenous drug users: a case report and literature review . J Community Hosp Intern Med Perspect \n2012 ;2 .\n12. Bakshi R Wright PD Kinkel PR \nCranial magnetic resonance imaging findings in bacterial endocarditis: the neuroimaging spectrum of septic brain embolization demonstrated in twelve patients . J Neuroimaging \n1999 ;9 :78 -84 .10208104 \n13. Novy E Sonneville M Mazighi IF \nNeurological complications of infective endocarditis: new breakthroughs in diagnosis and management . Med Mal Infect \n2013 ;43 :443 -50 .24215865 \n14. Darouiche R. \nSpinal epidural abscess . N Engl J Med \n2006 ;355 :2012 -20 .17093252 \n15. Ziu M Dengler B Cordell D Bartanusz V. \nDiagnosis and management of primary pyogenic spinal infections in intravenous recreational drug users . Neurosurg Focus \n2014 ;37 :e3 .25081963 \n16. Turnidge J. \nThe pharmacodynamics of beta-lactams . Clin Infect Dis \n1998 ;27 :10 -22 .9675443 \n17. Toumanen E Durack D Tomasz A \nAntibiotic tolerance among clinical isolates of bacteria . Antimicrob Agents Chemother \n1986 ;30 :521 -7 .3539006 \n18. Rahal J Chan Y Johnson G. \nRelationship of staphylococcal tolerance, teichoic acid antibody, and serum bactericidal activity to therapeutic outcome in Staphylococcus aureus bacteremia . Am J Med \n1986 ;81 :43 -52 .3524225 \n19. Gerber A Greter U Segessenmann C Kozak S. \nThe impact of the pre-treatment interval on antimicrobial efficacy in a biological model . J Antimicrob Chemother \n1993 ;31 :29 -39 .8335522\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-7430",
"issue": "7(2)",
"journal": "Infectious disease reports",
"keywords": "Bacteremia; Methicillin sensitive Staphylococcus aureus.; septic emboli",
"medline_ta": "Infect Dis Rep",
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"nlm_unique_id": "101537203",
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"pubdate": "2015-04-15",
"publication_types": "D002363:Case Reports",
"references": "17984229;21371655;22115070;15956145;23882351;9316542;9675443;3539006;8335522;25128919;10208104;24215865;3524225;25081963;22848719;11136954;17093252;14530782;11688900",
"title": "Rapid Progressive Seeding of a Community Acquired Pathogen in an Immune-Competent Host: End Organ Damage from Head to Bone.",
"title_normalized": "rapid progressive seeding of a community acquired pathogen in an immune competent host end organ damage from head to bone"
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"abstract": "OBJECTIVE\nThe objective of this study was to evaluate the safety and efficacy of tamsulosin hydrochloride 0.2 mg (TAM) and its combination with solifenacin succinate 5 mg (SOL) after transurethral resection of the prostate (TURP).\n\n\nMETHODS\nThe patients were randomized into three groups: TURP (group 1), TURP plus TAM (group 2), and TURP plus TAM + SOL (group 3). Patients in group 2 and group 3 received medication for 4 weeks. The primary efficacy end points were the mean change in total International Prostate Symptom Score (IPSS) and IPSS subscores. The secondary end points included quality-of-life score, Overactive Bladder Symptom Score, and short-form voiding and storage score of International Continence Society.\n\n\nRESULTS\nIn total, 37 men (31.8%) in group 1, 37 men (31.8%) in group 2, and 42 men (36.2%) in group 3 completed the study. In total IPSS, no significant improvement was seen from baseline to the end of treatment in groups 2 and 3 compared with group 1. However, in group 2, the decrement in the IPSS storage score was smaller than group 1 (P=0.02), and in group 3, the decrement in the IPSS voiding score was smaller than group 1 (P=0.05). In groups 2 and 3 compared with group 1, improvements in the quality of life score, total score of Overactive Bladder Symptom Score, and short-form voiding score and storage score of International Continence Society were not statistically significant.\n\n\nCONCLUSIONS\nTreatment with TAM and combination of TAM and SOL did not have significant additional benefits for lower urinary tract symptoms during the early recovery period after TURP.",
"affiliations": "Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Medical Device Clinical Trial Center of Chonbuk National University, Jeonju, Republic of Korea.;Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Medical Device Clinical Trial Center of Chonbuk National University, Jeonju, Republic of Korea.;Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Medical Device Clinical Trial Center of Chonbuk National University, Jeonju, Republic of Korea.;Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Medical Device Clinical Trial Center of Chonbuk National University, Jeonju, Republic of Korea.;Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, and Shanghai Institute of Andrology, Shanghai, People's Republic of China.;Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Medical Device Clinical Trial Center of Chonbuk National University, Jeonju, Republic of Korea.",
"authors": "Shin|Yu Seob|YS|;Zhang|Li Tao|LT|;You|Jae Hyung|JH|;Choi|In Sung|IS|;Zhao|Chen|C|;Park|Jong Kwan|JK|",
"chemical_list": "D013449:Sulfonamides; D064804:Urological Agents; D000077409:Tamsulosin; D000069464:Solifenacin Succinate",
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"fulltext": "\n==== Front\nClin Interv AgingClin Interv AgingClinical Interventions in AgingClinical Interventions in Aging1176-90921178-1998Dove Medical Press 10.2147/CIA.S115042cia-11-1301Original ResearchEfficacy and safety of tamsulosin hydrochloride 0.2 mg and combination of tamsulosin hydrochloride 0.2 mg plus solifenacin succinate 5 mg after transurethral resection of the prostate: a prospective, randomized controlled trial Shin Yu Seob 1*Zhang Li Tao 1*You Jae Hyung 1Choi In Sung 1Zhao Chen 2Park Jong Kwan 11 Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Medical Device Clinical Trial Center of Chonbuk National University, Jeonju, Republic of Korea2 Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, and Shanghai Institute of Andrology, Shanghai, People’s Republic of ChinaCorrespondence: Jong Kwan Park, Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Medical Device Clinical Trial Center of Chonbuk National University, Geonji-Ro 20, Deokjin-Gu, Jeonju 54907, Republic of Korea, Tel +82 63 250 1510, Fax +82 63 250 1564, Email rain@chonbuk.ac.kr* These authors contributed equally to this work\n\n2016 19 9 2016 11 1301 1307 © 2016 Shin et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objective\nThe objective of this study was to evaluate the safety and efficacy of tamsulosin hydrochloride 0.2 mg (TAM) and its combination with solifenacin succinate 5 mg (SOL) after transurethral resection of the prostate (TURP).\n\nPatients and methods\nThe patients were randomized into three groups: TURP (group 1), TURP plus TAM (group 2), and TURP plus TAM + SOL (group 3). Patients in group 2 and group 3 received medication for 4 weeks. The primary efficacy end points were the mean change in total International Prostate Symptom Score (IPSS) and IPSS subscores. The secondary end points included quality-of-life score, Overactive Bladder Symptom Score, and short-form voiding and storage score of International Continence Society.\n\nResults\nIn total, 37 men (31.8%) in group 1, 37 men (31.8%) in group 2, and 42 men (36.2%) in group 3 completed the study. In total IPSS, no significant improvement was seen from baseline to the end of treatment in groups 2 and 3 compared with group 1. However, in group 2, the decrement in the IPSS storage score was smaller than group 1 (P=0.02), and in group 3, the decrement in the IPSS voiding score was smaller than group 1 (P=0.05). In groups 2 and 3 compared with group 1, improvements in the quality of life score, total score of Overactive Bladder Symptom Score, and short-form voiding score and storage score of International Continence Society were not statistically significant.\n\nConclusion\nTreatment with TAM and combination of TAM and SOL did not have significant additional benefits for lower urinary tract symptoms during the early recovery period after TURP.\n\nKeywords\nbenign prostate hyperplasiatamsulosinsolifenacincombinationtransurethral resection of the prostate\n==== Body\nIntroduction\nBenign prostatic hyperplasia (BPH) is a common condition generally associated with aging. It is estimated that the prevalence of BPH already reaches 43% between 50 years and 59 years of age, 70% at 61–70 years of age, and as high as 82% in men >71 years of age.1 Lower urinary tract symptoms (LUTS) are commonly observed in BPH-associated bladder outlet obstruction and overactive bladder. Bladder outlet obstruction resulting from BPH can directly lead to voiding and postvoiding LUTS.2 Additionally, LUTS have adverse effects on health-related quality of life (QoL), including interference with daily activities and decreased psychological well-being, which worsens with symptom severity.3\n\nCurrent treatment options for BPH include medication and surgery, and transurethral resection of the prostate (TURP) is known to be the most effective among the traditional surgical methods. Within this context, TURP has become the standard treatment option, and it is regarded as an effective tool for the removal of obstructive prostatic tissue.4 However, not all patients demonstrate successful resolution of these symptoms after the prostate intervention. The morbidity of TURP is more or less inevitable in the clinical setting, and most patients complain of voiding and storage symptoms, hematuria, painful urination, and incontinence, leading to a negative impact on health-related QoL within the first 4–6 weeks after TURP.5\n\nSome patients with persistent urinary symptoms may benefit from medical therapy even after TURP. However, there has been little research as to whether antimuscarinics and α-blockers can alleviate voiding and storage symptoms and other symptoms in the patients during the early postoperative period after TURP. Therefore, we conducted an open-label, controlled, randomized clinical trial to evaluate the efficacy and safety of tamsulosin hydrochloride 0.2 mg (TAM) and combination of TAM plus solifenacin succinate 5 mg (SOL) in men who underwent TURP due to LUTS/BPH.\n\nPatients and methods\nStudy design and patients\nThis was a randomized, open-label, controlled study in men who underwent TURP due to BPH/LUTS with moderate-to-severe voiding and storage symptoms. All study materials were reviewed and approved by the Institutional Review Board of Chonbuk National University Hospital. All patients provided written informed consent before screening. Patients with more than 3 months of prior treatment with TAM or administration of antimuscarinics or 5-alpha-reductase inhibitors were eligible for inclusion in this study.\n\nThe inclusion criteria at baseline were total International Prostate Symptom Score (IPSS) ≥8, maximum urinary flow rate (Qmax) ≤15 mL/s, voided volume ≥125 mL, and prostate volume ≥30 mL and <100 mL.\n\nThe sample size was estimated by the following formula:\n n=2(zα2+zβ)2σ2(uc−ut)2(1) \n\nAccording to this formula, 43 patients were taken for each group. In consideration of 20% of dropout rates, 55 patients were taken in each group to obtain a significant value. Thus, 165 patients were taken in our study for three groups.\n\nAll the patients underwent a general and urological standard evaluation prior to surgery, including urine analysis and digital rectal and transrectal ultrasound (B&K 2102; Brüel & Kjær, Nærum, Denmark) evaluation of prostate size, and they were tested for prostate-specific antigen levels and performed self-assessments using the total IPSS and IPSS subscores, QoL score, Overactive Bladder Symptom Score (OABSS) questionnaire, and short-form voiding and storage score of International Continence Society (ICS). Additionally, all patients were older than 55 years, candidates for TURP, and lacked any evidence of symptomatic urinary tract infections and urinary stones.\n\nThe patients were excluded if they had a postvoid residual volume (PVR) >150 mL, evidence of suspected prostate cancer, a diagnosis of urinary retention, any previous surgery of the bladder neck or prostate, and any other relevant disease history, as determined by the investigator.\n\nSurgical procedure\nTURP was performed using a standard technique: bipolar resectoscope (Richard Wolf, Knittlingen, Germany) and standard bipolar wire loop. A 20 Fr Foley catheter was inserted at the end of the procedure. The catheter was removed when gross hematuria had resolved, 2–5 days post operation. After the patients were able to urinate, they underwent uroflowmetry, PVR, and transrectal ultrasonography. The patients were discharged from the hospital after the Foley catheter was removed.\n\nMedications\nAfter removal of the Foley catheter, all the patients were randomized into three groups: TURP (group 1), TURP plus TAM (group 2), and TURP plus TAM + SOL (group 3). Patients in group 2 and group 3 received treatment once daily for 4 weeks as open-label treatments. The usual dose of TAM is 0.4 mg once daily; however, in our study, we used 0.2 mg of TAM once daily.\n\nEfficacy assessments\nThe primary end point was the change in total IPSS and IPSS storage and voiding subscores. The secondary end points were QoL score, total OABSS questionnaire, and short-form voiding and storage score of ICS. Additionally, mean changes in measures were evaluated at baseline and the end point of therapy after TURP and also at 4 weeks and 8 weeks after removal of the Foley catheter. Micturition diary variables included volume voided (Vvoid) per micturition. Safety parameters included patient-reported adverse events, PVR, and Qmax.