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"abstract": "A 64-year-old man underwent implantation of a permanent His-bundle pacemaker. A marked rise in the selective His-bundle capture threshold was noted 1 month after the patient started flecainide acetate for rhythm control of recurrent, symptomatic atrial flutter and atrial fibrillation. The capture threshold subsequently normalized 4 days after discontinuing flecainide and switching to dofetilide. To our knowledge, this is the first documented case of a rise in selective His-bundle capture threshold associated with flecainide acetate. Further studies are needed to characterize this association which could result in higher capture thresholds, decreased battery longevity, and mimic His-bundle lead failure.",
"affiliations": "Division of Cardiology/Electrophysiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Cardiology/Electrophysiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Cardiology/Electrophysiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Cardiology/Electrophysiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.",
"authors": "Jiang|Michael|M|0000-0003-1324-9588;Wasserlauf|Jeremiah|J|0000-0002-4497-3520;Knight|Bradley P|BP|0000-0002-2129-0401;Verma|Nishant|N|0000-0003-4817-6614",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide",
"country": "United States",
"delete": false,
"doi": "10.1111/pace.13879",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-8389",
"issue": "43(4)",
"journal": "Pacing and clinical electrophysiology : PACE",
"keywords": "flecainide acetate; pacemaker; pacing; permanent His-bundle pacing",
"medline_ta": "Pacing Clin Electrophysiol",
"mesh_terms": "D000889:Anti-Arrhythmia Agents; D002036:Bundle of His; D002304:Cardiac Pacing, Artificial; D005424:Flecainide; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "7803944",
"other_id": null,
"pages": "360-363",
"pmc": null,
"pmid": "32010978",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Increased capture threshold in permanent His-bundle pacing associated with flecainide.",
"title_normalized": "increased capture threshold in permanent his bundle pacing associated with flecainide"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-50653",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"dr... |
{
"abstract": "Carcinoma of unknown primary represents a therapeutic challenge in oncological practice. Evidence lacks to support particular chemotherapy selection and empirical therapies are commonly extrapolated from data on patients where primary tumor site is known. Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil was previously developed to treat pancreatic cancer. These agents have also demonstrated activities in other gastrointestinal malignancies. Considering promising anti-tumor effects of GOLF, we performed a retrospective study to investigate anti-tumor activity and safety of a simplified Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil in patients with Carcinoma of unknown primary in whom immunohistostaining was suggestive of either upper gastrointestinal cancers or pancreatobiliary cancers.\nThis retrospective study included 18 patients recorded to have a diagnosis of Carcinoma of unknown primary between Aug 2010-Dec 2015, who received biweekly G 1000 mg/m2, O 85 mg/m2, L 200 mg/m2 and F 2400 mg/m2 over 46-h on day 1 with pegfilgrastim on day 3 every 14 days. IHC staining pattern favored upper GI origin, including stomach, bile duct or pancreas. Tumor assessments were repeated every 8 weeks.\nMedian age was 67 years (range: 46-76), with ECOG PS<2, and 50% were women. Median number of cycles was 4 (range: 3-14). 7 partial responses were obtained (RR: 39%) and 7 achieved stable disease with overall disease control of 78%. Median time to tumor progression was 4 months (range: 2-9). 8 (44%) patients received liver-directed therapy and 1 underwent HIPEC (5%). Median survival time was 10.5 months (range: 6.7-14.5) and 1-year overall survival rate was 35%. Grade 3-4 toxicities included neutropenia, febrile neutropenia, thrombocytopenia, nausea, diarrhea, mucositis and oxaliplatin-induced neuropathy.\nSimplified Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil regimen appears to be feasible with promising activity for Carcinoma of unknown primary and deserves to be evaluated in future trials.",
"affiliations": "Northwell Health Cancer Institute & Donald and Barbara Zucker School of Medicine, Hofstra, NY, USA.;Boston University, Boston, MA, USA.;Tufts University School of Medicine, Tufts Cancer Center, Boston, MA, USA.;Tufts University School of Medicine, Tufts Cancer Center, Boston, MA, USA.;Tufts University School of Medicine, Tufts Cancer Center, Boston, MA, USA.;Tufts University School of Medicine, Tufts Cancer Center, Boston, MA, USA.;Tufts University School of Medicine, Tufts Cancer Center, Boston, MA, USA.;Tufts University School of Medicine, Tufts Cancer Center, Boston, MA, USA.;Tufts University School of Medicine, Tufts Cancer Center, Boston, MA, USA.;Tufts University School of Medicine, Tufts Cancer Center, Boston, MA, USA.",
"authors": "Saif|Muhammad Wasif|MW|;Wasif|Komal|K|;Goodman|Martin D|MD|;Hegde|Sanjay|S|;Sterling|Mark|M|;Yacavone|Robert|R|;Jaiswal|Sunny|S|;Weinstein|Barbara|B|;Daly|Kevin|K|;Relias|Valerie|V|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8577",
"issue": "20(5)",
"journal": "JOP : Journal of the pancreas",
"keywords": "Bile Duct; Chemotherapy; Cholangiocarcinoma; Gastric Cancer; Genomics; Liver; Metastasis; Pancreatic Cancer",
"medline_ta": "JOP",
"mesh_terms": null,
"nlm_unique_id": "101091810",
"other_id": null,
"pages": "121-124",
"pmc": null,
"pmid": "32104166",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": "18343754;21427201;17956194;23813044;23641043;16041610;25866690;20095915;6400635;11398889;18762700;23799294;27189322;23518210;22115926;10883023;28664225",
"title": "Simplified/Same Day(s)-GOLF as First-line Treatment of Metastatic Carcinoma of Unknown Primary (CUP), Suggestive of Pancreatobiliary Tumors.",
"title_normalized": "simplified same day s golf as first line treatment of metastatic carcinoma of unknown primary cup suggestive of pancreatobiliary tumors"
} | [
{
"companynumb": "US-AMGEN-USASP2020036842",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Synthetic opioids (SO) associated with the recent alarming increase of deaths and intoxications in United States of America and Europe are not detected by the usual first-line opiates drug screening assays. We developed a liquid chromatography tandem mass spectrometry analytical method for the multiplex detection of 14 fentanyl analogues (2-furanylfentanyl, 4-ANPP, 4-methoxybutyrylfentanyl, acrylfentanyl, alfentanil, carfentanil, despropionyl-2-fluorofentanyl, fentanyl, methoxyacetylfentanyl, norfentanyl, ocfentanil, remifentanil, sufentanil and valerylfentanyl) and U-47700 in whole blood and urine samples. The method was validated according to the requirements of ISO 15189. A simple and fast liquid-liquid extraction (LLE) with De-Tox Tube-A was performed leading to better recovery of molecules in urine than in blood samples. Depending on the compound, the limits of detection (LODs) ranged from 0.01 to 0.10 ng/mL and from 0.02 to 0.05 ng/mL in whole blood and urine, respectively. Calibration curves were linear in the range 0.5-50.0 ng/mL and the limit of quantification (LOQ) ranged from 0.10 to 0.40 ng/mL in blood. Internal quality controls at 1 and 40 ng/mL showed intra-day and between-day precision and accuracy bias below 10% in urine and 15% in blood. The method was applied to the screening of 211 urine samples from patients admitted in emergency or addiction departments. The presence of legal fentanyl analogues in 5 urine samples was justified by their therapeutic use as analgesics. Only one patient was concerned by fentanyl misuse and addiction whereas no illegal SO was detected. This study is not in favor of a huge misuse of SO in the Lorraine region.",
"affiliations": "Université de Lorraine, CHRU-Nancy, Department of Clinical Pharmacology and Toxicology, F-54000, Nancy, France.;Université de Lorraine, CHRU-Nancy, Department of Clinical Pharmacology and Toxicology, F-54000, Nancy, France.;Université de Lorraine, CHRU-Nancy, Department of Clinical Pharmacology and Toxicology, F-54000, Nancy, France; Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France.;Pôle Hospitalo-Universitaire du Grand Nancy, Centre Psychothérapique de Nancy, Département d'Addictologie, F-54520 Laxou, France.;Université de Lorraine, CHRU-Nancy, Department of Clinical Pharmacology and Toxicology, F-54000, Nancy, France.;Université de Lorraine, CHRU-Nancy, Department of Clinical Pharmacology and Toxicology, F-54000, Nancy, France.;Université de Lorraine, CHRU-Nancy, Department of Clinical Pharmacology and Toxicology, F-54000, Nancy, France; Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France.;Université de Lorraine, CHRU-Nancy, Department of Clinical Pharmacology and Toxicology, F-54000, Nancy, France; Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France.;Université de Lorraine, CHRU-Nancy, Department of Clinical Pharmacology and Toxicology, F-54000, Nancy, France; Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France. Electronic address: n.gambier@chru-nancy.fr.",
"authors": "Jung|Jean|J|;Kolodziej|Allan|A|;Pape|Elise|E|;Bisch|Michael|M|;Javot|Lucie|L|;Gibaja|Valérie|V|;Jouzeau|Jean-Yves|JY|;Scala-Bertola|Julien|J|;Gambier|Nicolas|N|",
"chemical_list": "D000701:Analgesics, Opioid; D001549:Benzamides; D005663:Furans; D010880:Piperidines; C000614521:U-47700; D015760:Alfentanil; C080127:norfentanyl; C000620436:furanyl fentanyl; D017409:Sufentanil; C017114:carfentanil; C071395:ocfentanil; D000077208:Remifentanil; C000628275:acrylfentanyl; D005283:Fentanyl",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2020.110437",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "317()",
"journal": "Forensic science international",
"keywords": "Fentanyl analogues; HPLC-MS/MS; Misuse; Synthetic opioids; U-47700",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D015760:Alfentanil; D000701:Analgesics, Opioid; D001549:Benzamides; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D005260:Female; D005283:Fentanyl; D005602:France; D005663:Furans; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D057230:Limit of Detection; D008297:Male; D008875:Middle Aged; D009357:Neonatal Abstinence Syndrome; D010880:Piperidines; D000077208:Remifentanil; D012189:Retrospective Studies; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D017409:Sufentanil; D053719:Tandem Mass Spectrometry; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "110437",
"pmc": null,
"pmid": "33007729",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "Multiplex detection of 14 fentanyl analogues and U-47700 in biological samples: Application to a panel of French hospitalized patients.",
"title_normalized": "multiplex detection of 14 fentanyl analogues and u 47700 in biological samples application to a panel of french hospitalized patients"
} | [
{
"companynumb": "FR-TEVA-2020-FR-1851010",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"... |
{
"abstract": "Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1--12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 microg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3--6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2--5). Four patients developed delayed neutropenia (weeks 10--13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes>cm, lasting a median of 6.5 months (range 5--13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.",
"affiliations": "The Division of Hematology-Oncology, The Ohio State University, Columbus, OH 43210, USA. lin-1@medctr.osu.edu",
"authors": "Lin|T S|TS|;Flinn|I W|IW|;Lucas|M S|MS|;Porcu|P|P|;Sickler|J|J|;Moran|M E|ME|;Lucas|D M|DM|;Heerema|N A|NA|;Grever|M R|MR|;Byrd|J C|JC|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000074323:Alemtuzumab; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2403782",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "19(7)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000368:Aged; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000971:Antineoplastic Combined Chemotherapy Protocols; D004305:Dose-Response Relationship, Drug; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011994:Recombinant Proteins; D012008:Recurrence; D015996:Survival Rate; D013997:Time Factors",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1207-10",
"pmc": null,
"pmid": "15858611",
"pubdate": "2005-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia.",
"title_normalized": "filgrastim and alemtuzumab campath 1h for refractory chronic lymphocytic leukemia"
} | [
{
"companynumb": "PHHY2018US065165",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "Of 61 cases of ibuprofen overdosage reported consecutively to the Rocky Mountain Poison and Drug Center from September 1985 through April 1986, 16 were excluded because of incomplete follow-up or concurrent medication ingestion. A toxic reaction developed in 7 (16%) of the remaining 45 patients. Nausea, vomiting, abdominal cramps, mild central nervous system depression, coma, tachycardia, apnea, metabolic acidosis with or without respiratory alkalosis, hematemesis, and oliguric renal failure were noted. Two of six adults had a toxic reaction, and one died. Among pediatric patients, 5/39 (13%) had a toxic reaction. Of patients whose ibuprofen ingestion was less than 104 mg per kg, none became ill. All patients in whom the time of ingestion was known (six of seven) and who had a toxic reaction did so within four hours of ingestion. An ibuprofen overdose, although usually benign, can occasionally produce serious toxicity.",
"affiliations": null,
"authors": "Hall|A H|AH|;Smolinske|S C|SC|;Kulig|K W|KW|;Rumack|B H|BH|",
"chemical_list": "D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0093-0415",
"issue": "148(6)",
"journal": "The Western journal of medicine",
"keywords": null,
"medline_ta": "West J Med",
"mesh_terms": "D000293:Adolescent; D002675:Child, Preschool; D006801:Humans; D007052:Ibuprofen; D007223:Infant; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "0410504",
"other_id": null,
"pages": "653-6",
"pmc": null,
"pmid": "3176471",
"pubdate": "1988-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "5588731;7437834;6465161;6477656;6541425;3557476;2870244;3755329;3777588;3780253;3983674",
"title": "Ibuprofen overdose--a prospective study.",
"title_normalized": "ibuprofen overdose a prospective study"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP017911",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional"... |
{
"abstract": "Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT) associated with high morbidity and mortality. High-risk TA-TMA (hrTA-TMA) is characterized by multifactorial endothelial damage caused by environmental stressors, dysregulation of the complement system, and genetic predisposition. Complement inhibitors have significantly decreased mortality and are the current treatment of choice. In this article, we describe our experience with the use of eculizumab in pediatric patients diagnosed with hrT-TMA after HSCT. Method: Retrospective study of pediatric patients with hrTA-TMA treated with eculizumab between January 2016 and December 2020. Results: Four pediatric patients aged 1, 12, 14, and 17 years at the time of HSCT were diagnosed with hrTA-TMA and treated with eculizumab during the study. At diagnosis, they all had renal impairment with proteinuria, and hypertension under treatment with at least two antihypertensive drugs. The patient who presented multisystemic involvement died instead of treatment. The three patients with exclusive renal involvement achieved TA-TMA resolution after treatment with eculizumab for 65, 52, and 40.6 weeks and were able to stop treatment. The two patients with follow-up data one year after eculizumab withdrawal sustained a favorable response. Eculizumab was well tolerated, and with adequate vaccination and antibiotic prophylaxis, did not increase the risk of infection. Conclusions: Eculizumab appears to be both safe and effective for the treatment of hrTA-TMA in patients with renal impairment. Early diagnosis and initiation of treatment may improve response. Eculizumab withdrawal can be contemplated in patients who achieve laboratory and clinical resolution of TA-TMA.",
"affiliations": "Pharmacy Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Pediatric Oncology and Hematology Service, Hematopoietic Stem Cell Transplantation Section, Vall d'Hebron University Hospital, Barcelona, Spain.;Pharmacy Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Pediatric Nephrology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Pharmacy Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Pediatric Nephrology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Pediatric Oncology and Hematology Service, Hematopoietic Stem Cell Transplantation Section, Vall d'Hebron University Hospital, Barcelona, Spain.",
"authors": "Gomez-Ganda|Laura|L|;Benitez-Carabante|Maria Isabel|MI|;Fernandez-Polo|Aurora|A|;Muñoz-Lopez|Marina|M|;Renedo-Miro|Berta|B|;Ariceta|Gema|G|;Diaz De Heredia|Cristina|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2021.761726",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.761726\nPediatrics\nBrief Research Report\nUse of Eculizumab in Pediatric Patients With Transplant Associated Thrombotic Microangiopathy\nGomez-Ganda Laura 1\n\nBenitez-Carabante Maria Isabel 2\n\nFernandez-Polo Aurora 1\nMuñoz-Lopez Marina 3\nRenedo-Miro Berta 1\n\nAriceta Gema 3 *\n\nDiaz De Heredia Cristina 2\n\n1Pharmacy Department, Vall d'Hebron University Hospital, Barcelona, Spain\n2Pediatric Oncology and Hematology Service, Hematopoietic Stem Cell Transplantation Section, Vall d'Hebron University Hospital, Barcelona, Spain\n3Pediatric Nephrology Department, Vall d'Hebron University Hospital, Barcelona, Spain\nEdited by: Toshihiro Sawai, Shiga University of Medical Science, Japan\n\nReviewed by: Sonata Jodele, Cincinnati Children's Hospital Medical Center, United States; Hiroshi Hataya, Tokyo Metropolitan Children's Medical Center, Japan\n\n*Correspondence: Gema Ariceta gariceta@vhebron.net\nThis article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics\n\n11 11 2021\n2021\n9 76172620 8 2021\n06 10 2021\nCopyright © 2021 Gomez-Ganda, Benitez-Carabante, Fernandez-Polo, Muñoz-Lopez, Renedo-Miro, Ariceta and Diaz De Heredia.\n2021\nGomez-Ganda, Benitez-Carabante, Fernandez-Polo, Muñoz-Lopez, Renedo-Miro, Ariceta and Diaz De Heredia\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.\nBackground: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT) associated with high morbidity and mortality. High-risk TA-TMA (hrTA-TMA) is characterized by multifactorial endothelial damage caused by environmental stressors, dysregulation of the complement system, and genetic predisposition. Complement inhibitors have significantly decreased mortality and are the current treatment of choice. In this article, we describe our experience with the use of eculizumab in pediatric patients diagnosed with hrT-TMA after HSCT.\n\nMethod: Retrospective study of pediatric patients with hrTA-TMA treated with eculizumab between January 2016 and December 2020.\n\nResults: Four pediatric patients aged 1, 12, 14, and 17 years at the time of HSCT were diagnosed with hrTA-TMA and treated with eculizumab during the study. At diagnosis, they all had renal impairment with proteinuria, and hypertension under treatment with at least two antihypertensive drugs. The patient who presented multisystemic involvement died instead of treatment. The three patients with exclusive renal involvement achieved TA-TMA resolution after treatment with eculizumab for 65, 52, and 40.6 weeks and were able to stop treatment. The two patients with follow-up data one year after eculizumab withdrawal sustained a favorable response. Eculizumab was well tolerated, and with adequate vaccination and antibiotic prophylaxis, did not increase the risk of infection.\n\nConclusions: Eculizumab appears to be both safe and effective for the treatment of hrTA-TMA in patients with renal impairment. Early diagnosis and initiation of treatment may improve response. Eculizumab withdrawal can be contemplated in patients who achieve laboratory and clinical resolution of TA-TMA.\n\nthrombotic microangiopathy (TA-TMA)\nhrTA-TMA\neculizumab\ncomplement system\nhematopoietic stem cell transplant (HSCT)\nCH50\ncomplement inhibitor\nsC5b-9 (serum complement membrane attack complex)\n==== Body\npmcIntroduction\n\nTransplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT) associated with high morbidity and mortality. Survival in this setting, however, has improved significantly since the introduction of complement inhibitors (1–4).\n\nTA-TMA is characterized by multifactorial endothelial damage caused by environmental factors (chemotherapy, total body irradiation [TBI], human leukocyte antigen [HLA] mismatch, calcineurin inhibitors [CNIs], graft-vs.-host disease [GVHD], opportunistic viral and fungal infections, and antiviral drugs); complement dysregulation; and, in some cases, genetic predisposition (1, 2, 5–10). Patients with genetic variants and polymorphisms in genes involved in complement regulation seem to have increased susceptibility to TA-TMA (11).\n\nThe kidneys are often the main organs affected in TA-TMA, but this multisystem disease can also affect the lungs, heart, gastrointestinal tract, and central nervous system (1–3, 9, 12, 13). Early diagnosis is challenging due to the nonspecific nature of manifestations and the clinical and laboratory characteristics of patients following transplantation. The most widely used diagnostic criteria for high-risk TA-TMA (hrTA-TMA) in children were proposed by Jodele et al. (2) (Table 1).\n\nTable 1 Diagnostic criteria for high-risk TA-TMA proposed by Jodele et al. (2).\n\nHistologic diagnosis\t\nTMA confirmed by tissue biopsy\t\nLaboratory and clinical diagnosis (5 of 7 risk markers are required to make TA-TMA diagnosis, but features 6 and 7 should be present for high-risk TA-TMA diagnosis)\t\n1. LDH elevated above the upper limit of normal for age\t\n2. Presence of schistocytes in peripheral blood\t\n3. De novo thrombocytopenia or increased transfusion requirements\t\n4. De novo anemia or increased transfusion requirements\t\n5. Hypertension > 99% for age <18 years of age\t\n6. Proteinuria (≥ 30 mg/dL x 2 or random urine protein/creatinine ratio ≥ 2mg/mg)\t\n7. Elevated plasma concentration of sC5b-9 above upper normal laboratory limit\t\nTA-TMA with multiorgan dysfunction syndrome (MODS)\t\n5 of 7 high-risk markers present and must include markers 6 and 7\t\nEvidence of MODS\t\nHistologic evidence of TMA on a tissue specimen\t\nLDH, lactate dehydrogenase; MODS, multiorgan dysfunction syndrome; sC5b-9, soluble terminal complement complex; TA-TMA, transplant-associated thrombotic microangiopathy; TMA, thrombotic microangiopathy.\n\nTA-TMA treatment should be individualized in accordance with disease severity and clinical status. First-line therapy consists of minimizing exposure to potential triggers. This includes CNI withdrawal or dose reduction or replacement with an alternative immunosuppressant, such as mycophenolate mofetil (MMF). Careful monitoring for GVHD is essential in all cases (1, 2, 4, 6, 8, 13).\n\nPrevious treatments for hrTA-TMA included plasmapheresis, rituximab, and defibrotide, but their use was based on case series and retrospective studies and associated with high mortality (2, 5, 6). Evidence supporting a key role for complement dysregulation in TA-TMA led to the off-label use of complement inhibitors as first-line treatment. Eculizumab is a humanized monoclonal antibody against complement protein C5 that prevents tissue damage by blocking formation of the membrane attack complex (C5b-9). Early initiation of treatment is essential to achieve adequate response and hrTA-TMA resolution (1, 7, 9).\n\nPublications from a small number of expert centers recommend individualized pharmacokinetic monitoring to assess plasma levels of eculizumab (1–3, 6, 13). The technology needed, however, is not widely available and results can take time. Serum sC5b-9 (soluble membrane attack complex) and CH50 (total hemolytic complement activity) have been proposed as more accessible and rapidly available complement blockade markers (1, 4, 13). Endothelial risk factors associated with HSCT decrease during follow-up, and the tissue damage responsible for hrTA-TMA also diminishes as normal complement activity is restored. Since hrTA-TMA is a secondary form of TMA, eculizumab withdrawal can be considered in patients who respond favorably (1, 4, 12–14).\n\nPatients' survival has improved significantly with the use of eculizumab in hrTA-TMA, with one pediatric cohort reporting a survival rate of 66% 1 year after HSCT (13). Data, however, are scarce and are mainly based on retrospective observational studies. In this article, we share our experience with the use of eculizumab to treat hrTA-TMA in pediatric patients following HSCT. Although our series is small, we believe that our findings will help guide clinical practice in the treatment of this serious complication.\n\nMethods\n\nStudy Design\n\nRetrospective study of pediatric patients (aged ≤ 18 years at HSCT) with hrTA-TMA treated with eculizumab between January 2016 and December 2020 at a pediatric university hospital.\n\nDemographic, clinical, and treatment data were obtained from electronic health records and computer-assisted prescription systems. Ethical standards and legal requirements on the use of personal data were applied throughout the data collection stages. The use of eculizumab was approved by the institutional review board and the patients' parents or legal guardians gave their informed consent for its off-label use.\n\nStudy Endpoints\n\nThe main objective of our study was to share our experience with the use of eculizumab to treat hrTA-TMA in pediatric patients and to increase awareness of this serious complication. Our specific aims were to (i) define patient, clinical, and laboratory characteristics that could influence response to eculizumab treatment and (ii) study clinical outcomes following withdrawal of eculizumab after hrTA-TMA resolution.\n\nTA-TMA Screening\n\nAll HSCT patients at our hospital undergo strict blood pressure (BP) management and regular monitoring of renal function, blood count, hemolysis markers, and proteinuria. The clinical diagnosis of hrTA-TMA was established according to the criteria proposed by Jodele at al. (2) and confirmed by renal biopsy in stable patients. Cardiac and ocular impairment were evaluated by echocardiography and funduscopy.\n\nDiagnoses of immune hemolytic anemia and thrombotic thrombocytopenic purpura were ruled out by the direct antiglobulin test (DAT) and quantification of ADAMTS-13 activity.\n\nBiochemical, immunological, and genetic studies of the complement system were performed to investigate polymorphisms and risk variants for TA-TMA and rule out primary TMA. Because the patients had undergone HSCT, these studies were conducted using a saliva swab sample.\n\nThe biochemical and immunological studies of complement proteins included determination of plasma levels of C3, C4, factor I, and factor H; complement factor H (CFH) activity (functional assay); anti-factor H antibodies; and membrane cofactor protein (MCP) levels in polymorphonuclear cells. The molecular diagnostics included genetic variants of CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, C3, CFI, MCP, CFB, THBD, DGKE, and CFP, high-risk CFH polymorphisms [CFH-H3], high-risk MCP polymorphisms [MCPggaac], and CFH-CFHR rearrangements.\n\nEculizumab Therapy\n\nTreatment with eculizumab in our hospital was indicated for patients with diagnostic criteria for hrTA-TMA who do not respond to CNI withdrawal and/or treatment of possible triggers (e.g., active viral infection). The initial dosing schedule was based on pediatric recommendations for atypical hemolytic uremic syndrome (aHUS) and subsequently modified according to clinical and laboratory findings (15).\n\nAll patients received antibiotic prophylaxis with amoxicillin according to the hospital's guidelines, and those without contraindications were vaccinated against the encapsulated organisms Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae serotype b (16).\n\nEculizumab withdrawal was assessed in patients with TA-TMA resolution.\n\nTreatment Response\n\nResponse to eculizumab treatment was evaluated by monitoring renal function, BP, proteinuria, thrombocytopenia, anemia, transfusion requirements, presence of schistocytes, and lactate dehydrogenase (LDH).\n\nTo assess complement blockade, sC5b-9 and CH50 were measured prior to initiation of eculizumab and at least twice a month during treatment. Levels of sC5b-9 ≤ 303 ng/ml and CH50 ≤ 13 U/mL (the lowest cutoff detected) were used to indicate blockade.\n\nPatients who achieved resolution of hrTA-TMA were reassessed 1 year after eculizumab discontinuation using the same clinical and laboratory parameters.\n\nResults\n\nBetween January 2016 and December 2020, 178 HSCTs (147 allogeneic and 31 autologous) were performed at our hospital. Four pediatric patients diagnosed with hrTA-TMA were included in this study. Their demographic, clinical, and diagnostic characteristics are summarized in Table 2. They all had a negative DAT and ADAMTS-13 activity > 10%.\n\nTable 2 Demographic and disease characteristics.\n\nVariables\tPatient 1\tPatient 2\tPatient 3\tPatient 4\t\nSex\tM\tF\tF\tF\t\nAge at HSCT (years)\t1\t14\t12\t17\t\nDiagnosis\tAML\tSevere aplasic anemia\tB-cell ALL\tB-cell ALL\t\nType of HSCT\tAllogeneic\tAllogeneic\tAllogeneic\tAllogeneic\t\nType of donor\tHaploidentical\tUnrelated (9/10)\tHaploidentical\tUnrelated (9/10)\t\nStem cell source\tBM\tBM\tBM\tBM\t\nHSCT conditioning regimen\tRIC\tRIC\tMA\tMA\t\nTotal body irradiation\tNo\tYes\tYes\tYes\t\nInterval between HSCT and hrTA-TMA diagnosis (days)\t307\t136\t158\t97\t\nImmunosuppressive therapy at hrTA-TMA diagnosis\tMMF\tMMF, GC\tCyclosporine, GC\tGC\t\nRenal replacement therapy at hrTA-TMA diagnosis\t–\t–\t–\t–\t\nActive GVHD at hrTA-TMA diagnosis\t–\tCutaneous grade II\tCutaneous and gastrointestinal grade II/III\t–\t\nActive viral/fungal infections at hrTA-TMA diagnosis\t–\tPolyomavirus BK y RSV\t–\tCMV\t\nActive antiviral treatments at hrTA-TMA diagnosis\t–\tAcyclovir†\tAcyclovir†\tGanciclovir\t\nDiagnostic criteria for hrTA-TMA\t\nAffected organs\tKidney\tKidney and lung\tKidney\tKidney\t\nConfirmation of TMA by renal biopsy\t√\t–\t√\t√\t\nLDH elevated above upper limit for age\t√\t√\t√\t√\t\nProteinuria(urine protein/urine creatinine ratio > 0.2 mg/mg)\t√\t√\t√\t√\t\nNephrotic range proteinuria(urine protein/urine creatinine ratio ≥ 2 mg/mg)\t√\t√\t√\t–\t\nHypertension\t√\t√\t√\t√\t\nNumber of antihypertensive drugs\t2\t3\t3\t4\t\nDe novo thrombocytopenia\t–\t√\t√\t√\t\nDe novo anemia\t√\t√\t√\t√\t\nIncrease in transfusion requirements\t√\t√\t√\t√\t\nPresence of schistocytes in peripheral blood\t–\t√\t√\t–\t\nElevated plasma concentration of sC5b-9 (> 303 ng/ml)\t√\t√\t√\t√\t\nComplement profile\t\nBiochemical and immunological profile\tNormal\tUnrealized\tNormal\tPending results\t\nGenetic profile\tCarrier of risk haplotype in CFH-H3\tUnrealized\tNormal\tPending results\t\nhrTA-TMA treatments before eculizumab\t\nWithdrawal of calcineurin inhibitors\t√\t√\t√\t√\t\nPlasmapheresis\t–\t–\t–\t–\t\nDefibrotide\t–\t–\t–\t–\t\nRituximab\t–\t–\t–\t–\t\nAML, acute myeloid leukemia; B-cell ALL, B-cell acute lymphoblastic leukemia; BM, bone marrow; CFH, factor H; CMV, cytomegalovirus; F, feminine; GC, glucocorticoids; GVHD, graft vs. host disease; hrTA-TMA, high-risk transplant-associated thrombotic microangiopathy; HSCT, hematopoietic stem cell transplantation; LDH, lactate dehydrogenase; M, masculine; MA, myeloablative regimen; MMF, mycophenolate mofetil; RIC, reduced intensity regimen; RSV, respiratory syncytial virus; sC5b-9, soluble terminal complement complex; TMA, thrombotic microangiopathy.\n\n† In both cases, acyclovir had a prophylactic indication.\n\nThe median interval between HSCT and hrTA-TMA diagnosis was 147 days (range: 97–307 days). Patient 1 was included after a second haploidentical HSCT due to primary graft failure following a mismatched cord blood transplant from an unrelated donor. All four patients had renal impairment (confirmed by renal biopsy in 3 cases) with proteinuria and hypertension under treatment with at least two antihypertensive drugs (median 3, range: 2–4).\n\nCardiac involvement was monitored by echocardiography in all cases. Patient 2 was diagnosed with severe pulmonary hypertension (PH) associated with pulmonary TA-TMA. Patients 1 and 3 developed left ventricular hypertrophy secondary to systemic hypertension.\n\nThe funduscopic examination was normal in all patients, with no signs of hypertensive retinopathy.\n\nAll the patients had a history of risk factors for TA-TMA: chemotherapy (n = 4), TBI (n = 3), HLA antigen incompatibility (n = 4) (haploidentical family donor [(n = 2), 9/10 mismatched unrelated donor (n = 2)], initial immunosuppressive treatment with cyclosporine (n = 4), GVHD (n = 4), viral infections (n = 4), and antiviral treatment (n = 4).\n\nThe variables related to eculizumab treatment are shown in Table 3.\n\nTable 3 Eculizumab treatment data.\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\t\nInterval between hrTA-TMA and initiation of eculizumab therapy (days)\t48\t28\t49\t100\t\nDuration of treatment (weeks)\t65\t5.7\t52\t40.6\t\nNumber of eculizumab doses given\t34\t7\t29\t26\t\nWithdrawal of eculizumab due to resolution of hrTA-TMA\tYes\t-\tYes\tYes\t\nPrevious vaccination against encapsulated microorganisms†\tYes\tNo\tYes\tNo\t\nAntibiotic prophylaxis\tAmoxicillin\tAmoxicillin\tAmoxicillin\tAmoxicillin\t\nInfections by encapsulated microorganisms during treatment\tNone\tNone\tNone\tNone\t\nAdverse effects\tNone\tNone\tNone\tNone\t\nhrTA-TMA, transplant—associated thrombotic microangiopathy.\n\n† Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae serotype b.\n\nFigure 1 shows creatinine, proteinuria, LDH, sC5b-9, and CH50 levels before and during eculizumab treatment. Adequate complement blockade (low levels of sC5b-9 and CH50) was achieved after the first dose and during treatment in patients 1, 2, and 3. Patient 4 had normal sC5b-9 levels on initiation of eculizumab, but had high CH50 levels that decreased after the first dose and remained adequate during treatment.\n\nFigure 1 Changes in creatinine, proteinuria, LDH, and markers of eculizumab-induced complement blockade, sC5b-9 and CH50. Month 0 represents the start of treatment with eculizumab. Reference values: sC5b-9 < 303 ng/ml; CH50 < 34 U/ml; LDH 0-248 UI/L. CH50, total complement hemolytic activity; LDH, lactate dehydrogenase; sC5b-9, soluble membrane attack complex.\n\nBecause we were unable to assess changes in hemoglobin and platelet levels due to the patients' underlying pathology and the need for periodic transfusions, we studied transfusion patterns.\n\nThe four cases are presented below in chronological order of TA-TMA diagnosis and initiation of eculizumab therapy.\n\nPatient 1\n\nAt the time of eculizumab withdrawal, patient 1 showed improved renal function (creatinine, 0.69 mg/dL; glomerular filtration rate estimated using the Schwartz formula [eGFR], 60 mL/min) and no longer needed antihypertensive treatment. Proteinuria was 1.65 mg protein/mg creatinine prior to initiation of eculizumab and 0.64 mg protein/mg creatinine after its withdrawal. The patient's anemia had also improved and he no longer needed transfusions, although he was still receiving darbepoetin. His LDH values had also normalized.\n\nThe patient continued without signs of active TA-TMA 1 year after eculizumab discontinuation. He had stable creatinine values (creatinine, 0.65–0.69 mg/dl, eGFR 60–65 ml/min), adequate BP control on monotherapy, minimal proteinuria (0.44 mg protein/mg creatinine), and adequate LDH, hemoglobin (without darbepoetin), and platelets, without transfusion requirements.\n\nPatient 2\n\nPatient 2 was diagnosed with severe, progressive PH at the onset of hrTA-TMA. A diagnostic lung biopsy showed constrictive bronchiolitis and vasculopathy. Although she initially responded clinically to eculizumab and showed improved laboratory values, her clinical status worsened, with progression of PH. She did not respond to eculizumab intensification (weekly administration), and was started on defibrotide and rituximab and sildenafil to treat the PH. Despite aggressive supportive care and therapy with inhaled nitric oxide and vasoactive drugs, she died 76 days after hrTA-TMA diagnosis due to pulmonary edema related to cardiogenic shock.\n\nPatient 3\n\nOn withdrawal of eculizumab, patient 3 showed stable renal function (creatinine, 0.83 mg/dL; eGFR 75 mL/min) and an improvement in BP that enabled withdrawal of two of the three antihypertensive drugs she was taking. She did not have proteinuria (0.16 mg protein/mg creatinine) or schistocytes in peripheral blood. Hemoglobin (on darbepoetin treatment) and platelets were normal and she no longer required transfusions. LDH values had also normalized.\n\nThere were no signs of active TA-TMA 1 year after eculizumab withdrawal. Renal function remained stable (creatinine, 0.69 mg/dL; eGFR, > 90 mL/min) and hypertension was controlled with a single antihypertensive drug. The patient continued without proteinuria or schistocytes in peripheral blood and did not require transfusions. Hemoglobin values had increased slightly, although she continued to receive darbepoetin, and platelets were normal. LDH levels remained within the normal range.\n\nPatient 4\n\nEculizumab was withdrawn 1 month before the end of the study period in patient 4. This patient had required treatment intensification (administration every 7 or 10 days for 8 weeks) 172 days after initiation due to worsening of renal function, proteinuria, hypertension, and platelet transfusion requirements. Eculizumab levels were monitored during this period of worsening, as the assay was now available at our hospital. The measurements showed adequate levels, confirming adequate dosing.\n\nOn withdrawal of eculizumab, the patient's creatinine levels improved (creatinine, 1.1 mg/dL; eGFR, 66 mL/min). Her BP also improved and she was able to stop taking one of four antihypertensive drugs. She had stable proteinuria (0.72 mg protein/mg creatinine). Her hemoglobin and platelet values were adequate and she no longer required transfusions. One month after eculizumab withdrawal, she continued without signs of active TA-TMA.\n\nDiscussion\n\nOur results support the benefits of early complement blockade in patients with hrTA-TMA and add to the little information published on the use of eculizumab in HSCT patients.\n\nAll the patients in our study had several risk factors for TA-TMA, confirming the multifactorial nature of this disease (1, 2, 5–8, 11). They had all undergone allogeneic HSCT, which, compared with autologous HSCT, is associated with a higher risk of TA-TMA (2, 6, 9, 10). For one of the patients, this was his second transplant, meaning that he was possibly at increased risk.\n\nEarly diagnosis of TA-TMA in the setting of HSCT is challenging and requires experience to differentiate it from other conditions. Organ dysfunction, hypertension, anemia, and thrombocytopenia are all common in this setting and may be caused by drugs (e.g., cyclosporine), infections, or GVHD (2). In addition, schistocytes may not be visible in peripheral blood due to increased vascular permeability (3).\n\nAlthough TA-TMA is a multisystem disease, the kidneys appear to be the first organ affected (1–3, 12, 13). In our cohort, all the patients had renal involvement and the main manifestations were impaired kidney function, hypertension, and proteinuria. Moreover, recently, Dandoy et al. (9) reported that proteinuria is a high-risk marker TA-TMA. Creatinine may not be an adequate marker of kidney function in pediatric patients due to their low muscle mass. Where possible thus, hrTA-TMA should be diagnosed by renal biopsy, but a risk/benefit assessment should always be performed owing to high risk of bleeding due to thrombocytopenia and hypertension (2, 3, 5).\n\nWe did not detect any complement gene mutations in our series, supporting the important role played by non-genetic triggers in the development of TA-TMA in pediatric patients. Nonetheless, it has been demonstrated that secondary TMA is more common in patients with complement mutations (17). Carriage of the heterozygous CFHR3-CFHR1 deletion, for example, alongside exposure to other TA-TMA risk factors, seems to increase hrTA-TMA susceptibility in allogeneic HSCT recipients (11). In our cohort, just one patient was a carrier of a haplotype associated with an increased risk of TA-TMA. Although this finding does not support the diagnosis of complement-mediated primary, it could facilitate the development of developing TA-TMA when the patient is exposed to risk factors. Moreover, Jodele et al. (11) postulated that genetic screening for complement gene polymorphisms of risk prior to HSCT could be clinically useful for identifying patients with greater susceptibility to hrTA-TMA and for guiding decisions on CNI dose reduction. In the acute setting, involvement of complement in hrTA-TMA by CH50 and/or sC5b-9 elevation is relevant, as eculizumab has been shown to be effective in secondary TMA management (18).\n\nGenetic studies are also important for assessing long-term patient risk, but they cannot support acute management, as it may take months to receive results. One limitation of genetic studies in hrTA-TMA is that not all risk variants are known.\n\nAll our patients were hypertensive and required treatment with several antihypertensive drugs (a median number of 3, range: 2–4). We therefore consider that hypertension being treated with two or more drugs in an HSCT patient should alert clinicians to a possible diagnosis of hrTA-TMA.\n\nCNI withdrawal is one of the first steps in a patient with TA-TMA. In our series, cyclosporine was withdrawn in all four patients and replaced with MMF in two. None of the patients responded to this measure, however, and required eculizumab to treat active hrTA-TMA.\n\nAs in previous studies, our study shows that eculizumab effectively blocks complement in patients with hrTA-TMA and improves renal and hematological manifestations. The three patients with renal involvement only on initiation of eculizumab (patients 1, 3, and 4) achieved clinical resolution of TA-TMA and normalization of laboratory findings. Patient 2, however, who was diagnosed late with hrTA-TMA and had pulmonary manifestations did not survive.\n\nThe median interval between hrTA-TMA diagnosis and initiation of eculizumab therapy was 48.5 days (range: 28–100). It is similar to that reported previously by Jodele et al. (1) (median 33 days, range: 3–122) and de Fontbrune et al. (7) (median 31 days, range: 3–154).\n\nEculizumab has been shown to be more effective in hrTA-TMA when started early (19). We have described positive outcomes in three patients who were diagnosed early with hrTA-TMA and treated with eculizumab. The other patient, who was diagnosed late and had multisystemic involvement, did not respond. These results support the previous conclusions of previous studies that an early diagnosis and prompt initiation of treatment with eculizumab may improve therapeutic response (1, 7, 9).\n\nJodele et al. (1, 4) showed that pediatric patients with hrTA-TMA may have higher eculizumab dosage requirements than those with aHUS. Likewise, patients with higher sC5b-9 levels, indicating greater tissue damage and inflammation and a worse prognosis, require intensification of treatment to achieve adequate complement blockade at the beginning of treatment (2, 4). Treatment can be intensified by increasing the dose or reducing the dosing interval. Once sC5b-9 levels have normalized, the intensity can be reduced. Patients 1 and 3 in our series achieved complement blockade and clinical resolution of hrTA-TMA at the recommended dosage for aHUS, despite elevated sC5b-9 values on initiation of eculizumab (sC5b-9, 7593 and 966 ng/ml, respectively). Patient 2 also had elevated sC5b-9 (419 ng/ml) and she required eculizumab intensification due to the severity of her disease at diagnosis. At diagnosis, patient 4 had a slight elevation of sC5b-9 (333 ng/ml). Neverthless, she did not have elevated sC5b-9 on initiation of treatment (263 ng/ml) and she required intensification.\n\nThe complement blockade markers proposed to date, sC5b-9 and CH50, appear to be useful for evaluating response to eculizumab, although it should be noted that sC5b-9 levels may be normal. It should also be noted that clinical and laboratory improvements may not be observed for several weeks following adequate complement blockade.\n\nThe number of doses of eculizumab given in the responders (34, 29 and 26 doses) is similar to that reported by Schoettler et al. (10) (median 23 doses, range: 3–63), but it is higher than reported by Jodele et al. (13) (median 11 doses, range: 7–20). The duration of eculizumab treatment in the responders (65, 52, and 40.6 weeks) is similar to that reported by Jodele et al. in 2014 (1) (median 47.5 weeks, range: 38–72). Nevertheless, it is longer than reported by Jodele et al. in 2020 (13) (median 66 days, range: 41–110). The shorter duration of treatment in the latest study published by Jodele et al. (13) may be due to the increasing experience in the use of eculizumab in TA-TMA, which could lead to assess an earlier withdrawal of the drug. In our cohort, patient 4, who was the last to start treatment with eculizumab, had shorter treatment duration and received fewer doses.\n\nEculizumab was withdrawn safely in patients 1 and 3, and favorable laboratory and clinical outcomes were maintained throughout the year of follow-up. The effects of eculizumab withdrawal are not yet assessable in patient 4, but the findings at 1 month following discontinuation are favorable.\n\nAs previously reported, eculizumab is well tolerated, and with adequate vaccination and antibiotic prophylaxis, does not increase the risk of infection.\n\nThe main limitations and biases of this study are those inherent to any retrospective analysis. Our sample size was small, similar to that most of previous studies, but this is to be expected considering the low incidence of hrTA-TMA in pediatric patients.\n\nThe technology to monitor eculizumab levels only became available at our hospital during the treatment of patient 4. While the measurements did not indicate a need for dosage modifications, they did confirm the adequacy of the regimen.\n\nIn conclusion, eculizumab appears to be a safe, effective treatment for hrTA-TMA in patients with renal involvement. Early diagnosis and prompt initiation of eculizumab may improve response to treatment. Withdrawal of eculizumab can be contemplated in patients with laboratory findings of adequate complement blockade and clinical TA-TMA resolution.\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\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\n\nLG-G, MB-C, AF-P, and BR-M: data collection. LG-G, MM-L, GA, and CD: bibliographic search. LG-G, MB-C, AF-P, MM-L, BR-M, GA, and CD: data analysis and interpretation. LG-G, MB-C, AF-P, MM-L, and BR-M: writing the manuscript. GA and CD: revision and modification of the manuscript. All authors contributed to the article and approved the submitted version.\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\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAbbreviations\n\nAML acute myeloid leukemia\n\naHUS atypical hemolytic uremic syndrome\n\nB-cell ALL B-cell acute lymphoblastic leukemia\n\nBM bone marrow\n\nBP blood pressure\n\nC5b-9 terminal complement complex\n\nCH50 total hemolytic complement activity\n\nCNIs calcineurin inhibitors\n\nCMV cytomegalovirus\n\nCFH factor H\n\nDAT direct antiglobulin test\n\neGFR estimated glomerular filtration rate\n\nF femenine\n\nGC glucocorticoids\n\nGVHD graft vs. host disease\n\nHLA human leukocyte antigen\n\nhrTA-TMA high-risk transplant—associated thrombotic microangiopathy\n\nHSCT hematopoietic stem cell transplantation\n\nLDH lactate dehydrogenase\n\nM masculine\n\nMA myeloablative regimen\n\nMCP or CD46 membrane cofactor protein\n\nMMF mycophenolate mofetil\n\nMODS multiorgan dysfunction syndrome\n\nPH pulmonary hypertension\n\nRIC reduced intensity regimen\n\nRSV respiratory syncytial virus\n\nsC5b-9 soluble terminal complement complex\n\nTA-TMA transplant—associated thrombotic microangiopathy\n\nTBI total body irradiation\n\nTMA thrombotic microangiopathy.\n==== Refs\nReferences\n\n1. Jodele S Fukuda T Vinks A Mizuno K Laskin BL Goebel J . Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood Marrow Transplant. (2014) 20 :518–25. 10.1016/j.bbmt.2013.12.565 24370861\n2. Jodele S Laskin BL Dandoy CE Myers KC El-Bietar J Davies SM . A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. (2015) 29 :191–204. 10.1016/j.blre.2014.11.001 25483393\n3. Jodele S Dandoy CE Myers KC El-Bietar J Nelson A Wallace G Laskin BL . New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Transfus Apher Sci. (2016) 54 :181–90. 10.1016/j.transci.2016.04.007 27156964\n4. Jodele S Fukuda T Mizuno K Vinks AA Laskin BL Goebel J . Variable eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. (2016) 22 :307–315. 10.1016/j.bbmt.2015.10.002 26456258\n5. Elsallabi O Bhatt VR Dhakal P Foster KW Tendulkar KK . Hematopoietic stem cell transplant-associated thrombotic microangiopathy. Clin Appl Thromb Hemost. (2016) 22 :12–20. 10.1177/1076029615598221 26239316\n6. Dhakal P Bhatt VR . Is complement blockade an acceptable therapeutic strategy for hematopoietic cell transplant-associated thrombotic microangiopathy? Bone Marrow Transplant. (2017) 52 :352–6. 10.1038/bmt.2016.253 27775697\n7. de Fontbrune FS Galambrun C Sirvent A Huynh A Faguer S Nguyen S . Use of eculizumab in patients with allogeneic stem cell transplant-associated thrombotic microangiopathy: a study from the SFGM-TC. Transplantation. (2015) 99 :1953–9. 10.1097/TP.0000000000000601 25651309\n8. Gavriilaki E Sakellari I Anagnostopoulos A Brodsky RA . Transplant-associated thrombotic microangiopathy: opening pandora's box. Bone Marrow Transplant. (2017) 52 :1355–60. 10.1038/bmt.2017.39 28287636\n9. Christopher ED Seth R Priscila BA Anna K Catherine D John H . A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant. Blood Adv. (2021) 5 :1–11. 10.1182/bloodadvances.2020003455 33570619\n10. Schoettler M Lehmann LE Margossian S Lee M Kean LS Kao PC . Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort. Blood Adv. (2020) 4 :2536–2547. 10.1182/bloodadvances.2019001242 32516415\n11. Jodele S Zhang K Zou F Laskin B Dandoy CE Myers KC . The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. (2016) 127 :989–96. 10.1182/blood-2015-08-663435 26603840\n12. Genere L Bacchetta J Bertrand Y Javouhey E Cheikh N Sellier-Leclerc AL . Eculizumab and thrombotic microangiopathy after hematopoietic stem cell transplantation: a report on its efficacy and safety in two pediatric patients. Arch Pediatr. (2018) 25 :485–88. 10.1016/j.arcped.2018.09.011 30340942\n13. Jodele S Dandoy CE Lane A Laskin BL Teusink-Cross A Myers KC . Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. (2020) 135 :1049–57. 10.1016/j.bbmt.2019.12.663 31932840\n14. Olson SR Lu E Sulpizio E Shatzel JJ Rueda JF DeLoughery TG . When to stop eculizumab in complement-mediated thrombotic microangiopathies. Am J Nephrol. (2018) 48 :96–107. 10.1159/000492033 30110670\n15. Data sheet of Soliris® 300 mg concentrate for solution for infusion (Alexion Europe). Spanish Agency for Medicines and Health Products (Agencia Española del Medicamento y Productos Sanitarios, AEMPS). Available online at: https://cima.aemps.es/cima/pdfs/es/ft/07393001/FT_07393001.pdf (accessed August 11, 2021).\n16. Protocolo de profilaxis antiinfecciosa frente a microorganismos encapsulados en pacientes pediátricos con Síndrome Hemolítico Urémico atípico en tratamiento con eculizumab. Pediatric Infectious Pathology and Immunodeficiencies Unit, Vall d'Hebron University Hospital. 2017. Available online at: https://www.upiip.com/sites/upiip.com/files/Protocol%20profilaxi%20antibiotica%20pacient%20amb%20Eculizumab.pdf (accessed August 13, 2021).\n17. Vieira-Martins P El Sissy C Bordereau P Gruber A Rosain J Fremeaux-Bacchi V . Defining the genetics of thrombotic microangiopathies. Transfus Apher Sci. (2016) 54 :212–9. 10.1016/j.transci.2016.04.011 27177491\n18. Cavero T Rabasco C López A Román E Ávila A Sevillano Á . Eculizumab in secondary atypical haemolytic uraemic syndrome. Nephrol Dial Transplant. (2017) 32 :466–74. 10.1093/ndt/gfw453 28339660\n19. Walle JV Delmas Y Ardissino G Wang J Kincaid JF Haller H . Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment. J Nephrol. (2017) 30 :127–34. 10.1007/s40620-016-0288-3 26995002\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-2360",
"issue": "9()",
"journal": "Frontiers in pediatrics",
"keywords": "CH50; complement inhibitor; complement system; eculizumab; hematopoietic stem cell transplant (HSCT); hrTA-TMA; sC5b-9 (serum complement membrane attack complex); thrombotic microangiopathy (TA-TMA)",
"medline_ta": "Front Pediatr",
"mesh_terms": null,
"nlm_unique_id": "101615492",
"other_id": null,
"pages": "761726",
"pmc": null,
"pmid": "34858907",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "28287636;26995002;26603840;26456258;30110670;28339660;27156964;30340942;31932840;25651309;33570619;27177491;26239316;32516415;24370861;25483393;27775697",
"title": "Use of Eculizumab in Pediatric Patients With Transplant Associated Thrombotic Microangiopathy.",
"title_normalized": "use of eculizumab in pediatric patients with transplant associated thrombotic microangiopathy"
} | [
{
"companynumb": "ES-STRIDES ARCOLAB LIMITED-2022SP004045",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drug... |
{
"abstract": "FOLFIRINOX therapy has a high response rate for pancreatic carcinoma, but has serious adverse effects. FOLFIRINOX therapy was administered to 11 patients with locally advanced pancreatic carcinoma at our hospital. We investigated the usefulness of primary prophylactic administration of pegfilgrastim(PegG). In the group receiving PegG, as well as with onset of neutropenia and thrombocytopenia, febrile neutropenia was reduced. Rates of anorexia and fatigue were also lower than in those who did not receive PegG. The PegG group maintained a high average relative dose intensity, as well as a high response rate. Primary prophylactic administration of PegG in FOLFIRINOX therapy is valid for pancreatic carcinoma.",
"affiliations": "Dept. of Hepato-Biliary-Pancreatic Surgery, Saitama Medical Center, Saitama Medical University.",
"authors": "Ninomiya|Riki|R|;Nakazawa|Akiko|A|;Miyata|Youichi|Y|;Mitsui|Tetsuya|T|;Komagome|Masahiko|M|;Maki|Akira|A|;Ozawa|Fumiaki|F|;Beck|Yoshifumi|Y|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D010190:Pancreatic Neoplasms; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1678-1680",
"pmc": null,
"pmid": "28133096",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Primary Prophylactic Administration of Pegfilgrastim in FOLFIRINOX Therapy for Locally Advanced Pancreatic Carcinoma.",
"title_normalized": "primary prophylactic administration of pegfilgrastim in folfirinox therapy for locally advanced pancreatic carcinoma"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2016083105",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "A 59-year-old man with nonalcoholic steatohepatitis cirrhosis underwent an orthotopic liver transplant and experienced a complicated postoperative course, including a prolonged delirium. After discharge to rehabilitation, he had 2 subsequent admissions for delirium. On the first readmission, the transplant team started the patient on risperidone and resumed treatment with sertraline. On his second readmission, neurology and psychiatry were consulted. On evaluation, the patient demonstrated signs of catatonia. On the basis of recommendations from psychiatry, the risperidone and sertraline were stopped, and the patient was started on mirtazapine. He failed to demonstrate improvement within the next 48 hours. Extensive work-up demonstrated a multifactorial etiology for his delirium, including calcineurin-related neuropsychiatric toxicity from tacrolimus leading to possible posterior reversible encephalopathy syndrome. However, after the initiation of memantine on hospital day 3-before the cessation of tacrolimus-the patient demonstrated marked improvement in mental status and motor symptoms. His magnetic resonance imaging, in addition to findings that raised concerns about posterior reversible encephalopathy syndrome, had demonstrated bilateral basal ganglia abnormalities on T1 imaging of uncertain origin. It is postulated that these findings served as predisposing factors for the patient's catatonic symptoms. Although it has been described in case reports following liver transplant, catatonia remains an underrecognized neuropsychiatric complication following liver transplant. This case demonstrates the effectiveness of memantine, an N-methyl-D-aspartic acid antagonist that decreases glutamine excitotoxicity, as a potential treatment for catatonia in postliver transplant patients.",
"affiliations": "BROWN and PREUD'HOMME: Department of Psychiatry & Behavioral Sciences and Department of Medicine, Duke University Health System, Durham, NCMUZYK: Department of Psychiatry & Behavioral Sciences, Duke University Health System, Durham, NC; Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC; and Department of Pharmacy, Duke University Hospital, Durham, NC.",
"authors": "Brown|Gregory D|GD|;Muzyk|Andrew J|AJ|;Preud'homme|Xavier A|XA|",
"chemical_list": "D018691:Excitatory Amino Acid Antagonists; D012702:Serotonin Antagonists; D018967:Risperidone; D008559:Memantine",
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "22(2)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D002389:Catatonia; D003693:Delirium; D018691:Excitatory Amino Acid Antagonists; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008559:Memantine; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D010359:Patient Readmission; D011183:Postoperative Complications; D018967:Risperidone; D012702:Serotonin Antagonists",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "128-32",
"pmc": null,
"pmid": "27138082",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolonged Delirium With Catatonia Following Orthotopic Liver Transplant Responsive to Memantine.",
"title_normalized": "prolonged delirium with catatonia following orthotopic liver transplant responsive to memantine"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0080610",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "We report an HIV-positive renal transplant recipient with delayed graft function who was converted from tacrolimus to belatacept in an attempt to improve renal function. The patient had kidney biopsies at 4 and 8 weeks posttransplant that revealed acute tubular necrosis and mild fibrosis. After 14 weeks of delayed function, belatacept was initiated and tacrolimus was weaned off. Shortly after discontinuing tacrolimus, renal function began to improve. The patient was able to discontinue dialysis 21 weeks posttransplant. HIV viral load was undetectable at last follow-up. To our knowledge, this is the first report of belatacept use in a patient with HIV.",
"affiliations": "Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY.;Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY.;Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY.;Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY.;Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY.;Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.;Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY. vinay.nair@mountsinai.org.",
"authors": "Ebcioglu|Z|Z|;Liu|C|C|;Shapiro|R|R|;Rana|M|M|;Salem|F|F|;Florman|S|S|;Huprikar|S|S|;Nair|V|V|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069594:Abatacept",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.13923",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "16(11)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; delayed graft function (DGF); fusion proteins and monoclonal antibodies: belatacept; immunosuppressant; immunosuppression/immune modulation; immunosuppressive regimens; infection and infectious agents; infectious disease; kidney transplantation/nephrology; maintenance; viral: human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000069594:Abatacept; D051799:Delayed Graft Function; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "3278-3281",
"pmc": null,
"pmid": "27328903",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Belatacept Conversion in an HIV-Positive Kidney Transplant Recipient With Prolonged Delayed Graft Function.",
"title_normalized": "belatacept conversion in an hiv positive kidney transplant recipient with prolonged delayed graft function"
} | [
{
"companynumb": "US-PFIZER INC-2017032063",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "Misoprostol is a well known abortifacient. It can cause teratogenicity like Mobius sequence and terminal transverse limb defects. We report a rare case of proximal focal femoral deficiency with fibular hemimelia in a woman who had attempted abortion with self-administered misoprostol and later continued the pregnancy. Though the absolute risk of congenital malformations with its use is low ∼1%, this should be clearly communicated to the women requesting abortion to help them make fully informed reproductive health decisions.",
"affiliations": "a Department of Obstetrics and Gynaecology , Mahatma Gandhi Medical College and Research Institute , Pillaiyarkuppam , Pondy, Cuddalore Main Road , Puducherry , India.;a Department of Obstetrics and Gynaecology , Mahatma Gandhi Medical College and Research Institute , Pillaiyarkuppam , Pondy, Cuddalore Main Road , Puducherry , India.;a Department of Obstetrics and Gynaecology , Mahatma Gandhi Medical College and Research Institute , Pillaiyarkuppam , Pondy, Cuddalore Main Road , Puducherry , India.;a Department of Obstetrics and Gynaecology , Mahatma Gandhi Medical College and Research Institute , Pillaiyarkuppam , Pondy, Cuddalore Main Road , Puducherry , India.",
"authors": "Pallavee|P|P|;Samal|Rupal|R|;Begum|Jasmina|J|;Ghose|Seetesh|S|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D016595:Misoprostol",
"country": "England",
"delete": false,
"doi": "10.3109/01443615.2016.1157152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0144-3615",
"issue": "36(6)",
"journal": "Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology",
"keywords": "Foetal; abortion; hemimelia; misoprostol",
"medline_ta": "J Obstet Gynaecol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000020:Abortifacient Agents, Nonsteroidal; D000028:Abortion, Induced; D000328:Adult; D004480:Ectromelia; D005260:Female; D005313:Fetal Death; D005333:Fetus; D005360:Fibula; D006801:Humans; D008297:Male; D016595:Misoprostol; D011247:Pregnancy",
"nlm_unique_id": "8309140",
"other_id": null,
"pages": "760-761",
"pmc": null,
"pmid": "26979810",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Foetal fibular hemimelia with focal femoral deficiency following prenatal misoprostol use: A case report.",
"title_normalized": "foetal fibular hemimelia with focal femoral deficiency following prenatal misoprostol use a case report"
} | [
{
"companynumb": "IN-NOVEL LABORATORIES, INC-2016-05697",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MISOPROSTOL"
},
"drugadditional":... |
{
"abstract": "Peak oxygen uptake (VO2peak) remains low after lung transplantation (LTx). We evaluated the effect of high-intensity interval training (HIIT) on VO2peak, muscular strength, health-related quality of life (HRQOL), pulmonary function, and physical function after LTx.\n\n\n\nIn this randomized controlled trial, 54 participants were enrolled from 6 to 60 months after LTx. The HIIT group (n = 25) followed a supervised HIIT program, consisting of endurance and strength trainings 3 times a week for 20 weeks. The control group (n = 29) received usual care. The primary outcome was a change in VO2peak measured by cardiopulmonary exercise testing. The secondary outcomes were changes in 1-repetition maximum (1RM) for arm press and leg press, HRQOL (36-Item Short-Form Health Survey [SF-36]), pulmonary function (forced expiratory volume in 1 sec, diffusing capacity of the lungs for carbon monoxide), and physical function (1RM in handgrip, 15-sec stair run, and 30-sec chair stand).\n\n\n\nA total of 46 participants completed the study, including 23 of 25 in the intervention group. For the primary outcome, the intention-to-treat analysis revealed a non-significant between-group difference for change in VO2peak of 0.7 ml/(kg.min) (95% CI = ‒0.3, 1.8) (p = 0.17). The between-group differences for 1RM arm press and leg press and mental aspect of SF-36 were 4.9 kg (95% CI = ‒0.1, 9.9) (p = 0.05), 11.6 kg (95% CI = 0.1, 23.0) (p < 0.05), and 5.7 kg (95% CI = 0.9, 10.4) (p = 0.02), respectively. There were no between-group differences in pulmonary function or physical function. When excluding participants with an attendance of <70% (n = 16), the between-group difference for VO2peak was 1.2 ml/(kg.min) (95% CI = 0.1, 2.4) (p = 0.032).\n\n\n\nHIIT improved muscular strength and HRQOL but did not improve VO2peak more than usual care after LTx. However, with acceptable adherence, HIIT appears to have beneficial effects on VO2peak.",
"affiliations": "Department of Respiratory Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: mariannulv@gmail.com.;Department of Respiratory Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.;Department of Respiratory Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.;Department of Respiratory Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.;Department of Sports Medicine, Norwegian School of Sport and Sciences, Oslo, Norway; Department of Pulmonary Medicine, Oslo University Hospital Ullevål, Oslo, Norway.",
"authors": "Ulvestad|Mariann|M|;Durheim|Michael T|MT|;Kongerud|Johny S|JS|;Lund|May B|MB|;Edvardsen|Elisabeth|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.healun.2020.06.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "39(9)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": "cardiorespiratory fitness; high-intensity exercise training; lung transplantation; muscular strength; randomized controlled trial",
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D005080:Exercise Test; D005081:Exercise Therapy; D005260:Female; D005500:Follow-Up Studies; D000072696:High-Intensity Interval Training; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D053580:Muscle Strength; D010101:Oxygen Consumption; D011183:Postoperative Complications; D011788:Quality of Life",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "859-867",
"pmc": null,
"pmid": "32674956",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of high-intensity training on peak oxygen uptake and muscular strength after lung transplantation: A randomized controlled trial.",
"title_normalized": "effect of high intensity training on peak oxygen uptake and muscular strength after lung transplantation a randomized controlled trial"
} | [
{
"companynumb": "NVSC2020NO203746",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "A 48-year-old female with a past history of systemic lupus erythematosus had developed autoimmune hepatitis (AIH) at the age of 45 years, and administration of PSL 30 mg/day was initiated. However, AIH exacerbation was suspected based on elevation of hepatic and biliary tract enzymes such as ALP (1207U/L) with a fever of 38 degrees C after tapering off the steroids to PSL 7.5 mg daily, and she was thus hospitalized. A liver biopsy was recommended, but she refused. Thus, we suspected concomitant AIH and autoimmune cholangitis (AIC). Although high-dose steroid treatment including steroid pulse therapy was administered, there was no improvement. We performed a liver biopsy on the 66th hospital day, after obtaining the patient's consent. Epithelioid granuloma was detected in the liver leaflet as the background of the AIH and AIC findings. In addition, acid fast bacteria were detected with auramine and Ziehl-Neelsen staining, raising the possibility of tuberculosis. Additionally, granuloma was also seen in her bone marrow, and miliary tuberculosis was suspected. Anti-tuberculous therapy with isoniazid, rifampicin, ethambutol and pyrazinamide was initially administered, but the regimen was changed to levofloxacin, ethambutol, and streptomycin due to the side effects of the earlier medications. Liver functions improved and the inflammatory reaction became negative. The patient was discharged on the 138th hospital day. Ultimately, no acid fast bacteria were detected with culture, PCR of her bone marrow, or liver biopsy. However, miliary tuberculosis was definitively diagnosed from the pathological findings and her clinical course. AIH was an underlying disease, and the discrimination from AIH exacerbation was difficult. Consequently, the diagnosis was miliary tuberculosis without the lung involvement and the main lesion was in the liver. It is important to take account of miliary tuberculosis in the differential diagnosis of fevers of unknown origin with elevation of hepatic and biliary tract enzymes, and to make a definitive diagnosis with a liver biopsy.",
"affiliations": null,
"authors": "Yamashita|Hiroyuki|H|;Ueda|Yo|Y|;Takahashi|Yuko|Y|;Mimori|Akio|A|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin",
"country": "Japan",
"delete": false,
"doi": "10.11150/kansenshogakuzasshi.88.459",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-5911",
"issue": "88(4)",
"journal": "Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases",
"keywords": null,
"medline_ta": "Kansenshogaku Zasshi",
"mesh_terms": "D000995:Antitubercular Agents; D003937:Diagnosis, Differential; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D007538:Isoniazid; D008168:Lung; D008875:Middle Aged; D012293:Rifampin; D014391:Tuberculosis, Miliary",
"nlm_unique_id": "0236671",
"other_id": null,
"pages": "459-62",
"pmc": null,
"pmid": "25199380",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A miliary tuberculosis case without lung involvement difficult to distinguish from autoimmune hepatitis exacerbation.",
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"abstract": "A 46-year-old female patient with a known HIV-2-infection suffered from adult onset Still's disease, which was initially complicated by a macrophage activation syndrome (MAS). The required glucocorticoid treatment induced a psychosis and the patient developed an aversion to glucocorticoids. After failure of treatment with anakinra, an alternative option with the JAK-inhibitor tofacitinib was introduced because of the short half-life and to reduce glucocorticoid exposure. A switch to tofacitinib was only successful after an overlapping treatment with anakinra and tofacitinib for 3 weeks. The patient is currently being treated with monotherapy with tofacitinib as well as NSAID on demand, is in stable remission and can continue working as normal.",
"affiliations": "MVZ Endokrinologikum Berlin am Gendarmenmarkt, Friedrichstr. 76, 10117, Berlin, Deutschland. paula.hoff@endokrinologikum.com.;MVZ Endokrinologikum Berlin am Gendarmenmarkt, Friedrichstr. 76, 10117, Berlin, Deutschland.;HIV-Ambulanz-Praxis, Ambulantes Gesundheitszentrum der Charité am Campus Virchow, Berlin, Deutschland.;MVZ Endokrinologikum Berlin am Gendarmenmarkt, Friedrichstr. 76, 10117, Berlin, Deutschland.;Helios Fachklinik Vogelsang-Gommern, Vogelsang-Gommern, Deutschland.;Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Deutschland.",
"authors": "Hoff|P|P|;Walther|M|M|;Wesselmann|H|H|;Weinerth|J|J|;Feist|E|E|;Ohrndorf|S|S|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib",
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"doi": "10.1007/s00393-020-00853-9",
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"issn_linking": "0340-1855",
"issue": "79(10)",
"journal": "Zeitschrift fur Rheumatologie",
"keywords": "Adult-onset Still’s disease (AODS); Combination of JAK inhibitor and bDMARD; HIV; Rheumatoid arthritis; Tofacitinib",
"medline_ta": "Z Rheumatol",
"mesh_terms": "D000328:Adult; D005260:Female; D015658:HIV Infections; D015498:HIV-2; D006801:Humans; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D016706:Still's Disease, Adult-Onset; D016896:Treatment Outcome",
"nlm_unique_id": "0414162",
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"pages": "1046-1049",
"pmc": null,
"pmid": "32816071",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of adult Still's disease with tofacitinib in a HIV-2 positive female patient.",
"title_normalized": "successful treatment of adult still s disease with tofacitinib in a hiv 2 positive female patient"
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"abstract": "In patients with organ transplantation as compared to the general population the risk of cancer is significantly increased. The most common changes are malignant tumors of the skin, constituting 30-65% of malignant tumors found in recipients. Potential risk factors for skin cancer after a transplant operation are: solar radiation, immunosuppressive therapy, genetic factors, infection with HPV and skin cancer transmission before transplantation. In contrast to the immunocompetent population, skin cancers in transplant recipients are dominated by squamous cell carcinoma, followed by basal cell carcinoma. Squamous cell carcinoma in patients after transplantation is characterized by a strong tendency to give local recurrences and distant metastases. Due to the high risk of developing skin cancer in transplant recipients, preventive oncology plays an important role in the long-term care of patients after transplantation. This includes: sun protection, education, and early treatment of patients with precancerous lesions. It is also stressed that systematic dermatologic studies need to be carried out in patients after transplantation surgery. The paper contains basic information about skin cancers in organ transplant recipients: epidemiology, potential risk factors, treatment and prognosis. The paper presents also a case of patient who developed squamous cell carcinoma of the skin 3 years after renal transplantation.",
"affiliations": "Department of Plastic, Reconstructive and Aesthetic Surgery, Collegium Medicum , Nicolaus Copernicus University, Bydgoszcz, Poland. Head: Prof. Henryk Witmanowski MD, PhD ; Department of Physiology, Poznan University of Medical Sciences, Poland. Head: Prof. Hanna Krauss MD, PhD.",
"authors": "Witmanowski|Henryk|H|;Lewandowska|Małgorzata|M|;Szychta|Paweł|P|;Sporny|Stanisław|S|;Rykała|Jan|J|",
"chemical_list": null,
"country": "Poland",
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"doi": "10.5114/pdia.2013.33383",
"fulltext": "\n==== Front\nPostepy Dermatol AlergolPostepy Dermatol AlergolPDIAAdvances in Dermatology and Allergology/Postȩpy Dermatologii I Alergologii1642-395X2299-0046Termedia Publishing House 2029410.5114/pdia.2013.33383Case ReportThe development of squamous cell carcinoma in a patient after kidney transplantation: a case report Witmanowski Henryk 12Lewandowska Małgorzata 3Szychta Paweł 4Sporny Stanisław 5Rykała Jan 41 Department of Plastic, Reconstructive and Aesthetic Surgery, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland. Head: Prof. Henryk Witmanowski MD, PhD2 Department of Physiology, Poznan University of Medical Sciences, Poland. Head: Prof. Hanna Krauss MD, PhD3 Department of Pathology of the Age of Development, Medical University of Lodz, Poland. Head: Prof. Józef Kobos MD, PhD4 Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Lodz, Poland. Head: Prof. Bogusław Antoszewski MD, PhD5 Department of Dental Pathology, Medical University of Lodz, Poland. Head: Prof. Stanisław Sporny MD, PhDAddress for correspondence: Henryk Witmanowski MD, PhD, Department of Plastic, Reconstructive and Aesthetic Surgery, Collegium Medicum, Nicolaus Copernicus University, 9-11 M. Skłodowskiej-Curie Str., 85-094 Bydgoszcz, Poland. phone: +48 52 585 40 17. e-mail: hewit7@wp.pl20 2 2013 2 2013 30 1 65 71 30 11 2012 10 12 2012 10 2 2013 Copyright © 2013 Termedia2013This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.In patients with organ transplantation as compared to the general population the risk of cancer is significantly increased. The most common changes are malignant tumors of the skin, constituting 30-65% of malignant tumors found in recipients. Potential risk factors for skin cancer after a transplant operation are: solar radiation, immunosuppressive therapy, genetic factors, infection with HPV and skin cancer transmission before transplantation. In contrast to the immunocompetent population, skin cancers in transplant recipients are dominated by squamous cell carcinoma, followed by basal cell carcinoma. Squamous cell carcinoma in patients after transplantation is characterized by a strong tendency to give local recurrences and distant metastases. Due to the high risk of developing skin cancer in transplant recipients, preventive oncology plays an important role in the long-term care of patients after transplantation. This includes: sun protection, education, and early treatment of patients with precancerous lesions. It is also stressed that systematic dermatologic studies need to be carried out in patients after transplantation surgery. The paper contains basic information about skin cancers in organ transplant recipients: epidemiology, potential risk factors, treatment and prognosis. The paper presents also a case of patient who developed squamous cell carcinoma of the skin 3 years after renal transplantation.\n\nskin cancerssquamous cell carcinomabasal cell carcinomakidney transplantationimmunosuppression\n==== Body\nIntroduction\nPatients undergoing transplant surgery are a group with an increased risk of cancer. Cancers in transplant recipients are 3-4 times more likely than in the the general population and are one of the main causes of death in this group of patients [1]. It should also be noted that patients with organ transplants have an increased risk of certain but not all cancers. Cancers the risk of which is higher in recipients include: skin cancers, lymphomas, cancers of the urinary tract, gastrointestinal tract, larynx and bronchi [2, 3]. However, breast and prostate cancers have similar incidence in recipients compared to general population [4].\n\nThe paper contains basic information about skin cancers in organ transplant recipients: epidemiology, potential risk factors, treatment and prognosis. The paper presents also a case of patient who developed squamous cell carcinoma of the skin 3 years after renal transplantation.\n\nEpidemiology\nSkin cancers are the most common malignant changes in patients after organ transplantation [5]. Thirty–sixty-five percent of cancers are those found in recipients [6–9], and the type of organ transplant appears to have a significant effect on the occurrence of cancer. The risk of developing skin cancer in renal transplant recipients is higher than in the liver transplant recipients, but lower as compared to patients after heart transplantation [10–12]. Among recipients dominates squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) [13, 14], rarely are diagnosed elanoma, Kaposi's sarcoma and Merkel's cell carcinoma [15, 16]. In contrast to the immunocompetent population, SCC is more common in transplant recipients than BCC. The incidence ratio of squamous cell carcinoma (SCC) as compared to BCC in patients after transplantation is 3.8: 1 and 1: 4 in the general population [17].\n\nThe incidence of skin cancer is increasing with time after transplantation, and will vary depending on the geographical region. In Australia, 10 years after transplantation, cancer of skin was found in 45%, and after 20 years – in 75% of recipients [5]. The incidence of skin cancer in European countries as compared to Australia is lower and in the Netherlands, England and Italy it is 10-15% 10 years after transplantation [18–20]. In the German population, 10 years after transplantation skin cancer develops in 4.8% of recipients, after 20 years – in 8.8% [21]. However, in Asian countries, this type of cancer practically does not exist. Webb et al. found no SCC and BCC in 14% of patients of Asian and Afro-Caribbean patients, selected from a group of 1069 respondents. The incidence of skin cancer among other Caucasian patients was 16% at 10 years and 52% 20 years after the grafting [22]. The apparent connection between the disease and the latitude is closely related to exposure to solar radiation.\n\nRisk factors for the development of skin cancer in organ transplant recipients: immunosuppressive drugs, solar radiation, genetic factors, history of skin cancer before transplantation, HPV infection.\n\nImmunosuppressive therapy is undoubtedly one of the most important risk factors for cancer in organ transplant recipients. The effect of immunosuppressive therapy on tumor formation is both indirect and direct. Immunosuppression impairs organ recipient response to emerging cancer cells. In addition, immunosuppressive agents can act directly by not fully known mechanisms [15].\n\nCurrently, there are no clear data on the relationship between the treatment regimen and the risk of cancer. Numerous studies comparing two immunosuppressive regimens (first based on azathioprine (AZA), the second on cyclosporine (CsA)) reported a higher incidence of tumors in the CsA-treated group than in the group treated with AZA [23–28]. Shuttleworth et al. observed a higher incidence of skin dysplasia in recipients receiving CsA as compared to those receiving AZA [26]. Glover et al. showed a higher risk of SCC development and early development of cancer in patients who were treated with triple therapy (CsA + AZA + Pred (prednisolone)) than in the group which used Pred + AZA [27]. Similarly, Hiesse et al. showed an earlier and significantly higher incidence of non-melanoma skin cancer (NMSC) in patients treated with CsA [25]. Published studies also show that the incidence of skin cancers in recipients treated with AZA is comparable to the frequency of cancer development in patients treated with CsA [1, 28–30].\n\nIt seems that the drug the use of which may be associated with a lower risk of developing cancer as compared to AZA is mycophenolate mofetil (MMF). Studies comparing the group treated with AZA with an MMF-treated group favored MMF [31–34]. At a conference in Washington in 2004, Ulrich and Stockfleth presented the results of prospective studies on the development of cancer in kidney and heart transplant recipients receiving triple immunosuppression (CsA + AZA + Pred/CsA + MMF + Pred/TAC (tacrolimus) + AZA + Pred/TAC + MMF + Pred). The study material included 1500 recipients. A significantly lower incidence of SCC in patients treated with TAC + MMF + Pred as compared to patients treated with TAC + AZA + Pred was observed. In the group of recipients receiving CsA + MMF + Pred, a lower percentage of tumors was reported than in the group receiving CsA + AZA + Pred, although the difference was not statistically significant [31]. A lower incidence of cancer in patients treated with MMF as compared to AZA-treated patients confirmed the data from two registers: OPTN/UNOS (Organ Procurement and Transplant Network/United Network for Organ Sparing) and CTS (Collaborative Transplant Study) [31, 32]. The results in cited reports suggest higher oncological safety in renal transplant patients receiving MMF. Therefore, in transplant recipients at high risk of developing skin cancer AZA is often replaced by MMF [31].\n\nIn the case of TAC, a relatively low but increasing incidence of cancer was shown. The analysis of the OPTN/UNOS, which evaluated more than 62 thousand kidney transplants performed in 1998-2003, showed a smaller percentage of skin cancers and solid tumors in patients treated with TAC as compared to those treated with CsA [33]. Cowlrick et al. analyzed five prospective multicenter studies with TAC as the primary immunosuppressant. Among 2435 recipients treated with regimens: TAC + GS + AZA or TAC + MMF + GS, after a year of observation, cancer developed in 1.63%, after 2 years in 2.55% and after 3 years in 3.4% of transplant recipients. Skin cancers accounted for 37.3% of all cancers [35].\n\nAlthough so far it has been failed to clearly prioritize individual drugs according to their impact on the development of skin cancer, most authors agree on one thing, namely occurrence of cancer in transplant recipients is affected by the exposure time and the level of immunosuppression [15, 23, 36]. Patients receiving immunosuppressive drugs for a period of 5 years or longer [37] as well as the heart recipients, who have a higher level of immunosuppression [15, 23] are more likely to suffer from skin cancer.\n\nUltraviolet radiation is one of the better-known factors that cause the development of skin cancer in both the immunocompetent population and in organ transplant recipients [38, 39].\n\nSo far, many conflicting results have been published in studies evaluating the association of HLA risk of developing skin cancer in transplant recipients. A few works have shown a greater incidence of SCC among the recipients with such antigens as HLA-A11, -B27, -DR7 [37, 40, 41], by homozygote DR and in the case of incompatibility of antigens HLA-B between the donor and the recipient [40]. Other authors did not observe such a relationship [23, 42, 43]. One report suggests the protective effect of HLA-A11 antigen on the development of SCC [44]. More and more authors are inclined to take a position that there is no relationship between HLA antigens and the development of skin cancer after transplantation [23, 42].\n\nGenetic factors beyond the influence of HLA include the influence of antioxidant enzyme activity of GST (Glutathione-s-transferase). This enzyme inhibits the effects of free radicals, which are formed after exposure to UV radiation. This suggests the influence of polymorphisms of genes GSTM1, GSTT1 and GSTP1 on the development of SCC in patients after renal transplantation. The study conducted by Ramsay et al. has shown a correlation between the GSTM1 gene and an increased risk of SCC, especially in patients exposed to sunlight [45, 46].\n\nDanpanich and Kasiske observed a twofold increase in the risk of developing skin cancer in transplant recipients with a history of skin cancer [47]. According to the Clinical Transplant Tumor Registry, skin cancer (NMSC or melanoma) developed in 62% of patients after a transplant, who had been treated for cancer of the skin in the past [48].\n\nPrevention and treatment\nAn important issue in the care of chronic patients after organ transplantation is the selection of recipients at high risk of developing cancer and preventive oncology. Ways to reduce the risk of developing skin cancer in transplant recipients include:avoid exposure to UV radiation and use sun protection [5, 14, 49],\n\ntreatment of precancerous lesions [5, 49],\n\ntreatment of HPV infection [50].\n\n\n\n\nIn theory, reduction of exposure to UV radiation seems to be the simplest way. Organ recipients need to be educated about the need to use sunscreens and have periodic self-control. It turns out, however, that it is often an insufficient procedure practiced by patients. Studies have shown that only 40% of recipients follow sunscreen recommendations, and 90% use protective sunblocks with too low SPF [51].\n\nTreatment of skin cancers in organ transplant recipients consists of two basic strategies: to restore the efficiency of the immune system and to remove the tumor. The first of these objectives can be achieved by reduction in immunosuppression. The second objective is achieved by means of surgery, and sometimes radiotherapy. Dose reduction of immunosuppressive drugs is used in cases of SCC with a high risk of local recurrence or metastases (multiple tumors, low-differentiated, tumor size > 2 cm, the depth of infiltration of 3-4 mm, location on the forehead, ears, lips). Patients with SCC without high-risk factors may require surgery only [15].\n\nCase report\nA 54-year-old patient with end-stage renal disease in the course of diabetic nephropathy. Type 1 diabetes was diagnosed at the age of 28 years while she was treated in the Department of Internal Medicine in Zgierz (1983) due to urinary tract infections and dermatitis due to vitamin B complex administration. The treatment with ultralente and semilente insulin was introduced. In 1998, she was treated with radioiodine because of goiter. In December 2000, she was hospitalized in the Dialysis Center in Zgierz because of a severe heart failure in the form of lower leg edema. She had symptoms of kidney failure (increased urea and creatinine values). In an anamnesis, beside the complications of diabetes: nephropathy and hallux amputation of the right (diabetic) foot, high blood pressure was noted. She was treated by peritoneal dialysis renal replacement therapy from July 2002 to December 2003. On 31 December 2003 in the Department of Urology and Transplantation, allogeneic renal transplantation was performed. Immunosuppression regimen of prednisone + cyclosporine + azathioprin was used.\n\nIn 2005, she was treated in the Department of General Surgery in Zgierz due to an ulcer of the right hand back. The histopathological diagnosis was: ulceratio et granulatio. In February 2006, she was treated again because of the right hand ulcer, this time in histopathology: SCC invasivum G2, excisio incompleta. In April 2006, in the Department of Surgery and Oncological Gynecology, Medical University in Lodz, a radical excision was performed, and the defect was covered with a skin graft. In February 2009, there was a recurrence of skin cancer. In the Department of Plastic Surgery, Medical University in Lodz, a lump in the angle of the left eye was excised (Figure 1). Histological examination confirmed the suspicion of recurrence: carcinoma planoepitheliale praeinvasivum (Figure 2), but unfortunately there was no radical surgery, so in April the scar was widely excised and no cancer cells were found in histopathology, but features of keratosis senilis (keratosis senilis typus atrophicus) were observed (Figure 3). In December 2009, a small ulcer appeared at the skin graft on the back of the right hand, excision was performed and evaluated histopathologically: ca planoepitheliale intraepidermale (morbus Boweni) and elastosis cutis (Figure 4) was found. In March 2010, she was treated due to tumor of the nose with the following diagnosis: hyperplasia epithelii planners cum dysplasia gravis atque hyperkeratosi (Figure 5).\n\nFigure 1 A, B Women 59 years old. Dg.: Tumor of the left angle of the eye\n\nFigure 2 Ca planoepitheliale praeinvasivum. Staining: H + E, magnification 120×\n\nFigure 3 “Senile” keratosis: atrophic type of elastosis in the dermis. Staining: H + E, magnification 500×\n\nFigure 4 Bowen's disease. Staining: H + E, magnification 320×\n\nFigure 5 Acanthocytic epidermal hyperplasia with severe dysplasia and hyperkeratosis. Staining: H + E, magnification 200×\n\nDiscussion\nThis case is an illustration of an increased risk of cancer recurrence in organ recipients. In approximately 50% of patients after transplantation, SCC develops change as the plural [2, 52] with an aggressive course and tendency to frequent recurrence and metastasis [2, 53, 54]. The study, which covered 2075 Dutch recipients showed the development of skin cancer in 53% of patients. In 48% of patients after treatment another cancer of the same or different type of pathology developed. During follow-up 2 patients died: 1 due to SCC and 1 patient due to Merkel cells carcinoma metastases to the lung [55]. Aggressive cancerous disease was also reported by Australian researchers. Veness et al. reported that skin cancer developed in 41% of the observed recipients, half of these patients died [56]. According to another Australian study, skin cancer was the cause of death of 27% of recipients. Follow-up was 4 years [57]. However, Californian authors observed aggressive cancerous disease in 13% of patients after transplantation [58].\n\nIn the context of the presented patient it seems very important to screen for skin cancer in organ transplant recipients. In these patients, physical examination of the skin should be performed every 12 months [5, 15]. According to Otley and Berg, in cases where there are no other known risk factors for cancer except immunosuppression, the search for cancer and premalignant skin changes should be a part of the routine performed by the patient. Only patients with a high risk of developing skin cancer after transplantation should be referred to a dermatologist [15]. However, Dreno takes a position that dermatological care should be offered to all recipients of organs [5]. Monthly self-control in transplant patients is also recommended.\n\nSecondary prevention for recipients should include regular visits to the dermatologist every 6 months. According to the US recommendations, this interval should be shorter in the case of multiple tumors (2-4 months), a high risk of relapse (3 months), melanoma (2-3 months) and the presence of metastases (2 months) [15]. In recipients of multiple organs and/or recurrent skin cancer, prevention can be effective using systemic retinoid therapy, such as isotretin and recently acitretin [59, 60]. A randomized study performed on a small group of recipients showed a significant decrease in the number of new cases of SCC in patients treated with acitretin. During a 6-month follow-up, SCC developed in 2 patients treated with acitretin and in 18 in the placebo group [61]. Mc Kenna and Murphy confirmed a significant reduction in new cases of skin cancer after using acitretin. During a 5-year follow-up, the authors reported no serious side effects of this drug therapy [60]. Last but not least, remember that because of the numerous side effects of acitretin, such as liver failure or hyperlipidemia, observation of patients during therapy is required [59, 62].\n\nConclusions\nTransplant patients incur a higher risk of developing skin cancer as compared to the general population. Therefore, in the case of organ transplant, recipients should apply increased oncological vigilance. In recipients treated for skin cancer, recurrence of the disease is often observed. Therefore, it is very important to have regular dermatological control, enabling early diagnosis and effective therapy, thus to prevent a potential cancer recurrence.\n==== Refs\nReferences\n1 Sheil AG Development of malignancy following renal transplantation in Australia and New Zealand Transplant Proc 1992 24 1275 9 1496562 \n2 Penn I Post-transplant malignancy: the role of immunosuppression Drug Saf 2000 23 101 13 10945373 \n3 Penn I Cancers in renal transplant recipients Adv Ren Replace Ther 2000 7 147 56 10782732 \n4 Penn I Brunson ME Cancers after cyclosporine therapy Transplant Proc 1988 20 Suppl 3 885 92 3388524 \n5 Dreno B Skin cancers after transplantation Nephrol Dial Transplant 2003 18 1052 8 12748333 \n6 Penn I Post-transplant malignancies Transplant Proc 1999 31 1260 2 10083562 \n7 Birkeland SA Storm HH Lamm LU Cancer risk after renal transplantation in the Nordic countries, 1964-1986 Int J Cancer 1995 60 183 9 7829213 \n8 Gruber SA Gillingham K Sothern RB De novo cancer in cyclosporine-treated adult primary renal allograft recipients Clin Transplant 1994 8 388 95 7949545 \n9 Machnicki G Lentine KL Salvalaggio PR Kidney transplant Medicare payments and length of stay: associations with comorbidities and organ quality Arch Med Sci 2011 7 278 86 22291768 \n10 Jansen P Hansen S Moller B Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens J Am Acad Dermatol 1999 40 177 86 10025742 \n11 Gjersvik P Hansen S Moller B Are heart transplant recipients more likely to develop skin cancer than kidney transplant recipients? Transplant Int 2000 13 Suppl 1 380 1 \n12 Penn I Posttransplantation de novo tumors in liver allograft recipients Liver Transpl Surg 1996 2 52 9 9346628 \n13 Wyrzykowska N Rosińska-Więckowicz A Bartoszak L Bowen's disease and basal cell carcinoma in a renal transplant recipient – case report Postep Derm Alergol 2011 28 138 141 \n14 Witmanowski H Lewandowicz E Sobieszek D Facial skin cancers: general information and an overview of treatment methods Postep Derm Alergol 2012 29 240 55 \n15 Berg D Otley CC Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management J Am Acad Dermatol 2002 47 1 17 12077575 \n16 Douds AC Mellotte GJ Morgan SH Fatal Merkel-cell tumour (cutaneous neuroendocrine carcinoma) complicating renat transplantation Nephrol Dial Transplant 1995 10 1717 21 \n17 Ramsay HM Fryer AA Reece S Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients Am J Kidney Dis 2000 36 167 10873887 \n18 Hartevelt MM Bavinck JN Kootte AM Incidence of skin cancer after renal transplantation in the Netherlands Transplantation 1990 49 506 9 2316011 \n19 Naldi L Fortina AB Lovati S Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study Transplantation 2000 70 1479 84 11118094 \n20 London NJ Farmery SM Will EJ Risk of neoplasia in renal transplant patients Lancet 1995 346 403 6 7623570 \n21 Behrend M Kolditz M Kliem V Malignancies in patients under long-term immunosuppression after kidney transplantation Transplant Proc 1997 29 834 5 9123546 \n22 Webb MC Comptom F Andrews PA Koffman CG Skin tumours posttransplantation: a retrospective analysis of 28 year's experience at a single centre Transplant Proc 1997 29 828 30 9123544 \n23 Jensen P Hansen S Moller B Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regiment J Am Acad Dermatol 1999 40 177 86 10025742 \n24 Schmidt R Stippel D Schmitz-Rixen T Pollok M Tumors after renal transplantation Urol Int 1996 57 21 6 8840486 \n25 Hiesse C Larue JR Kriaa F Incidence and type of malignancies occurring after renal transplantation in conventionally and in cyclospone-treated recipients: single-center analysis of a 20-year period in 1600 patients Transplant Proc 1995 27 2450 1 7652877 \n26 Shuttleworth D Marks R Griffin PJ Salaman JR Epidermal dysplasia and cyclosporine therapy in renal transplant patients: a comparison with azathioprine Br J Dermatol 1989 120 551 4 2525045 \n27 Glover MT Deeks JJ Raftery MJ Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients Lancet 1997 34 398 9033469 \n28 Bouwes Bavinck JM Hardie DR Green A The risk of skin cancer in renal transplant recipients in Queensland, Australia: a follow-up study Transplantation 1996 61 715 21 8607173 \n29 Fortina AB Caforio AL Piaserico S Skin cancer in heart transplant recipients: frequency and risk factor analysis J Heart Lung Transplant 2000 19 249 55 10713249 \n30 Gruber SA Gillingham K Sothern RB De novo cancer in cyclosporine-treated and non-cyclosporine-treated adult primary Clin Transplant 1994 8 388 95 7949545 \n31 Ulrich C Stockfleth E Azathioprine, UV light, and skin cancer in organ transplant patients – do we have an answer? Nephrol Dial Transplant 2007 22 1027 9 17234668 \n32 Buell JF Gross TG Woodle ES Malignancy after transplantation Transplantation 2005 80 Suppl 2 254 64 \n33 Kauffman HM Cherikh WS McBride MA Post-transplant de novo malignancies in renal transplant recipients: the past and present Transplant Int 2006 19 607 20 \n34 Robson G Cecka JM Opelz G Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil Am J Transplant 2005 5 2954 60 16303010 \n35 Cowlrick I Delventhal H Kaipainen K Three-year follow-up of malignancies in tacrolimus-treated renal recipients – an analysis of European multicentre studies Clin Transplant 2008 22 372 7 18279418 \n36 Zamanian A Farshchian M Neoplastic skin lesions in Iranian renal transplant recipients: the role of immunosuppressive therapy J Drugs Dermatol 2007 6 703 6 17763593 \n37 Czarnecki D Watkins F Leahy S Skin cancers and HLA frequencies in renal transplant recipients Dermatology 1992 185 9 11 1638083 \n38 Jenerowicz D Silny W Dańczak-Pazdrowska A Environmental factors and allergic diseases Ann Agric Environ Med 2012 19 475 81 23020042 \n39 Śpiewak R The substantial differences between photoallergic and phototoxic reactions Ann Agric Environ Med 2012 19 888 9 23311823 \n40 Bouves Bavinck JN Vermeer BJ Van der Woude J Relation between skin cancer and HLA antigens in renal-transplant recipients N Engl J Med 1991 325 843 8 1875968 \n41 Bavinck JNB Class FHJ Hardie DR Relation between HLA antigens and skin cancer in renal transplant recipients in Queensland, Australia J Invest Dermatol 1997 108 708 11 9129219 \n42 Dyall-Smith D Ross JB Cutaneous malignancies in renal transplant recipients from Nova. Scotia, Canada Aust J Dermatol 1995 36 79 82 \n43 Glover MT Bodmer J Bodmer W HLA antigen frequencies in renal transplant recipients and non-immunosuppressed patients with non-melanoma skin cancer Eur J Cancer 1993 29A 520 4 8435203 \n44 Bavinck JNB Kootte AMM Van der Woude FJ On a possible protective effect of HLA-A11 against skin cancer and keratotic skin lesions in renal transplant recipients J Invest Dermatol 1991 97 269 72 1649229 \n45 Ramsay HM Harden PN Reece S Polymorphisms in glutathione S-transferases are associated with altered risk of nonmelonoma skin cancer in renal transplant recipients: a preliminary analysis J Invest Dermatol 2001 117 251 5 11511301 \n46 Osmola-Mańkowska A Silny W Dańczak-Pazdrowska A The sun – our friend or foe? Ann Agric Environ Med 2012 19 805 9 23311812 \n47 Danpanich E Kasiske BL Risk factors for cancer in renal transplant recipients Transplantation 1999 68 1859 64 10628765 \n48 Penn I Malignant melanoma in organ allograft recipients Transplantation 1996 61 274 8 8600636 \n49 Rubel JR Milford EL Abdi R Cutaneous neoplasms in renal transplant recipients Eur J Dermatol 2002 12 532 5 12459521 \n50 Hardwood CA Surentheran T McGregor JM Human papilloma virus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals J Med Virol 2000 61 289 97 10861635 \n51 Butt A Roberts DL Renal transplant recipients and protection from sun: need for education Lancet 1997 349 179 80 9111550 \n52 Ramsay HM Fryer AA Hawley CM Epidemiology and Health Services Research, Nonmelanoma skin cancer risk in the Queensland renal transplant population Br J Dermatol 2002 147 950 6 12410706 \n53 Euvrard S Kanitakis J Pouteil-Noble C Aggressive squamous cell carcinomas in organ transplant recipients Transplant Proc 1995 27 1767 8 7725494 \n54 Adamson R Obispo E Dychter S High incidence and clinical course of aggressive skin cancer in heart transplants: a single-center study Transplant Proc 1998 30 1124 6 9636456 \n55 Winkelhorst JT Brokelman WJ Tiggeler RG Incidence and clinical course of de-novo malignancies in renal allograft recipients Eur J Surg Oncol 2001 27 409 13 11417989 \n56 Veness MJ Quinn DI Ong CS Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience Cancer 1999 85 1758 64 10223570 \n57 Ong CS Keogh AM Kossard S Skin cancer in Australian heart transplant recipients J Am Acad Dermatol 1999 40 27 34 9922009 \n58 Pollard JD Hanasono MM Mikulec AA Head and neck cancer in cardiothoracic transplant recipients Laryngoscope 2000 110 1257 61 10942122 \n59 Di Giovanna JJ Posttransplantation skin cancer: scope of the problem, management, and role for systemic retinoid chemoprevention Transplant Proc 1998 30 2771 5 9745564 \n60 McKenna DB Murphy GM Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin Br J Dermatol 1999 140 656 60 10233316 \n61 Bavinck JN Tieben LM Van der Woude FJ Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study J Clin Oncol 1995 13 1933 8 7636533 \n62 Di Giovanna JJ Retinoid chemoprevention in high-risk skin cancer patients J Am Acad Dermatology 1998 39 Suppl 1 82 5\n\n",
