article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "Timothy syndrome (TS) is an extremely rare multisystem disorder characterized by marked QT prolongation, syndactyly, seizures, behavioural abnormalities, immunodeficiency, and hypoglycaemia. The aim of this study was to categorize the phenotypes and examine the outcomes of patients with TS.\n\n\n\nAll patients diagnosed with TS in the United Kingdom over a 24-year period were reviewed. Fifteen centres in the British Congenital Arrhythmia Group network were contacted to partake in the study. Six patients with TS were identified over a 24-year period (4 boys and 2 girls). Five out of the six patients were confirmed to have a CACNA1C mutation (p.Gly406Arg) and the other patient was diagnosed clinically. Early presentation with heart block, due to QT prolongation was frequently seen. Four are still alive, two of these have a pacemaker and two have undergone defibrillator implantation. Five out of six patients have had a documented cardiac arrest with three occurring under general anaesthesia. Two patients suffered a cardiac arrest while in hospital and resuscitation was unsuccessful, despite immediate access to a defibrillator. Surviving patients seem to have mild developmental delay and learning difficulties.\n\n\n\nTimothy syndrome is a rare disorder with a high attrition rate if undiagnosed. Perioperative cardiac arrests are common and not always amenable to resuscitation. Longer-term survival is possible, however, patients invariably require pacemaker or defibrillator implantation.",
"affiliations": "Bristol Royal Hospital for Children, University Hospital Bristol, Bristol, UK.;Department of Congenital Cardiology, Freeman Hospital, Newcastle upon Tyne, UK.;Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.;Department of Congenital Cardiology, Freeman Hospital, Newcastle upon Tyne, UK.;Department of Cardiology, The Yorkshire Heart Centre, Leeds General Infirmary, Leeds, UK.;School of Physiology, Pharmacology and Neuroscience Cardiovascular Research Laboratories, University of Bristol, Bristol, UK.;School of Physiology, Pharmacology and Neuroscience Cardiovascular Research Laboratories, University of Bristol, Bristol, UK.;Department of Cardiology, University Hospital Wales, Cardiff, UK.;Department of Plastic Surgery, University Hospital Wales, Cardiff, UK.;Bristol Royal Hospital for Children, University Hospital Bristol, Bristol, UK.;Department of Clinical Genetics, Freeman Hospital, Newcastle upon Tyne, UK.;Oxford Medical Genetics Laboratories, Cardiac Service, Oxford University Hospitals NHS Trust, The Churchill Hospital, Oxford, UK.;Oxford Medical Genetics Laboratories, Cardiac Service, Oxford University Hospitals NHS Trust, The Churchill Hospital, Oxford, UK.;Department of Clinical Genetics, University Hospital Bristol, Bristol, UK.;Department of Cardiology, Royal Hospital for Sick Children, Glasgow, UK.",
"authors": "Walsh|Mark A|MA|;Turner|Christian|C|;Timothy|Katherine W|KW|;Seller|Neil|N|;Hares|Dominic L|DL|;James|Andrew F|AF|;Hancox|Jules C|JC|;Uzun|Orhan|O|;Boyce|Dean|D|;Stuart|Alan G|AG|;Brennan|Paul|P|;Sarton|Caroline|C|;McGuire|Karen|K|;Newbury-Ecob|Ruth A|RA|;Mcleod|Karen|K|",
"chemical_list": "C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type",
"country": "England",
"delete": false,
"doi": "10.1093/europace/euw433",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1099-5129",
"issue": "20(2)",
"journal": "Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology",
"keywords": "Cardiac arrest; Defibrillator; Long QT; Paediatrics; Timothy syndrome",
"medline_ta": "Europace",
"mesh_terms": "D001321:Autistic Disorder; D020746:Calcium Channels, L-Type; D002304:Cardiac Pacing, Artificial; D017147:Defibrillators, Implantable; D004554:Electric Countershock; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006323:Heart Arrest; D006327:Heart Block; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008133:Long QT Syndrome; D008297:Male; D009154:Mutation; D010138:Pacemaker, Artificial; D010641:Phenotype; D011379:Prognosis; D012151:Resuscitation; D013576:Syndactyly; D013997:Time Factors; D006113:United Kingdom",
"nlm_unique_id": "100883649",
"other_id": null,
"pages": "377-385",
"pmc": null,
"pmid": "28371864",
"pubdate": "2018-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A multicentre study of patients with Timothy syndrome.",
"title_normalized": "a multicentre study of patients with timothy syndrome"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK201802537",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nIfosfamide, a widely used chemotherapeutic agent, has been frequently associated with encephalopathy. A larger-scale study was conducted to identify risk factors of ifosfamide-related encephalopathy, including hepatic function.\n\n\nMETHODS\nAdult patients who had completed at least one cycle of ifosfamide between January 2008 and December 2010 were included. Those with renal failure or liver failure were excluded. Data were collected through chart review. Patients with encephalopathy and patients without encephalopathy were compared on age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), baseline serum creatinine (SCr) level, albumin level, white blood cell count, liver function, brain metastasis, and dosage of ifosfamide. Chi-square test or Fisher's exact test, Student t test, and univariate and multivariate logistic regressions were used for analysis.\n\n\nRESULTS\nThis study enrolled 337 patients. Thirty-eight patients (11%) had ifosfamide-related encephalopathy. They had poorer ECOG PS; higher SCr level, white blood cell count, and aspartate aminotransferase level; and lower serum albumin level compared with patients without encephalopathy. Ifosfamide dosage, brain metastasis, and age were not significant risk factors. Multivariate analysis indicated that only ECOG PS, SCr level, and albumin level contributed significantly to the risk.\n\n\nCONCLUSIONS\nTo date, this is the largest-scale study to have analyzed the risk factors of ifosfamide-related encephalopathy. This study confirms that an ECOG PS of 2-4 and increased SCr level are significant risk factors of ifosfamide-related encephalopathy, whereas increased albumin level decreases the risk, consistent with previous reports. Higher aspartate aminotransferase levels have no significant impact. In contrast to previous studies, ifosfamide dosage and brain metastasis are not significant contributing factors.",
"affiliations": "Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan.;Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.;Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.;Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.;Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: flwu@ntu.edu.tw.",
"authors": "Lo|Yin|Y|;Shen|Li-Jiuan|LJ|;Chen|Wen-Hwei|WH|;Dong|Yaa-Hui|YH|;Wu|Fe-Lin Lin|FL|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003404:Creatinine; D007069:Ifosfamide",
"country": "Singapore",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-6646",
"issue": "115(9)",
"journal": "Journal of the Formosan Medical Association = Taiwan yi zhi",
"keywords": "adverse drug reaction; drug toxicity; encephalopathy; ifosfamide; neurotoxicity syndromes; risk factors",
"medline_ta": "J Formos Med Assoc",
"mesh_terms": "D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D001927:Brain Diseases; D003404:Creatinine; D005260:Female; D006801:Humans; D007069:Ifosfamide; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms; D012189:Retrospective Studies; D012307:Risk Factors; D013624:Taiwan",
"nlm_unique_id": "9214933",
"other_id": null,
"pages": "744-51",
"pmc": null,
"pmid": "26302952",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk factors of ifosfamide-related encephalopathy in adult patients with cancer: A retrospective analysis.",
"title_normalized": "risk factors of ifosfamide related encephalopathy in adult patients with cancer a retrospective analysis"
} | [
{