\n\nStatistical analysis\nStatistical analyses were performed on an intention-to-treat basis for all patients who were randomized and who completed the open-label study. Mean and proportion values for patient demographics and baseline characteristics were compared using one-way analysis of variance followed by Tukey’s post hoc test.\n\nIn each step, comparisons were made by variance analysis by using the treatment group as a fixed factor to analyze each of the secondary efficacy end points. We assessed the mean change in total IPSS and IPSS subscores, QoL score, OABSS total score, short-form voiding and storage score of ICS, Qmax, Vvoid, and PVR from baseline to end point (8 weeks) for medication treatment groups compared with group 1. Unless otherwise stated, efficacy data are expressed as mean ± standard error. Statistical calculations were performed using the SPSS software (Version 21.0; IBM Corporation, Armonk, NY, USA). P-values <0.05 were considered to indicate statistical significance.\n\nResults\nPatients and baseline characteristics\nOf the 169 men with LUTS who were screened, 151 were randomized to treatment (group 1, n=52; group 2, n=48; and group 3, n=51). In total, 37 men (31.8%) in group 1, 37 men (31.8%) in group 2, and 42 men (36.2%) in group 3 completed the study (Figure 1).\n\nThere were no significant differences in baseline characteristics among the three groups (Table 1). The majority of men were older than 65 years. In all treatment groups, at baseline, the range of the total IPSS was 16.35–17.58 and the range of the Vvoid per micturition was 152.14–162.17 mL (Table 1).\n\nEfficacy\nPrimary efficacy end point\nAll groups showed significant decrement in total IPSS and IPSS storage and voiding subscores at all points after TURP. However, there was no statistical significance between the groups in total IPSS and IPSS storage and voiding subscores from baseline to discharge day, week 1, and week 4. Also, with respect to total IPSS, no significant improvement was achieved from baseline to the end of treatment in group 2 compared with group 1 (P=0.73; Table 2). Decrement in total IPSS from baseline to the end of treatment was smaller in group 3, with no significant difference between groups 3 and 1 (P=0.69; Table 2). However, in group 2, decrement in the IPSS storage score from baseline to the end of treatment was smaller than group 1 (P=0.02; Table 2). Also, in group 3, decrement in the IPSS voiding score from baseline to the end of treatment was smaller than group 1 (P=0.05; Table 2). TURP plus TAM and TURP plus the combination of TAM and SOL did not have significant additional benefits for LUTS during the early recovery period after TURP.\n\nSecondary efficacy end points\nIn group 2 compared with group 1, improvements as assessed by mean changes from baseline to the end of treatment in QoL score (P=0.08), OABSS total score (P=0.36), short-form voiding score of ICS (P=0.42), and storage score of ICS (P=0.99) were not statistically significant. Also, in group 3 compared with group 1, improvements as assessed by mean changes from baseline to the end of treatment in QoL score (P=0.67), OABSS total score (P=0.51), short-form voiding score of ICS (P=0.47), and storage score of ICS (P=0.36) were not statistically significant. Numerical improvements were observed in Vvoid per micturition in group 3 at all time points compared with group 1; however, the improvements were not statistically significant (P=0.44; Table 2 and Figure 2A).\n\nSafety\nIn groups 2 and 3 compared with group 1, the mean changes in PVR from baseline to the end of treatment were significantly higher (P=0.03 and P=0.03, respectively; Table 2 and Figure 2B). At the end of the treatment, the adjusted mean change in PVR was 19.46 mL in group 3, 18.67 mL in group 2, and −1.50 mL in group 1 (Table 2 and Figure 2B). Treatment-emergent adverse events were mild to moderate, and they occurred in 14.2%, 8.1%, and 8.1% of patients in groups 3, 2, and 1, respectively. The most common adverse events in the treatment group that received SOL were dry mouth and constipation. Treatment-related dry mouth was reported in five (11.9%) patients in the combination-therapy group versus one (2.7%) patient in the TAM group and in none of the patients who underwent TURP alone. Urinary retention was only seen in one patient of group 2.\n\nDiscussion\nFor decades, TURP has been the gold standard therapy for elderly men (>60 years old) with LUTS caused by benign prostatic enlargement and benign prostatic obstruction.6,7 During the past 20 years, various technical improvements, such as video TURP, continuous-flow instruments, and bipolar TURP, have substantially decreased the morbidity associated with TURP.6 However, some postoperative complications of TURP occur in the patients, although minimally invasive procedures may be an alternative.5 Dissatisfaction may be attributable to an increase in the sensitivity of muscarinic receptors to acetylcholine in the smooth muscle of the bladder as opposed to a prostatic pathology that leads to overactive bladder after TURP surgery.2,8\n\nVarious drugs are available for men with LUTS suggestive of BPH. In 1994, Chapple and Smith9 referred to the possibility of combination treatment with antimuscarinics and α-blockers for LUTS. Since then, both antimuscarinics and α-blockers have been evaluated for the treatment of voiding and storage symptoms.9–11 More recent meta-analyses and systematic reviews have demonstrated that combination of antimuscarinics and α-blockers improved voiding and storage symptoms in patients compared to those treated with α-blocker monotherapy.12–16 Also, these medications are needed in post-TURP patients who have persistent or even worse urinary symptoms after TURP. Han et al reported ~205 (55.1%) patients who continued their LUTS/BPH medications for >3 months after TURP. Among the patients who continued their medications after TURP, 13.7% received α-blocker monotherapy and 12.2% received antimuscarinics.17 A theoretical basis exists for using α-blockers to treat irritative symptoms in the absence of bladder outlet obstruction, although antimuscarinics apparently remain the mainstay of treatment for overactive bladder.\n\nThe present study was performed to evaluate the efficacy and safety of combination therapy with the antimuscarinic SOL and the α-blocker TAM in the treatment of men with both voiding and storage symptoms of LUTS/BPH and bothersome symptoms, such as painful urination, incontinence, and urgency, during the early period after TURP surgery. Combination therapy did not show significant additional benefits in total IPSS, IPSS voiding and storage subscore, QoL score, Qmax, OABSS total score, or Vvoid per micturition when we compared group 1 vs groups 2 and 3. Furthermore, treatment with TAM and combination of TAM and SOL had a potential side effect of an increase in PVR.\n\nIn our study, many patients suffered from LUTS immediately after TURP. These bothersome symptoms may have been induced by inflammation of the prostatic urethra or edema that occurred during TURP. The major finding of the present study was that early initiation of LUTS medication did not have any benefit in patients who suffered from LUTS during the early recovery period after TURP.\n\nOne of the limitations of the study could be that it is a single-center study. We sought to determine the efficacy of the α-blockers or α-blockers plus anticholinergic in decreasing the LUTS that occurred within a short time period after TURP, which could be another limitation of the study. Further multicenter studies are needed in patients. Despite these limitations, to the best of our knowledge, the present study is the first reported prospective, randomized trial that analyzed the safety and efficacy of TAM and its combination with SOL during the early period after TURP.\n\nConclusion\nIn the present study, treatment with TAM and combination of TAM and SOL did not have significant additional benefits for LUTS during the early recovery period after TURP. Moreover, treatment with TAM and combination of TAM and SOL had a potential side effect of an increase in PVR.\n\nAcknowledgments\nJong Kwan Park received a grant from Astellas Pharma Korea, Inc. However, the funder had no involvement in study design, data collection, data analysis, manuscript preparation, and/or publication decisions. Jong Kwan Park also received an honorarium for a presentation and served as a consultant to Astellas Pharma Korea, Inc. during the study.\n\nAuthor contributions\n\nAll authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Consort study flow diagram.\n\nAbbreviations: IPSS, International Prostate Symptom Score; TURP, transurethral resection of the prostate; TAM, tamsulosin hydrochloride 0.2 mg; SOL, solifenacin succinate 5 mg; wk, week.\n\nFigure 2 Mean change from baseline in Vvoid per micturition (A), and PVR (B) before surgery and at the 1-month and 2-month visits after surgery.\n\nAbbreviations: Vvoid, volume voided; PVR, postvoid residual volume; TURP, transurethral resection of the prostate; TAM, tamsulosin hydrochloride 0.2 mg; SOL, solifenacin succinate 5 mg.\n\nTable 1 Demographic and other baseline characteristics\n\nCharacteristics\tGroup 1\n(n=37)\tGroup 2\n(n=37)\tGroup 3\n(n=42)\tP-value\t\nAge, years\t70.00±7.93\t69.62±6.33\t70.14±6.50\t0.73\t\nBody weight, kg\t63.4±8.72\t63.5±9.10\t63.2±8.30\t0.69\t\nBMI, kg/m2\t23.8±2.83\t23.6±2.74\t23.7±3.18\t0.84\t\nPSA, ng/mL\t4.56±4.04\t5.05±4.99\t4.17±3.60\t0.74\t\nTRUS\t\t\t\t\t\n Total prostate volume, cm3\t58.25±24.13\t51.92±18.34\t51.51±19.88\t0.96\t\n Transition zone volume, cm3\t36.08±20.01\t29.13±13.89\t30.00±15.32\t0.87\t\nUroflowmetry\t\t\t\t\t\n Qmax, mL/s\t10.77±4.95\t9.00±4.68\t10.22±5.70\t0.63\t\n Vvoid, mL\t182.26±109.45\t163.66±81.29\t193.90±112.41\t0.59\t\n PVR, mL\t99.56±120.50\t82.26±73.93\t92.32±97.24\t0.68\t\nIPSS questionnaires\t\t\t\t\t\n Total score\t17.64±8.40\t18.52±6.17\t18.51±7.70\t0.97\t\n Storage subscore\t8.05±3.58\t7.50±2.99\t8.09±3.69\t0.57\t\n Voiding subscore\t9.59±5.40\t11.02±4.10\t11.16±5.39\t0.86\t\n QoL subscore\t3.64±1.25\t3.86±1.22\t4.04±1.41\t0.74\t\nOABSS total score\t6.75±3.70\t7.16±2.87\t6.90±3.33\t0.53\t\nICS short form\t\t\t\t\t\n Voiding score\t8.83±5.26\t9.91±3.79\t9.75±4.89\t0.61\t\n Storage score\t2.78±2.88\t3.44±2.71\t3.25±3.13\t0.63\t\nNotes: Group 1, patients who underwent TURP; group 2, patients who underwent tamsulosin hydrochloride 0.2 mg after the removal of the Foley catheter after TURP; and group 3, patients who underwent tamsulosin hydrochloride 0.2 mg and solifenacin succinate 5 mg after the removal of the Foley catheter after TURP. Data represent mean ± SD.\n\nAbbreviations: BMI, body mass index; PSA, prostate-specific antigen; TRUS, transrectal ultrasonography; Qmax, maximum flow rate; Vvoid, volume voided; PVR, postvoid residual; IPSS, International Prostate Symptom Score; QoL, quality of life; OABSS, Overactive Bladder Symptom Score; ICS, International Continence Society; TURP, transurethral resection of the prostate; SD, standard deviation.\n\nTable 2 Mean change from baseline to the end of treatment\n\nParameters\tGroup 1\n(n=37)\tGroup 2\n(n=37)\t95% CIa\tP-value\tGroup 3\n(n=42)\t95% CIa\tP-value\t\nChange in efficacy assessments, adjusted mean ± SE\t\n IPSS total score\t−6.53±1.59\t−7.21±1.29\t−0.68 (−4.69, 3.33)\t0.73\t−6.35±1.31\t−0.82 (−4.85, 3.21)\t0.69\t\n IPSS storage score\t−2.41±0.73\t−2.26±0.90\t2.15 (0.44, 3.85)\t0.02\t−2.13±0.84\t1.28 (−0.06, 3.22)\t0.20\t\n IPSS voiding score\t−7.06±0.92\t−7.00±1.40\t0.06 (−2.57, 2.69)\t0.96\t−4.52±4.47\t2.54 (−0.05, 5.13)\t0.05\t\n IPSS QoL score\t−1.40±0.25\t−0.74±0.41\t0.67 (−0.10, 1.44)\t0.08\t−1.56±0.31\t−0.16 (−0.93, 0.61)\t0.67\t\n OABSS total score\t0.39±0.72\t−0.55±0.70\t−0.93 (−2.91, 1.04)\t0.36\t1.04±0.66\t0.65 (−1.27, 2.58)\t0.51\t\n ICS voiding score\t−4.30±0.65\t−5.04±0.62\t−0.75 (−2.51, 1.02)\t0.42\t−3.58±0.75\t0.72 (−1.24, 2.67)\t0.47\t\n ICS storage score\t0.43±0.50\t0.23±0.33\t−0.20 (−1.38, 0.97)\t0.75\t1.08±0.50\t0.65 (−0.74, 2.04)\t0.36\t\n Vvoid per micturition, mL\t18.25±8.05\t18.17±7.11\t−0.08 (−21.13, 20.97)\t0.99\t26.30±6.74\t6.77 (−12.53, 28.63)\t0.44\t\nChange in safety variable, adjusted mean ± SE\t\n PVR, mL\t−1.5±5.99\t18.67±6.65\t20.17 (2.63, 37.71)\t0.03\t19.46±7.41\t20.96 (2.28, 39.64)\t0.03\t\n Qmax, mL/s\t6.97±1.41\t7.01±0.74\t0.04 (−3.08, 3.16)\t0.97\t7.16±1.70\t0.19 (−4.13, 4.51)\t0.93\t\nNotes: Group 1, patients who underwent TURP; group 2, patients who underwent tamsulosin hydrochloride 0.2 mg after the removal of the Foley catheter after TURP; and group 3, patients who underwent tamsulosin hydrochloride 0.2 mg and solifenacin succinate 5 mg after the removal of the Foley catheter after TURP. Data represent mean ± SD.\n\na 95% CI for the treatment of medications versus TURP. Bold values indicate P<0.05.\n\nAbbreviations: SE, standard error; IPSS, International Prostate Symptom Score; QoL, quality of life; OABSS, Overactive Bladder Symptom Score; ICS, International Continence Society; Vvoid, volume voided; PVR, postvoid residual; Qmax, maximum flow rate; CI, confidence interval; TURP, transurethral resection of the prostate; SD, standard deviation.