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"journal": "Postepy dermatologii i alergologii",
"keywords": "basal cell carcinoma; immunosuppression; kidney transplantation; skin cancers; squamous cell carcinoma",
"medline_ta": "Postepy Dermatol Alergol",
"mesh_terms": null,
"nlm_unique_id": "101168357",
"other_id": null,
"pages": "65-71",
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"pmid": "24278050",
"pubdate": "2013-02",
"publication_types": "D002363:Case Reports",
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"title": "The development of squamous cell carcinoma in a patient after kidney transplantation: a case report.",
"title_normalized": "the development of squamous cell carcinoma in a patient after kidney transplantation a case report"
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"abstract": "BACKGROUND\nRelapse after achieving virologic response to anti-hepatitis C virus (HCV) treatment considerably reduces sustained virologic response rates. It is unclear what the main predictors of relapse in HCV/HIV-coinfected patients are.\n\n\nMETHODS\nThe Pegasys Ribavirina España Coinfección (PRESCO) study evaluated short and extended duration of treatment for chronic hepatitis C using pegylated interferon (peg-IFN)-alpha2a at a dose of 180 microg/wk plus weight-based ribavirin (RBV) at a dose of 1000 to 1200 mg/d in HIV-infected subjects. Patients with HCV-2/3 were treated for 6 or 12 months, and patients with HCV-1/4 were treated for 12 or 18 months.\n\n\nRESULTS\nOf 389 patients included in the trial, end-of-treatment response was achieved by 262 (67.3%): 106 with HCV-1 (55%), 137 with HCV-2/3 (90%), and 19 with HCV-4 (41%). Six patients were lost to follow-up after completing therapy. Of the remaining 256 patients, 62 (24%) relapsed: 33% of HCV-1 patients, 18% of HCV-2/3 patients, and 21% of HCV-4 patients. In multivariate logistic regression analysis, baseline serum HCV RNA level > or =500,000 IU/mL (relative risk [RR] = 4.81, 95% confidence interval [CI]: 1.52 to 15.22; P = 0.008) and lack of rapid virologic response, defined as undetectable HCV RNA level at week 4 (RR = 2.94, 95% CI: 1.22 to 7.09; P = 0.02) were the best independent predictors of HCV relapse. Use of concomitant antiretroviral therapy also predicted relapse (P = 0.04), and a trend toward a higher relapse rate was recognized for HCV genotypes 1 and 4 versus genotypes 2 and 3 (P = 0.08). Extended treatment did not result in a lower incidence of relapse, at least for HCV genotypes 2 and 3.\n\n\nCONCLUSIONS\nHigh baseline serum HCV RNA level and lack of undetectable viremia at week 4 are the most significant predictors of relapse in HCV/HIV-coinfected patients treated with peg-IFN plus weight-based RBV.",
"affiliations": "Department of Infectious Diseases. Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain.",
"authors": "Núñez|Marina|M|;Mariño|Ana|A|;Mariño|Angel|A|;Miralles|Celia|C|;Berdún|Miguel A|MA|;Sola|Julio|J|;Hernandez-Burruezo|Juan Jose|JJ|;Galindo|Maria Jose|MJ|;Barreiro|Pablo|P|;Martin-Carbonero|Luz|L|;Soriano|Vincent|V|",
"chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0b013e318061b5d9",
"fulltext": null,
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"issn_linking": "1525-4135",
"issue": "45(4)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D011092:Polyethylene Glycols; D011237:Predictive Value of Tests; D012367:RNA, Viral; D011994:Recombinant Proteins; D012008:Recurrence; D012254:Ribavirin; D016896:Treatment Outcome",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "439-44",
"pmc": null,
"pmid": "17468669",
"pubdate": "2007-08-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Baseline serum hepatitis C virus (HCV) RNA level and response at week 4 are the best predictors of relapse after treatment with pegylated interferon plus ribavirin in HIV/HCV-coinfected patients.",
"title_normalized": "baseline serum hepatitis c virus hcv rna level and response at week 4 are the best predictors of relapse after treatment with pegylated interferon plus ribavirin in hiv hcv coinfected patients"
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"companynumb": "ES-ROCHE-553136",
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"abstract": "Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has changed the focus of healthcare and become a public health challenge around the world. The coinfection of SARS-CoV-2 with other microorganisms, including fungi, can cause difficult diagnosis and a worse prognosis. Pneumocystis jirovecii pneumonia (PJP) is a common opportunistic infection in human immunodeficiency virus (HIV) patients. However, sometimes the diagnosis is late presented after PJP finding on chest X-ray. We report a 24-year-old man with COVID-19 and PJP. Reverse transcriptase-polymerase chain reaction showed positive for SARS-CoV-2. HIV diagnosis was late presented after PJP finding on chest X-ray examination. HIV serology was positive with an absolute CD4+ count was 16 cells/mm3. He was treated with remdesivir IV, methylprednisolone IV, heparin, and cefoperazone-sulbactam IV. He was discharged after being admitted for 25 days. HIV treatment was started in outpatient services. Radiological diagnostic to diagnose concurrent COVID-19 and PJP pneumonia are important, especially in the setting where microscopic examination of sputum or Bronchoalveolar Lavage Fluid (BALF) is not available, or because BAL and sputum induction are aerosol-generating procedures that potentially increase the risk of COVID-19 transmission. HIV testing in COVID-19 patients was also should be considered as part of directed screening in patients presenting with features of PJP, especially for those with unknown HIV status. The determination of an appropriate corticosteroid dose is important to treat both COVID-19 and PJP with severe clinical features. Proper diagnosis and treatment co-infections are urgently needed in this current pandemic to reduce morbidity and mortality.",
"affiliations": "Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Jl. Mayjen Prof. Dr. Moestopo No. 47 Surabaya, East Java, Surabaya, 60131, Indonesia.;Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Jl. Mayjen Prof. Dr. Moestopo No. 47 Surabaya, East Java, Surabaya, 60131, Indonesia.;Department of Radiology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.",
"authors": "Anggraeni|Amelia Tantri|AT|;Soedarsono|Soedarsono|S|;Soeprijanto|Bambang|B|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2021.09.002",
"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433\nElsevier\n\nS1930-0433(21)00648-8\n10.1016/j.radcr.2021.09.002\nCase Report\nConcurrent COVID-19 and Pneumocystis jirovecii pneumonia: The importance of radiological diagnostic and HIV testing\nAnggraeni Amelia Tantri MD a\nSoedarsono Soedarsono MD,PhD ssoedarsono@gmail.com\na⁎\nSoeprijanto Bambang MD,PhD b\na Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Jl. Mayjen Prof. Dr. Moestopo No. 47 Surabaya, East Java, Surabaya, 60131, Indonesia\nb Department of Radiology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia\n⁎ Corresponding author. Soedarsono Soedarsono ssoedarsono@gmail.com\n02 10 2021\n12 2021\n02 10 2021\n16 12 36853689\n23 7 2021\n29 8 2021\n4 9 2021\n© 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nCoronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has changed the focus of healthcare and become a public health challenge around the world. The coinfection of SARS-CoV-2 with other microorganisms, including fungi, can cause difficult diagnosis and a worse prognosis. Pneumocystis jirovecii pneumonia (PJP) is a common opportunistic infection in human immunodeficiency virus (HIV) patients. However, sometimes the diagnosis is late presented after PJP finding on chest X-ray. We report a 24-year-old man with COVID-19 and PJP. Reverse transcriptase-polymerase chain reaction showed positive for SARS-CoV-2. HIV diagnosis was late presented after PJP finding on chest X-ray examination. HIV serology was positive with an absolute CD4+ count was 16 cells/mm3. He was treated with remdesivir IV, methylprednisolone IV, heparin, and cefoperazone-sulbactam IV. He was discharged after being admitted for 25 days. HIV treatment was started in outpatient services. Radiological diagnostic to diagnose concurrent COVID-19 and PJP pneumonia are important, especially in the setting where microscopic examination of sputum or Bronchoalveolar Lavage Fluid (BALF) is not available, or because BAL and sputum induction are aerosol-generating procedures that potentially increase the risk of COVID-19 transmission. HIV testing in COVID-19 patients was also should be considered as part of directed screening in patients presenting with features of PJP, especially for those with unknown HIV status. The determination of an appropriate corticosteroid dose is important to treat both COVID-19 and PJP with severe clinical features. Proper diagnosis and treatment co-infections are urgently needed in this current pandemic to reduce morbidity and mortality.\n\nKeywords\n\nCOVID-19\nSARS-CoV-2\nHIV\nPJP\nRadiological Diagnosis\n==== Body\npmcIntroduction\n\nA current global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly causing varying degrees of illness and become a public health challenge all over the world [1], [2], [3]. Comorbidities such as hypertension, diabetes mellitus, obesity, cardiovascular disease, cerebrovascular disease, respiratory disease, kidney disease, and malignancy were reported as risk factors for more severe disease and worse prognosis [4], [5], [6], while many studies reported different results about the seriousness and outcomes of COVID-19 in patients with human immunodeficiency virus (HIV) infection, compared to the general population [3,7,8].\n\nMany drugs specifically targeting SARS-CoV-2 infection are under clinical trial. The coinfection of the SARS-CoV-2 with other microorganisms, such as viruses, bacteria, and fungi, is an important factor in COVID-19, and it can raise the difficulties of diagnosis, treatment, and even increase the disease symptom and mortality [2]. Pneumocystis jirovecii pneumonia (PJP) caused by fungal species of Pneumocystis jirovecii is a common opportunistic infection in patients infected with human immunodeficiency virus (HIV). However, some people are unaware they are infected with HIV because symptoms might not show for many years, then HIV diagnosis was found at the late stage of infection along with PJP diagnosis [9,10].\n\nWe report a 24-year-old man with fever, cough, sore throat, and dyspnea. He was admitted to our hospital which was a secondary referral hospital with reverse transcriptase-polymerase chain reaction (RT-PCR) positive for SARS-CoV-2. Initial chest X-ray showed ground-glass opacity diffuse bilateral suspicion caused by COVID-19 and differential caused by Pneumocystis jirovecii. Considering these results, we then decided to perform an HIV test. HIV test showed positive on the next day. Treatment for COVID-19 with coinfection PJP was then adjusted.\n\nCase presentation\n\nA 24-year-old man was admitted to our hospital as a secondary hospital. This patient presented fever, cough, sore throat, and dyspnea. The vital sign examination revealed a body temperature of 37.1°C, blood pressure of 110/70 mmHg, pulse rate of 96 beats per minute, respiratory rate of 24 breaths per minute, and PaO2 65 mmHg with oxygen saturation of 88% at room air. Oxygen support was directly given and oxygen saturation was 98% with O2 simple mask 8 lpm. Laboratory examination on hospitalization day 1 showed a low lymphocyte 13%, high CRP 48.45 mg/L, and procalcitonin 0.28 ng/ml (Table 1). The patient reported no comorbidity.Table 1 Summary of clinical features and laboratory results.\n\nTable 1 –Day of hosp\t\t1\t2\t3\t6\t7\t10\t13\t\nVital signs\t\t\t\t\t\t\t\t\t\nPulse rate\t\t96\t120\t114\t112\t104\t92\t82\t\nRR\t\t24\t26\t24\t26\t24\t20\t20\t\nSpO2 (%)\t\t98\t98\t99\t94\t96\t98\t97\t\nNote\t\tO2 SM 8 lpm\tO2 NRM 15 lpm\tO2 SM 6 lpm\t\nSign and symptoms\t\t\t\t\t\t\t\t\t\nFever\t\t\t\tY\t\t\t\t\t\nTemperature (°C)\t\t36.4\t37\t37.2\t36.4\t36\t36\t36.2\t\nCough\t\tY\tY\tY\tY\tY\tY\tY\t\nDyspnea\t\tY\tY\tY\tY\tY\t\t\t\nSore throat\t\tY\t\t\t\t\t\t\t\nNausea\t\t\t\t\t\tY\tY\t\t\nFatigue\t\t\t\t\tY\tY\tY\t\t\nDiagnosis\t\t\t\t\t\t\t\t\t\nRT-PCR\t\tPos\t\t\t\t\tNeg\t\t\nHIV test\t\t\t\tR\t\t\t\t\t\nLaboratory results\tReference range\t\t\t\t\t\t\t\t\nCD4 absolute\t404-1612\t\t\t\t16\t\t\t\t\nCD4 (%)\t33-58\t\t\t\t3\t\t\t\t\nCD8 absolute\t220-1129\t\t\t\t208\t\t\t\t\nCD8 (%)\t13-39\t\t\t\t37.71\t\t\t\t\nRatio CD4: CD8\t0.69-2.83\t\t\t\t0.08\t\t\t\t\nHb (g/dL)\t13-18\t13.9\t\t11.1\t\t11\t13.3\t14.2\t\nLeucocyte (10^3/uL)\t4-10\t13.78\t\t13.99\t\t12.96\t17.65\t15.42\t\nLymphocyte (%)\t25-33\t13\t\t13.6\t\t5.1\t5.7\t9.1\t\nTrombosit\t150-450\t450\t\t412\t\t528\t623\t505\t\nCRP\t0-3\t48.45\t\t\t\t\t8.32\t1.14\t\nD dimer (ng/mL)\t<0.5\t0.54\t\t\t\t\t0.87\t0.63\t\nPCT\t<0.05\t0.28\t\t\t\t\t0.17\t\t\nNeutrophil (%)\t54-62\t80.9\t\t83.9\t\t90.7\t88.9\t84.2\t\nHIV = human immunodeficiency virus; Pos = positive; R = reactive; RT-PCR = reverse transcriptase-polymerase chain reaction; Y = yes.\n\nThe initial RT-PCR showed positive for SARS-CoV-2 with a CT value of 32.01. The initial chest X-ray examination showed diffused bilateral ground-glass opacity on the upper two-thirds of the lung (Fig. 1A). A diagnosis of COVID-19 and suspicion of PJP was made. This patient was admitted to the isolation room and treated with remdesivir 200 mg QD IV and 100 mg QD IV on the following days, heparin 10000 IU QD syringe pump, vitamin D 5000 IU QD PO, vitamin C 1000 mg QD IV, zinc 50 mg QD PO, methylprednisolone 62.5 mg TID IV (planned for 21 days, tapering down) and oxygen support O2 simple mask 8 lpm. Cefoperazone-sulbactam injection was also given due to the presence of bacterial infection signs in the laboratory result.Fig. 1 Serial chest X-ray on hospitalization (A. Day 1; B. Day 4; C. Day 7; D. Day 10; E. Day 13; F. Day 18) and discharged on Day 39.\n\nFig 1 –\n\nConsidering the opacity pattern on the chest X-ray, an HIV test was performed and showed reactive on hospitalization day 3. PJP diagnosis was confirmed according to the positive results of the HIV test and diffused bilateral ground-glass opacity on chest X-ray. The drug of choice to treat PJP was cotrimoxazole forte 2 tablets PO TID for 21 days. Laboratory tests on hospitalization day 6 showed a low CD4 absolute (16 cells/mm3) and CD4 3% (Table 1). This patient had not received HIV therapy at that time. COVID-19 treatment was preferred, it was continued while evaluate and monitor the disease.\n\nEvaluation of serial chest X-ray showed an improvement with the opacity appearance was getting thinner on both lungs. RT-PCR showed negative for SARS-CoV-2 on hospitalization day 10 (Fig. 1). Clinical and vital signs were still fluctuating until hospitalization day 10. This patient was moved to a low care non-isolation room on hospitalization day 12 due to negative results of RT-PCR, SpO2 was 97% with O2 simple mask 6 lpm. This patient was discharged after being admitted for 25 days. HIV treatment was started in outpatient services. Efavir 600 mg, emtricitabine 200 mg, and tenofovir 300 mg were given. The treatment is still ongoing when this paper was written.\n\nDiscussion\n\nThis patient initially presented fever, cough, sore throat, and dyspnea when first admitted to our hospital. COVID-19 diagnosis was confirmed by RT-PCR which showed positive for SARS-CoV-2. Initial chest X-ray of this patient also showed suspected PJP. PJP and COVID-19 have similar characteristics such as fever, fatigue, dry cough, and dyspnea [11]. Chest radiography is the most commonly used imaging tool in pneumonia [12], while RT-PCR is the current gold standard to detect the infection of SARS-CoV-2 [13,14].\n\nPneumocystis cannot be cultured, and the diagnosis of PJP relies on microscopic examination in respiratory specimens obtained from sputum induction or bronchoscopy. Bronchoscopy with BAL is the gold standard procedure to diagnose PJP [9]. Culturing Pneumocystis jirovecii is extremely difficult. Confirmation of the diagnosis requires the identification of organisms in sputum or BALF [10]. HIV serology in this patient was positive with absolute CD4+ count was 16 cells/mm3 and chest X-ray showed diffused ground-glass opacity, then PJP diagnosis was confirmed without microscopic examination of sputum or Bronchoalveolar Lavage Fluid (BALF) because this examination was not available in a secondary hospital. This decision was also taken under the consideration of COVID-19 transmission risk because BAL and sputum induction are aerosol-generating procedures [13]. PJP is a common opportunistic infection in patients infected with HIV and occurs primarily among persons unaware that they have HIV infection and is an AIDS-defining illness [10]. PJP typically occurs with CD4 counts of less than 200 cells/mm [12]. HIV diagnosis in this patient is late presented after PJP finding on chest X-ray examination.\n\nAlthough the diagnosis of PJP is only presumptive without respiratory specimens, this finding showed the importance of radiological diagnosis to diagnose concurrent COVID-19 and PJP pneumonia, especially in the setting where microscopic examination of sputum or BALF is not available, or because BAL and sputum induction are aerosol-generating procedures that potentially increase the risk of COVID-19 transmission. In this patient, the finding of radiological diagnosis which showed COVID-19 and PJP also played a role to make a decision on HIV testing.\n\nInitial chest X-ray in this patient showed diffused bilateral ground-glass opacity (Fig. 1). Multifocal ground-glass opacities are the principal finding in both PJP and SARS-CoV-2 infection, making radiographic differentiation potentially difficult, especially in the immunocompromised host [15]. The radiographic finding of PJP typically demonstrates ground-glass opacities and increased interstitial markings. Other radiographic patterns of PJP include a predilection for upper lobes, a preference for central rather than peripheral zones [16,17]. In this patient, the diffused bilateral ground-glass pattern on the upper two-thirds of both lungs made us suspicious of the presence of PJP. Chest CT scan was not examined according to the policy in our hospital that patients with RT-PCR showed positive for SARS-CoV-2 are not allowed to have a chest CT scan examination, this policy aims to reduce the risk of COVID-19 transmission.\n\nRemdesivir was given to treat COVID-19, cefoperazone-sulbactam was due to a high PCT level, heparin was due to a high D-dimer, and adjunctive methylprednisolone therapy for PJP as a secondary infection in COVID-19 patient with severe clinical features. Treating both COVID-19 and PJP was challenging, especially in HIV-infected patients. The administration of adjunctive corticosteroids for the treatment of PJP in HIV patients may reduce the mortality rate of patients in the early phase of the disease [18]. Clinical management of PJP and COVID-19 is different, particularly high-dose corticosteroid therapy is recommended in severe PJP. However, there is no evidence for high-dose corticosteroid therapy in COVID-19 [19]. The use of corticosteroid treatment might not be associated with a lower mortality rate among hospitalized COVID-19 patients. However, in critically ill patients, it could improve outcomes. The effect of corticosteroid treatment on mortality might be limited to critically ill COVID-19 patients [20]. A previous study reported that corticosteroids may be beneficial in severely ill COVID-19 patients [21]. The World Health Organization (WHO) recommended using systemic corticosteroids rather than no corticosteroids for patients with severe or critical COVID-19-infection and against recommended to use corticosteroids for patients with non-severe COVID-19 infection, while CDC and NIH recommended corticosteroid only for hospitalized patients who required supplemental oxygen [13,22]. A study in the UK regarding the use of 6 mg of dexamethasone once a day showed that the efficacy was high and resulted in lower 28-day mortality among patients receiving supplemental oxygen [23]. In this patient, the clinical manifestations showed severe illness, both because of SARS-CoV-2 and Pneumocystis jirovecii infections. Administering corticosteroids is absolutely needed for this patient, both for COVID-19 and PJP.\n\nBased on the protocol for COVID-19 in our hospital, we use 6 mg of IV dexamethasone as the standard severe COVID-19 therapy. But in this case, we decided to give a methylprednisolone high dose, considering the low dose of corticosteroid might be useful for COVID-19 but not for PJP. RT-PCR showed negative for SARS-CoV-2 on hospitalization day 10 in this patient, which was different from the previous study by You et al (2020) that stated methylprednisolone could not improve the prognosis of patients with COVID-19. Another study stated that patients without the use of methylprednisolone were more quickly to obtain negative results (11 days) of their nasopharyngeal swab tests of SARS-CoV-2 nucleic acid after treatment, compared to those receiving methylprednisolone (13.5 days) [24].\n\nMonitored during treatment, liver function, renal function, and blood glucose were normal. This patient was discharged and started HIV therapy in outpatient services. HIV patients who are on treatment with antiretroviral therapy (ART) could have successful viral suppression, resulting in undetectable viral load and not a transmissible disease. People living with HIV (PLHIV) are not immunocompromised if ART is maintained [8].\n\nThis case showed that a high suspicion of PJP should be considered according to the clinical and radiological features. The clinician should maintain good clinical sense in making the diagnosis, especially PJP diagnosis in addition to COVID-19. The determination of all treatments is important to improve the outcomes in this HIV patient with concurrent COVID-19 and PJP. Previous studies reported different results about the severity and outcomes of COVID-19 in HIV patients. The clinical course of COVID-19 among HIV patients does not seem to be different than it is in the general population, but areas of concern include high inflammatory states, which could result in complications [25]. The presence of multimorbidity and older age appears to be the important factors for severe morbidity and mortality with COVID-19-HIV co-infection [26]. This case was a young HIV patient with concurrent COVID-19 and PJP. The clinical feature of this patient was severe, but he was successfully survived because the accurate diagnosis, appropriate and early treatment had been given for both COVID-19 and PJP.\n\nHIV testing is important for early treatment because HIV patients with well-controlled diseases are not at risk of poorer COVID-19 disease outcomes than the general population [8]. Early detection of HIV infection is a critical factor in controlling HIV. Timely ART is associated with a better prognosis among HIV-infected individuals and lower rates of disease progression. Individuals who present at an advanced stage of immune suppression are at high risk of clinical events and death. Individuals who present at an advanced stage of immune suppression are at high risk of AIDS-related diseases and death [27]. ART was started given in outpatient services with efavir 600 mg, emtricitabine 200 mg, and tenofovir 300 mg.\n\nConclusion\n\nRadiological diagnostic is important to diagnose concurrent COVID-19 and PJP pneumonia, especially in the setting where microscopic examination of sputum or Bronchoalveolar Lavage Fluid (BALF) is not available, or because BAL and sputum induction are aerosol-generating procedures that potentially increase the risk of COVID-19 transmission. HIV testing in COVID-19 patients was also should be considered as part of directed screening in patients presenting with features of PJP, especially for those with unknown HIV status. The determination of an appropriate corticosteroid dose is important to treat both COVID-19 and PJP with severe clinical features. Comprehensive diagnosis and proper treatment, both for primary and secondary infections are important in this current pandemic to reduce morbidity and mortality.\n\nEthics approval and consent to participate\n\nWe are exempt from ethical approval as it is not required in our hospital for a single case report.\n\nCompeting Interests: The authors declare that they have no competing interests.\n\nFunding Source: Nil.\n==== Refs\nReferences\n\n1 World Health Organization. Novel Coronavirus –China. http://www.who.int/csr/don/12-january-2020-novel-coronavirus-china/en/. Accessed on 15 January 2021.\n2 Chen X Liao B Cheng L Peng X Xu X Li Y The microbial coinfection in COVID-19 Appl Microbiol Biotechnol 104 18 2020 7777 7785 32780290\n3 Calza L Bon I Tadolini M Borderi M Colangeli V Badia L COVID-19 in patients with HIV-1 infection: a single-centre experience in Northern Italy Infection 2020 10.1007/s15010-020-01492-7\n4 Zhou Y Yang Q Chi J Dong B Lv W Shen L Comorbidities and the risk of severe or fatal outcomes associated with Coronavirus Disease 2019: a systematic review and meta-analysis Int J Infect Dis 99 2020 47 56 32721533\n5 Sanyaolu A Okorie C Marinkovic A Patidar R Younis K Desai P Comorbidity and its impact on patients with COVID-19 SN Compr Clin Med 25 2020 1 8\n6 Guan W Liang W Zhao Y Liang H Chen Z Li Y Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis Eur Respir J 55 5 2020 2000547\n7 Cipolat MM Sprinz E. COVID-19 pneumonia in an HIV-positive woman on antiretroviral therapy and undetectable viral load in Porto Alegre Brazil. Braz Infect Dis. 24 5 2020 455 457\n8 Cooper TJ Woodward BL Alom S Harky A. Coronavirus Disease 2019 (COVID-19) outcomes in HIV/AIDS patients: a systematic review HIV Medicine 21 2020 567 577 32671970\n9 Huang L Cattamanchi A Davis JL Boon S Kovacs J Meshnick S HIV-associated Pneumocystis pneumonia Proc Am Thorac Soc 8 2011 294 300 21653531\n10 Kanne JP Yandow DR Meyer CA. Pneumocystis jiroveci pneumonia: high-resolution CT findings in patients with and without HIV infection Cardiopulmonary Imaging 198 6 2012 555 561\n11 Choy CY Wong CS. It's not all about COVID-19: pneumocystis pneumonia in the era of a respiratory outbreak J Int AIDS Soc 23 2020 e25533 32558276\n12 Parekh M Donuru A Balasubramanya R Kapur S. Review of the chest CT differential diagnosis of ground-glass opacities in the COVID era Radiology 297 2020 E289 E302 32633678\n13 National Institutes of Health. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available from: URL: https://www.covid19treatmentguidelines.nih.gov/. 15 January 2021\n14 Indonesia Ministry of Health Guideline of Coronavirus Disease (COVID-19) prevention and management (COVID-19) 5th revision Indonesia Ministry of Health 2020\n15 Bhat P Noval M Doub JB Heil E. Concurrent COVID-19 and pneumocystis jirovecii pneumonia in a severely immunocompromised 25-year-old patient Int J Infect Dis 99 2020 119 121 32768700\n16 Block BL Mehta T Ortiz GM Ferris SP Vu TH Huang L Unusual radiographic presentation of Pneumocystis pneumonia in a patient with AIDS Case Rep Infect Dis 2017 10.1155/2017/3183525\n17 Hsu JM Hass A Gingras MA Chong J Costiniuk C Ezer N Radiographic features in investigated for Pneumocytis jirovecii pneumonia: a nested case-control study BMC Infect Dis 20 2020 492 32650730\n18 Wang L Liang H Ye L Jiang J Liang B Huang J. Adjunctive corticosteroids for the treatment of Pneumocystis jiroveci pneumonia in patients with HIV: a meta-analysis Exp Ther Med 11 2016 683 687 26893666\n19 Coleman H, Snell LB, Simons R, Douthwaite ST, Lee MJ. COVID-19 and Pneumocystis jirovecii pneumonia: a diagnostic dilemma in HIV. AID: Doi: 10.1097/QAD.0000000000002571.\n20 Bartoletti M Marconi L Scudeller L Pancaldi L Tedeschi S Giannella M Efficacy of corticosteroid treatment for hospitalized patients with severe COVID-19: a multicentre study Clin Microbiol Infect 27 2021 105 111 32971254\n21 Cano EJ Fuentes XF Campioli CC O'Horo JC Saleh OA Odeyemi Y Impact of corticosteroid in Coronavirus Disease 2019 outcomes Chest 2020 10.1016/j.chest.2020.10.054 Article in Press\n22 World Health Organization Therapeutics and COVID-19: Living Guideline 2020 World Health Organization Geneva, Switzerland 17 December 2020\n23 RECOVERY Collaborative Group Dexamethasone in hospitalized patients with Covid-19 - preliminary report N Engl J Med 2020 10.1056/NEJMoa2021436\n24 You X Wu C Fu Y He Z Huang P Chen G The use of methylprednisolone in COVID-19 patients: a propensity score matched retrospective cohort study PLoS ONE 15 12 2020 e0244128\n25 Prabhu S Poongulali S Kumarasamy N. Impact of COVID-19 on people living with HIV: a review J Virus Erad 6 2020 100019\n26 Mirzaei H McFarland W Karamouzian M Sharifli H. COVID-19 among people living with HIV: a systematic review AIDS Behav 2020 10.1007/s10461-020-02983-2\n27 Tang H Mao Y Tang W Han J Xu J Li J. Late for Testing, Early for Antiretroviral Therapy, Less Likely to Die”: results from a large HIV cohort study in China, 2006-2014 BMC Infect Dis 18 2018 272 29895275\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1930-0433",
"issue": "16(12)",
"journal": "Radiology case reports",
"keywords": "COVID-19; HIV; PJP; Radiological Diagnosis; SARS-CoV-2",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101467888",
"other_id": null,
"pages": "3685-3689",
"pmc": null,
"pmid": "34630801",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": "32633678;21653531;32734438;33083001;32866436;32678530;32780290;32971254;32768700;29895275;33382734;32748333;33129791;32838147;32650730;22623570;32558276;32501852;32671970;32217650;29362681;32721533;26893666",
"title": "Concurrent COVID-19 and Pneumocystis jirovecii pneumonia: The importance of radiological diagnostic and HIV testing.",
"title_normalized": "concurrent covid 19 and pneumocystis jirovecii pneumonia the importance of radiological diagnostic and hiv testing"
} | [
{
"companynumb": "ID-LUPIN PHARMACEUTICALS INC.-2022-03707",
"fulfillexpeditecriteria": "2",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "The incidence of drug-induced acute liver failure (ALF) has been increasing in recent years. Despite the complex intensive treatment, liver transplant should be performed in progressive cases. A systemic inflammatory response syndrome and the burden of surgical intervention promote abdominal compartment syndrome (ACS); observed preoperatively, they are significant negative prognostic factors. THE CASE: We demonstrate a young woman with liver transplant after ALF and a consecutive ACS. We presumed drug toxicity in the background of the rapidly progressive ALF, based on the preoperative hematologic examination and the histology of the removed liver. An ACS has occurred in the postoperative period that must have been resolved with mesh, and later, anatomic segment 2-3 resection had to be performed to further decrease the pressure. The patient left the hospital after 62 days with good graft function. DISCUSSION: A complex intensive care is mandatory in the case of orthotopic liver transplant for ALF. Outcomes are good after orthotopic liver transplant. An ACS might occur after surgery. In these rare cases a delayed abdominal closure or even a liver resection can be the only solution and sometimes an urgent need to resolve the life-threatening problem.",
"affiliations": "Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary. Electronic address: gergelynagymd@gmail.com.;Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.;Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.;2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.;Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.;Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.;Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.;Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.;Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.",
"authors": "Nagy|G|G|;Görög|D|D|;Kóbori|L|L|;Mihály|E|E|;Piros|L|L|;Pőcze|B|B|;Sandil|A|A|;Szabó|J|J|;Mathe|Z|Z|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.04.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D003161:Compartment Syndromes; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D011183:Postoperative Complications; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1289-1292",
"pmc": null,
"pmid": "31101216",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abdominal Compartment Syndrome After Liver Transplant in Drug-Induced Acute Liver Failure: A Case Report.",
"title_normalized": "abdominal compartment syndrome after liver transplant in drug induced acute liver failure a case report"
} | [
{
"companynumb": "HU-TEVA-2019-HU-1064897",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Opioid-induced neurotoxicity (OIN) is an underdiagnosed yet distressing symptom in palliative care patients receiving opioids. However, there have been only a limited number of studies on OIN. Our aim was to determine the frequency of and risk factors for OIN in patients receiving opioids during inpatient palliative care. We randomly selected 390 of 3014 eligible patients who had undergone palliative care consultations from January 2014 to December 2014. Delirium, drowsiness, hallucinations, myoclonus, seizures, and hyperalgesia were defined as OIN and were recorded. The other 10 common symptoms in cancer patients were assessed using the Edmonton Symptom Assessment Scale (ESAS). Patient demographics, morphine equivalent daily dose (MEDD), comorbidities, OIN management, and overall survival (OS) duration were also assessed. The associations between the incidence of OIN and MEDD, the other 10 symptoms, and OS were analyzed. Fifty-seven (15%) patients had OIN. The most common symptom was delirium (n = 27). On multivariate analysis, a high MEDD (p = 0.020), high ESAS pain score (p = 0.043), drowsiness (p = 0.007), and a poor appetite (p = 0.014) were significantly associated with OIN. OIN was not significantly associated with a shorter OS duration (p = 0.80). OIN was seen in 15% of patients receiving opioids as part of inpatient palliative care. Although OIN was not associated with OS, routine monitoring is especially needed in cancer patients.",
"affiliations": "Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea.;Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea.;Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Lim|Kyu-Hyoung|KH|;Nguyen|Nhu-Nhu|NN|;Qian|Yu|Y|;Williams|Janet L|JL|;Lui|Diane D|DD|;Bruera|Eduardo|E|;Yennurajalingam|Sriram|S|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2018.0169",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1557-7740",
"issue": "21(12)",
"journal": "Journal of palliative medicine",
"keywords": "delirium; drowsiness; myoclonus; opioids; palliative care",
"medline_ta": "J Palliat Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D000072716:Cancer Pain; D005260:Female; D006801:Humans; D007297:Inpatients; D008297:Male; D008485:Medical Audit; D008875:Middle Aged; D009369:Neoplasms; D020258:Neurotoxicity Syndromes; D017063:Outcome Assessment, Health Care; D010166:Palliative Care; D015995:Prevalence; D055815:Young Adult",
"nlm_unique_id": "9808462",
"other_id": null,
"pages": "1698-1704",
"pmc": null,
"pmid": "30260731",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "6869591;26051219;21514818;15591459;23930920;15353098;19735902;1714502;12836513;7673770;10737278;17358098;9114631;10522740;27258073;18980450;15907643;16624490;7688888;26417036;2880504;23238913",
"title": "Frequency, Outcomes, and Associated Factors for Opioid-Induced Neurotoxicity in Patients with Advanced Cancer Receiving Opioids in Inpatient Palliative Care.",
"title_normalized": "frequency outcomes and associated factors for opioid induced neurotoxicity in patients with advanced cancer receiving opioids in inpatient palliative care"
} | [
{
"companynumb": "US-JNJFOC-20190200132",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"drugadditional": null,
"... |
{
"abstract": "Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive condition affecting lipid metabolism with a prevalence of less than 1:1,000,000. Described here is the case of a 29-year-old pregnant woman with a diagnosis of LCAT deficiency (c.140G>A in exon 4), who had three episodes of hypertriglyceridemia-induced pancreatitis and nephrotic-range proteinuria throughout the pregnancy. Furthermore, fetal ultrasounds carried out during the second and third trimester revealed a steady reduction in fetal growth rate, and fetal growth restriction (FGR) was diagnosed. The woman underwent an elective caesarean section at 33 weeks of gestation and delivered a healthy neonate. This case report adds knowledge of the natural history of LCAT deficiency during pregnancy and will be useful in future patient management.",
"affiliations": "Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.",
"authors": "Leal-Gonzalez|Raul|R|;Ramos-Reyes|Álvaro|Á|https://orcid.org/0000-0001-5487-879X;Moncada-Madrazo|Mariana|M|https://orcid.org/0000-0003-1625-9546;Apodaca-Ramos|Irasema|I|;Morales-Palomino|Kimberly L|KL|;Valdés-Cepeda|Alejandro|A|;Marrufo-García|César A|CA|;Rangel-Nava|Hugo A|HA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X20950574",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "14(3)",
"journal": "Obstetric medicine",
"keywords": "LCAT deficiency; case report; fetal growth restriction; pancreatitis; pregnancy",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "193-196",
"pmc": null,
"pmid": "34646351",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "21327698;24083148;25005737;30226702;23620397;26919698;24355941;18397721;31901241;7900743;3510535;91022;28285426;30148167;30254776;28942093;32073411;25172171;23522979;30201532;29923163;14668345;3797244",
"title": "LCAT deficiency and pregnancy: Case report.",
"title_normalized": "lcat deficiency and pregnancy case report"
} | [
{
"companynumb": "MX-LUPIN PHARMACEUTICALS INC.-2021-24775",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LOSARTAN"
},
"drugadditional":... |
{
"abstract": "Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.",
"affiliations": "Pediatric Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.;Center for Cancer and Blood Disorders, Department of Pediatrics, Children's Hospital Colorado and the University of Colorado School of Medicine, Aurora, CO, USA.;Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Baylor College of Medicine, Houston, TX, USA.;Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Hackensack University Medical Center, Hackensack, NJ, USA.;Children's Hospital Los Angeles, Los Angeles, CA, USA.;Brown University, Providence, RI, USA.;University of Florida, Gainesville, FL, USA.;Oregon Health and Science University, Portland, OR, USA.;Johns Hopkins University, Baltimore, MD, USA.;Emory University, Atlanta, GA, USA.;Nationwide Childrens Hospital, Columbus, OH, USA.;Seattle Children's Hospital, Seattle, WA, USA.;Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA.;Indiana University School of Medicine, Indianapolis, IN, USA.;Duke Children's Hospital, Durham, NC, USA.;UCSF Benioff Children's Hospital, San Francisco, CA, USA.;Yale, New Haven, CT, USA.;Sick Kids Hospital, Toronto, Ontario, Canada.;Stanford University School of Medicine, Palo Alto, CA, USA.;University of Michigan, Ann Arbor, MI, USA.;Lurie Children's Hospital, Chicago, IL, USA.;Cleveland Clinic, Cleveland, OH, USA.;Hofstra Northwell School of Medicine, Hempstead, NY, USA.;Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA.;Division of Hematology and Oncology and Biostatistics and Research Design Center of the Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA.;Boston Children's Hospital and Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.;Boston Children's Hospital and Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA akiko.shimamura@childrens.harvard.edu.",
"authors": "Rogers|Zora R|ZR|;Nakano|Taizo A|TA|;Olson|Timothy S|TS|;Bertuch|Alison A|AA|;Wang|Winfred|W|;Gillio|Alfred|A|;Coates|Thomas D|TD|;Chawla|Anjulika|A|;Castillo|Paul|P|;Kurre|Peter|P|;Gamper|Christopher|C|;Bennett|Carolyn M|CM|;Joshi|Sarita|S|;Geddis|Amy E|AE|;Boklan|Jessica|J|;Nalepa|Grzegorz|G|;Rothman|Jennifer A|JA|;Huang|James N|JN|;Kupfer|Gary M|GM|;Cada|Michaela|M|;Glader|Bertil|B|;Walkovich|Kelly J|KJ|;Thompson|Alexis A|AA|;Hanna|Rabi|R|;Vlachos|Adrianna|A|;Malsch|Maggie|M|;Weller|Edie A|EA|;Williams|David A|DA|;Shimamura|Akiko|A|",
"chemical_list": "D000961:Antilymphocyte Serum; D016572:Cyclosporine",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2018.206540",
"fulltext": "\n==== Front\nHaematologicaHaematologicahaematolHaematologicaHaematologica0390-60781592-8721Ferrata Storti Foundation 3094848410.3324/haematol.2018.2065401041974ArticleBone Marrow FailureImmunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study Rogers Zora R. 1Nakano Taizo A. 2Olson Timothy S. 3Bertuch Alison A. 4Wang Winfred 5Gillio Alfred 6Coates Thomas D. 7Chawla Anjulika 8Castillo Paul 9Kurre Peter 10Gamper Christopher 11Bennett Carolyn M. 12Joshi Sarita 13Geddis Amy E. 14Boklan Jessica 15Nalepa Grzegorz 16Rothman Jennifer A. 17Huang James N. 18Kupfer Gary M. 19Cada Michaela 20Glader Bertil 21Walkovich Kelly J. 22Thompson Alexis A. 23Hanna Rabi 24Vlachos Adrianna 25Malsch Maggie 26Weller Edie A. 27Williams David A. 28Shimamura Akiko 28\n1 Pediatric Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA\n2 Center for Cancer and Blood Disorders, Department of Pediatrics, Children’s Hospital Colorado and the University of Colorado School of Medicine, Aurora, CO, USA\n3 Children’s Hospital of Philadelphia, Philadelphia, PA, USA\n4 Baylor College of Medicine, Houston, TX, USA\n5 Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, USA\n6 Hackensack University Medical Center, Hackensack, NJ, USA\n7 Children’s Hospital Los Angeles, Los Angeles, CA, USA\n8 Brown University, Providence, RI, USA\n9 University of Florida, Gainesville, FL, USA\n10 Oregon Health and Science University, Portland, OR, USA\n11 Johns Hopkins University, Baltimore, MD, USA\n12 Emory University, Atlanta, GA, USA\n13 Nationwide Childrens Hospital, Columbus, OH, USA\n14 Seattle Children’s Hospital, Seattle, WA, USA\n15 Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, AZ, USA\n16 Indiana University School of Medicine, Indianapolis, IN, USA\n17 Duke Children’s Hospital, Durham, NC, USA\n18 UCSF Benioff Children’s Hospital, San Francisco, CA, USA\n19 Yale, New Haven, CT, USA\n20 Sick Kids Hospital, Toronto, Ontario, Canada\n21 Stanford University School of Medicine, Palo Alto, CA, USA\n22 University of Michigan, Ann Arbor, MI, USA\n23 Lurie Children’s Hospital, Chicago, IL, USA\n24 Cleveland Clinic, Cleveland, OH, USA\n25 Hofstra Northwell School of Medicine, Hempstead, NY, USA\n26 Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, USA\n27 Division of Hematology and Oncology and Biostatistics and Research Design Center of the Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, USA\n28 Boston Children’s Hospital and Dana Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USACorrespondence: AKIKO SHIMAMURAakiko.shimamura@childrens.harvard.edu10 2019 04 4 2019 104 10 1974 1983 05 11 2018 28 3 2019 Copyright© 2019 Ferrata Storti Foundation2019Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.\n==== Body\nIntroduction\nAcquired severe aplastic anemia (SAA) is a rare disorder characterized by peripheral bi- or pancytopenia and bone marrow (BM) hypoplasia. Initial therapy for younger patients with SAA is a matched sibling hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST) if a matched sibling donor is not available.1 There is a paucity of data for children with SAA treated during the modern era from the ethnically and geographically diverse population of North America. Pediatric studies from the National Institutes of Health,2 the Japanese Childhood Aplastic Anemia Study Group,3-6 Brazil,7 and the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplant (SAAWP-EBMT)8,9 have been reported. However, diagnostic evaluation for constitutional disorders has been limited, and duration of follow up has often been variable and short. Many published studies report outcomes with rabbit anti-thymocyte globulin (rATG) due to the withdrawal of horse ATG (hATG) from some European and Asian markets in 2007; however, a large prospective study of upfront rATG versus hATG reported inferior response rates and lower survival with rATG.10 Thus, contemporary data to inform therapeutic decisions in pediatric patients treated with IST in North America are of interest given international differences in treatment regimens, recent advances in diagnosis of genetic marrow failure disorders, improvements in HSCT outcomes, and better supportive care.\n\nTo facilitate collaborative clinical studies of pediatric aplastic anemia, a consortium of 25 institutions (now numbering 39) across North America, named the North American Pediatric Aplastic Anemia Consortium (NAPAAC), was formed in 2014.11 The urgent need for evidence-based guidelines for patient management in pediatric SAA was highlighted by a NAPAAC survey of clinical practices of member institutions which revealed considerable variability in diagnostic evaluation and management.11 Recognizing the challenges of performing a prospective trial to address these critical knowledge gaps, NAPAAC conducted a retrospective study of presentation and outcomes of pediatric patients diagnosed from 2002 to 2014 with SAA and treated with IST with a minimum of two years of follow up in member institutions. The objectives of the study were to determine the rates of response and survival following IST, to assess rates of clonal abnormalities, and to explore patient-specific factors contributing to survival, refractory disease, relapse, and clonal progression following IST. This NAPAAC effort represents the first large study of pediatric SAA reflecting the racially diverse population of children afflicted by SAA across multiple centers in North America. These contemporary data from a large number of pediatric patients will inform future studies of additional diagnostic or prognostic testing, and guide evidence-based clinical management.\n\nMethods\nPatients\nA retrospective chart review was conducted by member institutions of all patients aged 1-20 years treated with IST as the first therapy for pediatric SAA between 1st January 2002 and 30th June 2014 for whom follow up was available for a minimum of 24 months or until death. This study was approved by the Institutional Review Board (IRB) at each participating institution or via a reliance agreement with the central study IRB at Boston Children’s Hospital. Each site abstracted data from the local medical record and entered them into a central Red Cap database. The data included demographics, disease characteristics at diagnosis, treatment, and outcomes. When available, the original anonymized written reports of specific studies including BM aspirate and biopsy, cytogenetics, fluorescence in situ hybridization (FISH), clonal analysis for paroxysmal nocturnal hemoglobinuria (PNH), telomere flow-FISH analysis, immunological analyses, and autopsies were uploaded for central review.\n\nSubmitted cases were included only if the diagnostic BM was reported as hypocellular and the patient had at least two peripheral cytopenias: 1) absolute neutrophil count (ANC) < 0.5 ×109/L; 2) platelet count (Plts) < 20×109/L; 3) hemoglobin (Hb) < 8 g/dL. Central review of diagnostic marrow slides was not feasible but marrow pathology reports were reviewed to confirm that the marrow cellularity was <25% or hypocellularity was stated to be consistent with the diagnosis of SAA without a specified percentage cellularity. Patients with a local diagnosis of an inherited BM failure syndrome were excluded from this study, as were subjects with an HLA-matched sibling who went to transplant upfront. Date of diagnosis was considered to be the date of the BM biopsy. Date of treatment was considered the first day of IST, and all outcomes were timed from the first day of treatment. Structured reporting of status and blood counts was required at initiation of IST, as well as at 3, 6, 12, 24, 36, 48, and 60 months, and at last follow up.\n\nDefinitions\nOverall survival (OS) was measured from the time from first day of IST until death or date last known alive. Event-free survival (EFS) was measured from the time from start of IST until an event (death or start of a second therapy for SAA, either HSCT or a second course of IST) or the date last known to be without an event.\n\nResponse12 was defined using hemoglobin (Hb), absolute neutrophil count (ANC) and platelets (Plts). Complete response (CR), very good partial response (VGPR) and partial response (PR) required the indicated levels in all three lineages as noted below; no response (NR) was defined as failure in any lineage:\nCR: Hb ≥10 g/dL and ANC ≥1×109/L and Plts ≥100×109/L\n\nVGPR: Hb ≥8 g/dL and ANC ≥0.5×109/L and Plts ≥50×109/L\n\nPR: Hb ≥8 g/dL and ANC ≥0.5×109/L and Plts ≥20×109/L\n\nNR: Hb <8 g/dL or ANC <0.5×109/L or Plts <20×109/L\n\n\n\nPatients receiving transfusions of packed red blood cells within six weeks or platelets or granulocyte-colony stimulating factor (G-CSF)/granulocyte/macrophage-colony stimulating factor (GM-CSF) within two weeks of evaluation were deemed to have had NR at that time point. An objective response (OR) was defined as at least a PR (PR+VGPR+CR) and a deep response (DR) was defined as at least a VGPR (VGPR+CR). Duration of response (DOR) was defined as time from start of response to an event (death or start of a second therapy for SAA, either HSCT or a second course of IST).\n\nStatistical analysis\nSummary statistics included median and range for continuous variables and frequency and proportion for binary variables. Fisher’s exact test and Wilcoxon rank sum test were used to compare proportions and medians, respectively. The proportion of subjects with an OR, DR, and CR were reported along with the exact binomial 95% confidence interval (95%CI). OS, EFS and DOR were estimated using the Kaplan-Meier method (log-log transformation for Confidence Interval) and compared using the log-rank test. A Cox proportional hazards model was used to compare EFS by treatment adjusting for covariates of interest [age, gender, time from initial IST treatment to 2nd treatment, and lymphocytopenia (lymphocyte count <1×109/L)]. Reference groups in this model were: IST treatment, age at second treatment ≥10 years, male gender, lymphocyte count at diagnosis ≥1×109/L. An indicator variable was included in the model for missing lymphocyte data as these data were not provided for all subjects. The median follow up among all subjects was 62 months. There was 80% power to detect differences of at least 16% difference in proportions for 314 and 264 subjects, respectively (two-sided Fishers exact test, alpha=0.05). In terms of precision, the maximum Confidence Interval width of the exact binomial 95%CI for an observed proportion was 0.12 and 0.11, respectively, with n=314 and n=264. R language was used for analysis (R Core Team, 2016, Vienna, Austria; https://www.R-project.org).\n\nResults\nPatients’ characteristics at diagnosis\nA total of 314 pediatric patients treated with IST for SAA were identified by systematic retrospective chart review across 25 NAPAAC institutions. Table 1 summarizes baseline demographics of study subjects. Nine patients (0.03%) were 1-2 years of age. Gender was evenly distributed. The population was racially diverse, reflecting the ethnic diversity of North America. A family history of aplastic anemia, none of whom were first-degree relatives, was noted in four patients.\n\nTable 1. Baseline demographics and characteristics.\n\nHepatitis was noted prior to diagnosis in 43 (13.7%) patients, of whom 33 (12.5%) were treated with hATG/cyclosporine (CyA). Laboratory features at diagnosis are summarized in Table 2. PNH test results were available at diagnosis for 140 patients and a PNH clone was noted in 55 (39.3%). In most cases, the clone size was small [interquartile range (IQR): 0-0.12%]. Only 5 patients had PNH clones larger than 10% (range: 12.56-28.4%) in the granulocyte lineage and none had clinically evident hemolysis or thrombosis at diagnosis.\n\nTable 2. Laboratory features at diagnosis.\n\nThe most commonly investigated inherited BM failure syndromes at diagnosis were Fanconi anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita. Fanconi anemia screening was negative for 292 patients (93%), 18 patients were not tested, and results were not available for four subjects. Genetic testing for Shwachman-Diamond syndrome was available for 46 patients (14.6%); all of these were negative. Perhaps reflecting the evolution of understanding the role of dyskeratosis congenita in BM failure over the past five years, telomere length was assessed at the time of diagnosis in only 115 patients (36.6%) and a report of a clinical telomere flow-FISH test was available for 93 patients (29.6%). No patient exhibited a pattern suspicious for a primary telomere disorder (telomeres <1st percentile in at least 3 different lymphocyte subsets).13 However, telomere lengths <1st percentile were found in total lymphocytes in six patients, of whom only two had a complete 6-panel analysis.\n\nThe current diagnostic criteria for SAA includes an ARC (absolute reticulocyte count) of <20-60×109/L.12,14,15 Many institutions relied on hemoglobin (Hb) rather than the ARC as a more clinically relevant indicator of erythroid hypoplasia to inform diagnosis and treatment decisions. Comparison of ARC versus Hb for the 231 subjects with ARC <100 revealed a lack of concordance [(estimated Pearson correlation coefficient of 0.15 (95%CI: 0.02, 0.27)] between the commonly utilized diagnostic criteria of ARC of <60 ×109/L and significant anemia defined as Hb <8 g/dL (Figure 1). A subset of patients meeting ARC criteria of ARC <60 ×109/L had Hb >8 g/dL (12.7%, 28 of 220), and conversely, some patients who did not meet diagnostic criteria for ARC had Hb levels <8 g/dL (74%, 26 of 35).\n\nFigure 1. Correlation between absolute reticulocyte count and hemoglobin at diagnosis. Absolute reticulocyte counts <100×109/L (n=231) were plotted against the hemoglobin at diagnosis. CI: Confidence Interval.\n\nTreatment\nTreatment groups are outlined in Table 3. The majority of patients (n=264) received hATG plus CyA. Of these subjects, one patient received hATG but switched to rabbit ATG (rATG) due to an anaphylactic reaction. Overall, the demographics of the hATG/CyA population was similar to that of the entire group (Tables 1-3). The small number of subjects in groups treated with alternative IST regimens limited intergroup comparisons, and so only outcomes of the entire population and that of the hATG/CyA group were analyzed.\n\nTable 3. Treatment.\n\nOf the 282 subjects who were treated with hATG,187 (71%) received 40 mg/kg/day for four days, 77 were dosed with a different regimen containing about the same total dose of hATG, and in 18 the dose was not available. CyA target trough levels were variable (100-400), with the majority 200-400. Following treatment with hATG/CyA, data regarding the cyclosporine taper were available for 194 patients. CyA was discontinued by six months for 13 subjects, between 6-12 months for 40 subjects, between 12-18 months for 34 subjects, between 18-24 months for 37 subjects, and after two years for 34 subjects. CyA was not discontinued at last follow up for 36 subjects.\n\nMedian time from diagnosis to treatment for all subjects was 24 days with an IQR of 12-40 days for the entire cohort. Similar time to treatment was noted for the hATG/CyA group, with a median time from diagnosis of 23 days and an IQ range of 12-40 days.\n\nResponse\nFor the cohort of 314 patients and for the subset treated with hATG/CyA, median time to initial response was six months (range: 3-48 months; IQR: 3-12 months). Best responses for all patients and for the hATG/CyA group are summarized in Tables 4 and 5.\n\nTable 4. Best response to immunosuppressive therapy.\n\nTable 5. Response outcome in each treatment group.\n\nFor the 264 subjects treated with hATG/CyA, OR was 71.2% (95%CI: 65.3,76.6), consistent with results from prior adult and pediatric studies.8,9,16-20 The quality of response to hATG/CyA was good, with 59.8% (95%CI: 53.7,65.8) achieving a CR. Further, since the magnitude of a partial platelet response carries clinical implications for quality of life, the group attaining a deep response (Plts ≥50×109/L) was separately analyzed. A deep response was achieved by 68.2% (95%CI: 62.2,73.8). No response (NR) was noted in 66 subjects (25%) and 10 subjects (3.8%) were not evaluable (NE, Tables 4 and 5). Responses at six months post hATG/CyA were as follows: CR 21.6%, VGPR 19.7%, PR 8%, NR 47%, NE 3.7%.\n\nThe duration of response among subjects who had any initial response (CR, VGPR, or PR) is shown for all subjects (Figure 2A) and for those treated with hATG/CyA (Figure 2B). The estimated probability of sustained response for all subjects was 94% (95%CI: 89,96) at 24 months and 83% (95%CI: 76,88) at 60 months. For the subset of subjects treated with hATG/CyA, the estimated probability of sustained response was 94% (95%CI: 90,97) at 24 months and 84% (95%CI: 76,90) at 60 months. However, there was no plateau for loss of response observed over time even after five years post treatment.\n\nFigure 2. Duration of response. Kaplan-Meier analysis of duration of response for (A) all subjects or (B) subjects treated with horse anti-thymocyte globulin (rATG)/cyclosporine (CyA) who achieved at least a partial response.\n\nFactors potentially affecting OR or DR for subjects treated with hATG/CyA were evaluated. No correlation with response was detected for telomere lengths <1st or <10th percentiles by flow-FISH, presence of a PNH clone, or red cell macrocytosis (mean corpuscular volume ≥100 fL) (P ≥0.17) (Online Supplementary Table S1). There was also no correlation between OR and median lymphocyte count (1.1 vs. 1.3;Wilcoxon rank sum test, P=0.51). There was no significant difference in median time from diagnosis to treatment between responders and non-responders (P≥0.29) (Online Supplementary Table S1).\n\nSurvival\nThe estimated overall survival is summarized in Figure 3. Median follow up amongst all 314 subjects was 62 months (59 months for those still alive) and 61 months among the hATG/CyA group (59 months for those still alive). At the time of this analysis, there were 29 (9.3%) deaths amongst all subjects; 21 (8%) amongst hATG/CyA-treated patients. Estimated OS (95%CI) for the entire cohort at 12, 24 and 60 months was 96% (95%CI: 94,98), 95% (92,97), and 92% (88,95), respectively (Figure 3A). Among the subjects who received hATG/CyA, estimated OS (95% CI) at 12, 24 and 60 months was 97% (94,99), 96% (93,98), and 93% (89,96), respectively (Figure 3B). Six individuals died after one treatment with hATG/CyA without receiving additional therapy.\n\nFigure 3. Immunosuppressive therapy: survival. Kaplan-Meier analysis of overall survival for (A) all subjects or (B) subjects treated with horse anti-thymocyte globulin (rATG) / cyclosporine (CyA). Kaplan-Meier analysis of event-free survival for (C) all subjects or (D) subjects treated with hATG/CyA.\n\nOf the 314 subjects, 119 (38%) died or required an additional therapy. The estimated EFS (95%CI) for all subjects at 12, 24, and 60 months was 76% (95%CI: 70,80), 71% (95%CI: 66,76), and 62% (95%CI: 56,68), respectively (Figure 3C). The estimated median EFS for all subjects was 133 months. For patients treated with hATG/CyA, 98 of 264 subjects (37%) had an event. Median estimated EFS was 133 months (Figure 3D). Estimated EFS (95%CI) at 12, 24, and 60 months was 76% (95%CI: 70,81), 72% (95%CI: 66,77), and 64% (95%CI: 57,69), respectively, with events continuing to accrue even after five years post treatment.\n\nNo differences were detected in OS (P=0.13), EFS (P=0.26), or response (P>0.25) versus age at diagnosis for all subjects. No differences were detected in OS (P=0.09), EFS (P=0.22), or response (P>0.20) versus age at diagnosis for subjects treated with hATG/CyA.\n\nCytogenetics and clonal progression\nOf the 271 patients in the cohort who had BM metaphase cytogenetics (n=254) and/or FISH (n=133) assessments performed at diagnosis, seven (3%) had detectable clonal chromosomal abnormalities (Table 6). Six of these patients had follow-up cytogenetic assessments. Two patients had a del(13q) clone at diagnosis, which remained detectable through the duration of follow up (range: 33-49 months) but was not associated with acquisition of additional chromosomal abnormalities. In contrast, other small clones present at diagnosis, including del(7q) in one patient and del(16q) in one patient, were no longer detectable at follow-up assessment.\n\nTable 6. Clonal cytogenetic abnormalities at diagnosis and at follow up.\n\nOf the 171 total patients who had follow-up BM metaphase cytogenetics (n=160) and/or FISH (n=109) assessment performed after IST initiation, 12 (7.0%) patients had evidence of new clonal chromosomal abnormalities (Table 7). One additional subject had a clonal abnormality [+der(14;21)(q10;q10)] at 143 months from the time of initial diagnosis; however, the baseline status was unknown. The most common genetic alteration after IST was loss of chromosome 7 [either −7 or del (7q)] occurring in six patients (3.5%), all of whom had normal cytogenetics at baseline. Three patients had a del(13q) clone detected during follow-up BM assessments of which one was acquired after treatment. Among those patients with no clonal abnormalities at presentation, but who subsequently developed abnormalities at follow up, the median time to observe an abnormality was 25.2 months (range: 4.3-71.0 months; IQ range: 5.3-66.6 months). Interestingly, only four patients had BM pathology reports confirming the diagnosis of myelodysplastic syndrome of whom two proceeded to HSCT prior to further clonal evolution. One patient developed acute lymphoblastic leukemia and three developed acute myeloid leukemia.\n\nTable 7. Comparison of baseline cytogenetic clones with subsequent clonal abnormalities.\n\nComplications\nComplications following initiation of IST were common with bleeding (gastrointestinal, intracranial, hematuria or other significant hemorrhage) being most frequent and reported in 74 (23.6%) of all subjects (23.5% of hATG/CyA subjects). Infections, including bacteremia, fungal infections, cellulitis, meningitis, or pneumonia, were reported in 177 (56.4%) of all subjects (53.4% of hATG/CyA subjects). Renal failure requiring dialysis was reported in five patients (1.6%), all in the hATG/CyA group (1.9%). Causes of death classified by type of therapy and survival interval are detailed in Online Supplementary Table S2.\n\nOutcomes after second-line therapy\nSubsequent treatments following upfront hATG/CyA are summarized in Table 8.\n\nTable 8. Subsequent treatments.\n\nOverall, 110 of 314 (35%) subjects received a second treatment, 35 of the 110 a third treatment, and three a fourth therapy.\n\nOf the 38 patients undergoing HSCT for second-line therapy, response to initial treatment with hATG/CyA was as follows: 31 had refractory disease and seven had relapsed disease. Of the seven patients undergoing HSCT for relapsed disease, responses to initial hATG/CyA at three months and six months were as follows: one CR and six NR at three months; three CR, one VGPR, two NR, and one NE at six months. Of the 52 patients receiving a second IST treatment, response to initial treatment with hATG/CyA was as follows: 36 had refractory disease, 15 had relapsed disease, and one patient lacked available response data. Of the 15 patients undergoing second IST for relapsed disease, responses to initial hATG/CyA at three months and six months were as follows: one CR, one VGPR, one PR, and 12 NR at three months; one CR, four VGPR, five PR, and five NR at six months. Two additional patients received tacrolimus for relapsed disease. Additional information is provided in the Online Supplementary Table S1.\n\nFor the 80 subjects who underwent second-line HSCT therapy, donors included 12 matched sibling donors, 61 matched unrelated donors (MUD), and 7 haplo-identical donors. Stem cell sources within the MUD cohort consisted of 42 from BM, five from peripheral blood, 12 from cord blood, and two without available data. Transplant preparative regimens varied widely both within and between institutions.\n\nOverall survival for patients receiving a second treatment is shown in Figure 4A. Among all subjects (n=110) and the hATG/CyA group (n=92) who received second-line treatment, 20 (18.2%) and 15 (16.3%) died, respectively. In a Cox proportional hazards model, there was no significant effect of time from IST to second treatment on OS for either the entire cohort (HR=1.0, 95%CI: 0.98,1.02; P=0.76) or the hATG/CyA group (HR=0.99, 95%CI: 0.98,1.03; P=0.69). EFS is shown in Figure 4B. Among all subjects receiving second-line treatment (n=110), 49 (44.6%) failed with a median time to failure of 88.5 months (95%CI: 45.6,131.5). Among the 92 subjects from the hATG/CyA group receiving second-line treatment, 43 (46.7%) failed with a median time to failure of 64.4 months (95%CI: 44.2,131.5)\n\nFigure 4. Outcomes after second-line therapy for relapsed/refractory disease. Kaplan-Meier analysis of (A) overall survival and (B) event-free survival for all subjects or subjects treated with horse anti-thymocyte globulin (rATG)/cyclosporine (CyA). (C) Log-rank test was used to compare event-free survival after second-line treatment with hematopoietic stem cell transplantation (HSCT) versus immunosuppressive therapy (IST) for all subjects or subjects treated with hATG/CyA.\n\nOutcomes of second-line treatment with HSCT versus IST were compared for all subjects and for the hATG/CyA treatment group. Among all subjects receiving subsequent treatment (n=110), 45 received HSCT and 65 received IST. Among the hATG/CyA group receiving second-line treatment (n=92), 38 received HSCT and 54 received a second course of IST. Due to the significantly longer follow up with second-line IST as compared to bone marrow transplantation for both the entire cohort (69 vs. 36 months; log rank, P=0.05) and the hATG/CyA group (74 vs. 36 months; log rank, P=0.026), the data were censored at 36 months in the analysis to minimize the impact of differential follow up. The analysis shows that EFS is significantly longer with the second-line treatment of HSCT compared with IST (log rank, P≤0.011) (Figure 4C); this effect remains after adjusting for other variables (Online Supplementary Figure S1).\n\nDiscussion\nWe report a multi-institutional study of the presentation and outcomes of 314 North American pediatric SAA patients treated with IST. Although retrospective studies are limited by potential confounding factors and data availability, this multicenter study provides a contemporary analysis of the diagnostic evaluation and treatment outcomes for pediatric SAA. Since the natural history, risks, benefits, and outcomes of treatments are not identical between children versus adults with SAA, the study of rare diseases such as pediatric SAA requires collaborative effort through large consortia with the goal of improving diagnosis and treatment. As with any rare disease, national registries would greatly advance the prospective study of pediatric aplastic anemia.\n\nAlthough traditionally reticulocytopenia has been used as a diagnostic criterion for SAA, in this large study, reticulocytopenia with an ARC <60×109/L did not correlate with a Hb <8 g/dL in a subset of patients. We found that the majority of clinicians were using clinically significant anemia and need for transfusion, rather than the ARC, to inform diagnosis and initiation of therapy. Indeed, in the setting of severe anemia without BM failure, the reticulocyte count would be expected to be markedly higher, so even an ARC within the normal range may be a sign of impaired erythropoiesis.\n\nRed cell macrocytosis may be indicative of the time frame from evolution of reduced hematopoietic stem cell numbers and clinically significant cytopenias. In addition, red cell macrocytosis may be associated with dysplastic processes. However, no association between macrocytosis and likelihood of hematologic response or survival was observed. Lymphopenia in pediatric patients with other cytopenias may be seen with primary immunological disorders; however, no association with response was observed. Development of cytogenetically abnormal clones or overt hematologic clonal disease was rare, although post-treatment marrow surveillance was not uniformly conducted or captured due to the retrospective nature of this analysis.\n\nA correlation between short leukocyte telomere length at diagnosis, measured by quantitative polymerase chain reaction, with increased risk of relapse, clonal evolution, and reduced survival has been reported.21 Since current clinically available telomere length testing utilizes flow-FISH,13 we explored whether the results of this clinical telomere length assay correlated with outcomes. We did not detect a correlation between telomere lengths less than either the 1st or 10th percentile for age with response to IST.\n\nWe observed some notable differences from reported outcomes for adult SAA patients treated with hATG/CyA. Since the magnitude of blood count recovery is especially important to support normal growth and activity in children, we examined the quality of response to IST. Of those pediatric patients who responded to hATG/CyA, the quality of response was high, with 59.8% achieving a CR and 68.2% achieving a DR. In contrast, typical rates of CR cited for adults is 10%.12 In addition, a lower rate of clonal progression was noted for children in comparison to the 10-15% clonal progression reported in adults, although this observation is potentially limited by the retrospective nature of this study and short follow-up time.22,23 However, EFS was low, with events continuing to accrue well past five years post IST without an apparent plateau. EFS is of particular concern for pediatric patients given their long future lifespan. Accordingly, both clinical decisions and evaluation of new therapies should be based on pediatric data whenever possible, rather than on extrapolation of data from adult cohorts. For patients with refractory or relapsed disease, EFS was superior for patients receiving second-line treatment with HSCT compared with IST even after adjusting for age, gender, time from initial IST to second treatment, and lymphocytopenia. A prospective study of 21 pediatric SAA patients receiving a second course of IST for refractory disease reported anaphylaxis in three patients and a trilineage response in only two (11%) of the remaining 18 patients, with a 5-year failure-free survival of only 9% at five years post second-line therapy.6 Together with the excellent contemporary outcomes of MUD transplantation,24-26 these data strongly suggest that allogeneic transplantation with a MUD is a superior second-line therapy for relapsed or refractory SAA after IST for pediatric patients. In addition, these data suggest a potential role for MUD HSCT as upfront therapy in young patients. A randomized pilot and feasibility trial comparing hATG/CyA versus MUD HSCT in newly diagnosed SAA patients lacking an HLA-matched family donor is currently underway.\n\nSupplementary Material\nRogers et al. Graphical Abstract\n Acknowledgments\nThe authors are grateful to Susan Kornetsky for her guidance and expertise. We also thank Tim Colby, Brian Sheehan, and Melissa Rose for their assistance with this project.\n\nCheck the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/10/1974\n\nFunding\n\nThis project was supported by the Copeman Fund, Julian’s Dinosaur Guild, and an NIH R24 DK 099808 to AS and DAW, the Rauch Family Foundation to TDC, the Campini Foundation to JNH and U54 DK106857 to GMK.\n==== Refs\nReferences\n1. Young NS Bacigalupo A Marsh JC \nAplastic anemia: pathophysiology and treatment . Biol Blood Marrow Transplant . 2010 ;16 (1 Suppl ):S119 -125 .19782144 \n2. Scheinberg P Wu CO Nunez O Young NS \nLong-term outcome of pediatric patients with severe aplastic anemia treated with antithymocyte globulin and cyclosporine . J Pediatr . 2008 ;153 (6 ):814 -819 .18672253 \n3. Kojima S Horibe K Inaba J \nLong-term outcome of acquired aplastic anaemia in children: comparison between immunosuppressive therapy and bone marrow transplantation . Br J Haematol . 2000 ; 111 (1 ):321 -328 .11091219 \n4. Yoshida N Kobayashi R Yabe H \nFirst-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy . Haematologica . 2014 ;99 (12 ):1784 -1791 .25193958 \n5. Kamio T Ito E Ohara A \nRelapse of aplastic anemia in children after immunosuppressive therapy: a report from the Japan Childhood Aplastic Anemia Study Group . Haematologica . 2011 ;96 (6 ):814 -819 .21422115 \n6. Kosaka Y Yagasaki H Sano K \nProspective multicenter trial comparing repeated immunosuppressive therapy with stem-cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia . Blood . 2008 ;111 (3 ):1054 -1059 .17989314 \n7. Garanito MP Carneiro JD Odone Filho V Scheinberg P \nOutcome of children with severe acquired aplastic anemia treated with rabbit antithymocyte globulin and cyclosporine A . J Pediatr (Rio J) . 2014 ; 90 (5 ):523 -527 .24878006 \n8. Dufour C Pillon M Passweg J \nOutcome of aplastic anemia in adolescence: a survey of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation . Haematologica . 2014 ;99 (10 ):1574 -1581 .25085353 \n9. Dufour C Pillon M Socie G \nOutcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant . Br J Haematol . 2015 ;169 (4 ):565 -573 .25683884 \n10. Scheinberg P Nunez O Weinstein B Biancotto A Wu CO Young NS \nHorse versus rabbit antithymocyte globulin in acquired aplastic anemia . N Engl J Med . 2011 ;365 (5 ):430 -438 .21812672 \n11. Williams DA Bennett C Bertuch A \nDiagnosis and treatment of pediatric acquired aplastic anemia (AAA): An initial survey of the North American Pediatric Aplastic Anemia Consortium (NAPAAC) . Pediatr Blood Cancer . 2014 ;61 (5 ):869 -874 .24285674 \n12. Townsley DM Scheinberg P Winkler T \nEltrombopag Added to Standard Immunosuppression for Aplastic Anemia . N Engl J Med . 2017 ;376 (16 ):1540 -1550 .28423296 \n13. Alter BP Baerlocher GM Savage SA \nVery short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita . Blood . 2007 ;110 (5 ):1439 -1447 .17468339 \n14. Camitta BM Storb R Thomas ED \nAplastic anemia (first of two parts): pathogenesis, diagnosis, treatment, and prognosis . N Engl J Med . 1982 ;306 (11 ):645 -652 .7035946 \n15. Camitta BM Storb R Thomas ED \nAplastic anemia (second of two parts): pathogenesis, diagnosis, treatment, and prognosis . N Engl J Med . 1982 ;306 (12 ):712 -718 .7038485 \n16. Frickhofen N Kaltwasser JP Schrezenmeier H \nTreatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group . N Engl J Med . 1991 ;324 (19 ):1297 -1304 .2017225 \n17. Rosenfeld SJ Kimball J Vining D Young NS \nIntensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia . Blood . 1995 ;85 (11 ):3058 -3065 .7756640 \n18. Fuhrer M Burdach S Ebell W \nRelapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group . Klin Padiatr . 1998 ; 210 (4 ):173 -179 .9743949 \n19. Kojima S Hibi S Kosaka Y \nImmunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia . Blood . 2000 ; 96 (6 ):2049 -2054 .10979946 \n20. Bacigalupo A Bruno B Saracco P \nAntilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO) . Blood . 2000 ;95 (6 ):1931 -1934 .10706857 \n21. Scheinberg P Cooper JN Sloand EM Wu CO Calado RT Young NS \nAssociation of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia . JAMA . 2010 ;304 (12 ):1358 -1364 .20858879 \n22. Socie G Rosenfeld S Frickhofen N Gluckman E Tichelli A \nLate clonal diseases of treated aplastic anemia . Semin Hematol . 2000 ;37 (1 ):91 -101 .10676914 \n23. Rosenfeld S Follmann D Nunez O Young NS \nAntithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome . JAMA . 2003 ;289 (9 ):1130 -1135 .12622583 \n24. Samarasinghe S Steward C Hiwarkar P \nExcellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience . Br J Haematol . 2012 ;157 (3 ):339 -346 .22372373 \n25. Anderlini P Wu J Gersten I \nCyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study . Lancet Haematol . 2015 ;2 (9 ):e367 -375 .26685770 \n26. Bacigalupo A Giammarco S Sica S \nBone marrow transplantation versus immunosuppressive therapy in patients with acquired severe aplastic anemia . Int J Hematol . 2016 ;104 (2 ):168 -174 .27278666\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0390-6078",
"issue": "104(10)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000741:Anemia, Aplastic; D000961:Antilymphocyte Serum; D002675:Child, Preschool; D016572:Cyclosporine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007165:Immunosuppression Therapy; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D014481:United States",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "1974-1983",
"pmc": null,
"pmid": "30948484",
"pubdate": "2019-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24878006;10706857;21422115;28423296;7038485;7756640;19782144;10676914;21812672;11091219;9743949;25193958;20858879;17989314;12622583;22372373;25085353;24285674;17468339;25683884;7035946;18672253;10979946;26685770;2017225;27278666",
"title": "Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study.",
"title_normalized": "immunosuppressive therapy for pediatric aplastic anemia a north american pediatric aplastic anemia consortium study"
} | [
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"companynumb": "US-TEVA-2019-US-1142760",
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"patient": {
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"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
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{
"abstract": "An 87-year-old woman with type 2 diabetes noticed a red itchy rash at the insulin injection sites 3 weeks after initiation of premixed insulin therapy. Laboratory data at that time showed marked eosinophilia and progression of renal dysfunction. Insulin treatment was discontinued, and antidiabetic oral drugs were used, as well as intravenous injection of dexamethasone. Her skin lesions disappeared, and both eosinophilia and renal dysfunction gradually improved. The results of skin prick tests and measurement of specific immunoglobulin E antibodies suggested that the insulin allergy was caused by protamine. Although cases of insulin allergy associated with renal dysfunction are rare, we must be aware, especially for elderly patients with poor renal function in the first application of insulin.",
"affiliations": "Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Nanjing Medical University affiliated Wuxi People's Hospital Jiangsu Wuxi, China.;Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Nanjing Medical University affiliated Wuxi People's Hospital Jiangsu Wuxi, China.;Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Nanjing Medical University affiliated Wuxi People's Hospital Jiangsu Wuxi, China.",
"authors": "Wu|Wenjun|W|;Cheng|Haiyan|H|;Bu|Ruifang|R|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1111/jdi.12332",
"fulltext": "\n==== Front\nJ Diabetes InvestigJ Diabetes InvestigjdiJournal of Diabetes Investigation2040-11162040-1124John Wiley & Sons, Ltd Chichester, UK 10.1111/jdi.12332ArticlesCase ReportProtamine-containing insulin allergy and renal dysfunction in a patient with type 2 diabetes Wu Wenjun Cheng Haiyan Bu Ruifang *Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Nanjing Medical University affiliated Wuxi People's HospitalJiangsu Wuxi, China*Correspondence Ruifang Bu Tel.: +86-510-8535-1193 Fax: +86-510-8535-0555 E-mail address: buruifang2003@outlook.com9 2015 03 3 2015 6 5 591 593 19 9 2014 20 12 2014 15 1 2015 © 2015 The Authors. Journal of Diabetes Investigation published by Asian Association of the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.An 87-year-old woman with type 2 diabetes noticed a red itchy rash at the insulin injection sites 3 weeks after initiation of premixed insulin therapy. Laboratory data at that time showed marked eosinophilia and progression of renal dysfunction. Insulin treatment was discontinued, and antidiabetic oral drugs were used, as well as intravenous injection of dexamethasone. Her skin lesions disappeared, and both eosinophilia and renal dysfunction gradually improved. The results of skin prick tests and measurement of specific immunoglobulin E antibodies suggested that the insulin allergy was caused by protamine. Although cases of insulin allergy associated with renal dysfunction are rare, we must be aware, especially for elderly patients with poor renal function in the first application of insulin.\n\nInsulin allergyRenal dysfunctionType 2 diabetes\n==== Body\nIntroduction\nAlthough the widespread use of recombinant human insulin and human insulin analog in patients with diabetes has greatly reduced the incidence of insulin allergy1–3, cases with insulin allergy continue to occasionally present in the clinic. Insulin allergies are varied and can be local or systemic, as well as immediate or delayed1,4. Reports of insulin allergy associated with renal dysfunction are extremely rare. We report herein the case of a patient with type 2 diabetes who showed skin rash, marked eosinophilia and progression of renal dysfunction after insulin therapy.\n\nCase Report\nAn 87-year-old woman had been suffering from type 2 diabetes since 1992. She was intermittently treated with oral hypoglycemic agents and had not been monitoring her blood glucose. The treatment with insulin aspart 30 (Novo Nordisk, Bagsvaerd, Denmark) started when she was admitted to the Neurology Department at Nanjing Medical University affiliated Wuxi People's Hospital, Jiangsu Wuxi, China, because of cerebral infarction. Three weeks later, she noticed a red itchy rash occurring several hours after insulin injection at the injection sites, but neither treatment for the skin lesions nor insulin cessation was practiced. Two months later, for management of her condition, she was admitted to the Endocrinology Department. She had a 50-year history of hypertension leading to renal complication (urinalysis white blood cells [WBC] 0/μL, red blood cells 3.2/μL, protein (+); serum urea 12.7 mmol/L; serum creatinine 203.3 μmol/L before insulin injection). She had been taking amlodipine, pravastatin and aspirin. There was no history of drug-induced or alimentary allergy.\n\nAt the time of admission, the patient had an intradermal induration ranging from 1 cm to 3 cm in diameter at the insulin injection sites. She had no diabetic retinopathy and neuropathy. Her laboratory data showed: peripheral blood WBC 8,900/mm3, eosinophils 9.0%; fasting blood glucose 132.5 mg/dL; glycated hemoglobin 10.9% (96 mmol/mol); urinalysis WBC 283.2/μL, red blood cells 25.9/μL, protein (+), glucose (−), ketone (−); negative urine culture; 24 h urine protein 0.36 g; serum urea 14.8 mmol/L; serum creatinine 250.5 μmol/L.\n\nAfter admission, blood sugar was controlled by subcutaneous injection of insulin aspart 30. On day 3, insulin aspart 30 was replaced by human insulin 30R (Novo Nordisk, Bagsvaerd, Denmark) because of the continuous emergence of a new rash at the insulin injection site. Then, the rash began to subside with oral ketotifen and topical corticosteroid ointment. However, biochemistry suggested a gradual deterioration of renal function. On day 9, there erupted similar skin lesions at the insulin injection sites, and laboratory data at that time showed progression of renal function (serum urea, 25.0 mmol/L; serum creatinine, 362.5 μmol/L) and marked eosinophilia (WBC 10,600/mm3, eosinophils 15.4%), so human insulin 30R was discontinued, and repaglinide (6 mg/day) treatment were initiated, as well as intravenous injection of dexamethasone (5 mg/day). On day 11, skin lesions began to disappear, and eosinophils decreased to 0.10%, but renal function (serum urea, 29.5 mmol/L; serum creatinine, 379.9 μmol/L) did not improve. To restore normal eosinophils, dxamethasone was reduced to 2.5 mg/day. Glutathione was applied intravenously to protect renal function. On day 13, the skin lesions disappeared completely, the eosinophils were maintained in the normal range and serum creatinine began to decline, so dexamethasone was stopped. On day 23, renal function (serum urea 14.4 mmol/L; serum creatinine 238.9 μmol/L) returned to a similar level to that before insulin therapy (Table 1). During hospitalization, immunological tests showed that antinuclear antibody, anti-extractable nuclear antigen antibody spectrum, anti-proteinase 3 antibody, anti-myeloperoxidase antibody and anti-glomerular base membrane antibody were negative, and immunoglobulin (Ig; IgA, IgM, IgG), complement (C3, C4), C-reactive protein and rheumatoid factor were within the normal range. Serum total IgE (68 U/L) was normal. IgE specific for human insulin was <0.35 UA/mL. With the patient's consent, skin prick tests were carried out after her renal function recovered. The results showed that protamine caused a skin reaction, whereas short-acting human insulin (insulin R) or insulin analog (aspart) did not.\n\nTable 1 Laboratory data after admission of the patient\n\nDay after admission\tBlood routine test\tRenal function\t\n\tLeukocyte (×109/L)\tEosinophil (%)\tSerum urea (mmol/L)\tSerum creatinine (μmol/L)\t\nReference normal values\t4–10\t0.5–5\t1.9–7.2\t50–120\t\n1\t8.90\t9.00\t14.80\t250.50\t\n3\t–\t–\t13.80\t255.80\t\n5\t–\t–\t17.50\t290.00\t\n8\t–\t–\t22.30\t338.20\t\n9\t10.60\t15.40\t25.00\t362.50\t\n11\t10.20\t0.10\t29.50\t379.90\t\n13\t11.40\t0.30\t32.20\t349.00\t\n16\t15.50\t3.10\t29.90\t292.00\t\n18\t12.60\t3.00\t21.10\t272.20\t\n23\t9.40\t4.70\t14.40\t238.90\t\nTwo months later, the patient consulted our hospital as an outpatient. Laboratory data showed: peripheral blood WBC 7,900/mm3, eosinophils 1.0%; urinalysis WBC 17.1/μL, red blood cells 4.3/μL, protein (−), glucose (−), ketone (−); serum urea 6.6 mmol/L; serum creatinine 235.3 μmol/L; fasting blood glucose 128.7 mg/dL; glycated hemoglobin 10.1% (87 mmol/mol); and serum C-peptide 7.71 ng/mL (fasting), 9.25 ng/mL (2-h postprandial). According to the result of serum C-peptide, the patient's endogenous insulin secretion was preserved with insulin resistance, and repaglinide was continued to control the blood sugar.\n\nRecently, we acquired information that the patient had passed away, and before her death she was treated with a short-acting insulin without insulin allergy for half a year, which was provided by her family.\n\nDiscussion\nBecause of that patient's clinical features (rash, urine WBC, eosinophilia, deterioration of renal function) acute interstitial nephritis (AIN) was suspected5. After withdrawal of insulin and corticosteroid therapy, her renal function returned to basal. Therefore, we concluded that renal dysfunction was induced by her insulin allergy. There is no relevant literature description, except a similar case reported by Naqai et al.6 in 2001. Common characteristics of two cases were elderly patients, pre-existing kidney disease, parallel changes of renal dysfunction progression with eosinophilia and the key treatment of stopping insulin. We speculate that eosinophilia can be the signal of kidney damage induced by insulin allergy, and that old age and pre-existing kidney disease seem to be predisposing factors for this condition7.\n\nIn their case, Naqai et al.6 confirmed the type of insulin allergy as immediate-type IgE-mediated reactions by skin prick test and increased insulin-specific IgE antibody. In the present case, because of patient's insulin-specific IgE and the skin prick test results, we speculated that protamine was the cause of her insulin allergy. This was further confirmed by the recent information that she was treated with a short-acting insulin without insulin allergy for half a year. Renal pathology showed that cell-mediated immune mechanisms seemed to be more important than humorally-mediated mechanisms in the pathogenesis of AIN5. However, renal biopsy was not made in the present case, because of the patient's refusal. Because of a delayed onset after insulin injection and induration at the injection site, we tend to consider the type of insulin allergy in our case as delayed type hypersensitivity reactions8.\n\nDisclosure\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Schernthaner G Immunogenicity and allergic potential of animal and human insulins Diabetes Care 1993 16 155 165 8299472 \n2 Kumar D Lispro analog for treatment of generalized allergy to human insulin Diabetes Care 1997 20 1357 1359 9283778 \n3 Airaghi L Lorini M Tedeschi A The insulin analog aspart: a safe alternative in insulin allergy Diabetes Care 2001 24 2000 11679473 \n4 Fernandez L Duque S Montalban C Allergy to human insulin Allergy 2003 58 1317 14616113 \n5 Kodner CM Kudrimoti A Diagnosis and management of acute interstitial nephritis Am Fam Physician 2003 67 2527 2534 12825841 \n6 Naqai Y Mori T Abe T Immediate-Type allergy against human insulin associated with marked eosinophilia in type 2 diabetic patient Endocr J 2001 48 311 316 11523901 \n7 Wang YC Lin YF Chao TK Acute interstitial nephritis with prominent eosinophil infiltration Clin Nephrol 2009 71 187 1891 19203513 \n8 Heinzerling L Raile K Rochlitz H Insulin allergy: clinical manifestations and management strategies Allergy 2008 63 148 155 18186805\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2040-1116",
"issue": "6(5)",
"journal": "Journal of diabetes investigation",
"keywords": "Insulin allergy; Renal dysfunction; Type 2 diabetes",
"medline_ta": "J Diabetes Investig",
"mesh_terms": null,
"nlm_unique_id": "101520702",
"other_id": null,
"pages": "591-3",
"pmc": null,