"companynumb": "TW-MYLANLABS-2016M1059307",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "In this retrospective multicentre study, we investigated the outcomes of elderly primary central nervous system lymphoma (PCNSL) patients (⩾65 years) who underwent high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) at 11 centres between 2003 and 2016. End points included remission, progression-free survival (PFS), overall survival (OS) and treatment-related mortality. We identified 52 patients (median age 68.5 years, median Karnofsky Performance Status before HDT-ASCT 80%) who all underwent thiotepa-based HDT-ASCT. Fifteen patients (28.8%) received HDT-ASCT as first-line treatment and 37 (71.2%) received it as second or subsequent line. Remission status before HDT-ASCT was: CR 34.6%, PR 51.9%, stable disease 3.8% and progressive disease 9.6%. Following completion of HDT-ASCT, 36 patients (69.2%) achieved CR (21.2% first-line setting and 48.1% second or subsequent line setting) and 9 (17.3%) PR (5.8% first-line setting and 11.5% second or subsequent line setting). With a median follow-up of 22 months after HDT-ASCT, median PFS and OS were reached after 51.1 and 122.3 months, respectively. The 2-year PFS and OS rates were 62.0% and 70.8%, respectively. We observed two HDT-ASCT-associated deaths (3.8%). In selected elderly PCNSL patients, HDT-ASCT, using thiotepa-based conditioning regimes, is feasible and effective. Further prospective and comparative studies are warranted to further evaluate the role of HDT-ASCT in elderly PCNSL patients.",
"affiliations": "Department of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Stuttgart Cancer Centre, Klinikum Stuttgart, Stuttgart, Germany.;Stuttgart Cancer Centre, Klinikum Stuttgart, Stuttgart, Germany.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Haematology, APHP, Sorbonne Universités, Hospital Pitié-Salpêtrière, Paris, France.;Department of Oncology, Oulu University Hospital, Oulu, Finland.;Department of Haematology, University College Hospital, London, UK.;Department of Haematology, University College Hospital, London, UK.;Department of Neurology, APHP, Sorbonne Universités, UPMC Hospital Pitié-Salpêtrière, LOC network, Paris, France.;Department of Neurology, APHP, Sorbonne Universités, UPMC Hospital Pitié-Salpêtrière, LOC network, Paris, France.;Department of Ophthalmolgy, APHP, Sorbonne Universités, UPMC Hospital Pitié-Salpêtrière, LOC network, Paris, France.;Department of Ophthalmology, Curie Institute-Rene Huguenin Hospital, LOC network, Saint-Cloud, France.;Department of Haematology, University Hospital, Amiens, LOC network, Amiens, France.;Department of Haematology, Cochin University Hospital, LOC network, Paris, France.;Department of Haematology, University Hospital, LOC network, Rennes, France.;Department of Haematology, University Hospital, LCO network, Poitiers, France.;Stuttgart Cancer Centre, Klinikum Stuttgart, Stuttgart, Germany.;Department of Haematology, Curie Institute-Rene Huguenin Hospital, LOC network, Saint-Cloud, France.;Stuttgart Cancer Centre, Klinikum Stuttgart, Stuttgart, Germany.",
"authors": "Schorb|E|E|;Fox|C P|CP|;Fritsch|K|K|;Isbell|L|L|;Neubauer|A|A|;Tzalavras|A|A|;Witherall|R|R|;Choquet|S|S|;Kuittinen|O|O|;De-Silva|D|D|;Cwynarski|K|K|;Houillier|C|C|;Hoang-Xuan|K|K|;Touitou|V|V|;Cassoux|N|N|;Marolleau|J-P|JP|;Tamburini|J|J|;Houot|R|R|;Delwail|V|V|;Illerhaus|G|G|;Soussain|C|C|;Kasenda|B|B|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D013852:Thiotepa",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2017.23",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "52(8)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating; D016543:Central Nervous System Neoplasms; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005060:Europe; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D012074:Remission Induction; D012189:Retrospective Studies; D016019:Survival Analysis; D013852:Thiotepa; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1113-1119",
"pmc": null,
"pmid": "28436974",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "25701456;20660832;24947495;21810685;26688235;25568347;25387088;17339189;24492141;7722560;22367772;22473593;16240449;16863926;19433528;25628469;18166803;27132696;27476790;25480497;18413641;21151188;17185743;25725080;19914958;17084198;22581000;17647247;12237919;18541205;25635006;11157026;24745937;16864853;12860951;15653703;22023529;20383213;18838474;23868695;23026829;25052698;23300179;10963643;16951691;23685932;14615443;16146534",
"title": "High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: a European retrospective study.",
"title_normalized": "high dose thiotepa based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma a european retrospective study"
} | [
{
"companynumb": "DE-ADIENNEP-2017AD000133",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THIOTEPA"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nNatalizumab is a drug used in multiple sclerosis (MS) and its main side effect is the development of progressive multifocal leukoencephalopathy (PML). Since this is potentially fatal or disabling, treatment must be stopped immediately if it is suspected, taking into account the possible later development of immune reconstitution syndrome or renewed exacerbation of MS.\n\n\nMETHODS\nWe report a case of initially asymptomatic PML within the context of treatment with natalizumab in a female patient with MS. High antibody titers to the John Cunningham virus (JCV) and over two years' treatment were established as risk factors. The polymerase chain reaction for the JCV in cerebrospinal fluid was negative in two determinations. The interval between the radiological diagnosis and the onset of the clinical features was two months. During the course of the disease, the patient developed immune reconstitution inflammatory syndrome and relapses, or renewed exacerbation, of her MS. She responded well after beginning treatment with fingolimod, once the PML had become stabilised.\n\n\nCONCLUSIONS\nThis case indicates the importance of close clinico-radiological monitoring in patients with MS treated with natalizumab, especially when they present risk factors for the development of PML, as well as its potential incidence on survival and final functional status.",
"affiliations": "Centre d'esclerosi multiple de Catalunya, Barcelona, Espana.",
"authors": "Martí|Glòria|G|;Río|Jordi|J|;Rovira|Àlex|À|;Auger|Cristina|C|;Tintoré|Mar|M|;Sastre-Garriga|Jaume|J|;Vidal|Anka|A|;Castilló|Joaquín|J|;Montalban|Xavier|X|",
"chemical_list": "D007155:Immunologic Factors; D000069442:Natalizumab",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0210-0010",
"issue": "60(4)",
"journal": "Revista de neurologia",
"keywords": null,
"medline_ta": "Rev Neurol",
"mesh_terms": "D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab",
"nlm_unique_id": "7706841",
"other_id": null,
"pages": "164-8",
"pmc": null,
"pmid": "25670046",
"pubdate": "2015-02-16",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy associated to natalizumab: the importance of magnetic resonance imaging in its early diagnosis.",
"title_normalized": "progressive multifocal leukoencephalopathy associated to natalizumab the importance of magnetic resonance imaging in its early diagnosis"
} | [
{
"companynumb": "ES-BIOGENIDEC-2013BI092296",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nNeoplastic pericardial effusion (NPE) is a rare consequence of rectal cancer and carries a poor prognosis. Optimal management has yet to be determined. Fruquintinib is an oral anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor approved by the China Food and Drug Administration in September 2018 as third-line treatment of metastatic colorectal cancer.\n\n\nMETHODS\nHerein, we report an elderly patient with NPE from rectal cancer who responded to the use of fruquintinib. In March 2015, a 65-year-old Chinese woman diagnosed with KRAS-mutated adenocarcinoma of the rectum was subjected to proctectomy, adjuvant concurrent chemoradiotherapy, and adjuvant chemotherapy. By October 2018, a mediastinal mass was detected via computed tomography. The growth had invaded parietal pericardium and left hilum, displaying features of rectal adenocarcinoma in a bronchial biopsy. FOLFIRI and FOLFOX chemotherapeutic regimens were administered as first- and second-line treatments. After two cycles of second-line agents, a sizeable pericardial effusion resulting in tamponade was drained by pericardial puncture. Fluid cytology showed cells consistent with rectal adenocarcinoma. Single-agent fruquintinib was initiated on January 3, 2019, as a third-line therapeutic. Ten cycles were delivered before the NPE recurred and other lesions progressed. The recurrence-free interval for NPE was 9.2 mo, attesting to the efficacy of fruquintinib. Ultimately, the patient entered a palliative care unit for best supportive care.\n\n\nCONCLUSIONS\nFruquintinib may confer good survival benefit in elderly patients with NPEs due to rectal cancer.",