\n==== Refs\nReferences\n1 Roberts RO Jacobsen SJ Jacobson DJ Reilly WT Talley NJ Lieber MM Natural history of prostatism: high American urological association symptom scores among community-dwelling men and women with urinary incontinence Urology 1998 51 2 213 219 9495700 \n2 Athanasopoulos A Chapple C Fowler C The role of antimuscarinics in the management of men with symptoms of overactive bladder associated with concomitant bladder outlet obstruction: an update Eur Urol 2011 60 1 94 105 21497434 \n3 Wasson JH Reda DJ Bruskewitz RC Elinson J Keller AM Henderson WG A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on transurethral resection of the prostate N Engl J Med 1995 332 2 75 79 7527493 \n4 Ho HS Yip SK Lim KB Fook S Foo KT Cheng CW A prospective randomized study comparing monopolar and bipolar transurethral resection of prostate using transurethral resection in saline (TURIS) system Eur Urol 2007 52 2 517 522 17416453 \n5 Rassweiler J Teber D Kuntz R Hofmann R Complications of transurethral resection of the prostate (TURP) – incidence, management, and prevention Eur Urol 2006 50 5 969 980 16469429 \n6 Marszalek M Ponholzer A Pusman M Transurethral resection of the prostate Eur Urol 2009 Suppl 8 504 512 \n7 Min DS Cho HJ Kang JY Yoo TK Cho JM Effect of transurethral resection of the prostate based on the degree of obstruction seen in urodynamic study Korean J Urol 2013 54 12 840 845 24363865 \n8 Kang YJ Kim KH Seo Y Lee KS Effect of transurethral resection of the prostate on storage symptoms in patients with benign prostatic hyperplasia of less than 30 ml World J Mens Health 2013 31 1 64 69 23658868 \n9 Chapple CR Smith D The pathophysiological changes in the bladder obstructed by benign prostatic hyperplasia Br J Urol 1994 73 2 117 123 7510572 \n10 Yamaguchi O Kakizaki H Homma Y Solifenacin as add-on therapy for overactive bladder symptoms in men treated for lower urinary tract symptoms – ASSIST, randomized controlled study Urology 2011 78 1 126 133 21601248 \n11 Oelke M Bachmann A Descazeaud A EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction Eur Urol 2013 64 1 118 140 23541338 \n12 Li MC Wang ZY Yang J Efficacy and safety of solifenacin plus tamsulosin oral controlled absorption system in men with lower urinary tract symptoms: a meta-analysis Asian J Androl 2015 17 1 124 134 25337836 \n13 Hao N Tian Y Liu W Antimuscarinics and alpha-blockers or alpha-blockers monotherapy on lower urinary tract symptoms – a meta-analysis Urology 2014 83 556 562 24361007 \n14 Johnson TM 2nd Markland AD Goode PS Efficacy of adding behavioural treatment or antimuscarinic drug therapy to alpha-blocker therapy in men with nocturia BJU Int 2013 112 100 108 23448285 \n15 Kaplan SA Roehrborn CG Abrams P Chapple CR Bavendam T Guan Z Antimuscarinics for treatment of storage lower urinary tract symptoms in men: a systematic review Int J Clin Pract 2011 65 4 487 507 21210910 \n16 Xin Z Huang Y Lu J Zhang Q Chen C Addition of antimuscarinics to alpha-blockers for treatment of lower urinary tract symptoms in men: a meta-analysis Urology 2013 82 2 270 277 23896090 \n17 Han HH Ko WJ Yoo TK Factors associated with continuing medical therapy after transurethral resection of prostate Urology 2014 84 3 675 680 25059592\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-9092",
"issue": "11()",
"journal": "Clinical interventions in aging",
"keywords": "benign prostate hyperplasia; combination; solifenacin; tamsulosin; transurethral resection of the prostate",
"medline_ta": "Clin Interv Aging",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D004359:Drug Therapy, Combination; D006801:Humans; D059411:Lower Urinary Tract Symptoms; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011788:Quality of Life; D000069464:Solifenacin Succinate; D013449:Sulfonamides; D000077409:Tamsulosin; D020728:Transurethral Resection of Prostate; D016896:Treatment Outcome; D053201:Urinary Bladder, Overactive; D064804:Urological Agents",
"nlm_unique_id": "101273480",
"other_id": null,
"pages": "1301-1307",
"pmc": null,
"pmid": "27698559",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "23896090;23658868;21601248;23448285;25337836;17416453;24363865;25059592;7527493;21497434;16469429;24361007;21210910;7510572;9495700;23541338",
"title": "Efficacy and safety of tamsulosin hydrochloride 0.2 mg and combination of tamsulosin hydrochloride 0.2 mg plus solifenacin succinate 5 mg after transurethral resection of the prostate: a prospective, randomized controlled trial.",
"title_normalized": "efficacy and safety of tamsulosin hydrochloride 0 2 mg and combination of tamsulosin hydrochloride 0 2 mg plus solifenacin succinate 5 mg after transurethral resection of the prostate a prospective randomized controlled trial"
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"abstract": "Eosinophilic annular erythema (EAE) is a rare condition with a chronic relapsing and remitting course, characterized by the presence of annular or polycyclic erythematous and plaque lesions and prominent tissue eosinophilia on histopathology. There is an ongoing discussion on whether EAE is a subset of Wells syndrome (eosinophilic cellulitis) or a separate entity. To date, few cases of EAE have been reported in the literature; of these, about 40 cases were in adults and fewer than ten cases were in children. Given the rarity of this condition, there are no clear recommendations for its management. Systemic corticosteroids and antimalarials are the most commonly used medications used to treat EAE, but many cases have been reported in the literature that are resistant to treatment with these medications. Here, we present a 65-year-old female with EAE refractory to numerous systemic therapies (corticosteroids, hydroxychloroquine, dapsone, doxycycline, methotrexate) who showed a good response to mepolizumab, a humanized monoclonal antibody that blocks interleukin-5. To the best of our knowledge, this is the first reported case of mepolizumab therapy in a patient with EAE. We also review other treatment strategies that have been used to manage this condition to date. Targeting cytokines crucial for the functioning of eosinophils may be a novel direction in the management of EAE, but prospective, double-blinded and placebo-controlled studies are needed to provide further evidence.",
"affiliations": "Department of Dermatology, University of Rzeszow, Rzeszow, Poland.;Department of Dermatology, University of Rzeszow, Rzeszow, Poland.;Department of Dermatology, University of Rzeszow, Rzeszow, Poland. adi_medicalis@go2.pl.",
"authors": "Żychowska|Magdalena|M|;Tutka|Klaudia|K|;Reich|Adam|A|http://orcid.org/0000-0002-5573-1754",
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"doi": "10.1007/s13555-020-00412-9",
"fulltext": "\n==== Front\nDermatol Ther (Heidelb)\nDermatol Ther (Heidelb)\nDermatology and Therapy\n2193-8210\n2190-9172\nSpringer Healthcare Cheshire\n\n32578132\n412\n10.1007/s13555-020-00412-9\nCase Report\nMepolizumab Therapy for Recalcitrant Eosinophilic Annular Erythema in an Adult: A Case Report and Review of Treatment Options\nŻychowska Magdalena\nTutka Klaudia\nhttp://orcid.org/0000-0002-5573-1754\nReich Adam adi_medicalis@go2.pl\n\ngrid.13856.39 0000 0001 2154 3176 Department of Dermatology, University of Rzeszow, Rzeszow, Poland\n23 6 2020\n23 6 2020\n8 2020\n10 4 893899\n19 5 2020\n© The Author(s) 2020\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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/.\nEosinophilic annular erythema (EAE) is a rare condition with a chronic relapsing and remitting course, characterized by the presence of annular or polycyclic erythematous and plaque lesions and prominent tissue eosinophilia on histopathology. There is an ongoing discussion on whether EAE is a subset of Wells syndrome (eosinophilic cellulitis) or a separate entity. To date, few cases of EAE have been reported in the literature; of these, about 40 cases were in adults and fewer than ten cases were in children. Given the rarity of this condition, there are no clear recommendations for its management. Systemic corticosteroids and antimalarials are the most commonly used medications used to treat EAE, but many cases have been reported in the literature that are resistant to treatment with these medications. Here, we present a 65-year-old female with EAE refractory to numerous systemic therapies (corticosteroids, hydroxychloroquine, dapsone, doxycycline, methotrexate) who showed a good response to mepolizumab, a humanized monoclonal antibody that blocks interleukin-5. To the best of our knowledge, this is the first reported case of mepolizumab therapy in a patient with EAE. We also review other treatment strategies that have been used to manage this condition to date. Targeting cytokines crucial for the functioning of eosinophils may be a novel direction in the management of EAE, but prospective, double-blinded and placebo-controlled studies are needed to provide further evidence.\n\nKeywords\n\nAnti-IL-5\nEosinophilic annular erythema\nEosinophilic cellulitis\nMepolizumab\nWells syndrome\nissue-copyright-statement© The Author(s) 2020\n==== Body\nKey Summary Points\n\nEosinophilic annular erythema is a rare, pruritic disease characterized by a chronic course and frequent resistance to treatment.\t\nThere is a need for effective and safe therapeutic options for the management of eosinophilic annular erythema.\t\nTargeting cytokines crucial for the functioning of eosinophils, mainly interleukin-5, may be a novel direction in the treatment of eosinophilic annular erythema, but prospective, double-blinded and placebo-controlled studies are needed to provide further evidence.\t\n\nIntroduction\n\nEosinophilic annular erythema (EAE) is a rare condition with a chronic relapsing and remitting course, characterized by the presence of annular or polycyclic erythematous and plaque lesions with a tendency to centrifugal spreading and prominent tissue eosinophilia on histopathology [1–14]. Skin lesions predominantly develop on the trunk and proximal aspects of the extremities. The condition was originally believed to be closely related to annular erythema of infancy (AEI). However, AEI and EAE are currently considered to be separate entities, with the former developing mainly in infants under the age of 1 year and spontaneously resolving, and the latter affecting predominantly adults [3].\n\nA search of the literature revealed that only about 40 cases of EAE in adults and fewer than 10 cases in children have been reported to date. Among adult patients, a slight female preponderance has been noted (female:male ratio 1.14:1), and age at onset varies from 20 to 85 years [1–17].\n\nThe aetiology of EAE remains unknown. Some authors consider this condition to be a result of a hypersensitivity reaction to an unidentified antigen [1, 4, 5]. EAE has been reported in association with autoimmune disorders, borreliosis, Helicobacter pylori infection, chronic hepatitis C, diabetes, and kidney disease [1, 4, 6, 7]. There are also a few reports of EAE developing in association with internal malignancy, such as thymoma [2], metastatic prostate adenocarcinoma [8], breast cancer, cervical cancer [9] and renal cancer [5]. In the reported case of EAE associated with thymoma, the lesions disappeared following thymectomy [2].\n\nGiven the rarity of this condition, there are no clear recommendations for its management. Here we report a patient with EAE refractory to numerous systemic therapies, who ultimately showed a good response to mepolizumab, a humanized monoclonal antibody that blocks interleukin (IL)-5. To the best of our knowledge, this is the first report of treating a patient with EAE with mepolizumab.\n\nInformed consent was obtained from the patient for publication of the article, including the publication of clinical photographs.\n\nCase report\n\nA 65-year-old woman was referred to the Department of Dermatology for evaluation of widespread, pruritic annular erythematous lesions of 2-month duration. This was the third episode of such annular eruption in this patient, with the first one observed at the age of 29 years. In the previous two episodes, the lesions had resolved spontaneously over months to years, but in the third episode the lesions were resistant to treatment despite application of a wide range of therapies.\n\nOn admission, the physical examination revealed annular erythematous plaques with central hyperpigmentation located predominantly on the extremities (Fig. 1a, b). Test results from complete blood cell count and routine biochemistry tests (C-reactive protein, renal and liver function tests) were normal. Thyroid-stimulating hormone level was elevated and anti-thyroid peroxidase antibodies were present. Further extended laboratory tests (antinuclear antibodies, including SS-A and SS-B, anti-neutrophil cytoplasmic antibodies, screening antibodies for syphilis, hepatitis B and C, human immunodeficiency virus 1/2, Helicobacter pylori, Borrelia burgdorferi and pemphigus/pemphigoid) and radiographic studies (chest X-ray, computed tomography of the abdomen and pelvis and ultrasound of the peripheral lymph nodes) did not reveal any significant abnormalities. Multiple biopsies had been taken over the years. Recent histopathologic examinations found a normal epidermis and dense perivascular infiltration in the dermis that was composed of lymphocytes, histiocytes and eosinophils (Fig. 2a, b). There were no findings of either mucin deposits to suggest lupus erythematosus or “flame figures” typical of eosinophilic cellulitis (Wells syndrome). Direct immunofluorescence was negative for lupus erythematosus and autoimmune bullous diseases.Fig. 1 Clinical presentation of the lesions. a, b Sharply demarcated erythematous annular plaques with central hyperpigmentation, located on the dorsal aspects on hands (a) and lower legs (b). c, d Significant flattening of the borders of the lesions after first subcutaneous injection of mepolizumab 100 mg. e, f Complete resolution of the lesions on the upper limbs (e) and residual erythematous plaques on the lateral aspects of lower legs (f) 1 month after the third dose of mepolizumab\n\nFig. 2 Histopathology of the erythematous border of the plaque. a Unchanged epidermis and dense perivascular infiltration in the dermis (×40, hematoxylin and eosin [H&E]). b Perivascular infiltration composed of numerous eosinophils, lymphocytes and histiocytes; “flame figures” were not found (×200, H&E)\n\nOn initial examination, several entities were taken into consideration in the differential diagnosis, including erythema annulare centrifugum, Wells syndrome, granuloma annulare, subacute cutaneous lupus erythematosus, erythema migrans, erythema gyratum repens and urticarial phase of bullous pemphigoid. However, based on the clinical presentation, laboratory findings (normal blood cell count without eosinophilia; negative antinuclear antibodies and negative serology for Borrelia burgdorferi, hepatitis B and C and screening antibodies for pemphigus/pemphigoid) and the histopathologic images (dense perivascular infiltration with abundant eosinophils and no “flame figures” or mucin deposits), these conditions were excluded and the diagnosis of EAE was made.