"pmid": "26417419",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": "14616113;9283778;19203513;18186805;11523901;12825841;8299472;11679473",
"title": "Protamine-containing insulin allergy and renal dysfunction in a patient with type 2 diabetes.",
"title_normalized": "protamine containing insulin allergy and renal dysfunction in a patient with type 2 diabetes"
} | [
{
"companynumb": "CN-NOVOPROD-464826",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INSULIN HUMAN"
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"drugadditional": null,
... |
{
"abstract": "Vasculitides, particularly those affecting small vessels, are known to complicate systemic lupus erythematosus (SLE); however, isolated venulitis of the mesenteric bed has rarely been reported. Here we relate the case of a 46-year-old woman with SLE who presented with acute abdominal pain due to artery thrombosis and extended splenic ischemia requiring splenectomy. The histological examination revealed diffuse venulitis in the absence of arterial vasculitis consistent with the definition of mesenteric inflammatory veno-occlusive disease (MIVOD). Furthermore, arterial wall thickening suggestive of uncomplicated atherosclerosis was observed. Two months later, the patient suffered of severe myocardial infarction (MI) resulting from thrombosis of the anterior interventricular coronary artery with otherwise no signs of coronary disease at coronarography. Extensive work-up to establish the cause of MI was negative, with the exception of marginal, isolated and transient elevation of cardiolipin IgG (14.5 GPL, n.v. 0-5 GPL). This patient's SLE history is dramatically marked by the previously non-described association of MIVOD and two arterial thrombotic events (splenic and coronary) occurring within a two months period, and stresses the need of better understanding and prevention of vascular complications in SLE.",
"affiliations": "1 Immunology and Allergy, Department of Internal Medicine Specialties, University Hospital and School of Medicine, Geneva, Switzerland.;2 Department of Pathology, University Hospital and School of Medicine, Geneva, Switzerland.;1 Immunology and Allergy, Department of Internal Medicine Specialties, University Hospital and School of Medicine, Geneva, Switzerland.",
"authors": "Allali|D|D|;Puppa|G|G|;Chizzolini|C|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0961203317700980",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "27(1)",
"journal": "Lupus",
"keywords": "MIVOD; SLE; Systemic lupus erythematosus; arterial thrombotic events; mesenteric inflammatory veno-occlusive disease",
"medline_ta": "Lupus",
"mesh_terms": "D005260:Female; D006801:Humans; D007511:Ischemia; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D009203:Myocardial Infarction; D013152:Splanchnic Circulation; D013156:Splenectomy; D013158:Splenic Diseases; D013927:Thrombosis",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "150-153",
"pmc": null,
"pmid": "28355983",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mesenteric inflammatory veno-occlusive disease of the spleen metasynchronous with two arterial thrombotic events in systemic lupus erythematosus.",
"title_normalized": "mesenteric inflammatory veno occlusive disease of the spleen metasynchronous with two arterial thrombotic events in systemic lupus erythematosus"
} | [
{
"companynumb": "CH-BAYER-2018-009053",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "ASPIRIN"
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{
"abstract": "Akathisia, a distressing movement disorder induced by butyrophenones, has been described with low doses of droperidol used for postoperative nausea and vomiting (PONV) prophylaxis, but the incidence remains unclear.\n\n\n\nTo determine the incidence of akathisia after PONV prophylaxis with two doses of droperidol in comparison with ondansetron, in patients undergoing ambulatory surgery. We hypothesised that the incidence of akathisia is higher with droperidol than that with ondansetron.\n\n\n\nRandomised controlled double blind trial.\n\n\n\nTwo University Hospital Centres and two private Clinics from January to September 2014.\n\n\n\nPatients (n=297) undergoing general anaesthesia for ambulatory surgery were randomly allocated to receive PONV prophylaxis with droperidol (0.625 or 1.25 mg) or ondansetron 4 mg; patients of the three groups also received 4 mg of dexamethasone. Exclusion criteria were contraindication to droperidol and ondansetron, use of psychotropic medications or benzodiazepines or history of psychotic illness.\n\n\n\nParticipants received droperidol (0.625 or 1.25 mg) or ondansetron 4 mg during general anaesthesia. After discharge from the postanaesthesia care unit presence and severity of akathisia were assessed using the Barnes Akathisia Rating Scale at 4 h postoperatively.\n\n\n\nScore of the Global Clinical Assessment of Akathisia of Barnes Akathisia Rating Scale.\n\n\n\nThe number of akathisia observed was 1/118 (0.8%) in the ondansetron group, 1/84 (1.2%) in droperidol 0.625 mg group, and 3/87 (3.4%) in droperidol 1.25 mg group. The akathisia rate difference among the three groups was not significant (P = 0.52). We could not demonstrate significant differences in the incidence of akathisia between the two doses of droperidol. The only case of marked akathisia treated with benzodiazepines was observed after droperidol 1.25 mg.\n\n\n\nThe use of droperidol or ondansetron for PONV prophylaxis is associated to a low incidence of akathisia (0.8 to 3.4%) after general anaesthesia for ambulatory surgery.\n\n\n\nClinicaltrials.gov: NCT01942343.",
"affiliations": "From the Department of Anaesthesiology and Intensive Care, Hautepierre-CCOM, and EA 3072, Strasbourg University Hospital (AC, AR, VF, PD), Department of Anaesthesiology, Clinique Rhéna, Strasbourg, France (NG, YN), Department of Anaesthesiology and Pain Management, University of Texas Southwestern Medical School, Dallas, Texas, USA (GPJ) and GMRC, Public Health Service, Strasbourg University Hospital, Strasbourg, France (NM).",
"authors": "Charton|Antoine|A|;Greib|Nicolas|N|;Ruimy|Aude|A|;Faitot|Valentina|V|;Noudem|Yves|Y|;Joshi|Girish P|GP|;Meyer|Nicolas|N|;Diemunsch|Pierre|P|",
"chemical_list": "D000932:Antiemetics; D017294:Ondansetron; D004329:Droperidol",
"country": "England",
"delete": false,
"doi": "10.1097/EJA.0000000000000821",
"fulltext": null,
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"issn_linking": "0265-0215",
"issue": "35(12)",
"journal": "European journal of anaesthesiology",
"keywords": null,
"medline_ta": "Eur J Anaesthesiol",
"mesh_terms": "D000328:Adult; D017109:Akathisia, Drug-Induced; D000556:Ambulatory Surgical Procedures; D000932:Antiemetics; D004311:Double-Blind Method; D004329:Droperidol; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D017294:Ondansetron; D056990:Post-Exposure Prophylaxis; D020250:Postoperative Nausea and Vomiting",
"nlm_unique_id": "8411711",
"other_id": null,
"pages": "966-971",
"pmc": null,
"pmid": "29746373",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Incidence of akathisia after postoperative nausea and vomiting prophylaxis with droperidol and ondansetron in outpatient surgery: A multicentre controlled randomised trial.",
"title_normalized": "incidence of akathisia after postoperative nausea and vomiting prophylaxis with droperidol and ondansetron in outpatient surgery a multicentre controlled randomised trial"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1081192",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Double- and triple-hit lymphomas (DHL/THL) are aggressive B-cell neoplasms characterized by translocation of MYC with concurrent BCL2 and/or BCL6 translocation. In this retrospective study from one institution, we report clinicopathologic features of 13 cases (9 DHL/4 THL). The median age was 59 years (range 30-74) and patients included eight females and five males. Presentation included enlarging lymphadenopathy/masses (11 patients) and abnormal peripheral blood findings (2 patients). Features which raised the differential of an immature neoplasm included terminal deoxynucleotidyl transferase positivity (four cases, two THL/two DHL); dim CD45 expression (seven cases), lack of CD20 (two cases), or lack of surface immunoglobulin light chain (three cases) by flow cytometry; and blastoid morphology (two cases). We conclude that expression of TdT in a B-cell lymphoma with mature features or expression of surface light chain in a case otherwise suggestive of B-lymphoblastic leukemia/lymphoma should prompt an expedited evaluation for DHL/THL.",
"affiliations": "a Department of Laboratory Medicine and Pathology , University of Minnesota , Minneapolis , MN , USA ;;b Department of Medicine, Division of Hematology, Oncology, and Transplantation , University of Minnesota , Minneapolis , MN , USA.;a Department of Laboratory Medicine and Pathology , University of Minnesota , Minneapolis , MN , USA ;;a Department of Laboratory Medicine and Pathology , University of Minnesota , Minneapolis , MN , USA ;;a Department of Laboratory Medicine and Pathology , University of Minnesota , Minneapolis , MN , USA ;;a Department of Laboratory Medicine and Pathology , University of Minnesota , Minneapolis , MN , USA ;",
"authors": "Moench|Laura|L|;Sachs|Zohar|Z|;Aasen|Garth|G|;Dolan|Michelle|M|;Dayton|Vanessa|V|;Courville|Elizabeth L|EL|",
"chemical_list": "D014408:Biomarkers, Tumor; D004253:DNA Nucleotidylexotransferase",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2016.1143939",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "57(11)",
"journal": "Leukemia & lymphoma",
"keywords": "B lymphoblastic leukemia/lymphoma; B-cell lymphoma unclassifiable; diffuse large B-cell lymphoma; double-hit lymphoma; triple-hit lymphoma",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D003131:Combined Modality Therapy; D004253:DNA Nucleotidylexotransferase; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012189:Retrospective Studies",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2626-35",
"pmc": null,
"pmid": "26892631",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": "3285208;20118770;23348205;21411790;25060588;8401180;24179151;23658934;10705823;23335369;25828391;21119107;25529125;25125624;20498406;21718139;26276770;19597184;17074591;23341189;1958753;22623514;23205706;18024371;3186743;19535347;20660329;23907319;21156254;23959583;12197512;23573328;24913655;24701632;2278969;18089500",
"title": "Double- and triple-hit lymphomas can present with features suggestive of immaturity, including TdT expression, and create diagnostic challenges.",
"title_normalized": "double and triple hit lymphomas can present with features suggestive of immaturity including tdt expression and create diagnostic challenges"
} | [
{
"companynumb": "US-JNJFOC-20161129061",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nNivolumab is a programmed death 1 (PD-1) inhibitor approved by the Food and Drug Administration (FDA) for the treatment of eight different cancers including metastatic melanoma. Immune checkpoint blockade may lead to a range of neurologic immune-related adverse events (irAEs) with severity varying from mild to life-threatening, including encephalitis.\n\n\nMETHODS\nWe describe a case of a 68-year-old man who developed alteration in mental status, physical weakness and fatigue after nine cycles of nivolumab 3 mg/kg every two weeks. These symptoms were compatible with a clinical diagnosis of autoimmune limbic encephalitis, although no specific antibodies were detected and the initial MRI was normal.\nThe patient received intravenous methylprednisolone 1 g daily for 5 days, which was then converted to a maintenance dose of oral prednisone. The patient made a full clinical recovery but relapsed clinically upon steroid tapering, while hypersignal in the left mesial temporal suggestive of limbic encephalitis was observed on repeated MRI.\n\n\nCONCLUSIONS\nBecause of the prevailing usage of nivolumab in many cancer protocols, this case highlights the importance of rapidly recognising neurological impairment in patients treated with nivolumab and of initiating very high doses of corticosteroids.",
"affiliations": "Faculty of Pharmacy, Université de Montréal, Montréal, Canada.;Faculty of Pharmacy, Université de Montréal, Montréal, Canada.;Faculty of Pharmacy, Université de Montréal, Montréal, Canada.;Department of Neurosciences, Centre hospitalier de l'Université de Montréal, Montréal, Canada.;CHUM Research Center, CHUM, Montréal, Canada.;CHUM Research Center, CHUM, Montréal, Canada.;Department of Pharmacy, Centre hospitalier de l'Universite de Montreal, Montreal, Canada.",
"authors": "Taillefer|Vincent-Thierry|VT|https://orcid.org/0000-0002-7844-1821;Pigeon|Marjorie|M|;Chen|Michelle|M|;Larochelle|Catherine|C|;Florescu|Marie|M|;Bélanger|Karl|K|;Adam|Jean-Philippe|JP|https://orcid.org/0000-0002-7938-0944",
"chemical_list": "D000077594:Nivolumab; D011241:Prednisone; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220904147",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(6)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Immunotherapy; immune-related adverse events; limbic encephalitis; neurotoxicity; nivolumab",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D001327:Autoimmune Diseases; D006801:Humans; D020363:Limbic Encephalitis; D008297:Male; D008545:Melanoma; D008775:Methylprednisolone; D000077594:Nivolumab; D011241:Prednisone",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1538-1543",
"pmc": null,
"pmid": "32063105",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Very high-dose methylprednisolone for treatment of nivolumab-induced limbic encephalitis: A case report.",
"title_normalized": "very high dose methylprednisolone for treatment of nivolumab induced limbic encephalitis a case report"
} | [
{
"companynumb": "CA-TEVA-2020-CA-1846367",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "A 45-year-old Japanese man presenting with leg purpura, abdominal pain, and arthralgia was diagnosed with IgA vasculitis. His symptoms resolved after the intravenous administration of prednisolone. However, on day 20 of admission, he experienced bloody discharge and hypovolemic shock. The bleeding point was not identified on contrast-enhanced computed tomography scanning. The blood loss was approximately 10800ml and the patient received transfusions of 48 units of concentrated red blood cells, 18 units of fresh frozen plasma, and 30 units of concentrated platelets. Laparotomy and enteroscopy were performed through the incision of the jejunum to detect the bleeding source. Spurting bleeding was observed during the enteroscopy and partial resection of the jejunum was performed. Histopathological examination of the resected specimen revealed large vessels beneath the jejunal ulcer scar, suggesting bleeding from a Dieulafoy's lesion. Leukocytoclastic vasculitis or cytomegalovirus infection was not observed in the resected specimen. Gastrointestinal symptoms in patients with IgA vasculitis usually improve with bowel rest and conservative treatment. Administration of steroids or factor XIII is recommended for patients with severe abdominal pain refractory to conservative management. Rarely, massive bleeding, perforation, intussusception, and/or intestinal obstruction occur in the gastrointestinal tract and these complications affect patients' prognoses. The clinical course in the present patient indicated that severe bleeding from the gastrointestinal tract can occur even after symptom remission in patients with IgA vasculitis. In such cases, prompt treatment, including laparotomy and/or enteroscopy, is essential.",
"affiliations": "Center for Graduate Medical Education, Okayama University Hospital.;Department of Gastroenterology and Hepatology, Okayama University Hospital.;Department of Gastroenterology and Hepatology, Okayama University Hospital.;Department of Gastroenterology and Hepatology, Okayama University Hospital.;Department of Gastroenterology and Hepatology, Okayama University Hospital.;Department of Gastroenterological Surgery, Okayama University Hospital.;Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center.;Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center.;Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center.;Department of Gastroenterology and Hepatology, Okayama University Hospital.",
"authors": "Yamauchi|Nao|N|;Iwamuro|Masaya|M|;Kawano|Seiji|S|;Yamazaki|Tatsuhiro|T|;Baba|Yuki|Y|;Tsumura|Tomoko|T|;Hara|Yuta|Y|;Kataoka|Junro|J|;Toyokawa|Tatsuya|T|;Okada|Hiroyuki|H|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007070:Immunoglobulin A; D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.117.64",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "117(1)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007070:Immunoglobulin A; D007583:Jejunum; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D014657:Vasculitis; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "64-71",
"pmc": null,
"pmid": "31941858",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "IgA vasculitis with massive hemorrhage from the jejunum after steroid administration.",
"title_normalized": "iga vasculitis with massive hemorrhage from the jejunum after steroid administration"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1796809",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "A 69-year-old man was diagnosed with multiple myeloma (IgG-κ) in January 2012. He received autologous hematopoietic stem cell transplantation in August 2012 and subsequently maintained a stringent complete remission. In March 2016, he relapsed and was treated with lenalidomide and low-dose dexamethasone (Ld). On day22, he developed an asymptomatic venous thromboembolism (VTE) despite receiving prophylactic aspirin treatment. Thus, heparin and warfarin were administered. However, his prothrombin time-international normalized ratio did not remain within the target range of 2-3. Therefore, 10 mg/day of apixaban, a factor Xa inhibitor, was administered. The apixaban treatment resulted in favorable and effective control of the patient's VTE on day33. He has continued to receive Ld treatment and has suffered no further VTE or bleeding. Further large studies are needed to assess the efficacy and safety of factor Xa inhibitors for the treatment of MM-associated VTE.",
"affiliations": "Division of Hematology, Japanese Red Cross Society Wakayama Medical Center.",
"authors": "Oka|Satoko|S|;Takeuchi|Suguru|S|;Shiragami|Hiroshi|H|;Hamahata|Keigo|K|;Nohgawa|Masaharu|M|",
"chemical_list": "D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.37",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(1)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D065427:Factor Xa Inhibitors; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D009101:Multiple Myeloma; D011720:Pyrazoles; D011728:Pyridones; D013792:Thalidomide; D016896:Treatment Outcome; D054556:Venous Thromboembolism",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "37-41",
"pmc": null,
"pmid": "28190864",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful management of venous thromboembolism with apixaban in a multiple myeloma patient on lenalidomide therapy.",
"title_normalized": "successful management of venous thromboembolism with apixaban in a multiple myeloma patient on lenalidomide therapy"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-146858",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "Alopecia areata is an autoimmune disease involving the hair follicle with a chronic, relapsing course. Tofacitinib is Janus kinase inhibitor approved for treatment of rheumatoid arthritis that has been shown to be effective in treatment of alopecia areata. We present a case series of 11 patients with severe alopecia areata on longstanding, regular to high dose oral tofacitinib with marked hair regrowth. Additionally, we present a case of moderate to severe alopecia areata successfully treated with topical tofacitinib cream. J Drugs Dermatol. 2018;17(7):800-803.",
"affiliations": null,
"authors": "Cheng|Michelle W|MW|;Kehl|Amy|A|;Worswick|Scott|S|;Goh|Carolyn|C|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "17(7)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000279:Administration, Cutaneous; D000284:Administration, Oral; D000328:Adult; D000506:Alopecia Areata; D005260:Female; D005500:Follow-Up Studies; D018859:Hair Follicle; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "800-803",
"pmc": null,
"pmid": "30005104",
"pubdate": "2018-07-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Severe Alopecia Areata With Oral or Topical Tofacitinib.",
"title_normalized": "successful treatment of severe alopecia areata with oral or topical tofacitinib"
} | [
{
"companynumb": "US-PFIZER INC-2019213446",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOFACITINIB CITRATE"
},
"drugadditional": null... |
{
"abstract": "Allograft infections post lung transplantation have a significant impact on morbidity and mortality. We report a rare case of triple viral infection with adenovirus, Herpes Simplex virus (HSV) and Cytomegalovirus (CMV) in a lung transplant recipient.",
"affiliations": "Newark Beth Israel medical Center, Division of Infectious Disesases, 201 Lyons Ave, G-3, Newark, NJ 07112, United States.;Newark Beth Israel medical Center, Division of Infectious Disesases, 201 Lyons Ave, G-3, Newark, NJ 07112, United States.;Newark Beth Israel medical Center, Division of Infectious Disesases, 201 Lyons Ave, G-3, Newark, NJ 07112, United States.",
"authors": "Nagarakanti|Sandhya|S|;Bishburg|Eliahu|E|;Bapat|Anita|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2018.01.011",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(17)30242-110.1016/j.idcr.2018.01.011ArticleAdenovirus, herpes simplex virus and cytomegalovirus infection in a lung transplant recipient Nagarakanti Sandhya snalmas@yahoo.com⁎Bishburg Eliahu Bapat Anita Newark Beth Israel medical Center, Division of Infectious Disesases, 201 Lyons Ave, G-3, Newark, NJ 07112, United States⁎ Corresponding author. snalmas@yahoo.com02 2 2018 2018 02 2 2018 11 91 93 15 12 2017 12 1 2018 12 1 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Allograft infections post lung transplantation have a significant impact on morbidity and mortality. We report a rare case of triple viral infection with adenovirus, Herpes Simplex virus (HSV) and Cytomegalovirus (CMV) in a lung transplant recipient.\n==== Body\nCase report\nA 24 year old female was admitted with shortness of breath of 2 weeks duration. The patient’s past medical history was significant for end stage bronchiectasis and common variable immunodeficiency for which she underwent double lung transplant (CMV donor negative/recipient positive) 3 months prior to the current admission. She denied any fever, chills, cough or diarrhea. There was no history of any sick contacts or recent travel. The patient was maintained on tacrolimus, prednisone, voriconazole, and valganciclovir post-transplant.\n\nOn admission, the patient was febrile to 101 °F, tachypneic with a respiratory rate of 36/min, blood pressure 90/55 mm Hg, and pulse rate 130 beats/min. On examination, she was noted to have blistering lesions with crusts over lips, coarse breath sounds bilaterally. The remainder of the examination was normal. Laboratory studies revealed W3200 BCE/cmm with 77% neutrophils, hemoglobin 7.5 g/dL, platelets 152 × 103/μL, blood urea nitrogen 37 mg/dL, creatinine 1.41 mg/dL with normal liver enzymes. Blood cultures remained sterile for 5 days. CT of the chest revealed bilateral patchy and confluent infiltrates with areas of consolidations with involvement of the lung apices and small bilateral pleural effusions. (Fig. 1) The patient was intubated and placed on mechanical ventilation.Fig. 1 CT Chest showing bilateral confluent infiltrates with consolidations and small bilateral pleural effusions.\n\nFig. 1\n\nRespiratory cultures grew vancomycin resistant Enterococcus faecalis and the patient was started on linezolid. She continued to require high oxygen. Bronchoscopy with bronchoalvelolar lavage (BAL) and a biopsy were performed. Immunohistochemical stains were positive for both adenovirus and HSV, but negative for CMV (Fig. 2). A BAL HSV1 PCR viral load was 1.3 × 107 copies/mL and BAL adenovirus PCR was positive but not quantified. Serum HSV PCR was 58,800 copies/mL, and serum adenovirus PCR was 1,56,460 copies/mL, serum CMV PCR was 646 copies/mL.Fig. 2 Immunohistochemical staining showing adenovirus (Low power).\n\nFig. 2\n\nThe patient was started on intravenous cidofovir at 1 mg/kg three times a week with pretreatment with probenecid and normal saline. Oral prophylactic valganciclovir was changed to intravenous ganciclovir. Antiviral treatment was given for 4 weeks with complete resolution of her respiratory distress with clearance of HSV, CMV and adenovirus viral loads, but without significant changes on CT scan of the chest. She was eventually extubated and was discharged to a rehabilitation facility on oral valganciclovir. Few weeks after discharge, she was readmitted with respiratory distress, again requiring mechanical ventilator. She had negative serum viral PCR for all 3 viruses but had progressive respiratory failure and expired. A limited lung autopsy was consistent with acute pneumonia associated with extensive necrosis and abscess formation and immunohistochemical stain was positive for adenovirus predominantly in the lower left lobe (the area of infarction). HSV and CMV stains were negative on immunohistochemical stain (Fig. 3).Fig. 3 Immunohistochemical stain showing adenovirus (high power).\n\nFig. 3\n\nDiscussion\nHSV is a double stranded DNA virus, belongs to the family Herpesviridae. The overall incidence of HSV infections in lung transplant recipients is about 18%. Most of the cases of HSV occur in the immediate post-transplant period. HSV pneumonia tends to be florid with extensive necrosis and the presence of infected cells with intranuclear ground glass inclusions and occasional Cowdry type A inclusions. Rapid treatment with high dose acyclovir (10 mg/kg) is critical as the disease may be fatal if untreated. The use of HSV PCR both in BAL and serum greatly improves the diagnostic accuracy.\n\nAdenovirus is a non-enveloped double stranded DNA virus, belongs to the family Adenoviridae. The incidence of adenovirus infection in solid organ transplant recipients is unknown [1]. Higher incidence is seen in patients with donor positive/recipient negative adenovirus status. BAL offers a good diagnostic and prognostic tool. Histopathology with immune-staining remains the gold standard. Early diagnosis is critical in the management of adenoviral infections as the delay of anti-viral treatment increases the likelihood of treatment failure [2]. Serum PCR testing offers the possibility for earlier diagnosis of adenovirus infection. A positive qualitative serum adenovirus PCR may predict subsequent disseminated infection in 75% [2]. The use of cidofovir in adenovirus infections is based on bone marrow transplant recipients’ data, with an efficacy of about 50% in patients with disseminated disease [3].\n\nThe incidence of CMV infection in solid organ transplant recipients varies according to the transplanted organ and is particularly high in lung transplantation, reaching 40–50% [4]. The incidence of CMV viremia without end organ damage is approximately 30% with high risk of infections seen in CMV donor positive and recipient negative. Prophylactic use of ganciclovir has significantly decreased the incidence. CMV viral loads >1000 copies/ml are more likely to be associated with high risk of CMV disease [5].\n\nOur patient had a low CMV viral load with no evidence of end organ damage. The low level CMV viremia could have possibly potentiated the pathogenicity of the other two viruses and thought that pneumonia was caused by adenovirus and HSV in our patient with CMV Viremia as reactivation of the virus. The concept of viral interaction in transplant recipients was hypothesized to enhance pathogenicity by either virus–virus interaction or virus – host interaction resulting from modulation of the host cell immune function or production of suppressive cytokines [6].\n\nTo our knowledge, there are no reported cases of co-Infection with HSV and adenovirus in a lung transplant recipient.\n==== Refs\nReferences\n1 Ison M.G. Adenovirus infections in transplant recipients Clin Infect Dis 43 August (3) 2006 331 339 16804849 \n2 Echavarría M. Adenoviruses in immunocompromised hosts Clin Microbiol Rev 21 October (4) 2008 704 715 18854488 \n3 Florescu M.C. Miles C.D. Florescu D.F. What do we know about adenovirus in renal transplantation? Nephrol Dial Transplant 28 August (8) 2013 2003 2010 23493328 \n4 Azevedo L.S. Pierrotti L.C. Abdala E. Costa S.F. Strabelli T.M. Campos S.V. Cytomegalovirus infection in transplant recipients Clinics (Sao Paulo) 70 July (7) 2015 515 523 26222822 \n5 Hadaya K. Wunderli W. Deffernez C. Martin P.Y. Mentha G. Binet I. Monitoring of cytomegalovirus infection in solid-organ transplant recipients by an ultrasensitive plasma PCR assay J Clin Microbiol 41 August (8) 2003 3757 3764 12904387 \n6 Singh N. Interactions between viruses in transplant recipients Clin Infect Dis 40 3 2005 30 436\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "11()",
"journal": "IDCases",
"keywords": null,
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "91-93",
"pmc": null,
"pmid": "29552490",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "18854488;26222822;15668868;12904387;16804849;23493328",
"title": "Adenovirus, herpes simplex virus and cytomegalovirus infection in a lung transplant recipient.",
"title_normalized": "adenovirus herpes simplex virus and cytomegalovirus infection in a lung transplant recipient"
} | [
{
"companynumb": "US-ASTELLAS-2018US010553",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Transplant centers have historically been reluctant to proceed with kidney transplantation in individuals with plasma cell dyscrasias (PCDs) due to concern for high rates of PCD recurrence and PCD-related mortality. As novel therapies for PCDs have improved hematologic outcomes, strategies to optimize kidney transplantation in individuals with PCD-mediated kidney disease are needed. In this single-center case series we discuss our protocol for the transplantation of individuals with ESKD attributed to PCD as well as the hematologic and allograft outcomes of 12 kidney transplant recipients with ESKD attributed to PCD. Median follow-up time after kidney transplantation was 44 months (IQR 36, 84). All patients had a functioning allograft 1 year after kidney transplantation. 9/12 patients were alive and had a functioning allograft 5 years after kidney transplantation. Five patients experienced relapse of PCD (of whom three responded well to subsequent therapies) and four patients developed secondary malignancies, including three patients with urologic malignancies. This case series demonstrates that patients with kidney disease attributed to PCD have favorable outcomes with kidney transplantation. Transplant evaluation in patients with PCDs should involve a multidisciplinary team of transplant nephrologists and oncologists to select appropriate candidates. Providers should consider screening for urologic malignancies pre- and post-transplantation.",
"affiliations": "Department of Medicine, Division of Nephrology, University of California, San Francisco, California, USA.;Department of Medicine, Division of Hematology/Oncology/Blood and Marrow Transplant, University of California, San Francisco, California, USA.;Department of Medicine, Division of Hematology/Oncology/Blood and Marrow Transplant, University of California, San Francisco, California, USA.;Department of Medicine, Division of Hematology/Oncology/Blood and Marrow Transplant, University of California, San Francisco, California, USA.;Department of Medicine, Division of Nephrology, University of California, San Francisco, California, USA.",
"authors": "Dinh|Alex R|AR|https://orcid.org/0000-0003-4548-9324;Wong|Sandy W|SW|;Martin|Thomas G|TG|;Wolf|Jeffrey L|JL|;Webber|Allison B|AB|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.14541",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": null,
"journal": "Clinical transplantation",
"keywords": "cancer; comorbidities; complication: malignant; malignancy; neoplasia; plasma cells; recipient selection",
"medline_ta": "Clin Transplant",
"mesh_terms": null,
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e14541",
"pmc": null,
"pmid": "34797567",
"pubdate": "2021-11-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of kidney transplant recipients with ESKD due to plasma cell dyscrasia: A case series.",
"title_normalized": "outcomes of kidney transplant recipients with eskd due to plasma cell dyscrasia a case series"
} | [
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"companynumb": "US-MYLANLABS-2022M1038570",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "DEXAMETHASONE"
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"abstract": "Metastatic sarcomatoid renal cell carcinoma (sRCC) is an aggressive variant of RCC with generally poor prognosis. Treatment with vascular endothelial growth factor inhibitors or chemotherapy generates only short-lived responses. Recent research has suggested a role for combination checkpoint inhibition as first line treatment for metastatic sRCC. This therapy consists of induction with cytotoxic T-lymphocyte-associated protein 4 inhibitor, ipilimumab, administered with programmed cell death protein 1 (PD-1) inhibitor, nivolumab. After completion of four cycles of combination therapy, single-agent maintenance nivolumab is recommended until progression. Patients who progress on maintenance nivolumab are switched to alternate therapy. Herein, we present a case of a patient with RCC who progressed on maintenance nivolumab who, on retreatment with ipilimumab, demonstrated a significant response In addition, we summarize important findings to support the role of salvage ipilimumab in patients with sRCC.\n\n\n\nA 46-year-old man presented with flank pain and hematuria, the work up of which noted a left kidney mass for which he underwent nephrectomy and was diagnosed with localized sRCC with 60% sarcomatoid differentiation. Within 3 months of nephrectomy, he presented with recurrent flank pain and was diagnosed with recurrence of disease. He was treated with ipilimumab 1 mg/kg and nivolumab 3 mg/kg for four doses and demonstrated a partial response. He was then transitioned to single agent nivolumab maintenance. After 3 months on maintenance therapy, he was noted to have progression of disease. Given prior response to immune check point combination, it was decided to rechallenge the patient with 1 mg/kg ipilimumab. After two doses of ipilimumab and nivolumab combination therapy, the patient was noted to have a partial response. He maintained a response for an additional 9 months and treatment was eventually discontinued due to grade 3 toxicity and progression.\n\n\n\nThis case report demonstrates the utility of retreatment with ipilimumab as a salvage option for patients progressing on maintenance PD-1 inhibitors in metastatic RCC. Further studies are needed to identify predictors of response and toxicity to this approach, as well as the optimal scheduling of ipilimumab with maintenance nivolumab.",
"affiliations": "Department of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.;Department of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.;Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.;Department of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.;Department of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA dkilari@mcw.edu.",
"authors": "George|Gemlyn|G|;Schmidt|Laura|L|;Tolat|Parag|P|;Riese|Mathew|M|;Kilari|Deepak|D|",
"chemical_list": "D000074324:Ipilimumab; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2020-000584",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32114501\njitc-2020-000584\n10.1136/jitc-2020-000584\nCase Report\n1506\nSalvage ipilimumab associated with a significant response in sarcomatoid renal cell carcinoma\nGeorge Gemlyn 1 Schmidt Laura 1 Tolat Parag 2 Riese Mathew 13 Kilari Deepak 1 \n1 \nDepartment of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA\n\n\n2 \nDepartment of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA\n\n\n3 \nBlood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI 53213, USA\n\nCorrespondence to Dr Deepak Kilari; dkilari@mcw.edu\n2020 \n28 2 2020 \n8 1 e00058404 2 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background\nMetastatic sarcomatoid renal cell carcinoma (sRCC) is an aggressive variant of RCC with generally poor prognosis. Treatment with vascular endothelial growth factor inhibitors or chemotherapy generates only short-lived responses. Recent research has suggested a role for combination checkpoint inhibition as first line treatment for metastatic sRCC. This therapy consists of induction with cytotoxic T-lymphocyte-associated protein 4 inhibitor, ipilimumab, administered with programmed cell death protein 1 (PD-1) inhibitor, nivolumab. After completion of four cycles of combination therapy, single-agent maintenance nivolumab is recommended until progression. Patients who progress on maintenance nivolumab are switched to alternate therapy. Herein, we present a case of a patient with RCC who progressed on maintenance nivolumab who, on retreatment with ipilimumab, demonstrated a significant response In addition, we summarize important findings to support the role of salvage ipilimumab in patients with sRCC.\n\nCase presentation\nA 46-year-old man presented with flank pain and hematuria, the work up of which noted a left kidney mass for which he underwent nephrectomy and was diagnosed with localized sRCC with 60% sarcomatoid differentiation. Within 3 months of nephrectomy, he presented with recurrent flank pain and was diagnosed with recurrence of disease. He was treated with ipilimumab 1 mg/kg and nivolumab 3 mg/kg for four doses and demonstrated a partial response. He was then transitioned to single agent nivolumab maintenance. After 3 months on maintenance therapy, he was noted to have progression of disease. Given prior response to immune check point combination, it was decided to rechallenge the patient with 1 mg/kg ipilimumab. After two doses of ipilimumab and nivolumab combination therapy, the patient was noted to have a partial response. He maintained a response for an additional 9 months and treatment was eventually discontinued due to grade 3 toxicity and progression.\n\nConclusions\nThis case report demonstrates the utility of retreatment with ipilimumab as a salvage option for patients progressing on maintenance PD-1 inhibitors in metastatic RCC. Further studies are needed to identify predictors of response and toxicity to this approach, as well as the optimal scheduling of ipilimumab with maintenance nivolumab.\n\ncase reportsspecial-featureunlocked\n==== Body\nIntroduction\nRenal cell carcinoma (RCC) accounts for approximately 65 000 new cancer cases and 15 000 deaths annually in the USA.1 Sarcomatoid RCC (sRCC) represent a relatively rare subset of cancers of kidney origin with aggressive growth characteristics and pathological similarities to spindle cell sarcomas, including dense cellularity and cellular atypia.2 Approximately 1%–5% of all diagnosed RCCs contain a component of sRCC, which usually becomes the predominant component of tumor during evolution of tumor development.3 Patients with sRCC typically present with metastatic disease at diagnosis.2\n\n\nIndependent of stage at diagnosis, patients with sRCC have a poorer prognosis than patients with pure clear cell RCC, and current treatment approaches have not yielded significant benefit.3 As with other forms of RCC, chemotherapy regimens such as gemcitabine and doxorubicin are of limited therapeutic utility, with median progression-free survival (PFS) and overall survival (OS) of 3.5 months and 8.8 months, respectively.4 Initial studies involving vascular endothelial growth factor (VEGF) inhibitors have not demonstrated improvement in survival3; however, a recent phase II study of sunitinib with gemcitabine demonstrated an overall response rate (ORR) of 26% with a stable disease rate of 38%.5\n\n\nSeveral reports have suggested that sRCC tumor cells express programmed cell death ligand 1 (PD-L1) more frequently when compared with clear cell tumors.6 7 This likely reflects a more inflamed milieu within sRCC, since PD-L1 upregulation is known to result from the presence of type II interferons within the tumor microenvironment.8 Retrospective and prospective data also supports the activity of checkpoint inhibitors in sRCC.9\n\n\nAn updated analysis of a phase II study of atezolizumab and bevacizumab in patients with clear cell sRCC demonstrated an ORR of 53%.10 In the CheckMate 214 study, an exploratory analysis of a sRCC cohort also demonstrated response to immunotherapy with an ORR of 56.7% with nivolumab plus ipilimumab (95% CI 43.2% to 69.4%) versus 19.2% (95% CI 9.6% to 32.5%) with sunitinib (p<0.0001).11\n\n\nWhile the data from immunotherapy in sRCC have been encouraging, many patients do not demonstrate a significant response, and responsive patients eventually develop progression. In this case report, we describe a patient with sRCC who had an initial response with ipilimumab and nivolumab, rapid progression on maintenance nivolumab, and subsequent response with rechallenge of ipilimumab. This report also provides a review of relevant literature on the efficacy of ipilimumab in sRCC.\n\nCase report\nA 46-year-old man presenting with hematuria underwent a diagnostic CT urogram revealing a 14.2×10.6×9.3 cm left renal mass with proximal renal vein thrombosis and retroperitoneal adenopathy. Chest imaging at the time identified small pulmonary nodules which were too small for characterization. The patient underwent a left radical nephrectomy with pathological evaluation identifying a T3N1M0 (14.2×10.6×9.3 cm) renal cell carcinoma with sarcomatoid differentiation (40%).\n\nTwo months after nephrectomy, surveillance scans identified extensive presumed metastases in the abdomen, pelvis and both lungs, with the largest mass consisting of a left renal fossa mass measuring 8.9×3.2 cm. Biopsy of a presumed metastatic lesion in left anterior abdominal wall was consistent with poorly differentiated carcinoma with 50%–60% rhabdoid and sarcomatoid differentiation that stained for Pax-8, suggesting metastatic renal cell carcinoma. The patient was considered poor risk as assessed by IInternational Metastatic RCC Database Consortium.\n\nAfter 3 months on maintenance nivolumab therapy, the size of the patient’s retroperitoneal and abdominal wall metastases approximately doubled as assessed by CT scanning of the abdomen and pelvis (figure 1). In consideration of possible subsequent treatments, we noted the patient’s prior response to ipilimumab, previous tolerance of combined immunotherapy, good performance status, and sRCC histology which has historically poor outcomes with VEGF inhibitors. Given this information, it was decided to retreat the patient with ipilimumab 1 mg/kg along with continued nivolumab 3 mg/kg every 3 weeks. A partial response was demonstrated on imaging after two additional doses of ipilimumab plus nivolumab, with all but one lesion shrinking by more than 50 per cent (see figure 2, table 1). The patient remained on combined immune checkpoint blockade therapy for a total of 9 months with stable disease before treatment was discontinued due to grade 3 fatigue, arthralgias and progression of disease in the right ventricle alone.\n\nFigure 1 Progression of disease while on nivolumab maintenance therapy only Follow-up CT with contrast after 4 months of nivolumab maintenance therapy only demonstrating marked progression of disease with enlarging left retroperitoneal (red arrows) and abdominal wall (orange arrows) metastases.\n\nFigure 2 Partial Response to therapy after re-challenge of ipilimumab + nivolumab Follow-up CT with contrast after 5 months of nivolumab and re-introduction of ipilimumab demonstrating partial response to therapy with substantially smaller left retroperitoneal (red arrows) and abdominal wall (orange arrows) metastases since previous CT (figure 1). Note the increased low-density central necrosis (*) in the abdominal wall metastasis indicating treatment response.\n\nTable 1 Target lesion changes with immunotherapy\n\nTarget lesion\tBasal CT in cm\tAfter four cycles IPI+nivo\tAfter four cycles of maintenance nivo\tAfter two doses of IPI and nivo (reintroduction)\t\nPre aortic LN\t8.9×3.2 cm\t3.1×2.6 cm\t4.2×2.4 cm\t2.1×2.5 cm\t\nRectus abdominis\t5.4×3.6 cm\t4.2×3.7 cm\t8.2×7.6 cm\t5.5×7.3 cm (central necrosis present)\t\nIPI, ipilumumab; LN, lymph node.\n\nDiscussion\nsRCC typically portends a poor prognosis as demonstrated by a review of clinical data presented in table 2. This may, in part be due to high PD-L1 expression on sRCC cells which has been independently associated with poor outcomes in renal cell cancer.12 In prior studies, BAP1 loss was associated with high tumor grade, sarcomatoid differentiation and poor outcomes, as noted in our patient.13 14 In RCC, BAP-1 mutations have been identified in approximately 15% of patients with RCC and was noted to enhance mesenchymal–epithelial transition, which could be one reason why our patient presented with metastatic disease within 3 months of diagnosis.15 16 The Checkmate 214 trial examined the safety and efficacy of anti-PD-1 with anti-CTLA4. A significant improvement in OS was noted in all RCC patients after treatment with ipilimumab and nivolumab compared with sunitinib (median not reached vs 26 months, HR 0.63).17 Among patients with sarcomatoid differentiation, the rate of complete response (CR) was 18.3% with nivolumab plus ipilimumab versus 0% with sunitinib with superior OS in the immunotherapy arm irrespective of PD-L1 expression. However, significant toxicity was noted with ipilimumab and nivolumab, with 46% of patients experiencing grade 3–4 toxicity. Even though the results with immunotherapy are promising for sRCC compared with historical data, a majority of patients do not respond and progression is inevitable, thus development of novel treatment strategies is urgently needed.\n\nTable 2 Summary of studies for sarcomatoid renal cell cancer\n\nAuthor\tN\tTreatment\tObjective response (%)\tPFS (months)\tOS (months)\t\nSella et al\n26\n\t8\tCyclophosphamide+vincristine + doxorubicin+dacarbazine\t25\tNA\t13\t\nMian et al\n27\n\t67\tInterferon based therapy\t21\tNA\t19\t\nEscudier et al\n28\n\t23\tDoxorubicin+ifosfamide\t0\t2.2\t3.3\t\nHaas et al\n4\n\t38\tGemcitabine+doxorubicin\t15.8\t3.5\t8.8\t\nGolshayan et al\n29\n\t26\tSunitinib\t19\t5.3\t11.8\t\nKyriakopoulous et al\n30\n\t230\tVEGF inhibitors\t21\t4.5\t10.4\t\nMckay et al\n10\n\t16\tAtezolizumab+bevacizumab\t44\tNA\tNA\t\nMcDermott et al\n11\n\t60\tIpilimumab+nivolumab\t56.7\t8.4\t31.2\t\nN, number of patients in the study; NA, not reported; OS, overall survival; PFS, progression-free survival; VEGF, vascular endothelial growth factor.\n\nCytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1 are inhibitory receptors on T cells that limit T cell activation and function. These proteins act through distinct mechanisms to block T cell activation. CTLA-4 is expressed after initial T cell activation and acts to sequester ligands B7-1 and B7-2 (CD80, CD86) that are required for signaling through the costimulatory receptor CD28.18 Blockade of CTLA-4 results in enhanced activation of primary T cells and clonal expansion of nascent CD8+T cell clones.18 Anti-CTLA4 antibodies with heavy chains capable of fixing complement may also eliminate inhibitory T cell subsets, such as regulatory foxP3+CD4+T cells, from the tumor microenvironment.19 In contrast, therapies targeting the PD-1/PD-L1 axis act on CD8+T cells that have undergone initial activation but acquired functional attenuation due to chronic exposure to antigen through a process termed T cell exhaustion.20 Thus, although the two therapeutic strategies both fall under the purview of immune checkpoint inhibition, they act through distinct mechanisms to selectively potentiate activation of naïve (anti-CTLA-4) or exhausted (anti-PD-1/PD-L1) CD8+T cells. A possible explanation for the secondary responsiveness to ipilimumab observed in this patient is that progression of RCC results in development of neoantigens that can be recognized by naïve T cells in a manner facilitated by anti-CTLA-4.\n\nThe use of ipilimumab is limited to four doses when given in combination with nivolumab given concerns for significant autoimmune toxicities.21 Checkmate 016 evaluated the role of intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) or nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity in RCC patients.22 The incidence of grade 3/4 AE was significant with N1I3 and N3I3 dosing and hence the regimen used in our patients is FDA approved.\n\nThe use of ipilimumab with nivolumab a salvage therapy has been reported in patients with melanoma, with approximately 50% of patients demonstrating disease control.23 Unfortunately, 68% of these patients experienced clinically significant toxicity resulting in 40% of patients discontinuing therapy.\n\nSalvage ipilimumab and nivolumab has been found to be safe and effective in immune checkpoint inhibitors (ICI) refractory melanoma and ccRCC patients.23–25 The TITAN trial that was discussed at European Society of Medical Oncology (ESMO) 2019 evaluated the role of salvage ipilimumab in combination with nivolumab for patients with stable disease/progressive disease on single agent nivolumab and noted a 10 per cent salvage rate with ipilimumab. This study is different from our approach as our patient had received prior ipilimumab and nivolumab, salvage ipilimumab was added when the patient had progressed on single agent nivolumab. In the TITAN trial, none of the patients had gotten upfront ipilimumab. In the TITAN trial, the CR rate was also significantly lower than checkmate 214 and with immature OS data, suggesting that upfront ipilimumab may be warranted for eligible patients. Another retrospective study evaluated the use of ipilimumab and nivolumab as salvage therapy in patients with clear cell mRCC refractory to immunotherapy therapy combinations and a 40% partial response rate was noted.24 It would also be worth further exploring the role of Ipilimumab with a dose of 3 mg/kg as salvage therapy if toxicity permits. Further studies are needed to determine which sRCC patients are appropriate for salvage ipilimumab with progression on nivolumab monotherapy. It is also unknown as to whether BAP1 loss in RCC defines a cohort that is immune responsive. Further, the optimal frequency and dose of ipilimumab treatment needs to be established.\n\nHere, we report the first case of reinvigoration of responses in an sRCC patient undergoing nivolumab maintenance monotherapy with the addition of ipilimumab. This suggests that ipilimumab could be used to salvage maintenance nivolumab in sRCC and indicates that enhancing activation of naïve T cell subsets could be an important mechanism to engage effective immune responses in sRCC. Further studies are needed to evaluate this approach.\n\nContributors: GG, LS, DK collected data and wrote the manuscript. MR appraised and edited the manuscript. PT provided images for publication.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nSiegel RL , Miller KD , Jemal A , et al \nCancer statistics, 2018\n. CA Cancer J Clin \n2018 ;68 :7 –30\n.10.3322/caac.21442 \n29313949 \n2 \nCheville JC , Lohse CM , Zincke H , et al \nSarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome\n. Am J Surg Pathol \n2004 ;28 :435 –41\n.10.1097/00000478-200404000-00002 \n15087662 \n3 \nShuch B , Bratslavsky G , Linehan WM , et al \nSarcomatoid renal cell carcinoma: a comprehensive review of the biology and current treatment strategies\n. Oncologist \n2012 ;17 :46 –54\n.10.1634/theoncologist.2011-0227 \n22234634 \n4 \nHaas NB , Lin X , Manola J , et al \nA phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECoG 8802\n. Med Oncol \n2012 ;29 :761 –7\n.10.1007/s12032-011-9829-8 \n21298497 \n5 \nMcKay RR , Choueiri TK , Werner L , et al \nA phase II trial of sunitinib and gemcitabine in sarcomatoid and/or poor-risk patients with metastatic renal cell carcinoma\n. JCO \n2015 ;33 :40810.1200/jco.2015.33.7_suppl.408 \n\n6 \nRaychaudhuri R , Riese MJ , Bylow K , et al \nImmune check point inhibition in Sarcomatoid renal cell carcinoma: a new treatment paradigm\n. Clin Genitourin Cancer \n2017 ;15 :e897 –901\n.10.1016/j.clgc.2017.05.018 \n28645484 \n7 \nJoseph RW , Millis SZ , Carballido EM , et al \nPD-1 and PD-L1 expression in renal cell carcinoma with Sarcomatoid differentiation\n. 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JCO \n2019 ;37 :54810.1200/JCO.2019.37.7_suppl.548 \n\n11 \nMcDermott DF , Choueiri TK , Motzer RJ , et al \nCheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features\n. JCO \n2019 ;37 :451310.1200/JCO.2019.37.15_suppl.4513 \n\n12 \nThompson RH , Kuntz SM , Leibovich BC , et al \nTumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up\n. Cancer Res \n2006 ;66 :3381 –5\n.10.1158/0008-5472.CAN-05-4303 \n16585157 \n13 \nKapur P , Christie A , Raman JD , et al \nBAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma\n. J Urol \n2014 ;191 :603 –10\n.10.1016/j.juro.2013.09.041 \n24076305 \n14 \nBrugarolas J \nPBRM1 and BAP1 as novel targets for renal cell carcinoma\n. Cancer J \n2013 ;19 :324 –32\n.10.1097/PPO.0b013e3182a102d1 \n23867514 \n15 \nPeña-Llopis S , Vega-Rubín-de-Celis S , Liao A , et al \nBAP1 loss defines a new class of renal cell carcinoma\n. Nat Genet \n2012 ;44 :751 –9\n.10.1038/ng.2323 \n22683710 \n16 \nKapur P , Peña-Llopis S , Christie A , et al \nEffects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation\n. Lancet Oncol \n2013 ;14 :159 –67\n.10.1016/S1470-2045(12)70584-3 \n23333114 \n17 \nMotzer RJ , Tannir NM , McDermott DF , et al \nNivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma\n. N Engl J Med \n2018 ;378 :1277 –90\n.10.1056/NEJMoa1712126 \n29562145 \n18 \nWei SC , Duffy CR , Allison JP \nFundamental mechanisms of immune checkpoint blockade therapy\n. Cancer Discov \n2018 ;8 :1069 –86\n.10.1158/2159-8290.CD-18-0367 \n30115704 \n19 \nSimpson TR , Li F , Montalvo-Ortiz W , et al \nFc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma\n. J Exp Med \n2013 ;210 :1695 –710\n.10.1084/jem.20130579 \n23897981 \n20 \nVirgin HW , Wherry EJ , Ahmed R \nRedefining chronic viral infection\n. Cell \n2009 ;138 :30 –50\n.10.1016/j.cell.2009.06.036 \n19596234 \n21 \nFecher LA , Agarwala SS , Hodi FS , et al \nIpilimumab and its toxicities: a multidisciplinary approach\n. Oncologist \n2013 ;18 :733 –43\n.10.1634/theoncologist.2012-0483 \n23774827 \n22 \nHammers HJ , Plimack ER , Infante JR , et al \nSafety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study\n. J Clin Oncol \n2017 ;35 :3851 –8\n.10.1200/JCO.2016.72.1985 \n28678668 \n23 \nGaughan EM , Petroni GR , Grosh WW , et al \nSalvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma\n. JCO \n2017 ;35 :e2100910.1200/JCO.2017.35.15_suppl.e21009 \n\n24 \nGul A , Shah NJ , Mantia C , et al \nIpilimumab plus nivolumab (Ipi/Nivo) as salvage therapy in patients with immunotherapy (IO)-refractory metastatic renal cell carcinoma (mRCC)\n. JCO \n2019 ;37 :66910.1200/JCO.2019.37.7_suppl.669 \n\n25 \nZimmer L , Apuri S , Eroglu Z , et al \nIpilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma\n. Eur J Cancer \n2017 ;75 :47 –55\n.10.1016/j.ejca.2017.01.009 \n28214657 \n26 \nSella A , Logothetis CJ , Ro JY , et al \nSarcomatoid renal cell carcinoma. A treatable entity\n. Cancer \n1987 ;60 :1313 –8\n.10.1002/1097-0142(19870915)60:6<1313::AID-CNCR2820600625>3.0.CO;2-1 \n2441841 \n27 \nMian BM , Bhadkamkar N , Slaton JW , et al \nPrognostic factors and survival of patients with sarcomatoid renal cell carcinoma\n. J Urol \n2002 ;167 :65 –70\n.10.1016/S0022-5347(05)65384-0 \n11743277 \n28 \nEscudier B , Droz JP , Rolland F , et al \nDoxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the genitourinary group of the French Federation of cancer centers\n. J Urol \n2002 ;168 :959 –61\n.10.1016/S0022-5347(05)64551-X \n12187199 \n29 \nGolshayan AR , George S , Heng DY , et al \nMetastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy\n. J Clin Oncol \n2009 ;27 :235 –41\n.10.1200/JCO.2008.18.0000 \n19064974 \n30 \nKyriakopoulos CE , Chittoria N , Choueiri TK , et al \nOutcome of patients with metastatic sarcomatoid renal cell carcinoma: results from the International metastatic renal cell carcinoma database Consortium\n. Clin Genitourin Cancer \n2015 ;13 :e79 –85\n.10.1016/j.clgc.2014.08.011 \n25450036\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "case reports",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell; D006801:Humans; D000074324:Ipilimumab; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077594:Nivolumab; D019233:Retreatment; D016879:Salvage Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32114501",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28214657;19596234;2441841;12187199;30115704;26307625;25450036;23867514;23333114;21298497;28645484;24076305;22234634;28494868;16585157;28678668;23774827;22683710;19064974;29313949;11743277;29562145;23897981;15087662",
"title": "Salvage ipilimumab associated with a significant response in sarcomatoid renal cell carcinoma.",
"title_normalized": "salvage ipilimumab associated with a significant response in sarcomatoid renal cell carcinoma"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-024641",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "BACKGROUND\nCryptococcosis is a deep fungal infection caused by Cryptococcus neoformans. The infection usually involves the lungs, the central nervous system as well as the skin, the bones and the urinary tract. Immunocompromised individuals, including solid organ transplant recipients, are at higher risk for cryptococcal infections.\n\n\nMETHODS\nWe present a 40-year-old renal transplant recipient who developed a slightly painful, erythematous, indurated plaque on his thigh several years after a kidney transplant. Histopathology revealed cryptococcal panniculitis and cryptococcus neoformans subsequently grew from the tissue culture. There was no other systemic involvement.\n\n\nCONCLUSIONS\nThe primary cutaneous form of cryptococcosis is extremely rare and early diagnosis and treatment is essential in view of possible dissemination and variable nonspecific clinical manifestations.",
"affiliations": "Department of Dermatology and Venereology, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan India;;Department of Dermatology and Venereology, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan India;;Department of Dermatology and Venereology, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan India;;Department of Pathology, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan India.",
"authors": "Kothiwala|Sunil K|SK|;Prajapat|Mahesh|M|;Kuldeep|Chhitar Mal|CM|;Jindal|Arpita|A|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.3315/jdcr.2015.1205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1898-7249",
"issue": "9(3)",
"journal": "Journal of dermatological case reports",
"keywords": "cryptococcus; fungal infection; immunosuppression; mycophenolate mofetil; panniculitis; prednisone; tacrolimus",
"medline_ta": "J Dermatol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101493700",
"other_id": null,
"pages": "76-80",
"pmc": null,
"pmid": "26512304",
"pubdate": "2015-09-30",
"publication_types": "D002363:Case Reports",
"references": "1562658;18840080;12539076;11477526;12627365;11384512;10570104;8188868;11526180;17262720;21482725;12219115;3533989;15814538;10770733;12535260;18086276;20666191;19000155;19422669;25942673;3308982;10602736;15636317",
"title": "Cryptococcal panniculitis in a renal transplant recipient: case report and review of literature.",
"title_normalized": "cryptococcal panniculitis in a renal transplant recipient case report and review of literature"
} | [
{
"companynumb": "IN-ACCORD-035427",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Atrial fibrillation is a commonly encountered arrhythmia associated with increased risk for thromboembolic events. Anticoagulation is necessary to decrease the risk of ischemic stroke. Traditionally, warfarin has been the only oral pharmacotherapeutic option for long-term anticoagulation in patients with nonvalvular atrial fibrillation (NVAF). Recently, non-vitamin K antagonist oral anticoagulants (NOAC), including dabigatran, rivaroxaban, apixaban, and edoxaban, have become available as alternatives for warfarin in the prevention of stroke in patients with NVAF. Recently published atrial fibrillation guidelines contain new recommendations for risk stratification tools in determining the need for anticoagulant therapy and incorporate NOAC pharmacotherapy options for stroke prevention in patients with NVAF. NOACs offer several advantages over warfarin, including the elimination of routine laboratory monitoring, fewer drug and food interactions, and rapid therapeutic onset and offset. However, the lack of antidote in the case of serious bleeding and lack of data for long-term use in patient populations at risk for bleeding is problematic. Older adults are at high risk for thromboembolic and bleeding events as a result of anticoagulation and require special consideration when selecting anticoagulant therapy. The risk of drug accumulation and bleeding is concerning in the presence of renal impairment. The objective of this review is to provide the clinician with an update on the use of NOACs for NVAF, focusing on older adults and patients with renal impairment in light of recently published atrial fibrillation guidelines. Available data on using NOACs in coronary artery stenting, cardioversion, and ablation are also reviewed.",
"affiliations": "Fairleigh Dickinson University, 230 Park Avenue, M-SP1-01, Florham Park, NJ, USA, Julie_kalabalik@fdu.edu.",
"authors": "Kalabalik|Julie|J|;Rattinger|Gail B|GB|;Sullivan|Jesse|J|;Slugocki|Malgorzata|M|;Carbone|Antonia|A|;Rivkin|Anastasia|A|",
"chemical_list": "D000925:Anticoagulants",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40265-015-0405-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-6667",
"issue": "75(9)",
"journal": "Drugs",
"keywords": null,
"medline_ta": "Drugs",
"mesh_terms": "D000284:Administration, Oral; D000367:Age Factors; D000925:Anticoagulants; D001281:Atrial Fibrillation; D003362:Cost-Benefit Analysis; D017408:Guidelines as Topic; D006801:Humans; D051437:Renal Insufficiency; D012307:Risk Factors; D020521:Stroke",
"nlm_unique_id": "7600076",
"other_id": null,
"pages": "979-98",
"pmc": null,
"pmid": "25998374",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "24275632;22315257;20200517;18955670;23000334;9809895;21200007;22800505;22843168;22595629;24508420;23219111;24685669;24800791;22246948;23158612;26090400;24128967;23389759;24251359;23160864;24906369;21874549;24672216;22997117;21955008;23625091;20214409;16818816;22891166;22375994;24657685;22386824;15911722;22496474;22122181;24076487;23651821;11401607;10029789;23953907;20352166;21576658;25064581;23415013;23212720;24151507;17061959;21872374;24668660;23036896;18396243;23470618;25298351;22575324;18076218;23369212;22782645;21788545;16676068;23389753;22383791;22970730;19717844;23101573;23577951;23237911;22933567;24383939;24755148;23474519;23071159;24315894;21956604;23484796;19762550;21488759;22761066;24315724;23500298;24682348;25154388;23625209;23221509;22869389;15947319;22922413;23585240;22305113;23991661;23591934;24373340;22315271;24895454;21870978;18250228;22196949;24786913;25119841;23657589;22786838;21873708;17158523;19092127;22584072;23740224;21830957;23796283;21039764;25056265;24412445;22488474;23549134;23770182;22787066;22669799;22394293;24211508;24319220;23381840;22872748;20694283;23597859;24323795;21900088;11343485",
"title": "Use of Non-Vitamin K Antagonist Oral Anticoagulants in Special Patient Populations with Nonvalvular Atrial Fibrillation: A Review of the Literature and Application to Clinical Practice.",
"title_normalized": "use of non vitamin k antagonist oral anticoagulants in special patient populations with nonvalvular atrial fibrillation a review of the literature and application to clinical practice"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-30619GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"d... |
{
"abstract": "Treatment of post-transplant focal segmental glomerulosclerosis (FSGS) recurrence is still debated. The use of the fully human anti-CD20 monoclonal antibody ofatumumab has been suggested.\n\n\n\nTwo boys with FSGS received a kidney transplantation at the age of 15 years from a deceased and a living donor. Maintenance therapy consisted of calcineurin inhibitors, antiproliferative agents, and prednisone. Early post-transplant FSGS recurrence was observed after 2 and 3 days. Rituximab infusion and plasmapheresis sessions were performed with transient clinical improvement in the first patient, and no apparent response in the second patient. Both patients were treated with two ofatumumab infusions, which induced in patient #1 a complete and stable remission for more than 12 months and in patient #2 a partial remission with a progressive reduction of proteinuria and normalization of serum protein levels.\n\n\n\nOfatumumab may be a therapeutic option for post-transplant FSGS recurrence in patients who respond poorly to rituximab.",
"affiliations": "Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Rome, Italy. manuela.colucci@opbg.net.;Division of Nephrology, Department of Pediatric Subspecialties, Rome, Italy.;Division of Nephrology, Department of Pediatric Subspecialties, Rome, Italy.;Department of Laboratories, Pathology Unit, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.;Division of Nephrology, Department of Pediatric Subspecialties, Rome, Italy.;Division of Nephrology, Department of Pediatric Subspecialties, Rome, Italy.",
"authors": "Colucci|Manuela|M|0000-0003-0969-7521;Labbadia|Raffaella|R|;Vivarelli|Marina|M|;Camassei|Francesca Diomedi|FD|;Emma|Francesco|F|;Dello Strologo|Luca|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; C527517:ofatumumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-019-04365-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "35(2)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Children; FSGS; Ofatumumab; Post-transplantation; Steroid-resistant nephrotic syndrome",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D012008:Recurrence",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "341-345",
"pmc": null,
"pmid": "31667616",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28879428;28314579;28992235;28213687;29189487;19384172;29962080;16303004;24619426;29247358;29436729;26585985;24670185;27473582;26567244",
"title": "Ofatumumab rescue treatment in post-transplant recurrence of focal segmental glomerulosclerosis.",
"title_normalized": "ofatumumab rescue treatment in post transplant recurrence of focal segmental glomerulosclerosis"
} | [
{
"companynumb": "NVSC2019IT021557",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "Atypical aortic coarctation is a rare condition associated with Takayasu arteritis, and is characterized by symptoms caused either by hypotension in the lower half of the body or secondary hypertension in the upper half of the body, and heart failure. We report a rare case of axillofemoral bypass to improve congestive heart failure for atypical aortic coarctation complicating Takayasu arteritis. Augmented vascular bed and retrograde renal blood flow after axillofemoral bypass surgery could achieve effective blood pressure control and improve renal function and cardiac function (LVEF: 30% → 55%, BNP: 2943 pg/mL → 128 pg/mL). There were two contributing factors for improvement of heart failure such as the increased vascular bed and the increase in retrograde renal blood flow. We believe that axillofemoral bypass is effective for Takayasu arteritis patients with refractory heart failure. In daily practice, careful attention should be paid to an impact of cardiorenal-aorta interaction in atypical aortic coarctation complicating Takayasu arteritis.",
"affiliations": "Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.;Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.;Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.;Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.;Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.",
"authors": "Hiraya|Daigo|D|;Sato|Akira|A|0000-0002-2438-1464;Watabe|Hiroaki|H|;Hoshi|Tomoya|T|;Ieda|Masaki|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ehf2.12855",
"fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822 John Wiley and Sons Inc. Hoboken \n\n10.1002/ehf2.12855\nEHF212855\nESCHF-20-00256\nCase Report\nCase Report\nAxillofemoral bypass to improve congestive heart failure for atypical aortic coarctation complicating Takayasu arteritis\nAtypical aortic coarctation on Takayasu arteritisD. Hiraya et al.Hiraya Daigo \n1\n Sato Akira https://orcid.org/0000-0002-2438-1464\n1\nasato@md.tsukuba.ac.jp Watabe Hiroaki \n1\n Hoshi Tomoya \n1\n Ieda Masaki \n1\n \n1 \nDepartment of Cardiology, Faculty of Medicine\nUniversity of Tsukuba\n1‐1‐1, Tennodai, Tsukuba\nIbaraki\n305‐8575\nJapan\n\n* \nCorrespondence to: Akira Sato, Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1‐1‐1, Tennodai, Tsukuba, Ibaraki 305‐8575, Japan. Tel: +81‐29‐853‐3143; Fax: +81‐29‐853‐3227.\n\nEmail: asato@md.tsukuba.ac.jp\n\n19 6 2020 \n10 2020 \n7 5 10.1002/ehf2.v7.53184 3188\n03 4 2020 16 5 2020 02 6 2020 © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of CardiologyThis 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\nAtypical aortic coarctation is a rare condition associated with Takayasu arteritis, and is characterized by symptoms caused either by hypotension in the lower half of the body or secondary hypertension in the upper half of the body, and heart failure. We report a rare case of axillofemoral bypass to improve congestive heart failure for atypical aortic coarctation complicating Takayasu arteritis. Augmented vascular bed and retrograde renal blood flow after axillofemoral bypass surgery could achieve effective blood pressure control and improve renal function and cardiac function (LVEF: 30% → 55%, BNP: 2943 pg/mL → 128 pg/mL). There were two contributing factors for improvement of heart failure such as the increased vascular bed and the increase in retrograde renal blood flow. We believe that axillofemoral bypass is effective for Takayasu arteritis patients with refractory heart failure. In daily practice, careful attention should be paid to an impact of cardiorenal‐aorta interaction in atypical aortic coarctation complicating Takayasu arteritis.\n\nTakayasu arteritisAxillofemoral bypassCongestive heart failureResistant hypertension source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.1 mode:remove_FC converted:29.09.2020\n\n\nHiraya , D. \n, \nSato , A. \n, \nWatabe , H. \n, \nHoshi , T. \n, and \nIeda , M. \n (2020 ) Axillofemoral bypass to improve congestive heart failure for atypical aortic coarctation complicating Takayasu arteritis\n. ESC Heart Failure , 7 : 3184 –3188\n. 10.1002/ehf2.12855 .\n==== Body\nIntroduction\nAtypical aortic coarctation (AAC) is a rare condition associated with Takayasu's arteritis (TA), fibromuscular dysplasia, and atherosclerosis and is characterized by symptoms caused either by hypotension in the lower half of the body or secondary hypertension in the upper half of the body, and heart failure.\n1\n Surgical interventions have been performed to ameliorate complications that would adversely affect the quality of life or life expectancy of patients with AAC.\n2\n However, aorto‐aortic bypass could be high risk for TA patients with steroid drugs.\n\nCase report\nA 48‐year‐old woman had a 20‐year history of rheumatoid arthritis and received prednisolone, methotrexate, and salazosulfapyridine. She presented with a 2 year history of repeated congestive heart failure. Recently, her arm systolic blood pressure was 180–200 mmHg in spite of taking five drugs, and heart failure increasingly worsened. A chest X‐ray showed cardiomegaly (cardiothoracic ratio [CTR]; 65%) (Figure\n\n1\nA\n). A blood sample test revealed elevated serum brain natriuretic peptide (BNP; 2,943 pg/mL), and eGFR was 64 mL/min. An echocardiography showed low ejection fraction (EF 30%) with concentric hypertrophy, increased left atrial volume index (LAVI; 53 mL/m2) (Figure\n\n1\nB\n and Supporting Information, Movie\n\nS1\n), and elevated left atrial pressure (E/A 3.1, deceleration time [DT] 128 ms, i.e. restrictive pattern) (Figure\n\n1\nC\n). Moreover, intrarenal venous flow pattern was monophasic pattern which suggests renal congestion\n3\n (Figure\n\n1\nD\n). The ankle‐brachial index (ABI) was 0.3 in both legs (Figure\n\n1\nE\n). The contrast enhanced computed tomography (CT) revealed atypical aortic coarctation (AAC) of the descending thoracic aorta with near‐total occlusion, occlusion or severe stenosis of major branch, and collateral circulation from bilateral internal mammary arteries (Figure\n\n2\nA–D\n and Supporting Information, Movie\n\nS2\n). The positron emission tomography revealed partial accumulation in the aortic arch, and she was diagnosed with Takayasu's arteritis (TA) (Figure\n\n2\nE\n).\n\nFigure 1 Preoperative examination. (A) A chest X‐ray showed cardiomegaly (cardiothoracic ratio [CTR]; 65%). (B, C) An echocardiography showed the low ejection fraction (EF 30%), increased left atrial volume index (LAVI; 53 mL/m2), and elevated left atrial pressure (E/A 3.1, deceleration time [DT] 128 ms, i.e. restrictive pattern). (D) The intrarenal venous flow pattern was monophasic pattern (yellow arrow) which suggests renal congestion. (E) The ankle‐brachial index (ABI) was 0.3 in both legs.\n\nFigure 2 Atypical aortic coarctation complicating Takayasu's arteritis. (A) The contrast enhanced computed tomography (CT) revealed atypical aortic coarctation (AAC) of the descending thoracic aorta (yellow arrow). (A–D) The CT also showed occlusion of left common carotid artery, right external iliac artery, superior mesenteric artery, and celiac artery (red arrows), and collateral circulation from bilateral internal mammary arteries (white arrow). (E) The positron emission tomography revealed partial accumulation in the aortic arch (yellow arrow), and the patient was diagnosed with Takayasu's arteritis (TA).\n\nThe axillobifemoral bypass was performed to augment vascular bed and retrograde renal blood flow (Figure\n\n3\nA–C\n) and reduce cardiac afterload. After surgery, effective blood pressure control was achieved (140 mmHg), ABI increased to 0.6 (Figure\n\n4\nE\n), and renal function improved to eGFR 110 mL/min. Moreover, congestive heart failure subsided, CTR decreased to 53% (Figure\n\n4\nA\n), and BNP remarkably decreased to 128 pg/mL. An echocardiography showed increased EF (55%), decreased LAVI (26 mL/m2), and improved left atrial pressure (E/A 0.5, DT 229 ms, i.e. abnormal relaxation pattern) (Figure\n\n4\nB,C\n and Supporting Information, Movie\n\nS3\n). In addition, intrarenal venous flow pattern improved to continuous pattern which suggests no renal congestion (Figure\n\n4\nD\n). The midgraft velocity was 200 cm/s.\n\nFigure 3 The contrast enhanced computed tomography and ultrasonography after axillobifemoral bypass. (A, B) The axillobifemoral bypass was performed to augment vascular bed and retrograde renal blood flow (yellow arrows). (C) The doppler ultrasound revealed excellent retrograde blood flow in left common femoral artery from anastomosis site directed to the abdominal aorta.\n\nFigure 4 Postoperative examination. (A) The CTR decreased to 53%. (B, C) An echocardiography showed increased EF (55%), decreased LAVI (26 mL/m2), and improved left atrial pressure (E/A 0.5, DT 229 ms, i.e. abnormal relaxation pattern). (D) The intrarenal venous flow pattern improved to continuous pattern (yellow arrow) which suggests no renal congestion. (E) ABI increased to 0.6.\n\n3 Discussion\nIn this case, while the patient had received steroid drugs for refractory rheumatoid arthritis, undiagnosed TA had potentially progressed. Because of marked calcification and stenosis of the descending thoracic aorta and occlusion of major branches, her vascular bed decreased, cardiac afterload increased, and she suffered from repeated congestive heart failure. The axillobifemoral bypass dramatically improved heart failure.\n\nWe supposed there were two contributing factors for improvement of heart failure. The first factor was the increased vascular bed. She had suffered from refractory hypertension in the upper half of the body for a long time. The echocardiography showed elevated left atrial pressure (E/A 3.1), which improved after the operation (E/A 0.5). These findings may reflect the decrease in systemic arterial resistance by axillobifemoral bypass, which could lead to the reduction of cardiac afterload. The second factor was the increase in retrograde renal blood flow. The contrast enhanced CT after the operation showed occlusion of descending aorta just above renal arteries, and the doppler ultrasound revealed excellent retrograde blood flow in left common femoral artery from anastomosis site directed to the abdominal aorta (Figure\n3).\n\nApproximately 20% of TA patients are resistant to any kind of treatment. Surgical treatment is generally warranted for, especially AAC, because the prognosis is poor when left untreated.\n4\n Among surgical treatments, an aorto‐aortic bypass has been the most frequent choice.\n5\n However, aorto‐aortic bypass has the possibility to hurt the collateral circulation around the stenotic site, and it is high risk for TA patients with steroid drugs. Although endovascular stent graft insertion is not very invasive, it was reported that surgical repair was associated with low mortality and morbidity compared with endovascular repair especially in TA patients.\n4\n In highly calcified lesions, under‐dilatation, fracture, and rupture of stent grafts were expected. Therefore, we chose extra‐anatomical axillobifemoral bypass. On the other hand, it was proposed that the patency of axillofemoral bypass graft was not high enough. A previous study showed that midgraft peak systolic velocities <80 cm/s were significantly correlated with thrombosis.\n6\n In this patient, midgraft velocity was 200 cm/s. We believe that axillofemoral bypass is effective for TA patients with refractory heart failure. In daily practice, careful attention should be paid to an impact of cardiorenal–aorta interaction in atypical aortic coarctation complicating Takayasu arteritis.\n\nConflict of interest\nNone declared.\n\nSupporting information\n\nMovie S1. Echocardiography showed severely reduced cardiac function with 35% of left ventricular ejection fraction.\n\nClick here for additional data file.\n\n \nMovie S2. The contrast enhanced computed tomography revealed marked calcification of the descending thoracic aorta with near‐total occlusion, and occlusion or severe stenosis of major branch.\n\nClick here for additional data file.\n\n \nMovie S3. Echocardiography showed improvement in cardiac function and improved left ventricular ejection fraction from 35 to 55% after operation.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nIshizuka \nM \n, \nYamada \nS \n, \nMaemura \nS \n, \nYamamoto \nK \n, \nTakizawa \nM \n, \nUozumi \nH \n, \nMinegishi \nS \n, \nKobayashi \nJ \n, \nIkenouchi \nH \n. Axillofemoral bypass markedly improved acute decompensated heart failure and kidney injury in a patient with severely calcified stenosis of thoracoabdominal aorta (atypical aortic coarctation)\n. Int Heart J \n2017 ; 58 : 820 –823\n.28966318 \n2 \n\nTaketani \nT \n, \nMiyata \nT \n, \nMorota \nT \n, \nTakamoto \nS \n. Surgical treatment of atypical aortic coarctation complicating Takayasu's arteritis—experience with 33 cases over 44 years\n. J Vasc Surg \n2005 ; 41 : 597 –601\n.15874922 \n3 \n\nIida \nN \n, \nSeo \nY \n, \nSai \nS \n, \nMachino‐Ohtsuka \nT \n, \nYamamoto \nM \n, \nIshizu \nT \n, \nKawakami \nY \n, \nAonuma \nK \n. Clinical implications of intrarenal hemodynamic evaluation by doppler ultrasonography in heart failure\n. JACC Heart Fail \n2016 ; 4 : 674 –682\n.27179835 \n4 \n\nSaadoun \nD \n, \nLambert \nM \n, \nMirault \nT \n, \nResche‐Rigon \nM \n, \nKoskas \nF \n, \nCluzel \nP \n, \nMignot \nC \n, \nSchoindre \nY \n, \nChiche \nL \n, \nHatron \nPY \n, \nEmmerich \nJ \n, \nCacoub \nP \n. Retrospective analysis of surgery versus endovascular intervention in Takayasu arteritis: a multicenter experience\n. Circulation \n2012 ; 125 : 813 –819\n.22230484 \n5 \n\nCohen \nJR \n, \nBirnbaum \nE \n. Coarctation of the abdominal aorta\n. J Vasc Surg \n1988 ; 8 : 160 –164\n.3398174 \n6 \n\nMusicant \nSE \n, \nGiswold \nME \n, \nOlson \nCJ \n, \nLandry \nGJ \n, \nTaylor \nLM \nJr\n, \nYeager \nRA \n, \nEdwards \nJM \n, \nMoneta \nGL \n. Postoperative duplex scan surveillance of axillofemoral bypass grafts\n. J Vasc Surg \n2003 ; 37 : 54 –61\n.12514578\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2055-5822",
"issue": "7(5)",
"journal": "ESC heart failure",
"keywords": "Axillofemoral bypass; Congestive heart failure; Resistant hypertension; Takayasu arteritis",
"medline_ta": "ESC Heart Fail",
"mesh_terms": "D001017:Aortic Coarctation; D001794:Blood Pressure; D006333:Heart Failure; D006801:Humans; D006973:Hypertension; D013625:Takayasu Arteritis",
"nlm_unique_id": "101669191",
"other_id": null,
"pages": "3184-3188",
"pmc": null,
"pmid": "32558325",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22230484;15874922;27179835;3398174;12514578;28966318;32558325",
"title": "Axillofemoral bypass to improve congestive heart failure for atypical aortic coarctation complicating Takayasu arteritis.",
"title_normalized": "axillofemoral bypass to improve congestive heart failure for atypical aortic coarctation complicating takayasu arteritis"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1848763",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nA potential interaction involving therapeutic doses of ascorbic acid and warfarin is described.\n\n\nCONCLUSIONS\nA 65-year-old Caucasian man with chronic cardiac and pulmonary disorders was admitted to the emergency room for chest pain, shortness of breath, nausea, and diaphoresis. Imaging scans showed acute pulmonary embolism and deep venous thrombosis of the lower extremities. Anticoagulation therapy (enoxaparin 60 mg twice daily) was initiated on the day of admission; warfarin sodium (5 mg daily) was initiated on the next day. After admission to the hospital, the patient continued to use several home medications and vitamins, including ascorbic acid, which he reported taking for three months to facilitate the absorption of oral supplemental iron. For more than a week, his International Normalized Ratio (INR) values remained below target as the dosage of warfarin was gradually increased to 20 mg daily. After potential contributors to warfarin resistance (e.g., impaired liver or renal function, clotting factor abnormalities) were ruled out, ascorbic acid use was discontinued on hospital day 8. The patient's INR rapidly increased to a high of 15.4 on hospital day 10, requiring intervention with phytonadione therapy and the suspension of warfarin use. On day 12, with an INR of 2.7, the patient was restarted on warfarin therapy; he was discharged three days later with stable INR values.\n\n\nCONCLUSIONS\nA patient who was unable to achieve anticoagulation during concurrent treatment with warfarin and ascorbic acid experienced a rapid increase in INR to above-target values after the discontinuation of ascorbic acid use, suggesting that the vitamin might have had an inhibitory effect on warfarin.",
"affiliations": "School of Medicine, Southern Illinois University, Springfield, IL, USA.",
"authors": "Sattar|Adil|A|;Willman|Jane E|JE|;Kolluri|Raghu|R|",
"chemical_list": "D014859:Warfarin; D001205:Ascorbic Acid",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp110704",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "70(9)",
"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": "D000368:Aged; D001205:Ascorbic Acid; D004347:Drug Interactions; D004351:Drug Resistance; D006331:Heart Diseases; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D014859:Warfarin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "782-6",
"pmc": null,
"pmid": "23592361",
"pubdate": "2013-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Possible warfarin resistance due to interaction with ascorbic acid: case report and literature review.",
"title_normalized": "possible warfarin resistance due to interaction with ascorbic acid case report and literature review"
} | [
{
"companynumb": "US-CIPLA LTD.-2020US00338",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASCORBIC ACID"
},
"drugadditional": "1",
... |
{
"abstract": "Through this brief report, we described our clinical considerations about the treatment of motor fluctuations and psychiatric comorbidities in Huntington's disease, for example, aggressiveness and obsessive-compulsive disorders. Indeed, as classical treatment, for example, olanzapine and risperidone, were inefficient to improve motor disorders in our patient, we postulated that motor fluctuations could be influenced by the pharmacokinetic profile of oral risperidone. So, in line with recent practice in schizophrenia, we proposed empirically paliperidone 1-month long-acting injections hypothesized to improve motor fluctuations, treatment so far reserved to Huntington's disease patients who are noncompliant to oral risperidone. Improvement was soon observed concerning motor fluctuations, but also aggressiveness, supporting our initial hypothesis.",
"affiliations": "Pharmacopsy Alsace, Etablissement Public de Santé Alsace Nord, Brumath.;Département de Neurologie.;Département de Neurologie.;Département de Neurologie.",
"authors": "Javelot|Hervé|H|;Meyer|Mylène|M|;Frismand|Solène|S|;Hingray|Coraline|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/YIC.0000000000000346",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1315",
"issue": "36(2)",
"journal": "International clinical psychopharmacology",
"keywords": null,
"medline_ta": "Int Clin Psychopharmacol",
"mesh_terms": null,
"nlm_unique_id": "8609061",
"other_id": null,
"pages": "101-103",
"pmc": null,
"pmid": "33492012",
"pubdate": "2021-03-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Benefit of long-acting paliperidone in Huntington's disease: a case report.",
"title_normalized": "benefit of long acting paliperidone in huntington s disease a case report"
} | [
{
"companynumb": "FR-ALKEM LABORATORIES LIMITED-FR-ALKEM-2021-01385",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"druga... |
{
"abstract": "This study examined the state of the literature on the effectiveness of medication assisted treatment (MAT; methadone, buprenorphine, naltrexone) delivered in prisons and jails on community substance use treatment engagement, opioid use, recidivism, and health risk behaviors following release from incarceration. Randomized controlled trials (RCTs) and quasi-experimental studies published through December 2017 that examined induction to or maintenance on methadone (n = 18 studies), buprenorphine (n = 3 studies), or naltrexone (n = 3 studies) in correctional settings were identified from PsycINFO and PubMed databases. There were a sufficient number of methadone RCTs to meta-analyze; there were too few buprenorphine or naltrexone studies. All quasi-experimental studies were systematically reviewed. Data from RCTs involving 807 inmates (treatment n = 407, control n = 400) showed that methadone provided during incarceration increased community treatment engagement (n = 3 studies; OR = 8.69, 95% CI = 2.46; 30.75), reduced illicit opioid use (n = 4 studies; OR = 0.22, 95% CI = 0.15; 0.32) and injection drug use (n = 3 studies; OR = 0.26, 95% CI = 0.12; 0.56), but did not reduce recidivism (n = 4 studies; OR = 0.93, 95% CI = 0.51; 1.68). Data from observational studies of methadone showed consistent findings. Individual review of buprenorphine and naltrexone studies showed these medications were either superior to methadone or to placebo, or were as effective as methadone in reducing illicit opioid use post-release. Results provide the first meta-analytic summary of MATs delivered in correctional settings and support the use of MATs, especially with regard to community substance use treatment engagement and opioid use; additional work is needed to understand the reduction of recidivism and other health risk behaviors.",
"affiliations": "Department of Psychology, East Tennessee State University, United States of America.;Department of Psychiatry, Yale University School of Medicine, United States of America.;Beaumont Health System, MI, United States of America.;Department of Psychiatry, Columbia University Medical Center/New York State Psychiatric Institute, United States of America.;Department of Psychiatry, Yale University School of Medicine, United States of America.;Department of Psychiatry, Yale University School of Medicine, United States of America. Electronic address: sherry.mckee@yale.edu.",
"authors": "Moore|Kelly E|KE|;Roberts|Walter|W|;Reid|Holly H|HH|;Smith|Kathryn M Z|KMZ|;Oberleitner|Lindsay M S|LMS|;McKee|Sherry A|SA|",
"chemical_list": "D002047:Buprenorphine; D009271:Naltrexone; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jsat.2018.12.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-5472",
"issue": "99()",
"journal": "Journal of substance abuse treatment",
"keywords": "Buprenorphine; Incarceration; Medication assisted treatment; Methadone; Naltrexone",
"medline_ta": "J Subst Abuse Treat",
"mesh_terms": "D002047:Buprenorphine; D006801:Humans; D008691:Methadone; D009271:Naltrexone; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011330:Prisons; D016032:Randomized Controlled Trials as Topic; D000075665:Recidivism; D012309:Risk-Taking",
"nlm_unique_id": "8500909",
"other_id": null,
"pages": "32-43",
"pmc": null,
"pmid": "30797392",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D000078182:Systematic Review",
"references": "3802833;27692182;20940383;19621072;7786990;23433809;28107680;24248468;17313907;29341974;10714729;19339140;25703440;24612249;26076211;26984133;15917502;23916321;18855822;29049469;22248184;26467975;16332415;29150198;9462324;19588333;9684390;15466845;19469745;29224503;20579009;27978771;11841899;26580136;21392250;26747509;18930603;20424458;27217808;22894706;28132702;19625142;24962326;23919595;24189594",
"title": "Effectiveness of medication assisted treatment for opioid use in prison and jail settings: A meta-analysis and systematic review.",
"title_normalized": "effectiveness of medication assisted treatment for opioid use in prison and jail settings a meta analysis and systematic review"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-03712",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "We herein describe the case of a 74-year-old man who experienced pulmonary consolidation and chest pain following administration of dabigatran, a novel oral anticoagulant. The consolidation settled spontaneously in another lung area, a condition sometimes referred to as \"wandering pneumonia.\" Although we did not find specific pathological evidence of interstitial lung disease on transbronchial lung biopsy, a lung opacity spontaneously disappeared following discontinuance of dabigatran, and there was no recurrence. There are no other reports of dabigatran-induced lung injury, except alveolar hemorrhage and eosinophilic pneumonia. We should consider that any novel drug could cause various types of pulmonary injuries.",
"affiliations": "Department of Pulmonary Medicine, Tokyo Rosai Hospital, Japan.",
"authors": "Kono|Masakazu|M|;Hirota|Kousuke|K|;Yokoe|Ayako|A|;Koumura|Chie|C|;Sakai|Toshihiko|T|;Tojima|Hirokazu|H|",
"chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.53.2307",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "53(16)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000991:Antithrombins; D001562:Benzimidazoles; D000069604:Dabigatran; D006801:Humans; D008168:Lung; D008297:Male; D011014:Pneumonia; D011859:Radiography; D012075:Remission, Spontaneous; D015091:beta-Alanine",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1825-7",
"pmc": null,
"pmid": "25130119",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Wandering pneumonia caused by dabigatran.",
"title_normalized": "wandering pneumonia caused by dabigatran"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-39095GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "To report a case of a habitual aborter that had a pregnancy reach near term and successfully delivered a viable female infant.\nReport of a unique case of a G10P1 that was successfully able to maintain a pregnancy by maintaining serum levels of estradiol and progesterone at or above 200 pg/dL and 25 ng/dL respectively. This case provides a benchmark for exogenous support of estradiol and progesterone throughout pregnancy.\nA private advanced reproductive center.\n39-year-old G10P1091 diagnosed to have antiphospholipid syndrome but continued to have continuous miscarriages despite accepted treatment. In addition, 8 products of conception were sent for cytogenetic testing and all were found to be normal.\nExamination, laboratory studies, imaging, clinical judgment, and knowledge of previous treatment failures were used to guide the treatment of this patient. Fertility was achieved with continuous supplementation of progesterone, estrogen, LMW-heparin, and prednisone.\nDelivery of viable infant.\nThis advanced reproductive age woman had three subsequent pregnancies. While compliant with our prescribed protocol, the patient successfully carried two pregnancies to viability.\nClinicians should be alert to the possibility of a luteal phase defect when a patient presents with recurrent fertility problems and multiple spontaneous abortions.",
"affiliations": "University of Illinois College of Medicine, Rockford, IL, United States.;University of Illinois College of Medicine, Rockford, IL, United States.;University of Illinois College of Medicine, Rockford, IL, United States.",
"authors": "Kratz|Bryan|B|;Rasheed|Amer|A|;Holden|John P|JP|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.crwh.2016.12.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2214-9112",
"issue": "14()",
"journal": "Case reports in women's health",
"keywords": "Infertility; Luteal phase defect; Progesterone; Spontaneous abortion",
"medline_ta": "Case Rep Womens Health",
"mesh_terms": null,
"nlm_unique_id": "101682122",
"other_id": null,
"pages": "1-3",
"pmc": null,
"pmid": "29593987",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports",
"references": "19007614;16603159;23440828;22819186;21975790;12202415;18425891;1642014;22552692",
"title": "Luteal phase support for documented failure of placental steroidogenesis: A case report.",
"title_normalized": "luteal phase support for documented failure of placental steroidogenesis a case report"
} | [
{
"companynumb": "US-MYLANLABS-2017M1017011",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMany patients with psoriasis have developed acute promyelocytic leukemia (APL) whereas few reports on psoriasis-associated APL were found in the published literature. This study was aimed to study the etiology, clinical characteristics, and prognosis of psoriasis-associated APL and to map a suitable treatment regime for this condition.\n\n\nMETHODS\nThis study retrospectively analyzed the clinical data of 17 patients with psoriasis-associated APL diagnosed and treated in our hospital in the past decade.\n\n\nRESULTS\nThe 17 patients accounted for 8.3% of the total patients diagnosed with de novo APL during the same period in our hospital. Their clinical characteristics of APL were similar to those of general APL. Four patients had a definite history of taking bimolane. All patients received arsenic trioxide (ATO)-based remission induction and postremission treatment. After induction, 15 patients (88%) achieved hematologic complete remission. With a median follow-up of 27 months, the 3-year estimates of overall survival were 77.2% ± 12.4% and the 3-year estimates of event-free survival were 70.6% ± 13.5%. In addition, the ATO-based remission induction and postremission treatment significantly improved psoriasis symptoms in 83 and 85.7% of patients, respectively. Through the final follow-up, no chronic arsenicosis or secondary malignancy was observed.\n\n\nCONCLUSIONS\nPsoriasis patients are at high risk for APL. The increased risk is most likely associated with the genetic background and bimolane treatment. The ATO-based therapy is especially suitable for patients with psoriasis-associated APL. Our study also brings a new treatment option for psoriasis.",