"affiliations": "Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China.;Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China.;Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China.;Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China. hejn@sj-hospital.org.",
"authors": "Zhang|Ying|Y|;Zou|Jia-Yun|JY|;Xu|Yan-Yan|YY|;He|Jing-Ni|JN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i21.6170",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i21.pg6170\n10.12998/wjcc.v9.i21.6170\nCase Report\nFruquintinib beneficial in elderly patient with neoplastic pericardial effusion from rectal cancer: A case report\nZhang Y et al. Fruquintinib beneficial in elderly patient\nZhang Ying Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China\n\nZou Jia-Yun Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China\n\nXu Yan-Yan Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China\n\nHe Jing-Ni Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China. hejn@sj-hospital.org\n\nAuthor contributions: Zhang Y wrote and edited the original draft; Zou JY contributed to data collection and analysis; Xu YY reviewed the literature, He JN reviewed and approved the final manuscript.\n\nCorresponding author: Jing-Ni He, MD, PhD, Associate Professor, Attending Doctor, Surgeon, Department of General Surgery, Shengjing Hospital of China Medical University, No. 39 Huaxiang Street, Shenyang 110022, Liaoning Province, China. hejn@sj-hospital.org\n\n26 7 2021\n26 7 2021\n9 21 61706177\n29 3 2021\n7 5 2021\n24 5 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.\nBACKGROUND\n\nNeoplastic pericardial effusion (NPE) is a rare consequence of rectal cancer and carries a poor prognosis. Optimal management has yet to be determined. Fruquintinib is an oral anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor approved by the China Food and Drug Administration in September 2018 as third-line treatment of metastatic colorectal cancer.\n\nCASE SUMMARY\n\nHerein, we report an elderly patient with NPE from rectal cancer who responded to the use of fruquintinib. In March 2015, a 65-year-old Chinese woman diagnosed with KRAS-mutated adenocarcinoma of the rectum was subjected to proctectomy, adjuvant concurrent chemoradiotherapy, and adjuvant chemotherapy. By October 2018, a mediastinal mass was detected via computed tomography. The growth had invaded parietal pericardium and left hilum, displaying features of rectal adenocarcinoma in a bronchial biopsy. FOLFIRI and FOLFOX chemotherapeutic regimens were administered as first- and second-line treatments. After two cycles of second-line agents, a sizeable pericardial effusion resulting in tamponade was drained by pericardial puncture. Fluid cytology showed cells consistent with rectal adenocarcinoma. Single-agent fruquintinib was initiated on January 3, 2019, as a third-line therapeutic. Ten cycles were delivered before the NPE recurred and other lesions progressed. The recurrence-free interval for NPE was 9.2 mo, attesting to the efficacy of fruquintinib. Ultimately, the patient entered a palliative care unit for best supportive care.\n\nCONCLUSION\n\nFruquintinib may confer good survival benefit in elderly patients with NPEs due to rectal cancer.\n\nNeoplastic pericardial effusion\nRectal cancer\nFruquintinib\nAnti-vascular endothelial growth factor receptor tyrosine kinase inhibitor\nCase report\n==== Body\nCore Tip: Neoplastic pericardial effusion (NPE) is a rare consequence of rectal cancer and carries a poor prognosis. We report an elderly patient with NPE from rectal cancer who responded to the use of fruquintinib. In March 2015, a 65-year-old Chinese woman diagnosed with adenocarcinoma of the rectum. By October 2018, FOLFIRI and FOLFOX chemotherapeutic regimens were administered as first- and second-line treatments. After two cycles of second-line agents, she was diagnosed with NPE. Single-agent fruquintinib was initiated as a third-line therapeutic. The recurrence-free interval for NPE was 9.2 mo, attesting to the efficacy of fruquintinib.\n\nINTRODUCTION\n\nColorectal cancer (CRC) is the third most common cancer diagnosed worldwide and ranks fourth in global cancer mortality, accounting for an estimated 1.4 million new cases and 700,000 deaths in 2012[1]. Metastasis to the heart is rare, one autopsy series showing a prevalence of 1.4%-2%, and most often involves pericardium[2]. To date, only seven cases of neoplastic pericardial effusion (NPE) due to CRC have been reported in the English literature, four of them stemming from rectal cancer[3-6].\n\nNPE typically indicates advanced disease and carries a poor prognosis[7]. Pericardiocentesis alone is the requisite emergency procedure to palliate life-threatening symptoms. Pericardiectomy, locoregional or systemic treatments, and best supportive care (BSC) may help prevent recurrences of NPE. In a retrospective study, median overall survival (OS) times of various treatment strategies were as follows: (1) Systemic therapy alone, 5 mo; (2) Systemic plus locoregional therapy, 2.1 mo; and (3) Locoregional therapy ± BSC, 1.6 mo[8].\n\nThe novel anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) fruquintinib (Elunate®, Eli Lilly, Indianapolis, IN, United States) has been approved by China Food and Drug Administration since September 2018. It is indicated in past recipients of at least two standard therapies for metastatic CRC (including fluoropyrimidine, oxaliplatin, and irinotecan), with or without prior use of VEGF inhibitors or epidermal growth factor receptor (EGFR) inhibitors[9]. This TKI is highly selectively for VEGFR-1, -2, and -3[10]. In the FRESCO phase 3 trial, fruquintinib (vs placebo) improved both OS (9.3 mo vs 6.6 mo; P < 0.001) and progression-free survival (PFS: 3.7 mo vs 1.8 mo; P < 0.001) of patients with metastatic CRC[11].\n\nHerein, we describe an elderly woman with NPE due to rectal cancer who benefitted from fruquintinib therapy.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 68-year-old Chinese woman with rectal adenocarcinoma suddenly experienced dyspnea and tachycardia.\n\nHistory of present illness\n\nIn March 2015, the patient received a diagnosis rectal adenocarcinoma. She had been troubled by constipation for approximately 2 years, claiming intermittent hematochezia for 1 wk. The cancer was discovered during outpatient colonoscopy and was subsequently removed via abdominoperineal resection (Miles proctectomy). Postoperative pathologic examination showed a stage IIIB, moderately differentiated, KRAS-mutated (exon 2) adenocarcinoma with nodal involvement (2/12) (Figure 1A). In April 2015, the patient began adjuvant concurrent chemoradiotherapy, receiving capecitabine and a total radiotherapy dose of 50GY. She continued adjuvant chemotherapy between June and October 2015, completing six cycles of oxaliplatin and capecitabine (CAPEOX).\n\nFigure 1 Photomicrographs (hematoxylin & eosin, × 200 magnification). A: Postoperative pathology showed moderately differentiated adenocarcinoma; B: Biopsy specimen showed that the metastatic tumor cells were similar to the adenocarcinoma cells in Figure 1A; C: Cytological examination revealed tumor-derived cells.\n\nBy October 2018, frequent bouts of cough and chest tightness prompted her return to the hospital. Chest computed tomography (CT) of October 13 showed a mediastinal mass (6.7 cm × 5.0 cm) invading parietal pericardium and left hilum, left obstructive atelectasis, and a metastatic nodule of right lung (Figure 2A and G). A bronchial biopsy was consistent with metastatic rectal cancer, proving positive for CDX2 protein and villin but negative for Napsin A and thyroid transcription factor-1 (TTF-1) in immunostained preparations (Figure 1B). The patient’s serum carcinoembryonic antigen (CEA) level was 11.44 ng/mL (Figure 3), and her condition was fair [Eastern Cooperative Oncology Group (ECOG) performance status of 1]. Based on CT and histologic findings, the diagnosis was stage IV rectal cancer, with mediastinal and lung metastases. A first-line regimen of irinotecan plus 5-fluorouracil/Leucovorin (FOLFIRI) was therefore begun. At the end of the first cycle, the patient experienced grade 3 nausea and vomiting, which abated through parenteral nutrition. On November 7, 2018, a repeat CT scan showed progression of both mediastinal (8.2 cm × 4.4 cm) and right lung lesions, with some accumulation of pericardial fluid (Figure 2B and H). This qualified as progressive disease (PD) by Response Evaluation Criteria in Solid Tumors (RECIST), despite a drop in serum CEA level (9.08 ng/mL) (Figure 3).