\n\nTreatment with oral prednisone (40 mg/day) was started, but the skin lesions continued to progress and the patient complained about gaining weight, leading to this therapy being discontinued after 1 month. Hydroxychloroquine (200 mg twice daily) was introduced and continued for 2 months, but this treatment did not lead to any improvement. Subsequent treatments with doxycycline (100 mg/day for 8 weeks) or methotrexate (10 mg/week for 6 weeks) were also not effective. Treatment with dapsone (100 mg/day) had to be discontinued after 1 month due to side effects (dyspnoea and haemolytic anaemia). While reviewing the literature, we came across a single case report of Wells syndrome that subsided completely following treatment with mepolizumab for eosinophilic granulomatosis with polyangiitis (EGPA; formerly referred to as Churg–Strauss syndrome) [18]. Mepolizumab is an anti-IL-5 monoclonal antibody that has proved to be effective in eosinophilic conditions, including asthma with eosinophilic phenotype, EGPA, chronic eosinophilic leukaemia and hypereosinophilic syndrome. Given the ineffectiveness of the standard treatment options to manage our patient’s condition, the presence of dense eosinophilic infiltrates on histopathologic images of the lesions and this report on the efficacy of mepolizumab in a presumably EAE-related entity, we considered initiating our patient on therapy with mepolizumab. Eventually, the patient was started on mepolizumab (100 mg subcutaneously every 4 weeks), as part of a 3-month program reimbursed by the public insurance by the National Health Found. Significant flattening of the lesions and alleviation of itching occurred after the first dose (Fig. 1c, d), and nearly complete resolution of skin changes was observed 1 month after the third injection of mepolizumab (Fig. 1e, f). In addition, the pruritus subsided completely. She did not report any side effects during therapy with mepolizumab. Given the patient’s good response, the treatment regimen was extended for another 3 months, but initiation of the treatment had to be postponed due to the outbreak of the coronavirus disease 2019 (COVID-19) pandemic. No relapse was observed within the 6-month period after the last (third) injection of mepolizumab, but some residual skin changes on the lower legs have persisted. At the time of writing this article, the patient has initiated the second cycle of mepolizumab treatment.\n\nDiscussion\n\nThe nosological position of EAE remains not fully elucidated. There is an ongoing discussion of whether EAE and Wells syndrome are related entities as both conditions share some similarities. It was initially believed that EAE may be differentiated from Wells syndrome by the absence of “flame figures” composed of eosinophilic major basic protein and degenerated collagen on histopathology and by a normal eosinophil count in peripheral blood (Table 1). Subsequently, however, several authors suggested that “flame figures” and peripheral blood eosinophilia may be present in well-developed and long-standing EAE and, therefore, the condition is currently considered by some to be a subset of Wells syndrome [4, 5].Table 1 Differentiating features between eosinophilic annular erythema and Wells syndrome\n\nDistinguishing features\tEosinophilic annular erythema\tWells syndrome\t\nProdromal symptoms\tAbsent, sometimes itching or tenderness\tBurning, painful edema\t\nClinical presentation\tFigurate/centrifugum-type pattern or urticarial/annular-type pattern\tTender cellulitis-like plaques\t\nResolution of the lesions\tWithout sequelae or rarely with hyperpigmentation\tUsually with atrophy or hyperpigmentation\t\nBlood eosinophilia\tAbsent (occasionally reported in well-developed and long-standing lesions)\tHallmark of the condition\t\n“Flame figures” on histopathology\tAbsent (occasionally reported in well-developed and long-standing lesions)\tHallmark of the condition\t\nOther histopathologic findings\tPerivascular inflammatory infiltration in the dermis with abundant eosinophils; eosinophils usually limited to the dermis; no nuclear dust or features of vasculitis; basal vacuolar changes and dermal mucin deposits may be present\tDiffuse inflammatory infiltration in the dermis with abundant eosinophils; eosinophils found in the dermis and subcutis; vasculitis and granulomatous inflammation usually present\t\n\nThere are no predefined diagnostic criteria for EAE, and the diagnosis should be based on: (1) presence of annular erythematous lesions characterized by a chronic relapsing and remitting course; (2) absence of blood eosinophilia (in the majority of cases); (3) histopathologic findings of dense perivascular infiltration composed of numerous eosinophils and absence of “flame figures” (except for long-lasting lesions); and (4) exclusion of other conditions (mainly Wells syndrome, urticaria, erythema annulare centrifugum, lupus erythematosus).\n\nAs the exact aetiology of EAE remains unknown, the treatment is mainly symptomatic and the mechanism of action is not fully elucidated. Systemic corticosteroids and antimalarials are the most commonly used treatment option. Antimalarials, when efficacious, lead to significant improvement within 2–4 weeks. Still, some authors reported observing a delayed response to chloroquine and decided to prolong treatment to avoid relapses [10]. Nevertheless, many cases resistant to treatment with systemic corticosteroids and antimalarials have been reported in the literature [1, 4, 5]. In one study, cyclosporine A was used mainly in combination with systemic corticosteroids, with several patients showing partial improvement [4]. A number of studies have reported some cases showing a good response to dapsone [11–13]. Howes et al. [14] presented a patient with EAE who had a striking response to indomethacin; however, the treatment had to be discontinued due to intolerable side effects. Nicotinamide (900 mg/day) was also successfully administered to one patient with EAE and autoimmune pancreatitis [6]. Methotrexate (10 mg/week) was found to be effective in a single case, but the treatment was discontinued after 2 weeks due to blood cell count abnormalities [7]. In the same patient, treatment with mycophenolate mofetil at a dose of 500 mg twice daily led to moderate improvement, but this treatment was stopped due to elevated liver enzyme levels, which were subsequently attributed to the onset of autoimmune hepatitis. There is also a single case report of an 8-year-old-boy who achieved complete resolution of EAE after eight sessions of narrow-band ultraviolet B phototherapy [15].\n\nEosinophils are considered to be the crucial cells in the development of EAE. The efficacy of antimalarials has been suggested to be associated to their ability to inhibit eosinophilotaxis and release proinflammatory cytokines [1]. Dapsone has been found to inhibit eosinophil peroxidase and block mast cell degranulation and activation. Data from recent case reports underscore the efficacy of targeting Th2-type cytokines in the treatment of EAE. Suplatast tosilate, an anti-allergic medication that suppresses the production of IgE and synthesis of IL-4 and IL-5, was administered to one patient with EAE, resulting in complete resolution of the lesions within 2 weeks [16]. Dupilumab, an IL-4 receptor alpha antagonist, was also successfully used in a 14-year-old African-American girl with EAE [17].\n\nMepolizumab is a humanized monoclonal antibody targeting IL-5, a cytokine that is crucial for the development and tissue migration of eosinophils. The medication is used in the treatment of severe eosinophilic asthma. It is also approved by the U.S. Food and Drug Administration for the treatment of EGPA. There has been one published report of a patient with EGPA coexisting with Wells syndrome, in whom treatment with mepolizumab resulted in complete resolution of the skin lesions [18]. To the best of our knowledge, mepolizumab has not been used previously to treat EAE. In the patient presented here, the initial dose of mepolizumab led to significant improvement of the skin condition and severity of pruritus. According to the patient, the effect was better than that of all previous treatment regimens. Skin lesions continued to subside after subsequent injections, and nearly complete remission was observed 1 month after the third dose of mepolizumab. Good response to an anti-IL-5 agent speaks for an important role of eosinophils in the pathogenesis of EAE and might set a new direction in the management of the condition.\n\nConclusion\n\nEosinophilic annular erythema is a pruritic disease with a chronic course and frequent resistance to treatment. There is a need for effective and safe therapeutic options for the condition. Targeting cytokines crucial for the functioning of eosinophils may be a novel direction in the treatment of EAE, but prospective, double-blinded and placebo-controlled studies are needed to provide further evidence.\n\nAcknowledgements\n\nWe would like to thank the patient for her cooperation.\n\nFunding\n\nTreatment with mepolizumab was initiated as part of 3-month program reimbursed by the National Health Found. No Rapid Service Fee was received by the journal for the publication of this article.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nAuthorship Contributions\n\nMagdalena Żychowska and Klaudia Tutka contributed equally to the article.\n\nDisclosures\n\nKlaudia Tutka and Magdalena Żychowska have nothing to disclose. Adam Reich is a member of the journal’s Editorial Board.\n\nCompliance with Ethics Guidelines\n\nInformed consent was obtained from the patient for publication of the article, including publication of clinical photographs.\n\nData Availability\n\nData sharing is not applicable to this article as no data sets were generated or analyzed during the current study.\n\nOpen Access\n\nThis 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/.\n\nDigital Features\n\nTo view digital features for this article go to 10.6084/m9.figshare.12458429.\n==== Refs\nReferences\n\n1. Kahofer P Grabmaier E Aberer E Treatment of eosinophilic annular erythema with chloroquine Acta Derm Venereol 2000 80 70 71 10.1080/000155500750012685 10721850\n2. Iga N Otsuka A Kaku Y Miyachi Y Kabashima K Eosinophilic annular erythema limited on the palms and the soles and possibly associated with thymoma J Eur Acad Dermatol Venereol 2016 30 1213 1214 10.1111/jdv.13139 25816730\n3. Peterson AO Jarrat M Annular erythema of infancy Arch Dermatol 1981 117 145 148 10.1001/archderm.1981.01650030023012 7212726\n4. El-Khalawany M Al-Mutairi N Sultan M Shaaban D Eosinophilic annular erythema is a peculiar subtype in the spectrum of Wells syndrome: a multicentre long-term follow-up study J Eur Acad Dermatol Venereol 2013 27 973 979 10.1111/j.1468-3083.2012.04616.x 22731886\n5. Rongioletti F Fausti V Kempf W Rebora A Parodi A Eosinophilic annular erythema: an expression of the clinical and pathological polymorphism of wells syndrome J Am Acad Dermatol 2011 65 e135 e137 10.1016/j.jaad.2011.05.049 21920240\n6. Ogawa K Fukumoto T Yoshida M Eosinophilic annular erythema in a patient with autoimmune pancreatitis: nicotinamide therapy may be beneficial for achieving remission J Dermatol 2016 43 1380 1381 10.1111/1346-8138.13411 27129768\n7. Awosika O Totoraitis K Eleryan M Rengifo-Pardo M Ehrlich A A case of eosinophilic annular erythema as a presenting sign for autoimmune hepatitis JAAD Case Rep 2017 4 84 86 10.1016/j.jdcr.2017.01.007 29387758\n8. Gonzalez-Lopez MA Lopez-Escobar M Fernandez-Llaca H Gonzalez-Vela MC Lopez-Brea M Eosinophilic annular erythema in a patient with metastatic prostate adenocarcinoma Int J Dermatol 2015 54 e80 e82 10.1111/ijd.12640 25515818\n9. Nakazato S Fujita Y Shinkuma S Nomura T Shimizu H Eosinophilic annular erythema is clinically characterized by central pigmentation reflecting basal melanosis: a clinicopathological study of 10 cases J Eur Acad Dermatol Venereol 2017 31 1916 1923 10.1111/jdv.14350 28543605\n10. Ljubojević Hadzavdić S Bartolić L Bradamante M Prolonged treatment of eosinophilic erythema annulare with chloroquine Acta Dermatovenereol Croat 2018 26 262 263\n11. Manriquez J Berroeta-Mauriziano D Andino-Navarrete R Vera-Kellet C Eosinophilic annular erythema: complete clinical response with dapsone Int J Dermatol 2015 54 e96 e98 10.1111/ijd.12736 25556880\n12. Wallis L Gilson RC Gilson RT Dapsone for recalcitrant eosinophilic annular erythema: a case report and literature review Dermatol Ther (Heidelb) 2018 8 157 163 10.1007/s13555-017-0214-1 29222624\n13. Alharbi R Peric J Wollf H Wollenberg A Dapsone treatment for eosinophilic annular erythema J Eur Acad Dermatol Venereol 2017 31 e153 e154 10.1111/jdv.13890 27616050\n14. Howes R Girgis L Kossard S Eosinophilic annular erythema: a subset of Wells’ syndrome or a distinct entity? Australas J Dermatol 2008 49 159 163 10.1111/j.1440-0960.2008.00456.x 18638225\n15. Thomas L Fatah S Nagarajan S Natarajan S Eosinophilic annular erythema: successful response to ultraviolet B therapy Clin Exp Dermatol 2015 40 883 886 10.1111/ced.12668 25958878\n16. Kanameishi S Goto K Ogawa M Fukumoto T Tanabe H Efficacy of suplatast tosilate in a case of recurrent eosinophilic annular erythema Int J Dermatol 2018 35 e255 e256\n17. Gordon SC Robinson SN Abudu M Eosinophilic annular erythema treated with dupilumab Pediatr Dermatol 2018 35 e255 e256 10.1111/pde.13533 29790187\n18. Herout S Bauer WM Schuster C Stingl G Eosinophilic cellulitis (Wells syndrome) successfully treated with mepolizumab JAAD Case Rep 2018 4 548 550 10.1016/j.jdcr.2018.02.011 29892672\n\n",