"affiliations": "a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;b Central Laboratory , The First Affiliated Hospital, Harbin Medical University , China.;b Central Laboratory , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.;a Department of Hematology , The First Affiliated Hospital, Harbin Medical University , China.",
"authors": "Ge|Fei|F|;Zhang|Yingmei|Y|;Cao|Fenglin|F|;Li|Jinmei|J|;Hou|Jinxiao|J|;Wang|Ping|P|;Li|Haitao|H|;Xu|Mengyuan|M|;Liu|Shuchuan|S|;Li|Limin|L|;Li|Xiaoxia|X|;Wang|Shuye|S|;Lv|Chengfang|C|;Su|Yanhua|Y|;Zhou|Jin|J|",
"chemical_list": "D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide",
"country": "England",
"delete": false,
"doi": "10.1080/10245332.2015.1115586",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-5332",
"issue": "21(5)",
"journal": "Hematology (Amsterdam, Netherlands)",
"keywords": "Acute promyelocytic leukemia; Arsenic trioxide; Bimolane; Psoriasis",
"medline_ta": "Hematology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000077237:Arsenic Trioxide; D001152:Arsenicals; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D010087:Oxides; D011565:Psoriasis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "9708388",
"other_id": null,
"pages": "287-94",
"pmc": null,
"pmid": "26871996",
"pubdate": "2016-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Arsenic trioxide-based therapy is suitable for patients with psoriasis-associated acute promyelocytic leukemia - A retrospective clinical study.",
"title_normalized": "arsenic trioxide based therapy is suitable for patients with psoriasis associated acute promyelocytic leukemia a retrospective clinical study"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201703615",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
"drugadditional": null,... |
{
"abstract": "Anti-arrhythmic drugs (AADs) uniquely affect the various electrolyte channels in the heart and can slow conduction, increase refractoriness, and/or decrease automaticity with the goal of preventing tachyarrhythmias. Due to these properties, these same drugs are by nature pro-arrhythmic. Vaughan-Williams classification Ic AADs belong to a class of medications that inhibit sodium channels, leading to decreased conduction velocity of myocytes and Purkinje fibers as well as to decreased automaticity of pacemaker cells. When present in toxic amounts, this leads to classic changes on the electrocardiogram (ECG) that are harbingers of potentially lethal arrhythmias. Presented is a clinical series of ECGs that occurred in a patient who presented with flecainide toxicity.",
"affiliations": "San Antonio Military Medical Center, Electrophysiology Division, Cardiology Section, 3551 Roger Brooke Drive, San Antonio, TX, 78234, USA. Electronic address: alexandra.j.smith2.mil@mail.mil.;San Antonio Military Medical Center, Electrophysiology Division, Cardiology Section, 3551 Roger Brooke Drive, San Antonio, TX, 78234, USA.",
"authors": "Smith|Alexandra|A|;Gerasimon|Gregg|G|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ipej.2018.11.012",
"fulltext": "\n==== Front\nIndian Pacing Electrophysiol JIndian Pacing Electrophysiol JIndian Pacing and Electrophysiology Journal0972-6292Elsevier S0972-6292(18)30168-210.1016/j.ipej.2018.11.012Case ReportAn electrocardiographic series of flecainide toxicity Smith Alexandra alexandra.j.smith2.mil@mail.mil∗Gerasimon Gregg San Antonio Military Medical Center, Electrophysiology Division, Cardiology Section, 3551 Roger Brooke Drive, San Antonio, TX, 78234, USA∗ Corresponding author. San Antonio Military Medical Center, Cardiology Section, 3551 Roger Brooke Drive, San Antonio, TX, 78234, USA. alexandra.j.smith2.mil@mail.mil28 11 2018 Mar-Apr 2019 28 11 2018 19 2 75 78 16 10 2018 8 11 2018 27 11 2018 © 2018 Indian Heart Rhythm Society. Production and hosting by Elsevier B.V.2018Indian Heart Rhythm SocietyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Anti-arrhythmic drugs (AADs) uniquely affect the various electrolyte channels in the heart and can slow conduction, increase refractoriness, and/or decrease automaticity with the goal of preventing tachyarrhythmias. Due to these properties, these same drugs are by nature pro-arrhythmic. Vaughan-Williams classification Ic AADs belong to a class of medications that inhibit sodium channels, leading to decreased conduction velocity of myocytes and Purkinje fibers as well as to decreased automaticity of pacemaker cells. When present in toxic amounts, this leads to classic changes on the electrocardiogram (ECG) that are harbingers of potentially lethal arrhythmias. Presented is a clinical series of ECGs that occurred in a patient who presented with flecainide toxicity.\n\nKeywords\nFlecainideAntiarrhythmic drugsToxicityAtrial fibrillation\n==== Body\nAbbreviations\nAADAntiarrhythmic drug\n\nAVAtrioventricular\n\nAFAtrial fibrillation\n\nECGElectrocardiogram\n\n1 Introduction\nAnti-arrhythmic drugs (AADs), like most medications, are toxins that, when used in the appropriate dose and clinical setting, are therapeutic. Sodium-channel blocking agents, using the Vaughan-Williams classification system, are known as Class I anti-arrhythmic drugs. Class Ic AADs, which include flecainide and propafenone, have both sodium channel (INa) and potassium-channel (Ikr) blocking properties. In normal cardiac tissues, at therapeutic doses these medications slow depolarization and conduction, leading to QRS and QT prolongation (QT prolongation due to the widening of the QRS complex) [1]. When present in toxic amounts, there are various abnormal ECG findings that become apparent.\n\nFlecainide toxicity can lead to bradycardia, sinoatrial block, and asystole, as well as to first and second degree atrioventricular block. Sinus bradycardia is more common in patients with pre-existing sinus node dysfunction [2]. Flecainide can also lead to conversion of atrial fibrillation to slow atrial flutter with one-to-one conduction [1]. Class Ic AADs, in general, are contraindicated in patients with ischemic heart disease and reduced ejection fraction due to an increased incidence of cardiovascular death which is believed to be secondary to arrhythmic events [3]. Early recognition of toxicity is important to prevent dangerous arrhythmias secondary to the properties of this medication. Presented is a series of ECGs demonstrating the ECG changes in serum doses of flecainide ranging from therapeutic to toxic. An overview of the underlying mechanism of these findings is also presented.\n\n2 Case report\nThe patient is a 66-year-old woman with a history of symptomatic paroxysmal atrial fibrillation (AF), no known structural heart disease, and a previously normal stress test. Her AF was diagnosed two months prior when she presented with a right middle cerebral artery stroke. The patient's baseline ECG in sinus rhythm and the patient's initial ECG when the atrial fibrillation was diagnosed are shown in Fig. 1 and in Fig. 2, respectively. She was started on flecainide 100 mg twice a day and extended-release metoprolol succinate 25 mg daily, as well as apixaban 5 mg twice daily for systemic anticoagulation.Fig. 1 Baseline ECG of patient prior to initiation of flecainide therapy.\n\nFig. 1Fig. 2 Atrial fibrillation with rapid ventricular response.\n\nFig. 2\n\nAdditional past medical history includes a history of bladder cancer and of rheumatoid arthritis. The patient's clinical presentation with the new ECG findings was after two months of flecainide therapy. The ECGs on demonstrating the flecainide toxicity are shown in Fig. 3 and in Fig. 4 below. Four days prior to presentation, the patient had symptoms of fatigue and lightheadedness. Labs on presentation demonstrated mild acute renal failure with a creatinine increased to 1.35 mg/dL and potassium of 5.4 mEq/L. It is postulated that the acute renal failure led to flecainide toxicity. Cessation of flecainide resulted in complete resolution of the ECG changes.Fig. 3 Sinus bradycardia, significantly widened QRS, 1st degree AV block.\n\nFig. 3Fig. 4 Second degree type 1 SA block, significantly widened QRS, 1st degree AV block.\n\nFig. 4\n\n3 Discussion\nFlecainide was developed originally as a fluorinated anesthetic agent [4]. In animal and human models, it was found to suppress ventricular arrhythmias. Through further human studies in the 1980's, it was found to be effective in suppressing tachyarrhythmias secondary to accessory pathways and AV nodal reentry tachycardias [4]. It's mechanism of action is predominately through inactivation of fast sodium channels (INa), however it also has effects at lower doses on rapid inward rectifying potassium channels (IKr). Class 1c AADs have affinity for the INa channel in the open state and dissociate very slowly from the channel during the inactivated state. This results in use dependence, meaning that the drug has minimal effect at normal cardiac rates and increased effect in the setting of tachycardia [5]. The reduced influx of sodium intracellularly results in a reduced phase 0 slope and slowed conduction velocity. In addition, the mild effect on IKr can also lead to increased refractory periods of atrial, His-Purkinje, and ventricular cells via prolonged action potential duration [5]. This is manifested on the ECG by a prolonged P-wave, prolonged QRS interval, and AV nodal block.\n\nWhen the balance of slowed conduction and increased refractory period is skewed, the risk of reentry and proarrhythmia increases. Hence, the use of type Ic AADs is typically restricted to patients with a structurally normal heart. Many side effects of flecainide toxicity are more common in those with underlying cardiac dysfunction. This includes patients with sinus node dysfunction, His-Purkinje disease, and any history of ischemic heart disease with reduced ejection fraction or prior myocardial infarction.\n\nFig. 1 is the baseline ECG of the patient prior to the diagnosis of atrial fibrillation, demonstrating sinus rhythm with a 1st-degree AV block and a right bundle branch block. Fig. 2 is the presenting ECG in the Emergency Department when the atrial fibrillation was initially diagnosed. Fig. 3 shows the ECG on clinical presentation after two months of flecainide therapy, when she had symptoms of fatigue and lightheadedness. It demonstrates a markedly prolonged QRS duration of more than 160 ms, a marked first-degree AV block (a PR interval of 480ms), and sinus bradycardia at a rate of 42 beats per minute. The various degrees of AV block are secondary to the effect of flecainide on slowing conduction velocity in atrial, ventricular, and His-Purkinje tissues. The effect on the sinoatrial node likely reveals underlying sinus node dysfunction. Fig. 4 demonstrates second-degree type 1 sinoatrial block, a first-degree AV block, and a significantly widened QRS.\n\nWith discontinuation of flecainide and the normalization of renal function, her symptoms and the abnormal ECG findings completely resolved.\n\nDisclosures\nNone.\n\nPeer review under responsibility of Indian Heart Rhythm Society.\n==== Refs\nReferences\n1 Benowitz N.L. Chapter 11. Antiarrhythmic drugs Olson K.R. Poisoning & drug overdose 2012 McGraw-Hill 6e New York, NY \n2 Vik-Mo H. Ohm O.J. Lund-Johansen P. Electrophysiologic effects of flecainide acetate in patients with sinus nodal dysfunction Am J Cardiol 50 5 1982 Nov 1090 1094 7137036 \n3 Pratt C. Moyé L. The cardiac arrhythmia suppression trial Circulation 91 1995 245 247 originally published January 1, 1995 7805210 \n4 Andrikopoulos G.K. Pastromas S. Tzeis S. Flecainide: current status and perspectives in arrhythmia management World J Cardiol 7 2 2015 76 85 25717355 \n5 Kowey P.R. Yan G. Chapter 45. Antiarrhythmic drugs Fuster V. Walsh R.A. Harrington R.A. Hurst's the heart 2011 McGraw-Hill 13e New York, NY\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0972-6292",
"issue": "19(2)",
"journal": "Indian pacing and electrophysiology journal",
"keywords": "Antiarrhythmic drugs; Atrial fibrillation; Flecainide; Toxicity",
"medline_ta": "Indian Pacing Electrophysiol J",
"mesh_terms": null,
"nlm_unique_id": "101157207",
"other_id": null,
"pages": "75-78",
"pmc": null,
"pmid": "30502382",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "25717355;7137036;7805210",
"title": "An electrocardiographic series of flecainide toxicity.",
"title_normalized": "an electrocardiographic series of flecainide toxicity"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-18-08908",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"dr... |
{
"abstract": "To determine whether primary delusional jealousy can be treated effectively with antipsychotics or antidepressants, and whether any clinical variables are associated with response to pharmacotherapy, we carried out a retrospective case series observational study by reviewing clinical records of patients with an International Classification of Disease, 9th ed., diagnostic code of 297 (delusional disorders) who were treated at the Department of Psychiatry of a university affiliated hospital from January 2010 to December 2015. Only those records showing obvious delusional jealousy not secondary to other medical conditions, dementia, or schizophrenia were scrutinized thoroughly with respect to types of pharmacotherapy, treatment response, and other demographic and clinical variables likely to be associated with clinical outcomes. All except one of 32 patients, 16 men and 16 women, between 37 and 79 (60.9±10.6) years of age, were treated with low-dose antipsychotics. The general response was favorable as 19 (59.4%) were rated as good and 13 as inadequate responders (seven partial and six limited). Compared with antipsychotic monotherapy, concomitant therapy with antidepressants had a higher rate of good response, although statistically insignificant (75 vs. 53%, P=0.21). Younger age (P=0.01) and presentation at the index visit with their suspected unfaithful spouse were associated with a good response (P=0.036); comorbidity with delusions other than the jealous type was associated with a poor response (P=0.006). The overall outcome for delusional jealousy looks promising if the patients can accept pharmacotherapy in an outpatient setting.",
"affiliations": "Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.",
"authors": "Liu|Chen-Chung|CC|;Wang|Yen-Chin|YC|;Hwang|Tzung-Jeng|TJ|",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate; D013469:Sulpiride",
"country": "England",
"delete": false,
"doi": "10.1097/YIC.0000000000000207",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1315",
"issue": "33(2)",
"journal": "International clinical psychopharmacology",
"keywords": null,
"medline_ta": "Int Clin Psychopharmacol",
"mesh_terms": "D000368:Aged; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D003702:Delusions; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D038801:International Classification of Diseases; D007578:Jealousy; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D000069348:Quetiapine Fumarate; D012563:Schizophrenia, Paranoid; D013469:Sulpiride; D013624:Taiwan; D016896:Treatment Outcome",
"nlm_unique_id": "8609061",
"other_id": null,
"pages": "92-97",
"pmc": null,
"pmid": "29389697",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacotherapy for primary delusional jealousy, a retrospective observational study of 32 cases with Othello syndrome.",
"title_normalized": "pharmacotherapy for primary delusional jealousy a retrospective observational study of 32 cases with othello syndrome"
} | [
{
"companynumb": "TW-ALKEM LABORATORIES LIMITED-TW-ALKEM-2018-02934",
"fulfillexpeditecriteria": "2",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "BACKGROUND\nGentamicin has a well-known potential for damaging the peripheral vestibular organs. However, it is considered to be innocuous to the CNS as it crosses the blood-brain barrier poorly. Here, we describe central neuro-otological abnormalities developed by a patient after deployment of gentamicin into his spinal space.\n\n\nMETHODS\nA 61-year-old male unintentionally received gentamicin during spinal locoregional anesthesia for a urological procedure. During the first 48 hours the patient presented upper extremity dysmetria, dysarthria, and bilateral abducens nerve paralysis from which he recovered completely. He remained asymptomatic from day 3 to 10 after the incident. On day 11 he presented an acute vestibular syndrome. Severe bilateral vestibulopathy was confirmed by means of video head impulse testing. From day 14 onwards, he presented a persistent horizontal left-beating nystagmus, showing no variation or signs of compensation after 14 months, not responding to intensive vestibular rehabilitation or vestibular suppressant drugs. During follow-up, intercurrent gaze-evoked/direction-changing nystagmus has been recorded in various opportunities.\n\n\nCONCLUSIONS\nWe interpreted these findings as signs of both severe peripheral bilateral vestibulopathy and cerebellar and/or midbrain late-onset neurotoxicity, which can be explained by the intrinsic neurotoxic capability of high doses of gentamicin in the CNS.",
"affiliations": "Department of Otolaryngology, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Concepción, Chile; Department of Neuroscience, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Otolaryngology, Facultad de Medicina, Universidad de Chile, Santiago, Chile. Electronic address: hbreinbauer@uchile.cl.;Department of Otolaryngology, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Concepción, Chile.;Department of Otolaryngology, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Concepción, Chile.;Department of Neuroscience, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Otolaryngology, Facultad de Medicina, Universidad de Chile, Santiago, Chile.",
"authors": "Breinbauer|H A|HA|;Eyzaguirre|M|M|;Herrero|D|D|;Delano|P H|PH|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.anorl.2021.07.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1879-7296",
"issue": null,
"journal": "European annals of otorhinolaryngology, head and neck diseases",
"keywords": "Adverse effects; Central vertigo; Gentamicin; Neurotoxicity; Ototoxicity",
"medline_ta": "Eur Ann Otorhinolaryngol Head Neck Dis",
"mesh_terms": null,
"nlm_unique_id": "101531465",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34561196",
"pubdate": "2021-09-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Central nystagmus and alterations in vestibular tests due to an inadvertent gentamicin administration into spinal space: A CARE case report.",
"title_normalized": "central nystagmus and alterations in vestibular tests due to an inadvertent gentamicin administration into spinal space a care case report"
} | [
{
"companynumb": "CL-LUPIN PHARMACEUTICALS INC.-2021-20141",
"fulfillexpeditecriteria": "2",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nMultiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease. This study evaluated pregnancy-related issues in patients with MS in one perinatological centre.\n\n\nMETHODS\nA single-centre, retrospective study of the perinatal period in patients with MS admitted at the Dpt. of Gynaecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University and the University Hospital in Martin, Slovak Republic, European Union from January 1, 2015 to December 1, 2020 was performed. Selected parameters from personal, obstetric, and neurological histories were analysed.\n\n\nRESULTS\nA cohort of 15 patients (32.5±5.3 years) with a relapsing-remitting form of MS gave birth to 16 children. The mean length of MS at the time of delivery was 9±3.6 years. The severity of the Expanded Disability Status Scale score was 2.0±1.5. Caesarean section (CS) was indicated in 14 deliveries (87.5%). It was elective CS in 10 patients. The most common indication for elective CS was a combination of significant chronic fatigue syndrome and neurological deficit (paresis).\n\n\nCONCLUSIONS\nThe basis for the management of pregnancy, childbirth, and the postpartum period in women with MS is a planned pregnancy based on close cooperation among patients, gynaecologists, and neurologists. Vaginal delivery is not primarily contraindicated. Indications for CS should be considered individually. One way to minimise the indications for CS is a more accurate diagnosis and personalised treatment of fatigue in pregnant women with MS. Presumably, both obstetricians and neurologists prefer vaginal delivery as the first choice in patients with fatigue syndrome.",
"affiliations": "Department of Gynaecology and Obstetrics, Jessenius Faculty of Medicine, University Hospital Martin, Slovakia.;Department of Neurology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia.;Department of Gynaecology and Obstetrics, Jessenius Faculty of Medicine, University Hospital Martin, Slovakia.;Department of Neurology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia.;Second Department of Neurology, Slovak Medical University, F. D. Roosevelt Faculty Hospital, Banská Bystrica, Slovakia.;Department of Neurology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia.;Department of Anesthesiology and Intensive Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia.;Department of Gynaecology and Obstetrics, Jessenius Faculty of Medicine, University Hospital Martin, Slovakia.;Department of Neurology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia.",
"authors": "Biringer|Kamil|K|;Sivak|Stefan|S|;Sivakova|Jana|J|;Ružiňák|Róbert|R|;Martiníková|Martina|M|;Kantorova|Ema|E|;Biringerová|Zuzana|Z|;Kudela|Erik|E|;Kurca|Egon|E|",
"chemical_list": null,
"country": "Sweden",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-780X",
"issue": "42(4)",
"journal": "Neuro endocrinology letters",
"keywords": null,
"medline_ta": "Neuro Endocrinol Lett",
"mesh_terms": null,
"nlm_unique_id": "8008373",
"other_id": null,
"pages": "222-228",
"pmc": null,
"pmid": "34436842",
"pubdate": "2021-08-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fatigue as the limiting factor for vaginal birth in patients with multiple sclerosis.",
"title_normalized": "fatigue as the limiting factor for vaginal birth in patients with multiple sclerosis"
} | [
{
"companynumb": "SK-BIOGEN-2021BI01050072",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INTERFERON BETA-1A"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nRarely, corticotrophic pituitary tumors take on an aggressive form characterized by rapid growth, invasion into local structures, compression of cranial nerves, and possible spread to distant sites. When conventional surgery, radiation therapy, and hormones fail to control progression and symptoms, alternative therapies are needed. A novel chemotherapeutic regimen of capecitabine and temozolomide (CAPTEM), originally designed in our laboratory, demonstrated dramatic antineoplastic effects against corticotrophic pituitary tumors.\n\n\nMETHODS\nWe present a case series of 4 patients with aggressive, adrenocorticotrophic hormone--producing pituitary tumors who had previously depleted all surgical, radiation, and hormonal therapies and were then treated with CAPTEM. Dramatic clinical improvements in neurological deficits and Cushing symptoms were evident in all patients after treatment was initiated. Confirmed by radiographic imaging, 2 of 4 patients demonstrated complete regression of disease, 1 patient had a 75% regression, and the fourth patient has ongoing stable disease for > 4.5 years at the time of this writing. Immunohistochemical analysis of patients' tumor samples showed low O-methyguanyl methyltransferase expression and adequate levels of mismatch repair enzymes (MLH-1, MSH-2, MSH-6, and PMS-2), which are important for the in vivo efficacy of CAPTEM.\n\n\nCONCLUSIONS\nThis is the first report of prolonged antitumor response to and radiographic complete remissions as a result of CAPTEM in patients with aggressive pituitary tumors who had exhausted all other therapies.",
"affiliations": "*Department of Neurological Surgery, ‡Experimental Therapeutics Program, Department of Medicine, Division of Medical Oncology, Pancreas Center at Columbia, §Department of Medicine, Neuroendocrine Unit, and ¶Department of Pathology, Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital-Columbia University Medical Center, New York, NY.",
"authors": "Zacharia|Brad E|BE|;Gulati|Anthony P|AP|;Bruce|Jeffrey N|JN|;Carminucci|Arthur S|AS|;Wardlaw|Sharon L|SL|;Siegelin|Markus|M|;Remotti|Helen|H|;Lignelli|Angela|A|;Fine|Robert L|RL|",
"chemical_list": "D003841:Deoxycytidine; D000069287:Capecitabine; D003606:Dacarbazine; D005472:Fluorouracil; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1227/NEU.0000000000000251",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "74(4)",
"journal": "Neurosurgery",
"keywords": null,
"medline_ta": "Neurosurgery",
"mesh_terms": "D049913:ACTH-Secreting Pituitary Adenoma; D000236:Adenoma; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D003606:Dacarbazine; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion; D000077204:Temozolomide",
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "E447-55; discussion E455",
"pmc": null,
"pmid": "24226425",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing disease from capecitabine and temozolomide (CAPTEM): a case series.",
"title_normalized": "high response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory cushing disease from capecitabine and temozolomide captem a case series"
} | [
{
"companynumb": "US-MYLANLABS-2015M1009528",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "OCTREOTIDE ACETATE"
},
"drugadditional": null... |
{
"abstract": "Fentanyl is a synthetic opioid agonist used for pain control. Often administered as a transdermal patch, it is an interesting drug for study of postmortem redistribution. We hypothesized that fentanyl concentrations would increase over time after death, as measured in blood drawn on the day prior to autopsy and in blood drawn at the time of autopsy in ten cases where fentanyl patches were identified at the scene. Concentrations were compared, and heart blood to femoral blood ratios were calculated as markers of postmortem redistribution. Fentanyl concentrations measured in peripheral blood drawn the day of autopsy (peripheral blood 2 [PB2]) were higher than those drawn the day prior to autopsy (peripheral blood 1 [PB1]) with a mean ratio (PB2/PB1) of 1.80. The ratio of heart blood concentrations (HB) to femoral blood concentrations drawn at autopsy (PB2) had a mean ratio (HB/PB2) of 1.08. Some cases had blood from the same source analyzed at two different laboratories, and concentrations of fentanyl in those samples showed inter- and intralaboratory differences up to 25 ng/mL. Postmortem fentanyl concentrations may be affected by antemortem factors, postmortem redistribution, and laboratory variability. Forensic pathologists must use caution in interpreting fentanyl levels as part of death investigation.",
"affiliations": "University of New Mexico Health Sciences Center, New Mexico Office of the Medical Investigator, MSC07 4040, 1 University of New Mexico, Albuquerque, NM, 87131.",
"authors": "Krinsky|Clarissa S|CS|;Lathrop|Sarah L|SL|;Zumwalt|Ross|R|",
"chemical_list": "D009294:Narcotics; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1111/1556-4029.12381",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "59(5)",
"journal": "Journal of forensic sciences",
"keywords": "fentanyl; forensic pathology; forensic science; interlaboratory variability; postmortem redistribution; toxicology",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D005283:Fentanyl; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007753:Laboratories; D009294:Narcotics; D011180:Postmortem Changes",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1275-9",
"pmc": null,
"pmid": "25065851",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "An examination of the postmortem redistribution of fentanyl and interlaboratory variability.",
"title_normalized": "an examination of the postmortem redistribution of fentanyl and interlaboratory variability"
} | [
{
"companynumb": "US-JNJFOC-20140911380",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy of direct-acting antivirals (DAAs) in Kanto Rosai Hospital.\n\n\nMETHODS\nAll patients with hepatitis C virus (HCV) who underwent DAA prescription were enrolled in this study. The present study was a single center retrospective analysis using patients infected with HCV genotype 1 or 2. Resistance analysis was performed by using direct sequencing and cycleave PCR in genotype 1 patients treated with interferon (IFN)-free DAA. The primary endpoint was sustained virologic response at 12 wk after therapy (SVR12).\n\n\nRESULTS\nA total of 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + IFN + ribavirin and all achieved SVR. Of the 119 patients who received IFN-free DAA (in different combinations), 102 achieved SVR and 9 failed (7/9 were on daclatasvir/asunaprevir and 2/9 on ledipasvir/sofosbuvir). Efficacy analysis was done only for 43 patients who received daclatasvir/asunaprevir. From this analysis, Y93 resistance-associated substitutions were significantly correlated with SVR.\n\n\nCONCLUSIONS\nThe SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A resistance-associated substitutions that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.",
"affiliations": "Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan.;Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan.;Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan.;Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan.;Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan.;Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan.",
"authors": "Kaneko|Rena|R|;Nakazaki|Natsuko|N|;Omori|Risa|R|;Yano|Yuichiro|Y|;Ogawa|Masazumi|M|;Sato|Yuzuru|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4254/wjh.v10.i1.88",
"fulltext": "\n==== Front\nWorld J HepatolWJHWorld Journal of Hepatology1948-5182Baishideng Publishing Group Inc jWJH.v10.i1.pg8810.4254/wjh.v10.i1.88Retrospective StudyEfficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience Kaneko Rena Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, JapanNakazaki Natsuko Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, JapanOmori Risa Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, JapanYano Yuichiro Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, JapanOgawa Masazumi Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, JapanSato Yuzuru Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, JapanAuthor contributions: Kaneko R collected and analyzed the data, and drafted the manuscript; Nakazaki N, Omori R and Yano Y contributed the clinical study; Ogawa M and Sato Y supervised the study; all authors have read and approved the final version to be published.\n\nCorrespondence to: Rena Kaneko, MD, Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Kizukisumiyoshi-cho 1-1, Nakahara-ku, Kawasaki City, Kanagawa 211-8510, Japan. rena@kantoh.johas.go.jp\n\nTelephone: +81-44-4113131 Fax: +81-44-4113150\n\n27 1 2018 27 1 2018 10 1 88 94 27 9 2017 6 12 2017 13 12 2017 ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.2018This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.AIM\nTo evaluate the efficacy of direct-acting antivirals (DAAs) in Kanto Rosai Hospital.\n\nMETHODS\nAll patients with hepatitis C virus (HCV) who underwent DAA prescription were enrolled in this study. The present study was a single center retrospective analysis using patients infected with HCV genotype 1 or 2. Resistance analysis was performed by using direct sequencing and cycleave PCR in genotype 1 patients treated with interferon (IFN)-free DAA. The primary endpoint was sustained virologic response at 12 wk after therapy (SVR12).\n\nRESULTS\nA total of 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + IFN + ribavirin and all achieved SVR. Of the 119 patients who received IFN-free DAA (in different combinations), 102 achieved SVR and 9 failed (7/9 were on daclatasvir/asunaprevir and 2/9 on ledipasvir/sofosbuvir). Efficacy analysis was done only for 43 patients who received daclatasvir/asunaprevir. From this analysis, Y93 resistance-associated substitutions were significantly correlated with SVR.\n\nCONCLUSION\nThe SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A resistance-associated substitutions that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.\n\nResistance-associated substitutionsDirect-acting antiviralsSustained viral responseHepatitis C\n==== Body\nCore tip: Direct-acting antivirals have been approved for the treatment of hepatitis C virus (HCV) genotype 1 and 2 infections in Japan since 2011. In the new era of DAA therapy, predictors who fail to respond to DAA might be compromised by resistance-associated substitutions. There have been few reports of daclatasvir/asunaprevir failure because daclatasvir/asunaprevir is limited in Japan. Therefore, it might be important to report these cases for future research and treatment of HCV.\n\nINTRODUCTION\nHepatitis C is a worldwide health problem with 170 million carriers globally and 4 million new cases appearing per year[1]. Approximately 70% of hepatocellular carcinoma cases in Japan are attributable to hepatitis C virus (HCV) infection[2,3]. Since the late 1990s in Japan, the management of HCV infection has improved and there has been a decrease in the widespread use of non-sterile needles and blood transfusions[4-7]. Protease inhibitors such as simeprevir or telaprevir resulting in highly sustained virologic responses (SVRs) in HCV patients were introduced in 2011[8-10]. More recently, interferon (IFN)-free DAAs inhibiting key viral functions have become the mainstay of anti-HCV treatment[11-13]. Prior to the introduction of these therapeutic agents, IFN-based treatments were the standard therapy against HCV infection[14], despite the suboptimal SVR induced by this treatment (40%-50%). However, patients responding to IFN therapy and sustaining a loss of HCV RNA are generally regarded as being at low risk of developing liver cirrhosis or hepatocellular carcinoma (HCC)[4]. However, these continuous efforts and advances in anti-HCV therapy may influence improvements in the long-term outcome of patients with HCV.\n\nIn the new era of DAA therapy, the reason for patients’ failure in responding to DAAs might be related to the presence or development of resistance-associated substitutions (RASs)[15,16]. The aim of this study was to characterize the treatment response of new DAAs in patients infected with HCV.\n\nMATERIALS AND METHODS\nPatients\nJapanese patients aged 30-87 years with chronic HCV genotype 1 and genotype 2 infections and without decompensated cirrhosis were commenced with DAA treatment. Overall, 177 participants treated with telaprevir or simeprevir with pegylated (PEG)-IFN and ribavirin (RBV) or IFN-free DAA, and in whom SVR12 was judged between November 2012 and March 2017 at Kanto Rosai Hospital were included. Treatment-naïve and treatment-experienced patients were included.\n\nAssessments\nParameters were defined by standard laboratory techniques in Kanto Rosai Hospital. HCV NS5A RASs at Y93 and L31 were detected by commercial direct sequencing and cycleave PCR (SRL Laboratory, Tokyo, Japan) as well as PCR-invader methods (BML Laboratory, Tokyo, Japan). HCV RNA was measured by COBAS TaqMan PCR assay version 2.0 (Roche, Tokyo, Japan), with a lower limit of quantification of 25 IU/mL. For 10 patients who received either telaprevir or simeprevir with PEG-IFN treatment, the IL28B genotype was defined by PCR amplification and sequencing of the rs8099917, rs1188122 and rs88103142 nucleotide polymorphisms (SRL Laboratory). HCV core amino acids 70 and 99 were defined by PCR direct sequencing (LSI Laboratory, Tokyo, Japan). Liver cirrhosis was diagnosed by ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) or a liver biopsy.\n\nThe primary efficacy end point was the proportion of patients with undetectable HCV RNA at 12 wk post-treatment (SVR12).\n\nStatistical analysis\nAnalyses were performed using STATA/MP14.0 software (Stata-Corp LP, College Station, TX, United States).\n\nEthical statement\nBefore any study procedures were undertaken, informed consent was obtained from all patients. This study conformed to the ethical guidelines of the Declaration of Helsinki, and was approved by the ethics committee of Japan Organization of Occupational Health and Safety Kanto Rosai Hospital (2015-2017).\n\nRESULTS\nBaseline demographics and characteristics\nAmong 177 cases, 16 patients with genotype 1 were assigned to telaprevir or simeprevir with PEG-IFN and RBV, and 119 were assigned to IFN-free DAA [daclatasvir/asunaprevir (DCV/ASV), ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)]. Forty-two patients were treated with SOF and RBV for genotype 2. The average age ± standard deviation of the patients was 67.8 ± 11.0 years. Of these, the group with the highest average age of 72.7 ± 8.3 years was prescribed DCV/ASV. The number and proportion of males and females were 79 (44.6%) and 98 (55.4%), respectively. There were 74 cases (46.2%) with cirrhosis, including 21 cases diagnosed pathologically and 45 (25.4%) patients who had experienced IFN-based treatment previously. Twenty-six (14.7%) patients had a history of curative HCC (Table 1).\n\nTable 1 Baseline demographics and patient characteristics\n\nParameter\tOverall, n = 177\tGenotype 1\tGenotype 2 SOF/RBV n = 42\t\nIFN/TVR/RBV n = 5\tIFN/SMV/RBV n = 11\tDCV/ASV n = 43\tLDV/SOF n = 66\tOBV/PTV/r n = 10\t\nAge, median1\t67.8 (11.0)\t62.9 (8.7)\t60.2 (8.9)\t72.7 (8.3)\t66.0 (11.2)\t70.9 (6.5)\t67.5 (12.6)\t\n> 65, n (%)\t118 (66.7)\t3 (60)\t4 (36.4)\t37 (88.1)\t39 (59.0)\t7 (70)\t29 (67.4)\t\nSex, n (%)\t\t\t\t\t\t\t\t\nMale\t79 (44.6)\t3 (60)\t7 (63.6)\t14 (32.6)\t31 (47.0)\t4 (40)\t20 (47.6)\t\nFemale\t98 (55.4)\t2 (40)\t4 (36.4)\t29 (67.4)\t35 (53.0)\t6 (60)\t22 (52.4)\t\nHCV RNA, median Log10 LGE1\t6.1 (0.8)\t6.5 (0.56)\t6.2 (1.1)\t6.30 (0.5)\t6.16 (0.6)\t5.4 (0.9)\t5.8 (0.9)\t\n> 100000 IU/mL, n (%)\t109 (61.6)\t4 (80)\t9 (81.8)\t32 (76.2)\t43 (0.7)\t2 (20)\t19 (45.2)\t\nCirrhosis present, n (%)\t\t\t\t\t\t\t\t\nYes\t74 (41.8)\t0 (0)\t0 (0)\t34 (79.0)\t29 (44.0)\t3 (30)\t8 (18.6)\t\nNo\t103 (58.2)\t5 (100)\t11 (100)\t9 (20.1)\t37 (56.0)\t7 (70)\t34 (81.4)\t\nHCV treatment history, n (%)\t\t\t\t\t\t\t\t\nNaïve\t132 (74.6)\t1 (20)\t2 (18.2)\t25 (58.1)\t63 (95.5)\t9 (90)\t32 (76.2)\t\nPrior IFN-based treatment\t45 (25.4)\t4 (80)\t9 (81.8)\t18 (41.8)\t3 (4.5)\t1 (1)\t10 (23.8)\t\nHistory of HCC, n (%)\t\t\t\t\t\t\t\t\nYes\t26 (14.7)\t1 (20)\t0 (0)\t19 (44.1)\t3 (4.5)\t0 (0)\t3 (9)\t\nNo\t151 (85.3)\t4 (80)\t11 (100)\t24 (55.8)\t63 (95.5)\t10 (100)\t39 (90.7)\t\nLaboratory values\t\t\t\t\t\t\t\t\nBaseline platelet count, mean (× 104/μL)1\t15.1 (6.5)\t15.4 (3.4)\t15.1 (6.2)\t11.5 (5.8)\t15.5 (6.5)\t18.0 (5.96)\t17.6 (6.0)\t\nBaseline ALT level, mean (IU/L)1\t51.2 (37.3)\t41.8 (9.7)\t50.1 (50.5)\t53.1 (27.8)\t60.3 (45.2)\t39.9 (26.8)\t38.9 (28.6)\t\nBaseline AFP level, mean (ng/mL)1\t12.1 (17.6)\t5.6 (1.6)\t7.18 (9.1)\t23.4 (27.2)\t8.99 (11.6)\t9.9 (11.6)\t6.8 (6.9)\t\n1 The standard deviation is given in parentheses. AFP: Alpha fetoprotein; ALT: Alanine aminotransferase; DCV/ASV: Daclatasvir/asunaprevir; HCV: Hepatitis C virus; IFN: Interferon; LDV/SOF: Ledipasvir/sofosbuvir; OBV/PTV/r: Ombitasvir/paritaprevir/ritonavir; RBV: Ribavirin; SMV: Simeprevir; TVR: Telaprevir.\n\nAmong 16 patients with IFN-based protease inhibitor treatment, 10 were tested for the polymorphism NS5A region of IL28B, and HCV core amino acids 70 and 91. In both treatment groups, patients with the mutation who were predicted to have a low treatment response were included (Table 2).\n\nTable 2 Baseline characteristics of IL28B and NS5A polymorphisms\n\n\tIFN/TVR/RBV n = 5\tIFN/SMV/RBV n = 5\t\nIL28B SNP (n)\t\t\t\nrs8099917\t\t\t\nT/T\t4\t1\t\nT/G\t1\t2\t\nG/G\t0\t1\t\nrs11881222\t\t\t\nA/A\t4\t1\t\nA/G\t0\t2\t\nG/G\t1\t1\t\nrs88103142\t\t\t\nT/T\t4\t1\t\nT/C\t1\t2\t\nC/C\t0\t1\t\nNS5A aa701\t\t\t\nWild-type\t3\t0\t\nMutant\t2\t4\t\nCompetitive\t0\t1\t\nNS5A aa911\t\t\t\nWild-type\t3\t0\t\nMutant\t2\t2\t\nCompetitive\t0\t3\t\n1 aa HCV core amino acid. IFN: Interferon; RBV: Ribavirin; SMV: Simeprevil; TVR: Telaprevir.\n\nTreatment response and efficacy of all DAA therapy\nSVR12 was achieved in 167 of 177 (94.4%) patients. All 16 who received protease inhibitor with PEG-IFN and RBV (5 with teraprevir, 11 with simeprevir) achieved SVR12. All 42 patients with genotype 2 who received the treatment with SOF with RBV achieved SVR12. There was no case of relapse to the date of this paper. The response rate of the IFN-free DAA regimen (DCV/ASV, LDV/SOF, OBV/PTV/r) is shown in Table 3. Of the 43 patients who were treated with DCV/ASV, 1 patient broke through and 6 relapsed. Of the 66 patients on LDV/SOF, 2 relapsed and 2 had severe adverse events, including subarachnoid hemorrhage and cerebral hemorrhage. Although medication was stopped at 8 wk and 6 wk after prescription, SVR was achieved. Two patients also relapsed with LDV/SOF treatment. Of the 10 patients who have been on OBV/PTV/r, 1 was lost to follow-up.\n\nTable 3 Response during and after treatment with direct-acting antivirals\n\nResponse\tOverall, n = 119\tGenotype 1\tGenotype 2 SOF + RBV n = 42\t\nDCV/ASV n = 43\tLDV/SOF n = 66\tOBV/PTV/r n = 10\t\nHCV RNA < LLOQ during treatment1, n (%)\t119 (100)\t41 (100)\t66 (100)\t9 (90)3\t42 (100)\t\nHCV RNA < LLOQ after end of treatment1, n (%)\t118 (98.3)\t42 (97.6)\t66 (100)\t9 (90)3\t42 (100)\t\nSVR122, n (%)\t109 (91.6)\t35 (83.3)\t64 (97)\t9 (90)3\t42 (100)\t\nOn-treatment failure, n (%)\t1 (0.8)\t1 (2.3)\t0 (0)\t0 (0)\t0 (0)\t\nRelapse, n (%)\t8 (6.7)\t6 (16.7)\t2 (3)\t0 (0)\t0 (0)\t\n1 LLOQ (lower limit of quantification) = 25 IU/ML; \n\n2 SVR: Sustained virologic response; \n\n3 One case lost to follow-up. DCV/ASV: Daclatasvir/asunaprevir; LDV/SOF: Ledipasvir/sofosbuvir; OBV/PTV/r: Ombitasvir/paritaprevir/ritonavir; RBV: Ribavirin.\n\nAnalysis of RASs\nNS5A RASs were analyzed in 82 patients with IFN-free DAA treatment (Figure 1). Of these, 2 relapsed patients with wild-type Y93 and 1 with Y93 hetero were treated with DCV/ASV. Three relapsed patients with wild-type L31 were also treated with DCA/ASV. Another 6 patients that failed to achieve SVR with DAA treatment had not obtained NS5A RASs prior to treatment. Of the 9 failure patients, 7 were diagnosed as cirrhosis before DAA treatment, and 4 had a history of curative HCC (Table 4).\n\nFigure 1 SVR rates for NS5A resistance-associated substitutions and each interferon-free agent. The number above each column is the number of cases with SVR (numerator) and total cases (denominator). Two relapsed patients with wild-type Y93, 1 with Y93 hetero and 3 relapsed patients with wild-type L31 were treated with DCV/ASV. Another 6 patients that failed to achieve SVR with DAA treatment had not obtained NS5A RASs prior to treatment. Another patient had no relapse regardless of the presence or absence of RASs. DAA: Direct-acting antivirals; DCV/ASV: Daclatasvir/asunaprevir; RAS: Resistance-associated substitution; SVR: Sustained virologic response.\n\nTable 4 NS5A RASs and clinical course in patients with failure of DAAs\n\nPatient No.\tSex\tAge in yr\tLC1\tHCC2\tInitial DAA\tNS5A RASs\tSecond DAA\tSecond result\t\nBefore DAA\tAfter DAA (invader)\tAfter DAA (cycleave)\t\n1\tFemale\t73\tNo\tNo\tDCV/ASV\tNA\tY93H L31F Q54H A92V\tY93 mutant L31 mutant\tLDV/SOF/RBV\tSVR\t\n2\tFemale\t77\tYes\tYes\tDCV/ASV\tNA\tY93H L31M Q24Q/R\tY93 mutant L31 mutant\tLDV/SOF/RBV\tRelapse\t\n3\tFemale\t71\tYes\tNo\tDCV/ASV\tNA\tNA\tY93 wild-type L31mutant\tLDV/SOF/RBV\tSVR\t\n4\tFemale\t78\tYes\tNo\tDCV/ASV\tNA\tNA\tY93 mutant L31 mutant\tLDV/SOF/RBV\tSVR\t\n5\tMale\t74\tYes\tYes\tDCV/ASV\tNA\tY93H L31V Q54y Q62D\tY93 mutant L31 mutant\tLDV/SOF\tSVR\t\n6\tFemale\t83\tYes\tYes\tDCV/ASV\tY93Y/H L31L\tY93H L31M L31V\tY93 mutant L31 wild-type\tNo\tNA\t\n7\tMale\t71\tYes\tNo\tDCV/ASV\tY93Y L31L\tNA\tY93 wild-type L31 mutant\tDCV-TRIO\tUndergoing\t\n8\tFemale\t66\tNo\tNo\tLDV/SOF\tY93Y L31L\tNA\tFailure\tWaiting\tNA\t\n9\tMale\t78\tYes\tYes\tLDV/SOF\tNA\tNA\tFailure\tWaiting\tNA\t\n1 Diagnosed as cirrhosis; \n\n2 A history of curative treatment for hepatocellular carcinoma. DAA: Direct-acting antivirals; DCV/ASV: Daclatasvir/asunaprevir; DCV-TRIO: Daclatasvir/asunaprevir/beclabuvir; LDV/SOF: Ledipasvir/sofosbuvir; NA: Data not available; RAS: Resistance-associated substitution; RBV: Ribavirin; SVR: Sustained virologic response. Failure: Could not be detected.\n\nPatients who failed to respond to the initial IFN-free DAA regimen were given second-line therapies. Four patients were enrolled to LDV/SOF with RBV therapy in another hepatitis core hospital in Kanagawa prefecture and SVR was achieved in 3 of these patients, with 1 relapsing. One patient treated with LDV/SOF achieved SVR. One patient is now undergoing daclatasvir/asunaprevir/beclabuvir (known as DCV-TRIO) treatment (Table 4).\n\nOf the 25 patients having HCC history and treated with IFN-free DAA, 4 had recurrence to date. Of these, 2 came back with extremely rapid growth of HCC.\n\nMultivariable logistic regression for SVR factors using patients with DCV/ASV treatment was performed using two models. Regression using all baseline variables as covariates (model 1) showed HCV RNA levels were independently associated with SVR. Model 2 was built with suspected variables from DAA failure patients (Table 5) and showed that only Y93 RAS was associated with SVR (Table 5).\n\nTable 5 Multivariable logistic regression models for SVR in patients with DCV/ASV\n\n\tOdds ratio\t95%CI\tP-value\t\nModel 1: All variables\t\t\t\t\nPlatelet count\t0.00\t-0.01-0.27\t0.71\t\nAFP level\t0.00\t-0.00-0.01\t0.44\t\nALT level\t0.00\t-0.00-0.01\t0.31\t\nHCV RNA level\t0.26\t0.02-0.45\t0.04a\t\nAge\t0.02\t-0.01-0.04\t0.14\t\nSex\t-0.13\t-0.39-0.12\t0.28\t\nY93\t0.23\t-0.31-0.77\t0.38\t\nL31\t-0.17\t-1.05-0.70\t0.68\t\nHistory of HCC\t-0.29\t-0.68-0.92\t0.13\t\nCirrhosis\t-0.30\t-0.38-0.26\t0.67\t\nPrior IFN\t-0.15\t-0.41-0.99\t0.21\t\nModel 2: Limited suspicious covariates\t\t\t\t\nAge\t0.00\t-0.13-0.14\t0.93\t\nY93\t0.48\t0.08-0.87\t0.02a\t\nL31\t-0.42\t-1.09-0.24\t0.2\t\nCirrhosis\t-0.15\t-0.37-0.08\t0.19\t\nModel 1: The baseline model considered with all covariates obtained. Model 2: Limited to covariates suspected from Table 4. \n\na P < 0.05 were considered statistically significant. AFP: Alpha fetoprotein; ALT: Alanine aminotransferase; HCC: Hepatocellular carcinoma; IFN: Interferon.\n\nDISCUSSION\nThis study of patients with HCV infection demonstrated that high SVR rates can be achieved with DAA regimens including IFN-based protease inhibitor and IFN-free DAAs. DAAs conferred good effectiveness and safety for both treatment-naïve patients and previously treated cases.\n\nUntil recently, PEG-IFN combined with RBV therapy was the only antiviral drug regimen capable of terminating HCV infection[8]. However, SVR was only achieved in about 50% of treated patients[17-19]. Many DAAs have been designed to improve this situation[20]. To activate the IFN pathway, telaprevir, boceprevir and simeprevir were introduced as 1st and 2nd generation HCV protease inhibitors[8-10,20]. However, these agents increase the risk of adverse events, such as anemia, renal failure and severe drug rash. In the initial IFN-free regimen, DCV/ASV eliminated IFN-related toxicity and achieved a SVR24 rate of 84% in chronic hepatitis C patients and 90.9% in liver cirrhosis cases in Japan[21]. The SVR12 rate of LDV/SOF was 100%[12] and for OBV/PTV/r it was 98%[22] in genotype 1 HCV. SOF/RBV and OBV/PTV/r have been approved for genotype 2 HCV, which accounts for up to 30% of chronic HCV infection and which is increasing in prevalence in Japan[23]. Although OBV/PTV/r was limited to use for genotype 2b, the SVR rate was 95-98% when RBV was used[23-25]. The use of IFN-free DAA enables the treatment of IFN ineligible/intolerant individuals with HCV infection.\n\nA low rate of virological failure in genotype 1 was observed in patients with baseline Y93 or L31 variants in NS5A receiving DCV/ASV or OBV/PTV/r treatment[13,22]. It has been reported that pretreatment with NS5A RASs did not impact LDV/SOF therapy[26].\n\nMoreover, there have been few reports of DCV/ASV failure because DCV/ASV is limited in Japan. Therefore, it might be important to report these cases for future research and treatment of HCV.\n\nIn the present report, the SVR rate of each therapy in Kanto Rosai Hospital was similar to previous reports[12,13,21,23,27]. In genotype 1 patients, 7 failures with DCV/ASV and 2 with LDV/SOF were reported. Among these, 7 patients were diagnosed cirrhosis and 4 patients who had a history of HCC were also reported. Y93 RAS was correlated to SVR failure in DCV/ASV cases. In 2 relapsers with LDV/SOF, DAA RAS could not detected. Subsequently, it was revealed that the core genotype of HCV was 1a and 2a in these patients.\n\nWe experienced 2 patients with subarachnoid hemorrhage and cerebral hemorrhage, and these discontinued LDV/SOF therapy. They were 51- and 68-year-old females without cirrhosis and other medical history. In 2016, postmarketing surveillance data were reported in Japan, and 31 cases of severe cerebrovascular disease were reported[28]. As far as we know, there is no detailed report about cerebrovascular adverse reaction. Therefore, the physiological mechanism underlying the cerebrovascular adverse events is unclear. Caution is needed when prescribing LDV/SOF therapy.\n\nTwo patients had aggressive and rapid HCC recurrence after treatment with DAA. The assumption that the use of DAAs may induce HCC relapse had been reported[29]. The surveillance of HCC must be taken strictly after DAA treatment in patients with prior HCC.\n\nRecent reports demonstrated that the SVR rate was only 69% for salvage therapy for patients who failed to respond to NS5A inhibitors[30]. Prior DCV/ASV treatment is associated with a failure of LDV/SOF for multiple HCV NAS5A RASs[30,31].\n\nWe could not treat patients with LDV/SOF and RBV simultaneously because this treatment regimen has not been approved for general insurance. However, the ratio of SVR increased to 75% in initial DAA failure patients, even though multiple NS5A RASs were observed.\n\nThe achievement of an SVR of 100% for overall patients with HCV infection may be accomplished in the future.\n\nThis study had some limitations. First, data for RASs were not available for all cases. Due to the small sample size, the power of the multiple regression analysis remains low. Second, because this was a study from one hospital, the total number of treatment cases was small. Third, because DCV/ASV has only been approved in Japan, there are some limitations regarding the generalizability of the results. However, this study provides some important knowledge about HCV treatment.\n\nIn conclusion, DAA treatment for HCV infection is highly effective in Kanto Rosai Hospital. However, caution is needed for HCV NS5A RASs that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.\n\nARTICLE HIGHLIGHTS\nResearch background\nIn a previous study, it was shown that resistance-associated substitutions (RASs) were predictors of direct-acting antiviral (DAA) failure. No significant adverse effect was reported in the DAA treatment in clinical trials. In this study, the prestudy hypothesis was that another predictor might exist concerning about DAA failure. Another hypothesis was that more severe adverse effects must occur in the real world because patients conditions were more severe than those of clinical trials.\n\nResearch motivation\nDAAs have been approved for the treatment of hepatitis C virus (HCV) genotype 1 and 2 infections in Japan since 2011. In the new era of DAA therapy, predictors who fail to respond to DAA might be compromised by RASs. There have been few reports of daclatasvir/asunaprevir (DCV/ASV) failure because DCV/ASV is limited in Japan. Therefore, it might be important to report these cases for future research and treatment of HCV.\n\nResearch objectives\nAll patients with HCV infection who underwent DAA prescription were enrolled in this study. Overall, 177 participants treated with DAAs and in whom sustained virologic response at 12 wk after therapy (SVR12) was judged between November 2012 and March 2017 at Kanto Rosai Hospital were included.\n\nResearch methods\nHCV patients who underwent DAA prescription were enrolled in this study. Resistance analysis was performed by using direct sequencing and cycleave PCR. Multiple regression analysis was performed to evaluate factors related to loss of HCV RNA.\n\nResearch results\nIn total, 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + interferon + ribavirin and all achieved SVR. Of the 119 patients who received interferon-free DAA (in different combinations), 102 achieved SVR while 9 failed, including 7/9 who were on DCV/ASV and 2/9 who were on ledipasvir/sofosbuvir. Efficacy analysis was done only for 42 patients who received DCV/ASV. From this analysis, Y93 RASs were significantly correlated with SVR.\n\nResearch conclusions\nThe SVR rate was 98% for genotype 1 and 100% for genotype 2. NS5A RASs are most likely to affect the outcomes of DAA therapy in our facility.\n\nResearch perspectives\nThe SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A RASs that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.\n\nSupported by research funds to promote the Hospital functions of the Japan Organization of Occupational Health and Safety; No. 359.\n\nInstitutional review board statement: This study was reviewed and approved by the Kanto Rosai Hospital Review Board.\n\nInformed consent statement: Written informed consent was obtained from the patient for this study.\n\nConflict-of-interest statement: The authors declare no potential conflict of interest.\n\nData sharing statement: Participants gave informed consent for data sharing.\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: October 2, 2017\n\nFirst decision: November 27, 2017\n\nArticle in press: December 13, 2017\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: Japan\n\nPeer-review report classification\n\nGrade A (Excellent): A, A\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP- Reviewer: Hann HW, Kao JT, Rezaee-Zavareh MS, Toyoda T S- Editor: Kong JX L- Editor: Filipodia E- Editor: Li D\n==== Refs\n1 Ray Kim W Global epidemiology and burden of hepatitis C Microbes Infect 2002 4 1219 1225 12467763 \n2 Lavanchy D Evolving epidemiology of hepatitis C virus Clin Microbiol Infect 2011 17 107 115 21091831 \n3 Zhu RX Seto WK Lai CL Yuen MF Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region Gut Liver 2016 10 332 339 27114433 \n4 Nishiguchi S Kuroki T Nakatani S Morimoto H Takeda T Nakajima S Shiomi S Seki S Kobayashi K Otani S Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis Lancet 1995 346 1051 1055 7564784 \n5 Tanaka H Imai Y Hiramatsu N Ito Y Imanaka K Oshita M Hijioka T Katayama K Yabuuchi I Yoshihara H Declining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990 to 2003 Ann Intern Med 2008 148 820 826 18519928 \n6 Umemura T Ichijo T Yoshizawa K Tanaka E Kiyosawa K Epidemiology of hepatocellular carcinoma in Japan J Gastroenterol 2009 44 Suppl 19 102 107 19148802 \n7 Goh GB Chang PE Tan CK Changing epidemiology of hepatocellular carcinoma in Asia Best Pract Res Clin Gastroenterol 2015 29 919 928 26651253 \n8 Kumada H Toyota J Okanoue T Chayama K Tsubouchi H Hayashi N Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan J Hepatol 2012 56 78 84 21827730 \n9 Hayashi N Izumi N Kumada H Okanoue T Tsubouchi H Yatsuhashi H Kato M Ki R Komada Y Seto C Simeprevir with peginterferon/ribavirin for treatment-naive hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial J Hepatol 2014 61 219 227 24727123 \n10 Izumi N Hayashi N Kumada H Okanoue T Tsubouchi H Yatsuhashi H Kato M Ki R Komada Y Seto C Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies J Gastroenterol 2014 49 941 953 24626851 \n11 Pawlotsky JM NS5A inhibitors in the treatment of hepatitis C J Hepatol 2013 59 375 382 23567084 \n12 Mizokami M Yokosuka O Takehara T Sakamoto N Korenaga M Mochizuki H Nakane K Enomoto H Ikeda F Yanase M Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial Lancet Infect Dis 2015 15 645 653 25863559 \n13 Suzuki Y Ikeda K Suzuki F Toyota J Karino Y Chayama K Kawakami Y Ishikawa H Watanabe H Hu W Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options J Hepatol 2013 58 655 662 23183526 \n14 Izumi N Diagnostic and treatment algorithm of the Japanese society of hepatology: a consensus-based practice guideline Oncology 2010 78 Suppl 1 78 86 20616588 \n15 Itakura J Kurosaki M Takada H Nakakuki N Matsuda S Gondou K Asano Y Hattori N Itakura Y Tamaki N Naturally occurring, resistance-associated hepatitis C virus NS5A variants are linked to interleukin-28B genotype and are sensitive to interferon-based therapy Hepatol Res 2015 45 E115 E121 25564756 \n16 Kinugasa H Ikeda F Takaguchi K Mori C Matsubara T Shiraha H Takaki A Iwasaki Y Toyooka S Yamamoto K Low frequency of drug-resistant virus did not affect the therapeutic efficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV genotype-1 infection Antivir Ther 2016 21 37 44 26115551 \n17 Shiffman ML Reddy KR Smith C Marinos G Goncales FL Jr Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection N Engl J Med 2002 347 975 982 12324553 \n18 Hadziyannis SJ Sette H Jr Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H, Jr., Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose Ann Intern Med 2004 140 346 355 14996676 \n19 Manns MP McHutchison JG Gordon SC Rustgi VK Shiffman M Reindollar R Goodman ZD Koury K Ling M Albrecht JK Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial Lancet 2001 358 958 965 11583749 \n20 Asselah T Marcellin P New direct-acting antivirals’ combination for the treatment of chronic hepatitis C Liver Int 2011 31 Suppl 1 68 77 21205141 \n21 Kumada H Suzuki Y Ikeda K Toyota J Karino Y Chayama K Kawakami Y Ido A Yamamoto K Takaguchi K Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection Hepatology 2014 59 2083 2091 24604476 \n22 Kumada H Chayama K Rodrigues L Jr Suzuki F, Ikeda K, Toyoda H, Sato K, Karino Y, Matsuzaki Y, Kioka K, Setze C, Pilot-Matias T, Patwardhan M, Vilchez RA, Burroughs M, Redman R. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis Hepatology 2015 62 1037 1046 26147154 \n23 Omata M Nishiguchi S Ueno Y Mochizuki H Izumi N Ikeda F Toyoda H Yokosuka O Nirei K Genda T Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial J Viral Hepat 2014 21 762 768 25196837 \n24 Shafran SD Shaw D Charafeddine M Agarwal K Foster GR Abunimeh M Pilot-Matias T Pothacamury RK Fu B Cohen E Efficacy and safety results of patients with HCV genotype 2 or 3 infection treated with ombitasvir/paritaprevir/ritonavir and sofosbuvir with or without ribavirin (QUARTZ II-III) J Viral Hepat 2017 \n25 Schnell G Tripathi R Krishnan P Beyer J Reisch T Irvin M Dekhtyar T Setze C Rodrigues-Jr L Alves K Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir J Med Virol 2018 90 109 119 28842997 \n26 Mizokami M Dvory-Sobol H Izumi N Nishiguchi S Doehle B Svarovskaia ES De-Oertel S Knox S Brainard DM Miller MD Resistance Analyses of Japanese Hepatitis C-Infected Patients Receiving Sofosbuvir or Ledipasvir/Sofosbuvir Containing Regimens in Phase 3 Studies J Viral Hepat 2016 23 780 788 27196675 \n27 Backus LI Belperio PS Shahoumian TA Loomis TP Mole LA Real-world effectiveness of ledipasvir/sofosbuvir in 4,365 treatment-naive, genotype 1 hepatitis C-infected patients Hepatology 2016 64 405 414 27115523 \n28 Giliead Post-marketing surveillance of ledipasvir/sofosbuvir 2015-2016 Available from: https://www.harvoni.jp/~/media/files/gilead/harvoni/proper/hvn_post_marketing_surveillance_final_report.pdf?la=ja-jp \n29 Reig M Marino Z Perello C Inarrairaegui M Ribeiro A Lens S Diaz A Vilana R Darnell A Varela M Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy J Hepatol 2016 65 719 726 27084592 \n30 Akuta N Sezaki H Suzuki F Fujiyama S Kawamura Y Hosaka T Kobayashi M Kobayashi M Saitoh S Suzuki Y Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens J Med Virol 2017 89 1248 1254 28079269 \n31 Iio E Shimada N Takaguchi K Senoh T Eguchi Y Atsukawa M Tsubota A Abe H Kato K Kusakabe A Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy Hepatol Res 2017\n\n",
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"issue": "10(1)",
"journal": "World journal of hepatology",
"keywords": "Direct-acting antivirals; Hepatitis C; Resistance-associated substitutions; Sustained viral response",
"medline_ta": "World J Hepatol",
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"title": "Efficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience.",
"title_normalized": "efficacy of direct acting antiviral treatment for chronic hepatitis c a single hospital experience"
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"abstract": "A 5 year old boy developed severe weakness after receiving vincristine for treatment of acute lymphoblastic leukaemia. Although weakness improved after the discontinuation of vincristine, other symptoms suggestive of a neuropathy persisted. Neurophysiological and genetic analysis at age 8 years indicated that vincristine had induced symptoms of a hereditary sensory motor neuropathy type 1A, which had previously been asymptomatic; his genetically affected mother was also asymptomatic.",
"affiliations": "Department of Paediatrics & Neonatal Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0HN, UK. e.mercuri@ic.ac.uk",
"authors": "Mercuri|E|E|;Poulton|J|J|;Buck|J|J|;Broadbent|V|V|;Bamford|M|M|;Jungbluth|H|H|;Manzur|A Y|AY|;Muntoni|F|F|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine",
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"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D002607:Charcot-Marie-Tooth Disease; D002675:Child, Preschool; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D014750:Vincristine",
"nlm_unique_id": "0372434",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "4348690;2685529;8608515;7603395;8600343;2091516",
"title": "Vincristine treatment revealing asymptomatic hereditary motor sensory neuropathy type 1A.",
"title_normalized": "vincristine treatment revealing asymptomatic hereditary motor sensory neuropathy type 1a"
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"activesubstancename": "VINCRISTINE SULFATE"
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"abstract": "A man in his 60s was diagnosed with esophageal cancer (T3, N0, StageII) and treated with 5-fluorouracil and cisplatin as neoadjuvant chemotherapy (NAC). On day 18 of the second NAC course, the patient developed febrile neutropenia, and a computed tomography (CT) scan showed pneumatosis cystoides intestinalis (PCI) of the ascending and transverse colon, free air around the ascending colon, thickening of the gallbladder wall, pleural effusion, and ascites. Because there were no signs of peritoneal irritation and intestinal perforation was ruled out, conservative treatment was selected. Seven days after PCI was diagnosed, CT showed improvement in PCI and the free air had disappeared, and 26 days after the diagnosis, a subtotal esophagectomy was performed. Observation of the abdomen did not show a thickened wall or stenosis of the ascending or transverse colon. PCI could be treated conservatively, even with free air in the abdominal cavity, by comprehensively assessing not only the imaging but also the physical findings. We were able to perform radical resection of the esophageal cancer without excessive treatment for PCI.",
"affiliations": "Dept. of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine.",
"authors": "Akasaka|Harue|H|;Wajima|Naoki|N|;Kimura|Akitoshi|A|;Sakuraba|Shingo|S|;Kubo|Norihito|N|;Yamana|Daisuke|D|;Okano|Kensuke|K|;Ichinohe|Daichi|D|;Shimada|Taku|T|;Hakamada|Kenichi|K|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
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"issue": "41(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D004938:Esophageal Neoplasms; D005472:Fluorouracil; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy; D011006:Pneumatosis Cystoides Intestinalis",
"nlm_unique_id": "7810034",
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"references": null,
"title": "A case of pneumatosis cystoides intestinalis after neoadjuvant chemotherapy for esophageal cancer.",
"title_normalized": "a case of pneumatosis cystoides intestinalis after neoadjuvant chemotherapy for esophageal cancer"
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"companynumb": "JP-MYLANLABS-2015M1042347",
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"abstract": "Donor-derived human parvovirus B19 (B19V) infections are rarely reported. Thus, its incidence in kidney transplantation is still unknown due to lack of surveillance studies. Similarly, whether the donor needs to be routinely screened for B19V and whether the kidneys from those with B19V DNAemia could be accepted also remain unknown.\n\n\n\nThis retrospective study aims to evaluate the donor-derived B19V infections occurring in 823 living and 1,225 deceased donor kidney transplantations from January 2016 to December 2020. The serum viral load of living donors and their corresponding recipients was evaluated before and after transplantation. Meanwhile, for the deceased donor kidney transplantation, the serum viral load of recipients was only tested after transplantation; if recipients of a deceased donor subsequently developed B19V infection, the serum viral load of recipients and their corresponding donors before transplantation would then be further traced.\n\n\n\nA total of 15 living donors were B19V DNAemia positive before the donation, of which B19V DNAemia occurred in three corresponding recipients. In deceased donor kidney transplantation, DNAemia occurred simultaneously in 18 recipients and their corresponding nine donors. A progressive decline in hemoglobin and reticulocyte count could be observed in one living donor recipient and other 11 deceased donor recipients, which were all well controlled by treatment eventually.\n\n\n\nThe incidence of donor-derived B19V infection was 0.4% and 1.5% in living and deceased kidney transplantations, respectively. B19V was seemingly unnecessary to be routinely screened for the donor. Moreover, kidneys of the donors with B19V infection were acceptable.",
"affiliations": "Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.;Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.;Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.;Department of Intensive Care Medicine, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.;Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.;Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.;Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.;Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.;Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.",
"authors": "Yu|Yedong|Y|;Wei|Chunchun|C|;Lyu|Junhao|J|;Wu|Xiaoliang|X|;Wang|Rending|R|;Huang|Hongfeng|H|;Wu|Jianyong|J|;Chen|Jianghua|J|;Peng|Wenhan|W|",
"chemical_list": "D004279:DNA, Viral",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fcimb.2021.753970",
"fulltext": "\n==== Front\nFront Cell Infect Microbiol\nFront Cell Infect Microbiol\nFront. Cell. Infect. Microbiol.\nFrontiers in Cellular and Infection Microbiology\n2235-2988\nFrontiers Media S.A.\n\n10.3389/fcimb.2021.753970\nCellular and Infection Microbiology\nOriginal Research\nDonor-Derived Human Parvovirus B19 Infection in Kidney Transplantation\nYu Yedong 1\nWei Chunchun 1 2 3 4 5\nLyu Junhao 1 2 3 4 5\nWu Xiaoliang 6\nWang Rending 1 2 3 4 5\n\nHuang Hongfeng 1 2 3 4 5\n\nWu Jianyong 1 2 3 4 5\nChen Jianghua 1 2 3 4 5\n\nPeng Wenhan 1 2 3 4 5 *\n\n1 Kidney Disease Center, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China\n2 Kidney Disease Immunology Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China\n3 Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China\n4 Institute of Nephrology, Zhejiang University, Hangzhou, China\n5 Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Hangzhou, China\n6 Department of Intensive Care Medicine, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China\nEdited by: Max Maurin, Université Grenoble Alpes, France\n\nReviewed by: Troy Quigg, Helen DeVos Children’s Hospital, United States; Rita De Cássia Nasser Cubel Garcia, Fluminense Federal University, Brazil\n\n*Correspondence: Wenhan Peng, 1198027@zju.edu.cn\nThis article was submitted to Clinical Microbiology, a section of the journal Frontiers in Cellular and Infection Microbiology\n\n15 10 2021\n2021\n11 75397005 8 2021\n23 9 2021\nCopyright © 2021 Yu, Wei, Lyu, Wu, Wang, Huang, Wu, Chen and Peng\n2021\nYu, Wei, Lyu, Wu, Wang, Huang, Wu, Chen and Peng\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.\nBackground\n\nDonor-derived human parvovirus B19 (B19V) infections are rarely reported. Thus, its incidence in kidney transplantation is still unknown due to lack of surveillance studies. Similarly, whether the donor needs to be routinely screened for B19V and whether the kidneys from those with B19V DNAemia could be accepted also remain unknown.\n\nMethods\n\nThis retrospective study aims to evaluate the donor-derived B19V infections occurring in 823 living and 1,225 deceased donor kidney transplantations from January 2016 to December 2020. The serum viral load of living donors and their corresponding recipients was evaluated before and after transplantation. Meanwhile, for the deceased donor kidney transplantation, the serum viral load of recipients was only tested after transplantation; if recipients of a deceased donor subsequently developed B19V infection, the serum viral load of recipients and their corresponding donors before transplantation would then be further traced.\n\nResults\n\nA total of 15 living donors were B19V DNAemia positive before the donation, of which B19V DNAemia occurred in three corresponding recipients. In deceased donor kidney transplantation, DNAemia occurred simultaneously in 18 recipients and their corresponding nine donors. A progressive decline in hemoglobin and reticulocyte count could be observed in one living donor recipient and other 11 deceased donor recipients, which were all well controlled by treatment eventually.\n\nConclusion\n\nThe incidence of donor-derived B19V infection was 0.4% and 1.5% in living and deceased kidney transplantations, respectively. B19V was seemingly unnecessary to be routinely screened for the donor. Moreover, kidneys of the donors with B19V infection were acceptable.\n\nkidney transplantation\nliving donor\ndeceased donor\npure red cell aplasia (PRCA)\nhuman parvovirus B19\nNational Health and Family Planning Commission of the People's Republic of China 10.13039/501100004572 WKJ-ZJ-1924 Foundation for Innovative Research Groups of the National Natural Science Foundation of China 10.13039/501100012659 81770752, 81970651 Basic Public Welfare Research Program of Zhejiang Province 10.13039/501100017577 GF20H150031\n==== Body\npmcIntroduction\n\nInfection transmission from donor to recipient is one of the primary causes that affect early survival rate of recipients after transplantation (Kirchner and Pruett, 2016). The use of intensive immunosuppressive drugs in the early stage after transplantation may amplify the risk of infection carried by the donor organ (Fishman and Grossi, 2014). Many serious donor-derived infections caused by virus, such as rabies, West Nile virus, and lymphocytic choriomeningitis virus (Fischer, 2008), fall into unexpected infections category, with human parvovirus B19 (B19V) infections also being part of this category. Only a few cases have been reported regarding donor-transmitted B19V infections (Bertoni et al., 1995; Yango et al., 2002; Wasak-Szulkowska et al., 2008).\n\nB19V is a small single-stranded DNA virus which is highly infectious and can cause a wide range of pathological conditions (Qiu et al., 2017). For immunocompromised patients, the most common clinical manifestation of B19V infection is pure red cell aplasia (PRCA) arising from the infection of erythroid progenitors in the bone marrow (Florea et al., 2007; Crabol et al., 2013). Furthermore, for kidney transplant recipients, B19V infection is associated with acute and chronic allograft injury (Barzon et al., 2009), antibody-mediated rejection, collapsing glomerulopathy (Moudgil et al., 2001), and thrombotic microangiopathy (Ardalan et al., 2008).\n\nHowever, due to the lack of surveillance studies, the incidence of donor-derived B19V infections in kidney transplantations still remains unknown. In addition, a series of clinical issues regarding donor-derived B19V infections are all uncertain currently, such as whether the kidney donor needs to be routinely screened for B19V, whether the kidneys from the donor with B19V DNAemia are acceptable, what are the clinical features of donor-derived B19V infections, how to treat donor-derived B19V infections, etc. Thus, this study provides further information on addressing these problems mentioned above.\n\nWe carried out this study with the purposes of determining the incidence, clinical features, and treatment of donor-derived B19V infections in kidney transplant recipients (includes living and deceased donor kidney transplantations).\n\nMethods\n\nThis was a single-center, retrospective, cohort study with the aim of evaluating the donor-derived B19V infections occurring in living and deceased donor kidney transplantations. For living donor kidney transplantation, all donors and the corresponding recipients included in this study were related. Since January 2015, the use of executed prisoners as a source of organs for transplantation had been comprehensively terminated in China (Zhang et al., 2015). For deceased donor kidney transplantation, all donor kidneys come from voluntary public donations. This study was approved (Reference Number: 2018-777) by the Ethics Committee of the First Affiliated Hospital of College of Medicine of Zhejiang University according to the Declaration of Helsinki and Istanbul on Organ Trafficking and Transplant Tourism. Before recruitment, written informed consents were obtained from all donors and recipients.\n\nPatient Selection\n\nFrom January 2016 to December 2020, we performed 927 living donor kidney transplants and 1,267 deceased donor kidney transplants in the Center of Kidney Disease, the First Affiliated Hospital, College of Medicine, Zhejiang University. The following exclusion criteria were applied for patients: 1) those who received an organ other than a kidney, 2) those who received ABO incompatible kidney transplantation, or 3) those whose blood specimens could not be retained. Demographics, clinical characteristics, laboratory findings, and outcomes of donors and recipients were collected from kidney transplantation electronic database and medical records.\n\nB19V Diagnosis\n\nCommercial human parvovirus B19 real-time polymerase chain reaction (PCR) kit (Liferiver™, Shanghai ZJ Bio-Tech Co., Ltd.) was used for the detection and quantification of B19V-DNA in serum. The lowest detection limit for this test was 1 × 103 copies/ml and the linear range of detection ranged from 2 × 103 to 1 × 108 copies/ml. A serum sample with viral load corresponding to ≥1 × 103 copies/ml was considered to be positive.\n\nBlood Specimen Collection\n\nThe serum of the living donors and their corresponding recipients were evaluated for B19V-DNA on the day before transplantation and within 7 days after the transplantation, while the serum from recipients of deceased donor were evaluated within 7 days after the transplantation. Furthermore, the serum from recipients with unexplained anemia and reticulocytopenia within 6 months after kidney transplantation were also tested. In post-transplantation setting, if recipients of deceased donor developed B19V infection, blood samples that were collected within 24 h before transplantation from both recipients and corresponding donors would be further evaluated for B19V-DNA.\n\nSerum creatinine and the estimated glomerular filtration rate (eGFR) of recipients with donor-derived B19V infections were checked prior to B19V infection, during B19V infection, and 12 months after B19V infection. The eGFR was estimated with the Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula.\n\nImmunosuppressant Regimen\n\nStandard triple-drug maintenance immunosuppression includes tacrolimus (serum trough level between 5 and 10 ng/ml in the first half year after transplantation), mycophenolic, and prednisone. All patients were treated with methylprednisolone 10 mg/kg/day on days 0, 1, and 2. Dosage of prednisone was slowly tapered from 60 to 10 mg/day in 1 month after transplantation. All patients received induction with antithymocyte globulin (ATG) or interleukin-2 receptor antagonist (basiliximab). Basiliximab was given with a dose of 20 mg on the operation day and the 4th day after transplantation. From baseline, ATG was administered at a dose of 1 mg/kg/day and a maximum of five doses was given. All recipients received prophylactic ganciclovir treatment with a dose of 500 mg three times daily for 3 months post-transplant. A daily dose of 40 mg/200 mg to 80 mg/400 mg sulfamethoxazole/trimethoprim was applied for 9–12 months to prevent pneumocystis carinii pneumonia (PCP) except patients with sulfa allergies.\n\nStatistical Analysis\n\nHemoglobin, serum creatinine, and eGFR in this article were described in the form of mean values plus standard deviations (SDs). Viral load and time of B19V infections were described as median values with ranges. Categorical variables were presented as percentages. For normally distributed data, continuous comparisons between the two groups were conducted using Student’s t-test, while the non-parametric Mann–Whitney U test was used for data that were not normally distributed. Chi-square or Fisher’s exact test was used for categorical data. All statistical tests were two-tailed, and p <0.05 was considered statistically significant.\n\nResults\n\nFrom January 2016 to December 2020, we performed 927 living and 1,267 deceased donor kidney transplantations. According to the exclusion criteria, 104 living and 42 deceased donor recipients were excluded in this study. Recipients were followed up for an average of 27.9 months.\n\nHuman Parvovirus B19 Infections in Living Donors and Their Corresponding Recipients\n\nAmong 823 living donors, for 15 (1.8%), it was possible to detect B19V-DNA in serum samples before donation. The median viral load was 3.1 × 103 copies/ml, ranging from 1 × 103 to 1.5 × 104 copies/ml. All 15 donors had no clinical manifestations of B19V infection such as fever, flu-like symptoms, weakness, dyspnea, arthralgias, rashes, and orthostatic hypotension during the follow-up period from 1 to 34 months. For these 15 corresponding recipients, B19V DNAemia (median, 2.8 × 103 copies/ml) could be detected in three patients within 7 days after transplantation ( Table 1 ). Hemoglobin and platelet counts of these three corresponding donors were both normal, and only two donors had mild leukopenia before donation. Without treatment, these three recipients had no clinical manifestations of B19V infection but with low-level DNAemia after transplantation. However, one recipient developed progressive anemia and reticulocytopenia and did not respond well to erythropoietin. Eventually, she was diagnosed with PRCA at the 24th day after transplantation ( Table 2 ). Viral load of the serum samples increased from 2.8 × 103 to 2.6 × 1010 copies/ml and the reticulocyte was 0.1%. In the process of infection, the lowest hemoglobin concentration was 7.4 g/dl. By adjusting for the immunosuppressant and administrating with immunoglobulin, her B19V DNAemia turned into negative at the 117th day after transplantation. In addition, the donor was her husband whose DNAemia was 2.2 × 103 copies/ml before donation, and the detailed information is shown in Tables 1 , 2 .\n\nTable 1 Clinical characteristics of donor-derived B19V infection in living or deceased donors and their corresponding kidney transplantation recipients.\n\nDonor no.\tAge (years)\tSex\tRelationship\tUnderlying disease\tWBC (×109/L)\tHgb (g/dl)\tPlt (×1012/L)\tNumber of B19V copies before Tx (copies/ml)\tRecipient no.\tAge (years)\tSex\tCause of ESRD\tDialysis mode\tDialysis time (months)\tNumber of B19V copies before Tx (copies/ml)\tNumber of B19V copies within 7 days after Tx (copies/ml)\t\nLiving donor transplantation\t\nA\t18\tM\tHusband\tNone\t8.4\t15.4\t210\t2.2 × 103\t1*\t44\tF\tGN\tNO\t/\tNegative\t2.8 × 103\t\nB\t25\tF\tMother\tNone\t3.6\t13.0\t199\t1.3 × 104\t2\t36\tF\tIgAN\tNO\t/\tNegative\t1.8 × 103\t\nC\t22\tF\tMother\tNone\t3.4\t13.3\t131\t1.0 × 104\t3\t25\tF\tGN\tHD\t4\tNegative\t4.6 × 103\t\nDeceased donor transplantation\t\nD\t18\tM\t/\tMD\t33.2\t13.2\t388\t5.1 × 105\t4\t49\tM\tGN\tPD\t37\tNegative\t1.2 × 104\t\n\t\t\t\t\t\t\t\t\t5\t31\tF\tGN\tHD\t44\tNegative\t1.1 × 104\t\nE\t25\tF\t/\tCR\t15.7\t7.1\t262\t1.0 × 1010\t6*\t34\tM\tGN\tPD\t54\tNegative\t7.3 × 109\t\n\t\t\t\t\t\t\t\t\t7*\t44\tM\tGN\tPD\t55\tNegative\t1.3 × 106\t\nF\t22\tM\t/\tCR\t11.8\t8.4\t151\t3.0 × 109\t8*\t29\tM\tGN\tPD\t46\tNegative\t2.3 × 109\t\n\t\t\t\t\t\t\t\t\t9\t58\tM\tGN\tHD\t86\tNegative\t3.7 × 105\t\nG\t37\tM\t/\tCR\t16.5\t6.5\tNA\t1.4 × 104\t10*\t30\tF\tIgAN\tHD\t50\tNegative\t4.8 × 106\t\n\t\t\t\t\t\t\t\t\t11\t51\tM\tGN\tPD\t10\tNegative\t3.6 × 103\t\nH\t41\tM\t/\tCR\t4.0\t5.4\t102\t1.2 × 104\t12\t36\tM\tIgAN\tPD\t38\tNegative\t6.2 × 103\t\n\t\t\t\t\t\t\t\t\t13\t41\tM\tHBV-GN\tPD\t58\tNegative\t1.8 × 104\t\nI\t61\tM\t/\tCR\t26.5\t8.9\t186\t2.5 × 104\t14*\t62\tM\tGN\tHD\t11\tNegative\t7.9 × 1010\t\n\t\t\t\t\t\t\t\t\t15*\t40\tM\tGN\tHD\t89\tNegative\t8.5 × 1010\t\nJ\t29\tM\t/\tCR\t8.8\t5.7\t347\t2.3 × 1010\t16*\t55\tM\tGN\tPD\t55\tNegative\t7.5 × 107\t\n\t\t\t\t\t\t\t\t\t17*\t53\tM\tGN\tPD\t57\tNegative\t9.2 × 109\t\nK\t65\tM\t/\tCR\t18.2\t6.8\t47\t1.9 × 106\t18*\t56\tF\tPK\tHD\t108\tNegative\t3.4 × 109\t\n\t\t\t\t\t\t\t\t\t19\t46\tF\tGN\tPD\t74\tNegative\t1.1 × 105\t\nL\t32\tM\t/\tCR\t15.2\t7.3\t432\t1.7 × 105\t20*\t34\tM\tGN\tHD\t58\tNegative\t1.3 × 1010\t\n\t\t\t\t\t\t\t\t\t21*\t43\tF\tFSGS\tPD\t57\tNegative\t1.9 × 105\t\n*The recipient developed pure red cell aplasia; the normal value of Hb ranges from 11.3 to 15.1 g/dl in female, 13.1 to 17.2 g/dl in male; WBC ranges from 4 to 10 × 109/L; Plt ranges from 100 to 300 × 1012/L.\n\nWBC, white blood cell; Hgb, hemoglobin; Plt, platelet; ESRD, end-stage renal disease; Tx, transplantation; GN, glomerulonephritis; IgAN, immunoglobulin A nephropathy; HBV-GN, HBV-associated glomerulonephritis; PK, polycystic kidney; FSGS, focal segmental glomerulosclerosis; NA, not available; HD, hemodialysis; PD, peritoneal dialysis; MD, muscular dystrophy; CR, craniocerebral trauma.\n\nTable 2 Clinical characteristic of recipients with pure red cell aplasia (PRCA) caused by B19V after kidney transplantation.\n\n\tRecipients\t\n\tLiving donor\tDeceased donor\t\nNo.\t1\t6\t7\t8\t10\t14\t15\t16\t17\t18\t20\t21\t\nGender\tF\tM\tM\tM\tF\tM\tM\tM\tM\tF\tM\tF\t\nAge, years\t44\t34\t44\t29\t30\t62\t40\t55\t53\t56\t34\t43\t\nNumber of B19V copies before Tx of the corresponding donor (copies/ml)\t2.2 × 103\t1.0 × 1010\t1.0 × 1010\t3.0 × 109\t1.4 × 104\t2.5 × 104\t2.5 × 104\t2.3 × 1010\t2.3 × 1010\t1.9 × 106\t1.7 × 105\t1.7 × 105\t\nNumber of B19V copies before Tx of recipients (copies/ml)\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\t\nNumber of B19V copies of recipients within 7 days after Tx (copies/ml)\t2.8 × 103\t7.3 × 109\t1.3 × 106\t2.3 × 109\t4.8 × 106\t7.9 × 1010\t8.5 × 1010\t7.5 × 107\t9.2 × 109\t3.4 × 109\t1.3 × 1010\t1.9 × 105\t\nTime to PRCA, number of days after Tx\t24\t7\t7\t7\t7\t7\t7\t7\t7\t7\t7\t39\t\nNumber of B19V copies of recipients at the day of PRCA diagnosis, (copies/ml)\t2.6 × 1010\t7.3 × 109\t1.3 × 106\t2.3 × 109\t4.8 × 106\t7.9 × 1010\t8.5 × 1010\t7.5 × 107\t9.2 × 109\t3.4 × 109\t1.3 × 1010\t2.1 × 106\t\nPercentage of reticulocytes at PRCA diagnosis (%)\t0.1\t0.1\t0.1\t0.1\t0.2\t0.1\t0.2\t0.1\t0.1\t0.1\t0.1\t0.1\t\nHb at the lowest value, g/dl\t7.4\t5.9\t8.4\t8.7\t6.1\t4.4\t6.6\t8.6\t5.5\t5.8\t7.2\t4.6\t\nDays after Tx\t34\t21\t21\t31\t65\t66\t45\t7\t59\t35\t49\t48\t\nTreatment\tIVIG\tIVIG\tConservative therapy\tIVIG\tIVIG\tIVIG\tIVIG\tIVIG\tIVIG\tIVIG\tIVIG\tIVIG\t\nNumber of B19V copies at the latest follow-up, copies/ml\tNegative\tNegative\tNegative\tNegative\tNegative\t2.0 × 103\tNegative\t4.7 × 103\t1.5 × 103\t8.5 × 104\t3.6 × 104\t2.3 × 104\t\nDays after Tx\t117\t141\t85\t33\t307\t172\t149\t38\t206\t128\t61\t101\t\nMonths of follow-up\t21.7\t24.7\t53.5\t45.8\t21.9\t6.8\t11.5\t8.0\t8.7\t6.5\t5.0\t5.1\t\nHb at latest follow-up, g/dl\t13.5\t13.3\t16.5\t16.9\t11.4\t12.1\t14.9\t13.0\t12.6\t12.4\t15.3\t13.9\t\n\nAmong 823 recipients, 16 (1.9%) were found to be B19-DNA positive before transplantation although no B19-DNA could be detected in the serum from their corresponding donors. The median viral load was 4.45 × 103 copies/ml, ranging from 2.2 × 103 to 2.5 × 105 copies/ml. The hemoglobin of 16 recipients raised from 10.3 ± 1.2 g/dl before transplantation to 11.4 ± 1.4 g/dl after 1-month transplantation. Two recipients with low-level DNAemia after transplantation had no clinical manifestation of B19V infection during follow-up. Moreover, B19V DNAemia of 14 recipients turned negative within 7 days after operation. However, one recipient was diagnosed with PRCA at the 41th day after transplantation. At that time, viral load of the serum sample was 6.06 × 109 copies/ml and the reticulocyte was 0.1%. During the course of infection, the lowest hemoglobin concentration was 5.6 g/dl. Eventually, his B19V DNAemia turned into negative at the 510th day after transplantation by treatment.\n\nB19V DNAemia, along with pure red cell aplasia, had occurred in 32 (3.9%) recipients at the median time of 42 days (ranging from 7 to 237 days) after transplantation, and their median viral load was 2.95 × 109 copies/ml, ranging from 3.4 × 107 to 1.1 × 1011 copies/ml. In addition, all of these recipients and their corresponding donors were both negative for B19V DNAemia before transplantations. In the process of infection, the mean lowest hemoglobin concentration was 6.4 ± 1.3 g/dl (ranging from 4.3 to 9.2 g/dl) and the reticulocyte was no more than 0.4%.\n\nHuman Parvovirus B19 Infections in Deceased Donor Kidney Transplantation\n\nAmong 1,225 deceased donor kidney transplantations, 48 (3.9%) recipients who were B19V DNAemia negative before transplantation switched to positive within 7 days after the transplantation. The median viral load was 2.1 × 105 copies/ml, ranging from 1.1 × 103 to 8.5 × 1010 copies/ml. It was noteworthy that 9 corresponding donors in 18 of 48 recipients were B19V DNAemia positive, and the detailed information is shown in Table 1 . Among the deceased donors, six had anemia and leukocytosis, two had anemia, and one had leukocytosis, but these results could be obscured by the primary disease. In addition, among 18 corresponding recipients, 11 were diagnosed with PRCA. By adjusting the dose of the immunosuppressant, the B19V DNAemia of one recipient (no. 7) turned into negative at the 85th day after transplantation. By adjusting the immunosuppressant and expanding the dose of immunoglobulin, the B19V DNAemia of four recipients turned into negative and six recipients with persistent low-level DNAemia had no clinical manifestation of B19V during follow-up, and the detailed information is shown in Table 2 . The other seven recipients had no clinical manifestations of B19V infection. As described in Table 3 , a total of 18 cases of donor-derived B19V infection were reported from deceased donor kidney transplantation, and there were no significant differences between PRCA recipients and non-PRCA recipients with respect to gender, age, dialysis mode, dialysis duration, and viral load of the corresponding donors before transplantation. However, the PRCA group had a higher B19V copy number within 7 days after transplantation than the non-PRCA group (p = 0.001).\n\nTable 3 Comparison between the PRCA group with the non-PRCA group in a total of 18 donor-deprived parvovirus B19 infection in deceased donor kidney transplantation.\n\nTotal (N = 18)\tPRCA (N = 11)\tNon-PRCA (N = 7)\tp-value\t\nGender, male %\t8 (72.7)\t5 (71.4)\t0.676\t\nAge, years, mean ± SD\t43.64 ± 11.43\t44.57 ± 9.25\t0.438\t\nDialysis, PD%\t6 (54.5)\t5 (71.4)\t0.637\t\nDialysis duration, days\t58.18 ± 24.42\t49.57 ± 25.44\t0.544\t\nNumber of B19 copies before Tx in the corresponding donor (log10 copies/ml), P50 (P25–P75)\t6.3 (5.0–10.0)\t5.7 (4.1–6.1)\t0.194\t\nB19 within 7 days after Tx (log10 copies/ml), P50 (P25–P75)\t9.5 (7.6–10.0)\t3.8 (3.4–4.8)\t0.001\t\n\nOf the remaining 30 recipients who developed B19V DNAemia within 7 days after transplantation, 13 recipients were diagnosed with PRCA at the median time of 14 days (ranging from 7 to 48 days) after transplantation. The median viral load was 7.5 × 109 copies/ml (ranging from 1.5 × 108 to 2.3 × 1010 copies/ml) at the diagnosis of PRCA. Seventeen recipients had no clinical manifestation of B19V infection during follow-up. Additionally, B19V DNAemia of these corresponding donors was negative before transplantation. Interestingly, the allograft of eight recipients came from the same four donors.\n\nAmong the other 1,177 deceased donor kidney transplantations, B19V infection occurred in 14 (1.2%) recipients who were B19V DNAemia negative before and within 7 days after transplantation. Moreover, these corresponding donors were both B19V DNAemia negative before donation. For the other 14 recipients who received the same donor kidney, B19V DNAemia was also negative. The median time of infection was 30 days (ranging from 21 to 666 days) after transplantation, and the median viral load was 7.85 × 109 copies/ml (ranging from 7.6 × 107 to 6.8 × 1010 copies/ml). In the process of infection, the mean lowest hemoglobin concentration was 5.6 ± 0.6 g/dl (ranging from 4.9 to 6.8 g/dl) and the reticulocytes were no more than 0.3%.\n\nAs noted in Table 4 , in the setting of donor-derived B19V infection after living or deceased donor kidney transplantations, the mean serum creatinine was 167.7 ± 77.0, 157.6 ± 68.2, and 110.8 ± 27.3 μmol/L prior to infection, during the infection, and 12 months after infection, respectively, and the eGFR was 48.5 ± 25.1, 51.3 ± 26.2, and 66.8 ± 18.9 ml/min/1.73 m2 prior to infection, during the infection, and 12 months after infection, respectively. In this study, recipients infected with B19V from the donor did not develop B19V-related graft damage that compromises allograft function. We can observe that transient elevated serum creatinine occurred in 6/21 (28.6%) recipients (nos. 1, 2, 16, 17, 19, 21). At the latest follow-up, these recipients were all alive with functioning allografts.\n\nTable 4 The impact of B19V on allograft function in donor-derived infection after kidney transplantation.\n\nRecipients, no.\tPrior to B19V infection\tAt the time of B19V infection\t12 months after B19V infection\t\nScr, μmol/L\teGFR, ml/min/1.73 m2\tScr, μmol/L\teGFR, ml/min/1.73 m2\tScr, μmol/L\teGFR, ml/min/1.73 m2\t\n1\t50\t112.6\t53\t110.5\t88\t68.1\t\n2\t128\t46.0\t134\t43.0\t153\t37.0\t\n3\t77\t92.1\t71\t101.6\t86\t90.0\t\n4\t150\t45.1\t133\t52.2\t75\t98.9\t\n5\t85\t76.8\t74\t90.7\t76\t87.2\t\n6\t270\t25.2\t235\t29.8\t100\t83.1\t\n7\t223\t29.0\t204\t32.2\t102\t74.0\t\n8\t121\t68.8\t110\t77.2\t96\t90.4\t\n9\t97\t72.8\t96\t73.7\t94\t75.1\t\n10\t213\t26.0\t195\t28.9\t120\t51.6\t\n11\t205\t31.2\t172\t38.5\t123\t57.0\t\n12\t213\t33.1\t191\t37.7\t141\t54.0\t\n13\t107\t73.4\t102\t77.7\t105\t75.0\t\n14\t163\t38.1\t149\t42.4\t144\t44.2\t\n15\t198\t35.1\t173\t41.0\t172\t41.0\t\n16\t143\t47.0\t138\t49.0\t90\t81.0\t\n17\t157\t42.0\t161\t41.0\t92\t81.0\t\n18\t382\t11.0\t345\t12.0\t144\t35.0\t\n19\t179\t29.0\t200\t25.0\t80\t75.0\t\n20\t269\t25.0\t263\t26.0\t137\t57.0\t\n21\t92\t60.0\t110\t48.1\t109\t48.0\t\nMean ± SD\t161.7 ± 77.0\t48.5 ± 25.1\t157.6 ± 68.2\t51.3 ± 26.2\t110.8 ± 27.3\t66.8 ± 18.9\t\nScr, serum creatinine; eGFR, estimated glomerular filtration rate; SD, standard deviation.\n\nDiscussion\n\nUnlike bacterial infections, donor-derived virus infections are rarely reported in the past due to difficulty of diagnosis, other than the hepatitis B virus, the hepatitis C virus, and the cytomegalovirus (Trotter et al., 2017). This study firstly investigates donor-derived B19V infection through monitoring DNAemia of the donors and corresponding recipients before and after transplantation in either living or deceased donor kidney transplantations.\n\nIn our study, kidney recipients with B19V infection predominantly presented with unexplained anemia, reticulocytopenia, and no response to erythropoietin therapy, and bone marrow examination (characteristic morphological findings) is also an important diagnostic basis (Waldman and Kopp, 2007b). Recipients with B19V infection were treated with intravenous immunoglobulin (IVIG) 20 g/day for 5–7 consecutive days and adjusted for the immunosuppressant. In case of non-response to the first IVIG course or recurrence, another course of IVIG (20 g/day for 5–7 days) may be given. Recipients with low-level B19V DNAemia and no clinical manifestations of B19V infection were left untreated but underwent regular follow-up.\n\nWe found that 15 (1.8%) living donors and 16 (1.9%) living recipients with low-level B19V DNAemia had no clinical manifestations of B19V infection before transplantation. The incidence of B19V DNAemia in living donors and recipients was very low before transplantation, and even if it occurred, the level of DNAemia was too low to cause serious consequences. Therefore, it did not appear to be necessary for the living donors and recipients to do the routine B19V screening before transplantation. Of course, if anemia of donors and recipients could not be explained clearly, B19V screening is still needed.\n\nFor 32 living recipients with pure red cell aplasia, the B19V infection seemed to be irrelevant to their corresponding donors. B19V has been shown to be transmitted mainly through inhalation of infected aerosol droplets in immunocompetent individuals (Waldman and Kopp, 2007a; Eid et al., 2013). As there was no transfusion of blood products during the transplantation, viral reactivation and/or the respiratory tract could be the route of B19V infection for those recipients who received kidneys from B19V-DNA-negative donors (Qiu et al., 2017). Therefore, we concluded that it was necessary to screen for B19V among recipients with anemia and reticulocytopenia after transplantation.\n\nUnlike screening in living transplantation, only recipients of deceased donor were routinely screened for the B19V within 7 days after transplantation. Eighteen (1.5%) recipients receiving the kidneys from the nine corresponding donors were positive for B19V DNAemia within 7 days after transplantation. By analyzing the pre-transplant blood samples of these recipients and their corresponding donors, we can conclude that the recipients were infected with B19V from the donor. Among these 18 recipients, 11 developed pure red cell aplasia. The viral loads of donors E, F, and J were more than 1.0 × 109 copies/ml, and five of the six corresponding recipients developed pure red cell aplasia. Although not statistically significant, it was noteworthy that the viral load of the donor was seemingly related to the incidence of developing pure red cell aplasia in recipients. What is more, our study demonstrated that a higher B19V viral load in recipients within 7 days after transplantation was positively correlated with the incidence of developing pure red cell aplasia in recipients with donor-derived B19V infection in deceased donor kidney transplantation. Thus, we need to pay more close attention to these patients and perform treatment in time. Moreover, we recommend that timely treatment is necessary if the B19V viral load is greater than 1.0 × 106 copies/ml in recipient within 7 days after transplantation, and conservative observation can be adopted if the B19V viral load is less than 1.0 × 106 copies/ml. For blood transfusion, as the B19V can also be transmitted by blood or pooled blood products, immunocompromised individuals were at high risk of severe complications due to B19V infection from contaminated blood products. Therefore, in 2004, the U.S. Food and Drug Administration suggested that a serum sample containing more than 1 × 104 copies/ml of B19V-DNA should be excluded because of the risk of transmission (Qiu et al., 2017).\n\nEid et al., in 2006, reported that allograft dysfunction after solid organ and hematopoietic stem cell transplant was observed in 10% of cases at the time of B19V disease (Eid et al., 2006). In kidney transplantation, graft loss/dysfunction occurred in 15.6% recipients but there was no death from B19V infection. Recently, there was a publication from Rattani et al. describing allogeneic bone marrow graft failure after B19V infection in two patients (Rattani et al., 2021). However, in our study, no allograft dysfunction was observed in 21 recipients with donor-derived B19V infection and only 6/21 (28.6%) recipients presented a transient elevation of serum creatinine. According to the literature reporting that B19V has an impact on allograft function, in 2019, Hai An et al. reported that graft dysfunction was observed in four out of nine (45%) kidney recipients with B19V-associated anemia (Hai An et al., 2019). What is more, in 2013, Xiao et al. suggested that recipients with B19V infection may develop delayed renal damage (Xiao et al., 2013). However, in our study, we did not observe any case of graft dysfunction in kidney recipients with donor-derived B19V infection. In our center, donor-derived B19V DNAemia was often detected within 7 days after transplantation in kidney recipients, while most of them showed a rapid decrease in serum creatinine levels in that period. What is more, recipients were monitored regularly for viral load, hemoglobin, reticulocyte, serum creatinine, etc., so that they can be treated timely. This may explain why graft dysfunction was rarely seen in our study.\n\nAll recipients with donor-derived B19V infections showed excellent prognosis, and the kidney graft survival rate at 1 year was 100%, which suggested that the kidneys from B19V-infected donors were acceptable for kidney transplantation. In particular, in cases where the donor had low-level B19 DNAemia, the recipients were less likely to have obvious clinical manifestations and the B19V could be quickly cleared even if the recipient was infected. If the donor had high-level B19V DNAemia, as well as the recipient, timely treatments including the adjustment of immunosuppressant and/or the infusion of large doses of immunoglobulin were needed to be given to the recipient (Egbuna et al., 2006; Jordan et al., 2011). This study also suggested that the donor-derived B19V infections could be detected within 7 days after transplantation in most occasions. As mentioned above, it was also unnecessary to perform routine screening for B19V among deceased donors before donation.\n\nSeveral limitations in our study are worth declaring. First, the present study was limited by its retrospective design. Another limitation was that we did not routinely detect for B19V in deceased donors. B19V of the donor would be retrospectively tested only when B19V infection occurred in their corresponding recipients. What is more, serological assays for detection of IgM/IgG antibodies from the living donors were not performed before transplantation. This may explain why B19 DNAemia was found only in three recipients of living donor transplantation. Lastly, there is still a lack of robust evidence to confirm that the infection was 100% derived from the donor.\n\nIn this study, we firstly reported the epidemiological data of donor-derived B19V infections in kidney transplantation through routinely monitoring B19V infection in living and deceased donors and recipients before and after transplantation. Considering the low incidence of donor-derived B19V infection and that the infection can be well controlled by treatment even if it happened, it seems unnecessary to screen for B19V among the donors. We reached the conclusion that kidneys from donors with B19V infection were acceptable for transplantation. Moreover, the DNAemia of the corresponding recipient should be closely monitored and early treatment should be initiated according to the virus level. We recommended that timely treatment is necessary if the viral load is greater than 1 × 106 copies/ml in recipients within 7 days after transplantation, and conservative observation can be adopted if the viral load is less than 1 × 106 copies/ml. We hope that our work will provide some theoretical basis for future research and clinical practices.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nAuthor Contributions\n\nWP conceived the study. YY, CW, JL, XW, RW, HH, and JW performed the data collection and analyses. YY prepared the first manuscript draft. WP and JC provided major revisions and comments to the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by the National Health and Family Planning Commission of the People’s Republic of China (WKJ-ZJ-1924), Basic Public Welfare Research Program of Zhejiang Province (GF20H150031), and National Natural Science Foundation of China (81770752, 81970651).\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\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nThe authors thank technician Yin Chen for the detection of parvovirus B19. Thanks are also extended to Xiaowei Shi for polishing this paper.\n==== Refs\nReferences\n\nArdalan M. R. Shoja M. M. Tubbs R. S. Esmaili H. Keyvani H. (2008). Postrenal Transplant Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy Associated With Parvovirus B19 Infection. Am. J. Transplant. 8 (6 ), 1340–1344. doi: 10.1111/j.1600-6143.2008.02244.x 18522549\nBarzon L. Murer L. Pacenti M. Biasolo M. A. Della Vella M. Benetti E. . (2009). Investigation of Intrarenal Viral Infections in Kidney Transplant Recipients Unveils an Association Between Parvovirus B19 and Chronic Allograft Injury. J. Infect. Dis. 199 (3 ), 372–380. doi: 10.1086/596053 19099488\nBertoni E. Rosati A. Zanazzi M. Azzi A. Zakrzewfka K. Guidi S. . (1995). Severe Aplastic Anaemia Due to B19 Parvovirus Infection in Renal Transplant Recipient. Nephrol. Dial Transplant. 10 (8 ), 1462–1463. doi: 10.1093/ndt/10.8.1462 8538947\nCrabol Y. Terrier B. Rozenberg F. Pestre V. Legendre C. Hermine O. . (2013). Intravenous Immunoglobulin Therapy for Pure Red Cell Aplasia Related to Human Parvovirus B19 Infection: A Retrospective Study of 10 Patients and Review of the Literature. Clin. Infect. Dis. 56 (7 ), 968–977. doi: 10.1093/cid/cis1046 23243178\nEgbuna O. Zand M. S. Arbini A. Menegus M. Taylor J. (2006). A Cluster of Parvovirus B19 Infections in Renal Transplant Recipients: A Prospective Case Series and Review of the Literature. Am. J. Transplant. 6 (1 ), 225–231. doi: 10.1111/j.1600-6143.2005.01139.x 16433780\nEid A. J. Brown R. A. Patel R. Razonable R. R. (2006). Parvovirus B19 Infection After Transplantation: A Review of 98 Cases. Clin. Infect. Dis. 43 (1 ), 40–48. doi: 10.1086/504812 16758416\nEid A. J. Chen S. F. Practice, A.S.T.I.D.C.o (2013). Human Parvovirus B19 in Solid Organ Transplantation. Am. J. Transplant. 13 (Suppl 4 ), 201–205. doi: 10.1111/ajt.12111 23465012\nFischer S. A. (2008). Emerging Viruses in Transplantation: There is More to Infection After Transplant Than CMV and EBV. Transplantation 86 (10 ), 1327–1339. doi: 10.1097/TP.0b013e31818b6548 19033999\nFishman J. A. Grossi P. A. (2014). Donor-Derived Infection–the Challenge for Transplant Safety. Nat. Rev. Nephrol. 10 (11 ), 663–672. doi: 10.1038/nrneph.2014.159 25178971\nFlorea A. V. Ionescu D. N. Melhem M. F. (2007). Parvovirus B19 Infection in the Immunocompromised Host. Arch. Pathol. Lab. Med. 131 (5 ), 799–804. doi: 10.5858/2007-131-799-PBIITI 17488170\nHai An H. P. Diem H. T. Cuong N. T. (2019). Parvovirus B19-Associated Anemia in Kidney Transplant Recipients: A Single-Center Experience. Transplant. Proc. 51 (8 ), 2693–2696. doi: 10.1016/j.transproceed.2019.03.076 31351772\nJordan S. C. Toyoda M. Kahwaji J. Vo A. A. (2011). Clinical Aspects of Intravenous Immunoglobulin Use in Solid Organ Transplant Recipients. Am. J. Transplant. 11 (2 ), 196–202. doi: 10.1111/j.1600-6143.2010.03400.x 21219579\nKirchner V. A. Pruett T. L. (2016). Receiving the Unwanted Gift: Infection Transmission Through Organ Transplantation. Surg. Infect. (Larchmt) 17 (3 ), 318–322. doi: 10.1089/sur.2016.009 27096745\nMoudgil A. Nast C. C. Bagga A. Wei L. Nurmamet A. Cohen A. H. . (2001). Association of Parvovirus B19 Infection With Idiopathic Collapsing Glomerulopathy. Kidney Int. 59 (6 ), 2126–2133. doi: 10.1046/j.1523-1755.2001.00727.x 11380814\nQiu J. Soderlund-Venermo M. Young N. S. (2017). Human Parvoviruses. Clin. Microbiol. Rev. 30 (1 ), 43–113. doi: 10.1128/CMR.00040-16 27806994\nRattani N. Matheny C. Eckrich M. J. Madden L. M. Quigg T. C. (2021). Parvovirus B19-Associated Graft Failure After Allogeneic Hematopoietic Stem Cell Transplantation. Cancer Rep. (Hoboken) 2021 :e1403. doi: 10.1002/cnr2.1403\nTrotter P. B. Summers D. M. Robb M. Hulme W. Ushiro-Lumb I. Watson C. J. E. . (2017). Deceased Organ Donors With a History of Increased Risk Behavior for the Transmission of Blood-Borne Viral Infection: The UK Experience. Transplantation 101 (7 ), 1679–1689. doi: 10.1097/TP.0000000000001727 28291157\nWaldman M. Kopp J. B. (2007a). Parvovirus-B19-Associated Complications in Renal Transplant Recipients. Nat. Clin. Pract. Nephrol. 3 (10 ), 540–550. doi: 10.1038/ncpneph0609 17895931\nWaldman M. Kopp J. B. (2007b). Parvovirus B19 and the Kidney. Clin. J. Am. Soc. Nephrol. 2 (Suppl 1) , S47–S56. doi: 10.2215/CJN.01060307 17699510\nWasak-Szulkowska E. Grabarczyk P. Rzepecki P. (2008). Pure Red Cell Aplasia Due to Parvovirus B19 Infection Transmitted Probably Through Hematopoietic Stem Cell Transplantation. Transpl. Infect. Dis. 10 (3 ), 201–205. doi: 10.1111/j.1399-3062.2007.00266.x 17631000\nXiao C. Wang C. X. Liu L. S. Fu Q. (2013). Clinical Investigation of Human Parvovirus B19 Infection After Renal Transplantation in China. Transplant. Proc. 45 (4 ), 1593–1599. doi: 10.1016/j.transproceed.2013.02.040 23726627\nYango A. Jr. Morrissey P. Gohh R. Wahbeh A. (2002). Donor-Transmitted Parvovirus Infection in a Kidney Transplant Recipient Presenting as Pancytopenia and Allograft Dysfunction. Transpl. Infect. Dis. 4 (3 ), 163–166. doi: 10.1034/j.1399-3062.2002.01007.x 12421463\nZhang L. Zeng L. Gao X. Wang H. Zhu Y. (2015). Transformation of Organ Donation in China. Transpl. Int. 28 (4 ), 410–415. doi: 10.1111/tri.12467 25267538\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2235-2988",