\n\nFigure 2 Treatment of rectal cancer metastatic lesions using different regimens. A-F: Computed tomography (CT) indicated changes in a right lung metastatic nodule; G-L: CT indicated changes in the mediastinal metastatic mass.\n\nFigure 3 The figure shows the detailed changes of carcinoembryonic antigen in different regimens. CEA: Carcinoembryonic antigen.\n\nDuring November 2018, the patient began a second-line FOLFOX regimen, barely completing two cycles before the abrupt onset of dyspnea and tachycardia on December 20, 2018.\n\nHistory of past illness\n\nThe patient had hypertension.\n\nPersonal and family history\n\nThe patient had no history of smoking, drinking, or familial cancers.\n\nPhysical examination\n\nThe patient’s temperature was 37.0 °C, heart rate was 130 bpm, respiratory rate was 24 breaths per minute, blood pressure was 90/60 mmHg and oxygen saturation in room air was 95%. The clinical examination revealed jugular venous distention and muted heart sounds were evident.\n\nLaboratory examinations\n\nOther parameters (myocardial enzymes, electrocardiogram) were normal.\n\nImaging examinations\n\nEchocardiography disclosed a voluminous pericardial effusion, reduced left ventricular diastolic function, and an ejection fraction of 50% (Figure 4), signaling cardiac tamponade.\n\nFigure 4 Echocardiography showed a large pericardial effusion.\n\nFurther diagnostic work-up\n\nUltrasound-guided pericardial puncture was performed at once, withdrawing 800 mL of bloody fluid. The patient’s discomfort readily dissipated, her ECOG performance status rebounding from 2 to 1. Fluid cytology confirmed tumor-derived cells, later found positive for CEA and CDX2 and negative for TTF-1 by immunostains, again compatible with metastatic rectal cancer (Figure 1C).\n\nFINAL DIAGNOSIS\n\nThe final diagnosis of the case was NPE due to rectal cancer.\n\nTREATMENT\n\nNPE was established, indicating PD (Figure 2C and I) and second-line regimen failure despite shrinkage of mediastinal (5.6 cm × 3.6 cm) and right lung metastases by CT.\n\nOn January 3, 2019, the patient began a third-line regimen of single-agent fruquintinib (5 mg once daily, 3 wk on/1 wk off). After 1 wk, hypertension developed (systolic ≤ 160 mmHg; diastolic ≤ 100 mmHg) but quickly resolved through nifedipine use, without altering fruquintinib dosage. A CT scan performed January 10, 2019, showed further shrinkage of the mediastinal metastasis (3.3 cm × 3.2 cm), persistent pericardial effusion, and left pulmonary atelectasis, but the right lung nodule had disappeared. An indwelling pericardial drainage tube was then removed. During the second cycle of fruquintinib, mild hoarseness occurred. It did not impact the quality of life, so fruquintinib was continued at 5 mg daily. On April 10, 2019, a partial remission was achieved, marked by continued shrinkage of the mediastinal mass (3.2 cm × 3.0 cm) and NPE resolution on repeat CT scan (Figure 2D and J). The CEA level was even lower (3.23 ng/mL) (Figure 3), with ECOG performance status still at 1. After 3 mo of continuous treatment, another CT scan showed stable disease, the mediastinal mass unchanged and no recurrence of NPE (Figure 2E and K). A transient grade 2 Leukopenia (WBC count, 2.0 × 109/L) noted on July 26, 2019 was promptly remedied by pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF). Fruquintinib dosing remained the same, checking WBCs frequently.\n\nOUTCOME AND FOLLOW-UP\n\nBy October 9, 2019, there was overt CT evidence of disease progression, including recurrent NPE, left pulmonary atelectasis, and regrowth of the right lung nodule (Figure 2F and L). An upturn in CEA level (6.59 ng/ mL) (Figure 3) and worsening of ECOG performance status (1→2) were also apparent. We informed the patient of ongoing events, advising her of new therapeutic (i.e. local radiotherapy plus chemotherapy) and BSC options. Ultimately, she was transferred to a palliative care unit for BSC management.\n\nDISCUSSION\n\nNPE occurs in 5%-15% of patients with advanced cancer, complicating therapeutic strategies[12]. It is often a secondary phenomenon due to metastasis. In a series of patient autopsies, pericardial metastasis resulted from lung cancer (35%), breast cancer (25%), lymphoma or leukemia (15%), and other malignancies (i.e. esophageal cancer, Kaposi’s sarcoma, or melanoma)[13-15]. Pericardial metastasis may result from either direct or blood vascular/Lymphatic spread[16]. Given the inherent lymphatic and venous return of rectal cancers, they often metastasize to lymph nodes, liver, or lungs and rarely involve pericardium[2].\n\nClinical manifestations of NPE may vary considerably or be absent at times for incidental discovery in sudden deaths. Dyspnea, orthopnea, pain, edema, or even hemoptysis may accompany sizeable effusions. During clinical examinations, jugular venous distention, hepatomegaly, muffling of heart sounds, rubs/murmurs, or electrocardiographic changes are encountered[15]. In a small percentage of cases, cardiac tamponade may ensue[17].\n\nEchocardiography, CT, and magnetic resonance imaging (MRI), are generally used to detect NPE. Because echocardiography is readily available, inexpensive, and free of ionizing radiation, it is deemed the best imaging technique for this purpose[18], enabling both comprehensive gauging of hemodynamic effects imposed by effusions (including cardiac tamponade) and continuous monitoring of pre- and post-treatment fluid volumes. CT and MRI are clearly advantageous for accurate pinpointing of pericardial tumors and assessing adjacent cardiac and non-cardiac structural effects[19]. On the other hand, fluid cytology or pericardial biopsy is essential for a definitive diagnosis of malignancy. Immunohistochemistry is frequently needed to help characterize the antigenicity and nature of cells[20]. In this patient, tumor-derived cells were indeed present in the fluid collected. By comparing outcomes of immunostained cytologic and biopsy specimens, both pericardial and mediastinal manifestations were similarly traced to rectal cancer.\n\nManaging NPE is focused on symptom relief and prevention of recurrence. Pericardiocentesis has dual roles (diagnostic and therapeutic) in symptomatic patients. Without additional treatment, however, NPE will recur at a high rate (up to 40%)[21]. Pericardiectomy, pericardial windows, and sclerotherapy are typically used to prevent recurrent symptomatic effusions[22]; but antineoplastic treatments, including chemotherapy (systemic or local) and radiotherapy, are reportedly quite effective against NPE caused by lymphoma or small cell lung cancer. A retrospective analysis of NPE treatments has credited the longest median OS to systemic therapy. Old age, extrahepatic metastasis, and NPE in midst of progression were considered poor prognostic factors[8]. There are no randomized controlled studies to date, so optimal management of NPE has yet to be determined. Especially in elderly patients with symptoms or with metastatic disease, optimal management of NPE is truly a personalized process.\n\nIn the past decade, targeted molecular therapy has become a promising strategy for effective clinical treatment of NPE due to various tumors: Pericardial perfusion of bevacizumab, a VEGF inhibitor (median OS, 168 d; range, 22-224 d), as one example[23]. Panitumumab is an anti-EGFR monoclonal antibody used to successfully treat cardiac metastasis of colonic adenocarcinoma[24], and the anti-EGFR TKI, gefitinib, has shown good anti-tumor effect against NPE linked to adenocarcinoma of the lung. Once initiated in our patient, the time-to-recurrence of NPE was 279 d for fruquintinib. It surpassed bevacizumab in progression-free survival and was well tolerated by an elderly woman with a high ECOG score. The convenient oral formulation also limits potential infectious complications of otherwise invasive therapies. We believe this is the first reported use of an anti-VEGFR TKI in effectively treating NPE due to rectal cancer. This novel molecular agent may well herald a new strategy for targeting NPE in patients with CRC.