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"keywords": "Anti-IL-5; Eosinophilic annular erythema; Eosinophilic cellulitis; Mepolizumab; Wells syndrome",
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"title": "Mepolizumab Therapy for Recalcitrant Eosinophilic Annular Erythema in an Adult: A Case Report and Review of Treatment Options.",
"title_normalized": "mepolizumab therapy for recalcitrant eosinophilic annular erythema in an adult a case report and review of treatment options"
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"abstract": "The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients.",
"affiliations": "Helen DeVos Children's Hospital, Grand Rapids, Michigan.;Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont.;Helen DeVos Children's Hospital, Grand Rapids, Michigan.;Helen DeVos Children's Hospital, Grand Rapids, Michigan.;Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont.;Children's Mercy Hospital, Kansas City, Missouri.;Cardinal Glennon Children's Hospital, St. Louis University, St. Louis, Missouri.;UC San Diego School of Medicine and Rady Children's Hospital, San Diego, California.;Arnold Palmer Hospital for Children, Orlando, Florida.;Medical University of South Carolina, Charleston, South Carolina.;Levine Children's Hospital, Charlotte, North Carolina.;Helen DeVos Children's Hospital, Grand Rapids, Michigan.;Connecticut Children's Medical Center, Hartford, Connecticut.;NCI Center for Cancer Research, Bethesda, Maryland.;Medical Biostatistics, University of Vermont College of Medicine, Burlington, Vermont.;Arnold Palmer Hospital for Children, Orlando, Florida.;Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, The Marine Biological Laboratory, Woods Hole, Massachusetts.;Translational Genomics Research Institute, Phoenix, Arizona.;Translational Genomics Research Institute, Phoenix, Arizona.;Translational Genomics Research Institute, Phoenix, Arizona.;Translational Genomics Research Institute, Phoenix, Arizona.",
"authors": "Saulnier Sholler|Giselle L|GL|;Bond|Jeffrey P|JP|;Bergendahl|Genevieve|G|;Dutta|Akshita|A|;Dragon|Julie|J|;Neville|Kathleen|K|;Ferguson|William|W|;Roberts|William|W|;Eslin|Don|D|;Kraveka|Jacqueline|J|;Kaplan|Joel|J|;Mitchell|Deanna|D|;Parikh|Nehal|N|;Merchant|Melinda|M|;Ashikaga|Takamaru|T|;Hanna|Gina|G|;Lescault|Pamela Jean|PJ|;Siniard|Ashley|A|;Corneveaux|Jason|J|;Huentelman|Matthew|M|;Trent|Jeffrey|J|",
"chemical_list": "D000970:Antineoplastic Agents; D012334:RNA, Neoplasm",
"country": "United States",
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"doi": "10.1002/cam4.436",
"fulltext": "\n==== Front\nCancer MedCancer Medcam4Cancer Medicine2045-76342045-7634BlackWell Publishing Ltd Oxford, UK 2572084210.1002/cam4.436Cancer ResearchOriginal ResearchFeasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma Saulnier Sholler Giselle L 12Bond Jeffrey P 3Bergendahl Genevieve 1Dutta Akshita 1Dragon Julie 3Neville Kathleen 4Ferguson William 5Roberts William 6Eslin Don 7Kraveka Jacqueline 8Kaplan Joel 9Mitchell Deanna 1Parikh Nehal 10Merchant Melinda 11Ashikaga Takamaru 12Hanna Gina 7Lescault Pamela Jean 13Siniard Ashley 14Corneveaux Jason 14Huentelman Matthew 14Trent Jeffrey 141 Helen DeVos Children's HospitalGrand Rapids, Michigan2 Michigan State University College of MedicineGrand Rapids, Michigan3 Department of Microbiology and Molecular Genetics, University of Vermont College of MedicineBurlington, Vermont4 Children's Mercy HospitalKansas City, Missouri5 Cardinal Glennon Children's Hospital, St. Louis UniversitySt. Louis, Missouri6 UC San Diego School of Medicine and Rady Children's HospitalSan Diego, California7 Arnold Palmer Hospital for ChildrenOrlando, Florida8 Medical University of South CarolinaCharleston, South Carolina9 Levine Children's HospitalCharlotte, North Carolina10 Connecticut Children's Medical CenterHartford, Connecticut11 NCI Center for Cancer ResearchBethesda, Maryland12 Medical Biostatistics, University of Vermont College of MedicineBurlington, Vermont13 Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, The Marine Biological LaboratoryWoods Hole, Massachusetts14 Translational Genomics Research InstitutePhoenix, ArizonaCorrespondence Giselle L. Saulnier Sholler, 100 Michigan Avenue NE MC 272, Grand Rapids, MI 49503. Tel: 616-267-0334; Fax: 616-391-2785; E-mail: Giselle.SaulnierSholler@helendevoschildrens.orgFunding Information We thank the Dell Corporation for their grant support for this clinical trial and their computational expertise. We would also like to thank the pediatric advocate foundations supporting our work to advance science including Beat NB, Arms Wide Open Foundation, Charles and Meryl Witmer Foundation, Owen Moscone Foundation, Because of Ezra Foundation, Max’s Ring of Fire, Lillie’s Friends Foundation, Brooke’s Blossoming Hope Foundation, Melina’s White Light, Ishan Gala Foundation, Ethan’s Rodeo, Daxton’s Fish.\n\n6 2015 26 2 2015 4 6 871 886 23 10 2014 20 1 2015 22 1 2015 © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.2015This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients.\n\nGenomic profilingmolecular-guided therapymolecular tumor boardneuroblastomapediatric oncology\n==== Body\nIntroduction\nPioneering a new chapter in medicine, this study is the first completed pediatric trial utilizing personalized medicine in the United States. We evaluated the feasibility and safety of using predictive modeling based on genome-wide mRNA expression profiles of neuroblastoma tumor biopsies to create therapeutic regimens individualized to each patient. Neuroblastoma is the most common extra cranial solid tumor in children. With 700 new diagnoses per year, it accounts for 7–10% of childhood cancers 1,2. Currently, children diagnosed after 12–15 months of age have a poor long-term survival rate despite aggressive multimodal therapies 3,4. Even for children who are able to complete high-dose chemotherapy (HDC) followed by hematopoietic stem cell transplantation (HSCT) and maintenance therapy consisting of immune therapy with antiGD2 antibody and retinoic acid, the 5-year event-free survival remains at only 50% 5,6. Long-term survival of patients following relapse is <5%, and neuroblastoma accounts for 15% of all pediatric cancer deaths in the United States 7. Given the small number of patients available, the diversity of genomic profiles 8,9, and the limited number of drugs available for testing, a deeper understanding of the genomics of neuroblastoma and its treatment is critical 10.\n\nThe management of relapsed neuroblastoma patients is particularly challenging: there are currently few treatment options from which tumor boards can select with any degree of confidence. There are no established standard-of-care treatments for relapsed neuroblastoma: options include a variety of Phase I or Phase II therapies with relatively modest response rates (10–35%) 4,11. Even in patients who initially respond to current therapies, tumors often progress on to further rapid relapses. Novel strategies are urgently needed. Recent evidence establishing the genetic heterogeneity of the disease reveals the existence of several major molecular subsets that collectively may provide prognostic value for future disease management 8,9. The identification of agents that target-specific molecular pathways associated with the development and/or progression of neoplastic diseases holds promise. Molecularly-guided approaches that identify existing agents which target-specific alterations in tumors may improve patient survival while avoiding the toxicity associated with agents that are unlikely to be beneficial 12.\n\nIt is now firmly established that cancer results from perturbations in the molecular pathways that disturb the normal cellular homeostatic state 13–16. Fluctuations in these networks may result from genetic or epigenetic events that cause gene expression changes in tumor cells. This study utilizes an approach by which the expanding knowledge of molecular pathways and the mechanisms of action of targeted drug therapies 17,18 can be utilized to create individualized therapeutic regimens using a Tumor Profiling Analysis Platform (TPAP) in real-time for patients with neuroblastoma. In our study, patients undergoing tumor biopsy have a sample sent for pathological evaluation and gene expression profiling from which bioinformatics analysis and generation of a drug prediction report is created. This is reviewed by a molecular tumor board which yields an individualized treatment plan for each patient, who is then followed for safety and response.\n\nMaterials and Methods\nStudy population\nThis was an open label, multicenter prospective feasibility study in patients with refractory or recurrent neuroblastoma. Patients were scheduled to undergo a standard-of-care surgical resection and/or diagnostic biopsy procedure and gave consent for additional samples to be collected during this procedure. A voluntary consent for optional biology studies was obtained. The Institutional Review Board (IRB) at WIRB, Helen DeVos Children's Hospital (MI), Arnold Palmer Children's Hospital (FL), National Cancer Institute (NCI), Children's Mercy Hospitals and Clinics (MO), Connecticut Children's Hospital (CT), Dell Children's Hospital (TX), Cardinal Glennon Children's Hospital (MO), and Levine Children's Hospital (NC) approved this trial. An IRB approved consent was obtained from each subject or subject guardian. (Clinical Trials identifier: NCT01355679; Study ID: NMTRC001). This study was conducted under FDA approval for IDE G100111.\n\nEligibility\nPatients with refractory or recurrent neuroblastoma disease initially diagnosed during or under the age of 21 years were eligible for this study. Current disease state was required to be one without any known curative therapy. Inclusion criteria also defined a Lansky Play score >50. Adequate bone marrow and liver function was required; no other significant organ toxicity as above Grade 2 by National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4 NCI-CTCAE.\n\nExclusion criteria included patients who were administered chemotherapy within 7 days prior to enrollment and 14 days prior to study treatment start; patients receiving antitumor therapy for their disease or any other investigational drug; patients who had received any radiotherapy within the last 30 days without another site of disease to follow; serious infections or a life-threatening illness that is >Grade 2 (NCI-CTCAE V4.0). There was no limit put on the number of previous treatments.\n\nStudy design\nPrimary objective\nThe primary objective of this study was to determine the feasibility of using predictive modeling based on genome-wide mRNA expression profiles of bone-marrow-derived neuroblastoma cells or tumor biopsies to make real-time treatment decisions. The measure was defined as “Enrollment onto study, quality mRNA obtained, gene chip completed, tumor board held, medical monitor review and approval, start of treatment by 21 days post biopsy/surgical resection date, and completion of 1 cycle of therapy.” For statistical reporting a binomial distribution was used for the testing process with a combination of Type I error levels (10%) and Power (70%) with an overall basic design as a MiniMax approach. The study accepted the null hypothesis if the observed feasibility rate was less than or equal to 9/14. Otherwise, stop and reject the null hypothesis.\n\nSecondary objectives\nThe secondary objectives of this study were to determine the safety of allowing a molecular tumor board to determine individualized treatment plans and to determine the activity of treatments chosen based on overall response rate (ORR) and progression free survival (PFS).