"issue": "11()",
"journal": "Frontiers in cellular and infection microbiology",
"keywords": "deceased donor; human parvovirus B19; kidney transplantation; living donor; pure red cell aplasia (PRCA)",
"medline_ta": "Front Cell Infect Microbiol",
"mesh_terms": "D001782:Blood Donors; D004279:DNA, Viral; D016731:Erythema Infectiosum; D006801:Humans; D016030:Kidney Transplantation; D010322:Parvoviridae Infections; D012189:Retrospective Studies",
"nlm_unique_id": "101585359",
"other_id": null,
"pages": "753970",
"pmc": null,
"pmid": "34722340",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12421463;23465012;25178971;28291157;23726627;27806994;19033999;17631000;17699510;16758416;17488170;16433780;33932151;18522549;11380814;17895931;27096745;31351772;8538947;19099488;21219579;23243178;25267538",
"title": "Donor-Derived Human Parvovirus B19 Infection in Kidney Transplantation.",
"title_normalized": "donor derived human parvovirus b19 infection in kidney transplantation"
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"abstract": "BACKGROUND\nSchizophrenia is the most severe psychiatric illness, with a biological support in the brain. There is evidence that the adequate dopamine balance in the frontal cortex is associated with a better outcome of the disorder, while the alteration of dopamine mechanism at this level may affect the vascular system leading to secondary neuronal alterations. Our study was conducted post-mortem and its objective was to identify the alterations in the neuronal architecture, in the integrity of the microvascular unit in the frontal cortex of patients treated with potent and excessive D2-blocking antipsychotics.\n\n\nMETHODS\nWe studied post-mortem sections of the frontal cortex of three patients (two women and one man) diagnosed with schizophrenia or schizophrenia-spectrum disorders and treated with antipsychotics for the last 24 months. The slides were prepared according to the classical histopathological protocols.\n\n\nRESULTS\nVarious alterations were found at the neural and vascular levels in the frontal cortex. The most significant was the neural loss as the result of severe changes in the microvessels (diameter reduction, hyaline and collagen deposits, edema, pinocytosis and vacuolization).\n\n\nCONCLUSIONS\nThe evidences shown in our study highlight the fact that antipsychotics with potent antagonist action on D2 receptors may affect the neurovascular unit and small vessels in frontal cortex by altering the balance vasoconstriction-vasodilatation, thus reducing the blood flow and metabolism and generating structural microvascular changes proportional with the level of apoptosis at this level. The functional integrity of the dopaminergic system in frontal cortex depends on the vascular support and the capabilities of the neurovascular unit and any dysfunction increases the neuronal loss with clinically significant changes.\n\n\nCONCLUSIONS\nThe pathological data of our study raises the hypothesis for the pathogenic stages at the level of microvessels in the frontal cortex of the patients with schizophrenia or schizophrenia-spectrum disorders treated with D2-blocking antipsychotics: a stage with functional, reversible alterations that may be correlated with the impairments of working memory and presence of extrapyramidal symptoms and a lesional, irreversible stage with significant deterioration of cognition and global functioning. Further studies are needed to verify this hypothesis.",
"affiliations": "Department of Psychiatry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania; marinescu_psy@yahoo.com.",
"authors": "Udriştoiu|Ion|I|;Marinescu|Ileana|I|;Pîrlog|Mihail Cristian|MC|;Militaru|Felicia|F|;Udriştoiu|Tudor|T|;Marinescu|Dragoş|D|;Mutică|Mihai|M|",
"chemical_list": "D014150:Antipsychotic Agents; D006220:Haloperidol",
"country": "Romania",
"delete": false,
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"issue": "57(2)",
"journal": "Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie",
"keywords": null,
"medline_ta": "Rom J Morphol Embryol",
"mesh_terms": "D000368:Aged; D014150:Antipsychotic Agents; D003710:Demography; D005260:Female; D005625:Frontal Lobe; D006220:Haloperidol; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D055806:Microvessels; D008875:Middle Aged; D008954:Models, Biological; D009474:Neurons; D011180:Postmortem Changes",
"nlm_unique_id": "9112454",
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"pmid": "27516025",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The microvascular alterations in frontal cortex during treatment with antipsychotics: a post-mortem study.",
"title_normalized": "the microvascular alterations in frontal cortex during treatment with antipsychotics a post mortem study"
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"abstract": "A 63-year-old male was diagnosed as having chronic phase CML in 2001. He obtained a major molecular response with imatinib (IM). In 2012, amulodipin was started for hypertension. In January 2013, IM was switched to nilotinib (NIL) in a clinical trial, and in February 2015, NIL was discontinued because MR4.5 had been maintained for two years. One month later, he was admitted to our hospital because of headache and high blood pressure (194/108 mmHg). His urine test showed protein 3+ and occult blood 2+. His eGFR rapidly deteriorated from 45.6 to 28.5 after admission. MR angiography showed left renal artery stenosis. He thus underwent angioplasty of the left renal artery with a stent implantation. His renal function subsequently improved. Cardiovascular events such as PAOD (peripheral artery occlusive disease) during NIL treatment were recently reported. However, to date, only four cases including our present patient with renal artery stenosis associated with NIL have been reported. These observations suggest assessment of risk factors for cardiovascular events at the start of NIL and careful monitoring to be important during tyrosine kinase inhibitor treatment of CML patients.",
"affiliations": "Department of Hematology, Japan Community Health care Organization, Kyoto Kuramaguchi Medical Center.",
"authors": "Hatsuse|Mayumi|M|;Daikoku|Yuka|Y|;Tamoto|Yuta|Y|;Uehara|Masahiro|M|;Kitani|Takashi|T|;Tamagaki|Keiichi|K|;Fuchida|Shin-Ichi|SI|;Okano|Akira|A|;Murakami|Satoshi|S|;Shimazaki|Chihiro|C|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.15",
"fulltext": null,
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"issn_linking": "0485-1439",
"issue": "58(1)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D017130:Angioplasty; D001794:Blood Pressure; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D012078:Renal Artery Obstruction",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "15-19",
"pmc": null,
"pmid": "28190859",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Renal artery stenosis following nilotinib administration in a patient with chronic myelogenous leukemia.",
"title_normalized": "renal artery stenosis following nilotinib administration in a patient with chronic myelogenous leukemia"
} | [
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"companynumb": "PHJP2016JP005834",
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"activesubstancename": "KETOPROFEN"
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"abstract": "BACKGROUND\nWe present a case of 72-year-old man with a history of metastatic melanoma diagnosed in 2015 presenting a stable disease in treatment with dabrafenib.\n\n\nMETHODS\nThe patient had been surgically treated for a presumed intracranial parietooccipital metastasis. He presented 1 month later with a meningeal lesion associated with a subdural hematoma. A second surgical treatment confirmed the diagnosis of meningeal recurrence of metastatic melanoma.\n\n\nCONCLUSIONS\nThe most recent literature lacks studies defining the clinical phenomena of an early recurrence of intracranial melanoma with de novo involvement of dural compartment in patients in treatment with a target immunotherapy. The aim of this present study is to report a case of early recurrence of intracranial melanoma metastases with evidence of fast immunohistochemical and macroscopical mutation of pathologic elements, with an analysis of literature that shows the lack of well-described occurrences.",
"affiliations": "Azienda Ospedaliero-Universitaria \"Policlinico Umberto I\", Neurosurgery Division, Human Neurosciences Department, Sapienza University, Rome, Italy. Electronic address: danielearmocida@yahoo.it.;Azienda Ospedaliero-Universitaria \"Policlinico Umberto I\", Neurosurgery Division, Human Neurosciences Department, Sapienza University, Rome, Italy.;A. O. \"Sant'Andrea\"-Neurosurgery Division, Sapienza University, Rome NESMOS Department, Rome, Italy.;Azienda Ospedaliero-Universitaria \"Policlinico Umberto I\", Neurosurgery Division, Human Neurosciences Department, Sapienza University, Rome, Italy.;Azienda Ospedaliero-Universitaria \"Policlinico Umberto I\", Neurosurgery Division, Human Neurosciences Department, Sapienza University, Rome, Italy.;Azienda Ospedaliero-Universitaria \"Policlinico Umberto I\", Neurosurgery Division, Human Neurosciences Department, Sapienza University, Rome, Italy.",
"authors": "Armocida|Daniele|D|;Marzetti|Francesco|F|;Pesce|Alessandro|A|;Caporlingua|Alessandro|A|;D'Angelo|Luca|L|;Santoro|Antonio|A|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D007093:Imidazoles; D010091:Oximes; C561627:dabrafenib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.10.101",
"fulltext": null,
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"issn_linking": "1878-8750",
"issue": "134()",
"journal": "World neurosurgery",
"keywords": "Brain metastasis; MRI; Melanoma; Meningeal metastases; Subdural hematoma",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D001932:Brain Neoplasms; D018450:Disease Progression; D006801:Humans; D007093:Imidazoles; D007167:Immunotherapy; D008297:Male; D008545:Melanoma; D008577:Meningeal Neoplasms; D010091:Oximes; D016634:Radiosurgery; D012878:Skin Neoplasms",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "150-154",
"pmc": null,
"pmid": "31751613",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Purely Meningeal Intracranial Relapse of Melanoma Brain Metastases After Surgical Resection and Immunotherapy as a Unique Disease Progression Pattern: Our Experience and Review of the Literature.",
"title_normalized": "purely meningeal intracranial relapse of melanoma brain metastases after surgical resection and immunotherapy as a unique disease progression pattern our experience and review of the literature"
} | [
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"companynumb": "NVSC2019IT061812",
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"activesubstancename": "DABRAFENIB"
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"abstract": "With less than 1% of patients who use benzodiazepines being affected, paradoxical responses to benzodiazepines are rare. In this case report, we outline the course of an 80-year-old female who developed a paradoxical response to benzodiazepines. Significant medical and psychiatric history includes anxiety, mood disorder, hypothyroidism, bilateral mastectomy, goiter removal, and triple bypass. The patient presented with mental status changes, anxiety, motor restlessness, and paranoia. Over time, a temporal relationship between the severity of the patient's motor agitation and intake of alprazolam was observed. As doses of alprazolam were decreased, her motor agitation became less severe. In addition to motor agitation, the patient also demonstrated increased aggressiveness, a subjective feeling of restlessness, and increased talkativeness. As her dose of alprazolam decreased, many of the patient's symptoms were observed to decrease. This case report also discusses theories regarding the pathophysiology of paradoxical reactions to benzodiazepines, known risk factors, and appropriate treatment.",
"affiliations": "Department of Psychiatry, Creighton University School of Medicine, Omaha, NE 68178, USA.;Department of Psychiatry, Creighton University School of Medicine, Omaha, NE 68178, USA.;Department of Psychiatry, Creighton University School of Medicine, Omaha, NE 68178, USA.;Creighton University School of Pharmacy & Health Professions, Omaha, NE 68178, USA.;Department of Psychiatry, Creighton University School of Medicine, Omaha, NE 68178, USA.;Department of Psychiatry, Creighton University School of Medicine, Omaha, NE 68178, USA.",
"authors": "Kirkpatrick|Daniel|D|;Smith|Tyler|T|;Kerfeld|Mitchell|M|;Ramsdell|Taylor|T|;Sadiq|Hasnain|H|;Sharma|Arun|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/6748947",
"fulltext": "\n==== Front\nCase Rep PsychiatryCase Rep PsychiatryCRIPSCase Reports in Psychiatry2090-682X2090-6838Hindawi Publishing Corporation 10.1155/2016/6748947Case ReportParadoxical Reaction to Alprazolam in an Elderly Woman with a History of Anxiety, Mood Disorders, and Hypothyroidism Kirkpatrick Daniel \n1\n\n*\nSmith Tyler \n1\nKerfeld Mitchell \n1\nRamsdell Taylor \n2\nSadiq Hasnain \n1\nSharma Arun \n1\n1Department of Psychiatry, Creighton University School of Medicine, Omaha, NE 68178, USA2Creighton University School of Pharmacy & Health Professions, Omaha, NE 68178, USA*Daniel Kirkpatrick: drk16318@creighton.eduAcademic Editor: Diego De Leo\n\n2016 22 3 2016 2016 674894719 1 2016 8 3 2016 8 3 2016 Copyright © 2016 Daniel Kirkpatrick et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.With less than 1% of patients who use benzodiazepines being affected, paradoxical responses to benzodiazepines are rare. In this case report, we outline the course of an 80-year-old female who developed a paradoxical response to benzodiazepines. Significant medical and psychiatric history includes anxiety, mood disorder, hypothyroidism, bilateral mastectomy, goiter removal, and triple bypass. The patient presented with mental status changes, anxiety, motor restlessness, and paranoia. Over time, a temporal relationship between the severity of the patient's motor agitation and intake of alprazolam was observed. As doses of alprazolam were decreased, her motor agitation became less severe. In addition to motor agitation, the patient also demonstrated increased aggressiveness, a subjective feeling of restlessness, and increased talkativeness. As her dose of alprazolam decreased, many of the patient's symptoms were observed to decrease. This case report also discusses theories regarding the pathophysiology of paradoxical reactions to benzodiazepines, known risk factors, and appropriate treatment.\n==== Body\n1. Introduction \nBenzodiazepines are commonly used in the treatment of anxiety, panic attacks, muscle spasms, seizures, agitation, and insomnia. The clinical action of benzodiazepines is mediated by gamma-aminobutyric acid (GABA) type A chloride channels. Benzodiazepines cause increased transmission of chloride ions by increasing the cycling rate of GABA channels. The inhibitory action of benzodiazepines typically causes relaxation, decreases anxiety, and can cause anterograde amnesia. It is estimated that less than 1% of patients experience atypical responses to benzodiazepines [1]. Though rare, the case report literature includes observations of atypical response to nearly every agent in the benzodiazepine family, with intravenous midazolam being the most represented [1–4]. Interestingly, despite an association between risk factors and advanced age, the authors observed more reports of atypical responses in pediatric populations than in geriatric populations [1–5].\n\nAtypical reactions include increased talkativeness, agitation, excessive movement, hostility, psychosis, and feelings of restlessness [1, 6]. The exact cause of paradoxical reactions to benzodiazepines is not well understood; however, several potential mechanisms have been proposed. Benzodiazepines cause cortical inhibition, which may contribute to the violent or agitated behavior experienced in some paradoxical reactions [3, 6, 7]. Benzodiazepines also alter neurotransmitter concentrations, including serotonin [3, 7]. Decreased serotonin transmission in the central nervous system may contribute to agitated behavior [3, 7].\n\nRisk factors for paradoxical reactions include age (with pediatric and geriatric patients being the most represented), genetics, psychological background, and alcohol use [1, 3, 5–7]. In a recent randomized controlled trial, Shin et al. [5] found paradoxical responses to benzodiazepines to be most influenced by the patient's age (with younger patients having more atypical reactions) and the dosage received (with higher doses being more likely to cause a paradoxical response). In a separate randomized controlled trial conducted by Moallemy et al. [6], an increased infusion rate of midazolam was also positively correlated with the development of paradoxical reactions.\n\n2. Case Presentation \n2.1. Background\nThe patient is an 80-year-old female with a medical history that includes significant anxiety, mood disorders, hypothyroidism, tremor, unsteady gait, coronary artery disease, and hyperlipidemia. Her surgical history was positive for goiter removal, bilateral mastectomy, hysterectomy, and triple bypass cardiac surgery. She was brought to the hospital by her family due to changes in her mental status, significant anxiety, gait disturbance, and motor restlessness. The patient has a significant family history of dementia and Alzheimer's Disease.\n\nFive years prior to this presentation, the patient had undergone an inpatient course for severe depression and anxiety. As part of this course, she received electroconvulsive therapy (ECT). Her treatment course was very effective and, after a short stay at an assisted living center, she was discharged back home at baseline. Despite the previous success of ECT, the patient and her family decided that they would not give consent for future ECT treatments.\n\nIn the week prior to her presentation at the hospital, the patient's dose of alprazolam was increased from 0.5 mg to 1 mg three times daily. She was also taking quetiapine three times daily and sertraline once daily.\n\n2.2. Presentation\nAt the time of her presentation, the patient was very fearful, anxious, and paranoid. She also perseverated on ECT, making frequent allegations that hospital physicians or staff would force her to undergo this treatment. She also presented with significant tremulousness, motor activation, and unsteady gait.\n\nOn admission, the laboratory results and studies in Table 1 were obtained (only responses outside the reference range are included).\n\nBased on her presentation in the emergency department, the patient was admitted to a geriatric inpatient psychiatry unit.\n\nEarly in her course, the patient's dosage of alprazolam was increased to 1 mg four times daily. Her symptoms were also noted to be “rapidly worsening.” Due to clinical suspicion of delirium, her mental status was rigorously followed up throughout her inpatient course to detect any change in memory, orientation, or onset of hallucinations. It was also noted that her agitation and inability to sit still were “akathisia-like.” Due to concerns over akathisia, the patient's dose of quetiapine was decreased. Additionally, benztropine 2 mg (twice daily) was added. Because of her low blood pressure and slow heart rate, the patient could not be started on propranolol at this time.\n\nDue to worsening motor agitation, the care team sought a neurology consult. Because of falling concerns, the patient was started on one-to-one care. Despite her frailty and age, she repeatedly leapt from her bed or chair and was constantly agitated and in motion. Still suspecting akathisia, her dose of quetiapine was further decreased and her benztropine dose was maintained. The care team also sought a pharmacy consult.\n\nAs per pharmacy consult, alprazolam 1 mg was decreased from four times daily to three times daily. Benztropine and sertraline were discontinued at this time. In this consult, the pharmacist mentioned the possibility that this patient's symptoms were the result of a paradoxical response to benzodiazepines.\n\nDue to concerns over signs of psychosis, the patient was briefly started on 0.5 mg of risperidone at bedtime. She continued to be particularly activated, anxious, and restless. Frequently, she would leap out of her chair during conversations. As the patient appeared to be poorly oriented at times, the care team became suspicious of “agitated delirium.” Previously, Montreal Cognitive Assessment (MOCA) testing and interview had largely shown the patient to have stable mental status and sensorium. Haloperidol 2 mg by mouth was provided as needed due to suspicion of agitated delirium. This addition was observed to improve the patient's ability to function normally. The care team continued weaning the patient from alprazolam.\n\nOn day 16 of the patient's stay, the laboratory results in Table 2 were obtained (only responses outside the reference range are included).\n\nAt this time, the dose of alprazolam had been reduced to 0.5 mg twice daily and the patient was experiencing visible “improvement in restless[ness] and agitation.” With continued tapering of the alprazolam dose, further improvement in restlessness and agitation was noted by the entire medical team. Significantly, she was able to sit through interviews without demonstrating significant motor agitation. The patient's anxiety remained marked; however, it translated less and less into motor agitation. Regardless of other improvements, she still complained of a subjective feeling of restlessness.\n\nBy the time alprazolam was completely discontinued, the patient reported being much closer to baseline. She was able to sit still during interview and exam. Discharge planning was begun. The patient remained anxious but had substantial relief from symptoms of motor agitation, subjective feelings of restlessness, and excessive talkativeness.\n\n3. Discussion \nBenzodiazepines are common pharmacologic agents prescribed for the treatment of generalized anxiety disorders and panic disorders and are given to induce sedation. The patient was prescribed benzodiazepine based on her history of crippling anxiety. Interestingly, although benzodiazepine administration typically precipitates rapid improvement in anxiety-related symptoms, this patient did not appear to improve after receiving her regular doses of alprazolam.\n\nAtypical symptoms of benzodiazepines include excessive talkativeness, excessive movement, increased emotional release, hostility and rage, and even new-onset psychosis [1, 6]. During her course, the patient demonstrated all of these symptoms. While increased motor restlessness was the most distinctive symptom, she also demonstrated increased emotionality, increased speech output, aggressiveness, and psychosis (for which she was treated with a short course of risperidone).\n\n3.1. Pathophysiology\nAlthough the precise pharmacologic mechanism that underlies paradoxical response to benzodiazepines is incompletely understood, researchers have proposed a few possible mechanisms. These mechanisms include altered neurotransmission, suppression of central nervous system (CNS) function, and compensatory responses to benzodiazepine effects.\n\n3.1.1. Altered Neurotransmission\nBenzodiazepines are known to act by increasing chloride transmission at GABA receptors. Increased GABA (neuroinhibitory) activity leads to sedation, decreased anxiety, and possible reductions in pain perception. One possible cause of paradoxical responses to benzodiazepines centers around genetic variability in GABA receptors. In fact, multiple allelic forms of the GABA receptor have been identified [1]. Although varied forms of GABA receptors are known to exist, clinically significant differences among different allelic groups have not been definitively established [1, 8]. It is, however, possible that certain allelic forms of GABA receptors respond differently to benzodiazepines. Some studies have also noted a decrease in the concentration of GABA neurotransmitter among those taking benzodiazepines [9]. It is thought that, in response to these agents, total GABA concentrations can become decreased, leading to heightened neural activation [9]. Other studies propose that changes in cholinergic receptors, serotonin, and other neurotransmitters may underlie atypical responses to benzodiazepines [7, 8, 10].\n\n3.1.2. Suppression of CNS Function\nBenzodiazepines suppress neural activity by increasing the effect of GABA (inhibitory) receptors. One theory suggests that increased GABA activity can inhibit the activity of the brain's frontal lobe [11]. Decreased frontal lobe activity could translate into erratic behavior, decreased inhibition, rage, excitement, impaired judgment, or decreased impulse control. In other words, benzodiazepines may decrease an individual's ability to control their impulses. Significantly, atypical responses to benzodiazepines have been observed to be more common in those with cortical loss [5, 7, 11].\n\n3.1.3. Compensatory Response\nSome researchers have proposed that paradoxical responses to benzodiazepines may be the result of compensatory reactions within the brain. For example, emergent and rebound withdrawal symptoms have been observed to occur between benzodiazepine doses. Similarly, benzodiazepines have been noted to lose effectiveness due to desensitization of receptors. Downregulation of GABA receptors in response to benzodiazepine use could theoretically explain withdrawal-like symptoms, despite intake of therapeutic doses. Interestingly, receptor desensitization is more likely when high-potency, short-acting benzodiazepines (like alprazolam) are used [9].\n\n3.2. Risk Factors\nWhile the exact mechanism for paradoxical reactions to benzodiazepines is unknown, certain behaviors and settings are known to be associated with paradoxical reactions. The most significant risk factors for developing an atypical response to benzodiazepines are age, genetic predisposition, significant history of alcohol use, large benzodiazepine doses, and psychiatric or personality disorders [1]. While this patient's genetic risk factors are unknown, this patient's advanced age, large doses of benzodiazepines (maximal dose four times per day plus additional doses as needed), and anxiety-rich psychiatric history place her at increased risk of responding poorly to benzodiazepines. Also, of note, the anticholinergic effects of her other medications could be an additional contributing factor [8].\n\nAs mentioned above, cortical thinning and alterations in neurotransmitters are proposed causes of paradoxical reactions [5, 7]. The patient has a significant family history of dementia and Alzheimer's Disease. Between this family history, her advanced age, and observations of decreased cognitive function, it is likely that she has a thinned cerebral cortex. This clinical observation was radiographically confirmed by a head CT that showed decreased cortical mass. The combination of age-related cortical thinning and benzodiazepine-induced inhibition of cortical function could make an atypical response more likely in this patient. Similarly, paradoxical response to benzodiazepines is linked to altered neurotransmitter levels, including serotonin [7, 8]. As this patient has a diagnosis of mood disorders, specifically major depressive disorder, she is likely to have lower-than-normal serotonin levels. Based on the rationale behind existing theories that explain the pathophysiology of paradoxical response to benzodiazepines, this patient is at a significantly elevated risk. It also bears mention that the proposed mechanisms of atypical benzodiazepine reactions are particularly likely in geriatric populations.\n\n3.3. Management\nTreatment of paradoxical response to benzodiazepines may include supportive administration of physostigmine, flumazenil, and haloperidol [1]. Physostigmine is an acetylcholinesterase inhibitor that crosses the blood-brain barrier and acts to reverse central nervous system depression. Regardless of these effects, physostigmine is thought to improve paradoxical response to benzodiazepines via a nonspecific antiepileptic effect [1]. Flumazenil antagonizes the benzodiazepine receptor and has clinical use in reversing benzodiazepine overdose. In pediatric populations, it has been observed to improve the symptoms of atypical responses to benzodiazepines [1]. During her clinical course, the patient was not treated with physostigmine or flumazenil. Haloperidol, a first-generation antipsychotic, is thought to improve atypical responses to benzodiazepines via action at dopamine receptors. This action has a calming effect on atypical responders to benzodiazepines. The patient was observed to receive clinically significant benefit from haloperidol administration during her clinical course.\n\nIn this patient's case, the factor that seems to have been most successful in decreasing motor agitation was a decrease in the dose of alprazolam. The medical record shows a relatively strong temporal relationship between the dose of alprazolam and her motor agitation.\n\nThis patient's paradoxical response to benzodiazepines complicated her clinical course and compromised the care team's ability to return her speedily to baseline. While cessation of benzodiazepines seems to have decreased her emotionality, restlessness, and motor agitation, she remained anxious and depressed.\n\nIn this patient's case, motor agitation led the care team to investigate a variety of clinical causes that were unrelated to her intake of alprazolam. These alternate diagnoses included akathisia, activated delirium, and anticholinergic side effects of medications. Interestingly, providing the appropriate clinical treatments for akathisia and activated delirium did not durably improve her symptoms; however, decreasing her dose of alprazolam provided visible relief of many of her symptoms.\n\n4. Conclusion \nThroughout the course of this patient's treatment for anxiety, increased motor agitation, and depression, we suspected different causes. At various points in the patient's care, we suspected exacerbation of anxiety, akathisia, agitated delirium, and anticholinergic reactions as the cause of her symptoms. Given the temporal relationship between her course and her intake of benzodiazepines, her continued anxiety after resolution of motor agitation, and the presence of significant risk factors, we believe paradoxical response to benzodiazepines to be the most likely cause of this patient's motor agitation, increased aggressiveness, increased talkativeness, and subjective feelings of restlessness. Given that benzodiazepines have the potential to decrease serotonin transmission in the central nervous system, added caution should be exercised when prescribing them for patients with major depressive disorder.\n\nAs this paradoxical response to benzodiazepines hindered our ability to achieve our patient's desired results for the inpatient course, we propose that paradoxical reaction to benzodiazepines be considered in the differential diagnosis of increased motor activity, aggressiveness, and subjective restlessness in the setting of geriatric benzodiazepine use.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nTable 1 UA\tNotable results\t\nBlood, UA\tSmall\t\nLeukocyte esterase\tTrace\t\nRBC, UA\t0–2\t\nBacteria, UA\t0–10\t\n\n\n\t\nCBC\tNotable results\t\n\n\n\t\nRBC\t3.48\t\nHemoglobin\t11.7\t\nHematocrit\t34.6\t\n\n\n\t\nCMP\tNotable results\t\n\n\n\t\nGlucose\t121\t\nAST\t9\t\nGFR MDRD Af Amer\t80\t\nGFR MDRD non-Af Amer\t69\t\n\n\n\t\nOther tests\tResult\t\n\n\n\t\nEKG\tNonspecific T-wave changes\t\nCT head without contrast\tNo evidence of mass or intracranial hemorrhage; mild/moderate ischemic change in white matter; mild/moderate cortical atrophy\t\nTable 2 CMP\tNotable result\t\nGlucose\t123\t\nGFR MDRD Af Amer\t78\t\nGFR MDRD\t67\n==== Refs\n1 Mancuso C. E. Gabay M. Tanzi M. G. Paradoxical reactions to benzodiazepines: literature review and treatment options Pharmacotherapy 2004 24 9 1177 1185 10.1592/phco.24.13.1177.38089 2-s2.0-4344712721 15460178 \n2 McKenzie W. S. Rosenberg M. Paradoxical reaction following administration of a benzodiazepine Journal of Oral and Maxillofacial Surgery 2010 68 12 3034 3036 10.1016/j.joms.2010.06.176 2-s2.0-78649452822 20950912 \n3 Robin C. Trieger N. Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature Anesthesia Progress 2002 49 4 128 132 2-s2.0-0041804117 12779114 \n4 Thurston T. A. Williams C. G. A. Foshee S. L. Reversal of a paradoxical reaction to midazolam with flumazenil Anesthesia a& Analgesia 1996 83 1 p. 192 10.1097/00000539-199607000-00036 2-s2.0-8944233865 \n5 Shin Y. H. Kim M. H. Lee J. J. The effect of midazolam dose and age on the paradoxical midazolam reaction in Korean pediatric patients Korean Journal of Anesthesiology 2013 65 1 9 13 10.4097/kjae.2013.65.1.9 2-s2.0-84880957225 23904933 \n6 Moallemy A. Teshnizi S. H. Mohseni M. The injection rate of intravenous midazolam significantly influences the occurrence of paradoxical reaction in pediatric patients Journal of Research in Medical Sciences 2014 19 10 965 969 2-s2.0-84915816602 25538781 \n7 Moon Y. E. Paradoxical reaction to midazolam in children Korean Journal of Anesthesiology 2013 65 1 2 3 10.4097/kjae.2013.65.1.2 2-s2.0-84880942767 23904931 \n8 Gutierrez M. A. Roper J. M. Hahn P. Paradoxical reactions to benzodiazepines: when to expect the unexpected American Journal of Nursing 2001 101 7 34 39 2-s2.0-0040027128 11469127 \n9 Breggin P. R. Analysis of adverse behavioral effects of benzodiazepines with a discussion on drawing scientific conclusions from the FDA's spontaneous reporting system Journal of Mind and Behavior 1998 19 1 21 50 2-s2.0-0031847403 \n10 Van Der Bijl P. Roelofse J. A. Disinhibitory reactions to benzodiazepines: a review Journal of Oral and Maxillofacial Surgery 1991 49 5 519 523 10.1016/0278-2391(91)90180-t 2-s2.0-0025845939 2019899 \n11 Paton C. Benzodiazepines and disinhibition: a review Psychiatric Bulletin 2002 26 12 460 462 10.1192/pb.26.12.460 2-s2.0-0036897827\n\n",
"fulltext_license": "CC BY",
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"journal": "Case reports in psychiatry",
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"pmid": "27092285",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "12779114;23904933;8659737;20950912;11469127;23904931;15460178;25538781;2019899",
"title": "Paradoxical Reaction to Alprazolam in an Elderly Woman with a History of Anxiety, Mood Disorders, and Hypothyroidism.",
"title_normalized": "paradoxical reaction to alprazolam in an elderly woman with a history of anxiety mood disorders and hypothyroidism"
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"abstract": "BACKGROUND\nPlatinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed.\n\n\nMETHODS\nWe conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate.\n\n\nRESULTS\nA total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p < .001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce.\n\n\nCONCLUSIONS\nThis review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated.\n\n\nCONCLUSIONS\nCisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.",
"affiliations": "Department of Otolaryngology and Head and Neck Surgery, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium olivier.vanderveken@uza.be.;Department of Medical Oncology, Antwerp University Hospital, Edegem, Antwerp, Belgium Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic School of Medicine, Masaryk University, Brno, Czech Republic.;Department of Medical Oncology, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.;Department of Oncology, Santa Croce e Carle General Hospital, Cuneo, Italy.;Department of Oncology, San Paolo Hospital, Savona, Italy.;Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium Department of Radiotherapy, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Scientific Coordination and Biostatistics, Antwerp University Hospital, Edegem, Antwerp, Belgium.;Department of Otolaryngology and Head and Neck Surgery, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.;Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium Department of Radiotherapy, Ziekenhuis Netwerk Antwerpen (ZNA), Antwerp, Belgium.;Department of Medical Oncology, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.;Department of Medical Oncology, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.",
"authors": "Vanderveken|Olivier M|OM|;Szturz|Petr|P|;Specenier|Pol|P|;Merlano|Marco C|MC|;Benasso|Marco|M|;Van Gestel|Dirk|D|;Wouters|Kristien|K|;Van Laer|Carl|C|;Van den Weyngaert|Danielle|D|;Peeters|Marc|M|;Vermorken|Jan|J|",
"chemical_list": "D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2015-0246",
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"issn_linking": "1083-7159",
"issue": "21(1)",
"journal": "The oncologist",
"keywords": "Chemotherapy; Concomitant chemoradiotherapy; Gemcitabine; Head and neck cancer; Neoplasms; Oncology; Radiation; Radiotherapy; Toxicity",
"medline_ta": "Oncologist",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D003841:Deoxycytidine; D006258:Head and Neck Neoplasms; D006801:Humans; D009364:Neoplasm Recurrence, Local; D011838:Radiation-Sensitizing Agents; D050397:Radiotherapy, Intensity-Modulated; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "59-71",
"pmc": null,
"pmid": "26712958",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review; D000078182:Systematic Review",
"references": "8609658;23414589;16424033;10768432;21324799;17434832;23723331;20026818;24820548;19660134;17327856;18423671;18980967;1988086;23182993;11801767;25049329;16149285;19357741;10072186;9552032;19446902;8363650;20555077;17823386;17438112;25171890;15297392;11756581;10643544;3383195;15128893;23043985;15033674;10769687;22085617;21570216;24256848;15958469;7918127;25176576;14760126;15846296;17538164;9816199;22112778;20421546;7481849;16331496;19672265;16238441;17011449;18559875;22708528;15036853;25154822;15128894;10550827;22687944;14645636;20882386;8205542;11157033;21279703;16467544;15632251;22678924;10679658",
"title": "Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis.",
"title_normalized": "gemcitabine based chemoradiation in the treatment of locally advanced head and neck cancer systematic review of literature and meta analysis"
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"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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"abstract": "The hallmark of gestational trophoblastic disease is the production of human chorionic gonadotropin (hCG) due to the hyperproliferation of extraembryonic trophoblast cells. Previous studies show hCG has thyrotropic action due to its structural similarity with thyroid stimulating hormone (TSH) molecules. Germ cell tumors represent 15-20% of all ovarian tumors and can be malignant or benign.\nWe present a case of a 53-year old African American female with a history of hyperthyroidism secondary to a complete hydatidiform mole and an associated finding of a mature cystic ovarian teratoma. She presented with nausea, vomiting, nervousness, weight gain, abdominal pain and a b-hCG of greater than 450,000mIU/mL. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed and curative for her symptoms. Lung nodules were noted with slight increases in b-hCG levels in the months following the surgery. Propranolol and methimazole were used to treat the acute hyperthyroid symptoms.\nThis case presents the rare occurrence of a complete hydatidiform mole causing hyperthyroidism and an associated finding of a mature cystic teratoma. It also highlights the importance of monitoring b-hCG levels following a complete molar pregnancy due to an increased risk of choriocarcinoma.",
"affiliations": "1Alabama College of Osteopathic Medicine, 445 Health Sciences Blvd, Dothan, AL 36303 USA.;1Alabama College of Osteopathic Medicine, 445 Health Sciences Blvd, Dothan, AL 36303 USA.;Northwest Florida Diagnostic Endocrinology Clinic, Tallahassee, FL USA.;Nature Coast Healthcare Center, Tallahassee, FL USA.",
"authors": "Simes|Bryce C|BC|0000-0003-3652-6955;Mbanaso|Alozie A|AA|;Zapata|Carlos A|CA|;Okoroji|Chukwuma M|CM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13044-018-0056-7",
"fulltext": "\n==== Front\nThyroid ResThyroid ResThyroid Research1756-6614BioMed Central London 5610.1186/s13044-018-0056-7Case ReportHyperthyroidism in a complete molar pregnancy with a mature cystic ovarian teratoma http://orcid.org/0000-0003-3652-6955Simes Bryce C. 1-904-504-8897simesbc@acom.edu 1Mbanaso Alozie A. mbanasoaa@acom.edu 1Zapata Carlos A. cazapmd@aol.com 2Okoroji Chukwuma M. chux62@gmail.com 31 0000 0004 1795 3860grid.459377.bAlabama College of Osteopathic Medicine, 445 Health Sciences Blvd, Dothan, AL 36303 USA 2 Northwest Florida Diagnostic Endocrinology Clinic, Tallahassee, FL USA 3 Nature Coast Healthcare Center, Tallahassee, FL USA 10 8 2018 10 8 2018 2018 11 1220 7 2018 3 8 2018 © The Author(s). 2018Open 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\nThe hallmark of gestational trophoblastic disease is the production of human chorionic gonadotropin (hCG) due to the hyperproliferation of extraembryonic trophoblast cells. Previous studies show hCG has thyrotropic action due to its structural similarity with thyroid stimulating hormone (TSH) molecules. Germ cell tumors represent 15–20% of all ovarian tumors and can be malignant or benign.\n\nCase presentation\nWe present a case of a 53-year old African American female with a history of hyperthyroidism secondary to a complete hydatidiform mole and an associated finding of a mature cystic ovarian teratoma. She presented with nausea, vomiting, nervousness, weight gain, abdominal pain and a b-hCG of greater than 450,000mIU/mL. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed and curative for her symptoms. Lung nodules were noted with slight increases in b-hCG levels in the months following the surgery. Propranolol and methimazole were used to treat the acute hyperthyroid symptoms.\n\nConclusion\nThis case presents the rare occurrence of a complete hydatidiform mole causing hyperthyroidism and an associated finding of a mature cystic teratoma. It also highlights the importance of monitoring b-hCG levels following a complete molar pregnancy due to an increased risk of choriocarcinoma.\n\nKeywords\nHydatidiform moleComplete molar pregnancyHyperthyroidismMature cystic ovarian teratomaBeta-human chorionic gonadotropin (b-hCG)Beta-carboxy-terminal peptide (b-CTP)issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are a family of heterodimeric glycoprotein hormones composed of an alpha and beta subunit. All members of the family share a common alpha-subunit and have a different functional beta-subunit [1, 2]. Studies have shown that LH and hCG compete with TSH to bind to TSH receptors. The beta subunits of both LH and hCG share an 85% sequence identity, but the presence of beta-carboxy terminal peptide (b-CTP), a 31-amino acid extension on the beta-subunit, is unique to hCG [3]. Both hormones have demonstrated thyrotropic action on the thyroid gland [4]. LH is a more potent stimulator of the TSH receptor, but when the b-CTP is removed from a hCG molecule, the stimulatory effect on TSH receptors is identical. It is likely that b-CTP’s role is to protect women from thyrotoxicosis during normal pregnancy when b-hCG is produced in large amounts by the placenta [3].\n\nPregnancy causes significant changes to the thyroid gland that are reversible. The hypothalamic-pituitary-thyroid feedback system is altered by the thyrotropic effect of b-hCG. A slight suppression in TSH and increase in T4 levels are seen in normal pregnancy. Hyperemesis gravidarum is a common presentation during the first trimester of pregnancy. It is a multifactorial disease, but hCG production and its thyrotropic action likely play a significant role. 70% of women with hyperemesis gravidarum have abnormal thyroid function. The hyperthyroid state reverses by the second trimester in almost all women during a normal pregnancy [3, 5]. Women with complete molar pregnancies also experience worse nausea and vomiting than those with normal pregnancies due to the significantly elevated hCG production [6].\n\nGestational trophoblastic disease (GTD) is a group of tumors characterized by the production of hCG due to the hyperproliferation of extraembryonic trophoblast cells. They are either hydatidiform moles or trophoblastic neoplasms [7]. Maternal age is the most significant risk factor for the development of a hydatidiform mole among all regions and ethnicities. Data shows that the there is higher risk in those above the age of 35 and an additional 10-fold increased risk in those above the age of 40 [8]. Gestational trophoblastic neoplasia (GTN) is a group of tumors with the possibility of local invasion and metastases. These include choriocarcinoma, placental site trophoblastic tumors and epithelioid trophoblastic tumors. Hydatidiform moles can sometimes be clinically considered GTN even though it is not an actual neoplasm due to its ability to invade locally and metastasize [9].\n\nGerm cell tumors represent 15–20% of all ovarian tumors. Most (95%) of these tumors are benign cystic teratomas but 5% are malignant. Mature cystic teratoma, choriocarcinoma and dysgerminoma are examples of germ cell tumors that can secrete hCG. Surgical management and chemotherapy are the main treatment options for those with germ cell ovarian tumors [10].\n\nCase presentation\nA 53-year-old African-American female with a history of uterine fibroids presented with a two-month history of nausea, vomiting, nervousness, weight gain and left lower quadrant abdominal pain. Weeks prior, she also went to the emergency department for similar symptoms where an abdominal computerized tomography (CT) scan showed an enlarged uterus along with fibroids, a hemorrhagic cyst of the right ovary and a teratoma of the left ovary (Fig. 1) (Fig. 2) (Fig. 3). Regions of calcification were present measuring a maximum of 1.8 cm.Fig. 1 Axial view – Abdominal CT scan showing a left sided ovarian teratoma with calcification\n\nFig. 2 Axial view – Abdominal CT scan with an enlarged uterus due to a complete molar pregnancy\n\nFig. 3 Coronal view – Abdominal CT scan showing a left sided ovarian teratoma and complete hydatidiform mole\n\n\n\nPhysical exam revealed a soft, non-distended abdomen with pain upon deep palpation localized to the left lower quadrant. The thyroid gland was palpable, with an estimated weight of thirty to forty grams. It was nodular and nontender. The Pemberton sign checking for venous obstruction due to a goiter was negative. Tachycardia was present with a normal rhythm. S1 and S2 were normal with no S3, S4, gallops or murmurs detected. Initial labs revealed a mild normocytic anemia, a low TSH level and slightly elevated transaminases (Table 1).Table 1 Initial laboratory values at admission\n\nWBC\t10,300/mm3\t\nHemoglobin\t10.7 gm/dL\t\nHematocrit\t31.3%\t\nPlatelets\t236,000/mm3\t\nSodium\t134 mmol/L\t\nPotassium\t3.7 mmol/L\t\nBUN\t9 mg/dL\t\nCreatinine\t0.5 mg/dL\t\nGlucose\t105 mg/dL\t\nAST\t89 units/L\t\nALT\t59 units/L\t\nAlkaline Phosphatase\t126 units/L\t\nPT\t11.7\t\nINR\t1.1\t\nPTT\t27.4\t\nBlood Acetone\tNegative\t\n\n\nAn endocrinology consultation was placed due to the abnormal TSH levels indicating hyperthyroidism. Baseline thyroid testing showed a TSH 0.04mIU/L (ref. range: 0.340–5.600mIU/L), free T4 level of 4.03 ng/dL (ref. range: 0.61–1.12 ng/dL) and total T3 of 451 ng/dL (ref. range: 60-181 ng/dL). A baseline thyroid ultrasound was also performed that showed a bilaterally enlarged thyroid gland, consistent with a goiter. Both lobes were heterogeneous. Multiple cystic and complex nodules were seen bilaterally. The largest of these measured 1.5 × 1.1 × 1.6 cm on the left lobe. There were small encapsulated nodules seen on each lobe. These findings were consistent with a multinodular goiter. The hyperthyroid symptoms improved after the administration of antithyroid medications: propranolol and methimazole.\n\nBeta-hCG intact was measured twice, showing a value greater than 450,000mIU/mL. Because of the combination of ovarian and uterine pathology present, the patient was recommended for a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Following surgery, b-hCG levels dropped from greater than 450,000mIU/mL to 200,000mIU/mL and continued to decrease over the course of the hospital stay (Fig. 4). The methimazole and propranolol doses were also titrated as the hyperthyroidism became less symptomatic. Tissue diagnosis by the pathology laboratory confirmed the ovarian teratoma (Fig. 5). Sections of the myometrial wall containing massive hydropic chorionic villi with the presence of intravillous vascular cistern were noted along with excess trophoblastic proliferation (Fig. 6). This, along with the extremely high b-hCG levels, was consistent with the presentation of a complete hydatidiform mole.Fig. 4 Post surgical measurements of b-hCG following total abdominal hysterectomy with bilateral salpingo-oophorectomy (POD: post-operative day)\n\nFig. 5 Left sided ovarian teratoma demonstrating cystic cavities lined by mature epidermis\n\nFig. 6 Complete molar pregnancy demonstrating massive hydropic chorionic villi, the presence of intravillous vascular cistern and excessive trophoblastic proliferation\n\n\n\nAfter discharge, the patient underwent serial b-hCG measurements until the levels were undetectable to monitor the potential development of GTN. Post-surgical management also included methotrexate for chemotherapy. During the course of chemotherapy, lung nodules were found on a subsequent CT scan along with a slight upswing in b-hCG. However, as more time passed, the levels of b-hCG were eventually undetectable, and there was no subsequent choriocarcinoma post complete molar pregnancy.\n\nThyroid hormone levels were also monitored after discharge from the hospital and low-dose methimazole was continued. There was a significant improvement in the thyroid hormone levels 1 month following the surgery: TSH 0.5mIU/L, free T4 0.77 ng/dL and free T3 2.26 pg/mL (ref. range: 2.3–4.2 pg/mL). TSH levels were continuously monitored for 12 months following the surgery and remained normal. A year after the surgery, the patient also sought treatment at the Mayo Clinic, who performed a fine needle aspiration biopsy (FNAB) of a thyroid nodule. The patient reported the FNAB results as negative and the methimazole was then discontinued.\n\nDiscussion and conclusions\nThe association between a molar pregnancy and hyperthyroidism was discovered by Tisne, Barzelatto and Stevenson in 1955 [11]. This case presents the rare occurrence of a complete hydatidiform mole causing hyperthyroidism and an associated finding of a mature cystic teratoma. It also serves as a reminder that in rare occasions, supraphysiologic levels of b-hCG can have a thyrotropic effect due to its structural similarity to TSH’s molecular structure. Antithyroid medications should be initiated for the management of hyperthyroid symptoms until surgical removal of the source of the b-hCG secretion can be completed.\n\nFollowing the resolution of gestational trophoblastic diseases, such as a hydatidiform mole, management should continue to evaluate for the development of gestational trophoblastic neoplasia. As many of 20% of complete hydatidiform moles develop GTN. Serum b-hCG should be measured weekly until levels are undetectable within 6 months. Once undetectable, serial b-hCG measurements should continue for three more weeks to confirm resolution. If the level remains undetectable, the timing of the b-hCG measurements should be switched to monthly for another three to 6 months. If the b-hCG remains elevated or unchanged, evaluation for metastatic disease should be initiated [12]. The most common location for GTN distal invasion include the lungs and vagina [13].\n\nAbbreviations\nb-CTPBeta-carboxy terminal peptide\n\nCTComputerized tomography\n\nFNABFine needle aspiration biopsy\n\nFSHFollicle stimulating hormone\n\nGTDGestational trophoblastic disease\n\nGTNGestational trophoblastic neoplasia\n\nhCGHuman chorionic gonadotropin\n\nLHLuteinizing hormone\n\nTSHThyroid stimulating hormone\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nAll authors have contributed to, read, and approved this manuscript. CAZ and CMO were directly involved in the endocrine and obstetrical management of this patient.\n\nThe need for ethics approval was waived by the Alabama College of Osteopathic Medicine.\n\nThe patient has provided their consent for the contents of this report to be published.\n\nThe authors declare that they have no competing interests.\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Fares FA Gruener N Kraiem Z The role of the asparagine-linked oligosaccharides of the alpha-subunit in human thyrotropin bioactivity Endocrinology 1996 137 2 555 560 10.1210/endo.137.2.8593802 8593802 \n2. Cahoreau C Klett D Combarnous Y Structure–function relationships of glycoprotein hormones and their subunits’ ancestors Front Endocrinol 2015 6 26 10.3389/fendo.2015.00026 \n3. Carayon P Lefort G Nisula B Interaction of human chorionic gonadotropin and human luteinizing hormone with human thyroid membranes Endocrinology 1980 106 6 1907 1916 10.1210/endo-106-6-1907 6245856 \n4. Yoshimura M Hershman JM Thyrotropic action of human chorionic gonadotropin Thyroid 1995 5 5 425 434 10.1089/thy.1995.5.425 8563483 \n5. Goodwin TM The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum J Clin Endocrinol Metab 1992 75 5 1333 1337 1430095 \n6. Bustos M Venkataramanan R Caritis S Nausea and vomiting of pregnancy - Whats new? Auton Neurosci 2017 202 62 72 10.1016/j.autneu.2016.05.002 27209471 \n7. Bruce S Sorosky J Gestational Trophoblastic Disease. [Updated 2017 Dec 4] StatPearls [Internet] 2018 Treasure Island StatPearls Publishing \n8. Bracken MB Brinton LA Hayashi K Epidemiology of Hydatidiform mole and Choriocarcinoma Epidemiol Rev 1984 6 1 52 75 10.1093/oxfordjournals.epirev.a036275 6386504 \n9. Shih I-M Gestational trophoblastic neoplasia—pathogenesis and potential therapeutic targets Lancet Oncol 2007 8 7 642 650 10.1016/S1470-2045(07)70204-8 17613426 \n10. Ray-Coquard I Ovarian tumors of sex cord-stromal origin. Orphanet Encyclopedia 2004 \n11. Tisne L Barzelatto J Stevenson C Study of thyroid function during pregnancy-puerperal state with radioactive iodine Bol Soc Chil Obstet Ginecol 1955 20 246 251 13342125 \n12. ACOG Practice bulletin #53: diagnosis and treatment of gestational trophoblastic disease Obstet Gynecol 2004 103 6 1365 1377 10.1097/00006250-200406000-00051 15172880 \n13. Hoskins WJ Perez CA Young RC Principles and practice of gynecologic oncology 1992 Philadelphia Lippincott\n\n",
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"abstract": "BACKGROUND\nPlatinum compounds are frequently used for the treatment of colorectal cancer as initial chemotherapy. Oxaliplatin is a third-generation platinum used for the treatment of stage III colorectal cancer and is associated with hypersensitivity reactions. The incidence of hypersensitivity reaction is approximately 12%, with 1-2% of patients developing moderate to severe reactions.\n\n\nMETHODS\nA 54-year-old male patient with stage III B colon cancer was diagnosed and chemotherapy with oxaliplatin was indicated by the oncology service. Within 20 min of the first cycle of oxaliplatin, he developed dyspnea, laryngeal spam, foreign body sensation in the throat, nausea, and diarrhea; therefore, the infusion of oxaliplatin was suspended, and intramuscular epinephrine was administered and intravenous hydrocortisone along with chlorpheniramine with adequate resolution of symptoms.Management and outcome: Intradermal skin test performed at the concentration of 5 mg/ml (dilution 1:100) was positive. Due to the symptoms presented we decided to perform desensitization to oxaliplatin (total dose: 250 mg) with three bags-12 steps protocol with an initial concentration dose of 1/100 of the total dose in a course of 5.56 h with no hypersensitivity reactions.\n\n\nCONCLUSIONS\nApproximately 50% of patients who are exposed to oxaliplatin may have hypersensitivity despite premedication. Desensitization protocol induces tolerance to a drug temporarily and is dependent on continuous exposure.",
"affiliations": "Regional Center of Allergy and Clinical Immunology, University Hospital \"Dr Jose Eleuterio Gonzalez\", Faculty of Medicine, Autonomous University of Nuevo León, Monterrey, Mexico.;Regional Center of Allergy and Clinical Immunology, University Hospital \"Dr Jose Eleuterio Gonzalez\", Faculty of Medicine, Autonomous University of Nuevo León, Monterrey, Mexico.;Regional Center of Allergy and Clinical Immunology, University Hospital \"Dr Jose Eleuterio Gonzalez\", Faculty of Medicine, Autonomous University of Nuevo León, Monterrey, Mexico.;Regional Center of Allergy and Clinical Immunology, University Hospital \"Dr Jose Eleuterio Gonzalez\", Faculty of Medicine, Autonomous University of Nuevo León, Monterrey, Mexico.",
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"abstract": "Zolpidem is a widely used ultrashort-acting non-benzodiazepine in clinical practice; compared with benzodiazepines, it does not have side effects such as daytime hangover, rebound insomnia, and development of tolerance. We report an autopsy case of abnormal behaviour induced by zolpidem. A man in his 60's had suffered from postherpetic neuralgia about 2 months ago and had been prescribed zolpidem for insomnia. According to his family, he had no memory of his actions such as striking a wall, taking his futon outside, and eating 5 times a day after he took zolpidem. Because his postherpetic neuralgia did not improve, he was hospitalized and treated with an epidural block. During hospitalization, he took off his clothes, removed the epidural block catheter by himself, and slept on others' beds. He disappeared from the hospital one day; the next day, he was found dead in a narrow water storage tank 10 km away from the hospital. He was thought to have driven a car by himself to reach the place. Forensic autopsy revealed that the cause of death was drowning. Zolpidem and several other drugs were detected by toxicological analysis of his blood; the concentrations of these drugs were within therapeutic range. There are several reports about somnambulism induced by zolpidem such as sleepwalking, sleep driving, and eating. Considering the strange episodes following zolpidem administration, his behaviour on the day of his death was considered abnormal behaviour induced by zolpidem.",
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"authors": "Usumoto|Yosuke|Y|;Kudo|Keiko|K|;Sameshima|Naomi|N|;Sato|Kazuo|K|;Tsuji|Akiko|A|;Ikeda|Noriaki|N|",
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"abstract": "Drug reaction with eosinophilia and systemic symptom syndrome (DRESS) is a hypersensitivity drug reaction, most frequently associated with antiepileptic drugs, characterized by skin rash, fever, pharyngitis, lymphadenopathy, and visceral organ involvement, typically presenting within 8 weeks of initiation of therapy. Management involves prompt withdrawal of the offending drug and use of systemic corticosteroids. We here present a rare case of DRESS secondary to levetiracetam. Only few case reports of DRESS secondary to levetiracetam have been published so far.",
"affiliations": "Department of Internal Medicine, Shere Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medicine, Shere Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medicine, Shere Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medicine, Shere Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medicine, Shere Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.",
"authors": "Dar|Waseem Raja|WR|;Sofi|Najeebullah|N|;Latief|Muzamil|M|;Dar|Imtiyaz Ahmad|IA|;Kasana|Basharat Ahmad|BA|",
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"fulltext": "\n==== Front\nIndian J DermatolIndian J DermatolIJDIndian Journal of Dermatology0019-51541998-3611Medknow Publications & Media Pvt Ltd India IJD-61-235a10.4103/0019-5154.177777E-IJD Case ReportLevetiracetam Induced Drug Reaction with Eosinophilia and Systemic Symptom Syndrome Dar Waseem Raja Sofi Najeebullah 1Latief Muzamil 1Dar Imtiyaz Ahmad 1Kasana Basharat Ahmad 1From the Department of Internal Medicine, Shere Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India1 Department of Medicine, Shere Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, IndiaAddress for correspondence: Dr. Waseem Raja Dar, Department of Internal Medicine, Shere Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India. E-mail: drwaseem.mw@gmail.comMar-Apr 2016 61 2 235 235 4 2015 9 2015 Copyright: © 2016 Indian Journal of Dermatology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Drug reaction with eosinophilia and systemic symptom syndrome (DRESS) is a hypersensitivity drug reaction, most frequently associated with antiepileptic drugs, characterized by skin rash, fever, pharyngitis, lymphadenopathy, and visceral organ involvement, typically presenting within 8 weeks of initiation of therapy. Management involves prompt withdrawal of the offending drug and use of systemic corticosteroids. We here present a rare case of DRESS secondary to levetiracetam. Only few case reports of DRESS secondary to levetiracetam have been published so far.\n\nDrug reaction with eosinophilia and systemic symptomlevetiracetamsteroids\n==== Body\nWhat was known?\n\n\nDrug reaction with eosinophilia and systemic symptom is a severe hypersensitivity reaction most often associated with antiepileptics like phenytoin\n\nWithdrawal of offending drug and steroids form the basis of the management.\n\n\n\n\nIntroduction\nCutaneous reactions are among most frequent adverse reactions to drugs. Most are benign, but a few can be life-threatening. Evidence suggests an immunologic basis for most acute drug eruptions.[1] Drug reaction with eosinophilia and systemic symptom (DRESS) is a severe adverse drug-induced reaction with an annual incidence of 1 in 1000 to 1 in 10,000 drug exposures. Although antiepileptics are the major culprit drugs, a variety of other pharmacological agents cause DRESS. We here report a case of levetiracetam induced DRESS that has rarely been reported in the literature previously.\n\nCase Report\nA 40-year-old male presented to our emergency department with acute subdural hematoma secondary to a road traffic accident. The patient was managed conservatively. However during hospital stay patient developed a generalized tonic-clonic seizure. The patient was put on phenytoin and discharged home in a stable condition. The patient was readmitted 4 weeks later with generalized weakness and fatigue. Investigations revealed pancytopenia. Phenytoin was stopped. During hospital stay, his counts became normal, and his general condition improved. In view of the history of seizure, patient was switched over to levetiracetam and advised close follow-up after discharge. Patient, however, returned after 1 week with high-grade fever (103–104 F] and rash. Rash was itchy and erythematous and started from the chest and progressed to involve other body parts. On examination, the patient was conscious and oriented. Generalized erythematous maculopapular rash seen predominantly on the face, chest, trunk, back, upper limbs, and the proximal portion of lower limbs was present [Figures 1–4]. Cervical and axillary lymphadenopathy was also present. Rest of the examination was normal. The investigation revealed transaminitis [Table 1]. In view of fever, rash, transaminitis and exposure to levetiracetam, the patient was diagnosed as a case of levetiracetam induced DRESS. Calculated RegiSCAR score was 4 (probable case). Levetiracetam was stopped. The patient was managed with antihistaminics and dexamethasone 4 mg tid for 2 weeks followed by a taper. The patient became afebrile on day 4 of admission and transaminitis started resolving on day 4. The patient was seizure free and was discharged after 6 days of hospital stay. On follow-up, the patient is doing well and seizure free. Transaminitis has resolved, and the rash has subsided [Figures 5 and 6].\n\nFigure 1 Rash on face\n\nFigure 2 Rash on chest and abdomen\n\nFigure 3 Rash on back\n\nFigure 4 Rash on legs\n\nTable 1 Investigation\n\nFigure 5 Resolution of rash from face\n\nFigure 6 Resolution of rash from back\n\nDiscussion\nDRESS syndrome was first described in 1959 associated with phenytoin and was previously referred to as drug-induced pseudolymphoma.[2] The term DRESS syndrome was proposed by Bocquet et al., describing it as a potentially life-threatening syndrome. The syndrome is characterized by severe skin eruption, fever, hematologic abnormalities (eosinophilia or atypical lymphocytes) and internal organ involvement. Most cases occur within 8 weeks of exposure to the drug.[4567891011] Although most commonly associated with antiepileptic drugs like phenytoin, DRESS syndrome has also been reported after exposure to a large number of medications including oxcarbazepine, vancomycin, doxycycline, linezolid, nitrofurantoin, atorvastatin, and esomeprazole.[12] The first case of levetiracetam induced DRESS was reported in 2010. Since then only a few cases have been reported so far.[131415]\n\nThe pathogenesis of DRESS syndrome is partially understood. Different mechanisms have been implicated in its development that include slow acetylation and detoxification defects leading to reactive metabolite formation and subsequent immunological reactions.[16] Reactivation of human herpes, including Epstein–Barr virus and human herpes virus (HHV)-6 and 7 has also been implicated.\n\nDiagnosis of DRESS syndrome is clinical. Laboratory tests that will help to differentiate DRESS syndrome from other severe drug reactions and to identify internal organ involvement include complete blood cell count, liver function tests, serum creatinine level and urinalysis. Skin biopsy shows a nonspecific lymphocytic infiltrate of the papillary dermis, which may contain eosinophils and which is generally denser than in other drug reactions. A scoring system [RegiSCAR scoring, Table 2] has been devised that helps clinicians to make a diagnosis of DRESS in a suspected case.\n\nTable 2 RegiSCAR scoring for drug reaction with eosinophilia and systemic symptom syndrome\n\nPrompt treatment is important for speedy recovery. The offending drug should be discontinued and pharmacological treatment instituted. Systemic corticosteroids have become a mainstay of therapy in severe cases. The French Society of Dermatology recommends systemic corticosteroids at a dose equivalent to 1 mg/kg/day of prednisone in patients with any sign of severity that include transaminitis, renal involvement, pneumonia, and cardiac involvement. They further recommend the use of intravenous immunoglobulin at a dose of 2 g/kg over 5 days for a patient with life-threatening signs such as renal failure and respiratory failure. In addition, they also propose the use of steroids in combination with ganciclovir in patients with signs of severity and confirmation of a major viral reactivation of HHV-6.\n\nConclusion\nDRESS syndrome is a life-threatening condition with mortality of 10%. Diagnosis remains clinical although scoring systems may be helpful in a suspected case. Treatment should be urgent. The offending drug should be stopped and steroids given immediately.\n\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nWhat is new?\n\n\nDrug reaction with eosinophilia and systemic symptom (DRESS) is a very rare but possible side effect of levetiracetam and should be borne in mind if a patient on levetiracetam develops a skin rash\n\nThe outcome is good if DRESS is recognized early and appropriate treatment instituted.\n==== Refs\n1 Patrice C Musette P Descamps V Meyer O Speirs C Finzi L The DRESS syndrome: A literature review Am J Med 2011 124 588 97 21592453 \n2 Saltzstein SL Ackerman LV Lymphadenopathy induced by anticonvulsant drugs and mimicking clinically pathologically malignant lymphomas Cancer 1959 12 164 82 13618867 \n3 Bocquet H Bagot M Roujeau JC Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS) Semin Cutan Med Surg 1996 15 250 7 9069593 \n4 D’Orazio JL Oxcarbazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) Clin Toxicol (Phila) 2008 46 1093 4 18821094 \n5 Vauthey L Uçkay I Abrassart S Bernard L Assal M Ferry T Vancomycin-induced DRESS syndrome in a female patient Pharmacology 2008 82 138 41 18607115 \n6 Mailhol C Tremeau-Martinage C Paul C Godel A Lamant L Giordano-Labadie F Severe drug hypersensitivity reaction (DRESS syndrome) to doxycycline Ann Dermatol Venereol 2010 137 40 3 20110067 \n7 Savard S Desmeules S Riopel J Agharazii M Linezolid-associated acute interstitial nephritis and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome Am J Kidney Dis 2009 54 e17 20 19733945 \n8 Velema MS Voerman HJ DRESS syndrome caused by nitrofurantoin Neth J Med 2009 67 147 9 19581659 \n9 Gressier L Pruvost-Balland C Dubertret L Viguier M Atorvastatin-induced drug reaction with eosinophilia and systemic symptoms (DRESS) Ann Dermatol Venereol 2009 136 50 3 19171231 \n10 Giri PP Roy S Bhattyacharya S Pal P Dhar S Dress syndrome with sepsis, acute respiratory distress syndrome and pneumomediastinum Indian J Dermatol 2011 56 763 5 22345792 \n11 Giri PP Roy S Bhattyacharya S Pal P Dhar S Esomeprazole induced DRESS syndrome. Studies of cross-reactivity among proton pump inhibitors Allergy 2007 62 342 3 \n12 Lens S Crespo G Carrión JA Miquel R Navasa M Severe acute hepatitis in the DRESS syndrome: Report of two cases Ann Hepatol 2010 9 198 201 20526017 \n13 Gómez-Zorrilla S Ferraz AV Pedrós C Lemus M Peña C Levetiracetam-induced drug reaction with eosinophilia and systemic symptoms syndrome Ann Pharmacother 2012 46 e20 22764327 \n14 Hall DJ Fromm JS Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking phenytoin and levetiracetam: A case report J Med Case Rep 2013 7 2 23286229 \n15 Eleni K Dress syndrome induced by levetiracetam J Eur Acad Dermatol Venereol 2015 29 377 8 24397826 \n16 Tohyama M Hashimoto K New aspects of drug-induced hypersensitivity syndrome J Dermatol 2011 38 222 8 21342223\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0019-5154",
"issue": "61(2)",
"journal": "Indian journal of dermatology",
"keywords": "Drug reaction with eosinophilia and systemic symptom; levetiracetam; steroids",
"medline_ta": "Indian J Dermatol",
"mesh_terms": null,
"nlm_unique_id": "0370750",
"other_id": null,
"pages": "235",
"pmc": null,
"pmid": "27057042",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "13618867;17711546;18607115;18821094;19171231;19581659;19733945;20110067;20526017;21342223;21592453;22345792;22764327;23286229;24397826;9069593",
"title": "Levetiracetam Induced Drug Reaction with Eosinophilia and Systemic Symptom Syndrome.",
"title_normalized": "levetiracetam induced drug reaction with eosinophilia and systemic symptom syndrome"
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"companynumb": "IN-WATSON-2016-07286",
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"abstract": "Synthetic tracheal grafts seeded with autologous bone marrow-mononuclear cells (BM-MNCs) have been described as becoming living and functional grafts representing a promising option for tracheal replacement for pathologies unamenable by segmental resection or autologous repair. This study aimed to present the first long-term follow-up of these procedures in humans.\n\n\n\nWe retrospectively analyzed 3 patients who received synthetic tracheal grafts seeded with BM-MNCs implanted.\n\n\n\nPatient 1 was a 37-year-old man with mucoepidermoid carcinoma, the first-ever human to receive a synthetic tracheal graft seeded with BM-MNCs. Patient 2 was a 30-year-old man with adenoid cystic carcinoma, and patient 3 was a 22-year-old woman with an iatrogenic tracheal injury. All patients developed graft-related complications necessitating multiple surgical reinterventions. Patient 1 was hospitalized for 8 months before dying from respiratory failure secondary to graft dehiscence 32 months after implantation. Patient 2 died 3.5 months after implantation from undisclosed causes. Patient 3 received a second synthetic tracheal graft after 11 months and an allogeneic trachea and lung transplantation 45 months after the primary implantation. Patient 3 underwent 191 surgical interventions after the primary implantation and spent 55 months in the intensive care unit before dying from airway bleeding. All patients' bronchoscopic, histologic, and radiologic investigations demonstrated graft-associated complications, including anastomotic fistulae and obstructive granulation tissue, without graft vascularization, mucosal lining, or integration into adjacent tissues.\n\n\n\nSynthetic tracheal grafts seeded with BM-MNCs do not become living functional tracheal grafts and lead to debilitating complications and death.",
"affiliations": "Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Section Cardiothoracic Surgery and Anesthesiology, Division of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden. Electronic address: thomas.fux@sll.se.;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Division of Radiology, Karolinska University Hospital, Stockholm, Sweden.;Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Uppsala University Hospital, Uppsala, Sweden.;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Uppsala University Hospital, Uppsala, Sweden.;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Heart and Vascular Division, Karolinska University Hospital, Stockholm, Sweden.",
"authors": "Fux|Thomas|T|;Österholm|Cecilia|C|;Themudo|Raquel|R|;Simonson|Oscar|O|;Grinnemo|Karl-Henrik|KH|;Corbascio|Matthias|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtcvs.2019.09.185",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-5223",
"issue": "159(6)",
"journal": "The Journal of thoracic and cardiovascular surgery",
"keywords": "airway surgery; synthetic tracheal graft; tracheal prosthesis; tracheal replacement",
"medline_ta": "J Thorac Cardiovasc Surg",
"mesh_terms": "D000328:Adult; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D003528:Carcinoma, Adenoid Cystic; D018277:Carcinoma, Mucoepidermoid; D002478:Cells, Cultured; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D008297:Male; D012189:Retrospective Studies; D013898:Thoracic Injuries; D023822:Tissue Engineering; D054457:Tissue Scaffolds; D014132:Trachea; D014134:Tracheal Neoplasms; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0376343",
"other_id": null,
"pages": "2525-2537.e23",
"pmc": null,
"pmid": "31859073",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "Synthetic tracheal grafts seeded with bone marrow cells fail to generate functional tracheae: First long-term follow-up study.",
"title_normalized": "synthetic tracheal grafts seeded with bone marrow cells fail to generate functional tracheae first long term follow up study"
} | [
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"activesubstancename": "FILGRASTIM"
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"abstract": "BACKGROUND\nIntrapleural fibrinolytic enzyme therapy is a potentially surgery-sparing treatment for poorly resolving parapneumonic effusion and empyema. It is safe in the majority of patients, however the most significant risk associated with this treatment is severe bleeding secondary to pleural hemorrhage. Contraindications for intrapleural enzyme therapy are not widely agreed upon and little is known about how to treat this difficult and potentially lethal hemorrhagic complication.\n\n\nMETHODS\nAn independent 82-year-old Caucasian man presented to hospital with an empyema complicating community-acquired pneumonia and coincidental pulmonary embolus. He was initially commenced on intravenous antibiotics, pleural drainage and anticoagulation, however failed to improve significantly and was commenced on intrapleural fibrinolytic enzyme therapy. Shortly after, he suffered severe pleural hemorrhage that was uncontrollable despite emergency thoracotomy and washout. Subsequent hemostasis was achieved after re-exploration and application of topical fibrin-thrombin sealant spray. The patient survived and was discharged home.\n\n\nCONCLUSIONS\nIntrapleural enzyme therapy can be effective in loculated parapneumonic effusion and empyema, but massive pleural hemorrhage can complicate its use. Pleural hemorrhage appears to be associated with anticoagulation or coagulopathy, and can be difficult to manage. This case adds to the body of data on bleeding complications following intrapleural enzyme therapy, and to the best of our knowledge is the first report of fibrin-thrombin sealant use in this setting.",
"affiliations": "Cardiac and Thoracic Surgical Unit, Flinders University, Sturt Road, Bedford Park, SA, 5042, Australia. Simon.Vun@sa.gov.au.;Cardiac and Thoracic Surgical Unit, Flinders University, Sturt Road, Bedford Park, SA, 5042, Australia. David.Lance@sa.gov.au.",
"authors": "Vun|Simon V|SV|;Lance|David G|DG|",