\n\nCONCLUSION\n\nNPE is rarely caused by rectal cancer but must be considered if cardiopulmonary symptoms and a voluminous pericardial effusion coexist. Fruquintinib may provide good survival benefit in elderly patients with NPE due to rectal cancer.\n\nInformed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.\n\nConflict-of-interest statement: The authors declare that they have no conflicts of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: March 29, 2021\n\nFirst decision: April 28, 2021\n\nArticle in press: May 24, 2021\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): 0\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Mikulic D S-Editor: Gong ZM L-Editor: Filipodia P-Editor: Yuan YY\n==== Refs\n1 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D Bray F Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 2015 136 E359 E386 25220842\n2 Choufani EB Lazar HL Hartshorn KL Two unusual sites of colon cancer metastases and a rare thyroid lymphoma. Case 2. Chemotherapy-responsive right artial metastasis from colon carcinoma J Clin Oncol 2001 19 3574 3575 11481366\n3 Chen JL Huang TW Hsu PS Chao-Yang Tsai CS Cardiac tamponade as the initial manifestation of metastatic adenocarcinoma from the colon: a case report Heart Surg Forum 2007 10 E329 E330 17650460\n4 Kwon JT Lee DH Jung TE Gu MJ Epicardial metastasis of rectal neuroendocrine tumour Eur J Cardiothorac Surg 2014 46 504 24401688\n5 Zhu H Booth CN Reynolds JP Clinical presentation and cytopathologic features of malignant pericardial cytology: a single institution analysis spanning a 29-year period J Am Soc Cytopathol 2015 4 203 209 31051755\n6 Ben Yosef R Warner E Gez E Catane R Malignant pericardial effusion associated with metastatic rectal cancer: case report J Chemother 1989 1 342 345\n7 Gornik HL Gerhard-Herman M Beckman JA Abnormal cytology predicts poor prognosis in cancer patients with pericardial effusion J Clin Oncol 2005 23 5211 5216 16051963\n8 Di Liso E Menichetti A Dieci MV Ghiotto C Banzato A Bianchi A Pintacuda G Padovan M Nappo F Cumerlato E Miglietta F Mioranza E Zago G Corti L Guarneri V Conte P Neoplastic Pericardial Effusion: A Monocentric Retrospective Study J Palliat Med 2019 22 691 695 30888908\n9 Burki TK Fruquintinib for previously treated metastatic colorectal cancer Lancet Oncol 2018 19 e388 29983343\n10 Zhang Y Zou JY Wang Z Wang Y Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer Cancer Manag Res 2019 11 7787 7803 31496821\n11 Li J Qin S Xu RH Shen L Xu J Bai Y Yang L Deng Y Chen ZD Zhong H Pan H Guo W Shu Y Yuan Y Zhou J Xu N Liu T Ma D Wu C Cheng Y Chen D Li W Sun S Yu Z Cao P Chen H Wang J Wang S Wang H Fan S Hua Y Su W Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial JAMA 2018 319 2486 2496 29946728\n12 Ghosh AK Crake T Manisty C Westwood M Pericardial Disease in Cancer Patients Curr Treat Options Cardiovasc Med 2018 20 60 29936603\n13 Buck M Ingle JN Giuliani ER Gordon JR Therneau TM Pericardial effusion in women with breast cancer Cancer 1987 60 263 269 3594362\n14 HANFLING SM Metastatic cancer to the heart. Review of the literature and report of 127 cases Circulation 1960 22 474 483 13711211\n15 Adenle AD Edwards JE Clinical and pathologic features of metastatic neoplasms of the pericardium Chest 1982 81 166 169 7056081\n16 Katz WE Ferson PF Lee RE Killinger WA Thompson ME Gorcsan J 3rd Images in cardiovascular medicine. Metastatic malignant melanoma to the heart Circulation 1996 93 1066 8598069\n17 Levitan Z Kaplan AL Gordon AN Survival after malignant pericardial effusion and cardiac tamponade in advanced ovarian cancer South Med J 1990 83 241 242 2305307\n18 Refaat MM Katz WE Neoplastic pericardial effusion Clin Cardiol 2011 34 593 598 21928406\n19 Maleszewski JJ Anavekar NS Neoplastic Pericardial Disease Cardiol Clin 2017 35 589 600 29025549\n20 Gupta RK Kenwright DN Fauck R Lallu S Naran S The usefulness of a panel of immunostains in the diagnosis and differentiation of metastatic malignancies in pericardial effusions Cytopathology 2000 11 312 321 11014658\n21 Tsang TS Seward JB Barnes ME Bailey KR Sinak LJ Urban LH Hayes SN Outcomes of primary and secondary treatment of pericardial effusion in patients with malignancy Mayo Clin Proc 2000 75 248 253 10725950\n22 Lestuzzi C Berretta M Tomkowski W 2015 update on the diagnosis and management of neoplastic pericardial disease Expert Rev Cardiovasc Ther 2015 13 377 389 25797903\n23 Chen D Zhang Y Shi F Zhu H Li M Luo J Chen K Kong L Yu J Intrapericardial bevacizumab safely and effectively treats malignant pericardial effusion in advanced cancer patients Oncotarget 2016 7 52436 52441 27203219\n24 Tsujii Y Hayashi Y Maekawa A Fujinaga T Nagai K Yoshii S Sakatani A Hiyama S Shinzaki S Iijima H Takehara T Cardiac metastasis from colon cancer effectively treated with 5-fluorouracil, leucovorin, and oxaliplatin (modified FOLFOX6) plus panitumumab: a case report BMC Cancer 2017 17 152 28228152\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "9(21)",
"journal": "World journal of clinical cases",
"keywords": "Anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor; Case report; Fruquintinib; Neoplastic pericardial effusion; Rectal cancer",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "6170-6177",
"pmc": null,
"pmid": "34368339",
"pubdate": "2021-07-26",
"publication_types": "D002363:Case Reports",
"references": "27203219;8598069;2685189;28228152;29983343;10725950;7056081;16051963;25797903;30888908;11014658;31496821;25220842;31051755;2305307;13711211;29946728;29025549;29936603;11481366;17650460;24401688;3594362;21928406",
"title": "Fruquintinib beneficial in elderly patient with neoplastic pericardial effusion from rectal cancer: A case report.",
"title_normalized": "fruquintinib beneficial in elderly patient with neoplastic pericardial effusion from rectal cancer a case report"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-316325",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
... |
{
"abstract": "BACKGROUND\nMyelodysplastic syndrome (MDS) comprises a heterogeneous group of clonal disorders of haematopoietic stem cells, characterised by dysplastic haematopoiesis and dysregulated apoptosis resulting in various degrees of cytopenia, whereas canonical cytologic, cytogenetic and histopathologic findings guiding the diagnosis MDS are widely accepted, the MDS-phenotype can be masked by coexisting/paraneoplastic immunologic disease. Autoimmune disorders have an estimated incidence of 10% among patients suffering from MDS and are causally related to increased morbidity and mortality, younger age at diagnosis and more complex genetics. Conversely, systemic inflammatory disorders may be an early manifestation of MDS, show good response to immunosuppressive therapy and frequently disappear during the course of specific haematologic therapy.\n\n\nOBJECTIVE\nMonocentric report on clinical phenotypes found in MDS or bone marrow failure with paraneoplastic inflammatory disease.\n\n\nMETHODS\nClinical case reports and systematic review about MDS pathophysiology and treatment.\n\n\nRESULTS\nWe report eight patients diagnosed with MDS or bone marrow failure, who presented with paraneoplastic autoimmune diseases. Six of eight patients were treated with the hypomethylating agent 5-azacytidine, three of which achieved meaningful response with regard to inflammation control and haematologic recovery.\n\n\nCONCLUSIONS\nAs paraneoplastic syndromes are often mistakenly diagnosed as idiopathic autoimmune disorders, we propose that coexistence of an underlying myelodysplastic syndrome should be considered early in the diagnostic work up. 5-Azacytidine is effective in controlling paraneoplastic inflammation.",
"affiliations": "Klinik für Innere Medizin II, Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.",
"authors": "Frietsch|Jochen J|JJ|;Dornaus|Sebastian|S|;Neumann|Thomas|T|;Scholl|Sebastian|S|;Schmidt|Volker|V|;Kunert|Christa|C|;Sayer|Herbert G|HG|;Hochhaus|Andreas|A|;La Rosée|Paul|P|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12311",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "93(3)",
"journal": "European journal of haematology",