\n\nDefinition of overall response for each patient\nThis definition is utilized to describe response in all lesions defined as measurable in this study, including CT/MRI lesions which meet RECIST criteria, MIBG-positive lesions, and bone marrow disease. These criteria are used in the statistical analysis to define the overall response of the patient. Complete response (CR) was defined as the disappearance of all target lesions. No evidence of tumor at any site (chest, abdomen, liver, bone, bone marrow, nodes, etc.), and homovanillic acid/vanillyl mandelic acid (HVA/VMA) normal. Partial response (PR) was defined as at least a 30% decrease in the disease measurement for CT/MRI target lesions, taking as reference the disease measurement done to confirm measurable disease in target lesions at study entry. Bone marrow with CR. MIBG with either PR/CR in bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. HVA/VMA may still be elevated. Progressive disease (PD) was defined as any one of the following: at least a 20% increase in the disease measurement for CT/MRI target lesions, taking as reference the smallest disease measurement recorded since the start of treatment, appearance of one or more new lesions or new sites of tumor, or new disease in either the bone marrow or new MIBG lesions. Stable disease (SD) was defined as no new lesions; no new sites of disease, and they do not fit the criteria for PD/PR/CR as above.\n\nTime to progression was defined as the period from the first day of study drug administration until the criteria for progression was met. Duration of response was defined as the period of time from when measurement criteria are met for CR or PR, whichever is first recorded, until the first date that recurrent or PD is objectively documented. The assessment of response included the initial measurable targets, was performed again after the first and second cycle, then performed again after every other cycle.\n\nSample procurement and gene expression profiling\nPatients enrolled on this study were scheduled to undergo a biopsy or resection per treating oncologist as part of their treatment plan. At the time of biopsy, a fresh tumor sample was committed for this research study and prepared immediately. This subject sample was de-identified and sent to various sites for assessments: A single tumor biopsy in RNAlater was shipped to the CLIA-certified laboratory Clinical Reference Laboratory (CRL) for mRNA expression analysis using U133 Plus 2.0 GeneChip and from which the remaining mRNA was sent to Translational Genomics Research Institute (TGen) for high-performance RNA-seq analysis. A biopsy sample was sent to the Pediatric Oncology Translational Research Laboratory (POTRL) for in vitro/in vivo biology studies (Fig. 1).\n\nFigure 1 Study flow diagram. Patient biopsy was sent directly to CLIA-certified laboratory CRL and POTRL. CRL, Clinical Reference Laboratory; TGEN, Translational Genomics Research Institute; POTRL, Pediatric Oncology Translational Research Laboratory at Helen DeVos Children's Hospital.\n\nSample quality control\nTo pass quality control, tumor samples were read by clinical pathology for a ≥75% viable tumor by nuclei, and <20% necrosis. Sample was then processed by CRL. The RNA extraction, amplification, Affymetrix U133 Plus 2.0 GeneChip® hybridization (Santa Clara, CA), and scanning procedures utilized CLIA-certified CRL standard protocols. Passing criteria include: (1) RNA integrity number (RIN) >6.5 using the Agilent (Waldbronn, Germany) 2100 BioAnalyzer; (2) RNA 260/280 and 260/230 absorbance ratios >1.8 by NanoDrop; (3) total cDNA yield ≥5 μg/30 μL; (4) cDNA 260/280 and 260/230 absorbance ratios ≥1.8 by NanoDrop. Data files were processed using the Affymetrix Expression Console™ and the MAS5.0 statistical algorithm.\n\nDrug prediction report\nThe reported drugs were predicted using microarray expression data from patient tumors which were compared to a series of normal biological controls. In this preprocessing step, each probe set was represented by a Z-score, which is a measure of relative expression of genes in tumor versus normal reference as described previously 19. The normal reference set is a whole body bank of 45 normal tissue gene expression levels which are used as the reference set for the normalization calculations. A whole body reference was chosen to provide a wider variance of tissue-specific gene expression for comparison in order to best identify expression differences from tumor tissue. The reference also helps to decrease toxicity risk by not identify targets that are highly expressed in normal tissues. Data were submitted to a database of algorithms designed to predict relevant medications which are then presented in a report to the molecular tumor board 18. These algorithms included; biomarker rules, drug target expression, network-based methods, drug response, and drug sensitivity signatures.\n\nThe biomarker rules method employed predefined and published rules maintained in a drug-biomarker knowledge base in which the efficacy of a specific drug has been associated with the expression of a specific molecular marker 20. Unlike the other methods described, this method has rules that predict both drug sensitivity and drug resistance based on the expression of biomarkers. The drug target expression method identifies genes overexpressed in the tumor (Z-scores ≥ +3) that represented a therapeutic target which was submitted and therapeutic compounds that met the rule requirement based upon their confirmed mechanism of action (MOA). The MOA of drugs and the alignment to therapeutic targets was performed using a variety of public and commercial knowledge bases including DrugBank 17, PharmGKB 21, GeneGo-Thomson Reuters (www.genego.com), UptoDate (www.uptodate.com), MedTrack (www.medtrack.com) and DrugDex (http://thomsonreuters.com/products_services/healthcare/healthcare_products/a-z/drugdex_system/) as well as extensive literature searches to confirm the drug target evidence.\n\nThe network-based methods, developed in partnership with Gene-Go-Thomson Reuters 22–24, predicted activity of drug targets is based on topological analysis. Various derivatives of this tool (referred to as the “hidden nodes” algorithms) are described in detail and freely available at http://www.genego.com/hidden_nodes.php. In brief, these systems biology based methodologies were developed to identify key regulators of the observed transcriptional profile after constructing molecular networks on the basis of prior protein–protein interaction knowledge. The key nodes (putative targets) within the identified and topologically enriched networks may be “hidden” as they do not necessarily represent genes differentially expressed in the patient's tumor. Derivatives of this methodology included the analysis of target genes that represent key points of information convergence and divergence, which can be considered putative effectors and drivers respectively. After these respective analyses, the overlay of the drug target knowledge base with topologically significant nodes provided a method to predict drug efficacy.\n\nThe drug response signatures reproduced the Connectivity Map concept initially developed by the Broad Institute 25 in which the genomic consequence of drug exposure is used to connect drug effect to disease signatures. The hypothesis underlying this method is that drugs that reverse the disease genotype (gene expression profile) toward normalcy have the potential to reverse the disease phenotype. Up to 500 of the most over and underexpressed genes in the patient's tumor (Z-scores ≥ +1.5 or ≤ −1.5, respectively) were submitted to this method. Rank-based statistics were used to identify drugs with a significant inverse connectivity to the disease genotype.\n\nThe drug sensitivity signatures implemented the Parametric Gene Set Enrichment Analysis method to align NCI-60 cell line sensitivity signatures that are predictive across at least two independent cell contexts with the patient's differentially expressed genes. All genes that passed the preprocessing thresholds were evaluated. The NCI-60 drug signature mapped over and under expressed genes (determined by predrug treatment) to the observed in vitro drug sensitivity as measured by the half maximal inhibitory concentration (IC50) of the various cell lines studied 26,27.\n\nUpon execution of these analyses, a compiled report was generated. The report allowed the molecular tumor board to quickly navigate to the underlying knowledge and evidence at multiple levels, including the molecular predictions and inferring methodologies, and any evidence from published literature and clinical trials that may support the use of the predicted agent in the patient's disease context. The total FDA approved drugs with pediatric dosing available at the time of this study was 108 drugs.\n\nTreatment protocol decision\nTreatment protocols were devised by a tumor board which consisted of pediatric oncologists, pharmacists, bioinformaticians, and pathologists utilizing the drug prediction report which was generated through analysis of the gene expression profile of the patient's tumor. The drug prediction report provided a list of potentially effective agents based on the analyses described above. Decision rules for the tumor board included: (1) All drugs with predicted efficacy were reported to the tumor board with an associated predicted efficacy score and rank. (2) Drugs chosen must be FDA approved with established standard and safe dosing schedules (see Table S3 for the clinical trial drug list). Those without known pediatric dosing were excluded. (3) Potential drug choices were analyzed with regards to safety, mechanism, availability, and cost. Focus was on low-toxicity, targeted therapies. (4) Drug combinations were allowed, up to a maximum of four agents. Literature searches were conducted to assemble data on previously established and tested regimens which were given priority. (5) The pharmacist performed analysis of possible drug interactions between the potentially effective agents and the subject's routine medications and supplements. For drug interactions and known toxicities the following databases were used: MicroMedex (Greenwood Village, CO), LexiComp (Hudson, OH), E-facts and Natural Medicines Database. (6) Patients' history and previously received treatments were reviewed. Drugs which a patient had failed were given low priority and used only if there was a rationale for synergy in combination therapy.\n\nPrioritization rules\nThe following prioritization rules were used to choose drugs for each patient's individualized treatment plan. For a given proposed combination of drugs, the first priority to establish doses was to identify the same combination of drugs in a peer-reviewed journal article or presented as a reviewed abstract, or part of an ongoing peer-reviewed clinical trial registered with clinical trials.gov. When a proposed combination of drugs had not previously been reported, dosing was established by studying how each component of the proposed combination had been combined with other cytotoxic agents similar to those being considered for combination therapy. Again, the source of information was a peer-reviewed journal article or presented as a reviewed abstract, or part of an ongoing peer-reviewed clinical trial registered with clinical trials.gov. When a proposed combination of drugs had no available combination data, dosing guidelines started with the maximum tolerated dose (MTD) determined by a phase I/II pediatric study. Per pharmacy review, doses were reduced to compensate for potential additive toxicities of combination agents.\n\nThe treatment regimens were discussed with families and included review of known side effects, serious adverse effects of possible new drug combinations and any additional clinical monitoring that might be recommended by the FDA and/or the tumor board. The families were given the option to proceed with therapy and were asked to sign a treatment-specific memo.\n\nSafety measures\nAll adverse events, whether serious or not, were described in the source documents and Grade 2 or higher (per CTCAE 4.0) adverse events were captured on the adverse event case report forms. All Grade 2 or higher new events were captured, including those that worsened in intensity or frequency relative to baseline, and those which occurred after administration of study drug through the period of protocol-specified follow up. Regardless of suspected cause, adverse events were collected for 30 days following the last treatment and any suspected study drug-related toxicities at the 30 day follow-up visit were followed until resolution to baseline or ≤Grade 2 or stabilization of the event.\n\nResearch methods\nRNA-sequencing research studies\nRNA sequencing was performed using 1.0 µg of total RNA quantified via Nanodrop (Thermo Scientific, Pittsburgh, PA). A sequencing library was prepared with Illumina's Truseq RNA Sample Preparation Kit v2 (Illumina Inc, San Diego, CA) following the manufacturer's protocol. In brief, poly-A containing mRNA molecules were purified using poly-T oligo attached magnetic beads. The mRNA was then thermally fragmented and converted to double-stranded cDNA. The cDNA fragments were end-repaired, a single “A” nucleotide was incorporated, sequencing adapters were ligated, and fragments were enriched with 15 cycles of PCR. Final PCR-enriched fragments were validated on a 2100 Bioanalyzer (Agilent Technologies, Waldbronn, Germany) and quantified by qPCR using Kapa's Library Quantification Kit (Kapa Biosystems, Woburn, MA) on the 7900HT (Applied Biosystems, Foster City, CA). The final library was sequenced by 50 bp paired-end sequencing on a HiSeq2000 (Illumina, San Diego, CA).