"chemical_list": "D015718:Fibrin Tissue Adhesive",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-015-0775-5",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 77510.1186/s13256-015-0775-5Case ReportLife-threatening pleural hemorrhage following intrapleural enzyme therapy and successful treatment with fibrin-thrombin sealant pleurodesis: a case report http://orcid.org/0000-0002-6159-2340Vun Simon V. +61 8 8204 5623Simon.Vun@sa.gov.au Lance David G. +61 8 8204 5623David.Lance@sa.gov.au Cardiac and Thoracic Surgical Unit, Flinders University, Sturt Road, Bedford Park, SA 5042 Australia Cardiac and Thoracic Surgical Unit, Flinders Medical Centre, Flinders Drive, Bedford Park, SA 5042 Australia 18 12 2015 18 12 2015 2015 9 2878 9 2015 24 11 2015 © Vun and Lance. 2015\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.Introduction\nIntrapleural fibrinolytic enzyme therapy is a potentially surgery-sparing treatment for poorly resolving parapneumonic effusion and empyema. It is safe in the majority of patients, however the most significant risk associated with this treatment is severe bleeding secondary to pleural hemorrhage. Contraindications for intrapleural enzyme therapy are not widely agreed upon and little is known about how to treat this difficult and potentially lethal hemorrhagic complication.\n\nCase presentation\nAn independent 82-year-old Caucasian man presented to hospital with an empyema complicating community-acquired pneumonia and coincidental pulmonary embolus. He was initially commenced on intravenous antibiotics, pleural drainage and anticoagulation, however failed to improve significantly and was commenced on intrapleural fibrinolytic enzyme therapy. Shortly after, he suffered severe pleural hemorrhage that was uncontrollable despite emergency thoracotomy and washout. Subsequent hemostasis was achieved after re-exploration and application of topical fibrin-thrombin sealant spray. The patient survived and was discharged home.\n\nConclusions\nIntrapleural enzyme therapy can be effective in loculated parapneumonic effusion and empyema, but massive pleural hemorrhage can complicate its use. Pleural hemorrhage appears to be associated with anticoagulation or coagulopathy, and can be difficult to manage. This case adds to the body of data on bleeding complications following intrapleural enzyme therapy, and to the best of our knowledge is the first report of fibrin-thrombin sealant use in this setting.\n\nissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nPleural infection is common and is increasing globally. Unfortunately, patients experience high morbidity and mortality nearing 20 % [1]. Conventional treatment strategies consist of appropriate antibiotics and drainage of the pleural space with tube thoracostomy. However, pleural collections are often viscous and loculated by fibrinous septations, resulting in inadequate drainage and necessitating surgery [2].\n\nThe intrapleural administration of agents to improve drainage was first described using streptokinase and streptococcal deoxyribonuclease (DNase) nearly 65 years ago [3]. Since then, there have been studies showing varied results, and a number of randomized controlled trials (RCTs) have attempted to address this. The first Multicenter Intrapleural Sepsis Trial (MIST1), that randomized patients with parapneumonic effusions to intrapleural streptokinase or placebo, surprisingly failed to show any benefit in clinical outcomes such as length of stay, need for surgery or mortality [4]. The subsequent MIST2 trial attempted to assess the efficacy of alteplase alone or in combination with DNase, since DNase is thought to decrease effusion viscosity [5]. Combination treatment significantly improved radiological resolution, reduced frequency of surgical referral, and hospital length of stay compared to placebo. Overall serious adverse effects did not differ statistically significantly between treatment groups, however two patients who experienced intrapleural hemorrhage were both in the combination group.\n\nWhether or not anticoagulation constitutes an absolute contraindication is not widely agreed upon. And although bleeding complications seem to be perceived as rare [6], there are a number of reports of severe pleural bleeding requiring transfusion or emergency surgery [7–9]. In those requiring surgery, an active focal bleeding site is infrequently found and thoracotomy and decortication is often described [7–9].\n\nWe present a case of a patient with life-threatening refractory pleural hemorrhage following the intrapleural administration of alteplase and DNase that was managed successfully by thoracotomy and adjunctive topical fibrin-thrombin sealant.\n\nCase presentation\nAn 82-year-old Caucasian man was admitted to a local private hospital with a 6-day history of cough, malaise and left-sided pleuritic chest pain. A chest radiograph demonstrated left basal consolidation consistent with community-acquired pneumonia (Fig. 1a). Blood tests on admission are shown in Table 1. A computed tomography (CT) pulmonary angiogram demonstrated a right-sided pulmonary embolism, left lower lobe consolidation and moderate left-sided pleural effusion. (Fig. 1d-e). Intravenous piperacillin/tazobactam, subcutaneous enoxaparin (65 mg twice daily) was commenced, and a 6 French pigtail tube thoracostomy was performed under ultrasound guidance (Fig. 1b). Turbid yellow fluid was drained and results of the analysis are shown in Table 2. After 3 days, suboptimal clinical and radiologic resolution resulted in transfer to our institution under the respiratory physicians where intrapleural enzyme therapy was commenced with alteplase (10 mg in 50 mL of saline, 12-hourly) and dornase alfa (Roche AG, Basel, Switzerland)) (5 mg in 50 mL of saline 12-hourly).Fig. 1 \na Chest radiograph on presentation at hospital. b Chest radiograph after initial pigtail drain insertion. c Portable chest radiograph during medical emergency call. d Transverse contrast-enhanced computed tomography image on presentation to hospital – lung window. e Pulmonary embolus in division of right pulmonary artery. f Computed tomography angiogram following medical emergency team call\n\nTable 1 Admission blood tests\n\nHemoglobin\t135 g/L\t\nWhite cell count\t10.3 × 10^12/L\t\nNeutrophils\t8.2 × 10^9/L\t\nPlatelets\t318 × 10^9/L\t\nC-reactive protein\t132.9 mg/L\t\nSodium\t130 mmol/L\t\nPotassium\t4.2 mmol/L\t\nUrea\t10.6 mmol/L\t\nCreatinine\t91 umol/L\t\nAlbumin\t25 g/L\t\nTotal protein\t68 g/L\t\nLactate dehydrogenase\t258 U/L\t\nD-dimer\t2310 ng/mL\t\nAPTT\t52 seconds\t\nINR\t1.2\t\n\nAPTT activated partial thromboplastin time, INR international normalized ratio\n\nTable 2 Pleural fluid analysis\n\npH\t7.8\t\nAlbumin\t14 g/L\t\nTotal protein\t42 g/L\t\nLactate dehydrogenase\t3570 U/L\t\nGlucose\t<1.0 mmol/L\t\nCytology\tMesothelial cells, macrophages and mixed inflammatory cells. No atypical or malignant cells. No micro-organisms seen\t\n\tAcid-fast bacilli not detected\t\nCulture\tLight growth of Staphylococcus aureus\n\t\n\n\nOn the second day (after the third dose) of enzyme therapy, a medical emergency call was activated for sudden hypotension (blood pressure 70 mmHg systolic) and respiratory distress. Drainage had become sanguineous and then ceased, presumably due to obstruction of the small-bore drainage tube. An examination revealed hypovolemic shock and a chest X-ray demonstrated complete opacification of the left hemithorax with mediastinal deviation toward the right (Fig. 1c). His hemoglobin level dropped to 91 g/L, and our patient was transferred to the intensive care unit (ICU) and was transiently responsive to fluid boluses. An urgent CT angiogram demonstrated collapse of the left upper and lower lobes due to a massive pleural effusion, but no contrast extravasation to indicate active bleeding (Fig. 1f). A 32 French tube thoracostomy was performed in intensive care, resulting in the immediate drainage of over 3000 mL of sanguineous fluid. Our patient remained unstable and was transferred to the operating theater for left thoracotomy and exploration for bleeding.\n\nA posterolateral thoracotomy was performed through the fifth intercostal space. On entering the pleural cavity, a further 3600 mL of blood was immediately evacuated with cell salvage. The pleural cavity was then explored systematically. Anteriorly, a small adhesion from the superior segment of the lower lobe appeared to have torn and was bleeding and was controlled with point diathermy. The lung appeared inflamed, hyperemic and a small abscess cavity was noted in the lower lobe, which was evacuated. The entirety of the pleural cavity was then examined directly and with the assistance of vidoeoscope. This revealed widespread hyperemic pleural surfaces, which bled on contact. No focal cause for massive hemorrhage could be found. Pleural biopsy would later show fibrous and fibrinous pleuritis thickened with abundant inflammatory granulation tissue. Following copious washout the incision was closed with two drains and our patient was returned to the ICU. A total of 2500 mL of cell-salvaged blood was returned to the patient.\n\nDespite aggressive correction of coagulopathy, the drains accumulated over 1800 mL of blood over 3 hours, and our patient was returned to theater for repeat exploration and hemostasis. Again, only diffuse pleural hemorrhage was encountered and no discrete bleeding point was seen. The pleural cavity was packed extensively with gauze packs for 20 minutes in an attempt to gain control, but was not successful. The pleural cavity was then sprayed with fibrin-thrombin sealant (Tisseel, Baxter AG, Vienna, Austria), the lungs re-inflated, and the chest closed in an attempt to control bleeding via pleurodesis.\n\nOur patient was returned to the ICU and required vasopressor support and ongoing transfusions despite minimal drain output. A moderate apical effusion developed on chest X-ray, but this was managed expectantly. Hepatic and renal dysfunction ensued requiring hemofiltration. Extubation was achieved on the fifth postoperative day and drains removed on the ninth after draining a total of 2760 mL. A further 14 days in the ICU were required for weaning of renal support and subsequently our patient was transferred to the ward. After a brief period of rehabilitation, our patient was discharged home. Table 3 shows total blood products administered.Table 3 Blood products administered from date of surgery (units)\n\nDay 0\tPacked red blood cells\t21\t\n\tFresh frozen plasma\t17\t\n\tPlatelets\t5\t\n\tCryoprecipitate\t15\t\n\tRecombinant factor VII\t6.0 mg\t\n\tAlbumin 4 %\t1\t\nDay 1\tPacked red blood cells\t3\t\n\tFresh frozen plasma\t4\t\n\tPlatelets\t1\t\nDay 2\tPacked red blood cells\t2\t\n\tFresh frozen plasma\t4\t\n\tPlatelets\t2\t\nDay 3\tPacked red cells\t1\t\nDay 4\tPacked red cells\t2\t\nTable 4 Summary of results of literature review\n\nStudy\tStudy type\tSample\tIntrapleural therapy used\tAnticoagulation or antiplatelet use\tHemorrhagic complications\t\nThommi et al. 2012 [11]\tSingle centre placebo controlled randomized controlled trial\t68 adults\tPlacebo or alteplase\tUnspecified\tHemorrhage requiring transfusion in two patients\t\nRahman et al. 2011 [5]\tMulticentre placebo controlled randomized trial\t210 adults\tPlacebo or alteplase or DNase or alteplase + DNase\tUnspecified\tTwo intrapleural hemorrhages and one hemoptysis in alteplase + DNase group. Two episodes of gastrointestinal bleeding in the DNase group.\t\nMaskell et al. 2005 [4]\tMulti-centre placebo controlled randomized trial\t427 adults\tPlacebo or streptokinase\tUnspecified\tSeven hemorrhages (local or systemic) in streptokinase group, six in placebo group\t\nNie et al. 2014 [10]\tMeta-analysis of randomized trials\t879 adults, 98 children\tPlacebo, streptokinase, urokinase, tPA\tUnspecified\tNonsignificant increase in severe side effects\t\nPiccolo et al. 2014 [13]\tRetrospective observational study\t107 adults\ttPA and DNase\tUnfractionated heparin × 1, chronic liver disease and ↑prothrombin time × 1\tHemorrhage requiring transfusion in two patients\t\nAnevlavis et al. 2011 [7]\tCase series\tTwo adults\tAlteplase\tTherapeutic dose tinzaparin (14,000 IU), Prophylactic tinzaparin (3500 IU)\tTwo massive pleural hemorrhages\t\nChai and Kuan, 2011 [17]\tCase report\tOne adult\tStreptokinase\tNil\tMassive pleural hemorrhage\t\nGoralski et al. 2009 [9]\tCase report and literature review\tOne adult\tAlteplase\tNil\tSevere pleural hemorrhage\t\nGervais et al. 2008 [12]\tRetrospective observational study\t66 adults\tAlteplase\tWarfarin × 1, low-molecular-weight heparin (dalteparin 5000U TDS) × 2, unfractionated heparin × 1\tFive major pleural hemorrhages in four patients who were anticoagulated. No hemorrhage in those receiving prophylactic anticoagulation or clopidogrel\t\nRuiz et al. 2006 [8]\tCase report\tOne adult\tAlteplase\tNil\tMassive pleural hemorrhage\t\n\nDNase deoxyribonuclease, tPA tissue plasminogen activator\n\n\n\nDiscussion\nDespite first being performed over 65 years ago, understanding of the use of intrapleural therapy continues to evolve. A recent meta-analysis of ten randomized controlled trials concluded that compared to placebo, intrapleural fibrinolytic therapy decreased the chance of needing surgical intervention and length of hospital stay, but lead to a nonsignificant increase in severe side effects [10]. In severely ill patients who pose high surgical risk, intrapleural therapy may mitigate the need for thoracic surgery. A particularly high-risk situation exists where one-lung ventilation is complicated by ipsilateral pulmonary emboli, as was present in this case. However, contraindications to intrapleural enzyme therapy, in particular regard to therapeutic anticoagulation, are not widely agreed upon. In MIST 1 and 2, anticoagulation did not constitute exclusion criteria [4, 5], and in the recent RCT by Thommi et al. patients were still eligible too as long as international normalized ratio (INR) was <4, partial thromboplastin time <100 s, platelets >60,000 [11]. Their most recent recommendation is that the INR and partial thromboplastin time be <4 and <50 s, respectively [6]. However, there have been a number of cases reporting major hemorrhage in patients who are coagulopathic or anticoagulated. Gervais et al. reported a series of 66 patients who received intrapleural tissue plasminogen activator (tPA), of which there were five major pleural hemorrhages in four patients, all of whom were therapeutically anticoagulated at the time [12]. Notably, of those who did not bleed, 38 were receiving prophylactic subcutaneous heparin or dalteparin, 12 were receiving aspirin, and two were receiving clopidogrel. Piccolo et al. described a series of 107 patients treated with intrapleural tPA/DNase in which two patients experienced nonfatal hemorrhage requiring blood transfusion [13]. One was coagulopathic from chronic liver disease, the other dialysis dependent and anticoagulated for concurrent pulmonary embolism. The latter patient died 19 days later due to sepsis. In addition, there have been a number of individual case reports of pleural hemorrhage, causing hemorrhagic shock, following intrapleural enzyme therapy. Ruiz et al. reported massive hemothorax, following intrapleural alteplase for complicated parapneumonic effusion in a 31-year-old woman [8]. The patient was not reported as being coagulopathic or anticoagulated at the time, was resuscitated, and underwent thoracotomy. No source of bleeding was seen and it could not be attributed to traumatic drain insertion. A further two case reports of massive hemothorax, resulting in hypovolemic shock, were reported by Anevlavis et al. [7] in adults who received intrapleural alteplase while receiving low-molecular-weight heparin (tinzaparin). Additionally, Goralski et al. report a 40-year-old man with human immunodeficiency virus (HIV) on antiretrovirals and end-stage renal failure who received intrapleural alteplase for a parapneumonic effusion, suffered a cardiac arrest due to hemorrhagic shock [9]. He was resuscitated, underwent an emergency thoracotomy for evacuation of hemothorax. No bleeding source was identified and bleeding continued until administration of platelets, fresh frozen plasma, cryoprecipitate, and activated factor VII, returned his coagulation profile to baseline. Table 4 summarizes the findings of the literature review. The above cases indicate that serious bleeding complications may be more common than they are perceived, and a recent review of intrapleural enzyme therapy called for further documentation of complications and their management [14].\n\nOur case is similar to those discussed above, in that the patient developed massive hemothorax in the setting of therapeutic anticoagulation, however different in that he received combination alteplase with DNase intrapleurally. The contribution of DNase to bleeding is uncertain. This case report adds to the body of data on severe pleural hemorrhage following intrapleural enzyme therapy in patients who are anticoagulated, raising the awareness of this complication among clinicians. In such patients, it is recommended that the risks and benefits of intrapleural therapy versus surgery should be carefully evaluated in a multidisciplinary team environment. Moreover, those who receive intrapleural enzymes in the setting of bleeding risk factors should be closely monitored. This report is also unique given that hemorrhage continued despite thoracotomy, aggressive correction of coagulopathy, and hemostasis was achieved only after the application of topical fibrin-thrombin sealant, Tisseel. Fibrin-thrombin sealants were first used during hemostasis by Bergal in 1909 [15]. Modern fibrin-thrombin sealants, which consist of human origin fibrinogen and thrombin, and antifibrinolytic, aprotinin, have been approved by the FDA for hemostasis, adhesion and sealing. In thoracic surgery, they have been successfully employed to treat persistent bronchopleural fistulas following lung resection or recurrent pneumothorax [16]. Although not a new method of hemostasis per se, this is the first case report to describe the use of fibrin-thrombin sealant to successfully treat refractory pleural hemorrhage following intrapleural fibrinolytic enzyme therapy and anticoagulation. For junior surgeons, including trainees, who have not yet come across severe refractory pleural hemorrhage in practice, we believe this case report to offer valuable reference of the successful use of topical fibrin-sealant in this context.\n\nConclusions\nSevere pleural bleeding may complicate the use of intrapleural enzyme therapy for complicated parapneumonic effusion or empyema, particularly in anticoagulated or coagulopathic patients. In severe refractory pleural hemorrhage, the use of topical fibrin-thrombin sealant can be an effective life-saving adjunct to surgery.\n\nConsent\nWritten informed consent was obtained from the patient for the 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\nAPTTActivated partial thromboplastin time\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nDNaseDeoxyribonuclease\n\nHIVhuman immunodeficiency virus\n\nICUIntensive care unit\n\nINRInternational normalized ratio\n\nRCTRandomized controlled trial\n\ntPATissue plasminogen activator\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nSV initiated the case report, drafted and prepared the manuscript. DL critically reviewed the manuscript. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Lisboa T Waterer GW Lee YCG Pleural infection: changing bacteriology and its implications Respirology. 2011 16 598 603 10.1111/j.1440-1843.2011.01964.x 21382129 \n2. Brims FJH Lansley SM Waterer GW Lee YCG Empyema thoracis: new insights into an old disease Eur Respir Rev. 2010 19 220 8 10.1183/09059180.00005610 20956197 \n3. Tillett WS Sherry S The effect in patients of streptococcal fibrinolysin and streptococcal desoxyribonuclease on fibrinous, purulent, and sanguinous pleural exudations J Clin Invest. 1949 28 173 90 10.1172/JCI102046 \n4. Maskell NA Davies CWH Nunn AJ Hedley EL Gleeson FV Miller R U.K. Controlled trial of intrapleural streptokinase for pleural infection N Engl J Med 2005 352 865 74 10.1056/NEJMoa042473 15745977 \n5. Rahman NM Maskell NA West A Teoh R Arnold A Mackinlay C Intrapleural use of tissue plasminogen activator and DNase in pleural infection N Engl J Med. 2011 365 518 26 10.1056/NEJMoa1012740 21830966 \n6. Thommi G Shehan CJ Mcleay MT Fibrinolytics in parapneumonic effusions/empyemas Chest. 2014 146 e103 4 10.1378/chest.14-0706 25180732 \n7. Anevlavis S Archontogeorgis K Tzouvelekis A Kouliatsis G Pozova S Bougioukas I Intrapleural r-tPA in association with low-molecular heparin may cause massive hemothorax resulting in hypovolemia Respiration. 2011 81 513 6 10.1159/000321249 21063075 \n8. Ruiz A Porcel JM Madroñero AB Galindo C Hemothorax following administration of intrapleural alteplase Respiration. 2006 73 715 17008788 \n9. Goralski JL Bromberg PA Haithcock B Intrapleural hemorrhage after administration of tPA: a case report and review of the literature Ther Adv Respir Dis. 2009 3 295 300 10.1177/1753465809350748 19934281 \n10. Nie W Liu Y Ye J Shi L Shao F Ying K Efficacy of intrapleural instillation of fibrinolytics for treating pleural empyema and parapneumonic effusion: a meta-analysis of randomized control trials Clin Respir J. 2014 8 281 91 10.1111/crj.12068 24428897 \n11. Thommi G Shehan JC Robison KL Christensen M Backemeyer LA McLeay MT A double blind randomized cross over trial comparing rate of decortication and efficacy of intrapleural instillation of alteplase vs placebo in patients with empyemas and complicated parapneumonic effusions Respir Med. 2012 106 716 23 10.1016/j.rmed.2012.02.005 22398159 \n12. Gervais DA Levis DA Hahn PF Uppot RN Arellano RS Mueller PR Adjunctive intrapleural tissue plasminogen activator administered via chest tubes placed with imaging guidance: effectiveness and risk for hemorrhage Radiology. 2008 246 956 63 10.1148/radiol.2463070235 18309017 \n13. Piccolo F Pitman N Bhatnagar R Popowicz N Smith NA Brockway B Intrapleural tissue plasminogen activator and deoxyribonuclease for pleural infection. An effective and safe alternative to surgery Ann Am Thorac Soc 2014 11 1419 25 10.1513/AnnalsATS.201407-329OC 25296241 \n14. Piccolo F Popowicz N Wong D Lee YCG Intrapleural tissue plasminogen activator and deoxyribonuclease therapy for pleural infection J Thorac Dis. 2015 7 999 1008 26150913 \n15. Bergel S Uber Wirkungen des Fibrins Deutsch Wochenschr. 2009 35 663 5 10.1055/s-0029-1201395 \n16. Matthew TL Spotnitz WD Kron IL Daniel TM Tribble CG Nolan SP Four years’ experience with fibrin sealant in thoracic and cardiovascular surgery Ann Thorac Surg. 1990 50 40 4 10.1016/0003-4975(90)90080-P 2369228 \n17. Chai FY Kuan YC Massive hemothorax following administration of intrapleural streptokinase Ann Thorac Med. 2011 6 149 51 10.4103/1817-1737.82451 21760848\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000369:Aged, 80 and over; D016724:Empyema, Pleural; D057487:Enzyme Therapy; D015718:Fibrin Tissue Adhesive; D006801:Humans; D008297:Male; D010996:Pleural Effusion; D018700:Pleurodesis; D011014:Pneumonia; D015912:Thrombolytic Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101293382",
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"pmid": "26683839",
"pubdate": "2015-12-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22398159;24428897;21830966;2369228;26150913;25180732;21382129;19934281;21760848;15745977;16695653;18309017;21063075;17008788;25296241;20956197",
"title": "Life-threatening pleural hemorrhage following intrapleural enzyme therapy and successful treatment with fibrin-thrombin sealant pleurodesis: a case report.",
"title_normalized": "life threatening pleural hemorrhage following intrapleural enzyme therapy and successful treatment with fibrin thrombin sealant pleurodesis a case report"
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"abstract": "We report here a case of intestinal obstruction occurring during anti-tuberculous therapy for tuberculous peritonitis. An 89-year-old woman, who had been treated for tuberculous spondylitis and operated for tuberculous mastitis and peritonitis, was transferred to our hospital with high grade fever, lower abdominal pain and vomiting. An enhanced abdominal computed tomography (CT) revealed ascites and hypertrophy of the parietal peritoneum. Puncture and drainage of ascites were performed and revealed that a smear examination of the specimen was positive for acid-fast bacilli (Gaffky 1). Treatment by rifampicin, isoniazid and ethambutol for tuberculous peritonitis was started then halted because of drug-induced liver injury. After recovery of the liver damage improved, anti-tuberculosis drugs (rifampicin and streptomycin) were restarted. However two days after recommencing administration, repeated vomiting occurred. An abdominal X-ray showed intestinal obstruction. An ileus tube was inserted and she was treated conservatively, but her symptoms did not improve. Injection of contrast medium through the ileus tube showed obstruction of the upper jejunum, so open surgery was performed. Disseminated yellowish miliary tubercles were seen on the peritoneum and severe inflammatory adhesions were found between the jejunum and the ileum. After ablation of the adhesions, partial resections of jejunum and ileum were performed. Histological examination confirmed the diagnosis of tuberculous peritonitis.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Kawasaki Hospital, Japan. takeuchi_nobuhiro@kawasaki-hospital-kobe.or.jp",
"authors": "Takeuchi|Nobuhiro|N|;Maeda|Tetsuo|T|;Tada|Hidetoshi|H|;Nishida|Yu|Y|;Nomura|Yusuke|Y|;Inoue|Yoshifumi|Y|;Makino|Tetsuya|T|;Semba|Shuho|S|",
"chemical_list": "D000995:Antitubercular Agents",
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"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000369:Aged, 80 and over; D000995:Antitubercular Agents; D005260:Female; D006801:Humans; D045823:Ileus; D007579:Jejunal Diseases; D014395:Peritonitis, Tuberculous",
"nlm_unique_id": "2984683R",
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"references": null,
"title": "A case of intestinal obstruction occurring during anti-tuberculous therapy for tuberculous peritonitis.",
"title_normalized": "a case of intestinal obstruction occurring during anti tuberculous therapy for tuberculous peritonitis"
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"abstract": "Liver transplantation (LT) is a widely-accepted, definitive therapy of irreversible liver diseases including hepatitis C, alcoholic liver disease and metabolic liver disease. After transplantation, patients generally use a variety of immunosuppressive medications for the rest of their lives to prevent rejection of transplanted liver. Mortality after LT is mainly caused by recurrence of alcoholic hepatitis which is mostly seen in the patients who resume heavy drinking. On the other hand, de-novo malignancies after LT are not seldom. Skin cancers make up 13.5% of the de-novo malignancies seen in these patients. Malignancies tend to affect survival earlier in the course with a 53% risk of death at 5 years after diagnosis. We aimed to report a case who underwent LT secondary to alcoholic liver disease and developed squamous cell carcinoma of the skin eighteen years after transplantation. In summary, transplant recipients are recommended to be educated on self examination for skin cancer; health care providers should be further suspicious during routine dermatological examinations of the transplant patients and biopsies of possible lesions for skin cancer is warranted even many years after transplantation.",
"affiliations": "Ozan Unlu, Didem Uzunaslan, Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44106, United States.;Ozan Unlu, Didem Uzunaslan, Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44106, United States.;Ozan Unlu, Didem Uzunaslan, Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44106, United States.;Ozan Unlu, Didem Uzunaslan, Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44106, United States.;Ozan Unlu, Didem Uzunaslan, Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44106, United States.;Ozan Unlu, Didem Uzunaslan, Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44106, United States.;Ozan Unlu, Didem Uzunaslan, Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44106, United States.",
"authors": "Unlu|Ozan|O|;Roach|Emir Charles|EC|;Okoh|Alexis|A|;Olayan|May|M|;Yilmaz|Bulent|B|;Uzunaslan|Didem|D|;Shatnawei|Abdullah|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4254/wjh.v7.i4.717",
"fulltext": null,
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"issue": "7(4)",
"journal": "World journal of hepatology",
"keywords": "Alcoholic liver disease; Liver transplantation; Non-squamous; Sirolimus; Skin cancer",
"medline_ta": "World J Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101532469",
"other_id": null,
"pages": "717-20",
"pmc": null,
"pmid": "25866609",
"pubdate": "2015-04-08",
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"references": "11267383;23370710;22609307;24621534;24409048;15233824;19951276;24106395;11087149;21792049;12360438;18825704;19341415;16123952;20845504;22887956",
"title": "Skin cancer in immunosuppressed transplant patients: Vigilance matters.",
"title_normalized": "skin cancer in immunosuppressed transplant patients vigilance matters"
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"abstract": "We report a case of metastatic pancreatic-head mucinous carcinoma (with multiple lymph node and bone metastases) and review the relevant literature. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was useful for diagnosis, and a satisfactory outcome was achieved after systemic chemotherapy with FOLFIRINOX followed by resection of the primary lesion as conversion surgery. The patient was a 55-year-old man. Hematological findings included elevated serum tumor marker levels: CEA 12.7 ng/mL, DUPAN-2 400 U/mL. Findings from several imaging modalities and EUS-FNA confirmed a clinicopathological diagnosis of metastatic pancreatic mucinous carcinoma with multiple bone and lymph node metastases. Five courses of modified FOIFIRINOX (m-FFX) were given as systemic chemotherapy, which had an antitumor effect. Subtotal stomach-preserving pancreaticoduodenectomy and extensive lymph-node dissection were thus performed. Histopathological analysis showed invasive ductal carcinoma, muc (pT3, pN1b, cM1). After surgery, the clinical course was notable for the absence of complications. Tegafur/gimeracil/oteracil (S-1) was started as maintenance adjuvant chemotherapy postoperatively, and no disease progression has been observed at 10 months after surgery.",
"affiliations": "Department of Surgery, Tama Nagayama Hospital, Nippon Medical School.;Department of Surgery, Tama Nagayama Hospital, Nippon Medical School.;Department of Surgery, Tama Nagayama Hospital, Nippon Medical School.;Department of Surgery, Tama Nagayama Hospital, Nippon Medical School.;Department of Surgery, Tama Nagayama Hospital, Nippon Medical School.;Department of Surgery, Tama Nagayama Hospital, Nippon Medical School.;Department of Surgery, Tama Nagayama Hospital, Nippon Medical School.;Department of Gastroenterology, Tama Nagayama Hospital, Nippon Medical School.;Department of Pathology, Tama Nagayama Hospital, Nippon Medical School.;Department of Gastroenterological Surgery, Nippon Medical School.;Department of Gastroenterological Surgery, Nippon Medical School.;Department of Gastroenterological Surgery, Nippon Medical School.",
"authors": "Yokoyama|Tadashi|T|;Makino|Hiroshi|H|;Hirakata|Atsushi|A|;Ueda|Junji|J|;Takata|Hideyuki|H|;Okusa|Mikihiro|M|;Kawashima|Manpei|M|;Tsujino|Takeshi|T|;Hosone|Masaru|M|;Matsushita|Akira|A|;Nakamura|Yoshiharu|Y|;Yoshida|Hiroshi|H|",
"chemical_list": "C000627770:folfirinox; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.1272/jnms.JNMS.2019_86-502",
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"issue": "86(5)",
"journal": "Journal of Nippon Medical School = Nippon Ika Daigaku zasshi",
"keywords": "conversion surgery; modified FOLFIRINOX; pancreatic mucinous carcinoma",
"medline_ta": "J Nippon Med Sch",
"mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000971:Antineoplastic Combined Chemotherapy Protocols; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008198:Lymph Nodes; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077150:Oxaliplatin; D010179:Pancreas; D010190:Pancreatic Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100935589",
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"pages": "284-290",
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"pmid": "31105119",
"pubdate": "2019-12-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Conversion Surgery for Metastatic Pancreatic Mucinous Carcinoma Responsive to Systemic Chemotherapy with Modified FOLFIRINOX: A Case Report.",
"title_normalized": "conversion surgery for metastatic pancreatic mucinous carcinoma responsive to systemic chemotherapy with modified folfirinox a case report"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1827241",
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{
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"activesubstancename": "IRINOTECAN"
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{
"abstract": "To explore the decision-making process in women who do not pursue treatment with onabotulinumtoxinA, sacral neuromodulation, or percutaneous nerve stimulation in patients with overactive bladder (OAB).\n\n\n\nThis was a qualitative research study. Participants were females aged 18-80 years with a diagnosis of OAB and were evaluated by a urologic or urogynecologic physician between January 2017 and March 2018. Patients who were counseled for third-line therapy, refractory to two or more medications, or lost to follow-up after initiating a second medication were considered study candidates. Data were gathered using a semi-structured phone interview. Interview topics included medical knowledge and beliefs, quality of life, and treatment experience. The interviews were transcribed and coded thematically using grounded theory.\n\n\n\nOf a total of 381 women, 56 women qualified for our study. The average interview length was 30 minutes, and theoretical saturation occurred at 30 interviews. General themes included treatment delay, education, treatment attitudes, and office factors. The most common modifiable barrier to third-line therapy was insufficient in-office education. Participants expressed a poor understanding of the etiology, natural history, and treatment options for OAB. Participants were heavily influenced by outside factors including the opinions of friends and the media. Negative experiences with less-advanced options and treatment fatigue negatively affected participants' perceptions of third-line therapies. Office factors such as wait times and male physicians also negatively affected participants' ability to discuss their bladder symptoms.\n\n\n\nIn conclusion, office education is tremendously important to patients' understanding of OAB, expectations of therapy, and treatment compliance. Education about third-line therapy counseling should be incorporated into the initial office visit. This may mitigate expectations, improve patient compliance, and promote graduation to advanced therapy in women who later go on to develop refractory symptoms.",
"affiliations": "MetroHealth Medical Center and Case Western Reserve University, Cleveland, Ohio; Vanderbilt University School of Medicine, Nashville, Tennessee; and University Hospitals Cleveland Medical Center, Cleveland, Ohio.",
"authors": "Davenport|Abigail|A|;Stark|Sydney|S|;Quian|Anna|A|;Sheyn|David|D|;Mangel|Jeffrey|J|",
"chemical_list": "D019274:Botulinum Toxins, Type A",
"country": "United States",
"delete": false,
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"issue": "134(1)",
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"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019274:Botulinum Toxins, Type A; D003657:Decision Making; D005260:Female; D006297:Health Services Accessibility; D006801:Humans; D008875:Middle Aged; D009820:Ohio; D018802:Patient-Centered Care; D004561:Transcutaneous Electric Nerve Stimulation; D053201:Urinary Bladder, Overactive; D016387:Women's Health; D055815:Young Adult",
"nlm_unique_id": "0401101",
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"pages": "141-148",
"pmc": null,
"pmid": "31188332",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Patient-Centered Approach to Refractory Overactive Bladder and Barriers to Third-Line Therapy.",
"title_normalized": "a patient centered approach to refractory overactive bladder and barriers to third line therapy"
} | [
{
"companynumb": "US-ALLERGAN-1925773US",
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"activesubstancename": "BOTULINUM TOXIN TYPE A"
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"abstract": "A 47-year-old woman ingested 7.2 gm of sustained-release verapamil. She developed hypotension, idioventricular rhythm, mild acidosis, mild hyperglycemia, and aspiration pneumonia that required antibiotics and mechanical ventilatory support. In addition, she had a stroke, which resulted from left cerebral hemispheric damage, an unusual complication. Stroke is reported only once in the literature. Special problems related to slow release medication and the need to be aware of them are discussed.",
"affiliations": "Department of Cardiology, UNR Medical School, NV.",
"authors": "Shah|A R|AR|;Passalacqua|B R|BR|",
"chemical_list": "D003692:Delayed-Action Preparations; D014700:Verapamil",
"country": "United States",
"delete": false,
"doi": "10.1097/00000441-199212000-00005",
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"issue": "304(6)",
"journal": "The American journal of the medical sciences",
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"mesh_terms": "D002561:Cerebrovascular Disorders; D003692:Delayed-Action Preparations; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008875:Middle Aged; D014700:Verapamil",
"nlm_unique_id": "0370506",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report: sustained-release verapamil overdose causing stroke: an unusual complication.",
"title_normalized": "case report sustained release verapamil overdose causing stroke an unusual complication"
} | [
{
"companynumb": "US-RECRO GAINESVILLE LLC-REPH-2019-000156",
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"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
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{
"abstract": "Large cell neuroendocrine carcinoma (LCNC) of the ovary is a rare tumor in gynecologic oncologic field. An 18-year-old woman presented with abdominal distention and a pelvic mass measuring ten cm in diameter, who previously underwent laparoscopic ovarian cystectomy due to large borderline mucinous ovarian neoplasm 18 months prior. A debulking operation was optimally performed, which included total abdominal hysterectomy with bilateral salpingo-oophorectomy, bilateral pelvic lymph node dissection, bilateral paraaortic lymph node dissection, omentectomy, optimal debulking of gastrohepatic mass and subdiaphragmatic mass, and pelvic peritonectomy. Despite adjuvant chemotherapy with paclitaxel and carboplatin, the patient died of progressive disease seven months after surgery. The authors report the youngest case of LCNC of the ovary, that failed chemotherapy and had the previous history of the conservative surgical treatment due to mucinous borderline tumor.",
"affiliations": null,
"authors": "Kwon|Y S|YS|;Im|K S|KS|;Choi|D I|DI|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "China",
"delete": false,
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"issue": "37(2)",
"journal": "European journal of gynaecological oncology",
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"medline_ta": "Eur J Gynaecol Oncol",
"mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D018287:Carcinoma, Large Cell; D018278:Carcinoma, Neuroendocrine; D017024:Chemotherapy, Adjuvant; D065426:Cytoreduction Surgical Procedures; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007044:Hysterectomy; D064847:Multimodal Imaging; D010051:Ovarian Neoplasms; D010052:Ovariectomy; D017239:Paclitaxel; D049268:Positron-Emission Tomography; D058994:Salpingectomy; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure",
"nlm_unique_id": "8100357",
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"pages": "244-6",
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"pmid": "27172753",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ovarian large cell neuroendocrine carcinoma in the youngest woman.",
"title_normalized": "ovarian large cell neuroendocrine carcinoma in the youngest woman"
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"abstract": "In rare cases the implantation or use of a port-a-cath can be complicated by venous perforation or catheter-related infection. We describe a patient with these two complications resulting in Staphylococcus aureus mediastinitis. Removal of the device and prolonged antibiotic therapy cured the infection.",
"affiliations": "Intensive Care Unit, Boulogne-sur-mer Hospital, Boulogne-sur-mer, France.;Infectious Diseases Department, Lille University Hospital, Lille, France.;Centre Oscar-Lambret, Lille, France.;Radiology Department, Lille University Hospital, Lille, France.;Medical Oncology Department, Boulogne-sur-mer Hospital, Boulogne-sur-mer, France.;Centre Joliot-Curie, Saint-Martin Boulogne, France.;Centre Joliot-Curie, Saint-Martin Boulogne, France.;Medical Oncology Department, Boulogne-sur-mer Hospital, Boulogne-sur-mer, France.",
"authors": "Rivière|Pierre|P|;Bauer|Jules|J|;Hégo|Florent|F|;Raad|Naji|N|;Najem|Abeer|A|;Tomaszewski|Aurélie|A|;Dandoy|Simon|S|;Marie|Guillaume|G|",
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"doi": "10.1016/j.idcr.2020.e01044",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30352-8\n10.1016/j.idcr.2020.e01044\ne01044\nCase Report\nStaphylococcus aureus mediastinitis due to subclavian vein perforation and catheter-related-infection\nRivière Pierre pierre.rivierepr@gmail.coma⁎ Bauer Jules b Hégo Florent c Raad Naji d Najem Abeer e Tomaszewski Aurélie f Dandoy Simon f Marie Guillaume e a Intensive Care Unit, Boulogne-sur-mer Hospital, Boulogne-sur-mer, France\nb Infectious Diseases Department, Lille University Hospital, Lille, France\nc Centre Oscar-Lambret, Lille, France\nd Radiology Department, Lille University Hospital, Lille, France\ne Medical Oncology Department, Boulogne-sur-mer Hospital, Boulogne-sur-mer, France\nf Centre Joliot-Curie, Saint-Martin Boulogne, France\n⁎ Corresponding author at: Intensive Care Unit, Boulogne-sur-mer Hospital, 33 rue Jacques Monod, 62200, Boulogne-sur-mer, France. pierre.rivierepr@gmail.com\n02 1 2021 \n2021 \n02 1 2021 \n23 e010449 11 2020 30 12 2020 30 12 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Very rare cause of acute infectious mediastinitis.\n\n• Second description in the literature and the first in an oncologic patient.\n\n• Treatment via adapted and prolonged antibiotic therapy, without requiring surgery.\n\n• Radiation therapy may have favoured venous perforation and thrombosis.\n\n• Questions about the safety of the surgical version of the PAC.\n\n\n\nIn rare cases the implantation or use of a port-a-cath can be complicated by venous perforation or catheter-related infection. We describe a patient with these two complications resulting in Staphylococcus aureus mediastinitis. Removal of the device and prolonged antibiotic therapy cured the infection.\n\nKeywords\nMediastinitisVenous perforationPort-a-cathCatheter-related infectionPost-radiation\n==== Body\nIntroduction\nCentral venous catheters are widely used. To deliver chemotherapy, the use of a port-a-cath (PAC) is recommended. Complications such as venous perforation or catheter-related infection (CRI) may occur in this context; however, the combination of these two events is exceptional.\n\nWe describe a patient undergoing treatment for metastatic cancer of the left breast who presented with acute infectious mediastinitis secondary to left subclavian vein perforation and Staphylococcus aureus CRI.\n\nCase presentation\nA 58-year-old woman presented to the emergency department with a three-day history of fever and chills. She had a history of cancer of the left breast with metastatic recurrence. Three weeks prior, chemotherapy had been initiated with targeted therapy combining paclitaxel, pertuzumab and trastuzumab. A positron emission tomography (PET) was performed before initiation of treatment (Fig. 1A) as well as a contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2A). A PAC had been implanted at the left subclavian vein. Two weekly courses of chemotherapy had been administered with no significant adverse reactions. Due to PAC rotation and malposition, operative surgical revision had been performed one week prior and chemotherapy was held.Fig. 1 PET scan.\n\nA) Before the infectious episode.\n\nB) At the time of the infection, showing the anterior mediastinal uptake (red arrow).\n\nC) At the end of the antibiotic treatment.\n\nFig. 1Fig. 2 Contrast-enhanced chest scans.\n\nA: scan before the start of the oncology treatment.\n\nB: scan performed at the time of the infection, showing anterior mediastinal infiltration (red arrow).\n\nC: disappearance of anterior mediastinal uptake, persistence of adenopathies in the paratracheal area.\n\nFig. 2\n\nOn admission the patient complained of chest pain and dyspnea that had progressed over three days. Clinical examination revealed a temperature of 39 °C and tachycardia (110 beats). The skin at the port-a-cath chest wall site was erythematous and tender. Laboratory evaluation revealed a normal complete blood count and an elevated C-reactive protein (CRP) of 97.2 mg/L. Two blood cultures were collected from the PAC and two from a peripheral site. Empiric therapy with intravenous daptomycin 10 mg/kg daily was initiated.\n\nOn the second day of hospitalization, methicillin-susceptible S. aureus (MSSA) was recovered from all blood cultures. Blood cultures drawn from the peripheral site became positive two hours after those drawn from the PAC, indicating a CRI. The PAC was surgically removed and sent for culture, pus was noted in the area at the time of removal. Antibiotic therapy was changed to continuous infusion cloxacillin at a dose of 12 g every 24 h due to the possibility of infective endocarditis. However, no signs of endocarditis were observed on a transthoracic cardiac ultrasound. The culture of the PAC also grew MSSA, with the same antibiogram. A transoesophageal ultrasound performed one week after admission revealed no evidence of endocarditis. The patient's blood cultures were rapidly sterilized. However, despite ten days of antibiotic therapy, a persistent inflammatory syndrome was observed with fever and elevated CRP reaching a plateau of 50 mg/L. There were no focal findings on clinical examination to suggest uncontrolled infection. A contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2B) identified a thrombosis in the left subclavian vein associated with anterior mediastinal infiltration suggestive of mediastinitis. Myocardial PET scan (Fig. 1B) revealed thrombophlebitis. There was no evidence of endocarditis.\n\nGiven these findings, a second reading of radiographs following the surgical revision of the PAC, demonstrated that the tip of the catheter was located outside of the left subclavian vein in the mediastinum, a finding not noted on the prior reading (Fig. 3).Fig. 3 Frontal and profile chest x-rays showing the extremity of the intra-mediastinal and extra-vascular PAC (red arrows) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).\n\nFig. 3\n\nExpert opinion was sought from a regional referral center for infectious diseases. The case was reviewed by a multidisciplinary panel and the consensus was that the patient had acute S. aureus mediastinitis due to procedure-related venous perforation and CRI. A decision was taken to continue the high-dose intravenous cloxacillin for a total of six weeks in combination with oral levofloxacin (750 mg/24 h) for six weeks. Her inflammatory improved rapidly with this regimen. Six weeks after starting the treatment, the patient was changed to oral levofloxacin and clindamycin to provide coverage for possible mediastinal osteomyelitis.\n\nTargeted therapies were resumed after completion of intravenous cloxacillin therapy given peripherally. Follow-up PET CT showed absence of residual infectious focus (Fig. 1C). Regression of the mediastinitis was observed on follow-up chest CT (Fig. 2C). Paclitaxel therapy was resumed after placement of a right subclavian PAC and the completion of the oral clindamycin and levofloxacin.\n\nDiscussion\nAcute mediastinitis is a rare and fatal infection. The condition is frequently described following heart surgery where it can trigger anterior infections. It can also be caused directly by injury, sternal osteomyelitis, oesophageal wound, or indirectly but by propagation where it triggers posterior necrotising mediastinitis. Rarely, mediastinitis can be spontaneously spread by hematogenous dissemination. In the literature, one similar case of acute infectious mediastinitis secondary to the implantation of a central venous catheter, the perforation of the superior vena cava and a CRI has been described [1].\n\nOur patient was diagnosed with treatment-related acute infectious mediastinitis secondary to a CRI following traumatic perforation of the left subclavian vein. The combination of these two complications is very unusual. The frequency of jugular venous puncture as a complication of implanting a central venous catheter using ultrasound guidance is report at 1 % [2]. In a meta-analysis of more than 200 prospective studies, the risk of catheter-associated with bacteremia in patients with PACs is 0.1/1000 catheter days [3].\n\nOur patient had received adjuvant radiation therapy to the left breast and axilla, five years prior to metastatic recurrence. Although arterial complications secondary to radiation therapy are widely described in the literature [4], little is known of the impact of radiation on the venous system. However, venous thrombosis in the radiated area has been reported [5]. In addition, radiation-induced fibrosis of healthy tissues is one of the potential late-onset complications of radiation therapy [6]. Despite involving a large vessel and the administration of very low doses, the left brachiocephalic venous trunk was located in the area of radiation. It is thus hypothesised that this adjuvant radiotherapy may have triggered changes to the vessel enhancing the likelihood of venous perforation and thrombosis.\n\nRare cases of mediastinitis caused by chemotherapy extravasation have been reported in the literature [7]. In these cases, the origin of the mediastinitis was chemical, irritative and non-infectious. Blood cultures from periphery and PAC were sterile.\n\nWhen infectious acute mediastinitis is diagnosed based on the criteria of the Centers for Disease Control and Prevention [8], the collection of a mediastinal sample for culture is not necessary for diagnosis. In our patient, her mediastinal infection was almost certainly due to MSSA in view of the clinical and microbiological findings.\n\nThe role and utility of PET scans in the diagnosis of mediastinitis is unknown. In one case of descending necrotising mediastinitis [9] the uptake of the mediastinal infiltrate on the PET scan was intense. However, in our patient, the mediastinal infiltration was absent. We can hypothesize that the lack of uptake was related to ten days of effective antibiotic therapy in our patient.\n\nEmpiric broad-spectrum antibiotic therapy of mediastinitis should be initiated as soon as possible while awaiting blood or mediastinal culture results. Therapy is prolonged initially at least three weeks of intravenous therapy followed by oral therapy for three weeks [10].\n\nThese recommendations also apply to mediastinitis following heart surgery. In our patient, empiric daptomycin that provided coverage for S. aureus (the most likely pathogen) was initiated in the setting of CRI, followed by a change to cloxacillin when susceptibility results were available. High dose cloxacillin was used due to the concern for endocarditis. There is no consensus on the length of antibiotic therapy. It is possible that a shorter course of therapy would have been equally effective in our patient.\n\nWhile infectious mediastinitis was the reason for suspending targeted cancer therapy for six weeks and chemotherapy for 12 weeks, it did not appear to have any clinical consequences. Six months after this complication, our patient continues to receive targeted maintenance therapies and her response is still complete.\n\nConclusion\nWe describe the second case of infectious mediastinitis secondary to venous perforation and CRI. The combined complications of venous perforation and CRI leading to mediastinitis are extremely rare but should be given consideration and investigated based on clinical presentation.\n\nFunding\nAuthors did not have any funding source.\n\nThese informations have not been presented in a meeting.\n\nAuthor agreement statement\nAll authors declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.\n\nWe confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed.\n\nWe further confirm that the order of authors listed in the manuscript has been approved by all of us.\n\nWe understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.\n\nDeclaration of Competing Interest\nThe authors declare that they have no conflict of interest.\n\nAcknowledgements\nPR suggested this clinical case. He was involved in the bibliographic research, the drafting, proofreading and submission of the article.\n\nJB was involved in the bibliographic research and proofreading of the article.\n\nFH was involved in the bibliographic research and proofreading of the article.\n\nNR provided a radiological opinion and reviewed the various images.\n\nAN was involved in the proofreading of this article.\n\nAT was involved in the proofreading of this article and provided a radiotherapist opinion.\n\nSD was involved in the proofreading of this article and provided a radiotherapist opinion.\n\nGM was involved in the bibliographic research, the drafting, proofreading and correction of the article.\n==== Refs\nReferences\n1 Valat P. Pellerin C. Cantini O. Jougon J. Delcambre F. Morales P. Infected mediastinitis secondary to perforation of superior vena cava by a central venous catheter Br J Anaesth 88 February (2) 2002 298 300 11878666 \n2 Hayashi H. Amano M. Does ultrasound imaging before puncture facilitate internal jugular vein cannulation? Prospective randomized comparison with landmark-guided puncture in ventilated patients J Cardiothorac Vasc Anesth 16 October (5) 2002 572 575 12407608 \n3 Maki D.G. Kluger D.M. Crnich C.J. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies Mayo Clin Proc 81 September (9) 2006 1159 1171 16970212 \n4 Jurado J.A. Bashir R. Burket M.W. Radiation-induced peripheral artery disease Catheter Cardiovasc Interv Off J Soc Card Angiogr Interv 72 October (4) 2008 563 568 \n5 Wilson C.B. Lambert H.E. Scott R.D. Subclavian and axillary vein thrombosis following radiotherapy for carcinoma of the breast Clin Radiol 38 January (1) 1987 95 96 3816073 \n6 Delanian S. Lefaix J.-L. Current management for late normal tissue injury: radiation-induced fibrosis and necrosis Semin Radiat Oncol 17 April (2) 2007 99 107 17395040 \n7 Anderson C.M. Walters R.S. Hortobagyi G.N. Mediastinitis related to probable central vinblastine extravasation in a woman undergoing adjuvant chemotherapy for early breast cancer Am J Clin Oncol 19 December (6) 1996 566 568 8931672 \n8 NHSN patient safety component manual. 2020 2020 434 \n9 Carandini T. Longari V. Mendogni P. Gaffuri M. Ceriani E. Utility of PET scan in diagnosis and monitoring descending necrotizing mediastinitis complicating Lemierre’s syndrome Intern Emerg Med 13 1 2018 129 131 28776174 \n10 Ambrosch A. Rational antibiotic treatment of mediastinitis Chir Z Alle Geb Oper Medizen 87 June (6) 2016 497 503\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "23()",
"journal": "IDCases",
"keywords": "Catheter-related infection; Mediastinitis; Port-a-cath; Post-radiation; Venous perforation",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e01044",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Staphylococcus aureus mediastinitis due to subclavian vein perforation and catheter-related-infection.",
"title_normalized": "staphylococcus aureus mediastinitis due to subclavian vein perforation and catheter related infection"
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"abstract": "BACKGROUND\nCyclosporin A (CyA) can suppress relapses and reduce proteinuria in frequent-relapse nephrotic syndrome (FRNS) and steroid-resistant nephrotic syndrome (SRNS). However, some patients remain resistant to CyA therapy. The purpose of the present paper was to evaluate mycophenolate mofetil (MMF) treatment in pediatric patients with CyA-resistant intractable nephrotic syndrome.\n\n\nMETHODS\nMMF therapy was given to 11 patients with FRNS who had relapse despite CyA therapy, and one patient with SRNS who had been receiving combined therapy using steroid and CyA until immediately before the start of MMF. MMF was administered at a daily dose of 750-1000 mg/m(2) in two divided doses.\n\n\nRESULTS\nTen of the 11 patients with FRNS were able to maintain remission. Among them, seven patients remained relapse free for 1 year, and two patients had a decrease in the frequency of relapse after initiation of MMF therapy. One patient, however, had repeated cycles of remission and relapse, and was considered resistant to MMF therapy. The total prednisolone dose during the period from month 6 to month 12 after the start of MMF therapy was significantly lower than that during the 6 month period before the start of MMF therapy. The patient with SRNS, who had not achieved remission despite CyA administration, had complete remission on MMF. No serious adverse effects were seen in any of the present patients.\n\n\nCONCLUSIONS\nMMF could be useful in CyA-treatment-refractory FRNS and CyA-resistant SRNS.",
"affiliations": "Department of Pediatrics, Kinki University School of Medicine, Osaka-Sayama, Japan.",
"authors": "Okada|Mitsuru|M|;Sugimoto|Keisuke|K|;Yagi|Kazuro|K|;Yanagida|Hidehiko|H|;Tabata|Nobutada|N|;Takemura|Tsukasa|T|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; D009173:Mycophenolic Acid",
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"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
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"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D016572:Cyclosporine; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009173:Mycophenolic Acid; D009404:Nephrotic Syndrome; D011239:Prednisolone; D012074:Remission Induction; D016896:Treatment Outcome",
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"title": "Mycophenolate mofetil therapy for children with intractable nephrotic syndrome.",
"title_normalized": "mycophenolate mofetil therapy for children with intractable nephrotic syndrome"
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"abstract": "To describe the characteristics of infants evaluated for serious bacterial infection, focusing on empirical testing and treatment of herpes simplex virus (HSV) and describe the characteristics of HSV-positive patients.\n\n\n\nWe included infants aged 0 to 60 days undergoing evaluation for serious bacterial infection in the emergency department. This descriptive study was conducted between July 2010 and June 2014 at a tertiary-care children's hospital. Eligible patients were identified on the basis of age at presentation to the hospital and laboratory specimens. Infant characteristics, symptoms on presentation, and laboratory workup were compared between HSV-positive and HSV-negative patients by using the 2-sample t test or the Wilcoxon rank test.\n\n\n\nA total of 1633 infants were eligible for inclusion, and 934 (57.2%) were 0 to 28 days of age. HSV was diagnosed in 19 infants, 11 of whom had disseminated disease. Compared with those without HSV, HSV-positive infants were younger, less likely to be febrile and to present with nonspecific symptoms, and more likely to have a mother with HSV symptoms (P < .05). Testing from all recommended locations was only performed in 22% of infants. Infants tested or empirically treated with acyclovir had a longer median length of stay compared with children who were not tested or treated (P < .01).\n\n\n\nThe absence of fever should not preclude a workup for HSV in neonates, and when a workup is initiated, emphasis should be placed on obtaining samples from serum, cerebrospinal fluid, and surface specimens. Physicians may benefit from a guideline for evaluation of HSV with specific guidance on high-risk features of presentation and recommended testing.",
"affiliations": "Divisions of Hospital Medicine, laura.brower@cchmc.org.;Emergency Medicine, and.;Emergency Medicine, and.;Division of Pharmacy and.;Divisions of Hospital Medicine.;Divisions of Hospital Medicine.",
"authors": "Brower|Laura H|LH|;Wilson|Paria M|PM|;Murtagh-Kurowski|Eileen|E|;Courter|Joshua D|JD|;Shah|Samir S|SS|;Schondelmeyer|Amanda C|AC|",
"chemical_list": "D000212:Acyclovir",
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"doi": "10.1542/hpeds.2020-0033",
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"issue": "10(6)",
"journal": "Hospital pediatrics",
"keywords": null,
"medline_ta": "Hosp Pediatr",
"mesh_terms": "D000212:Acyclovir; D001424:Bacterial Infections; D002648:Child; D005260:Female; D006561:Herpes Simplex; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D012189:Retrospective Studies; D018139:Simplexvirus",
"nlm_unique_id": "101585349",
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"pages": "463-470",
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"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "26960921;25708691;18360301;21159118;31570510;23023459;30776077;18639724;1849612;22123868;27941084;29875197;18639725;25868428;24785561;18929686;23481105;25491092;18534225;24892851;24919712;25646205;15685144;18606938;19617865;29668856;31345997;22608699;14520181;24719742;12517231;16237221;25677996;29784511;15236921;21304419;11483782;21992471;11483781;31112493;30923058;23087395;26169430;29298827",
"title": "Evaluation for Neonatal HSV in Infants Undergoing Workup for Serious Bacterial Infection: A 5-Year Retrospective Review.",
"title_normalized": "evaluation for neonatal hsv in infants undergoing workup for serious bacterial infection a 5 year retrospective review"
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"abstract": "An 82-year-old white woman presented at our Internal Medicine ward with flaccid tetraparesis. Two months earlier, she had suffered a non-ST elevation myocardial infarction treated with percutaneous coronary intervention (PCI) and stenting, and she had been prescribed the classical post-PCI therapy (β-blockers, statins and antiplatelet agents). At admission, she was haemodynamically stable and the physical examination revealed reduced reflexes in the four limbs. Urgent laboratory findings revealed mild hypokalaemia. Considering the high statin doses she was taking, we also performed an urgent creatine phosphokinase test, which indicated rhabdomyolysis. Statin therapy was immediately stopped and aggressive fluid treatment begun, supplemented with potassium for increased urinary potassium losses. The patient progressively regained muscle strength.",
"affiliations": "Internal Medicine 2, Pisa's Hospital, Pisa, Tuscany, Italy.;Internal Medicine 2, Pisa's Hospital, Pisa, Tuscany, Italy.;Internal Medicine 2, Pisa's Hospital, Pisa, Tuscany, Italy.;Internal Medicine 2, Pisa's Hospital, Pisa, Tuscany, Italy.",
"authors": "Rosada|Javier|J|;Rebelos|Eleni|E|;Petruccelli|Stefania|S|;Taddei|Marco|M|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D000069059:Atorvastatin",
"country": "England",
"delete": false,
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"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000369:Aged, 80 and over; D000069059:Atorvastatin; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009203:Myocardial Infarction; D010291:Paresis; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D012206:Rhabdomyolysis; D015607:Stents",
"nlm_unique_id": "101526291",
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"pmid": "25903205",
"pubdate": "2015-04-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11573861;23355775;22922416;2716281;21961482;17466224;18988647;9824780",
"title": "Protocols cure diseases, not patients: flaccid paresis in post-NSTEMI statin treatment.",
"title_normalized": "protocols cure diseases not patients flaccid paresis in post nstemi statin treatment"
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... |
{
"abstract": "The objective was to describe the incidence, nature, and risk factors for adverse events (AEs) among patients who received parenteral sedation for acute agitation in an emergency department (ED) setting.\n\n\n\nWe undertook a prospective observational study and a clinical trial of parenteral sedation for the management of acute agitation. We included agitated adult patients who required parenteral sedation from 2014 to 2017 in 12 Australian EDs, excluding those with incomplete information or aged under 18 years. The primary outcome was the number of patients who experienced at least one AE. Multivariable logistic regression was used to determine factors associated with AEs.\n\n\n\nA total of 904 patients were included in the analyses (62.3% male; median age = 34 years, range = 18 to 95 years). Of these, 144 (15.9%) patients experienced at least one AE. The most common AEs were oxygen desaturation (7.4%), airway obstruction (3.6%), bradycardia (1.9%), hypotension (1.7%), and prolonged QTc interval (1.3%). No deaths or serious AEs were reported. The following factors had an increased adjusted odds ratio (OR) for experiencing an AE: age 65 years and older (OR = 2.8, 95% confidence interval [CI] = 1.2 to 7.2), more than one type of parenteral sedation administered within 60 minutes (OR = 2.1, 95% CI = 1.4 to 3.1), and alcohol intoxication (OR = 1.8, 95% CI = 1.2 to 2.6).\n\n\n\nSedation-related AEs are common, especially respiratory events. Elderly patients, sedation with multiple sedatives within 60 minutes, and alcohol intoxication increased the risk.",
"affiliations": "Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria.;Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria.;Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria.;Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria.;Pharmacy Department, Austin Health, Heidelberg, Victoria.",
"authors": "Yap|Celene Y L|CYL|0000-0001-8359-0605;Taylor|David McD|DM|0000-0002-8986-9997;Kong|David C M|DCM|;Knott|Jonathan C|JC|0000-0003-1503-0440;Taylor|Simone E|SE|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/acem.13826",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1069-6563",
"issue": "26(10)",
"journal": "Academic emergency medicine : official journal of the Society for Academic Emergency Medicine",
"keywords": null,
"medline_ta": "Acad Emerg Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000758:Anesthesia; D001315:Australia; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011446:Prospective Studies; D011595:Psychomotor Agitation; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "9418450",
"other_id": null,
"pages": "1135-1143",
"pmc": null,
"pmid": "31265756",
"pubdate": "2019-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk Factors for Sedation-related Events During Acute Agitation Management in the Emergency Department.",
"title_normalized": "risk factors for sedation related events during acute agitation management in the emergency department"
} | [
{
"companynumb": "AU-JNJFOC-20191125032",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"drugadditional": "3",
"d... |
{
"abstract": "While autonomic dysreflexia caused by severe spinal cord lesions can be life-threatening, relevant reports on non-traumatic spinal lesions are rare. Furthermore, modes of innervation of the supraspinal inhibitory pathways at each spinal sympathetic segment remain unknown. Herein, I report the case of a patient with autonomic dysreflexia and radiation myelopathy. The laterality of autonomic dysreflexia was investigated with special reference to the sudomotor function.\n\n\n\nA 51-year-old man with a history of epipharynx carcinoma, radiotherapy, and cisplatin chemotherapy was referred for the evaluation of autonomic function. He was ambulant but displayed spastic tetraparesis, areflexia of the extremities, sensory disturbance below C4 dermatome, dysuria, and impotence. Spinal magnetic resonance imaging demonstrated a cervical lesion involving the lateral portion of C2-C5, bilaterally. The thermal sweating test showed that sweating was lower on the left side of the face and neck, left shoulder, and arm than the corresponding parts on the right side. The rest of the body was anhidrotic. Sweating due to autonomic dysreflexia was symmetric, but more abundant on the left side of the face. Acetylcholine-induced sweating was markedly reduced on the left leg.\n\n\n\nThis might be the first documentation of autonomic dysreflexia observed in a patient with radiation myelopathy. The present observations suggested that the supraspinal inhibitory pathway to spinal preganglionic neurons may descend on the same side as thermal sudomotor facilitatory pathways at the cervical level. Furthermore, autonomic dysreflexia was more prominent in the standing position suggesting that the pressure stimulus might enhance autonomic dysreflexia.",
"affiliations": "Department of Neurology, Sendai Eastern Neurosurgical Hospital, 1-12-1 Iwakiri, Sendai, 983-0821, Japan. saito-tubame@jcom.home.ne.jp.",
"authors": "Saito|Hiroshi|H|",
"chemical_list": "D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1038/s41394-020-00322-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2058-6124",
"issue": "6(1)",
"journal": "Spinal cord series and cases",
"keywords": null,
"medline_ta": "Spinal Cord Ser Cases",
"mesh_terms": "D020211:Autonomic Dysreflexia; D001794:Blood Pressure; D002945:Cisplatin; D006801:Humans; D008297:Male; D008875:Middle Aged; D011115:Polyneuropathies; D011782:Quadriplegia; D013118:Spinal Cord Diseases; D013119:Spinal Cord Injuries",
"nlm_unique_id": "101680856",
"other_id": null,
"pages": "71",
"pmc": null,
"pmid": "32792478",
"pubdate": "2020-08-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autonomic dysreflexia in a case of radiation myelopathy and cisplatin-induced polyneuropathy.",
"title_normalized": "autonomic dysreflexia in a case of radiation myelopathy and cisplatin induced polyneuropathy"
} | [
{
"companynumb": "JP-ACCORD-200196",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Small cell lung cancer (SCLC) is a deadly and rapidly progressive disease that can present with various paraneoplastic syndromes on initial workup. Acquired factor VIII (FVIII) deficiency, also known as acquired haemophilia A (AHA), has been identified as a rare paraneoplastic syndrome in SCLC. Here, we present a 61-year-old woman with a massive gastrointestinal bleed and prolonged activated partial thromboplastin time (PTT) in the emergency department. She was diagnosed with rare paraneoplastic AHA secondary to extensive-stage SCLC (ES-SCLC). She was treated with high-dose steroids and factor bypassing agents, which led to the resolution of bleeding and undetectable FVIII inhibitor levels. She was subsequently treated for ES-SCLC with carboplatin, etoposide and atezolizumab. This case report highlights a rare clinical presentation of paraneoplastic AHA that necessitates prompt recognition in patients with SCLC with ongoing bleeding and elevated PTT.",
"affiliations": "Medical Oncology, University of Ottawa, Ottawa, Canada Mehrnoosh.pauls@gmail.com.;Division of Hematology and Hematologic Malignancies, University of Calgary, Calgary, Canada.;Medicine, University of Calgary, Calgary, Canada.;Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Canada.",
"authors": "Pauls|Mehrnoosh|M|;Rydz|Natalia|N|;Nixon|Nancy A|NA|;Ezeife|Doreen|D|",
"chemical_list": "D000970:Antineoplastic Agents; D001323:Autoantibodies; D003029:Coagulants; D007166:Immunosuppressive Agents; D005169:Factor VIII; D015942:Factor VIIa",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "GI bleeding; haematology (incl blood transfusion); lung cancer (oncology)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000005:Abdomen; D000310:Adrenal Gland Neoplasms; D000740:Anemia; D000970:Antineoplastic Agents; D001323:Autoantibodies; D003029:Coagulants; D017707:Erythrocyte Transfusion; D005169:Factor VIII; D015942:Factor VIIa; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006467:Hemophilia A; D006801:Humans; D007166:Immunosuppressive Agents; D008175:Lung Neoplasms; D000072281:Lymphadenopathy; D008482:Mediastinum; D008875:Middle Aged; D010257:Paraneoplastic Syndromes; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33509862",
"pubdate": "2021-01-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paraneoplastic acquired haemophilia A in extensive-stage small cell lung cancer (ES-SCLC) in the era of immunotherapy.",
"title_normalized": "paraneoplastic acquired haemophilia a in extensive stage small cell lung cancer es sclc in the era of immunotherapy"
} | [
{
"companynumb": "CA-BEH-2021128504",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Development of malignancy after solid-organ trans?lant is a well-known long-term complication of immunosuppressive therapy. Thus far, there are no specific oncologic recommendations regarding management of de novo tumors in transplanted kidneys. Here, we present the case of a 63-year-old male patient who developed a de novo renal cell carcinoma 6 years after the transplant procedure. The patient underwent nephron-sparing surgery with transperitoneal enucleation of the tumor. We discuss the decision-making process and the operative challenges that we faced. We conclude that this technique should be considered as a therapeutic strategy for selected patients so that transplant nephrectomy can be avoided.",
"affiliations": "From the Department of Renal and Pancreas Transplantation, Manchester Royal Infirmary, Manchester, United Kingdom.",
"authors": "Sarantitis|Ioannis|I|;Pararajasingam|Ravi|R|;Forgacs|Bence|B|;Denley|Helen|H|;Wood|Grahame|G|;Augustine|Titus|T|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2016.0037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "16(5)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D064591:Allografts; D002292:Carcinoma, Renal Cell; D000066491:Clinical Decision-Making; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D059351:Organ Sparing Treatments; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "614-616",
"pmc": null,
"pmid": "27855588",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Transperitoneal Enucleation of a Kidney Transplant Allograft Renal Cell Carcinoma.",
"title_normalized": "transperitoneal enucleation of a kidney transplant allograft renal cell carcinoma"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1053760",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pregenomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies. A combination of high-depth whole-genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were used. Treatment with radiation and chemotherapies resulted in a substantial increase in mutational burden and diversification of the tumor subclonal architecture without eradication of the founding clone. Notable somatic alterations included a MEN1 driver, several epigenetic modifiers, and therapy-induced mutations that impacted multiple other cancer-relevant pathways and altered the neoantigen landscape. These genomic data provided new mechanistic insights into the genesis of ependymoma and pathways of resistance. They also revealed that radiation and chemotherapy were significant forces in shaping the increased subclonal complexity of each tumor recurrence while also failing to eradicate the founding clone. This raises the question of whether standard-of-care treatments have similar consequences in other patients with ependymoma and other types of brain tumors. If so, the perspective obtained by real-time genomic characterization of a tumor may be essential for making effective patient-specific and adaptive clinical decisions.",
"affiliations": "Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.;Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.;McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA.;McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA.;Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.;Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.;Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.;Institute for Genomic Medicine, Nationwide Children's Hospital, and The Ohio State University College of Medicine, Columbus, Ohio 43205, USA.",
"authors": "Miller|Christopher A|CA|;Dahiya|Sonika|S|;Li|Tiandao|T|;Fulton|Robert S|RS|;Smyth|Matthew D|MD|;Dunn|Gavin P|GP|;Rubin|Joshua B|JB|;Mardis|Elaine R|ER|",
"chemical_list": "D000951:Antigens, Neoplasm; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins",
"country": "United States",
"delete": false,
"doi": "10.1101/mcs.a002444",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 10.1101/mcs.a002444MCS002444MilResearch ArticleResistance-promoting effects of ependymoma treatment revealed through genomic analysis of multiple recurrences in a single patient Treatment-linked resistance in an ependymomaTreatment-linked resistance in an ependymomaMiller Christopher A. 12Dahiya Sonika 3Li Tiandao 2Fulton Robert S. 2Smyth Matthew D. 4Dunn Gavin P. 4Rubin Joshua B. 5Mardis Elaine R. 61 Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;2 McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;4 Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA;5 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA;6 Institute for Genomic Medicine, Nationwide Children's Hospital, and The Ohio State University College of Medicine, Columbus, Ohio 43205, USACorresponding authors: Elaine.Mardis@nationwidechildrens.org; Rubin_J@wustl.edu4 2018 4 2 a00244415 11 2017 26 12 2017 © 2018 Miller et al.; Published by Cold Spring Harbor Laboratory Press2018This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted reuse and redistribution provided that the original author and source are credited.As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pregenomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies. A combination of high-depth whole-genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were used. Treatment with radiation and chemotherapies resulted in a substantial increase in mutational burden and diversification of the tumor subclonal architecture without eradication of the founding clone. Notable somatic alterations included a MEN1 driver, several epigenetic modifiers, and therapy-induced mutations that impacted multiple other cancer-relevant pathways and altered the neoantigen landscape. These genomic data provided new mechanistic insights into the genesis of ependymoma and pathways of resistance. They also revealed that radiation and chemotherapy were significant forces in shaping the increased subclonal complexity of each tumor recurrence while also failing to eradicate the founding clone. This raises the question of whether standard-of-care treatments have similar consequences in other patients with ependymoma and other types of brain tumors. If so, the perspective obtained by real-time genomic characterization of a tumor may be essential for making effective patient-specific and adaptive clinical decisions.\n\nependymomaneoplasm of the central nervous systemneoplasm of the nervous system\n==== Body\nINTRODUCTION\nEpendymomas are a heterogeneous group of primary central nervous system (CNS) tumors with multiple histological, brain region, age, and molecular features distinguishing between different prognostic groups (Pajtler et al. 2015; Dorfer et al. 2016; Khatua et al. 2017). Based on standard histological features, ependymal neoplasms can be diagnosed as World Health Organization (WHO) Grade I, II, or III tumors. However, in contrast to other brain tumors, histological grading has proven to be a weak prognostic indicator of outcome for ependymomas (Pajtler et al. 2017). In the largest published study of ependymoma outcome involving 282 patients, gross total resection (GTR) was the only prognostic factor associated with increased survival (Vera-Bolanos et al. 2015). Strikingly, in this study, GTR and postsurgical radiation therapy associated with a shorter progression-free survival than GTR alone. These data indicate that, as yet, we do not know enough about the molecular mechanisms of ependymoma, or about the appropriate indications for, and most effective modes of, adjuvant therapies.\n\nA means to generating the necessary insights to address these concerns is comparative genomic analyses of primary and posttreatment specimens. To date, there is a paucity of information regarding the genomic changes in ependymomas that recur serially through multiple treatment regimens. This is largely due to the rarity of the disease and a failure to consistently bank and analyze recurrent samples. To determine the temporal genomic changes that occurred in one patient's ependymoma disease as it recurred after several different therapeutic modalities, we characterized the genomic landscape of serial resections with high-depth whole-genome and exome sequencing. These data provided an evaluation of putative driver mutations, mutational signatures resulting from therapy, mechanisms for therapy response and resistance, and shifts in the neoantigen profile from the initial disease presentation through four recurrences.\n\nCLINICAL PRESENTATION AND FAMILY HISTORY\nThe initial diagnosis was made in a 16-yr-old right-handed female who presented to the St. Louis Children's Hospital Emergency Department with a 3-d history of headache and vomiting (Table 1). Magnetic resonance imaging (MRI) scan revealed a 6 × 4 cm enhancing mass in the right frontotemporal region (Fig. 1A, initial diagnosis). The patient underwent a GTR via a right frontotemporal craniotomy. Pathological evaluation was significant for a hypercellular glial tumor with prominent pseudo-rosettes, increased mitoses, vascular proliferation and necrosis, and perinuclear dot-like expression of epithelial membrane antigen (EMA) (Fig. 1B,C) along with diffuse glial fibrillary acidic protein immunoreactivity. A diagnosis of anaplastic ependymoma (WHO Grade III) was made. Evaluations for CNS dissemination were negative. The patient received 59.4 Gy of fractionated photon irradiation to the tumor bed plus a 1-cm margin, which is standard for supratentorial ependymoma. Forty-four months after the initial diagnosis, the patient suffered a seizure and an MRI revealed a 13 × 15 × 16 mm nodular recurrence in the right frontal lobe along the posterior margin of the initial resection cavity (Fig. 1A, first recurrence). MRI of spine and cerebrospinal fluid cytology were negative. The patient underwent complete resection of the recurrent tumor, which exhibited similar histology to the initial tumor. The resection cavity and margin were reirradiated with an additional 59.4 Gy of fractionated photon irradiation and the patient received 10 mo of standard dose temozolomide treatment.\n\nFigure 1. Radiographic and pathological evaluation of initial and recurrent ependymoma. (A) Serial MRIs over a 9-yr period demonstrating a heterogeneously enhancing mass in the right frontotemporal region at the time of initial diagnosis and four enhancing recurrent lesions adjacent to the initial resection cavity. (B) Hematoxylin and eosin (H&E) stain of formalin-fixed paraffin-embedded primary resection material revealed a densely cellular tumor with increased mitotic activity, necrosis, and microvascular proliferation. (C) Immunostain for epithelial membrane antigen (EMA) shows multifocal perinuclear dot-like positivity, which is characteristic of ependymal differentiation along with concomitant cytoplasmic expression of glial fibrillary acidic protein (not shown). (D) H&E stain of each recurrent tumor revealed persistence of the ependymal phenotype. Pictured is the third recurrence. All the photomicrographs are taken at 40× magnification.\n\nTable 1. Clinical history\n\nDate\tEvent\t\nMonth 1\tInitial GTR of anaplastic ependymoma WHO Grade III\t\nMonths 2–3\tIrradiation of tumor bed to 59.4 Gy\t\nMonth 45\tGTR of first recurrent anaplastic ependymoma\t\nMonths 47–48\tReirradiation with 59.4 Gy with 10 months of temozolomide\t\nMonths 48–58\tTemozolomide chemotherapy\t\nMonth 63\tGTR of second recurrent anaplastic ependymoma\t\nMonth 65\tLapatinib and Avastin therapy initiated\t\nMonth 69\tLapatinib discontinued secondary to toxicity\t\nMonth 77\tAvastin discontinued\t\nMonth 83\tGTR of third recurrence of anaplastic ependymoma\t\nMonths 84–104\tAvastin therapy\t\nMonth 104\tGTR of fourth recurrent anaplastic ependymoma\t\nGTR, gross total resection; WHO, World Health Organization.\n\nA surveillance scan 17 mo after the second resection demonstrated a 7-mm enhancing nodule in the temporal surface of the right sylvian fissure near the resection cavity, consistent with recurrence (Fig. 1A, second recurrence). Following a third complete resection, histopathology was again consistent with anaplastic ependymoma and analysis for dissemination was negative. The patient was enrolled on CERN-0801 at Children's Memorial Hospital in Chicago and received combined Avastin and lapatinib. Lapatinib was discontinued 4 mo later because of toxicity, and Avastin was continued for an additional 8 mo for a total of 1 yr of treatment every 2 wk. Six months later, an MRI revealed a new right perisylvian lesion and right thalamic enhancing nodule (Fig. 1A, third recurrence). Complete resection of the perisylvian lesion was performed and pathology again indicated anaplastic ependymoma (Fig. 1D) with no evidence of dissemination. Avastin was restarted and continued for 20 mo until new evidence from serial MRI indicated progression in a perisylvian lesion that had remained following the most recent surgery (Fig. 1A, fourth recurrence). This lesion also was completely resected and diagnosed as anaplastic ependymoma. The patient continues on treatment at the time of this report, >11 yr from original diagnosis, without evidence of dissemination beyond this loco-regional area.\n\nGENOMIC ANALYSES\nAnalysis of the Matched Normal Sample\nTo determine whether the patient possessed a germline predisposition to cancer, we analyzed the sequence data obtained from her leukocyte-derived DNA (normal, Supplemental Table S1) and identified 176 protein-altering constitutional variants that were rare in the population and fell into highly damaging classes of mutations (frameshifts, nonsense, nonstop, or splice-site). Variants were observed in several genes known to be important for immune function, including splice site SNPs in RAG1, HLA-DRB1, and HLA-DRB5, as well as a nonsense mutation in HLA-DRB5. Several cancer-relevant genes were also observed: splice-site alterations in DDX3X (Dahlin et al. 2015) and MAD2L2 (alias: REV7) (Boersma et al. 2015; Xu et al. 2015) and in-frame insertions in MNX1 (Das 2016) and ZFHX3 (Mabuchi et al. 2010). Some with direct glioma relevance were also observed: FOXD1 (in-frame deletion) (Koga et al. 2014; Cheng et al. 2016; Gao et al. 2017), BCL2L2 (SNP) (Chung et al. 2015), and RYK (frameshift insertion) (Adamo et al. 2017). Although MNX1 functions as an oncogene to promote pancreatic islet cell tumors in multiple endocrine neoplasia type 1 (MEN1) (Scacheri et al. 2006), this particular mutation is common in the population and unlikely to be relevant to predisposition.\n\nLandscape of Somatic Mutations during Disease Progression\nWe identified 1332 somatic mutations across the five resection specimens, 162 of which were in protein-coding regions, and 110 of which were nonsilent (Fig. 2; Supplemental Table S2). The primary tumor sample contained only one overtly cancer-related gene mutation, an expressed frameshift insertion in MEN1 (K237fs) (Table 2). We also observed several large copy-number alterations (CNAs) in this sample, including deletions of 6p, 15q, 22, and the first 22 Mb of Chromosome 1, that were shared with the recurrent tumors (Supplemental Fig. S1, Table S3). Chromosome 11 was heavily rearranged, with multiple distinct regions of amplification and deletion, one of which deleted the second copy of MEN1. Integrated analysis of the DNA and RNA did not detect any gene fusion events, although many putative structural variants were detected (Supplemental Tables S4 and S5).\n\nFigure 2. Variant allele fractions of nonsilent mutations in protein-coding genes in all five resections.\n\nTable 2. Functions and cancer-relatedness of mutated genes\n\nCategory\tGene\tChrom\tHGVS DNA reference\tHGVS protein reference\tVariant type\tPredicted effect\tdbSNP ID\tGenotype\tComments\tPMID references\t\nEpigenetic modifiers\tMEN1\t11\tENST00000337652.5:c.711_712insG\tENSP00000337088.1:p.Lys237GlnfsTer?\tframe_shift_ins\tp.K237fs\t–\thom\tH3K4 trimethylation, DNA methylation\t23850066\t\n\tGON4L\t1\tENST00000368331.1:c.2455A>G\tENSP00000357315.1:p.Asn819Asp\tmissense\tp.N819D\t–\thet\tHDAC1 interactor\t21454521\t\n\tHDAC3\t5\tENST00000305264.3:c.50_55+5del\tENSP00000302967:p.His17?\tframe_shift_del\tp.H17fs\t–\thet\tHistone deacetylase\t25313724\t\n\tSETD9\t5\tENST00000285947.2:c.788_796del\tENSP00000285947.2:p.Ile263_Tyr265del\tin_frame_del\tp.IAY263in_frame_del\t–\thet\tHistone methyltransferase\t20930037\t\n\tBANP\t16\tENST00000286122.7:c.668A>G\tENSP00000286122.7:p.Asn223Ser\tmissense\tp.N223S\t–\thet\tRecruits HDAC1 and deacetylation of H3K9\t16166625\t\n\tSUV39H1\tX\tENST00000337852.6:c.448C>T\tENSP00000337976.6:p.Arg150Cys\tmissense\tp.R150C\trs368779259\thet\tH3K9 trimethylase\t26807716\t\n\tFAM208A\t3\tENST00000355628.5:c.97G>A\tENSP00000347845.5:p.Glu33Lys\tmissense\tp.E33K\t–\thet\tComponent of HUSH complex; required for H3K9me3\t26022416\t\n\tPOU3F4\tX\tENST00000373200.2:c.1013C>T\tENSP00000362296.2:p.Pro338Leu\tmissense\tp.P338L\t–\thet\tEpigenetics of neuronal fate\t23933087\t\n\tPATZ1\t22\tENST00000266269.5:c.562G>T\tENSP00000266269.5:p.Asp188Tyr\tmissense\tp.D188Y\t–\thet\tRegulates chromatin openness and pluripotency\t25515777\t\n\tKAT6B\t10\tENST00000287239.4:c.3827C>T\tENSP00000287239.4:p.Pro1276Leu\tmissense\tp.P1276L\t–\thet\tHistone acetyltransferase\t26208904\t\nIntracellular signaling\tKREMEN2\t16\tENST00000303746.5:c.494G>T\tENSP00000304422.5:p.Gly165Val\tmissense\tp.G165V\t–\thet\tInhibitor of WNT signaling\t20846389\t\n\tDEPDC5\t22\tENST00000266091.3:c.2939G>A\tENSP00000266091.3:p.Trp980Ter\tnonsense\tp.W980*\t–\thet\tInhibitor of mTORC signaling\t23723238\t\n\tNET1\t10\tENST00000355029.4:c.498G>T\tENSP00000347134.4:p.Glu166Asp\tmissense\tp.E166D\t–\thet\trhoGEF required for proliferation\t23864709\t\n\tSPRY3\tX\tENST00000302805.2:c.55C>T\tENSP00000302978.2:p.Arg19Cys\tmissense\tp.R19C\t–\thet\tInhibitor of FGF signaling\t18219583\t\n\tVBP1\tX\tENST00000286428.5:c.331C>A\tENSP00000286428.5:p.Leu111Met\tmissense\tp.L111M\t–\thet\tVHL protein interactor\t23964080\t\n\tARHGAP32\t11\tENST00000310343.9:c.4703C>G\tENSP00000310561.8:p.Thr1568Ser\tmissense\tp.T1568S\t–\thet\tInhibitor of RHOA, CDC42, and RAC1 signaling\t12857875\t\n\tOTUD5\tX\tENST00000156084.4:c.1702C>A\tENSP00000156084.4:p.Pro568Thr\tmissense\tp.P568T\t–\thet\tActivator of p53\t24143256\t\n\tKLHL21\t1\tENST00000377658.4:c.501G>C\tENSP00000366886.4:p.Glu167Asp\tmissense\tp.E167D\t–\thet\tRegulator of mitosis\t19995937\t\n\tNF2\t22\tENST00000338641.4:c.551G>A\tENSP00000344666.4:p.Trp184Ter\tnonsense\tp.W184*\t–\thet\tTumor suppressor, regulator of hippo pathway\t25893302\t\n\tLATS1\t6\tENST00000253339.5:c.2365G>C\tENSP00000253339.5:p.Asp789His\tmissense\tp.D789H\t–\thet\tMediator of hippo pathway, regulated by NF2\t25026211\t\n\tMAP4K3\t2\tENST00000263881.3:c.899T>C\tENSP00000263881.3:p.Phe300Ser\tmissense\tp.F300S\t–\thet\tComponent of MAPK pathway regulator of LATS1\t26437443\t\n\tTRAF3\t14\tENST00000392745.2:c.53C>G\tENSP00000376500.2:p.Pro18Arg\tmissense\tp.P18R\t–\thet\tTNFR-associated regulator of MAPK and NF-κB pathways\t28098136\t\nMetabolism\tLETM1\t4\tENST00000302787.2:c.286G>A\tENSP00000305653.2:p.Val96Met\tmissense\tp.V96M\t–\thet\tMitochondrial structural protein\t25077561\t\n\tTXNRD2\t22\tENST00000535882.1:c.1429G>C\tENSP00000439314.1:p.Ala477Pro\tmissense\tp.A477P\t–\thet\tThioredoxin reductase 2\t25647640\t\n\tHSD3B2\t1\tENST00000369416.3:c.1004G>A\tENSP00000358424.3:p.Arg335Gln\tmissense\tp.R335Q\t–\thet\tRequired for steroid biosynthesis\t22262841\t\n\tGLB1\t3\tENST00000445488.2:c.2047G>C\tENSP00000393377.2:p.Ala683Pro\tmissense\tp.A683P\t–\thet\tβ-galactosidase\t23011886\t\n\tMT-ND4\tMT\tENST00000361381.2:c.279del\tENSP00000354961.2:p.Lys93AsnfsTer?\tframe_shift_del\tp.K93fs\t–\thet\tCore component of mitochondrial NADH dehydrogenase\t25909222\t\nNeuro-developmental disorders\tSYNE1\t6\tENST00000265368.4:c.11097C>G\tENSP00000265368.4:p.Phe3699Leu\tmissense\tp.F3699L\t–\thet\tSYNE1 ataxia\t27086870\t\n\tGPR124\t8\tENST00000412232.2:c.1316_1334del\tENSP00000406367.2:p.Asn439ThrfsTer16\tframe_shift_del\tp.N439fs\t–\thet\tCNS angiogenesis\t21071672\t\n\tCACNG2\t22\tENST00000300105.6:c.541T>C\tENSP00000300105.6:p.Tyr181His\tmissense\tp.Y181H\t–\thet\tBipolar disorder\t25730879\t\n\tSH3TC2\t5\tENST00000515425.1:c.3016del\tENSP00000423660.1:p.Ser1006ProfsTer9\tframe_shift_del\tp.S1006fs\t–\thet\tCharcot–Marie–Tooth\t20028792\t\nOther cancer-related genes\tSLC39A11\t17\tENST00000542342.2:c.616G>T\tENSP00000445829.2:p.Val206Phe\tmissense\tp.V206F\t–\thet\tOvarian cancer\t26091520\t\n\tTRPM1\t15\tENST00000542188.1:c.334A>C\tENSP00000437849.1:p.Ile112Leu\tmissense\tp.I112L\t–\thet\tMelanoma\t22897572\t\nhom, homozygous; het, heterozygous; frame_shift_ins, frameshift insertion; frame_shift_del, frameshift deletion.\n\nAll SNVs, indels, and CNAs found in the initial resection were retained in the first recurrence, which was diagnosed after radiation therapy and a 44-mo interval. An additional 12 new protein-coding somatic mutations were identified in the recurrent tumor, including a nonsense mutation in DEPDC5, an inhibitor of mTORC signaling. Missense mutations were observed in KREMEN2 (G165V), a gene that has been linked to melanoma, and in BANP (N223S), an epigenetic regulator. None is obviously expressed in this tumor, but the variants in both KREMEN2 and BANP are expressed in subsequent tumors with higher quality and higher-depth RNA-seq, so it is likely that these variants are expressed below our level of sensitivity in this resection sample. Mutated DEPDC5 may have been undetectable because of undergoing nonsense-mediated decay.\n\nThe second recurrent tumor emerged after additional radiation therapy and treatment with temozolomide. It was resected and the genomic analysis of this specimen indicated that essentially all previously observed mutations were retained, with the exception of two low-VAF protein-coding variants from the previous recurrence, including loss of the DEPDC5 nonsense mutation. An additional 66 protein-coding SNVs and indels were acquired, including a 19-bp frameshift deletion in GPR124 and low-VAF missense mutations in SEPT5 (T260A), MAP4K3 (F300S), and KAT6B (P1276L). Of these, only the MAP43K and KAT6B mutations were observably expressed. The copy-number landscape was identical to the previous tumors, with the exception of a new homozygous deletion on Chromosome 2p.\n\nThe third recurrence occurred after treatment with Avastin and lapatinib. Genomic analysis of this resection specimen revealed that all coding mutations specific to the second recurrence, including the Chromosome 2 copy-number loss, were undetectable at the third recurrence. In contrast, virtually all mutations identified in the first two resections persisted, the only exception being two low-VAF events in MYH10 and OR1L1. Fifty-six new protein-coding mutations were acquired, including missense mutations in POU3F4 (P568T), an epigenetic regulator, OTUD5 (P338L), a p53 activator, and SPRY3 (R19C), a regulator of FGF signaling. None has been previously implicated in ependymoma, and their relevance for disease progression and therapy resistance is unclear.\n\nThe fourth recurrence was resected after continued Avastin treatment. In this sample, 29 of the protein-coding mutations newly acquired in the prior (third) recurrence were no longer detected, but 18 new protein-coding mutations were identified. These included nonsense mutations in CREB3L3 and NF2, a gene previously linked to ependymoma. A missense mutation in the chromatin/transcriptional regulator PATZ1 was also observed. In addition to the NF2 mutation, we identified two point mutations that potentially impact Hippo pathway signaling in LATS1 and MAP4K3 (Meng et al. 2015; Oh et al. 2015).\n\nClonal Heterogeneity and Mechanisms of Tumor Evolution\nTo characterize the changing clonal architecture of this tumor, the variant allele fractions of copy-number neutral SNVs were clustered in five dimensions using the sciClone algorithm (Fig. 3A). Eight clusters were detected, and the mutation spectrum for each was identified. The first recurrent tumor after radiation therapy was dominated by cluster 2, which emerged from a population of cells undetectable in our analysis of the original biopsy data (with a sensitivity of ∼2% VAF). The mutation spectrum shows a notable decrease in C>T transitions in cluster 2, when compared with those in cluster 1 from the original tumor (Fig. 3B).\n\nFigure 3. (A) Subclonal clustering of the five tumor samples. Points represent the VAFs of individual SNVs at each time point, and lines connect the mean VAF of each cluster in each sample. Each sample is labeled with the number of detectable mutations at that time point. (B) Mutation spectrum of each cluster. (C) The number of high-quality MHC Class I neoantigens found in each subclonal population.\n\nIn the second recurrence, following additional radiation and treatment with temozolomide, we identified the emergence of two new subclonal populations (clusters 3 and 4) that were likewise undetectable in the prior two samples’ data. Cluster 4, and all subsequently appearing clusters, each have a significantly higher proportion of A>G transitions than the founding clone, a pattern consistent with temozolomide-induced mutagenesis (all P < 0.03) (Supplemental Table S6; Bodell et al. 2003). In the third recurrence, following Avastin treatment, both clusters 3 and 4 were undetectable, but clusters 5 and 6 emerged. Although cluster 6 was cleared in the final resection sample we studied, cluster 5 persisted and two rare subclonal populations expanded into clusters 7 and 8, which make up a substantial portion of the final tumor. Some mutations in these two clusters were just above the level of detection in the third resection.\n\nThough there were too few mutations to perform per-cluster mutational signature analysis (Rosenthal et al. 2016), we did compare the deletion/substitution ratio between mutations that predated irradiation (cluster 1) and those that arose after radiotherapy (clusters 2–8). We observed a significant increase in the proportion of deletions postirradiation (Pearson's χ2\nP = 1.657 × 10−05), a finding that is consistent with previously reported mutational signatures of ionizing radiation (Behjati et al. 2016).\n\nIn addition to identifying mutations correlated with specific subclonal expansions, we also examined the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to drive brain tumor recurrence through increased expression in post-temozolomide lesions (Bocangel et al. 2002; Hegi et al. 2005). In this case, MGMT RNA expression levels were not clearly correlated with the emergence of post-temozolomide recurrences, suggesting that they relied upon alternative mechanisms of resistance (Supplemental Fig. S2).\n\nEvolving Landscape of Targets for Immunotherapy\nTo understand how the immunogenicity of this tumor evolved over the course of treatment, we applied the pVACSeq neoantigen prediction pipeline (Hundal et al. 2016) to the protein-altering mutations that we observed in each tumor studied. The patient's HLA haplotypes were inferred to be A*24:02, A*26:01, B*40:02, B*38:01, C*12:03, and C*03:05. We identified only 14 expressed mutations that produce “high-quality” predicted MHC Class I neoantigens (Fig. 2C), which we define as having median binding affinity (ic50) of <500 nM, and with a higher binding affinity to the mutant than the wild-type peptide (Supplemental Table S7). As overall mutation burden is highly correlated with neoantigen load, this is perhaps unsurprising. Only three neoantigens were present in the founding clone, whereas 11 of the 14 were specific to a subclonal population and therefore not present in all cells of the tumor.\n\nDISCUSSION\nIn this study, we found that standard-of-care and experimental approaches to treatment of an ependymoma increased its mutational burden and diversified its subclonal architecture. The diagnosis of a supratentorial anaplastic ependymoma, not arising from the ventricles, is uncommon. Ependymomas, which occur in both pediatric and adult patients, display age-dependent patterns of location and histology. Overall, the majority of ependymomas occur in the spine, though this location is involved in only 20% of pediatric cases (McGuire et al. 2009a, 2009b). As was evident in this case, supratentorial ependymomas are most common in older children and adolescents. In addition, anaplastic histology is also more common in pediatric cases. Recent genomic analyses have indicated that most supratentorial anaplastic ependymomas are associated with fusion events involving RELA or YAP1 (Pajtler et al. 2015). Neither of these fusion events was detected in this case.\n\nThe Role of MEN1 Mutations\nNotable in the evaluation of the primary diagnostic specimen was the biallelic somatic disruption of MEN1. MEN1 mutations, typically biallelic, have been infrequently reported in ependymoma, both in the context of familial MEN1 syndrome and sporadically (Kato et al. 1996; Urioste et al. 2002; Al-Salameh et al. 2010; Lee et al. 2016b), and appear to occur in both high- and low-grade tumors of any location. Although MEN1 mutation has been associated with recurrence and progression from grade II to III ependymoma (Urioste et al. 2002; Funayama et al. 2013), we offer the first clear evidence that MEN1 mutation is a driver of the founding clone.\n\nFunctionally, MEN1 mutations are known to increase DNMT1 activity, which leads to global increases in CpG island methylation, a characteristic of other tumors (Funayama et al. 2013; Mack et al. 2014; Yuan et al. 2016), and silences key tumor suppressor genes, including CDKN1B, CDKN2A, APC, and RASSF1A (Karnik et al. 2005; Lindberg et al. 2008; Juhlin et al. 2010). Coupled with the observed mutations in other epigenetic regulators, these data add new evidence for epigenetic dysregulation in the genesis and progression of ependymoma.\n\nLoss of menin function also leads to activation of the RAS (Wu et al. 2012), MAP kinase (Gallo et al. 2002), PI3 kinase (Wang et al. 2011), Sonic Hedgehog (Gurung et al. 2013), Wnt (Cao et al. 2009), and TGF-β signaling pathways, all with established roles in gliomagenesis (Matkar et al. 2013). Their role is underscored by the accumulation of mutations in additional regulators of their activation during the course of this tumor's treatment: MAPK (SPRY3) (Cabrita and Christofori 2008), PI3K (DEPDC5) (Cabrita and Christofori 2008; Bar-Peled et al. 2013), and WNT (KREMEN2, NET1, GPR124) (Orlow et al. 1987; Mao et al. 2002; Posokhova et al. 2015; Wei et al. 2017).\n\nDrivers of Recurrence and Susceptibility\nAlthough more cases will be needed to confidently identify the specific mutations that drive the expansion of therapy resistant subclones, the Hippo pathway stands out as a compelling potential driver of the fourth recurrence, induced by new mutations in LATS1 (missense) and in NF2 (nonsense). NF2 loss-of-function mutations have been previously associated with spinal ependymomas (Lee et al. 2016a), and recent evidence suggests that YAP1, the nuclear target of Hippo signaling, mediates aberrant proliferation upon NF2 loss during tumorigenesis (Shi et al. 2016). Furthermore, oncogenic YAP1 activation occurs as a consequence of a loss in NF2-dependent inactivation of LATS1 (a key inhibitor of YAP1), and decreased LATS1 activity has also been associated with glioma progression (Ji et al. 2012; Oh et al. 2015; Shi et al. 2016). YAP1 fusions are a key characteristic of one subgroup of supratentorial ependymomas (Archer and Pomeroy 2015) and we hypothesize that these mutations may represent convergent evolution, producing similar phenotypic effects via a different mechanism.\n\nOnly one substantial subclone was clearly responsive to therapy (cluster 3) and it was eradicated after treatment of recurrence 2 with Avastin and lapatinib. Among the compelling target mediators of response or biomarkers of response is the mutation in GPR124. This orphan member of the adhesion G protein–coupled receptor family is required specifically for the development of the brain vasculature in a VEGF-dependent manner (Kuhnert et al. 2010; Cullen et al. 2011; Zhou and Nathans 2014), and GPR124 may be a biomarker of Avastin response (Wang et al. 2014). GPR124 activates canonical Wnt signaling, which, as described above, is normally directly inhibited by MEN1 and KREMEN2. The genes for both of these proteins were mutated in this tumor, suggesting a model for Avastin response that might involve enhanced activation of a VEGF–Wnt axis.\n\nChanges to the Neoantigen Landscape during Progression\nOverall, the number of expressed MHC Class I neoantigens that we predicted was low, as expected in a tumor with only 110 protein-altering mutations. The presence of a relatively high burden in the founding clone suggests that mechanisms of immune evasion were already present when the initial tumor presented and may explain why there was no relationship between neoantigen load and subclonal response in subsequent tumors. This is supported by the observation that expression markers of T-cell activation were low in all five tumors.\n\nOrigin of New Subclones in Later Recurrences\nAlthough we present evidence suggesting that radiation and temozolomide treatment increased the mutation burden of this tumor, new mutations continued to be observed after their use was discontinued. It is important to note that this is not necessarily indicative of a continued elevated mutation rate. Mutations first observed in the last two recurrences may have existed at very low frequencies in prior time points, and the observed mutation spectrum in the new subclones is consistent with damage from previous therapies. Our prior work with ultradeep sequencing suggests that many rare subclones often exist in a tumor (with neutral fitness) and only become detectable after their fitness increases, either via acquisition of one or more driver mutations or because the therapeutic regimen changes the environment (Griffith et al. 2015b; Uy et al. 2017).\n\nFuture Directions\nThese results suggest that radiation and chemotherapy contributed to the increasing complexity of this tumor by both adding to the mutational burden and expanding the subclonal architecture. Determining whether this natural history is generally true in ependymoma progression, and what impact therapy-induced tumor evolution has on outcome, is an important area of investigation with the potential to alter how we treat patients with both completely resected supratentorial ependymoma and other brain tumors that are treated with irradiation but frequently recur. In the largest published study of ependymoma outcome involving 282 patients, GTR was the only prognostic factor associated with increased survival (Vera-Bolanos et al. 2015). In that analysis, GTR and postsurgical radiation therapy were associated with a shorter progression-free survival than GTR alone. Data presented here raise the alarming hypothesis that time-to-progression was shortened because irradiation promoted tumor evolution.\n\nThese clinical observations together with the sequencing-based characterizations presented here suggest that under some circumstances, adjuvant therapy may not be providing a benefit, and indeed may hasten recurrence by promoting molecular diversification of the tumor. We propose that this phenomenon be studied prospectively. In particular, our data suggest that completely resected supratentorial ependymomas, and possibly other brain tumors, should be sequenced at the time of diagnosis and again if there is a recurrent tumor. Over time, this might reveal the genotypes for which radiation therapy eradicates the founding clone, resulting in a cure, and in those for which it does not, but instead contributes to evolving tumor complexity. Ultimately, it may be prudent to initially observe those patients with complete resections without additional therapy or to treat those patients whose tumors are likely to evolve in response to radiation therapy with targeted agents only as dictated by genomic analysis. Critically important to this effort will be the use of unbiased sequencing approaches like whole-exome or whole-genome sequencing rather than sequencing of targeted gene panels. Although identification of druggable targets is important, it may be equally important to construct more global models of tumor evolution.\n\nFinally, it will be important to investigate further the utility of genomic characterization to inform therapeutic options in this disease type. Although not all of the variants we identified were “druggable” in the classical sense, a subset were found to comprise predicted high-affinity neoantigen targets that, ultimately, formed the basis of a polyvalent personalized vaccine, administered after recurrence 4. Such cancer immunogenomics approaches to clinical care are only made possible through comprehensive genomic approaches to tumor characterization. Although the efficacy of these treatments awaits large-scale studies and clinical trials that are ongoing, our case highlights the potential to consider the pursuit of a personalized vaccine in extremely challenging settings of multiply recurrent disease such as the one herein, where few to no other options exist.\n\nMETHODS\nDNA Sequencing\nDNA was isolated from fresh frozen sections of each tumor resection using the QIAGEN Dual Prep and evaluated for quality and concentration using established methods. DNA was isolated from PBMC after Ficoll-based isolation to provide a normal comparator and was evaluated for quality and concentration. Using 500 ng input for all five tumors and the blood normal DNA, we generated two indexed whole-genome sequencing libraries by standard methods (Kapa Biosystems) for each sample. One library per sample was processed through exome hybrid capture using the IDT xGEN research exome capture reagent (Integrated DNA Technologies), quantitated and amplified postcapture using the manufacturer's protocol. Each of the corresponding WGS libraries was amplified by PCR, quantitated, and diluted as appropriate for Illumina sequencing. The final libraries for each sample (WGS + exome) were pooled to produce combined tumor and normal WGS- and exome-sequencing data in a specific proportion, yielding ∼10-fold WGS and ∼1000-fold exome coverage (Supplemental Table S1). The resulting library pools were loaded onto the HiSeqX platform and sequenced using 150-bp paired end reads.\n\nSomatic Variant Analysis\nAfter index-based binning of the reads into WGS- and exome-derived tumor and normal data, sequence data were aligned to reference sequence build GRCh37-lite-build37 using BWA-mem (Li, H. arXiv:1303.3997 [q-bio.GN]) version 0.7.10 (params: -t 8::), then merged and deduplicated using Picard version 1.113 (https://broadinstitute.github.io/picard/). Somatic variants were called from the combined data using our Genome Modeling System (Griffith et al. 2015a) as follows.\n\nSNVs were detected using the union of four callers: (1) SAMtools (Li et al. 2009) version r982 (params: mpileup -BuDs) intersected with Somatic Sniper (Larson et al. 2012) version 1.0.4 (params: -F vcf –G -L -q 1 -Q 15) and processed through false-positive filter v1 (params: --bam-readcount- version 0.4 --bam-readcount-min-base-quality 15 --min-mapping-quality 40 --min-somatic-score 40), (2) VarScan (Koboldt et al. 2012) version 2.3.6 filtered by varscan-high-confidence filter version v1 and processed through false-positive filter v1 (params: --bam-readcount-version 0.4 --bam-readcount-min-base-quality 15), (3) Strelka (Saunders et al. 2012) version 1.0.11 (params: isSkipDepthFilters = 0), and (4) Mutect (Cibulskis et al. 2013) v1.1.4.\n\nIndels were detected using the union of three callers: (1) GATK (McKenna et al. 2010) somatic-indel version 5336; (2) VarScan version 2.3.6 filtered by varscan-high-confidence-indel version v1, and (3) Strelka version 1.0.11 (params: isSkipDepthFilters = 0).\n\nSNVs and Indels were further filtered by removing artifacts found in a panel of 905 normal exomes, removing sites that exceeded 0.1% frequency in the 1000 genomes or NHLBI exome-sequencing projects, and then using a Bayesian classifier (https://github.com/genome/genome/blob/master/lib/perl/Genome/Model/Tools/Validation/IdentifyOutliers.pm) and retaining variants classified as somatic with a binomial log-likelihood of at least 10.\n\nFor protein-coding mutation counts described in the results below, a variant was considered to be present in a sample if it appeared with at least three variant supporting reads and a VAF of >2.5%. As some sites had low or variable coverage, a variant was only considered to be completely cleared if it did not appear in any subsequent samples.\n\nCopy-number aberrations were detected using bam-window (window-size 10,000) and copy-cat version 1.6.11 (params: --per-read-length –per-library) (https://github.com/chrisamiller/copyCat). Uneven sequence coverage of the normal sample required us to run copyCat in tumor-only mode, followed by manual review to differentiate somatic from germline copy-number events.\n\nPutative structural variants were detected using the union of BreakDancer 1.4.5 (Chen et al. 2009) filtered by novo-realign and tigra-sv, and squaredancer 0.1 (https://github.com/genome/genome/blob/master/lib/perl/Genome/Model/Tools/Sv/SquareDancer.pl).\n\nRNA Sequencing\nTotal RNA was concurrently isolated from each fresh frozen tumor resection (QIAGEN Dual Prep), and evaluated for quality and concentration using the Agilent Tapestation. RNA-seq libraries were constructed using the TruSeq Stranded RNAseq library kit (Illumina, Inc.) according to the manufacturer's protocol, quantitated and diluted for sequencing. Using the HiSeq 2500, we produced sequencing data from each RNA-seq library in a single flow cell lane by paired end 100 bp reads, yielding between 96 and 655 million reads per sample. The fourth recurrence sample was subjected to a capture step before sequencing, using the IDT xGEN research exome capture reagent. This sample yielded 856 million reads, with a much higher coding-region percentage (Supplemental Table S1).\n\nRNA-seq Analysis\nThe resulting read data were aligned to the human reference with TopHat v2.0.8 (denovo mode, params: --library-type fr-firststrand --bowtie-version=2.1.0). Expression levels were calculated with Cufflinks v2.1.1 (params: --max-bundle-length 10000000 --max-bundle-frags 10000000) (Trapnell et al. 2012).\n\nGene Fusions\nGene fusions were detected from RNA and DNA using Integrate v0.2.0 (Zhang et al. 2015) with default parameters.\n\nHeterogeneity Analysis\nUsing the high depth of coverage from combining exome and WGS data sets for these tumors, we characterized the heterogeneity of each tumor specimen and compared it to the others in the series. Here, copy-number-neutral variants and their attendant VAFs were clustered in five dimensions using the sciClone algorithm v1.1 (Miller et al. 2014) (parameters: minimumDepth = 300, maximumClusters=15), followed by phylogeny reconstruction with clonEvol (Dang et al. 2017).\n\nNeoantigen Predictions\nSomatic mutations and RNA-seq data from tumors were input into our pVACSeq pipeline (Hundal et al. 2016). WGS data from the normal blood was used to identify the patient's HLA haplotypes for Class I, using Laminar (Warren et al. 2012). MHC Class I binding predictions were generated through pVACSeq using NetMHC v3.4, as well as five other algorithms from the Immune Epitope Database and Analysis resource (IEDB, iedb.org): netMHC, netmhccons, netmhcpan, pickpocket, smm, and smmpmbec. Predictions were retained if the median score had an ic50 < 500 and better binding of the mutant peptide than the wild type (fold-change > 1). Results were then filtered to require expression of the mutant allele (FPKM > 1 and at least one variant-supporting read in the RNA). These combined data sets were used to identify neoantigenic peptide sequences in all five tumor samples, as illustrated in Figure 3C.\n\nPathology Methods\nAll the resection specimens (original and recurrences) were handled as regular surgical neuropathology cases. Although H&E stain and Ki-67 immunostain were performed on all the specimens, glial fibrillary acidic protein and EMA were limited to the initial and 2014 resections.\n\nADDITIONAL INFORMATION\nData Deposition and Access\nSequence data are available at dbGaP, under accession id phs001461.v1.p1. The Germline mutation list is accessible via the same dbGaP study. The variant was deposited in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV000678435–SCV000678467.\n\nEthics Statement\nThe patient had written and parental consent and the study was approved under Washington University in St. Louis IRB ID no. 201102299.\n\nAcknowledgments\nWe thank early analysis efforts on this project from Charles Lu. We also gratefully acknowledge the sample intake, project tracking, and data production teams at the McDonnell Genome Institute. Funding for this project was generously provided from the McDonnell Genome Institute endowment and from the Robert E. and Louise F. Dunn Distinguished Professorship endowment to Washington University School of Medicine. We gratefully acknowledge the patient and her family.\n\nAuthor Contributions\nC.A.M., R.S.F., J.B.R., and E.R.M. contributed to conceptualization; C.A.M. and T.L. did formal analysis/data curation; S.D., M.D.S., J.B.R., and G.P.D. contributed to resources; C.A.M., J.B.R., and E.R.M. wrote the original draft; C.A.M., S.D., T.L., R.S.F., M.D.S., G.P.D., J.B.R., and E.R.M. did review and editing; C.A.M. did visualization; C.A.M., J.B.R., and E.R.M. supervised the study; and E.R.M. acquired funding.\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n\nSupplementary Material\nSupplemental Material\n [Supplemental material is available for this article.]\n==== Refs\nREFERENCES\nAdamo A , Fiore D , De Martino F , Roscigno G , Affinito A , Donnarumma E , Puoti I , Ricci-Vitiani L , Pallini R , Quintavalle C , \n2017 \nRYK promotes the stemness of glioblastoma cells via the WNT/β-catenin pathway . 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"fulltext_license": "CC BY",