"keywords": "autoimmune; autoimmunity; immunotherapy; myelodysplasia; myelodysplastic syndrome",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic; D000964:Antimetabolites, Antineoplastic; D015551:Autoimmunity; D001374:Azacitidine; D001853:Bone Marrow; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D003937:Diagnosis, Differential; D005260:Female; D006457:Hemoglobinuria, Paroxysmal; D006801:Humans; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D010257:Paraneoplastic Syndromes; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "247-59",
"pmc": null,
"pmid": "24635656",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Paraneoplastic inflammation in myelodysplastic syndrome or bone marrow failure: case series with focus on 5-azacytidine and literature review.",
"title_normalized": "paraneoplastic inflammation in myelodysplastic syndrome or bone marrow failure case series with focus on 5 azacytidine and literature review"
} | [
{
"companynumb": "DE-CELGENE-062-50794-10071752",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Central nervous system melioidosis is an uncommon presentation of melioidosis infection. We report a case of a disseminated melioidosis infection with central nervous system, pulmonary, spleen, bone and cutaneous involvement in a patient with underlying systemic lupus erythematous. The diagnosis was confirmed based on positive blood and cerebrospinal fluid cultures coupled with radiological findings. Agriculture contact and underlying immunocompromised state were the predisposing risk factors for melioidosis infection in this case. Our patient was successfully treated with 10 weeks of intensive antibiotics therapy and 1 year of eradication antibiotics therapy with significant clinical and radiological improvement.",
"affiliations": "Department of Internal Medicine, Miri Hospital, Sarawak, Ministry of Health, Malaysia.;Department of Internal Medicine, Miri Hospital, Sarawak, Ministry of Health, Malaysia.;Department of Internal Medicine, Miri Hospital, Sarawak, Ministry of Health, Malaysia.;Department of Radiology, Miri Hospital, Sarawak, Ministry of Health, Malaysia.;Rheumatology Unit, Department of Internal Medicine, Sarawak General Hospital, Ministry of Health, Malaysia.;Department of Internal Medicine, Miri Hospital, Sarawak, Ministry of Health, Malaysia.;Department of Internal Medicine, Miri Hospital, Sarawak, Ministry of Health, Malaysia.;Infectious Disease Unit, Department of Internal Medicine, Sarawak General Hospital, Ministry of Health, Malaysia.;Rheumatology Unit, Department of Internal Medicine, Sarawak General Hospital, Ministry of Health, Malaysia.",
"authors": "Cheok|Lay Hock|LH|;Tang|Andy Sing Ong|ASO|;Desmond|Samuel|S|;Wong|Yi-Li|YL|;Cheong|Yaw Kiet|YK|;Ng|Say Chiew|SC|;Cheng|Wee Mee|WM|;Chua|Hock Hin|HH|;Teh|Cheng Lay|CL|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2021.e01255",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00211-0\n10.1016/j.idcr.2021.e01255\ne01255\nCase Report\nCentral nervous system melioidosis in systemic lupus erythematosus: A clinical vignette\nCheok Lay Hock hock977@hotmail.com\na⁎\nTang Andy Sing Ong a\nDesmond Samuel a\nWong Yi-Li b\nCheong Yaw Kiet c\nNg Say Chiew a\nCheng Wee Mee a\nChua Hock Hin d\nTeh Cheng Lay c\na Department of Internal Medicine, Miri Hospital, Sarawak, Ministry of Health, Malaysia\nb Department of Radiology, Miri Hospital, Sarawak, Ministry of Health, Malaysia\nc Rheumatology Unit, Department of Internal Medicine, Sarawak General Hospital, Ministry of Health, Malaysia\nd Infectious Disease Unit, Department of Internal Medicine, Sarawak General Hospital, Ministry of Health, Malaysia\n⁎ Correspondence to: Department of Internal Medicine, Miri Hospital, Jalan Cahaya, 98000 Miri, Sarawak, Malaysia. hock977@hotmail.com\n12 8 2021\n2021\n12 8 2021\n26 e0125519 3 2021\n29 7 2021\n11 8 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHighlights\n\n• A case of a disseminated melioidosis infection with central nervous system, pulmonary, spleen, bone and skin involvement.\n\n• Central nervous system melioidosis in a patient with underlying systemic lupus erythematosus.\n\n• Agriculture contact and underlying immunocompromised state predispose to melioidosis infection.\n\n• Positive cerebrospinal fluid cultures to confirm central nervous system melioidosis.\n\n• Extension of eradication therapy in view of osteomyelitis and residual cerebral lesion.\n\nCentral nervous system melioidosis is an uncommon presentation of melioidosis infection. We report a case of a disseminated melioidosis infection with central nervous system, pulmonary, spleen, bone and cutaneous involvement in a patient with underlying systemic lupus erythematous. The diagnosis was confirmed based on positive blood and cerebrospinal fluid cultures coupled with radiological findings. Agriculture contact and underlying immunocompromised state were the predisposing risk factors for melioidosis infection in this case. Our patient was successfully treated with 10 weeks of intensive antibiotics therapy and 1 year of eradication antibiotics therapy with significant clinical and radiological improvement.\n\nKeywords\n\nCentral nervous system melioidosis\nSystemic lupus erythematosus\n==== Body\nIntroduction\n\nMelioidosis is an endemic infectious disease in Southeast Asia and Northern Australia [1]. It has a wide spectrum of clinical presentations including severe sepsis, involvement of pulmonary, genitourinary, soft tissues and other organ systems [2]. Central nervous system (CNS) melioidosis is rare with a reported incidence of approximately one percent [2]. Fever (82%), headache (54%), unilateral weakness (57%) and cranial nerve deficits (52%) are among the common symptoms. Mortality rate can be up to 20% in delayed diagnosis [3]. We present a case of disseminated melioidosis infection with CNS, pulmonary, spleen, bone and cutaneous involvement in a female patient with underlying systemic lupus erythematosus (SLE).\n\nCase presentation\n\nA thirty eight years old female was diagnosed with SLE with mucocutaneous, musculoskeletal, haematological and renal involvement in April 2020. She is a dedicated kindergarten teacher who frequently involved in gardening work in the kindergarten compound for the past 15 years. The antinuclear antibody (ANA) and double-stranded DNA antibodies were positive. The ANA showed homogenous pattern with the titre of 1:1280. She was started on hydroxychloroquine 200 mg OD and prednisolone 40 mg OD upon diagnosis of SLE. She was treated as active lupus nephritis in view of heavy proteinuria of 3.39 g/24 h. Intravenous (IV) cyclophosphamide 500 mg was then given to treat her active lupus nephritis. 1 month after her first dose of IV cyclophosphamide treatment, she presented with high grade fever and altered consciousness with Glasgow Coma Scale of 14/15. On physical examination, she had left hemiparesis with 2/5 strength in both upper and lower extremities. There was neck stiffness but all the cranial nerves function were intact. Crepitations were heard over the right lung and a few rounded erythematous subcutaenous nodules were found over the forearms which may represent septic nodules. Abdominal examination was unremarkable. She was initially treated as meningoencephalitis with IV ceftriaxone 2 g BD and IV acyclovir 500 mg TDS.\n\nThe initial laboratory tests result were as shown in Fig. 1a. Hepatitis C virus, Hepatitis B virus and human immunodeficiency virus (HIV) screening were all negative. The sputum samples were negative for tuberculosis. Plain computed tomography (CT) brain was done which showed hypodensities at the right frontal region and right parieto-occipital region which may represents infective cerebritis or lupus cerebritis. Lumbar puncture was performed with an opening pressure of 15cmH2O and the cerebrospinal fluid (CSF) results were as shown in Fig. 1b. Her antibiotic was subsequently escalated to IV meropenem 2 g TDS and IV immunoglobulin 0.4 g/kg was given for 5 days in view of worsening sepsis.Fig. 1 (a) Initial laboratory test results. (b) CSF investigation results, CSF = Cerebrospinal Fluid, PCR = Polymerase chain reaction. (c) Baseline MRI Brain T1WI post gadolinium axial images demonstrated rim enhancing right frontal and right parietal intraaxial lesions (red arrows). (d) Post eradication therapy MRI after 20 weeks demonstrated treatment response with near resolution of lesions with a small residual right frontal lobe enhancing focus (arrowhead). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 1\n\nSubsequent Magnetic Resonance Imaging (MRI) of the brain revealed more than two multifocal rim-enhancing intraaxial brain lesions with the largest lesion measured at 1.5 cm × 1.4 cm. Serial chest radiographs (CXRs) showed pulmonary nodules of varying sizes with upper lobe predominance and bilateral moderate pleural effusion. Contrast enhanced CT thorax demonstrated scattered clusters of lung nodules, mostly peripherally located, a few cavitations with air-fluid levels, suspicious of infective cavitating nodules. One liver and multiple splenic hypodense lesions were seen in the visualised upper abdomen, suspicious of microabscesses. Given the progressive imaging findings and lack of clinical improvement, anti-tuberculous agents were started empirically.\n\n5 days later, both the blood and CSF cultures grew Burkholderia Pseudomallei. Her diagnosis was revised to disseminated melioidosis with CNS, pulmonary, spleen, bone and cutaneous involvement and the anti-tuberculous agents were discontinued. 2 weeks later, the full sensitivity report showed susceptible B. Pseudomallei towards trimethoprim/sulfamethoxazole, ceftazidime and meropenem with minimum inhibitory concentration of 2 ug/mL, 2 ug/mL and 1.5 ug/mL respectively. The antibiotics was then de-escalated to IV ceftazidime 2 g QID based on the sensitivity report. Blood cultures were repeated 1 week and 2 weeks post treatment which showed clearance of bacteraemia. MRI brain 3 weeks post treatment demonstrated treatment response as evidenced by reduction in the size of the largest brain lesion from 1.5 cm × 1.4cm to 0.9 cm × 0.8 cm. The number of intraaxial brain lesions was also reduced. However, new C2 and C3 vertebrae marrow osteomyelitis were observed. She completed 10 weeks of intensive therapy (2 weeks of IV meropenem and 8 weeks of IV ceftazidime) and was started on single strength trimethoprim/sulphamethoxazole (80 mg/400 mg) three tablets twice a day as eradication therapy. The strength of the left upper and lower extremities improved to 3/5 upon discharge.\n\nThe liver and spleen microabscesses resolved based on the repeated imaging. MRI brain and cervical was performed 20 weeks post treatment to decide on the duration of eradication therapy. MRI brain demonstrated a small residual right frontal lobe enhancing focus measuring 0.4 cm with no new cerebral lesion. MRI cervical showed improved osteomyelitis changes at C2 vertebrae. The strength of the left upper and lower extremities improved to 4/5 at this time. The eradication therapy was extended to 12 months in view of presence of cervical vertebral osteomyelitis and residual cerebral lesion. Currently, the strength of her left upper and lower extremities further improved to 5/5 and she is ambulating independently. Her SLE activity was well controlled with hydroxychloroquine 200 mg OD, azathioprine 50 mg OD and prednisolone 10 mg OD.\n\nDiscussion\n\nMelioidosis infection is caused by B. Pseudomallei, a saprophytic gram negative bacillus which is commonly found in Southeast Asia and northern Australia. Modes of transmission include inhalation, direct contact with infected food, soil, water, excreta or inoculation from contaminated soil. The risks of infection is higher among those with high risks occupation with exposure to the contaminated soil and water. According to one local study in Malaysia, the proportion of cases is significantly greater among people involved in forestry, farming and fishing [4]. Paul Vijay Kingsley et.al conducted a computerised review of case reports of melioidosis in Malaysia from 1975 to 2015. A total of 67 cases were reported and 5 (7.5%) were found to have primary neurological manifestation [5]. Diabetes mellitus remained as one of the most important risk factors for melioidosis. SLE could also be one of the risk factors for melioidosis infection. A young girl with underlying SLE was reported by Prayong Vachvanichsanong et.al to have melioidosis with cerebral abscess [6]. Our patient was empirically treated as active lupus nephritis in view of heavy proteinuria. She was planned for six cycles of monthly IV cyclophosphamide based on the National Institute of Health (NIH) guideline. Unfortunately, she had melioidosis infection 1 month after her first dose of IV cyclophosphamide. B. pseudomallei infection can remain latent for a long period of time after the initial exposure and cause clinically significant infection when the host immune system is suppressed. Wells et.al reported a case of melioidosis septic arthritis which presented 36 years post exposure [7]. Our patient could have exposed to the contaminated soil for the past 15 years in conjunction with her gardening work. The bacteria likely remained latent in her body and clinically manifested post immunosuppressants for her newly diagnosed SLE.\n\nImaging demonstrated disseminated pulmonary and extra-pulmonary (CNS, spinal, visceral) infective seeding in this case. However, distinguishing melioidosis and tuberculosis based on imaging alone is difficult due to non-specific overlapping radiological signs. Harvey J et.al described findings of cerebral abscesses, isolated encephalitis, and leptomeningeal enhancement in melioidosis which is seen in our case [8]. In the lungs, preferential upper lobe pulmonary involvement and multiple cavitating nodules may be present in both disease pathologies. Confluent consolidations which coalesce before thin wall cavity formation are more often seen in Bukholderia [9]. Co-infections with melioidosis and pulmonary tuberculosis have also been reported in patients with diabetes mellitus [10]. Hence, cultures or tissue diagnoses are of paramount importance in confirming the exact causative organism for disseminated infection. According to a systemic review of CNS melioidosis in 2019, 41% has positive blood cultures and 19% has positive CSF cultures out of 110 patients with CNS melioidosis [3].\n\nMelioidosis therapy is divided into an intravenous intensive phase and an oral eradication phase. According to the 2010 census recommendation, IV ceftazidime and IV meropenem are recommended for intensive-phase therapy, while trimethoprim/sulfamethoxazole is the first-line drug for eradication-phase therapy [11]. According to the 2020 Review and revision of the 2015 Darwin melioidosis treatment guideline, the recommended minimum intensive-phase therapy and eradication-phase therapy for CNS melioidosis are 8 weeks and 6 months respectively [12]. The cause of recrudescence and relapse is usually due to unidentified osteomyelitis and deep-seated abscess. In our case, the intensive-phase therapy was extended to 10 weeks and eradication-phase therapy was extended to 12 months in view of presence of cervical vertebrae osteomyelitis and residual cerebral lesion on repeated scan at 20 weeks of eradication therapy.\n\nConclusion\n\nOur case highlighted the challenges faced in managing a SLE patient with disseminated melioidosis infection post cyclophosphamide treatment. High clinical suspicion in immunocompromised patients with epidemiological exposure is the key for prompt empirical treatment prior to the confirmatory culture results.\n\nInformed Consent\n\nInformed consent was obtained from all individual participants included in the study.\n\nConsent\n\nThis article does contain studies with human participant and was registered via National Medical Research Register Malaysia with a Research ID of NMRR-20-1721-55996.\n\nFunding\n\nThe authors declare no financial disclosure.\n\nCredit authorship contribution statement\n\nLHC was responsible for the study design, data collection, and manuscript writing. ASOT, SD, YLW, YKC, SCN and WMC participated in data collection and contributed to case illustration and discussion. HHC and CLT were involved in the manuscript editing and language proofreading. All authors read and approved the final manuscript.\n\nAcknowledgement\n\nThe authors would like to thank the Director General of Health Malaysia and Clinical Research Centre (CRC) Miri Hospital for the permission to publish this paper. Acknowledgement to Drs. Law Huong Ling, Md Hanif Bin Md Arif & Emie Isma Binti Ismail for access to CT & MRI images.\n\nConflict of Interest\n\nThe authors declare that they have no conflict of interest and financial disclosure.