\n\nRaw reads passing Illumina quality filters were converted to FASTQ format in Phred33 scale with CASAVA 1.8.3. RNA-Seq reads were aligned with TopHat (v2.0.8) 28 which first utilizes Bowtie (v2.1.0.0) 29 to map reads with “splice-aware” alignments to the Homo Sapiens build GRCh37 from Ensembl 30. To estimate the library fragment size for TopHat, we initially mapped a subset of 1 million reads with bwa (v0.6.1) to the human genome, followed by picard version 1.80 31 module CollectInsertSizeMetrics and provided these values to TopHat options “–mate-inner-dist 87 –mate-std-dev 86.” Additional TopHat flags utilized were –transcriptome-index (to Ensembl GRCh37.70), –no-coverage-search, –b2-sensitive and –keep-fasta-order. Next, we calculated gene expression values expressed as fragments per kilobase pair of exon per million fragments mapped using cufflinks version 2.1.1 28. We used the –GTF option in cufflinks to annotate to human gene models GRCh37.70. Additionally we used the –multi-read-correct and –frag-bias-correct options in cufflinks and masked tRNAs, rRNAs, and mtRNAs as suggested in the cufflinks documentation.\n\nIon torrent\nIon torrent deep amplicon sequencing of tumor samples: deoxyribonucleic acid was extracted from tumor tissues and quantitated using the Qubit2 fluorometer (Invitrogen, Grand Island, NY). Ten nanograms of DNA was used for multiplex PCR of a panel covering 739 mutations in 46 cancer-related genes (Ion AmpliSeq Cancer Panel, Life Technologies, Grand Island, NY). Subsequent processing of samples was performed according to the manufacturer's protocol. Library constructions of the amplicons and subsequent enrichment of the sequencing beads was performed using the OneTouch (Grand Island, NY) system. Sequencing was done on the 314 chip with 10 megabases capacity using the Ion Torrent Personal Genome Machine (Life Technologies) as per the manufacturer's protocol. Data analysis, including alignment to the hg19 human reference genome and base calling, was done using built-in software.\n\nResults\nFeasibility and safety\nThe primary objective of this study was to evaluate the feasibility and safety of a process using predictive modeling based on genome-wide mRNA expression profiles of neuroblastoma tumor biopsies to make real-time treatment decisions. Feasibility was defined as “completion of enrollment onto study, quality mRNA obtained, gene chip completed, tumor board held, medical monitor review and approval, start of treatment by 21 days post biopsy/surgical resection date, and completion of 1 cycle of therapy.”\n\nThere were 16 subjects enrolled with multiply relapsed or refractory neuroblastoma of which 14 were eligible: eight males and six females with a median age of 10.1 years (see Table 1A). Subjects were between 1–11 years post diagnosis. The patients presented with actively progressing neuroblastoma and had exhausted relapse therapies (see Table S1). All subjects had soft tissue disease in which biopsy was possible. All biopsies were adequate by pathology evaluation (>75% viable tumor) and RNA quality (>6.5 RIN). Two subjects were deemed ineligible due to benign tumor type after biopsy, therefore 14 subjects were eligible to remain on study. Gene chips were completed in 3–8 days (95% CI: 3.8–6.8), report generation took 0–3 days (95% CI: 0.0–1.5), tumor board took 1–6 days (95% CI: 1.6–4.2), medical monitor sign off took 1–2 days (95% CI: 0.8–1.4). The total time from date of biopsy to tumor board was 6–11 days (95% CI: 7.5–10.2) for all subjects and 7–20 days to treatment (95% CI: 8.9–16.1) (Fig. 2). The tumor board successfully created individualized therapy regimens for all subjects. Patients received between 2–4 drugs chosen from the predicted list. All patients completed at least one cycle of therapy, resulting in 100% feasibility.\n\nTable 1 Clinical trial patient data\n\n\t\nN\n\t\n(A) Patient characteristics\t\n Patients enrolled\t14\t\n Male\t8\t\n Female\t6\t\n Median age at enrollment (range)\t10.1 (5–22)\t\n Median age at diagnosis\t4\t\n Race\t\n Caucasian\t11\t\n Black or African American\t1\t\n Other\t2\t\nDisease status on entry\tResponse\tBone marrow response\t>15% LDH decrease\t>15% VMA decrease\tMedian PFS (95% CI)\tYears post diagnosis (range)\tNo. of previous treatments (range)\tNo. of cycles completed (range)\t\n(B) Response assessment\t\n PD 100% (14/14)\tPD\t36% (5/14)\t7% (1/4)\t42% (6/14)\t50% (7/14)\t59 (43)\t4.75 (1–11)\t5.71 (1–18)\t3.07 (1–7)\t\nPR\t7% (1/14)\t\nSD\t57% (8/14)\t\nPFS, progression free survival; PD, progressive disease; PR, partial response; SD, stable disease.\n\nFigure 2 Box-and-whisker representation of the completion times (Days) for each step in the study process relative to the date of biopsy. The median, interquartile range, and range are represented by the central band, box, and whiskers, respectively.\n\nThere were no serious adverse events reported on this study. The most common adverse events were the effects on bone marrow (neutropenia, anemia, thrombocytopenia) see Table 2A. These adverse events are expected with chemotherapy, generally occurring in greater than 50% of patients receiving standard chemotherapy for neuroblastoma 32. In this study, the incidence of grade 3 and 4 events was found to be neutropenia (43%), anemia (14%), and thrombocytopenia (36%).\n\nTable 2 Adverse events\n\n\tNo. subjects (n = 14)\t\n\tGrade\t\nAdverse event\t2\t3\t4\t\n(A) Related adverse events by event name\t\n Abdominal pain\t1 (7%)\t\t\t\n ALT elevated\t\t2 (14%)\t\t\n AST elevated\t1 (7%)\t1 (7%)\t\t\n Anemia\t4 (29%)\t2 (14%)\t\t\n Bilirubin increase\t\t2 (14%)\t\t\n Constipation\t1 (7%)\t\t\t\n Dehydration\t1 (7%)\t\t\t\n Fatigue\t1 (7%)\t\t\t\n Fever\t1 (7%)\t\t\t\n Hypoalbuminemia\t1 (7%)\t1 (7%)\t\t\n Hypocalcemia\t1 (7%)\t\t\t\n Hypophosphatemia\t1 (7%)\t\t\t\n Infection\t\t2 (14%)\t\t\n Leukopenia\t3 (21%)\t3 (21%)\t1 (7%)\t\n Lymphocytopenia\t1 (7%)\t2 (14%)\t\t\n Mucositis\t2 (14%)\t\t\t\n Myalgia\t1 (7%)\t\t\t\n Nausea\t1 (7%)\t\t\t\n Neutropenia\t\t1 (7%)\t6 (43%)\t\n Pain\t2 (14%)\t\t\t\n Rash\t\t1 (7%)\t\t\n Tachycardia\t1 (7%)\t\t\t\n Thrombocytopenia\t1 (7%)\t1 (7%)\t6 (43%)\t\n Vomiting\t1 (7%)\t\t\t\n Weight loss\t1 (7%)\t\t\t\nEligible pt no.\tDrug and dose chosen\tTargets\tMethod used to choose drug\tCycles completed\tRelated adverse events experienced (grade)\t\n(B) Targeted therapeutic recommendations with adverse events by individual patient/drug combination\t\n MGT-002-13\tTopotecan 0.75 mg/m2 per dose\tTOP1\tDrug target expression\t1\tThrombocytopenia (4)\t\n\tBupropion 1.5 mg/kg per day\tSLC6A2\tDrug target expression\t\t\t\n\tRadiation\t–\t–\t\t\t\n MGT-003-08\tBortezomib 1 mg/m2 per dose\tNFKB1, NFKB2\tNetwork target activity\t3\tALT increase (3)\t\n\tVorinostat 230 mg/m2 per day\tHDAC1, HDAC2, HDAC4\tDrug response signatures\t\tAST increase (2)\t\n\t\t\tNetwork target activity\t\tLeukopenia (3)\t\n\t\t\tDrug target expression\t\t\t\n\tDoxorubicin 30 mg/m2 per dose\tTOP2A\tDrug target expression\t\tNeutropenia (4)\t\n\t\t\t\t\tThrombocytopenia (4)\t\n MGT-004-13\tBevacizumab 625 mg/day\tVEGFA\tNetwork target activity\t1\tFever (2)\t\n\tVorinostat 300 mg/day\tHDAC1\tDrug response signatures\t\t\t\n\t\t\tNetwork target activity\t\t\t\n MGT-006-13\tTopotecan 1 mg/m2 per dose\tTOP1\tDrug target expression\t1\tLeukopenia (4)\t\n\tBupropion 1.5 mg/kg per day\tSLC6A2\tDrug target expression\t\tLymphopenia (3)\t\n\tVinblastine 3 mg/m2 per dose\tTUBB\tDrug target expression\t\tNeutropenia (4)\t\n\tZometa 4 mg/m2 per dose\tFDPS\tDrug target expression\t\tElevated Bilirubin (3)\t\n\tMax: 4 mg\t\t\t\tPain (Esophagus) (2)\t\n\t\t\t\t\tThrombocytopenia (4)\t\n MGT-007-04\tBortezomib 1.3 mg/m2 per dose\tAKT1, NFKB1\tNetwork target activity\t2\tPain (abdominal) (2)\t\n\t\t\tDrug target expression\t\tNeutropenia (3)\t\n\tVorinostat 230 mg/m2 per day\tHDAC1, HDAC3, HDAC7\tNetwork target activity\t\tAnemia (2)\t\n\t\t\tDrug target expression\t\tMyalgia (2)\t\n\tDoxorubicin25 mg/m2 per dose\tTPO2B\tDrug sensitivity signatures\t\tLeukopenia (2)\t\n\t\t\tNetwork target activity\t\tThrombocytopenia (2)\t\n\tSimvastin 20 mg/day\tIGF1, RHOA\tNetwork target activity\t\t\t\n\t\t\tDrug target expression\t\t\t\n MGT-008-08\tDonepezil 5 mg QOD\tACHE\tDrug target expression\t6\tAnemia (2)\t\n\tVorinostat 230 mg/m2 per day\tHDAC2, HDAC6\tDrug target expression\t\tLeukopenia (3)\t\n\tVinblastine 4 mg/m2 per dose\tTUBB\tDrug target expression\t\tNeutropenia (4)\t\n\tZometa 4 mg/m2 per dose\tFDPS\tDrug target expression\t\tThrombocytopenia (4)\t\n\tMax: 4 mg\t\t\t\t\t\n MGT-009-08\tBortezomib 1.3 mg/m2 per dose\tAKT1, NFKB1, NFKB2\tNetwork target activity\t1\tConstipation (2)\t\n\t\t\tDrug target expression\t\tDehydration (2)\t\n\tSorafenib 150 mg/m2 per dose BID\tRET\tDrug target expression\t\tHypoalbunemia (3)\t\n\tDoxorubicin 30 mg/m2 per dose\tTOP2A, TOP2B\tDrug sensitivity signatures\t\tHypophosphatemia (2)\t\n\t\t\tNetwork target activity\t\tNausea (2)\t\n\t\t\tDrug target expression\t\tThrombocytopenia (4)\t\n MGT-010-08\tCytarabine 50 mg/m2 per dose\tSLC29A1\tBiomarker-based rules\t2\tNeutropenia (4)\t\n\tSorafenib 200 mg/m2 per BID\tPDGFRB, FLT3, FLT4, RET\tNetwork target activity\t\tAnemia (4)\t\n\t\t\tDrug target expression\t\tThrombocytopenia (4)\t\n\t\t\t\t\tLeukopenia (4)\t\n\t\t\t\t\tPain (2)\t\n MGT-011-13\tVorinostat 230 mg/m2 per day\tHDAC3, HADC6\tNetwork target activity\t5\tNeutropenia (2)\t\n\t\t\tDrug target expression\t\tAnemia (3)\t\n\tSorafenib 200 mg/m2 per day\tPDGFRB, RET\tNetwork target activity\t\tHypoalbunemia (2)\t\n\t\t\tDrug target expression\t\tThrombocytopenia (3)\t\n\tVinblastine 4 mg/m2 per dose\tTUBB\tDrug target expression\t\tVomiting (2)\t\n\t\t\t\t\tLeukopenia (3)\t\n\t\t\t\t\tLymphocytopenia (3)\t\n\t\t\t\t\tTachycardia (2)\t\n MGT-012-08\tLapatinib 700 mg/m2 per dose BID\tEGFR, ERBB2\tNetwork target activity\t5\tALT increase (3)\t\n\tDoxycycline 4 mg/kg per day\tMMP3, MMP9, IL1A, TNF\tNetwork target activity\t\tAST increase (2)\t\n\t\t\tDrug target expression\t\tHypokalemia (3)\t\n\tMitoxantrone 12.5 mg/m2 per dose start Cycle 2\tTOP2A, DHFR\tDrug target expression\t\tPain-Stomach (2)\t\n\tRadiation- Cycle 1 only\t—\t—\t\tRash (2)\t\n MGT-013-08\tBortezomib 1.3 mg/m2 per dose\tAKT1, NFKB1\tNetwork target activity\t1\tALT increase (3)\t\n\tSorafenib 200 mg/m2 per dose BID\tRAF1, KDR, FLT1, KIT\tNetwork target activity\t\tAST increase (3)\t\n\tDoxycycline 2 mg/kg per dose BID\tMMP9, MMP13, IL1A, TNF\tNetwork target activity\t\tAnemia (3)\t\n\t\t\tDrug target expression\t\tElevated Bilirubin (2)\t\n\t\t\t\t\tHypocalcemia (2)\t\n\t\t\t\t\tLeukopenia (2)\t\n\t\t\t\t\tMucositis (2)\t\n MGT-014-11\tVinblastine 3.7 mg/m2 per dose\tTUBB\tDrug target expression\t2\tAnemia (2)\t\n\tSorafenib 400 mg BID\tRET, RAF1\tNetwork target activity\t\tFatigue (2)\t\n\t\t\tDrug target expression\t\tPain-Skin (2)\t\n\tBupropion 100 mg BID\tSLC6A2\tDrug target expression\t\tLeukopenia (2)\t\n\t\t\t\t\tLymphocytopenia (2)\t\n\t\t\t\t\tNeutropenia (4)\t\n\t\t\t\t\tRash (3)\t\n\t\t\t\t\tWeight loss (2)\t\n MGT-015-08\tTopotecan 0.75 mg/m2 per dose\tTOP1\tDrug target expression\t6\tNeutropenia (4)\t\n\tSorafenib 160 mg/m2 per dose BID\tRET\tDrug target expression\t\tThrombocytopenia (4)\t\n\tVorinostat 230 mg/m2 per day\tHDAC4\tDrug target expression\t\tAnemia (2)\t\n\tDoxycycline 4 mg/kg per day\tMMP9, MMP13\tDrug target expression\t\tAnorexia (2)\t\n\t\t\t\t\tWeight loss (2)\t\n\t\t\t\t\tSinus Infection (2)\t\n MGT-016-08\tDoxorubicin 30 mg/m2 per dose\tTOP2A\tDrug sensitivity signatures\t7\tRash (2)\t\n\t\t\tDrug target expression\t\tNeutropenia (4)\t\n\tSorafenib 200 mg/m2 per dose BID\tRET, FLT1, PDGFRB\tNetwork target activity\t\tAnemia (2)\t\n\t\t\tDrug target expression\t\tFungal Pneumonia (3)\t\n\tVorinostat 230 mg/m2 per dose\tHDAC2, HDAC3, HDAC6\tNetwork target activity\t\tBacterial Blood Infection (3)\t\n\t\t\tDrug target expression\t\tMucositis (2)\t\n\t\tDoxycycline 4 mg/kg per day\tMMP1, MMP9, MMP13\tNetwork target activity\t\t\n\t\t\t\tDrug target expression\t\t\nALT, alanine transaminase; AST, aspartate aminotransferase.\n\nResponse and PFS\nOf the 14 patients enrolled on study, 100% of patients had PD as indicated by radiologic imaging prior to study entry. All patients were able to complete one cycle of molecular-guided therapy and were evaluable for response. There was one patient who met PR criteria with a greater than 50% decrease in brain lesions by MRI (7%), 8/14 had stable disease (57%) and 5/14 had PD (36%) (Table 1B).\n\nThe median PFS from entry onto study was 59 days with a lower 95% confidence interval of 43 days (Table 1B).\n\nRNA expression and sequencing\nReproducibility of profiling\nA reproducibility study was performed within the study to evaluate the variation among multiple biopsy sections from the same tumor. Expression profiling and drug predictions based on triplicate sections were analyzed. Distance-based nonparametric multivariate analysis of variance 33,34 allowed us to reject the null hypothesis that variation between biopsies can be accounted for by the variation within biopsies (P = 0.001). That the variation among expression profiles associated with the same biopsy is small compared with the variation between expression profiles associated with different biopsies is also apparent from Multidimensional Scaling (Fig. 3; 19). Similarly, the variation among drug sets associated with the same biopsy was small compared with the variation among drug lists associated with different biopsies (P = 0.001). The reproducibility averaged over patients, replicates, and drugs is 0.68. As the threshold score increased to score >10, the reproducibility increased to 1 35. Table S2 provides the RNA expression profiles for study patients.