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"issue": "4(2)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "ependymoma; neoplasm of the central nervous system; neoplasm of the nervous system",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000293:Adolescent; D000483:Alleles; D000951:Antigens, Neoplasm; D001706:Biopsy; D018450:Disease Progression; D004806:Ependymoma; D005260:Female; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms; D011518:Proto-Oncogene Proteins",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Resistance-promoting effects of ependymoma treatment revealed through genomic analysis of multiple recurrences in a single patient.",
"title_normalized": "resistance promoting effects of ependymoma treatment revealed through genomic analysis of multiple recurrences in a single patient"
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"abstract": "A 47-year-old Japanese woman died unexpectedly 11 days after admission due to acute cerebellar infarction. The patient had a history of Sjögren syndrome with long-term steroid therapy, hypertension, thalamic infarction and amphetamine psychosis. Multiple pseudoaneurysms in both the aorta and coronary artery were found at autopsy, and one located in the aortic root had ruptured into the pericardium resulting in sudden unexpected death. The detailed examination suggested that the pseudoaneurysms resulted from microbial infection to the arterial wall via the vasa vasorum. Immunosuppression induced by the long-term steroid therapy and abused drug injection could have influenced the formation of pseudoaneurysms.",
"affiliations": "Department of Legal Medicine, Division of Preventive and Social Medicine, Faculty of Medicine, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, Japan. Electronic address: zelkova@art.osaka-med.ac.jp.;Department of Pathology, Division of Comprehensive Medicine, Faculty of Medicine, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, Japan.;Department of Legal Medicine, Division of Preventive and Social Medicine, Faculty of Medicine, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, Japan.;Department of Legal Medicine, Division of Preventive and Social Medicine, Faculty of Medicine, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, Japan.",
"authors": "Abe|Shuntaro|S|;Okada|Yoshikatsu|Y|;Sato|Takako|T|;Suzuki|Koichi|K|",
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"country": "Ireland",
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"issn_linking": "1344-6223",
"issue": "17(6)",
"journal": "Legal medicine (Tokyo, Japan)",
"keywords": "Infectious arteritis; Intravenous drug abuse; Multiple pseudoaneurysm; Steroid therapy; Vasculitic syndrome",
"medline_ta": "Leg Med (Tokyo)",
"mesh_terms": "D017541:Aneurysm, False; D000785:Aneurysm, Infected; D001344:Autopsy; D003645:Death, Sudden; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "100889186",
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"pages": "517-20",
"pmc": null,
"pmid": "26594001",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple infectious pseudoaneurysms: An autopsy case.",
"title_normalized": "multiple infectious pseudoaneurysms an autopsy case"
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"abstract": "In the last decade, prescription of anticonvulsants for treatment of low back pain (LBP) increased 4-fold. Among them, topiramate has frequent side effects and a mechanism of action that is not fully understood. The authors describe a 65-year-old woman with dependence on topiramate prescribed for chronic LBP and discuss how she was successfully weaned off topiramate using duloxetine. A significant agonistic effect by topiramate on α-2 adrenergic receptors in the brain likely accounts for the symptoms of withdrawal that were seen. We attribute the resolution of her topiramate withdrawal symptoms to reduced norepinephrine (NE) release, a known effect of duloxetine administration.",
"affiliations": "From the James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.;Pain Medicine Associates, PC, Johnson City, Tennessee.",
"authors": "Bratton|Roscoe H|RH|;Ward|Sameh A|SA|",
"chemical_list": "D000927:Anticonvulsants; D018341:Receptors, Adrenergic, alpha-2; D000077236:Topiramate; D000068736:Duloxetine Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "13(10)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D017116:Low Back Pain; D018341:Receptors, Adrenergic, alpha-2; D013375:Substance Withdrawal Syndrome; D000077236:Topiramate; D016896:Treatment Outcome",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "376-378",
"pmc": null,
"pmid": "31449076",
"pubdate": "2019-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Physical Dependence in Patient With Chronic Low Back Pain Treated With Topiramate: A Case Report.",
"title_normalized": "physical dependence in patient with chronic low back pain treated with topiramate a case report"
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"companynumb": "US-CIPLA LTD.-2019US06339",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
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{
"abstract": "GREEN (NCT01905943) is a non-randomized, open-label phase IIIb study investigating obinutuzumab alone or plus chemotherapy in chronic lymphocytic leukemia (CLL). We report a preplanned subgroup analysis of 158 previously untreated CLL patients receiving obinutuzumab-bendamustine (G-B). Patients received six 28-day cycles (C) of G-B: obinutuzumab day (D)1/D2 of C1 (25 mg D1/975 mg D2), 1000 mg D8 and D15 of C1, and D1 of C2-6; and bendamustine 70/90 mg/m2 D1 and D2 of C1-6. The primary endpoint was safety/tolerability. Grade ≥3 adverse events (AEs) occurred in 82.3% of patients, including neutropenia (49.4%), thrombocytopenia (12.0%) and febrile neutropenia (10.8%). Serious AEs included neutropenia (12.7%), febrile neutropenia (9.5%) and pneumonia (7.6%). Rates of grade ≥3 infections and infusion-related reactions were 20.3% and 17.1%, respectively. Due to tumor lysis syndrome (TLS; 8.2%), including two associated fatalities (one in another study cohort), additional risk-minimization measures were implemented. Overall response rate was 81.0%. After 32.8 months' median observation time, 2-year progression-free survival was 81.8%. Minimal residual disease was undetectable in 59.5% (94/158) and 27.8% (44/158) of patients for blood and bone marrow, respectively. Frontline G-B appears to have manageable toxicity with clinical activity in CLL. Careful TLS risk assessment, pretreatment and monitoring is required.",
"affiliations": "Department of Internal Medicine III, Ulm University, Ulm, Germany. Stephan.Stilgenbauer@uniklinik-ulm.de.;UPMC GRC11-GRECHY, AP-HP Hôpital Pitié Salpêtrière, Paris, France.;Department of Cellular Biotechnologies and Hematology, 'Sapienza' University, Rome, Italy.;Second Department of Medicine, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany.;Ankara University, Ankara, Turkey.;Onkologische Gemeinschaftspraxis, Agaplesion Bethanien Krankenhaus, Frankfurt, Germany.;National Cancer Institute, Bratislava, Slovakia.;OnkoZentrum Zürich, Zürich, Switzerland.;Department of Internal Medicine III, Ulm University, Ulm, Germany.;State Hospital, Opole, Poland.;F. Hoffmann-La Roche Ltd, Basel, Switzerland.;F. Hoffmann-La Roche Ltd, Basel, Switzerland.;F. Hoffmann-La Roche Ltd, Basel, Switzerland.;F. Hoffmann-La Roche Ltd, Basel, Switzerland.;F. Hoffmann-La Roche Ltd, Basel, Switzerland.;University Hospital Vall d'Hebron, Barcelona, Spain.",
"authors": "Stilgenbauer|Stephan|S|;Leblond|Veronique|V|;Foà|Robin|R|;Böttcher|Sebastian|S|;Ilhan|Osman|O|;Knauf|Wolfgang|W|;Mikuskova|Eva|E|;Renner|Christoph|C|;Tausch|Eugen|E|;Woszczyk|Dariusz|D|;Gresko|Ekaterina|E|;Lundberg|Linda|L|;Moore|Tom|T|;Morris|Thea|T|;Robson|Susan|S|;Bosch|Francesc|F|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride; C543332:obinutuzumab",
"country": "England",
"delete": false,
"doi": "10.1038/s41375-018-0146-5",
"fulltext": "\n==== Front\nLeukemiaLeukemiaLeukemia0887-69241476-5551Nature Publishing Group UK London 14610.1038/s41375-018-0146-5ArticleObinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study Stilgenbauer Stephan +49-731-500-45521Stephan.Stilgenbauer@uniklinik-ulm.de 12Leblond Veronique 3Foà Robin 4Böttcher Sebastian 56Ilhan Osman 7Knauf Wolfgang 8Mikuskova Eva 9Renner Christoph 10Tausch Eugen 1Woszczyk Dariusz 1112Gresko Ekaterina 13Lundberg Linda 13Moore Tom 13Morris Thea 13Robson Susan 13Bosch Francesc 141 0000 0004 1936 9748grid.6582.9Department of Internal Medicine III, Ulm University, Ulm, Germany 2 grid.411937.9Present Address: Klinik für Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg, Germany 3 0000 0001 2150 9058grid.411439.aUPMC GRC11-GRECHY, AP-HP Hôpital Pitié Salpêtrière, Paris, France 4 grid.7841.aDepartment of Cellular Biotechnologies and Hematology, ‘Sapienza’ University, Rome, Italy 5 0000 0004 0646 2097grid.412468.dSecond Department of Medicine, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany 6 0000000121858338grid.10493.3fClinic III, Hematology, Oncology and Palliative Medicine, University of Rostock, Rostock, Germany 7 0000000109409118grid.7256.6Ankara University, Ankara, Turkey 8 grid.427812.aOnkologische Gemeinschaftspraxis, Agaplesion Bethanien Krankenhaus, Frankfurt, Germany 9 0000 0004 0607 7295grid.419188.dNational Cancer Institute, Bratislava, Slovakia 10 OnkoZentrum Zürich, Zürich, Switzerland 11 State Hospital, Opole, Poland 12 Present Address: Haematology Department, University of Opole, Provincial Hospital, Opole, Poland 13 0000 0004 0374 1269grid.417570.0F. Hoffmann-La Roche Ltd, Basel, Switzerland 14 0000 0001 0675 8654grid.411083.fUniversity Hospital Vall d’Hebron, Barcelona, Spain 27 4 2018 27 4 2018 2018 32 8 1778 1786 22 11 2017 13 3 2018 28 3 2018 © The Author(s) 2018Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.GREEN (NCT01905943) is a non-randomized, open-label phase IIIb study investigating obinutuzumab alone or plus chemotherapy in chronic lymphocytic leukemia (CLL). We report a preplanned subgroup analysis of 158 previously untreated CLL patients receiving obinutuzumab–bendamustine (G-B). Patients received six 28-day cycles (C) of G-B: obinutuzumab day (D)1/D2 of C1 (25 mg D1/975 mg D2), 1000 mg D8 and D15 of C1, and D1 of C2–6; and bendamustine 70/90 mg/m2 D1 and D2 of C1–6. The primary endpoint was safety/tolerability. Grade ≥3 adverse events (AEs) occurred in 82.3% of patients, including neutropenia (49.4%), thrombocytopenia (12.0%) and febrile neutropenia (10.8%). Serious AEs included neutropenia (12.7%), febrile neutropenia (9.5%) and pneumonia (7.6%). Rates of grade ≥3 infections and infusion-related reactions were 20.3% and 17.1%, respectively. Due to tumor lysis syndrome (TLS; 8.2%), including two associated fatalities (one in another study cohort), additional risk-minimization measures were implemented. Overall response rate was 81.0%. After 32.8 months’ median observation time, 2-year progression-free survival was 81.8%. Minimal residual disease was undetectable in 59.5% (94/158) and 27.8% (44/158) of patients for blood and bone marrow, respectively. Frontline G-B appears to have manageable toxicity with clinical activity in CLL. Careful TLS risk assessment, pretreatment and monitoring is required.\n\nissue-copyright-statement© Springer Nature Limited 2018\n==== Body\nIntroduction\nChronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world [1]. The standard first-line treatment for physically fit CLL patients is chemoimmunotherapy with fludarabine–cyclophosphamide–rituximab (R-FC) [2–6]. However, many CLL patients are elderly with comorbidities and ineligible for fludarabine-based treatment [7, 8]. New combinations with less toxicity and alternative chemotherapy backbones are needed.\n\nChemoimmunotherapy with rituximab–bendamustine (R-B) is effective and well tolerated in fit patients with previously untreated or relapsed/refractory CLL [9, 10], although its efficacy was inferior to R-FC in the phase III CLL10 study [5]. The pivotal CLL11 study demonstrated that the glycoengineered, type II anti-CD20 antibody obinutuzumab (GA101) was superior to rituximab (combined with chlorambucil; G-Clb vs R-Clb) in treatment-naive patients with CLL and coexisting conditions [11]. Thus, there is a rationale for evaluating obinutuzumab–bendamustine (G-B) in CLL.\n\nGREEN (NCT01905943) is an ongoing phase IIIb study investigating obinutuzumab alone or with chemotherapy in previously untreated or relapsed/refractory CLL [12]. Here, we report on a preplanned safety and efficacy analysis from a subgroup of previously untreated CLL patients who received G-B in GREEN.\n\nPatients and methods\nStudy design\nGREEN is a non-randomized, open-label, non-comparative, multicenter study in previously untreated or relapsed/refractory CLL. The primary objective is to evaluate the safety/tolerability of obinutuzumab alone or combined with various chemotherapy regimens; the secondary objective is to assess efficacy. The exploratory objective is to investigate alternative obinutuzumab administration measures to mitigate/reduce infusion-related reactions (IRRs). For this, patients included in GREEN were assigned to three different cohorts (Supplementary Figure S1).\n\nPlanned analyses for GREEN were to report safety and efficacy summaries for each treatment regimen separately as well as pooled overall safety. Here, we report the subgroup of previously untreated patients receiving G-B assigned to cohort 1 of GREEN (trial fully accrued since 30 March 2016 (first enrolled, 24 October 2013), with follow-up ongoing), who received a modified obinutuzumab dosing regimen to mitigate IRRs: the initial dose was given in two parts on consecutive days (25 mg on day (D) 1 of cycle (C) 1 at an infusion rate of 12.5 mg/h, followed by 975 mg on D2 at an initial rate of 50 mg/h, then 1000 mg on D8 and D15 of C1, and D1 of C2–6 as standard).\n\nChemotherapy options (28-day cycles) in all cohorts were partly dependent on patient fitness and based on investigator choice (Supplementary Figure S1). Bendamustine was dosed at 90 mg/m2 (or 70 mg/m2 in unfit patients at the investigator’s discretion) on D1 and D2 of C1–6. Granulocyte colony-stimulating factor (G-CSF) use was permitted; primary prophylaxis was advised for patients aged ≥60 years and/or with comorbidities.\n\nRisk-minimization measures (including adequate hydration (fluid intake 3 l/day, starting 1–2 days before first obinutuzumab dose) and allopurinol (or similar e.g. rasburicase) prophylaxis for at least 72 h prior to first obinutuzumab dose) for tumor lysis syndrome (TLS) [13], an identified risk in patients treated with obinutuzumab, were included in the protocol from the start. Patients were considered at risk of TLS if they had node(s) ≥10 cm; or node(s) ≥5 cm and <10 cm, and an absolute lymphocyte count (ALC) ≥25 × 109/l or renal impairment (creatinine clearance (CrCl) <70 ml/min); or ALC ≥25 × 109/l and CrCl <70 ml/min. After two reports of fatal TLS cases in G-B-treated patients (including one in cohort 1), additional risk-minimization measures, including investigator training to emphasize the importance of TLS prophylaxis, were instigated for all cohorts, as described in the supplement. However, these additional measures did not apply to patients in cohort 1 as they had already completed treatment.\n\nGREEN was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines and local laws and was approved by institutional review boards/ethics committees at participating centers. Patients provided written informed consent. All authors had access to the primary clinical data and were involved in the data analysis.\n\nPatient population\nCohort 1 enrolled previously untreated CLL patients only. Inclusion criteria were: age ≥18 years; requiring treatment per International Workshop on CLL (iwCLL) criteria; [14] adequate hematologic function; and Eastern Cooperative Oncology Group performance status ≤2. Patients with a 17p deletion could be enrolled; those with severe renal impairment (CrCl <30 ml/min) were excluded. Full inclusion/exclusion criteria for previously untreated CLL patients (cohorts 1–3) are detailed in the supplement.\n\nStudy endpoints\nThe primary endpoint of GREEN was safety/tolerability. Secondary endpoints were overall response rate (ORR) including complete response (CR), progression-free survival (PFS) and minimal residual disease (MRD).\n\nAssessments\nSafety\nAdverse events (AEs), serious AEs (SAEs) and AEs of special or particular interest (AESI/AEPI) were monitored and graded using National Cancer Institute Common Terminology Criteria for AEs version 4.0. IRRs were defined as any AE occurring during or within 24 h of obinutuzumab infusion and considered related to obinutuzumab.\n\nEfficacy\nORR was assessed by the investigator per iwCLL criteria [14] at the ‘final response assessment’ visit (scheduled 84 days after last treatment dose). A computed tomography (CT) scan was required to confirm CR and partial response (PR); patients lacking a valid CT scan were classed as stable disease (SD). A bone marrow biopsy was required for confirmation of CR; patients otherwise meeting CR criteria but lacking a valid biopsy were classed as PR. Other efficacy assessments including PFS, MRD measurement and analysis of prognostic markers are detailed in the supplement.\n\nStatistical methodology\nDetails of the sample size estimation are provided in the supplement. Safety variables were analyzed in the safety population (N = 158), i.e., all patients who received at least one dose of study treatment. Efficacy variables were analyzed in the intent-to-treat (ITT) population (N = 158), comprising all patients from cohort 1 who received at least a partial dose of both obinutuzumab and bendamustine (data cut-off, 29 December 2016). For the MRD analyses, the ‘intent-to-ship’ population (N = 140) comprised all patients whose MRD samples at the final response assessment could be shipped to the central laboratory within 48 h (thus excluding Argentina, Brazil, Canada, China, Korea, Mexico, Thailand and Uruguay). The ‘MRD-evaluable’ population (N = 105) comprised all patients with an available MRD result (blood or bone marrow).\n\nFor ORR, patients with a missing response assessment during the defined time window (D56–168 after last treatment dose) were considered non-responders. Response rates were presented with two-sided, 95% Clopper–Pearson confidence intervals (CIs). Estimates for the survival functions for PFS were obtained using the Kaplan–Meier approach. After the data snapshot was taken for analysis, a further 5 AEs related to 4 patients in this subgroup were reported late by the sites on the database that remained open to continue collecting information until the final analysis. In addition, one patient with SD at the final response assessment had this changed to PR. These updates are not part of the statistical analysis summary tables and listings presented. Please see Supplementary Tables S1 and S2.\n\nResults\nPatient, treatment exposure and observation time\nThe ITT population comprised 158 patients with CLL (70 fit, 88 unfit) (Table 1; Supplementary Figure S2). Mean number of obinutuzumab administrations was 8.4 (planned, 9) and 149 (94.3%) patients received ≥90% of the planned dose (based on actual/planned doses). Mean number of bendamustine cycles was 5.3 (planned, 6), with 142 (89.9%) patients receiving ≥90% of the planned dose (68 patients received bendamustine 70 mg/m2 and 90 patients received 90 mg/m2). Median observation time was 32.8 (range, 0.5–37.5) months.Table 1 Baseline patient characteristics in patients receiving G-B in cohort 1 of the GREEN study (intent-to-treat population)\n\nCharacteristic\tAll patients (N = 158)\t\nMedian age, years (range)\t69.0 (42–83)\t\nMale/female, n (%)\t103/55 (65.2/34.8)\t\nCIRS >6, n (%)\t28 (17.7)\t\nCrCl <70 ml/min, n (%)\t73 (46.2)\t\nCrCl <50 ml/min, n (%)\t21 (13.3)\t\nCIRS >6 and CrCl <70 ml/min, n (%)\t13 (8.2)\t\nFitness, n (%)\t\n Fita\t70 (44.3)\t\n Unfitb\t88 (55.7)\t\nBinet stage at screening, n (%)\t\n A\t48 (30.4)\t\n B\t57 (36.1)\t\n C\t53 (33.5)\t\nAbsolute lymphocyte count, N = 155, n (%)\t\n ≥50 × 109/l\t88 (56.8)\t\nTumor bulk, N = 139, n (%)\t\n ≥5 cm\t95 (68.3)\t\nGenomic aberrations, N = 146, n (%)c\t\n 17p deletion\t11 (7.5)\t\n 11q deletion\t26 (17.8)\t\n 12q trisomy\t26 (17.8)\t\n 13q deletion\t52 (35.6)\t\n Other abnormality\t6 (4.1)\t\n Normal\t25 (17.1)\t\nIGHV, N = 136, n (%)\t\n Unmutated\t92 (67.6)\t\n Mutated\t44 (32.4)\t\nZAP70, N = 129, n (%)\t\n Positive\t82 (63.6)\t\n Negative\t47 (36.4)\t\nCD38, N = 129, n (%)\t\n Positive\t70 (54.3)\t\n Negative\t59 (45.7)\t\nCIRS Cumulative Illness Rating Scale, CrCl creatinine clearance, G-B obinutuzumab plus bendamustine, IGHV immunoglobulin heavy variable chain\n\na CIRS ≤6 and CrCl ≥70 ml/min\n\nb CIRS >6 and/or CrCl <70 ml/min\n\nc According to the hierarchical model of genomic aberrations [29]\n\n\n\nSafety\nMost patients (96.8%, 153/158) reported at least one AE; neutropenia (62.7%), pyrexia (41.8%) and thrombocytopenia (32.3%) were the most frequent. Overall, 88.6% of patients experienced at least one treatment-related AE, most commonly neutropenia (57.0%), pyrexia (31.0%) and thrombocytopenia (29.1%). Twenty-six patients (16.5%) discontinued at least one study treatment prematurely due to an AE, 11 (7.0%) of whom did so because of neutropenia. G-CSF was administered to 107/158 (67.7%) patients at least once during the study. Common grade ≥3 AEs, serious AEs and grade ≥3 AESI are summarized in Table 2.Table 2 Grade 3 or higher adverse events and serious adverse events in patients receiving G-B in cohort 1 of the GREEN study (safety population)\n\nn (%)\tAll patients (N = 158)\tFit patientsa (n = 70)\tUnfit patientsb (n = 88)\t\nGrade ≥3 AEs (reported by ≥2% patients in overall population) by preferred term\t\n Any\t130 (82.3)\t52 (74.3)\t78 (88.6)\t\n Neutropenia\t78 (49.4)\t34 (48.6)\t44 (50.0)\t\n Thrombocytopenia\t19 (12.0)\t8 (11.4)\t11 (12.5)\t\n Febrile neutropenia\t17 (10.8)\t8 (11.4)\t9 (10.2)\t\n Lymphopenia\t14 (8.9)\t6 (8.6)\t8 (9.1)\t\n Anemia\t13 (8.2)\t3 (4.3)\t10 (11.4)\t\n Leukopenia\t13 (8.2)\t6 (8.6)\t7 (8.0)\t\n Tumor lysis syndrome\t13 (8.2)\t2 (2.9)\t11 (12.5)\t\n Pneumonia\t12 (7.6)\t5 (7.1)\t7 (8.0)\t\n Hypertension\t11 (7.0)\t5 (7.1)\t6 (6.8)\t\n Hyperglycemia\t6 (3.8)\t4 (5.7)\t2 (2.3)\t\n Squamous cell carcinoma\t5 (3.2)\t1 (1.4)\t4 (4.5)\t\n Diarrhea\t4 (2.5)\t0\t4 (4.5)\t\n Hyperuricemia\t4 (2.5)\t4 (5.7)\t0\t\nSerious AEs (reported by ≥2% patients in overall population) by preferred term\t\n Any\t96 (60.8)\t37 (52.9)\t59 (67.0)\t\n Neutropenia\t20 (12.7)\t9 (12.9)\t11 (12.5)\t\n Febrile neutropenia\t15 (9.5)\t6 (8.6)\t9 (10.2)\t\n Pneumonia\t12 (7.6)\t5 (7.1)\t7 (8.0)\t\n Pyrexia\t11 (7.0)\t4 (5.7)\t7 (8.0)\t\n Tumor lysis syndrome\t6 (3.8)\t0\t6 (6.8)\t\n Squamous cell carcinoma\t4 (2.5)\t1 (1.4)\t3 (3.4)\t\n Thrombocytopenia\t4 (2.5)\t1 (1.4)\t3 (3.4)\t\nGrade ≥3 AESI/AEPIc\t\n Neutropenia\t84 (53.2)\t37 (52.9)\t47 (53.4)\t\n Infections\t32 (20.3)\t11 (15.7)\t21 (23.9)\t\n IRRs\t27 (17.1)\t9 (12.9)\t18 (20.5)\t\n Thrombocytopenia\t19 (12.0)\t8 (11.4)\t11 (12.5)\t\n Second malignancies\t13 (8.2)\t4 (5.7)\t9 (10.2)\t\n Tumor lysis syndrome\t13 (8.2)\t2 (2.9)\t11 (12.5)\t\nAE adverse event, AEPI adverse events of particular interest, AESI adverse events of special interest, CIRS Cumulative Illness Rating Scale, CrCl creatinine clearance, G-B obinutuzumab plus bendamustine, IRR infusion-related reaction, MedDRA Medical Dictionary for Regulatory Activities\n\na CIRS ≤6 and CrCl ≥70 ml/min\n\nb CIRS >6 and/or CrCl <70 ml/min\n\nc IRRs were defined as any AE occurring during or within 24 h of obinutuzumab infusion and considered related to obinutuzumab; infection selection was via the MedDRA system order class ‘Infections and Infestations’; second malignancy selection was via the MedDRA system organ class ‘Neoplasms Benign, Malignant, and Unspecified’ starting 6 months after the first study drug intake; neutropenia and thrombocytopenia selection was via their MedDRA basket dataset subgroups; and tumor lysis syndrome was defined by its preferred term\n\n\n\nIRRs occurred in 57.6% (n = 91) of patients; 17.1% (n = 27) experienced grade ≥3 IRRs. Serious IRRs occurred in 10.1% (n = 16) of patients (no fatal cases). Infections occurred in 54.4% (n = 86) of patients; 20.3% reported grade ≥3 infection. Grade ≥3 infections (by preferred term) in more than one patient were: pneumonia (n = 12); sepsis and urinary tract infection (n = 3 each); and cytomegaloviral pneumonia, erysipelas, herpes zoster and lung infection (n = 2 each). Serious infections occurred in 19.6% of patients, including (≥1%): pneumonia (n = 12); sepsis (n = 3); and herpes zoster, lung infection, cytomegaloviral pneumonia and urinary tract infection (n = 2 each). Grade ≥3 AEs related to neutropenia were reported by 53.2% of patients. TLS (grade ≥3) was observed in 13 (8.2%) patients, and included one fatality. TLS was one of the most common SAEs (n = 6; 3.8%) by preferred term, along with neutropenia (12.7%), febrile neutropenia (9.5%), pneumonia (7.6%) and pyrexia (7.0%) (Table 2).\n\nThe tolerability of G-B appeared more favorable in fit vs unfit patients based on rates of grade ≥3 AEs and SAEs (Table 2). Rates of grade ≥3 TLS, infections and IRRs were numerically lower in fit vs unfit patients. Serious TLS events occurred in 6.8% of unfit patients, but were not observed in fit patients.\n\nSeventeen deaths (10.8%) were reported (fit n = 6; unfit n = 11), two of which occurred on, or within 28 days of last, study treatment; five deaths (all resulting from AEs) were considered related to treatment (West Nile virus infection, acute liver failure, febrile neutropenia with TLS, arrhythmia and brain metastasis of adenocarcinoma). Four deaths were due to disease progression and 13 were due to AEs (two with prior progressive disease (PD]) (Supplementary Table S3).\n\nResponse assessment\nORR at the final response assessment was 81.0% (95% CI, 74.0–86.8; CR (including CR with incomplete marrow recovery (CRi)), 34.8%; Table 3). Overall, 9.5% of patients had a missing assessment and were classed as non-responders. ORR was broadly similar in unfit and fit patients (Table 3), and of those patients who reported TLS in the ITT population, 69.3% (9/13) responded to treatment. Response rates were also similar between bendamustine dose groups (70 mg/m2: ORR, 83.8% (57/68; 95% CI, 72.9–91.6); CR/CRi, 38.2% (26/68); 90 mg/m2: ORR, 78.9% (71/90; 95% CI, 69.0–86.8); CR/CRi, 32.2% (29/90)).Table 3 Response in patients receiving G-B in cohort 1 of the GREEN study at final response assessment (intent-to-treat population)\n\nResponse, n (%)\tAll patients (N = 158)\tFit patientsa (n = 70)\tUnfit patientsb (n = 88)\t\nOverall response\t128 (81.0)\t60 (85.7)\t68 (77.3)\t\nComplete responsec\t55 (34.8)\t23 (32.9)\t32 (36.4)\t\nPartial response\t73 (46.2)\t37 (52.9)\t36 (40.9)\t\nStable disease\t13 (8.2)\t4 (5.7)\t9 (10.2)\t\nProgressive disease\t2 (1.3)\t1 (1.4)\t1 (1.1)\t\nFailure (due to missing assessment)\t15 (9.5)\t5 (7.1)\t10 (11.4)\t\nCIRS Cumulative Illness Rating Scale, CrCl creatinine clearance, G-B obinutuzumab plus bendamustine\n\na CIRS ≤6 and CrCl ≥70 ml/min\n\nb CIRS >6 and/or CrCl <70 ml/min\n\nc Including complete response with incomplete marrow recovery\n\n\n\nMedian PFS was not reached; at data cut-off, 23.4% of patients had experienced an event (Fig. 1a). Estimated PFS at 12 and 24 months was 92.3% and 81.8%, respectively. PFS appeared similar in fit vs unfit patients (Fig. 1b). Despite the limited size of subgroups, there was a trend for shorter PFS in older patients (≥65 years), and in patients with a 17p or 11q deletion, 12q trisomy, unmutated immunoglobulin heavy variable chain (IGHV) or CD38+ CLL (Supplementary Table S4; Fig. 1c, d).Fig. 1 Progression-free survival in patients receiving G-B in cohort 1 of GREEN: a in the overall study population; b in fit vs unfit patients; c by genomic aberrations, according to the hierarchical model [29]; d by IGHV mutation status; and e by MRD status at final response assessment in blood (intent-to-treat population). *CIRS ≤6 and CrCl≥ 70 ml/min; †CIRS >6 and/or CrCl <70 ml/min; ‡these data should be interpreted with caution as the subgroups are based on a study outcome, not baseline characteristics. There was also a low number of events (n = 20) and small number of MRD-positive patients (n = 9). The MRD-evaluable subgroup comprised patients who did not progress or die and had an MRD result available at the final response assessment in either blood or bone marrow (n = 105). The time window for MRD assessment was 77 to 168 days after last treatment. The MRD-‘missing’ subgroup included 54 patients. In addition, 1 out of 105 patients had a result available only in bone marrow and therefore came out as ‘missing’ in the blood population (therefore the ‘missing’ group in e is n = 55 and not 54). Reasons for ‘missing’ included sample not taken (n = 20), shipment could not take place within 48 h (n = 18), measurement was outside the time window for the final response assessment (n = 9) or other reason (n = 7). Eleven patients with missing MRD status (in blood and bone marrow) progressed (n = 5) or died (n = 6) within the period since last treatment dose up to 168 days. CIRS Cumulative Illness Rating Scale, CrCl creatinine clearance, G-B obinutuzumab plus bendamustine, IGHV immunoglobulin heavy variable chain, MRD minimal residual disease, PFS progression-free survival\n\n\n\nMRD analysis at final response assessment\nFor the ITT population, undetectable MRD (<10-4, i.e., MRD-negativity (MRD–)) was observed in 59.5% (94/158) and 27.8% (44/158) for blood and bone marrow samples, respectively. MRD– rates in the intent-to-ship population were 67.1% (94/140; blood) and 31.4% (44/140; bone marrow). The MRD-evaluable population comprised 104 patients with an evaluable blood sample and 65 with an evaluable bone marrow sample (64 with blood and bone marrow and 1 with bone marrow only). MRD– rates in the MRD-evaluable population were 90.4% (94/104) and 67.7% (44/65) for blood and bone marrow, respectively (Table 4).Table 4 Disease characteristics and response (MRD or clinical) at the final response assessment in patients receiving G-B in cohort 1 of the GREEN study\n\nFactor, n/N (%) patients\tMRD negativea (blood)\tMRD negativea (bone marrow)\tCR/Crib\t\nAll patients\t94/104 (90.4)\t44/65 (67.7)\t55/158 (34.8)\t\nBinet stage A\t32/32 (100)\t13/18 (72.2)\t19/48 (39.6)\t\nBinet stage B+C\t62/72 (86.1)\t31/47 (66.0)\t36/110 (32.7)\t\nDisease bulk ≥5 cm\t57/64 (89.1)\t27/39 (69.2)\t29/95 (30.5)\t\nALC ≥50 × 109/l\t52/59 (88.1)\t25/38 (65.8)\t33/88 (37.5)\t\n17p deletion\t3/6 (50.0)\t2/3 (66.7)\t2/11 (18.2)\t\n11q deletion\t18/23 (78.3)\t5/15 (33.3)\t7/26 (26.9)\t\n12q trisomy\t18/20 (90.0)\t12/14 (85.7)\t8/26 (30.8)\t\n13q deletion\t32/32 (100)\t13/19 (68.4)\t22/52 (42.3)\t\nCD38 positive\t49/55 (89.1)\t17/28 (60.7)\t22/70 (31.4)\t\nCD38 negative\t37/41 (90.2)\t22/30 (73.3)\t22/59 (37.3)\t\nZAP70 positive\t54/60 (90.0)\t22/34 (64.7)\t30/82 (36.6)\t\nZAP70 negative\t32/36 (88.9)\t17/24 (70.8)\t14/47 (29.8)\t\nIGHV mutated\t31/31 (100)\t12/17 (70.6)\t17/44 (38.6)\t\nIGHV unmutated\t58/68 (85.3)\t28/44 (63.6)\t30/92 (32.6)\t\nALC absolute lymphocyte count, CR complete response, CRi complete response with incomplete marrow recovery, G-B obinutuzumab plus bendamustine, IGHV immunoglobulin heavy variable chain, MRD minimal residual disease\n\na Patients with evaluable (laboratory sample with a valid result at the final response assessment) MRD\n\nb Patients who achieved CR/CRi at the final response assessment in the intent-to-treat population\n\n\n\nMRD– rates were similar for bendamustine dose groups: 92.3% (36/39; 95% CI, 79.1–98.4) and 89.2% (58/65; 95% CI, 79.1–95.6) for 70 and 90 mg/m2, respectively.\n\nPatients who were MRD negative in blood at final response assessment had longer PFS than those who were not (Fig. 1e); however, this may be biased as all early withdrawals had no MRD assessment at the final response assessment by definition.\n\nDiscussion\nIn the phase Ib GALTON and phase II GIBB studies, G-B appeared to have acceptable toxicity and was active in previously untreated CLL patients [15, 16]. Our subgroup analysis of a cohort of first-line patients receiving G-B indicates a similar trend in a larger international, multicenter study, and suggests that G-B may have manageable toxicity and promising efficacy in most patients. However, it also highlights the need for effective monitoring and management of TLS in G-B-treated patients. Thirteen (8.2%) patients herein experienced TLS with one associated death, whereas the incidence of TLS with G-Clb in the pivotal CLL11 trial was 4% with no associated deaths [11]. With the development of increasingly efficacious treatments, recognition and management of TLS in CLL is of ever-greater importance, especially when such treatments are given to patients with comorbidities, such as renal impairment. Specific guidance for the prevention and treatment of TLS and IRRs is provided in the labeling for obinutuzumab [17, 18], and a manuscript reporting the outcome of different IRR risk-mitigation strategies employed in GREEN will be published separately.\n\nIn addition, as detailed in the supplement, at-risk patients must be recognized prior to treatment initiation, receive appropriate prophylaxis and be monitored closely for occurrence of TLS signs during initial treatment. Any additional guidelines according to standard practice should be followed.\n\nAEs were consistent with the known safety profile of obinutuzumab. Rapid B-cell depletion with obinutuzumab, accompanied by rapid release of cytokines including interleukin-6, interleukin-8 and tumor necrosis factor alpha, may explain the frequency and intensity of IRRs with obinutuzumab vs rituximab [11, 19]. Grade ≥3 IRRs developed in 20.5% of unfit patients (17.1% of G-B patients overall), which was comparable with that (20%) reported for G-Clb in CLL11 [11]. As with G-Clb in CLL11, no IRRs were fatal. Obinutuzumab administration in this subcohort of GREEN differed from that in CLL11 for the initial 1000 mg, with an alternative split dose (25 mg on D1 at 12.5 mg/h, and 975 mg on D2) [11]. Although split dosing did not appear to substantially reduce the incidence of IRRs vs CLL11, differences in study designs, treatment regimens and patient populations limit this comparison. Grade ≥3 TLS and IRRs, and TLS as an SAE, were more frequently reported in unfit compared with fit patients, highlighting the need to monitor unfit patients and provide appropriate prophylaxis.\n\nGrade ≥3 neutropenia was reported in approximately half of patients, which was higher than that previously reported with G-Clb and R-B, but similar to that seen with G-B and G-FC [9, 11, 16]; importantly, grade ≥3 neutropenia with G-B in the present study was not associated with a marked increase in infections.\n\nSeventeen deaths were reported in this cohort; 13 were due to AEs, of which 5 were considered related to G-B and 2 occurred post PD (Supplementary Table S3). No deaths were reported in the phase Ib GALTON study in fit patients with previously untreated CLL treated with G-B; however, this was a relatively small study (20 patients received G-B) undertaken at select sites [16]. Three deaths were reported among 102 patients in the phase II GIBB trial, but none were deemed related to treatment or CLL [15]. In CLL11, the percentage of patients with a fatal AE was lower with G-Clb (4%) than with rituximab-chlorambucil (R-Clb) or chlorambucil alone (6% and 9%, respectively) [11].\n\nPatients receiving G-B achieved an ORR of 81.0%, with CR/CRi and PR in 34.8% and 46.2% of patients, respectively. Notably, response data were missing for 9.5% of patients (classed as non-responders). Despite some differences in response assessment (timing and criteria) between studies, response rates in all patients were broadly comparable with those reported for R-B in CLL10 (fit patients: ORR 96%, CR 31%) [5], G-Clb in CLL11 (unfit patients: ORR 78.4%, CR 20.7%) [11], and G-B in the GALTON (fit patients: ORR 90%, CR/CRi 45%) [16] and GIBB (ORR 89.2%; CR/CRi 49.0%) [15] studies. Efficacy (response and PFS) was also similar to R-FC in CLL8 (fit patients) [3]. Importantly, response rates were similar between fit and unfit patients, and a high CR rate was noted in patients with Binet stage B+C CLL, showing that G-B is efficacious in this population. The high CR/CRi rate in patients with unmutated IGHV (34.8%) was reassuring given the association between unmutated IGHV status and poor prognosis [20].\n\nMRD status has been identified as a strong post-treatment prognostic factor after chemoimmunotherapy, with MRD– independently associated with superior PFS and overall survival [21–24]. The sensitive quantification of MRD using flow cytometry in patients with CLL is well documented [25–28]. MRD– in blood after G-B is expected to be associated with a favorable course during follow-up, as reported with G-Clb in CLL11 or R-FC in CLL8 [4, 11]. Despite the limited sample size and potential for bias, as patients were categorized based on outcome rather than baseline characteristics, the PFS data obtained so far in the present analysis are suggestive of a favorable prognosis in MRD-negative patients. The apparent discord between the high rate of MRD– but slightly lower than expected CR rates likely reflects the rigorous iwCLL assessment criteria [14] used for response classification and that patients with missing assessments within the required time window were down-classed.\n\nGenomic factors, such as 11q and 17p chromosome deletions, mutated TP53, unmutated IGHV status, ZAP70 expression, and markers including increased serum β2-microglobulin, are associated with poor prognosis [4, 29–34]. In GREEN, patients with an ALC ≥50 × 10-9/l, disease bulk ≥5 cm, Binet stage B+C or unmutated IGHV achieved high MRD– remission levels, while lower levels were seen in patients harboring 17p or 11q deletions. The low MRD– and response rates, and shorter PFS in patients with a 17p deletion, reflects the known poor prognosis of this subgroup and emphasizes that these patients need alternative treatment. As numbers in the GREEN analysis were relatively small, the promising MRD– data warrant further investigation of the G-B regimen.\n\nIn summary, G-B may represent a new option for previously untreated CLL patients regardless of fitness. Although the non-comparative design of GREEN prevents formal statistical analysis, frontline G-B appeared to have manageable toxicity in fit or unfit patients with CLL. Nonetheless, the TLS rate and associated fatalities highlights the need for careful risk assessment, prophylaxis and monitoring. The low rate of progression and excellent rates of MRD– with G-B indicate that this combination is clinically active. Further follow-up is required to confirm these observations.\n\nElectronic supplementary material\n\nStilgenbauer_Green_supplement_revised_clean\n\n \n\n\nElectronic supplementary material\nThe online version of this article (10.1038/s41375-018-0146-5) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nThe authors would like to thank the patients and their families, and the GREEN study investigators, coordinators, and nurses. Additionally, the authors would like to acknowledge the scientists and technicians at the German CLL Study Group laboratories who undertook the molecular and laboratory analyses, and Kerstin Trunzer (Roche) for her contribution to the minimal residual disease analyses. We would also like to thank Nicola Tyson (F. Hoffmann-La Roche Ltd) for her support and guidance with these analyses, as well as Corinna Miede (Accovion GmBH, Marburg, Germany) who also provided invaluable support regarding the data. Editorial support under the direction of the lead author was provided by Cheryl Wright and Scott Malkin of Gardiner-Caldwell Communications (Macclesfield, UK), funded by F. Hoffmann-La Roche Ltd. GREEN was sponsored by F. Hoffmann-La Roche Ltd.\n\nFunding\nThis study was sponsored by F. Hoffmann-La Roche Ltd.\n\nCompliance with ethical standards\nSS reports consulting fees, research funding, honoraria and membership of advisory committees from Roche. VL reports speaker’s bureau fees, consulting fees, research funding, honoraria and membership of advisory committees from Roche; speaker’s bureau fees, consulting fees, honoraria and membership of advisory committees from Janssen; speaker’s bureau fees, honoraria and membership of advisory committees from Gilead and GSK; membership of advisory committees for AbbVie; and speaker’s bureau fees from Mundipharma. RF reports speaker’s bureau fees, consulting fees, honoraria and membership of advisory committees from Roche, Janssen, Celgene, AbbVie, Amgen and Novartis. SB reports consulting fees from Roche and AbbVie; research funding from Roche, AbbVie and Celgene; and honoraria from Roche, AbbVie and Beckton Dickinson. WK reports honoraria and participation in advisory boards for Roche and Mundipharma. CR reports research funding and membership of advisory committees from Roche and Celgene. FB reports consulting fees and honoraria from Roche, Novartis, Janssen, AbbVie, Gilead and Mundipharma; and research funding from Roche and Janssen. OI, EM, ET and DW report research funding from Roche. EG, LL, T Moore, T Morris and SR report employment from Roche.\n==== Refs\nReferences\n1. Tadmor T Polliack A Optimal management of older patients with chronic lymphocytic leukemia: some facts and principles guiding therapeutic choices Blood Rev 2012 26 15 23 10.1016/j.blre.2011.09.002 21955980 \n2. 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"fulltext_license": "CC BY",
"issn_linking": "0887-6924",
"issue": "32(8)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D018365:Neoplasm, Residual; D011379:Prognosis; D012074:Remission Induction; D000069283:Rituximab; D016879:Salvage Therapy; D015996:Survival Rate",
"nlm_unique_id": "8704895",
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"pages": "1778-1786",
"pmc": null,
"pmid": "29749403",
"pubdate": "2018-08",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "21955980;27573660;26447188;26486789;18216293;24735016;12149225;24652989;26314781;24401022;18577710;15738539;25213181;22869884;21561350;25769620;22331940;26492934;20888994;27216274;16449533;12111110;19641522;21844497;20511662;26576865;11418459;26181643;11136261;12149195",
"title": "Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study.",
"title_normalized": "obinutuzumab plus bendamustine in previously untreated patients with cll a subgroup analysis of the green study"
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"abstract": "Pediatric RCC is a rare pediatric neoplasm and is distinctly different compared to adult RCC, often demonstrating translocation morphology evidenced by unique histopathological features and TFE3 or TFEB nuclear expression. We report three cases of pediatric TFE3 positive RCC (TFE3-RCC) occurring in the setting of chronic kidney disease and long-term pharmacological immunosuppression, including two cases that developed in the native kidney following kidney transplantation. Together, these cases suggest that the kidney microenvironment in combination with immune dysregulation is likely contributing factors in the pathogenesis of some pediatric RCC, warranting further study. Long-term post-transplant surveillance may warrant screening for RCC.",
"affiliations": "Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.;Division of Pediatric Hematology/Oncology, Medical College of Georgia, Augusta University, Augusta, GA, USA.;Division of Pediatric Nephrology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.;Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.;Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.",
"authors": "Schaefer|Beverly A|BA|http://orcid.org/0000-0001-5427-9666;Johnson|Theodore S|TS|;Hooper|David K|DK|;Nathan|Jaimie D|JD|;Geller|James I|JI|",
"chemical_list": "D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents; C069203:TFE3 protein, human",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12912",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(4)",
"journal": "Pediatric transplantation",
"keywords": "TFE3-positive RCC; pediatric renal transplant; renal cell carcinoma",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; D002292:Carcinoma, Renal Cell; D002648:Child; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D007676:Kidney Failure, Chronic; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D008297:Male; D011183:Postoperative Complications; D059016:Tumor Microenvironment",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28322484",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "TFE3-positive renal cell carcinoma occurring in three children with dysfunctional kidneys on immunosuppression.",
"title_normalized": "tfe3 positive renal cell carcinoma occurring in three children with dysfunctional kidneys on immunosuppression"
} | [
{
"companynumb": "US-PFIZER INC-2017289365",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Medium-vessel hemorrhage is a rare occurrence in ANCA-associated vasculitis, and has been previously described in only a few patients with microscopic polyangiitis. We report a case of renal hemorrhage in a patient with microscopic polyangiitis that was successfully managed by transcatheter arterial embolization of the active bleeding sites. The early clinical findings included necrotizing arteritis, as indicated by skin biopsy; rapidly progressive glomerulonephritis; mononeuritis multiplex; positive screening for myeloperoxidase-specific antineutrophil cytoplasmic antibody. Corticosteroid therapy was initiated. The patient's health deteriorated at 1 week, with rapidly progressing anemia. Computerized tomography identified a large, right-sided, perirenal hematoma, with active bleeding. Bleeding was successfully managed via segmental embolization of the renal artery. The patient was treated with steroid therapy and MZR, and subsequently underwent maintenance hemodialysis treatment for end-stage renal disease. Spontaneous renal hemorrhage is a rare but fatal clinical condition. A ruptured renal artery should be considered in a patient with microscopic polyangiitis, even in the absence of previous trauma and renal biopsy, when unexplained anemia or signs of shock occur.",
"affiliations": "Department of Nephrology, Okubo Hospital, 2-44-1 Kabuki-cho, Shinjuku-ku, Tokyo, 160-8488, Japan. ayumi_ishiwatari@tokyo-hmt.jp.;Department of Nephrology, Okubo Hospital, 2-44-1 Kabuki-cho, Shinjuku-ku, Tokyo, 160-8488, Japan.;Department of Nephrology, Okubo Hospital, 2-44-1 Kabuki-cho, Shinjuku-ku, Tokyo, 160-8488, Japan.",
"authors": "Ishiwatari|Ayumi|A|;Endo|Mariko|M|;Wakai|Sachiko|S|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D012263:Ribonucleosides; D013256:Steroids; C010052:mizoribine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-018-0347-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "7(2)",
"journal": "CEN case reports",
"keywords": "Antineutrophil cytoplasmic antibody (ANCA); Artery embolization; Microscopic polyangiitis; Perirenal hematoma; Renal hemorrhage",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D000903:Antibiotics, Antineoplastic; D004621:Embolization, Therapeutic; D005260:Female; D006406:Hematoma; D006470:Hemorrhage; D006801:Humans; D007668:Kidney; D007676:Kidney Failure, Chronic; D055953:Microscopic Polyangiitis; D012077:Renal Artery; D006435:Renal Dialysis; D012263:Ribonucleosides; D012421:Rupture; D013256:Steroids; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "301-306",
"pmc": null,
"pmid": "29951966",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18344639;645752;20052390;23045170;12413009;11912370;6847264;19054820;20860908;23956316;16901958;8883433;19379174;13159085;13217492;21974709;17888497;34221;14605297;15211438",
"title": "Ruptured renal artery in microscopic polyangiitis: a case report and literature review.",
"title_normalized": "ruptured renal artery in microscopic polyangiitis a case report and literature review"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1090089",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIANSERIN"
},
"drugadditional": "3",
... |
{
"abstract": "The adverse impact of chronic corticosteroid therapy on wound healing has been well characterized, as has abnormal wound healing known to occur in the classic type of Ehlers-Danlos syndrome (EDS). In contrast, abnormal wound healing is absent in cases of EDS benign hypermobility type (EDS-BHT). We present the case of a patient with EDS-BHT with no history of abnormal wound healing who developed large nonhealing ulcers to sites of minor trauma after initiating therapy with high-dose systemic corticosteroids for dermatomyositis. This case provides a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect of the connective tissue.",
"affiliations": "Ohio State University, Columbus, USA.;Ohio State University, Columbus, USA.",
"authors": "Jacks|Stephanie K|SK|;Zirwas|Matthew J|MJ|",
"chemical_list": "D005938:Glucocorticoids; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "98(4)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D003882:Dermatomyositis; D004535:Ehlers-Danlos Syndrome; D004550:Elbow; D005938:Glucocorticoids; D006229:Hand Dermatoses; D006801:Humans; D007717:Knee; D008297:Male; D009205:Myocarditis; D011241:Prednisone; D012883:Skin Ulcer; D014945:Wound Healing; D055815:Young Adult",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "E20-E23",
"pmc": null,
"pmid": "27874893",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abnormal wound healing related to high-dose systemic corticosteroid therapy in a patient with Ehlers-Danlos syndrome benign hypermobility Type.",
"title_normalized": "abnormal wound healing related to high dose systemic corticosteroid therapy in a patient with ehlers danlos syndrome benign hypermobility type"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-01840",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"... |
{
"abstract": "Intra-arterial infusion chemotherapy for locally advanced breast cancer (LABC) has been previously performed. However, the main complications of this type of chemotherapy remain to be clarified. In the present study, catheterization chemotherapy was carried out for 53 LABC cases (stage IIIa-IIIc) between May, 2006 and March, 2007. For IIIB and IIIC patients, the catheters were guided to the opening of the subclavian artery. For stage IIIa patients, the catheters were placed into the thoracic artery through a subcutaneous femoral artery puncture. One to four cycles of chemotherapy (mean, 1.6 cycles) were administered for the patients using taxotere, epidoxorubicin, 5-fluorouracil and/or cyclophosphamide. The interval time between the two cycles was 21 days. Seven cases were identified as complete response (CR, 13.2%), 41 cases were partial response (PR, 77.4%) with a rate of effectiveness of (CR + PR, 90.6%), 5 cases were stable disease (SD, 9.40%) and no case was progressive. Pain of the ipsilateral upper extremity was present in 7 cases. Two cases exhibited ipsilateral upper extremity atrophy following drug administration from the opening of the subclavian artery. One case experienced neck pain and headache, while in one case necrosis of local skin was evident. Hematological toxicity over grade 3 was observed in 6 cases (11.30%). Systemic toxicity was mild and did not affect the quality of life of the patients. Overall survival was identified as 18/51 (35.3%), and free-disease survival as 10/51 (19.6%). In conclusion, intra-arterial infusion chemotherapy is an effective local control treatment for LABC. The main complications are pain of the ipsilateral upper extremity and neck as well as headache. Severe complications are ipsilateral upper extremity atrophy and necrosis of local skin. During the treatment, controlling the pressure of the tourniquet and velocity of drug administration are crucial for reducing local complications.",
"affiliations": "Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China ;;Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China ;;Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China ;;Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China ;;Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China ;;Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China ;;Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China ;;Department of Surgical Oncology, Paul Strauss Cancer Center, 67065 Strasbourg, France.;Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China ;",
"authors": "Wang|Xiaoyi|X|;Gan|Changing|C|;Li|Hongyuan|H|;Wei|Yuxian|Y|;Zhu|Donchang|D|;Yang|Guanglun|G|;Su|Xinliang|X|;Rodier|Jean-François|JF|;Ren|Guosheng|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2013.129",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2013.129mco-01-04-0745ArticlesMain complications and results of treatment with intra-arterial infusion chemotherapy through the subclavian and thoracic arteries for locally advanced breast cancer WANG XIAOYI 1GAN CHANGING 1LI HONGYUAN 1WEI YUXIAN 1ZHU DONCHANG 1YANG GUANGLUN 1SU XINLIANG 1RODIER JEAN-FRANÇOIS 2REN GUOSHENG 11 Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, \nP.R. China;2 Department of Surgical Oncology, Paul Strauss Cancer Center, 67065 Strasbourg, \nFranceCorrespondence to: Professor Guosheng Ren, Department of Breast and Endocrine Surgery, First Affiliated Hospital, Chongqing Medical University, 1 You Yi Road, Chongqing 400016, P.R. China, E-mail: rgs726@163.com7 2013 23 5 2013 23 5 2013 1 4 745 748 11 11 2012 16 4 2013 Copyright © 2013, Spandidos Publications2013This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.Intra-arterial infusion chemotherapy for locally advanced breast cancer (LABC) has been previously performed. However, the main complications of this type of chemotherapy remain to be clarified. In the present study, catheterization chemotherapy was carried out for 53 LABC cases (stage IIIa–IIIc) between May, 2006 and March, 2007. For IIIB and IIIC patients, the catheters were guided to the opening of the subclavian artery. For stage IIIa patients, the catheters were placed into the thoracic artery through a subcutaneous femoral artery puncture. One to four cycles of chemotherapy (mean, 1.6 cycles) were administered for the patients using taxotere, epidoxorubicin, 5-fluorouracil and/or cyclophosphamide. The interval time between the two cycles was 21 days. Seven cases were identified as complete response (CR, 13.2%), 41 cases were partial response (PR, 77.4%) with a rate of effectiveness of (CR + PR, 90.6%), 5 cases were stable disease (SD, 9.40%) and no case was progressive. Pain of the ipsilateral upper extremity was present in 7 cases. Two cases exhibited ipsilateral upper extremity atrophy following drug administration from the opening of the subclavian artery. One case experienced neck pain and headache, while in one case necrosis of local skin was evident. Hematological toxicity over grade 3 was observed in 6 cases (11.30%). Systemic toxicity was mild and did not affect the quality of life of the patients. Overall survival was identified as 18/51 (35.3%), and free-disease survival as 10/51 (19.6%). In conclusion, intra-arterial infusion chemotherapy is an effective local control treatment for LABC. The main complications are pain of the ipsilateral upper extremity and neck as well as headache. Severe complications are ipsilateral upper extremity atrophy and necrosis of local skin. During the treatment, controlling the pressure of the tourniquet and velocity of drug administration are crucial for reducing local complications.\n\nlocally advanced breast cancerefficacy and complicationintra-arterial chemotherapysubclavian arterythoracic artery\n==== Body\nIntroduction\nLocally advanced breast cancer (LABC) is defined as patients who present with the clinical stages of T4 N0-1M0 and T3N1 (stage IIIa), T0-3 N2M0 (stage IIIb), and T0-4 N3M0 (stage IIIc), without distant metastasis. T and N staging were as per the 6th edition of the American Joint Committee on Cancer, the TNM staging classification and revision of the American Joint Committee on Cancer staging system for breast cancer (1). LABC is characterized by large breast tumors involving the skin or muscles of the chest wall and extensive involvement of the local lymph nodes. Therefore treatment involves combined modality including systemic chemotherapy, surgery and radiotherapy (2,3).\n\nGood local control and down-staging increase the possibility for surgery. Intra-arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutics, generating higher local drug concentrations at the tumor cell membrane and therefore enhancing cellular drug uptake. Drug exposure to the tumor starts at the time of drug uptake through the cell membrane. Studies have focused on intra-arterial infusion chemotherapy for LABC and results have demonstrated high local control (4–9). However, the main complications of intra-arterial infusion chemotherapy have yet to be reported. In the present study, we report on the results and main complications of intra-arterial infusion chemotherapy through the subclavian and thoracic arteries for 53 LABC cases for the period December, 2006 to December, 2010. The results demonstrated the efficacy of good local control for LABC and revealed serious complications with intra-arterial infusion chemotherapy.\n\nMaterials and methods\nSubjects\nThe patients with LABC were recruited from the Department of Breast and Endocrine Surgery, The First Affiliated Hospital of Chongqing Medical University, between December, 2006 and December, 2010. Clinical stage IIIa was identified in 10 patients, stage IIIb in 24 patients and stage IIIc in 19 patients. The patients were female with a mean age of 47.7 years (range, 28–67 years). Histological examination confirmed carcinoma of the breast (left side in 30 and right side in 23) by pathological diagnosis via fine needle biopsy pre-operative intra-arterial infusion chemotherapy. The findings of the chest X-ray, ventral ultrasonography, radioisotope scan and head nuclear magnetic resonance did not provide evidence of distant metastasis. This study was approved by the Ethics Committee of Chongqing Medical University. All patients provided written consent.\n\nTreatment\nThe patients were treated with angiography (Siemens Coroskop Plus, Germany) under local anesthesia. According to the Seldinger technique, a 6F catheter was inserted percutaneously into the femoral artery. Subsequently, the catheter was guided to the opening of the subclavian artery. An arteriogram of the subclavian, thoracic and vertebral arteries was obtained for the patients (Fig. 1). For patients in stage IIIa, the catheter was inserted into the thoracic artery (Fig. 2). For patients in stage IIIb and IIIc, the catheter was guided to the opening of the subclavian and lateral thoracic arteries (Fig. 1). Prior to drug administration, contrast agent (iohexol) was injected to comfirm the location of the catheter again and the ipsilateral upper arm was bundled with a tourniquet, at a pressure of 260–280 mmHg.\n\nDrug doses administered included taxotere (100 mg/m2), epidoxorubicin (100 mg/m2), 5-fluorouracil (1,000 mg) and/or cyclophosphamide (800 mg/m2). The tumor response, local lymph nodes and occurrence of local or systemic complications determined the number of cycles of chemotherapy for which there was an interval time of 21 days between two cycles.\n\nResponse criteria\nBased on the WHO criteria the response was estimated according to the clinical features following treatment and all the patients were evaluated by computerised tomography scan preoperation. Complete disappearance of all the lesions was considered a complete response (CR); macroscopic reduction in size by ≥50% was considered a partial response (PR); a reduction of 25–50% was designated as stable disease (SD); and the appearance of any new lesions not previously identified or an estimated increase of 25% in existent lesions was considered progressive disease.\n\nResults\nOf the 53 patients, 7 cases (13.2%) were CR; 41 cases (77.4%) were PR, with a rate of effectiveness of (CR + PR: 90.6%, 48/53); 5 cases (9.4%) were SD and no case was progressive. The treatment results of LABC are provided in Table I.\n\nMain complications\nComplications occurred mainly in the local areas. Pain of the ipsilateral upper extremity was noted in 7 cases. One case experienced neck pain and headache; this patient recovered 2 weeks later without any special treatment. Two cases had ipsilateral upper extremity atrophy and disability and did not recover within a time period of 6 months, following drug administration from the opening of the subclavian and lateral thoracic arteries. One case had necrosis of local skin, but recovered with conservative treatment. The systemic toxicity was mild and did not affect the quality of life of patients (Table I).\n\nOther complications\nOf the 53 patients, no complications related to the angiographic technique were observed. Hematological toxicity over grade 3 such as fever and without bleeding was observed in 6 cases (11.3%), while 9 patients had gastrointestinal symptoms including nausea, vomiting, diarrhea and stomachache. Cardiovascular toxicity was not observed (Table I).\n\nDiscussion\nAt present, a combination of systemic therapy with locoregional treatment (surgery and/or radiotherapy) constitutes the standard of care in LABC patients since improving locoregional control is associated with improved survival (10). In patients with stage III breast cancer treated with induction chemotherapy followed by surgery, radiotherapy or combination therapy, the risk of locoregional recurrence is at a range of 20% (9). The use of induction systemic therapy results in tumor downstaging and in selected LABC patients even allows for breast conserving surgery (11–14).\n\nIntra-arterial infusion chemotherapy is an effective and safe treatment for the local tumor control of LABC (7). In our data, which also demonstrated the good local control of LABC with intra-arterial infusion chemotherapy, the CR + PR was 90.6%, which was higher than that reported by Shimamoto et al (8), who noted that the local response rate was 77.3% (at least more than two regimens) and Pacetti et al (7) who noted that the response rate was 80%. Factors such as the drugs used and administration of chemotheraputic cycles likely affected the results of those authors. However, in the present study, treatment involved different methods of drug administration. For patients in stage IIIa, large breast tumors and the skin or muscles of the chest wall were usually involved, thus local control tumors were primary tumors. We inserted a catheter into the thoracic artery and administered the majority of the drugs into the chest area, as there would be more effective local control and downstaging. For patients in stage IIIb and IIIc, the local lymph nodes were usually extensively involved. Control of the regional lymph nodes was considered crucial, therefore, the catheter was guided to the opening of the subclavian and lateral thoracic arteries, allowing more drugs to be administered in the subclavian, superclavian and axilla regions These methods contributed to improving the response rate of local lesions and increased the possibility of surgery. However, results of the follow-up revealed that overall and disease-free survival had not improved.\n\nFew studies have reported on local complications following intra-arterial infusion chemotherapy for LABC. In the present study, severe complications were observed during treatment. Two patients in stage IIIb had ipsilateral upper extremity atrophy leading to disability, and these patients did not recover within a 6-month time period. Pain of the ipsilateral upper extremity was noted in 7 cases that recovered two weeks later without any special treatment. The reasons for these complications included the loosening of the tourniquet during drug administration, which caused the drugs to flow into the ipsilateral upper extremity, and/or rapid drug administration. One patient experienced neck pain and headache, but recovered without any special treatment. The reason for the symptoms involved drugs flowing into the vertebral artery.\n\nPrevious studies have reported toxicity with systemic chemotherapy and hematological toxicity over grade 3 in 4–65% of patients (15,16). Of the 53 patients included in the present study, no complications associated with the angiographic technique were observed. Hematological toxicity over grade 3 such as fever and without bleeding was observed in 6 cases (11.3%). The patients were treated with human granulocyte colony-stimulating factor (human GCSF) and recovered. Nine patients had gastrointestinal symptoms including nausea, vomiting, diarrhea and stomachache. The patients were administered timely symptomatic treatment and recovered. Cardiovascular toxicity was not observed.\n\nIn conclusion, intra-arterial infusion chemotherapy is an effective treatment for local tumor control and tumor downstaging of LABC, thereby increasing the possibility for surgery. Low systemic toxicity and good patient compliance are also beneficial. However, severe complications may occur during treatment. Thus, controlling the pressure of the tourniquet and velocity of drug administration are crucial for reducing local complications.\n\nFigure 1. For patients in stage IIIb and IIIc, the catheter was guided to the opening of the subclavian and lateral thoracic arteries. Prior to drug administration, a contrast agent (iohexol) was injected to comfirm the location of the catheter. An arteriogram of the subclavian, thoracic and vertebral arteries was obtained.\n\nFigure 2. Arteriogram of the thoracic artery. For patients in stage IIIa, the catheter was inserted into the thoracic artery. Prior to drug administration, contrast agent (iohexol) was injected to comfirm the location of the catheter.\n\nTable I. Patient characteristics, treatment, response and complications.\n\nNo.\tAge (years)\tStage\tLocation\tCycles\tDrugs\tResponse\tComplication\t\n1\t32\tIIIb\tLeft\t2\tEPI\tPR\tNo\t\n2\t28\tIIIb\tRight\t1\tEPI+CTX+5-FU\tSD\tInappetence\t\n3\t53\tIIIb\tRight\t1\tEPI+CTX+5-FU\tPR\tNo\t\n4\t67\tIIIb\tLeft\t1\tEPI\tPR\tPain of upper extremity\t\n5\t65\tIIIb\tLeft\t3\tEPI+CTX+5-FU\tCR\tInappetence\t\n6\t52\tIIIb\tRight\t1\tEPI+5-FU\tPR\tNo\t\n7\t51\tIIIa\tLeft\t1\tEPI+CTX+5-FU\tPR\tNo\t\n8\t47\tIIIa\tRight\t1\tEPI+CTX+5-FU\tPR\tNo\t\n9\t28\tIIIa\tLeft\t2\tT\tPR\tHematological toxicity over grade 3\t\n10\t32\tIIIb\tLeft\t4\tT\tCR\tNo\t\n11\t57\tIIIa\tRight\t1\tEPI+CTX+5-FU\tSD\tPain of upper extremity\t\n12\t67\tIIIc\tLeft\t4\tT\tCR\tHematological toxicity over grade 3\t\n13\t31\tIIIa\tLeft\t1\tEPI+CTX+5-FU\tPR\tNo\t\n14\t34\tIIIc\tRight\t1\tEPI+CTX+5-FU\tPR\tNo\t\n15\t51\tIIIa\tLeft\t1\tT\tPR\tNo\t\n16\t66\tIIIc\tRight\t1\tT\tPR\tPain of upper extremity\t\n17\t56\tIIIc\tRight\t2\tT\tPR\tNecrosis of local skin\t\n18\t41\tIIIa\tLeft\t1\tT\tPR\tNo\t\n19\t46\tIIIc\tRight\t2\tEPI+CTX+5-FU\tPR\tNo\t\n20\t39\tIIIc\tLeft\t2\tT\tPR\tNo\t\n21\t41\tIIIb\tLeft\t2\tEPI+CTX+5-FU\tPR\tNo\t\n22\t45\tIIIa\tLeft\t1\tEPI+CTX+5-FU\tPR\tPain of upper extremity\t\n23\t50\tIIIb\tRight\t1\tT\tPR\tPain of upper extremity; nausea\t\n24\t50\tIIIb\tLeft\t2\tEPI+CTX+5-FU\tPR\tNo\t\n25\t50\tIIIc\tLeft\t1\tEPI+CTX+T\tPR\tNo\t\n26\t49\tIIIb\tLeft\t2\tEPI+CTX+T\tCR\tPain of upper extremity\t\n27\t48\tIIIb\tLeft\t2\tEPI+CTX+T\tPR\tDiarrhea\t\n28\t43\tIIIb\tRight\t1\tEPI+CTX+5-FU\tPR\tNo\t\n29\t36\tIIIc\tLeft\t1\tEPI+CTX+5-FU\tPR\tNausea\t\n30\t36\tIIIb\tRight\t2\tEPI+CTX+T\tPR\tHematological toxicity over grade 3\t\n31\t54\tIIIb\tLeft\t1\tEPI+CTX+T\tPR\tNo\t\n32\t60\tIIIc\tRight\t2\tEPI+CTX+T\tCR\tPain of upper extremity\t\n33\t66\tIIIc\tRight\t1\tEPI+CTX+T\tPR\tDiarrhea\t\n34\t53\tIIIc\tLeft\t1\tEPI+CTX+T\tPR\tNo\t\n35\t42\tIIIc\tRight\t1\tEPI+CTX+T\tPR\tNo\t\n36\t42\tIIIb\tRight\t1\tEPI+CTX+T\tPR\tStomachache\t\n37\t42\tIIIa\tRight\t2\tEPI+CTX+T\tPR\tNo\t\n38\t47\tIIIb\tLeft\t2\tEPI+CTX+5-FU\tSD\tNo\t\n39\t45\tIIIb\tRight\t3\tEPI+CTX+T\tCR\tIpsilateral upper extremity atrophy\t\n40\t29\tIIIb\tRight\t2\tEPI+CTX+T\tPR\tHematological toxicity over grade 3\t\n41\t53\tIIIc\tLeft\t2\tEPI+CTX+T\tPR\tNausea\t\n42\t29\tIIIb\tRight\t2\tEPI+CTX+T\tPR\tNo\t\n43\t60\tIIIc\tLeft\t1\tEPI+CTX+T\tPR\tNo\t\n44\t61\tIIIc\tLeft\t3\tEPI+CTX+T\tPR\tHematological toxicity over grade 3\t\n45\t60\tIIIc\tLeft\t1\tEPI+CTX+5-FU\tSD\tNo\t\n46\t52\tIIIb\tLeft\t2\tEPI+CTX+5-FU\tPR\tPain of neck and headache\t\n47\t47\tIIIb\tLeft\t1\tEPI+CTX+5-FU\tSD\tNo\t\n48\t61\tIIIc\tLeft\t2\tEPI+CTX+T\tPR\tNo\t\n49\t62\tIIIc\tRight\t1\tT\tPR\tNo\t\n50\t54\tIIIb\tRight\t1\tEPI+CTX+T\tPR\tNo\t\n51\t42\tIIIb\tRight\t2\tEPI+CTX+T\tPR\tHematological toxicity over grade 3\t\n52\t55\tIIIa\tLeft\t2\tEPI+CTX+T\tCR\tVomiting\t\n53\t60\tIIIb\tLeft\t1\tEPI+CTX+T\tPR\tIpsilateral upper extremity atrophy\t\nEPI, epidoxorubicin; CTX, cyclophosphamide; 5-FU, 5-fluorouracil; CR, complete response; PR, partial response; SD, stable disease; T, taxotere.\n==== Refs\nReferences\n1. Singletary SE Allred C Ashley P Revision of the American Joint Committee on Cancer staging system for breast cancer J Clin Oncol 20 3628 3636 2002 12202663 \n2. Kaufmann M von Minckwitz G Bear HD Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006 Ann Oncol 18 1927 1934 2007 17998286 \n3. Olson JE Neuberg D Pandya KJ The role of radiotherapy in the management of operable locally advanced breast carcinoma: results of a randomized trial by the Eastern Cooperative Oncology Group Cancer 79 1138 1149 1997 9070491 \n4. Murakami M Kuroda Y Nishimura S Intraarterial infusion chemotherapy and radiotherapy with or without surgery for patients with locally advanced or recurrent breast cancer Am J Clin Oncol 24 185 191 2001 11319296 \n5. Kitagawa K Yamakado K Nakatsuka A Preoperative transcatheter arterial infusion chemotherapy for locally advanced breast cancer (stageIIIb) for down-staging and increase of respectability Eur J Radiol 43 31 36 2002 12065118 \n6. Fiorentini G Tsetis D Bernardeschi P First-line intra-arterial chemotherapy (IAC) with epirubicin and mitoxantrone in locally advanced breast cancer Anticancer Res 23 4339 4345 2003 14666649 \n7. Pacetti P Mambrini A Paolucci R Intra-arterial chemotherapy: a safe treatment for elderly patients with locally advanced breast cancer In Vivo 20 761 764 2006 17203763 \n8. Shimamoto H Takizawa K Ogawa Y Clinical efficacy and value of redistributed subclavian arterial infusion chemotherapy for locally advanced breast cancer Jpn J Radiol 29 236 243 2011 21607836 \n9. Shenkier T Weir L Levine M Steering committee on clinical practice guidelines for the care and treatment of breast cancer. Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer CMAJ 170 983 994 2004 15023926 \n10. Huang EH Tucker SL Strom EA Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiotherapy Int J Radiat Oncol Biol Phys 62 351 357 2005 15890574 \n11. Fisher B Bryant J Wolmark N Effect of preoperative chemotherapy on the outcome of women with operable breast cancer J Clin Oncol 16 2672 2685 1998 9704717 \n12. Wolmark N Wang J Mamounas E Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National surgical adjuvant breast and bowel project B-18 J Natl Cancer Inst Monogr 30 96 102 2001 11773300 \n13. van der Hage JA van de Velde CJ Julien JP Preoperative chemotherapy in primary operable breast cancer: results from the European organization for Research and Treatment of Cancer trial 10902 J Clin Oncol 19 4224 4237 2001 11709566 \n14. Mauriac L MacGrogan G Avril A Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: a unicentre randomized trial with a 124-month medial follow-up. Institut Bergonié Bordeaux Groupe Sein (IBBGS) Ann Oncol 10 47 52 1999 10076721 \n15. Eniu A Palmieri FM Perez EA Weekly administration of docetaxel and paclitaxel in metastatic or advanced breast cancer Oncologist 10 665 685 2005 16249346 \n16. Heller W Mazhar D Ward R Neoadjuvant 5-fluorouracil epirubicin and cyclophosphamide chemotherapy followed by docetaxel in refractory patients with locally advanced breast cancer Oncol Rep 17 253 259 2007 17143506\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2049-9450",
"issue": "1(4)",
"journal": "Molecular and clinical oncology",
"keywords": "efficacy and complication; intra-arterial chemotherapy; locally advanced breast cancer; subclavian artery; thoracic artery",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "745-748",
"pmc": null,
"pmid": "24649239",
"pubdate": "2013-07",
"publication_types": "D016428:Journal Article",
"references": "14666649;17143506;17203763;16249346;11709566;17998286;9704717;9070491;15023926;21607836;11773300;11319296;10076721;12202663;15890574;12065118",
"title": "Main complications and results of treatment with intra-arterial infusion chemotherapy through the subclavian and thoracic arteries for locally advanced breast cancer.",
"title_normalized": "main complications and results of treatment with intra arterial infusion chemotherapy through the subclavian and thoracic arteries for locally advanced breast cancer"
} | [
{
"companynumb": "PHHY2014CN160910",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nClinical trials for patients with multiple myeloma (MM) using novel agent (NA)-based regimens before autologous stem cell transplantation (SCT) have shown improvement in response rates and progression-free survival (PFS); however they have failed to identify a significant overall survival (OS) benefit. The aim of this study was to analyze the potential impact of initial induction on the feasibility and outcome of subsequent treatment lines in a real clinical practice setting.\n\n\nMETHODS\nPatients with consecutive MM <70 years of age diagnosed between 1999 and 2009 were prospectively registered and classified as having received conventional chemotherapy induction regimens with new agents available at relapse (CC cohort, 89 patients) or as treated with NAs upfront (NA cohort, 65 patients).\n\n\nRESULTS\nPatients in the NA cohort demonstrated a superior median PFS (2.8 years vs 1.6 years, P=.03) and also a median PFS from diagnosis to second progression (5.2 years vs 2.7 years, P=.003). After a median follow-up of 7 years, clear differences in OS were observed (7.97 years in NA cohort compared to 3.35 years in CC cohort, P<.001).\n\n\nCONCLUSIONS\nNew agent-based first-line induction treatments provide benefits in both PFS and beyond that point, contributing to a significant improvement in OS.",
"affiliations": "ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain.;ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain.;Universitat de Barcelona, Barcelona, Spain.;ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain.;ICO-Hospital Josep Trueta, Girona, Spain.;ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain.;ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain.;ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain.",
"authors": "Gassiot|Susanna|S|http://orcid.org/0000-0001-5506-0244;Motlló|Cristina|C|;Llombart|Inuska|I|;Morgades|Mireia|M|;González|Yolanda|Y|;Garcia-Caro|Montse|M|;Ribera|Josep-Maria|JM|;Oriol|Albert|A|",
"chemical_list": "D018943:Anthracyclines; D007155:Immunologic Factors; D061988:Proteasome Inhibitors; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12869",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "98(6)",
"journal": "European journal of haematology",
"keywords": "bone marrow transplantation; induction treatment; multiple myeloma",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007155:Immunologic Factors; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011446:Prospective Studies; D061988:Proteasome Inhibitors; D012008:Recurrence; D012044:Regression Analysis; D012074:Remission Induction; D016019:Survival Analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "569-576",
"pmc": null,
"pmid": "28208219",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of induction treatment before autologous stem cell transplantation on long-term outcome in patients with newly diagnosed multiple myeloma.",
"title_normalized": "impact of induction treatment before autologous stem cell transplantation on long term outcome in patients with newly diagnosed multiple myeloma"
} | [
{
"companynumb": "ES-JNJFOC-20170809171",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy and safety of aripiprazole versus placebo in preventing relapse of irritability symptoms associated with autistic disorder in pediatric patients.\n\n\nMETHODS\nThis multicenter, double-blind, randomized, placebo-controlled, relapse-prevention trial enrolled patients (6-17 years) who met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DMS-IV-TR) criteria for autistic disorder and who also had serious behavioral problems (ie, tantrums, aggression, self-injurious behavior, or a combination of these behavioral problems) between March 2011 and June 2012. In phase 1, single-blind aripiprazole was flexibly dosed (2-15 mg/d) for 13-26 weeks. Patients with a stable response (≥ 25% decrease in Aberrant Behavior Checklist-irritability subscale score and a rating of \"much improved\" or \"very much improved\" on the Clinical Global Impressions-Improvement scale) for 12 consecutive weeks were randomized into phase 2 to continue aripiprazole or switch to placebo. Treatment was continued until relapse or up to 16 weeks. The primary end point was time from randomization to relapse.\n\n\nRESULTS\nEighty-five patients were randomized in phase 2. The difference in time to relapse between aripiprazole and placebo was not statistically significant (P = .097). Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo (hazard ratio [HR] = 0.57; number needed to treat [NNT] = 6). The most common adverse events during phase 1 were weight increase (25.2%), somnolence (14.8%), and vomiting (14.2%); and, during phase 2 (aripiprazole vs placebo), they were upper respiratory tract infection (10.3% vs 2.3%), constipation (5.1% vs 0%), and movement disorder (5.1% vs 0%).\n\n\nCONCLUSIONS\nIn this study, there was no statistically significant difference between aripiprazole and placebo in time to relapse during maintenance therapy. However, the HR and NNT suggest some patients will benefit from maintenance treatment. Patients receiving aripiprazole should be periodically reassessed to determine the continued need for treatment.\n\n\nBACKGROUND\nClinicalTrials.gov identifier: NCT01227668.",
"affiliations": "Child & Adolescent Psychiatry, Johns Hopkins Hospital, Bloomberg Children's Center, 1800 Orleans St, Ste 12344A, Baltimore, MD 21287 rfindli1@jhmi.edu.",
"authors": "Findling|Robert L|RL|;Mankoski|Raymond|R|;Timko|Karen|K|;Lears|Katherine|K|;McCartney|Theresa|T|;McQuade|Robert D|RD|;Eudicone|James M|JM|;Amatniek|Joan|J|;Marcus|Ronald N|RN|;Sheehan|John J|JJ|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D010919:Placebos; D015363:Quinolones; D000068180:Aripiprazole",
"country": "United States",
"delete": false,
"doi": "10.4088/JCP.13m08500",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "75(1)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001321:Autistic Disorder; D002648:Child; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007508:Irritable Mood; D053208:Kaplan-Meier Estimate; D008134:Long-Term Care; D008297:Male; D010879:Piperazines; D010919:Placebos; D015363:Quinolones; D055502:Secondary Prevention; D016896:Treatment Outcome",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "22-30",
"pmc": null,
"pmid": "24502859",
"pubdate": "2014-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A randomized controlled trial investigating the safety and efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irritability associated with autistic disorder.",
"title_normalized": "a randomized controlled trial investigating the safety and efficacy of aripiprazole in the long term maintenance treatment of pediatric patients with irritability associated with autistic disorder"
} | [
{
"companynumb": "US-OTSUKA-2020_011537",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPsoriasis is a chronic, inflammatory disease affecting 2-3% of the worldwide population, and it may worsen with HIV or be detected as HIV cutaneous manifestation. HIV-related psoriasis shows a severe and prolonged clinical course with more frequent exacerbations. The management of this condition is challenging because immunomodulating and immunosuppressant agents may have variable and partial efficacy, and therefore, antiretroviral treatment represents a potential adjunctive therapeutic option.\n\n\nRESULTS\nIn the case we report, the HIV test was shown to be crucial for driving the therapeutic approach. Indeed, antiretroviral agents have been proven to be effective in the treatment of HIV+ psoriasis as first-line therapy.\n\n\nCONCLUSIONS\nThe HIV test should be considered in high-risk patients affected by severe psoriasis and resistant to conventional and biological treatments.",
"affiliations": "Department of Dermatology, University of Rome 'Tor Vergata', Rome, Italy. chiricozziandrea@gmail.com",
"authors": "Chiricozzi|Andrea|A|;Saraceno|Rosita|R|;Cannizzaro|Maria Vittoria|MV|;Nisticò|Steven P|SP|;Chimenti|Sergio|S|;Giunta|Alessandro|A|",
"chemical_list": "D019380:Anti-HIV Agents; D009842:Oligopeptides; D063065:Organophosphonates; D011725:Pyridines; D003841:Deoxycytidine; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; D019438:Ritonavir",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000345762",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "225(4)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dermatology",
"mesh_terms": "D000225:Adenine; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate; D003841:Deoxycytidine; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D015658:HIV Infections; D019698:Hepatitis C, Chronic; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D063065:Organophosphonates; D011565:Psoriasis; D011725:Pyridines; D019438:Ritonavir; D000068698:Tenofovir; D016896:Treatment Outcome",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "333-7",
"pmc": null,
"pmid": "23295963",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Complete resolution of erythrodermic psoriasis in an HIV and HCV patient unresponsive to antipsoriatic treatments after highly active antiretroviral therapy (Ritonavir, Atazanavir, Emtricitabine, Tenofovir).",
"title_normalized": "complete resolution of erythrodermic psoriasis in an hiv and hcv patient unresponsive to antipsoriatic treatments after highly active antiretroviral therapy ritonavir atazanavir emtricitabine tenofovir"
} | [
{
"companynumb": "US-JNJFOC-20130504751",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the impact of previous administration of gadodiamide and neural tissue gadolinium deposition in patients who received gadobenate dimeglumine.\n\n\nMETHODS\nOur population included 62 patients who underwent at least three administrations of gadobenate dimeglumine, plus an additional contrast-enhanced last MRI for reference, divided into two groups: group 1, patients who in addition to gadobenate dimeglumine administrations had prior exposure to multiple doses of gadodiamide; group 2, patients without previous exposure to other gadolinium-based contrast agent (GBCAs). Quantitative analysis was performed on the first and last gadobenate dimeglumine MRIs in both groups. Dentate nucleus-to-middle cerebellar peduncle signal intensity ratios (DN/MCP) and relative change (RC) in signal over time were calculated and compared between groups using generalized additive model.\n\n\nRESULTS\nGroup 1 showed significant increase in baseline and follow-up DN/MCP compared to group 2 (p < 0.0001). The RC DN/MCP showed a non-statistically significant trend towards an increase in patients who underwent previous gadodiamide (p = 0.0735).\n\n\nCONCLUSIONS\nThere is increased T1 signal change over time in patients who underwent gadobenate dimeglumine and had received prior gadodiamide compared to those without known exposure to previous gadodiamide. A potentiating effect from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur.\n\n\nCONCLUSIONS\n• Neural gadolinium deposition is associated with multiple administrations of less stable GBCAs. • Less stable GBCA effect on subsequent more stable GBCA administrations is undetermined. • Significant increase of DN/MCP was seen in patients with previous gadodiamide exposure. • RC DN/MCP showed a non-significant increase in patients who received previous gadodiamide. • Potentiating effects from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur.",
"affiliations": "University of North Carolina Hospital, Chapel Hill, NC, United States.;University of North Carolina Hospital, Chapel Hill, NC, United States.;University of North Carolina Hospital, Chapel Hill, NC, United States.;University of North Carolina Hospital, Chapel Hill, NC, United States. miguel-ramalho@netcabo.pt.;University of North Carolina Hospital, Chapel Hill, NC, United States.;University of North Carolina Hospital, Chapel Hill, NC, United States.",
"authors": "Ramalho|Joana|J|;Semelka|Richard C|RC|;AlObaidy|Mamdoh|M|;Ramalho|Miguel|M|;Nunes|Renato H|RH|;Castillo|Mauricio|M|",
"chemical_list": "D003287:Contrast Media; D009942:Organometallic Compounds; C064572:gadobenic acid; D008536:Meglumine; C064925:gadodiamide; D005682:Gadolinium; D019786:Gadolinium DTPA",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00330-016-4269-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0938-7994",
"issue": "26(11)",
"journal": "European radiology",
"keywords": "Dentate nucleus; Gadobenate dimeglumine; Gadodiamide; Gadolinium deposition; Neural tissue",
"medline_ta": "Eur Radiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002529:Cerebellar Nuclei; D002531:Cerebellum; D003287:Contrast Media; D005260:Female; D005682:Gadolinium; D019786:Gadolinium DTPA; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008536:Meglumine; D008875:Middle Aged; D009942:Organometallic Compounds",
"nlm_unique_id": "9114774",
"other_id": null,
"pages": "4080-4088",
"pmc": null,
"pmid": "26911888",
"pubdate": "2016-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": "25942417;2720055;25848905;25756685;26523910;26352749;24872007;17109649;8428083;19002053;26700156;26107651;26606549;26079490;25742194;25633504;19401576;21045180;24475844",
"title": "Signal intensity change on unenhanced T1-weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide.",
"title_normalized": "signal intensity change on unenhanced t1 weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide"
} | [
{
"companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OSCN-PR-1603L-0022",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOBENATE DIMEGLUMINE"
... |
{
"abstract": "BACKGROUND\nCryptococcus neoformans is known to be a cause of meningitis. However, as cryptococcal endocarditis is rare, it is not well understood. Here, we describe a case with Implantable Cardioverter Defibrillator associated endocarditis and meningitis caused by Cryptococcus neoformans and we review the literature associated cryptococcal endocarditis.\n\n\nMETHODS\nA 72 years old Japanese male presented in emergency department with non-productive cough and respiratory discomfort. His past medical history was ischemic heart disease four years ago and ICD was implanted. Physical examination was unremarkable. Chest computer tomography revealed ground glass opacity in the right lung. He received a diagnosis of amiodarone-induced interstitial pneumonitis and high dose steroid pulse therapy. Septic shock and acute respiratory failure occurred after steroid therapy. Cryptococcus neoformans was identified by blood culture and cerebral spinal fluid. Intravenous liposomal Amphotericin B and oral flucytosine were initiated. Transesophageal echocardiography revealed vegetation on the lead of the ICD. Diagnosis of cryptococcal endocarditis was made. The patient died despite antifungal therapy was continued.\n\n\nCONCLUSIONS\nWe analyzed our case and 8 cases of cryptococcal endocarditis in the literature for 40 years. Almost all of the patients had previous valve replacement surgery or immunocompromised state. Three cases had meningitis. Surgery performed in 3 cases. The overall mortality rate were 44.4%.\n\n\nCONCLUSIONS\nCryptococcal endocarditis is rare and carries a high mortality. Almost all of the patients had underlying diseases. Diagnosis needs repeating blood culture and echocardiogram, sometimes. Cryptococcal endocarditis needs lumber puncture for rule out meningitis.",
"affiliations": "Division of General Internal Medicine, Akashi Medical Center, 743-33, Okubocho-Yagi, Akashi City, Hyogo, 674-0063, Japan. Electronic address: doragoarrow@yahoo.co.jp.;Department of General Internal Medicine, Osaka General Medical Center, 3-1-56, Mandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan.;Department of Respiratory Medicine, Sakai City Medical Center, 1-1-1, Eharaji, Nishi-ku, Sakai City, Osaka, 593-8304, Japan.;Department of Respiratory Medicine, Osaka General Medical Center 3-1-56, Mandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan.;Department of Cardiology, Osaka General Medical Center, Mandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan.;Department of Cardiology, Osaka General Medical Center, Mandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan.;Department of Cardiology, Osaka General Medical Center, Mandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan.",
"authors": "Nakajima|Takahiro|T|;Oba|Yuichirou|Y|;Takashima|Junpei|J|;Ueno|Kiyonobu|K|;Kikuchi|Atsushi|A|;Yamada|Takahisa|T|;Fukunami|Masatake|M|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2019.05.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "25(11)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Cardiac device associated infection; Cryptococcal neoformans; Fungal endocarditis",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "901-905",
"pmc": null,
"pmid": "31182330",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cryptococcus endocarditis: A case report and review of the literature.",
"title_normalized": "cryptococcus endocarditis a case report and review of the literature"
} | [
{
"companynumb": "PHHY2019JP149762",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Perfusion imaging is being evaluated in acute ischemic stroke patients to identify those who may benefit from reperfusion therapies beyond the standard thrombolytic time window but limited data are available on its utility in patients presenting within the standard thrombolytic time window. We report a case of a patient presenting within the 3-hour time window where computerized tomographic perfusion imaging before intravenous thrombolysis identified a large volume of severely ischemic tissue and where intravenous tissue plasminogen activator administration subsequently resulted in a fatal intracerebral hemorrhage. Whether perfusion imaging can predict an increased risk of tissue plasminogen activator-associated symptomatic hemorrhage in patients presenting within the standard thrombolytic time window requires further study.",
"affiliations": "Departments of *Neurology †Radiology, Emory University, Atlanta, GA.",
"authors": "Rangaraju|Srikant|S|;Edwards|Adam|A|;Dehkharghani|Seena|S|;Nahab|Fadi|F|",
"chemical_list": "D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "19(3)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D002545:Brain Ischemia; D005260:Female; D006801:Humans; D055420:Perfusion Imaging; D011379:Prognosis; D020521:Stroke; D013997:Time Factors; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "68-9",
"pmc": null,
"pmid": "25692511",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "7477192;16497977;17515473;21474799;19478221;19938071;18815396",
"title": "Perfusion imaging in the 3-hour time window predicts a tPA-associated hemorrhage in acute ischemic stroke.",
"title_normalized": "perfusion imaging in the 3 hour time window predicts a tpa associated hemorrhage in acute ischemic stroke"
} | [
{
"companynumb": "US-ROCHE-1548114",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Prescription of proton pump inhibitors (PPIs) may be a source of potentially clinically relevant drug-drug interactions (DDIs) and related complications for elderly patients with complex polytherapy at discharge from hospital. The aim of the study was to identify, through the analysis of hospital discharge records, the co-administrations (PPIs + one or more drugs potentially generating DDIs) hypothetically leading to severe consequences according to the literature and online databases. Subsequently, alternatives to PPIs were evaluated for the treatment of gastric acidity and ulcers.\n\n\n\nThe medical records of 1288 patients, discharged from a geriatric ward at the Città della Salute e della Scienza Hospital in Turin from January 2012 to December 2013, were collected in an Excel database for analysis of DDIs using the literature and online sources such as Micromedex. RESULTS : Six hundred and sixty-three of the 1288 clinical folders had a PPI prescription. A list of 18 drugs considered potentially hazardous and able to trigger a DDI when co-administrated with PPIs was drafted; the frequencies of the co-prescriptions of each PPI with one of the listed drugs were esomeprazole 65.38%, lansoprazole 52.87%, omeprazole 48.19% and pantoprazole 37.11%. An analysis of these co-prescriptions, according to Micromedex classification, gave a percentage of major interactions of 11.01% over 663 clinical folders including a PPI.\n\n\n\nThis study provides a collection of potentially hazardous drug associations and helpful suggestions to improve the quality of prescriptions for elderly patients and strengthens the case for synergic work between doctors and pharmacists in the wards.",
"affiliations": "Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Torino, Italy clara.cena@unito.it.;Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Torino, Italy.;Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Torino, Italy.;Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy.;Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy.;Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Torino, Italy.",
"authors": "Cena|Clara|C|;Traina|Sara|S|;Parola|Beatrice|B|;Bo|Mario|M|;Fagiano|Riccardo|R|;Siviero|Carlotta|C|",
"chemical_list": "D054328:Proton Pump Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/ejhpharm-2018-001697",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2047-9956",
"issue": "27(6)",
"journal": "European journal of hospital pharmacy : science and practice",
"keywords": "co-administration; drug-drug interactions; elderly; polytherapy; proton-pump inhibitor",
"medline_ta": "Eur J Hosp Pharm",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D004347:Drug Interactions; D011307:Drug Prescriptions; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D008297:Male; D019338:Polypharmacy; D054328:Proton Pump Inhibitors",
"nlm_unique_id": "101578294",
"other_id": null,
"pages": "341-345",
"pmc": null,
"pmid": "33097617",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22762246;20458084;26446832;19176635;24566821;9224780;18679061;29265509;27166129;22347824;9825878;8540719;3689634;20102352;23420793;22261200;23134100;28851511;25828419;2276389;28395507;28770276;25597570;28849627;22525304;24147143;24887634",
"title": "Prescription of proton pump inhibitors in older adults with complex polytherapy.",
"title_normalized": "prescription of proton pump inhibitors in older adults with complex polytherapy"
} | [
{
"companynumb": "IT-ACCORD-210721",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Kounis syndrome is a clinical condition due to hypersensitivity that culminates into acute coronary syndrome (ACS) which can be fatal. A 36-year-old male with no conventional coronary risk factors presented elsewhere with a history of fever for 4 days, cough with expectoration, diarrhea and was treated with cephalosporin (Inj. Cefotaxime as an infusion) along with analgesics. He experienced generalized itching 5 minutes after cefotaxime infusion followed by sweating, headache, chest pain with facial and periorbital swelling for which he was rushed to our hospital. On examination he was afebrile with a low blood pressure. Electrocardiogram taken at an outside hospital revealed incomplete right bundle branch block and ST depression V3-V5. Investigations showed increase in troponin T. He was managed with anti-histamines and standard protocol for treatment of ACS. Coronary angiogram revealed normal coronaries. The patient improved symptomatically with treatment and was discharged on an anti-platelet, nitrate and a statin.",
"affiliations": "Department of Pharmacy Practice, PSG College of Pharmacy, Coimbatore, Tamil Nadu, India.;Department of Cardiology, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India.;Department of Cardiology, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India.;Department of Pharmacy Practice, PSG College of Pharmacy, Coimbatore, Tamil Nadu, India.",
"authors": "Venkateswararao|Sunkavalli|S|;Rajendiran|Gopalan|G|;Sundaram|Rathakrishnan Shanmuga|RS|;Mounika|Godavarthi|G|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0976-500X.171877",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-6-22510.4103/0976-500X.171877Case ReportKounis syndrome secondary to intravenous cephalosporin administration Venkateswararao Sunkavalli Rajendiran Gopalan 1Sundaram Rathakrishnan Shanmuga 1Mounika Godavarthi Department of Pharmacy Practice, PSG College of Pharmacy, Coimbatore, Tamil Nadu, India1 Department of Cardiology, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, IndiaAddress for correspondence: G Rajendiran, Department of Cardiology, PSG Institute of Medical Sciences and Research, Coimbatore - 641 004, Tamil Nadu, India. E-mail: rajeng68@gmail.comOct-Dec 2015 6 4 225 227 03 10 2014 25 5 2015 29 5 2015 Copyright: © Journal of Pharmacology and Pharmacotherapeutics2015This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Kounis syndrome is a clinical condition due to hypersensitivity that culminates into acute coronary syndrome (ACS) which can be fatal. A 36-year-old male with no conventional coronary risk factors presented elsewhere with a history of fever for 4 days, cough with expectoration, diarrhea and was treated with cephalosporin (Inj. Cefotaxime as an infusion) along with analgesics. He experienced generalized itching 5 minutes after cefotaxime infusion followed by sweating, headache, chest pain with facial and periorbital swelling for which he was rushed to our hospital. On examination he was afebrile with a low blood pressure. Electrocardiogram taken at an outside hospital revealed incomplete right bundle branch block and ST depression V3–V5. Investigations showed increase in troponin T. He was managed with anti-histamines and standard protocol for treatment of ACS. Coronary angiogram revealed normal coronaries. The patient improved symptomatically with treatment and was discharged on an anti-platelet, nitrate and a statin.\n\nAcute coronary syndromecephalosporinhypersensitivityKounis syndrome\n==== Body\nINTRODUCTION\nKounis syndrome (KS) is defined as the concurrence of acute coronary syndrome (ACS) with conditions associated with mast cell activation relating to hypersensitivity.[1] The incidence of KS is not established due to lack of well-defined studies to record the events; the available evidence is based on case series and case reports. Multiple agents have been described to trigger KS including drugs, contrast media, stent material, insect stings, food, environmental exposures and medical conditions like asthma.[123] Among drugs antibiotics were reported as important cause of KS. Here we report a case presented with features of anaphylactic reaction after cefotaxime injection and features of ACS, which was considered rare compared to other cephalosporins.\n\nCASE REPORT\nA 36-year-old male with no conventional coronary risk factors was treated elsewhere for fever, cough with expectoration and diarrhea with antibiotic (Inj. Cefotaxime 1 gm as an infusion) and analgesics. He experienced generalized itching 5 minutes after cefotaxime infusion along with sweating, headache, chest pain and facial swelling for which he was brought to our hospital. His medical records revealed the administration of corticosteroid (Betamethasone) injection along with analgesics after the onset of reaction. Five years ago he had hypersensitivity to an unknown tablet. On examination he was afebrile, mildly tachycardic and tachypneic with a blood pressure of 80/60 mmHg.\n\nAn electrocardiogram (ECG) taken immediately after the reaction and subsequent ECG taken at our hospital are similar and revealed sinus rhythm, ST depression V3–V5 and incomplete right bundle branch block, ST elevation-I, aVR [Figure 1]. Hemogram revealed relative neutrophilia (92.7%), normal ESR and eosinophil count with normal red blood cells. Serum electrolytes, creatinine and random blood sugar were normal while potassium was low (3.24 mEq/L). Arterial blood gases revealed mild hypocapnia [pCo2-31.9 mmHg, pO2-111.9 mmHg]. Troponin T was elevated (1027 pg/ml) and liver enzymes were slightly increased. The patient was immediately administered with intravenous antihistaminic, a H2 receptor blocker, and an anti-emetic. He was started on a standard protocol for the management of ACS including dual anti-platelets, statin, betablocker, low-molecular-weight heparin after which the patient improved symptomatically. Echocardiogram showed good left ventricular (LV) systolic function with no regional wall motion abnormality (RWMA). A coronary angiogram performed on the subsequent day revealed normal epicardial coronaries with no evidence of spasm or thrombus. Work up for young myocardial infarction was negative with an exception of serum homocysteine levels (49.3 µmol/L). The patient was diagnosed with KS and was treated suitably which lead to his discharge after 4 days with an anti-platelet, nitrate and a statin.\n\nFigure 1 ECG showing abnormality after the reaction\n\nDISCUSSION\nOur case presented with ACS and anaphylactic reaction (caused by a previous antibiotic injection). Though an acute coronary event unrelated to anaphylaxis cannot be completely ruled out, totally asymptomatic state before the antibiotic administration, chronology of events and normal coronaries favor ACS related to anaphylactic reaction possibly due to coronary vasospasm. A majority of case reports showed ECG abnormality as ST segment elevation, but in our case the ECG revealed ST depression.[34]\n\nKounis and Zavrae first described the simultaneous appearance of acute coronary events and anaphylactic reaction, called Kounis syndrome or allergic angina which could be due to coronary vasospasm or rupture of pre-existing atheromatous plaque.[5]\n\nInflammatory mediators such as histamine, neutral proteases like chymase, tryptase, platelet-activating factor and variety of cytokines and chemokines constitute the pathophysiologic basis of KS.[1236] Histamine released during anaphylactic reaction acts on H1 receptors causing coronary vasoconstriction and its action on H2 and H3 receptors causes hemodynamic instability. It also promotes platelet aggregation. Chymase converts angiotensin I into angiotensin II, which acts synergically with histamine upon receptors in the cells of coronary arteries, aggravating coronary spasm.[2] Anaphylactic cardiac damage may be dissociated into two sets of events: (i) Initial primary cardiac reaction caused by the intracardiac release of histamine (ii) a subsequent cardiovascular reaction secondary to systemic release of mediators.[17] Several antibiotics and few nonsteroidal anti-inflammatory drugs (NSAIDs) were reported as a cause of KS [Table 1].[356]\n\nTable 1 Antibiotics and NSAIDs reported to cause Kounis syndrome\n\nAmong third generation cephalosporins, cefotaxime rarely causes anaphylaxis yet in this case the patient was presented with severe anaphylaxis.[8]\n\nMajority of literatures identify three variants of Kounis syndrome that has been established. Type I includes patients with normal coronary arteries without predisposing factors for coronary artery disease (CAD), where the acute release of inflammatory mediators can result in ACS with or without raised cardiac enzymes and troponins. Type II KS is a group with quiescent pre-existing atheromatous disease, in which the acute release of inflammatory mediators can result in ACS. Type III are patients with coronary artery thrombosis (including stent thrombosis) in whom aspirated thrombus specimens stained with hematoxylin-eosin and giemsa demonstrate the presence of eosinophils and mast cells.[1236] In this patient no coronary risk factors were identified except increase in serum homocysteine level. Elevated homocysteine level was reported as a risk factor for CAD, but a large meta analysis including prospective studies concluded that while serum homocysteine is elevated in patients with CAD, elevated homocysteine probably does not itself cause the disease.[9] Thus, we classified our case as type 1 KS. Causality assessment of KS using Naranjo's algorithm, confirmed the event as “probable” adverse drug reaction.\n\nSimilar to the earlier published case reports relative neutrophilia and elevated troponin levels were observed in this patient also. There is no specific investigation to diagnose KS-associated ACS and treatment of KS involves administration of antihistamines, corticosteroids and/or ACS management protocol.[410] A recent review reported that majority of the cases have been treated with corticosteroids (76%), H1 blockers (70%), nitroglycerin (47%) and H2 blockers (35%), while adrenalin was only used in 23% of the cases and aspirin in 18%.[10]\n\nCONCLUSION\nKounis syndrome is a clinical feature difficult to diagnose, but is important that a possibility of KS as a cause of acute coronary syndrome be considered when patients present with features suggestive of anaphylactic reaction and ACS. Although a few cases of cephalosporin-related KS was reported, to the best of our knowledge, evidence of KS pertaining to cefotaxime was not recorded in earlier reports.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Kounis NG Coronary hypersensitivity disorder: The kounis syndrome Clin Ther 2013 35 563 71 23490289 \n2 Rico Cepeda P Palencia Herrejón E Rodríguez Aguirregabiria MM Kounis syndrome Med Intensiva 2012 36 358 64 22154226 \n3 Laschos N Tzerefos S Katsaros A Chrissos D Kounis syndrome manifesting as acute st-segment elevation due to coronary vasospasm after cefuroxime-induced anaphylactic shock Hosp Chron 2013 8 34 8 \n4 Kounis NG Soufras GD Hahalis G Anaphylactic shock: Kounis hypersensitivity-associated syndrome seems to be the primary cause N Am J Med Sci 2013 5 631 6 24404540 \n5 Kounis NG Grapsas ND Goudevenos JA Unstable angina, allergic angina, and allergic myocardial infarction Circulation 1999 100 e156 10604922 \n6 Tiwari AK Tomar GS Ganguly S Kapoor MC Kounis syndrome resulting from anaphylaxis to diclofenac Indian J Anaesth 2013 57 282 4 23983288 \n7 Zavecz JH Levi R Separation of primary and secondary cardiovascular events in systemic anaphylaxis Circ Res 1977 40 15 9 63338 \n8 Babu TA Sharmila V Cefotaxime-induced near-fatal anaphylaxis in a neonate: A case report and review of literature Indian J Pharmacol 2011 43 611 2 22022015 \n9 Christen WG Ajani UA Glynn RJ Hennekens CH Blood levels of homocysteine and increased risks of cardiovascular disease: Causal or casual? Arch Intern Med 2000 160 422 34 10695683 \n10 Ridella M Bagdure S Nugent K Cevik C Kounis syndrome following beta-lactam antibiotic use: Review of literature Inflamm Allergy Drug Targets 2009 8 11 6 19275688\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-500X",
"issue": "6(4)",
"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Acute coronary syndrome; Kounis syndrome; cephalosporin; hypersensitivity",
"medline_ta": "J Pharmacol Pharmacother",
"mesh_terms": null,
"nlm_unique_id": "101552113",
"other_id": null,
"pages": "225-7",
"pmc": null,
"pmid": "26813799",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "23490289;10695683;10604922;19275688;63338;22154226;23983288;22022015;24404540",
"title": "Kounis syndrome secondary to intravenous cephalosporin administration.",
"title_normalized": "kounis syndrome secondary to intravenous cephalosporin administration"
} | [
{
"companynumb": "IN-SA-2016SA005427",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of carbamazepine-induced 2:1 atrioventricular (AV) block. A 56-year-old man was admitted to our emergency department for recurrent attacks of dizziness and syncope. His serum carbamazepine level was within therapeutic range, and his electrocardiogram revealed 2:1 AV block. After withdrawal of carbamazepine therapy, the arrhythmia completely resolved. This report suggests that carbamazepine-induced AV block can occur even in therapeutic serum concentrations and that it can be reversible.",
"affiliations": "Ankara Education and Research Hospital, Department of Cardiology, Ankara, Turkey. Electronic address: etem84@gmail.com.;Dışkapı Yıldırım Beyazıt Education and Research Hospital, Department of Cardiology, Ankara, Turkey.;Siirt Government Hospital, Cardiology, Siirt, Turkey.;Türkiye Yüksek İhtisas Education and Research Hospital, Department of Cardiology, Ankara, Turkey.",
"authors": "Celik|Ibrahim Etem|IE|;Akyel|Ahmet|A|;Colgecen|Metin|M|;Ozeke|Ozcan|O|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "33(10)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000927:Anticonvulsants; D054537:Atrioventricular Block; D002220:Carbamazepine; D004562:Electrocardiography; D004636:Emergency Service, Hospital; D004833:Epilepsy, Temporal Lobe; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1541.e3-4",
"pmc": null,
"pmid": "26306438",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare cause of 2:1 atrioventricular block: carbamazepine.",
"title_normalized": "a rare cause of 2 1 atrioventricular block carbamazepine"
} | [
{
"companynumb": "TR-VALIDUS PHARMACEUTICALS LLC-TR-2015VAL000728",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drug... |
{
"abstract": "Acquired resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been developed as an important clinical problem though EGFR-TKI such as gefitinib, erlotinib and afatinib [1,2] has achieved 8-14 months of progression free survival in advanced non-small cell lung cancer (NSCLC) patient with EGFR mutation. We report a case here that an advanced lung adenocarcinoma with L858R mutation responded well to pemetrexed rechallenge after acquired resistance of erlotinib.",
"affiliations": "Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, People's Republic of China. Electronic address: rogerlee1989@foxmail.com.;Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, People's Republic of China. Electronic address: 191z@tongji.edu.cn.;Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, People's Republic of China. Electronic address: harry_ren@126.com.;Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, People's Republic of China. Electronic address: caicunzhoudr@163.com.",
"authors": "Li|Shuai|S|;Zhou|Fangyu|F|;Ren|Shengxiang|S|;Zhou|Caicun|C|",
"chemical_list": "D005971:Glutamates; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "84(2)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Acquired resistance; Chemotherapy; EGFR-TKI; NSCLC; Pemetrexed; Rechallenge",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005971:Glutamates; D006147:Guanine; D006801:Humans; D008175:Lung Neoplasms; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009364:Neoplasm Recurrence, Local; D000068437:Pemetrexed; D011799:Quinazolines; D011859:Radiography; D016896:Treatment Outcome",
"nlm_unique_id": "8800805",
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"pages": "203-5",
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"title": "Response to pemetrexed rechallenge after acquired resistance of EGFR-TKI in a patient with advanced NSCLC.",
"title_normalized": "response to pemetrexed rechallenge after acquired resistance of egfr tki in a patient with advanced nsclc"
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"abstract": "The rate of ventriculoperitoneal (VP) shunt infection is reported between 3% and 20%. Vancomycin-Resistant Enterococci (VRE) are increasingly prevalent nasocomial pathogens worldwide and they rarely cause infections to the central nervous system. Daptomycin is a cyclic lipopeptide effective antibiotic due to its rapid bactericidal effect. It is a life-saving treatment option for meningitis, bacteriemia, sepsis, endocarditis and urinary system infections caused by VRE. Here, we presented a 2.5-month-old male patient diagnosed with ventriculoperitoneal shunt infection caused by VRE faecium. This is the first pediatric VP shunt infection caused by VRE and treated with a combination of intravenous (IV) linezolid IV and intraventricular (IVT) daptomycin. The patient was admitted to the medical center with the complaint of umbilical discharge and shunt revision was applied with the thought of shunt dysfunction. Intermittent umbilical cerebrospinal fluid (CSF) leakage continued and the patient developed fever 2 weeks after the operation. VRE growth in his CSF culture was treated by meropenem and linezolid treatment. Upon continuation of the growth afterwards, the patient who was referred to our hospital underwent extra ventricular drainage (EVD), and IV linezolid, IV daptomycin (8 mg/kg day) and IVT daptomycin (2.5 mg/kg day) was scheduled as treatment. On the 5th day of treatment, there was no growth in the culture and no side effects were observed during the treatment. VP shunt was placed in the patient for the 15 days of daptomycin IV plus IVT treatment, and 36 days of linezolid. No infection was observed in the 8-month follow-up period.",
"affiliations": "Departments of Pediatric Infectious Diseases, University of Health Sciences, Sisli Hamidiye Etfal Research and Education Hospital, Istanbul, Turkey. Electronic address: ayseturgutsahin@gmail.com.;Departments of Pediatric Infectious Diseases, University of Health Sciences, Sisli Hamidiye Etfal Research and Education Hospital, Istanbul, Turkey.",
"authors": "Şahin|Ayse|A|;Dalgic|Nazan|N|",
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"journal": "World neurosurgery",
"keywords": "daptomycin; infant; shunt infection",
"medline_ta": "World Neurosurg",
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"pmid": "30685371",
"pubdate": "2019-01-24",
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"title": "Intravenous and intraventricular daptomycin plus intravenous linezolid treatment of an infant with Vancomycin-Resistant Enterococci induced ventriculoperitoneal shunt infection.",
"title_normalized": "intravenous and intraventricular daptomycin plus intravenous linezolid treatment of an infant with vancomycin resistant enterococci induced ventriculoperitoneal shunt infection"
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"abstract": "Clinicians are confronted with challenging situations when working with women who are pregnant and have a co-existing mental illness. A risk benefit assessment is helpful when identifying possible care interventions. Psychopharmaceutical intervention is a consideration when nonpharmacological interventions are ineffective or inappropriate. Informed consent based on known and unknown risks to the mother and fetus should be obtained. Literature and case reports are contradictory and not conclusive about the risks of medications used for psychiatric illnesses. This article reviews the literature and provides clinical guidelines for antipsychotic medications, antidepressant medications, mood stabilizing medications, and antianxiety medications.",
"affiliations": "Fairview Psychiatry and Behavioral Services, Fairview-University Medical Center, Minneapolis, Minnesota, USA.",
"authors": "Gjere|N A|NA|",
"chemical_list": "D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D011619:Psychotropic Drugs",
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"issue": "14(4)",
"journal": "The Journal of perinatal & neonatal nursing",
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"mesh_terms": "D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D005260:Female; D005333:Fetus; D006801:Humans; D001523:Mental Disorders; D011247:Pregnancy; D011248:Pregnancy Complications; D011619:Psychotropic Drugs",
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"title": "Psychopharmacology in pregnancy.",
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"abstract": "Antipsychotic drug treatment can potentially lead to adverse events such as leukopenia and neutropenia. Although these events are rare, they represent serious and life-threatening hematological side effects.\n\n\n\nWe present a case study of a patient with schizoaffective disorder in a 50-year-old woman. We report a case of paliperidone extended-release (ER)-induced leukopenia and neutropenia in a female patient with schizoaffective disorder. Initiating lithium carbonate treatment and decreasing the dose of valproic acid improved the observed leukopenia and neutropenia. This treatment did not influence psychotic symptoms.\n\n\n\nThe combination of paliperidone ER and valproic acid induces increased paliperidone ER plasma levels. Lithium carbonate was successfully used to treat paliperidone ER-induced leukopenia and neutropenia.",
"affiliations": "Department of Psychiatry, Tenri Hospital, Tenri, Japan.;Department of Psychiatry, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.;Department of Psychiatry, Tenri Hospital, Tenri, Japan.;Department of Psychiatry, Tenri Hospital, Tenri, Japan.;Department of Psychiatry, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan. muro@naramed-u.ac.jp.;Department of Psychiatry, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.",
"authors": "Matsuura|Hiroki|H|;Kimoto|Sohei|S|;Harada|Izumi|I|;Naemura|Satoshi|S|;Yamamuro|Kazuhiko|K|;Kishimoto|Toshifumi|T|",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D016651:Lithium Carbonate; D000068882:Paliperidone Palmitate",
"country": "England",
"delete": false,
"doi": "10.1186/s12888-016-0874-x",
"fulltext": "\n==== Front\nBMC PsychiatryBMC PsychiatryBMC Psychiatry1471-244XBioMed Central London 87410.1186/s12888-016-0874-xCase ReportLithium carbonate as a treatment for paliperidone extended-release-induced leukopenia and neutropenia in a patient with schizoaffective disorder; a case report Matsuura Hiroki Kimoto Sohei Harada Izumi Naemura Satoshi Yamamuro Kazuhiko +81-744-22-3051+81-744-22-3854muro@naramed-u.ac.jp Kishimoto Toshifumi Department of Psychiatry, Tenri Hospital, Tenri, Japan Department of Psychiatry, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521 Japan 26 5 2016 26 5 2016 2016 16 16120 9 2015 16 5 2016 © Matsuura et al. 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\nAntipsychotic drug treatment can potentially lead to adverse events such as leukopenia and neutropenia. Although these events are rare, they represent serious and life-threatening hematological side effects.\n\nCase presentation\nWe present a case study of a patient with schizoaffective disorder in a 50-year-old woman. We report a case of paliperidone extended-release (ER)-induced leukopenia and neutropenia in a female patient with schizoaffective disorder. Initiating lithium carbonate treatment and decreasing the dose of valproic acid improved the observed leukopenia and neutropenia. This treatment did not influence psychotic symptoms.\n\nConclusion\nThe combination of paliperidone ER and valproic acid induces increased paliperidone ER plasma levels. Lithium carbonate was successfully used to treat paliperidone ER-induced leukopenia and neutropenia.\n\nKeywords\nSchizoaffective disorderSchizophreniaPaliperidone extended-releaseNeutropeniaLeukopeniaLithium carbonateValproic acidissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nSchizoaffective disorder refers to the coexistence of generally continuous schizophrenic symptoms plus intermittent mood episodes. The dopamine hypothesis of schizophrenia is attributable to the principal descriptive model of antipsychotic drug action. However, leukopenia and neutropenia are known to be serious adverse effects of antipsychotic drug treatment. Although clozapine has been most strongly associated with such events, similar side effects have been reported with risperidone [1, 2], olanzapine [3, 4], and quetiapine [5, 6]. Moreover, paliperidone extended-release (ER), which is chemically a major active metabolite of risperidone (9-hydroxyrisperidone), has also been found to elicit leukopenia and neutropenia in rare cases [7, 8]. Leukopenia is characterized by a decrease in the number of white blood cells, often due to neutropenia. Neutropenia can be defined as a neutrophil count of < 1.50 × 109/L. There are two well-known treatment strategies: the adjuvant use of lithium carbonate and granulocyte colony-stimulating factor [9, 10]. No studies to date, however, have reported the use of lithium carbonate in the case of paliperidone ER-induced leukopenia and neutropenia.\n\nConsequently, this report focuses on the use of lithium carbonate in the treatment of paliperidone ER-induced leukopenia and neutropenia in a female patient with schizoaffective disorder. We believe our study to be novel as a survey of the literature failed to identify any current reports describing the use of lithium carbonate in this setting.\n\nCase presentation\nPatient A is a 50-year-old woman who started to present psychotic symptoms fulfilling DSM-IV-TR diagnostic criteria for schizoaffective disorder at age 46 years. She experienced positive symptoms (paranoid delusions and auditory hallucinations), as well as disorganized thinking and behavior, and affective symptoms. There were neither previous reports of premorbid symptoms, nor a family history of psychosis, nor other mental disorders. She has been hospitalized on three occasions owing to exacerbation of psychotic symptoms. Two months after the last hospitalization, she has again developed auditory hallucinations and aggressive behavior despite taking quetiapine 200 mg/day, olanzapine 10 mg/day, and valproic acid 200 mg/day.\n\nThese symptoms had her admitted to the hospital where the dosage amount was gradually increased to quetiapine 200 mg/day, olanzapine 20 mg/day, and valproic acid 1000 mg/day. At this point, a laboratory assessment showed normal levels of white blood cell (WBC; 4.04 × 109/L) and neutrophil counts (2.01 × 109/L), respectively. The valproic acid plasma level was 70.6 mg/L. Since she still had refractory auditory hallucinations in spite of active medications, paliperidone ER was added on at 28 days after admission when WBC and neutrophil counts were 4.03 × 109/L and 2.26 × 109/L, respectively. Then, dosage was increased to 12 mg/day over 2 weeks. At 55 days, she exhibited a sudden drop in WBC count (2.83 × 109/L) and neutrophil count (0.79 × 109/L), while liver function and renal function were both within normal levels.\n\nBecause of these sudden changes at day 55, paliperidone ER treatment was immediately stopped, the dose of valproic acid was decreased to 600 mg/day, and lithium carbonate was initiated (200 mg/day). At four days after lithium carbonate administration, the blood composition of the patient had returned to normal levels (WBC count of 4.34 × 109/L, neutrophil count of 2.29 × 109/L). The valproic acid plasma level had decreased to 32.8 mg/L. Twenty-eight days later, the WBC count had increased to 6.86 × 109/L and the neutrophil count was 4.74 × 109/L. Finally, lithium carbonate was gradually decreased and stopped because neither leukopenia nor neutropenia were observed over the following 6 months. She is currently stable taking quetiapine 200 mg/day, olanzapine 20 mg/day, and valproic acid 600 mg/day. Her symptoms have not worsened any longer since the cessation of paliperidone ER therapy.\n\nDiscussion\nTo the best of our knowledge, no studies have yet reported on paliperidone ER-induced neutropenia in patients with schizoaffective disorder. Moreover, few studies have yet reported on paliperidone ER- or combination paliperidone ER and risperidone-induced neutropenia even in patients with schizophrenia [7, 8]. The case presented here is the first to demonstrate the therapeutic effect of add-on lithium for paliperidone ER-induced neutropenia.\n\nUnexpectedly, antipsychotic drugs have numerous adverse effects, the most serious of which involve hematologic toxicity such as leukopenia and neutropenia. While these adverse effects are frequently occurred with clozapine treatment [11], other antipsychotic drugs have been found to induce similar side effects. Although the pathophysiological mechanisms underlying antipsychotic-induced neutropenia/leukopenia remain unknown, some potential mechanisms have been proposed as follows: direct bone marrow suppression, antibody formation against hematologic precursors, and peripheral destruction of cells [12].\n\nIn our patient, leukopenia and neutropenia were normalized in 4 days after discontinuing paliperidone ER, tapering valproate acid, and starting lithium carbonate. Of course, we cannot exclude the possibility that we only had to stop paliperidone ER and/or valproate acid treatment to normalize leukopenia and neutropenia. However, lithium carbonate treatment might be efficacious in shortening the time required for the recovery from leukopenia and neutropenia [10]. Moreover, during severe leukopenia and neutropenia, morbidity and risk of mortality increases owing to the risk of infection and the complications of infection. Therefore, the present case suggests that administration of lithium carbonate should be appropriate at an early stage.\n\nThe present case has important implications for the safety of valproic acid as a potential causative agent of the above-mentioned adverse effects, especially given that a previous case study reported severe neutropenia accompanied by valproic acid administration [13]. In our case, valproic acid treatment could not be completely discontinued due to her persistent affective symptoms with aggressive behavior. However, valproic acid was unlikely to be the causative agent as the patient had been taking valproic acid prior to admission to the hospital. Instead valproic acid might play a critical role in combination with paliperidone ER because valproic acid is known to increase paliperidone ER plasma levels [14]. Alternatively, a combination pharmacotherapy itself might be intricately involved with leukopenia and neutropenia, while such phenomena had not been observed before administration of paliperidone ER. Overall, this case report suggests that paliperidone ER-induced leukopenia and neutropenia might be dose-dependent.\n\nConclusion\nA 50-year-old female patient with schizoaffective disorder developed paliperidone ER-induced leukopenia and neutropenia. Initiating lithium carbonate, discontinuing paliperidone ER, and decreasing the dose of valproic acid might reverse leukopenia and neutropenia. This case strongly suggests that blood composition and other health indicators should be monitored carefully when using antipsychotics including paliperidone ER, especially combined therapy with valproic acid. Moreover, lithium carbonate should be considered in the treatment of paliperidone ER-induced leukopenia and neutropenia.\n\nAbbreviations\nER, extended-release; WBC, white blood cell.\n\nWe would like to thank the patient and her family for their collaboration.\n\nFunding\nThis article did not support any funding.\n\nAvailability of data and materials\nAll the data supporting our findings will be shared upon request.\n\nAuthors’ contributions\nHM was the primary clinician involved in the assessment, management, and follow up of the patients and HM and KY wrote the first draft of the manuscript. HM, IH, and SN were involved in the management of the patients. SK, KY and TK supervised the entire project, were critically involved in the design, and contributed to the editing of the final manuscript. All authors have read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent to Publish\nWritten informed consent was obtained from the patient for the publication of this case report.\n\nEthics approval and consent to participant\nNot applicable.\n==== Refs\nReferences\n1. Manfredi G Solfanelli A Dimitri G Cuomo I Sani G Kotzalidis GD Risperidone-induced leukopenia: a case report and brief review of literature Gen Hosp Psychistry 2013 35 1 102.e3 6 \n2. Sluys M Guzelcan Y Casteelen G de Haan L Risperidone-induced leucopenia and neutropenia: a case report Eur Psychiatry 2004 19 2 117 10.1016/j.eurpsy.2003.03.009 15051112 \n3. Buchman N Strous RD Ulman AM Lerner M Kotler M Olanzapine-induced leukopenia with human leukocyte antigen profiling Int Clin Psychopharmacol 2001 16 1 55 7 10.1097/00004850-200101000-00007 11195261 \n4. Stergiou V Bozikas VP Garyfallos G Nikolaidis N Lavrentiadis G Fokas K Olanzapine-induced leucopenia and neutropenia Prog Neuropsychopharmacol Biol Psychiatry 2005 29 6 992 4 10.1016/j.pnpbp.2005.04.025 15950350 \n5. Alexander J Tibrewal P Quetiapine-induced leucopenia Aust N Z J Psychiatry 2010 44 8 767 8 10.3109/00048674.2010.495707 20636202 \n6. Cowan C Oakley C Leukopenia and neutropenia induced by quetiapine Prog Neuropsychopharmacol Biol Psychiatry 2007 31 1 292 4 10.1016/j.pnpbp.2006.07.003 16930797 \n7. Kim JN Lee BC Choi IG Jon DI Jung MH Paliperidone-induced leukopenia and neutropenia: a case report Prog Neuropsychopharmacol Biol Psychiatry 2011 35 1 284 5 10.1016/j.pnpbp.2010.09.018 20920543 \n8. Raj V Druitt T Purushothaman S Dunsdon J Risperidone/paliperidone induced neutropenia and lymphopenia Aust N Z J Psychiatry 2013 47 3 291 2 10.1177/0004867412460594 22984110 \n9. Sperner-Unterweger B Czeipek I Gaggl S Geissler D Spiel G Fleischhacker WW Treatment of severe clozapine-induced neutropenia with granulocyte colony-stimulating factor (G-CSF): remission despite continuous treatment with clozapine Br J Psychiatry 1998 172 82 4 10.1192/bjp.172.1.82 9534838 \n10. Sporn A Gogtay N Ortiz-Aguayo R Alfaro C Tossell J Lenane M Clozapine-induced neutropenia in children: management with lithium carbonate J Child Adolesc Psychopharmacol 2003 13 3 401 4 10.1089/104454603322572697 14642024 \n11. Papetti F Darcourt G Giordana JY Spreux A Thauby S Feral F Treatment of clozapine-induced granulocytopenia with lithium (two observations) Encéphale 2004 30 6 57 82 10.1016/S0013-7006(04)95473-5 \n12. Flanagan RJ Dunk L Haematological toxicity of drugs used in psychiatry Hum Psychopharmacol 2008 23 Suppl 1 27 41 10.1002/hup.917 18098216 \n13. Vesta KS Medina PJ Valproic acid-induced neutropenia Ann Pharmacother 2003 37 6 819 21 10.1345/aph.1C381 12773069 \n14. INVAGA® prescribing information. July 2009. Available from http://www.janssencns.com/invega-prescribing-information. (Accessed on 13 Jan 2010).\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-244X",
"issue": "16()",
"journal": "BMC psychiatry",
"keywords": "Leukopenia; Lithium carbonate; Neutropenia; Paliperidone extended-release; Schizoaffective disorder; Schizophrenia; Valproic acid",
"medline_ta": "BMC Psychiatry",
"mesh_terms": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D007970:Leukopenia; D016651:Lithium Carbonate; D008875:Middle Aged; D009503:Neutropenia; D000068882:Paliperidone Palmitate; D011618:Psychotic Disorders; D016896:Treatment Outcome",
"nlm_unique_id": "100968559",
"other_id": null,
"pages": "161",
"pmc": null,
"pmid": "27229149",
"pubdate": "2016-05-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12773069;14642024;15051112;9534838;15738861;15950350;11195261;18098216;20636202;20920543;22520716;22984110;16930797",
"title": "Lithium carbonate as a treatment for paliperidone extended-release-induced leukopenia and neutropenia in a patient with schizoaffective disorder; a case report.",
"title_normalized": "lithium carbonate as a treatment for paliperidone extended release induced leukopenia and neutropenia in a patient with schizoaffective disorder a case report"
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"abstract": "Medication-related osteonecrosis of the jaw (MRONJ) is a well-recognized complication of drug therapies for bone metabolic disorders or cancer related to administration of antiresorptive (bisphosphonates and denosumab) and antiangiogenic drugs. This report describes an advanced and unusual case of stage III peri-implantitis-induced MRONJ involving the right upper jaw which was attempting to self-exfoliate. A 61-year-old male patient, rehabilitated with the placement of two implants when he was still healthy, was suffering from metastatic renal cancer previously treated with bevacizumab, interleukin-2, zoledronic acid, denosumab, cabozantinib and nivolumab. He had been under treatment of nonsurgical therapy over a year, based on antibiotic and antiseptic mouth rinse, without improvement of oral conditions. Surgical treatment consisted of massive sequestrectomy and complete surgical debridement of necrotic bone tissues. The specimen was sent for histopathologic analysis, which confirmed bone tissue necrosis with no evidence of metastatic disease. Two-month follow-up revealed a considerable life quality improvement. Although this complication is well known, the uniqueness of this case is given by its severity, related to the administration of multiple antiresorptive and antiangiogenic drugs, by the natural response of the oral cavity with the almost complete self-exfoliation of the massive necrotic zone. This case is emblematic in highlighting the controversies in the management of MRONJ, which certainly require effective collaboration of the multidisciplinary health care team that could improve patient safety and reduce the risk of developing MRONJ.",
"affiliations": "School of Dentistry, Department of Health Sciences, Magna Graecia University of Catanzaro, Viale Europa, Catanzaro 88100, Italy.;School of Dentistry, Department of Health Sciences, Magna Graecia University of Catanzaro, Viale Europa, Catanzaro 88100, Italy.;School of Dentistry, Department of Health Sciences, Magna Graecia University of Catanzaro, Viale Europa, Catanzaro 88100, Italy.;School of Dentistry, Department of Health Sciences, Magna Graecia University of Catanzaro, Viale Europa, Catanzaro 88100, Italy.;School of Dentistry, Department of Health Sciences, Magna Graecia University of Catanzaro, Viale Europa, Catanzaro 88100, Italy.",
"authors": "Bennardo|F|F|https://orcid.org/0000-0002-6528-2681;Buffone|C|C|;Muraca|D|D|;Antonelli|A|A|;Giudice|A|A|",
"chemical_list": null,
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"doi": "10.1155/2020/8093293",
"fulltext": "\n==== Front\nCase Rep Med\nCase Rep Med\nCRIM\nCase Reports in Medicine\n1687-9627 1687-9635 Hindawi \n\n10.1155/2020/8093293\nCase Report\nMedication-Related Osteonecrosis of the Jaw with Spontaneous Hemimaxilla Exfoliation: Report of a Case in Metastatic Renal Cancer Patient under Multidrug Therapy\nhttps://orcid.org/0000-0002-6528-2681Bennardo F. fbennardo92@gmail.com Buffone C. Muraca D. Antonelli A. Giudice A. School of Dentistry, Department of Health Sciences, Magna Graecia University of Catanzaro, Viale Europa, Catanzaro 88100, Italy\nAcademic Editor: Hakan Yaman\n\n\n2020 \n22 10 2020 \n2020 809329327 2 2020 9 9 2020 12 10 2020 Copyright © 2020 F. Bennardo et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Medication-related osteonecrosis of the jaw (MRONJ) is a well-recognized complication of drug therapies for bone metabolic disorders or cancer related to administration of antiresorptive (bisphosphonates and denosumab) and antiangiogenic drugs. This report describes an advanced and unusual case of stage III peri-implantitis-induced MRONJ involving the right upper jaw which was attempting to self-exfoliate. A 61-year-old male patient, rehabilitated with the placement of two implants when he was still healthy, was suffering from metastatic renal cancer previously treated with bevacizumab, interleukin-2, zoledronic acid, denosumab, cabozantinib and nivolumab. He had been under treatment of nonsurgical therapy over a year, based on antibiotic and antiseptic mouth rinse, without improvement of oral conditions. Surgical treatment consisted of massive sequestrectomy and complete surgical debridement of necrotic bone tissues. The specimen was sent for histopathologic analysis, which confirmed bone tissue necrosis with no evidence of metastatic disease. Two-month follow-up revealed a considerable life quality improvement. Although this complication is well known, the uniqueness of this case is given by its severity, related to the administration of multiple antiresorptive and antiangiogenic drugs, by the natural response of the oral cavity with the almost complete self-exfoliation of the massive necrotic zone. This case is emblematic in highlighting the controversies in the management of MRONJ, which certainly require effective collaboration of the multidisciplinary health care team that could improve patient safety and reduce the risk of developing MRONJ.\n==== Body\n1. Introduction\nMedication-related osteonecrosis of the jaw (MRONJ) is a well-recognized complication of drug therapies for bone metabolic disorders or cancer, defined as a persistent bone exposure within the oral cavity for a minimum period of 8 weeks in patients without a history of radiotherapy in the head and neck region. Antiresorptive drugs, such as bisphosphonates (BPs) and denosumab, are successfully used in low-dose therapy to prevent bone pathological fractures in patients with osteoporosis and to treat other bone metabolic diseases such as Paget's disease and in high-dose therapy to prevent bone metastasis in patients with cancer [1].\n\nA recent literature review identified a wide range of medications classified as tyrosine kinase inhibitors, monoclonal antibodies, mammalian target of rapamycin inhibitors, radiopharmaceuticals, selective estrogen receptor modulators, and immunosuppressants that have been implicated in MRONJ in addition to the drugs already mentioned [2].\n\nMRONJ treatment initially involved nonsurgical therapy in mild cases and surgical therapy in severe cases, but currently, the indication for surgical therapy seems to prevail even in less severe cases [3, 4].\n\nThis article presents an unusual and extreme case of MRONJ triggered by peri-implantitis in a metastatic renal cancer patient under multidrug therapy.\n\n2. Presentation of Case\nA 61-year-old male was referred in October 2019 to the Academic Hospital of Magna Graecia University of Catanzaro by his family dentist for the evaluation and treatment of a probable upper jaw osteonecrosis.\n\nHis medical history revealed he was under treatment since April 2017 for a metastatic renal carcinoma with brain and vertebral osseous metastasis without jaw involvement. Additional medical conditions included arterial hypertension (treated with enalapril 10 mg twice daily), hypothyroidism (treated with levothyroxine 60 mg daily), and no history of smoking.\n\nStarting from May 2017, he received interleukin-2 (500.000 UI) subcutaneously 3 weeks a month, twice a day for 5 days a week. From June 2017, bevacizumab (25 mg/ml), every 2 weeks, for 6 months, was administered. He had also undergone a monthly 4 mg infusion of zoledronic acid (4 mg) for 5 cycles which was then replaced, in December 2017, by denosumab (120 mg) every 4 weeks, until September 2019. Moreover, from May to September 2019, he also received nivolumab (10 mg/ml). Now, he is in treatment only with daily oral doses of cabozantinib (60 mg).\n\nHe had been on treatment of nonsurgical therapy over a year (amoxi/clav 875 mg/125 mg, 2 times a day; metronidazole 500 mg, 3 times a day; and antiseptic mouth rinse with chlorhexidine 0.12%, 2 times a day) without improvement of oral conditions. Periodic follow-up had not been performed by his family dentist.\n\nAt clinical examination, two implants placed by his general dentist in the upper right jaw were found, only with the abutments of a cemented prosthesis (this is no longer present in the oral cavity). The implant rehabilitation, not combined with normal teeth, had been performed, in June 2015, before developing renal carcinoma and starting medical therapy, with two-stage surgical approaches. A partially edentulous maxilla with a totally exposed and necrotic sequestrum in the right hemimaxilla was observed, and there were signs of active infection and purulent exudate with no evidence of fistula formation. Spontaneous avulsion of a tooth was detected laterally to the right hemimaxilla. No implants had been lost prior to decementation of the prosthesis (Figure 1).\n\nObjective exam also revealed a moderate tissue swelling and an asymmetrical face aspect. The patient reported apparently spontaneous painful symptoms. Exposed necrotic tissue emanated a persistent fetor. The patient did not remember when the osseous tissue exposure had begun because in the initial phase, the exposed bone did not give any discomfort. There were no signs of other pathologies. Signs of peri-implantitis with clinical inflammation and peri-implant bone loss were detected.\n\nVarious radiological tests have been performed, and an X-ray of the brain has revealed the presence of various brain metastatic lesions.\n\nComputerized axial tomography with three-dimensional reconstruction revealed an extensive structural destruction of the right maxillary bone (Figure 2) with fractures and continuous solution of the anterior, inferior, lateral, and medial walls of the maxillary sinus. The lesion also involved the hard palate, with bone detachment of the right maxillary arch. Diagnosis of stage III MRONJ according to American Association of Oral and Maxillofacial Surgeons (AAOMS) classification was done.\n\nConsidering the severity of the clinical conditions, the patient received prophylactic antibiotic therapy with amoxi/clav 875 mg/125 mg. On the same day, the patient underwent surgery under local anesthesia.\n\nBone sequestrectomy was performed involving the entire right hemimaxilla held in place by inflammatory tissues. Removal of the sequestrum exposed the ipsilateral nasal cavity. Therefore, careful curettage was performed in order to remove granulation tissues and fragments of the residual necrotic bone.\n\nThe obtained surgical sample (Figure 3) was sent for histopathologic analysis, which revealed “compact bone tissue with morphological aspects coherent with the proposed diagnosis of osteonecrosis.”\n\nMedical therapy with antiseptic mouth rinse (nonalcoholic chlorhexidine 0.12% at least 2 times a day) and systemic antibiotic administration with amoxi/clav 875 mg/125 mg (2 times a day) and metronidazole 500 mg (3 times a day) for 2 weeks after surgery was suggested. The patient was discharged with strict advice to maintain a liquid diet for 2 weeks and an accurate oral hygiene.\n\nAfter 2 months of follow-up, persistence of oronasal antral communication and presence of mucus (discharged from nasal cavity) in the postoperative site were observed (Figure 4). No further regions of bone necrosis were found, and the patient was sent to his dentist for rehabilitation with an obturator prosthesis.\n\nUnfortunately, the prosthetic rehabilitation was never finalized because the patient's condition deteriorated, and he died.\n\n3. Discussion\nMRONJ lesions induced by pamidronate and zoledronate were first reported by Marx in 2003 in oncologic patients [5]. The risk of developing MRONJ and the response to treatment are mainly influenced by the type and dose of drug therapy, in relation to the patient's primary disease [1]. With the recent development of antiresorptive medications and antiangiogenics used alone or in combination, it seems to be important to understand the molecular mechanisms that lead to MRONJ: the evidence-based mechanisms of pathogenesis include disturbed bone remodeling, inflammation or infection, altered immunity, soft tissue toxicity, and angiogenesis inhibition [6].\n\nThe guidelines for MRONJ treatment, assessed by the AAOMS in 2014, suggested a conservative nonsurgical treatment for early stages (I and II) of MRONJ and surgery for advanced stages (III) and mild stages refractory to the nonsurgical approach [1].\n\nAlthough nonsurgical conservative therapy could be successful to control pain and reduce infection, the high success rate of tissue healing was reported in literature after surgical necrotic bone resection and also in mild stage, improving clinical condition of the patient often expecting downstaging of the lesions [3, 4, 7–12].\n\nIn many cases, surgical treatment of stage III MRONJ patients leads to oroantral communication in the posterior maxilla. The closure of these defects represents an additional challenge to the oral surgeon and is essential to improve the long‐term life quality [13].\n\nIn recent years, pedicled buccal fat pad (PBFP), combined with ultrasonic bone surgery and L-PRF, has shown some effectiveness in exposed bone coverage and soft tissue healing at the posterior maxillary region. This technique supplies a rich vascular source of adipose-derived adult stem cells that could contribute to the esthetic healing of mucosal defects, prevent further bone weakening, and maximize the success for prosthetic rehabilitation [14].\n\nThe treatment of patients with a medical history of malignant diseases and a high-dose drug administration is more complicated with a slower tendency to full healing [15].\n\nTo date, many different surgical approaches have been proposed in the treatment of MRONJ lesions: laser therapy, piezoelectric surgery, use of fluorescence for the identification of healthy bone margins, and application of platelet concentrates have become important tools to minimize the invasiveness of surgical therapy and improve tissue healing [15–18].\n\nThe patient described in this case report had a metastatic renal cancer treated with multidrug therapy. He was initially managed with nonsurgical therapy that could have eased the halitosis and pain, for more than one year, without an improvement of clinical conditions and with a worsening of MRONJ stage and quality of life. Association of BPs and antiangiogenic drugs leads to more severe and frequent cases of MRONJ than BPs alone [19]. Furthermore, the replacement of a zoledronic acid with denosumab is an additional risk factor for the development of MRONJ [20].\n\nWhen the patient came to our attention, the surgical therapy choice was mandatory with the removal of the wide sequestrum.\n\nThis case is emblematic in pointing out controversies in MRONJ management according to Schiodt et al [4]:Early surgical intervention on localized disease may prevent progression and the need for subsequent extensive surgery\n\nAccurate risk assessment with evaluation of antiresorptive and antiangiogenetic therapies is mandatory before starting MRONJ lesion treatment\n\n\n\nIn our opinion, the lack of interdisciplinary collaboration and accurate follow-up played a key role in the development of this advanced stage of MRONJ case. The role of general dental practitioners, maxillofacial and oral surgeons, and oncologists in this area must be regularly checked for oral and dental health and must be motivated before starting antiresorptive and antiangiogenic drugs.\n\nPatients continue to be at risk of developing MRONJ with a significant detrimental impact on quality of life due to limited preventive multidisciplinary interventions. MRONJ-education programs and an effective collaboration with the other professional groups could potentially reduce the risk of MRONJ and improve patient safety [21].\n\n4. Conclusion\nIn conclusion, though surgical therapy already in the early stages of MRONJ might prevent the progression of the disease, a multidisciplinary approach to the prevention of MRONJ is essential to optimize high-risk cancer patient management and to improve quality of life.\n\nThis outcome, in addition to a better communication among dentists and other health care personnel experienced is the best choice both for primary prevention (improvement of periodontal and peri-implant status and restoration of compromised teeth) and for secondary prevention with follow-up in order to identify MRONJ lesions in the early stage.\n\nConsent\nAccording to the Declaration of Helsinki on medical protocol and ethics, informed consent was obtained from the patient.\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nFigure 1 Patient's preoperative clinical condition: necrotic bone exposure and purulent exudate in quadrant I.\n\nFigure 2 Three-dimensional reconstruction of CT scans that highlighted the detachment of the right hemimaxilla.\n\nFigure 3 The wide bone sequestration of the right hemimaxilla obtained after sequestrectomy.\n\nFigure 4 Patient's clinical condition at 2-month follow-up visit: persistence of oroantral communication and presence of mucus.\n==== Refs\n1 Ruggiero S. L. Dodson T. B. Fantasia J. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw—2014 update Journal of Oral and Maxillofacial Surgery 2014 72 10 1938 1956 10.1016/j.joms.2014.04.031 2-s2.0-84909619222 25234529 \n2 King R. Tanna N. Patel V. Medication-related osteonecrosis of the jaw unrelated to bisphosphonates and denosumab–a review Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 2019 127 4 289 299 10.1016/j.oooo.2018.11.012 2-s2.0-85060847421 \n3 Ristow O. Rückschloß T. Müller M. Is the conservative non-surgical management of medication-related osteonecrosis of the jaw an appropriate treatment option for early stages? a long-term single-center cohort study Journal of Cranio-Maxillofacial Surgery 2019 47 3 491 499 10.1016/j.jcms.2018.12.014 2-s2.0-85059736104 30642734 \n4 Schiodt M. Otto S. Fedele S. Workshop of European task force on medication-related osteonecrosis of the jaw–current challenges Oral Diseases 2019 25 7 1815 1821 10.1111/odi.13160 2-s2.0-85071236602 31325201 \n5 Marx R. E. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic Journal of Oral and Maxillofacial Surgery 2003 61 9 1115 1117 10.1016/s0278-2391(03)00720-1 2-s2.0-0042861578 12966493 \n6 Chang J. Hakam A. E. McCauley L. K. Current understanding of the pathophysiology of osteonecrosis of the jaw Current Osteoporosis Reports 2018 16 5 584 595 10.1007/s11914-018-0474-4 2-s2.0-85053251123 30155844 \n7 Carlson E. R. Basile J. D. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws Journal of Oral and Maxillofacial Surgery 2009 67 5 85 95 10.1016/j.joms.2009.01.006 2-s2.0-64249172682 19371819 \n8 Coropciuc R. G. Grisar K. Aerden T. Schol M. Schoenaers J. Politis C. Medication-related osteonecrosis of the jaw in oncological patients with skeletal metastases: conservative treatment is effective up to stage 2 British Journal of Oral and Maxillofacial Surgery 2017 55 8 787 792 10.1016/j.bjoms.2017.06.014 2-s2.0-85026329583 28760314 \n9 Favia G. Tempesta A. Limongelli L. Crincoli V. Maiorano E. Medication‐related osteonecrosis of the jaw: surgical or non‐surgical treatment? Oral Disease 2018 24 1-2 238 242 10.1111/odi.12764 2-s2.0-85042496540 \n10 Reich W. Bilkenroth U. Schubert J. Wickenhauser C. Eckert A. W. Surgical treatment of bisphosphonate-associated osteonecrosis: prognostic score and long-term results Journal of Cranio-Maxillofacial Surgery 2015 43 9 1809 1822 10.1016/j.jcms.2015.07.035 2-s2.0-84945452795 26321065 \n11 Kang S. H. Won Y. J. Kim M. K. Surgical treatment of stage 2 medication-related osteonecrosis of the jaw compared to osteomyelitis Cranio 2018 36 6 373 380 10.1080/08869634.2017.1365413 2-s2.0-85028530088 28854059 \n12 El-Rabbany M. Sgro A. Lam D. K. Shah P. S. Azarpazhooh A. Effectiveness of treatments for medication-related osteonecrosis of the jaw: a systematic review and meta-analysis The Journal of the American Dental Association 2017 148 8 584 594 10.1016/j.adaj.2017.04.002 2-s2.0-85019647730 28527518 \n13 Aljohani S. Troeltzsch M. Hafner S. Kaeppler G. Mast G. Otto S. Surgical treatment of medication-related osteonecrosis of the upper jaw: case series Oral Diseases 2019 25 2 497 507 10.1111/odi.12992 2-s2.0-85056195682 30325561 \n14 Şahin O. Odabaşi O. Ekmekcioğlu C. Ultrasonic piezoelectric bone surgery combined with leukocyte and platelet-rich fibrin and pedicled buccal fat pad flap in denosumab-related osteonecrosis of the jaw Journal of Craniofacial Surgery 2019 30 5 e434 e436 10.1097/SCS.0000000000005472 2-s2.0-85069854069 31299805 \n15 Giudice A. Barone S. Giudice C. Bennardo F. Fortunato L. Can platelet-rich fibrin improve healing after surgical treatment of medication-related osteonecrosis of the jaw? A pilot study Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 2018 126 5 390 403 10.1016/j.oooo.2018.06.007 2-s2.0-85051408205 \n16 Giudice A. Bennardo F. Barone S. Antonelli A. Figliuzzi M. M. Fortunato L. Can autofluorescence guide surgeons in the treatment of medication-related osteonecrosis of the jaw? A prospective feasibility study Journal of Oral and Maxillofacial Surgery 2018 76 5 982 995 10.1016/j.joms.2017.10.024 2-s2.0-85039456800 29175416 \n17 Voss P. J. Poxleitner P. Schmelzeisen R. Stricker A. Semper-Hogg W. Update MRONJ and perspectives of its treatment Journal of Stomatology, Oral and Maxillofacial Surgery 2017 118 4 232 235 10.1016/j.jormas.2017.06.012 2-s2.0-85025461892 \n18 Fortunato L. Bennardo F. Buffone C. Giudice A. Is the application of platelet concentrates effective in the prevention and treatment of medication-related osteonecrosis of the jaw? A systematic review Journal of Cranio-Maxillofacial Surgery 2020 48 3 268 285 10.1016/j.jcms.2020.01.014 32063481 \n19 Christodoulou C. Pervena A. Klouvas G. Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone Oncology 2009 76 3 209 211 10.1159/000201931 2-s2.0-59749100961 19212145 \n20 Higuchi T. Soga Y. Muro M. Replacing zoledronic acid with denosumab is a risk factor for developing osteonecrosis of the jaw Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 2018 125 6 547 551 10.1016/j.oooo.2018.02.010 2-s2.0-85044271287 \n21 Sturrock A. Preshaw P. M. Hayes C. Wilkes S. General dental practitioners’ perceptions of, and attitudes towards, improving patient safety through a multidisciplinary approach to the prevention of medication-related osteonecrosis of the jaw (MRONJ): a qualitative study in the North East of England BMJ Open 2019 9 6 e029951 10.1136/bmjopen-2019-029951 2-s2.0-85067452244\n\n",
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"title": "Medication-Related Osteonecrosis of the Jaw with Spontaneous Hemimaxilla Exfoliation: Report of a Case in Metastatic Renal Cancer Patient under Multidrug Therapy.",
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"abstract": "We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.",
"affiliations": "Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.;Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.;Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.;Department of Hepatology and Pancreatology, Kawasaki Medical School, Japan.;Department of Clinical Pathology and Laboratory, Kawasaki Medical School, Japan.;Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.;Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.;Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.;Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.;Department of Pathology, Kawasaki Medical School General Medical Center, Japan.;Department of Surgery, Ishikawa Hospital, Japan.;Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.;Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan.",
"authors": "Nishino|Ken|K|;Kawanaka|Miwa|M|;Suehiro|Mitsuhiko|M|;Yoshioka|Naoko|N|;Nakamura|Jun|J|;Urata|Noriyo|N|;Tanigawa|Tomohiro|T|;Sasai|Takako|T|;Oka|Takahito|T|;Monobe|Yasumasa|Y|;Saji|Yoshiaki|Y|;Kawamoto|Hirofumi|H|;Haruma|Ken|K|",
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"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33116013\n10.2169/internalmedicine.5837-20\nCase Report\nGastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the “Gastrin Link Theory”\nNishino Ken 1\nKawanaka Miwa 1\nSuehiro Mitsuhiko 1\nYoshioka Naoko 2\nNakamura Jun 3\nUrata Noriyo 1\nTanigawa Tomohiro 1\nSasai Takako 1\nOka Takahito 1\nMonobe Yasumasa 4\nSaji Yoshiaki 5\nKawamoto Hirofumi 1\nHaruma Ken 1\n1 Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Japan\n2 Department of Hepatology and Pancreatology, Kawasaki Medical School, Japan\n3 Department of Clinical Pathology and Laboratory, Kawasaki Medical School, Japan\n4 Department of Pathology, Kawasaki Medical School General Medical Center, Japan\n5 Department of Surgery, Ishikawa Hospital, Japan\nCorrespondence to Dr. Miwa Kawanaka, m.kawanaka@med.kawasaki-m.ac.jp\n\n28 10 2020\n1 4 2021\n60 7 10191025\n11 7 2020\n7 9 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.\n\ngastric polyp\nhypergastrinemia\nargon plasma coagulation\nproton pump inhibitor\ngastric antral vascular ectasia\n==== Body\nIntroduction\n\nEsophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia (GAVE) are common and characteristic findings observed by endoscopic examinations in patients with liver cirrhosis (1-6). They are the cause of anemia and acute or chronic gastrointestinal bleeding in patients with liver cirrhosis (1-6).\n\nAlthough GAVE was first described in 1953 by Rider et al. as a cause of massive gastric bleeding (7), its etiology is not fully understood. Treatment includes conservative measures, such as acid suppression agents, blood transfusion, and endoscopic therapy. Endoscopic therapy, especially coagulation with argon plasma coagulation (APC), has become increasingly popular for the treatment of GAVE (8-10). In general, complications of APC for GAVE such as perforation and bleeding, are rare because of the superficial coagulation effect (11-13). However, rare cases of gastric polyps developing after APC therapy for GAVE have been reported (14-20) and termed “portal hypertension-associated polyps” or “portal hypertensive polyps” (21-24). The pathogenesis of gastric hyperplastic polyps is still unknown, but it is thought that the exaggerated repair of mucosal damage (25,26) or hypergastrinemia may play a role in the development of the polyps (27-29).\n\nWe herein report a rare case of gastric hyperplastic polyps following APC of GAVE. In this case, hypergastrinemia was caused by the prolonged use of a proton pump inhibitor (PPI) at the time of the diagnosis of gastric hyperplastic polyps. The discontinuance of PPIs and change to an H2-receptor antagonist with rebamipide normalized the level of serum gastrin and promoted the natural disappearance of gastric polyps with a good prognosis of GAVE.\n\nCase Report\n\nA 65-year-old man with liver cirrhosis and portal hypertension associated with hepatitis C virus was referred to us from an outside facility for the further evaluation of refractory iron deficiency anemia (Hb, 9.1 g/mL). He had a history of long-term use of PPIs because of suspicion of gastrointestinal bleeding.\n\nInitial upper gastrointestinal endoscopy revealed mild esophageal varix in the lower esophagus and multiple red spots in the antrum with multiple low polyploid lesions, which were diagnosed as GAVE associated with portal hypertension and raised type-erosive gastritis. No atrophy and no polyps were found in the stomach, and APC therapy was performed for GAVE (Fig. 1). After APC therapy, a PPI (esomeprazole 20 mg/day) was subsequently readministered. Repeated endoscopies (second and third) showed multiple ulcers in the antrum at one week after APC (Fig. 2a, b), as well as multiple scars and reddish small polypoid lesions in the antrum at two months after APC (Fig. 2c, d). PPI treatment was continued for the patient, and the clinical course was good except for moderate iron deficiency anemia (Hb, 11.0 g/mL).\n\nFigure 1. Initial endoscopic findings. Endoscopy revealed mild esophageal varix in the lower esophagus (a) and multiple red spots in the antrum with multiple low polyploid lesions (b). No atrophy or polyps were present (c). Multiple erosions after APC therapy (d). APC: argon plasma coagulation\n\nFigure 2. Repeated endoscopies (second and third). Multiple ulcers in the antrum at one week after APC (a, b) and multiple scars and reddish small polypoid lesions in the antrum at two months after APC (c, d). APC: argon plasma coagulation\n\nFive months after APC therapy, he was diagnosed with hepatocellular carcinoma (HCC) (size 1×1 cm) and treated with radiofrequency ablation without recurrence. Eight months later, he was treated for hepatitis C using direct acting antivirals and went into remission. Two years and six months after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach (Fig. 3). Biopsy specimens from gastric polyps in the antrum and angle indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Fig. 4), and the lesions were diagnosed as gastric hyperplastic polyps. The level of fasting serum gastrin was 817 pg/mL (normal range: 50-150 pg/mL), and serum Helicobacter pylori antibody was negative on the day of endoscopy. Therefore, we considered the cause of gastric hyperplastic polyps to be hypergastrinemia induced by PPIs and switched from a PPI to an H2 blocker antagonist (famotidine 40 mg/day) and a mucoprotective agent (rebamipide 300 mg/day).\n\nFigure 3. Two years after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach. APC: argon plasma coagulation\n\nFigure 4. Biopsy specimens from gastric polyps of the antrum (a) and angle (b) indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Hematoxylin and Eosin staining, ×100).\n\nOne year later, a fifth endoscopy revealed that all polyps had completely disappeared, and GAVE was not present (Fig. 5). The fasting level of serum gastrin was in the normal range (121 pg/mL). In addition, a complete improvement in iron deficiency anemia was found (Hb, 15.4 g/mL). Four and five years after APC therapy, the sixth and seventh endoscopic examinations were performed, respectively, and no polyps or GAVE were observed. The clinical course of liver cirrhosis was stable during the follow-up period (Fig. 6).\n\nFigure 5. One year after the fourth endoscopy, a fifth endoscopy revealed that all polyps and the remaining GAVE had completely disappeared (a-d). GAVE: gastric antral vascular ectasia\n\nFigure 6. Four and five years after APC therapy, the sixth (a, b) and seventh (c, d) endoscopic examinations, respectively, indicated the polyps and GAVE had not reappeared. Esophageal varix was not markedly different from that at the initial endoscopy (a). APC: argon plasma coagulation, GAVE: gastric antral vascular ectasia\n\nDiscussion\n\nHyperplastic gastric polyps developing after electrocoagulation therapy for GAVE were first reported after endoscopic laser therapy by Geller et al. in 1996 (14). In 1998, Dohmen et al. reported the first Japanese case of gastric hyperplastic polyps at four months after heater probe therapy in a patient with liver cirrhosis (15). Subsequent reports described the development of gastric polyps as a complication of endoscopic therapy, especially APC, for the treatment of GAVE (16-20). This is the first reported case whereby switching from a PPI to an H2 blocker antagonist led to the disappearance of gastric polyps that appeared after endoscopic therapy for GAVE.\n\nThe histological findings of gastric polyps after the endoscopic treatment of GAVE indicated hyperplastic foveolar epithelium with the dilation and increase of capillaries, similar to common gastric hyperplastic polyps (14-20). The gastric polyps in our case showed a similar histology. Previous studies of gastric polyps in patients with portal hypertension used the terms “portal hypertensive polyp,” “gastric polyps in patients with portal hypertension,” or “portal hypertension-associated gastric polyp” (21-24).\n\nThe pathogenic mechanism of gastric hyperplastic polyps in patients with liver cirrhosis or portal hypertension is currently unclear, but several previous studies have suggested that congestion caused by elevated portal pressure might have an important role in inducing mucosal proliferation and angiogenesis (14-20). Furthermore, mucosal and vascular structural damage induced by APC might be involved in the pathogenesis rather than the superficial inflammation of the mucosa. In general, common gastric hyperplastic polyps arise from atrophic gastric mucosa caused by H. pylori infection (25-27) or autoimmune gastritis (27,30,31). In our case, H. pylori infection was negative, and no atrophy of the gastric mucosa evaluated by endoscopy was found. Moreover, previous studies of the pathogenesis of gastric hyperplastic polyps have shown that hypergastrinemia induced by severe atrophic gastritis of the corpus (25-29) or prolonged use of PPIs might induce the development of gastric hyperplastic polys (28,32,33). Gastrin has trophic effects on the gastrointestinal mucosa (34) and may repair gastric mucosal damage caused by APC. When gastric hyperplastic polyps were diagnosed in the present case, hypergastrinemia (817 pg/mL) caused by PPIs was found, and the gastrin level was normalized (121 pg/mL) by changing the treatment to an H2 blocker antagonist and rebamipide, with all gastric polyps and iron deficiency anemia completely disappearing. Rebamipide was used because it decreases gastrin levels in the blood and repairs damaged gastric mucosal tissues (35-37). PPIs were reported to be related to iron deficiency anemia (38,39); therefore, the discontinuation of PPIs might have been involved in the improvement of anemia in this case.\n\nRecently, Okazaki et al. reported gastric hyperplastic polyps in a patient with gastroesophageal reflux disease, which might have been caused by the prolonged use of PPIs, disappeared one year after switching from a PPI to an H2 receptor antagonist (40). PPIs were suspected to have caused the development of gastric hyperplastic polyps because H. pylori infection was negative and atrophic gastritis was not found. In general, common gastric hyperplastic polyps develop from atrophic gastritis induced by H. pylori infection (25-27) or autoimmune gastritis with hypergastrinemia (30,31). Unfortunately, the level of serum gastrin was not described in that case study. Anjiki et al. reported a case of multiple hyperplastic polyps with adenocarcinoma in which hypergastrinemia was induced by the long-term use of PPIs; however, the gastric polyps disappeared and gastrin levels normalized after the discontinuation of PPIs (41). That case was H. pylori-positive, and H. pylori eradication therapy was performed in addition to the discontinuation of PPIs. H. pylori eradication therapy was reported to normalize serum gastrin levels (42,43) and reduce gastric hyperplastic polyps (43,44). In our case, which was negative for H. pylori and atrophic gastritis, the gastric hyperplastic polyps disappeared completely with the normalization of gastrin levels.\n\nOur patient had liver cirrhosis with hepatocellular carcinoma, and various factors might have been involved in the disappearance of the polyps over a long period; however, such polyps do not disappear spontaneously. PPIs are useful for treating reflux esophagitis and peptic ulcer diseases as well as for H. pylori eradication therapy and the prevention of peptic ulcer diseases. Furthermore, they are often used long-term in general practice. When hyperplastic polyps are diagnosed after APC treatment of GAVE, hypergastrinemia induced by PPIs should be considered, as in the present case, and treatment by decreasing the PPI dose or switching from a PPI to an H2 receptor antagonist with rebamipide might be suitable.\n\nInformed consent was obtained from the patient.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nWe thank J. Ludovic Croxford, PhD for editing a draft of this manuscript.\n==== Refs\n1. Toyonaga A , Iwao T . Portal-hypertensive gastropathy. J Gastroenterol Hepatol 13 : 865-877, 1998.9794183\n2. Burak KW , Lee SS , Beck PL . Portal hypertensive gastropathy and gastric antral vascular ectasia (GAVE) syndrome. Gut 49 : 866-872, 2001.11709525\n3. Merli M , Nicolini G , Angeloni S , et al . The natural history of portal hypertensive gastropathy in patients with liver cirrhosis and mild portal hypertension. Am J Gastroenterol 99 : 1959-1965, 2004.15447756\n4. Fontana RJ , Sanyal AJ , Ghany MG , et al . Development and progression of portal hypertensive gastropathy in patients with chronic hepatitis C. Am J Gastroenterol 106 : 884-893, 2011.21139575\n5. Patwardhan VR , Cardenal A . Review article: the management of portal hypertensive gastropathy and gastric antral ectasia in cirrhosis. Aliment Pharmacol Ther 40 : 354-362, 2014.24889902\n6. Gjeorgjievski M , Cappell MS . Portal hypertensive gastropathy: a systematic review of the pathophysiology, clinical presentation, natural history and therapy. World J Hepatol 8 : 231-262, 2016.26855694\n7. Rider JA , Klotz AP , Kirsner JB . Gastritis with veno capillary ectasia as a source of massive gastric hemorrhage. Gastroenterology 24 : 118-123, 1953.13052170\n8. Herrera S , Bordas JN , Llach J , et al . The beneficial effects of argon plasma coagulation in the management of different types of gastric vascular ectasia lesions in patients admitted for GI hemorrhage. Gastrointest Endosc 68 : 440-446, 2008.18423466\n9. Fuccio L , Zagari RM , Serrani M , et al . Endoscopic argon plasma coagulation for the treatment of gastric antral vascular ectasia - Related bleeding in patients with liver cirrhosis. Digestion 79 : 143-150, 2009.19329853\n10. Chiu YC , Lu LS , Wu KL , et al . Comparison of argon plasma coagulation in management of upper gastrointestinal angiodysplasia and gastric antral vascular ectasia hemorrhage. BMC Gastroenterol 12 : 67, 2012.22681987\n11. Dulai GS , Jensen DM , Kovacs TOG , et al . Endoscopic treatment outcomes in watermelon stomach patients with and without portal hypertension. Endoscopy 36 : 68-72, 2004.14722858\n12. Sato T , Yamazaki K , Toyota J , et al . Efficacy of argon plasma coagulation for gastric antral vascular ectasia associated with chronic liver disease. Hepatol Res 32 : 121-126, 2005.15967712\n13. Kwan V , Bourke MJ , Williamas SJ , et al . Argon plasma coagulation in the management of symptomatic gastrointestinal vascular lesions: experience in 100 consecutive patients with long-term follow-up. Am J Gastroenterol 101 : 58-63, 2006.16405534\n14. Geller A , Gostout CJ , Balm RK . Development of hyperplastic polyps following laser therapy for watermelon stomach. Gastrointest Endosc 43 : 54-56, 1996.8903819\n15. Dohmen K , Ohtsuka Y , Takahashi K , et al . A case of multiple hyperplastic polyps arosen from scars caused by heater probe treatment for gastric antral vascular ectasia. Gastrointest Endosc 40 : 901-906, 1998(in Japanese, Abstract in English).\n16. Izquierdo S , Rey E , del Olmo G , et al . Polyps as a complication of argon plasma coagulation in watermelon stomach. Endoscopy 37 : 921, 2005.16116545\n17. Farooq FT , Wong RCK , Yang P , et al . Gastric outlet obstruction as a complication of argon plasma coagulation for watermelon stomach. Gastrointest Endosc 65 : 1090-1092, 2007.17451706\n18. Ghabril M , Gross S , Krishna M , et al . Hyperplastic polyposis following treatment of gastric vascular ectasia: a case report and review of clinical correlates. Case Rep Gastroenterol 1 : 48-52, 2007.21487471\n19. Shah N , Cavanagh Y , Kaswala DH , et al . Development of hyperplastic polyps following argon plasma coagulation of gastric antral vascular ectasia. J Nat Sci Biol Med 6 : 479-482, 2015.26283860\n20. Kawaguchi K , Haratake J . Multiple hyperplastic polyps following argon plasma coagulation of gastric antral vascular ectasia. Gastroenterol Endosc 57 : 52-53, 2015(in Japanese).\n21. Lam MCW , Tha S , Owen D , et al . Gastric polyps in patients with portal hypertension. Eur J Gastroenterol Hepatol 23 : 1245-1249, 2011.22002002\n22. Amarapurkar AD , Amarapurkar D , Choksi M , et al . Portal hypertensive polyps: distinct entity. Indian J Gastroenterol 32 : 195-199, 2013.23512212\n23. Livovsky DM , Pappo O , Skarzhinsky G , et al . Gastric polyp growth during endoscopic surveillance for esophageal varices or Barrett's esophagus. Isr Med Assoc J 18 : 267-271, 2016.27430081\n24. Kara D , Husing-Kabar A , Schmidt H , et al . Portal hypertensive polyposis in advanced liver cirrhosis: the unknown entity? Can J Gastroenterol Hepatol 2018 : 2182784, 2018.30155451\n25. Jain R , Chetty R . Gastric hyperplastic polyps: a review. Dig Dis Sci 54 : 1839-1846, 2009.19037727\n26. Abraham Sc , Singh VK , Yardley JH , et al . Hyperplastic polyps of the stomach. Associations with histologic patterns of gastritis and gastric atrophy. Am J Surg Pathol 25 : 500-507, 2001.11257625\n27. Haruma K , Yoshihara M , Sumii K , et al . Gastric acid secretion, serum pepsinogen I, and serum gastrin in Japanese with gastric hyperplastic polyps or polypoid-type early gastric carcinoma. Scand J Gastroenterol 28 : 633-637, 1993.8362219\n28. Hongo M , Fujimoto K ; Gastric Polyps Study Group. Incidence and risk factor of fundic gland polyp and hyperplastic polyp in long-term proton pump inhibitor therapy: a prospective study in Japan. J Gastroenterol 45 : 618-624, 2010.20177714\n29. Hu H , Zhang Q , Chen G , et al . Risk factors and clinical correlates of neoplastic transformation in gastric hyperplastic polyps in Chinese patients. Sci Rep 10 : 2582, 2020.32054871\n30. Stockbrugger RW , Menon GG , Beilby JOW , et al . Gastroscopic screening in 80 patients with pernicious anaemia. Gut 24 : 1141-1147, 1983.6642278\n31. Terao S , Suzuki S , Yaita H , et al . Multicenter study of autoimmune gastritis in Japan: clinical and endoscopic characteristics. Dig Endosc 32 : 364-372, 2020.31368581\n32. Choudhry U , Boyce HW , Coppola D . Proton pump inhibitor-associated gastric polyps. A retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics. Am J Clin Pathol 110 : 615-621, 1998.9802346\n33. Miyamoto S , Kato m , Matsuda K , et al . Gastric hyperplastic polyps associated with proton pump inhibitor use in a case without a history of Helicobacter pylori infection. Intern Med 56 : 1825-1829, 2017.28717077\n34. Haruma k , Kamada T , Manabe N , et al . Old and new gut hormone, gastrin and acid suppressive therapy. Digestion 97 : 340-344, 2018.29587283\n35. Haruma K , Ito M , Kido S , et al . Long-term rebamipide therapy improves Helicobacter pylori-associated chronic gastritis. Dig Dis Sci 47 : 862-867, 2002.11991622\n36. Kinjo N , Kawanaka H , Akshodhi T , et al . Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications. Am J Physiol Gastrointest Liver Physiol 295 : G1016-G1024, 2008.18787063\n37. Haruma K , Ito M . Review article: clinical significance of mucosal-protective agents: acid, inflammation, carcinogenesis and rebamipide. Aliment Pharmacol Ther 18 : 153-159, 2003.12925154\n38. Sarzynski E , Putarajappa C , Xie Y , et al . Association between proton pump inhibitor use and anemia: a retrospective cohort study. Dig Dis Sci 56 : 2349-2353, 2011.21318590\n39. Lam JR , Schneider JL , Quesenberry CP , et al . Proton pump inhibitor and histamine-2 receptor antagonist use and iron deficiency. Gastroenterology 152 : 821-829, 2017.27890768\n40. Okazaki Y , Kotani K , Higashi Y . Vanishing gastric hyperplastic polyps. BMJ Case Rep 12 : e231341, 2019.\n41. Anjiki H , Mukaisho K , Kadomoto Y , et al . Adenocarcinoma arising in multiple hyperplastic polyps in a patient with Helicobacter pylori infection and hypergastrinemia during long-term proton pump inhibitor. Clin J Gastroenterol 10 : 128-136, 2017.28160247\n42. Wagner S , Haruma K , Gladziwa U , et al . Helicobacter pylori infection and serum pepsinogen A, pepsinogen C, and gastrin in gastritis and peptic ulcer: significance of inflammation and effect of bacterial eradication. Am J Gastroenterol 89 : 1211-1218, 1994.8053437\n43. Ohkusa T , Takashimizu I , Fujiki K , et al . Disappearance of hyperplastic polyps in the stomach after eradication of Helicobacter pylori. A randomized, controlled trial. Ann Intern Med 129 : 712-715, 1998.9841603\n44. Ji F , Wang ZW , Ning JW , et al . Effect of drug treatment on hyperplastic gastric polyps infected with Helicobacter pylori: a randomized, controlled trial. World J Gastroenterol 12 : 1770-1773, 2006.16586550\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(7)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "argon plasma coagulation; gastric antral vascular ectasia; gastric polyp; hypergastrinemia; proton pump inhibitor",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D057908:Argon Plasma Coagulation; D020252:Gastric Antral Vascular Ectasia; D005755:Gastrins; D006801:Humans; D008103:Liver Cirrhosis; D008297:Male; D011127:Polyps; D013274:Stomach Neoplasms",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1019-1025",
"pmc": null,
"pmid": "33116013",
"pubdate": "2021-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19037727;21139575;29587283;9802346;16116545;26855694;8903819;8362219;11257625;19329853;16586550;21318590;27430081;31368581;31511271;16405534;11991622;26283860;18787063;12925154;11709525;9841603;27890768;24889902;20177714;6642278;22681987;28160247;15967712;8053437;32054871;15447756;28717077;30155451;9794183;18423466;17451706;14722858;21487471;22002002;23512212;13052170",
"title": "Gastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the \"Gastrin Link Theory\".",
"title_normalized": "gastric hyperplastic polyps after argon plasma coagulation for gastric antral vascular ectasia in patients with liver cirrhosis a case suggesting the gastrin link theory"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-318081",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ESOMEPRAZOLE"
},
"dr... |
{
"abstract": "Malignant pleural mesothelioma (MPM) has limited treatment options and a poor outcome. Programmed death 1/programmed death ligand 1 (PD-L1) checkpoint inhibitors have proven efficacious in several cancer types. Nivolumab is a fully humanized monoclonal antibody against programmed death 1 with a favorable toxicity profile. In MPM, the immune system is considered to play an important role. We therefore tested nivolumab in recurrent MPM.\n\n\n\nIn this single-center trial, patients with MPM received nivolumab 3 mg/kg intravenously every 2 weeks. Primary endpoint was the disease control rate at 12 weeks. Pre- and on-treatment biopsy specimens were obtained to analyze biomarkers for response.\n\n\n\nOf the 34 patients included, 8 patients (24%) had a partial response at 12 weeks and another 8 had stable disease resulting in a disease control rate at 12 weeks of 47%. One reached a partial response at 18 weeks. In 4 patients with stable disease, the tumor remained stable for more than 6 months. Treatment-related adverse events of any grade occurred in 26 patients (76%), most commonly fatigue (29%) and pruritus (15%). Grades 3 and 4 treatment-related adverse events were reported in 9 patients (26%), with pneumonitis, gastrointestinal disorders, and laboratory disorders mostly seen. One treatment-related death was due to pneumonitis and probably initiated by concurrent amiodarone therapy. PD-L1 was expressed on tumor cells in nine samples (27%), but did not correlate with outcome.\n\n\n\nSingle-agent nivolumab has meaningful clinical efficacy and a manageable safety profile in pre-treated patients with mesothelioma. PD-L1 expression does not predict for response in this population.",
"affiliations": "Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: thoraxoncologie@nki.nl.;Biometrics Department, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Biometrics Department, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Division of Oncogenomics, Oncode Institute within Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.",
"authors": "Quispel-Janssen|Josine|J|;van der Noort|Vincent|V|;de Vries|Jeltje F|JF|;Zimmerman|Marion|M|;Lalezari|Ferry|F|;Thunnissen|Erik|E|;Monkhorst|Kim|K|;Schouten|Robert|R|;Schunselaar|Laurel|L|;Disselhorst|Maria|M|;Klomp|Houke|H|;Hartemink|Koen|K|;Burgers|Sjaak|S|;Buikhuisen|Wieneke|W|;Baas|Paul|P|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtho.2018.05.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-0864",
"issue": "13(10)",
"journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer",
"keywords": "Checkpoint inhibitor; Immunotherapy; Mesothelioma; Nivolumab; Programmed death ligand 1",
"medline_ta": "J Thorac Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008654:Mesothelioma; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D000077594:Nivolumab; D010997:Pleural Neoplasms; D000077982:Progression-Free Survival; D011446:Prospective Studies",
"nlm_unique_id": "101274235",
"other_id": null,
"pages": "1569-1576",
"pmc": null,
"pmid": "29908324",
"pubdate": "2018-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma.",
"title_normalized": "programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma"
} | [
{
"companynumb": "NL-PFIZER INC-2018327832",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugadditional":... |
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