\n\nFigure 3 Exploratory multivariate analysis of combined microarray and RNA-Seq gene expression profiles. (A) Heat map and sample dendrogram. Red indicates relatively high expression while green indicates relatively low expression. The first character of the sample label indicates a GeneChip (G) or an RNA-Seq (R) profile, the following integer indicates the biopsy, and the final two characters (e.g., S3) indicate the biopsy section. (B) Multidimensional scaling. Samples are represented by their biopsy number, colored by the technology (GeneChip, red; RNA-Seq, blue).\n\nComparison between RNA expression profiling and RNA sequencing\nDifferences between samples from the same patient (arising either from differences between biopsy sections or from differences between oligonucleotide microarrays and sequencing) is shown to be much smaller than differences between patients (Fig. 3). We found agreement between RNA sequencing and gene chip differential expression levels (Fig. 4). Analysis of the variation within biopsy suggests that it is dominated by biology and not the technology (Fig. 4B). The correlation between gene expression profiles is high (Fig. 4C). Oligonucleotide microarrays and RNA-Seq mutually validate.\n\nFigure 4 Comparison of microarray and RNA-Seq gene expression statistics. (A) Effect size, expressed as log2(fold change), estimated using microarray or RNA-Seq. Each point corresponds to a gene and a pair of samples. The line corresponds to agreement of the two technologies. (B) Variation within tumors, expressed as the standard deviation, estimated using microarray or RNA-Seq. Each point corresponds to a gene. The line corresponds to agreement. (C) Correlation of each microarray expression profile of a gene across samples with the RNA-Seq profile.\n\nIon torrent analysis\nWhile not included in the decision-making process in this clinical trial, the Ion Torrent Cancer Panel gene chip was performed to assess use in future studies. One actionable mutation was found, (7% of patients), which was in the ALK gene and was validated by Sanger sequencing. In this study, actionable mutations are defined as: “mutations which can be targeted by an existing drug as reported in the current body of evidence.”\n\nDiscussion\nThe benefits of a molecular-guided treatment plan are easy to conceptualize: a more targeted approach, a reduction in unnecessary interventions, and the potential for improved outcomes. To date, there have been significant barriers to this approach: the amount of time necessary for genomic profiling, the ability to identify actionable targets, the availability of therapies to act on those targets, and the need for rebiopsy. This study is the first completed pediatric clinical trial in the US which evaluates the feasibility and safety of using a TPAP based on genome-wide mRNA expression profiles of neuroblastoma tumor biopsies to create individualized therapeutic regimens.\n\nAs we enter an era where individualized medicine is increasingly possible, a high degree of cooperation among many disciplines will be critical. Oncologists, bioinformaticians, geneticists, pharmacists, pathologists, information services, and computational experts will provide key input to the discussion of the target gene and its role in molecular-guided therapy. This will enable the creation of individualized treatment plans which more effectively target the disease.\n\nPredictive biomarkers may be based on any of a variety of molecular features; possibilities include genomic sequence, epigenetic modification, transcription, protein expression, posttranslational modification, and metabolite profiles. FDA-approved companion diagnostics used in the treatment of adult cancers have been based on DNA sequence (for example, BRAF V600E/K) or on protein expression (for example, HER2/neu). An important hypothesis underlying our work is that expression technologies will supplement DNA sequence and protein expression information by quantifying the summary effects of genetic and epigenetic drivers genome-wide.\n\nThe primary endpoint of this study was to determine the feasibility of using this process (TPAP) for the treatment of children with neuroblastoma. We have shown that this was feasible in all 14 patients. Initially, there was a concern with regard to the amount of time required for profiling and the generation of a tumor board treatment plan. However, the mean of 12 days was sufficient: no patients experienced significant disease progression prior to initiation of therapy.\n\nThe second primary endpoint of safety for this study showed that there were no serious or unexpected adverse events. The events seen were those typically seen in children with neuroblastoma receiving the medications prescribed. Our observation is that the approach used in this study appeared to result in less severe side effects than we have observed in children who receive nontargeted therapy for relapsed disease and warrants further evaluation in a larger study.\n\nAs all patients had shown radiological progression of disease prior to study enrollment, the expectation would be continued progression if the molecular-guided therapy were not effective. In this heavily pretreated patient population, stabilization of disease in 57% and response in 7% may suggest benefit and should be further studied. The combined clinical benefit in 64% of patients suggests an improvement over the 17–48% combined benefit of recent Phase I neuroblastoma studies 36–41.\n\nThe clustering analysis demonstrates that genetic differences occur even within the same class of tumor, emphasizing the need for personalized and highly targeted therapies. In addition, patients may group into “treatment clusters,” which may lead to novel clinical trial designs that classify patients to a particular treatment plan based on genomic expression differences. The regimens chosen in this study suggest that treatment clusters may occur. Certain medications emerged repeatedly from the drug prediction report: vorinostat (HDAC overexpression), and sorafenib (RET overexpression) were each used in eight of 16 patients (see Table 2B). A larger patient sample would be required to test this.\n\nAnother important aspect of this study was the importance of biopsy. Biopsy of one patient revealed a neuroendocrine carcinoma which had been incorrectly diagnosed as neuroblastoma. This subject was allowed to remain on study. Biopsy of two other patients revealed ganglioneuroma (benign tumor) making them ineligible for this study. One patient was enrolled a second time with biopsy revealing that genomic differences had occurred between relapses, suggesting that prior therapy may have had an impact which would have been undetected without biopsy: this subject counted as two separate encounters in the enrollment numbers. These examples clearly emphasize the need for rebiopsy at relapse for all patients since 3/16 (19%) would have been inappropriately treated without biopsy. Rebiopsy has not been favored due to ethical considerations of an unnecessary procedure. Yet, in this study, rebiopsy revealed critical information about 3/16 patients who would have been misdiagnosed or inappropriately treated. In addition, this study demonstrates that rebiopsy can safely be performed with minimal risk as there were no adverse events associated with any patient biopsies.\n\nA reproducibility analysis of triplicate biopsy sampling was undertaken during this study. This showed significant correlation in overall expression profiling as well as drug predictions confirmed in RNA Sequencing. High-throughput Sequencing (HTS) to determine changes in gene expression is rapidly becoming a viable choice and is referred to as RNA-seq. The methods studied appear to mutually validate each other and therefore either could be used in the same context (such as drug prediction). RNA sequencing may add further understanding through identification of gene fusions or possibly greater sensitivity. As such, RNA sequencing may provide greater transcriptome coverage, and further allow complete annotation and quantification of all genes and their isoforms in a given sample. An important development during this study was that previously RNA sequencing required up to 2 months but has now been optimized to completion in 2 weeks in a CLIA-certified laboratory. As we move toward deeper RNA-Seq, we chose to evaluate this in comparison to RNA expression profiling and found that these methods do correlate in patient samples.\n\nWe also evaluated the ability of the Ion Torrent DNA mutation panel to find actionable mutations in our patients for incorporation into future studies. We found that 7% of patients in this small sample size had identified actionable mutations. This was in the low range of the literature reports of ∽10–22% actionable mutation rate in adults 42. The actionable mutation identified was ALK, which has been identified in 7% of neuroblastoma patients 43 and ALK inhibitors, such as Crizotinib are currently being tested in pediatrics. This method was validated with Sanger sequencing, although this should continue to be evaluated in a larger sample set to show statistical power prior to recommending this test alone. This method was integrated into the decision-making process for the tumor board in the follow-up clinical trial.\n\nUnderstanding of known genetic mutations and their effects on therapeutic choices such as undertaken in this trial will help us gain the knowledge to improve predictions. With the establishment of patient cell lines and mice models in over 50% of cases it is possible to study drug effectiveness in vitro and in vivo. Future directions include an ongoing validation study using patient-derived cell lines and mice models to improve drug prediction algorithms.\n\nThe future of oncology lies in a process using data-driven genetic and mechanistic understanding of patients' tumors for choosing therapies. A better understanding of tumor-specific information will pave the way for individualized, targeted treatment plans. The continued development of a TPAP will allow improved and more accurate predictions in the future. We believe that this study is an initial step pointing the way toward future advances in molecular-guided therapy which will improve the selection of treatment options and open new avenues of investigation.\n\nWe thank the Dell Corporation for their grant support for this clinical trial and their computational expertise. We thank Maja Sholler for her support in editing of this manuscript. We would also like to thank the pediatric advocate foundations supporting our work to advance science including Beat NB, Arms Wide Open Foundation, Charles and Meryl Witmer Foundation, Owen Moscone Foundation, Because of Ezra Foundation, Max's Ring of Fire, Lillie's Friends Foundation, Brooke's Blossoming Hope Foundation, Melina's White Light, Ishan Gala Foundation, Ethan's Rodeo, Daxton's Fish.\n\nConflict of Interest\nNone declared.\n\nSupporting Information\nTable S1. Enrollment characteristics and previous relapse therapies prior to enrollment.\n\n Table S2. Oligonucleotide microarray gene expression data. Each row is a probe set on the Affymetrix GeneChip® Human Genome U133 Plus 2.0 Array. Columns are labelled <Enrollment ID>. <Feature> where <Enrollment ID> is one of 15 enrollment identifiers (‘MGT-001-13’ … ‘MGT-016-08’) and <Feature> reflects whether it was included in the analysis (‘MAS5’), whether it was called present or absent (‘PMed’), the MAS5 expression statistic (‘Raw’) and the Z-score (‘ZScore’).\n\n Table S3. Clinical trial drug list.\n==== Refs\nReferences\nSociety AC Cancer facts and figures 2008 Atlanta, GA American Cancer Society \nBernstein ML Leclerc JM Bunin G Brisson L Robison L Shuster J A population-based study of neuroblastoma incidence, survival, and mortality in North America J. Clin. Oncol 1992 10 323 329 1732433 \nBrodeur GM Pritchard J Berthold F Carlsen NL Castel V Castelberry RP Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment J. Clin. 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Blood Cancer 2012 58 372 379 21509928 \nSequist LV Heist RS Shaw AT Fidias P Rosovsky R Temel JS Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice Ann. Oncol 2011 22 2616 2624 22071650 \nMosse YP Laudenslager M Longo L Cole KA Wood A Attiyeh EF Identification of ALK as a major familial neuroblastoma predisposition gene Nature 2008 455 930 935 18724359\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "4(6)",
"journal": "Cancer medicine",
"keywords": "Genomic profiling; molecular tumor board; molecular-guided therapy; neuroblastoma; pediatric oncology",
"medline_ta": "Cancer Med",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D005240:Feasibility Studies; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma; D061214:Patient Safety; D011446:Prospective Studies; D012334:RNA, Neoplasm; D017423:Sequence Analysis, RNA; D061665:Time-to-Treatment; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "871-86",
"pmc": null,
"pmid": "25720842",
"pubdate": "2015-06",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "23956145;19309513;1732433;21509928;20676069;17139284;8336186;9787315;20532174;19289445;15466177;23802080;24476821;22086963;17666531;18242317;19277986;20921468;18048412;10231141;23792563;23255319;23334666;22071650;18772397;23813912;21671363;17008526;23000897;22388286;21690471;10519894;23539594;11481351;19417665;16875833;19946221;18724359",
"title": "Feasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma.",
"title_normalized": "feasibility of implementing molecular guided therapy for the treatment of patients with relapsed or refractory neuroblastoma"
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"companynumb": "US-TAKEDA-2015MPI004582",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
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