\n==== Refs\nReferences\n\n1 Deuble M. Aquilina C. Norton R. Neurologic melioidosis Am J Trop Med Hyg 89 3 2013 535 539 23836574\n2 Madi D. Rai S.P.V. Vidyalakshmi K. Chowta K.N. Neurological melioidosis presenting as intracranial abscess Indian J Pathol Microbiol 59 3 2016 417 419 27510695\n3 Wongwandee M. Linasmita P. Central nervous system melioidosis: a systematic review of individual participant data of case reports and case series PLoS Negl Trop Dis 13 4 2019 0007320\n4 Hassan M.R. Pani S.P. Peng N.P. Voralu K. Vijayalakshmi N. Mehanderkar R. Aziz N.A. Michael E. Incidence, risk factors and clinical epidemiology of melioidosis: a complex socio-ecological emerging infectious disease in the Alor Setar region of Kedah, Malaysia BMC Infect Dis 10 2010 302 20964837\n5 Kingsley P.V. Leader M. Nagodawithana N.S. Tipre M. Sathiakumar N. Melioidosis in Malaysia: a review of case reports PLoS Negl Trop Dis 10 12 2016 0005182\n6 Vachvanichsanong P. Dissaneewate P. Prukprasert P. Wongchanchailert M. Thongmak S. Janjindamai S. Melioidosis and brain abscess in a girl with systemic lupus erythematosus Infect Dis Clin Pract 11 4 2002 211 213\n7 Wells E.V. Cinti S.K. Clark T.A. Rudrik J.T. Boulton M.L. Melioidosis-reactivation of latent disease: case presentation and review Infect Dis Clin Pract 19 3 2011 161 166\n8 Harvey J. Boles B. Brown D. A review of imaging findings in melioidosis: revealing the tropics’ dirty secret Int J Infect Dis 7 4 2020 176 185\n9 Mukhopadhyay C. Krishna S. Vandana Ke Saravu K. Balasubramaniam R. Tuberculosis or melioidosis? - Look twice in south-western coastal India SAARC J Tuberc Lung Dis HIV/AIDS IX 2 2012 15 18\n10 Shetty A.K. Boloor R. Sharma V. Bhat G.H.K. Melioidosis and pulmonary tuberculosis co-infection in a diabetic Ann Thorac Med 5 2 2020 113 115\n11 Lipsitz R. Garges S. Aurigemma R. Baccam P. Blaney D.D. Cheng A.C. Currie B.J. Dance D. Gee J.E. Larsen J. Limmathurotsakul D. Morrow M.G. Norton R. O'Mara E. Peacock S.J. Pesik N. Rogers L.P. Schweizer H.P. Steinmetz I. Tan G. Tan P. Wiersinga W.J. Wuthiekanun V. Smith T.L. Workshop on treatment of and postexposure prophylaxis for Burkholderia pseudomallei and B. mallei infection. 2010. Emerg Infect Dis 18 2012 2\n12 Sullivan R.P. Marshal C.S. Anstey N.M. Ward L. Currie B.J. 2020 Review and revision of the 2015 Darwin melioidosis treatment guideline; paradigm drift not shift PLoS Negl Trop Dis 14 9 2020 e0008659\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "26()",
"journal": "IDCases",
"keywords": "Central nervous system melioidosis; Systemic lupus erythematosus",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e01255",
"pmc": null,
"pmid": "34458097",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "20964837;20582178;27510695;23171644;23836574;32986699;28005910;31022232",
"title": "Central nervous system melioidosis in systemic lupus erythematosus: A clinical vignette.",
"title_normalized": "central nervous system melioidosis in systemic lupus erythematosus a clinical vignette"
} | [
{
"companynumb": "MY-STRIDES ARCOLAB LIMITED-2022SP006710",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nCorneal damage associated with abuse of topical anesthetics is a rare clinic entity. Topical anesthetic abuse is one of the causes of ring keratitis. Ring keratitis is easily overlooked because it can mimic acanthamoeba keratitis or other infectious keratitis. The outcome is often poor, leading to persistent epithelial defects, corneal scarring, and perforations.\n\n\nMETHODS\nWe report the clinical presentation, diagnosis, and treatment of a 65-year-old Caucasian man, who worked as a health care worker, with bilateral toxic keratopathy caused by topical anesthetic abuse. Nonpreserved amniotic membrane transplantation was performed for both eyes of the patient.\n\n\nCONCLUSIONS\nIt is important to identify and treat patients who abuse topical anesthetics before permanent vision loss ensues. Nonpreserved amniotic membrane transplantation may be useful in relieving pain and improving corneal surface in anesthetic agent abusers.",
"affiliations": "Eye Clinic I, Ulucanlar Eye Education and Research Hospital, Ankara, Turkey. ayse_altinok@yahoo.com.tr.",
"authors": "Altinok|Ayse Asyali|AA|;Balikoglu|Melike|M|;Sen|Emine|E|;Serdar|Kurtulus|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-4-262",
"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-4-2622069897310.1186/1752-1947-4-262Case ReportNonpreserved amniotic membrane transplantation for bilateral toxic keratopathy caused by topical anesthetic abuse: a case report Altinok Ayse Asyali 1ayse_altinok@yahoo.com.trBalikoglu Melike 1drmelkebalkoglu@yahoo.comSen Emine 1eminesentr@yahoo.comSerdar Kurtulus 1kurtulusdr@gmail.com1 Eye Clinic I, Ulucanlar Eye Education and Research Hospital, Ankara, Turkey2010 10 8 2010 4 262 262 21 10 2009 10 8 2010 Copyright ©2010 Altinok et al; licensee BioMed Central Ltd.2010Altinok et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nCorneal damage associated with abuse of topical anesthetics is a rare clinic entity. Topical anesthetic abuse is one of the causes of ring keratitis. Ring keratitis is easily overlooked because it can mimic acanthamoeba keratitis or other infectious keratitis. The outcome is often poor, leading to persistent epithelial defects, corneal scarring, and perforations.\n\nCase presentation\nWe report the clinical presentation, diagnosis, and treatment of a 65-year-old Caucasian man, who worked as a health care worker, with bilateral toxic keratopathy caused by topical anesthetic abuse. Nonpreserved amniotic membrane transplantation was performed for both eyes of the patient.\n\nConclusion\nIt is important to identify and treat patients who abuse topical anesthetics before permanent vision loss ensues. Nonpreserved amniotic membrane transplantation may be useful in relieving pain and improving corneal surface in anesthetic agent abusers.\n==== Body\nIntroduction\nCorneal damage associated with abuse of topical anesthetics has been reported by various sources [1-3]. Topical anesthetic abuse is one of the causes of ring keratitis [2]. This rare clinic entity is easily overlooked because it can mimic acanthamoeba keratitis or other infectious keratitis. The outcome is often poor, leading to persistent epithelial defects, corneal scarring, and perforations [1-3].\n\nA case of bilateral toxic keratopathy caused by topical anesthetic abuse that was treated with nonpreserved amniotic membrane transplantation (NP-AMT) has been reported. To the best of our knowledge, this is the first report of NP-AMT use for the treatment of bilateral toxic keratopathy caused by topical anesthetic abuse.\n\nCase presentation\nA 65-year-old Caucasian man, who worked as a health care worker, was admitted to our hospital with a history of severe eye pain, redness, and blurred vision in both eyes. His complaints had started with a mild eye itching six weeks prior to admission. He had a history of psychoactive substance carbamazepine and topical proparacaine abuse of three years. Our initial ocular examination showed bilateral intense conjunctival injection, corneal edema, diffuse corneal vascularization, and ring shaped stromal infiltration. There were also central epithelial defects of 3 × 1 mm with mid-stromal ring infiltrates in the right eye (Figure 1) and 6 × 8 mm with mid-stromal ring infiltrates in the left eye. Visual acuity of the right and left eyes was hand motions and finger counting at a distance of one meter, respectively.\n\nFigure 1 Photograph demonstrating a central epithelial defect of 3 × 1 mm with mid-stromal ring infiltrates in the right eye.\n\nThe cultures of corneal scrapings were negative. Proparacaine drops were discontinued, and our patient was prescribed preservative-free artificial tear drops and prophylactic topical antibiotic (ciprofloxacin 0.3%) five times a day. For his pain, oral indomethacin (75 mg three times a day) and topical ketorolac tromethamine (0.5% four drops a day) were added. Psychiatric counseling revealed psychoactive substance abuse and psychiatric disturbances. Despite medical treatment and conservative approach, the condition of our patient did not improve. Then, to achieve rapid epithelization, NP-AMT was planned for both eyes of our patient, as was previously described [4]. Initially, NP-AMT was used on the right eye. Owing to the pain in the right eye of our patient and persistent corneal epithelial defect decreased during the follow-up period, we performed NP-AMT on the left eye from another donor. At this stage, our patient's visual acuity was hand motions in both eyes. Three weeks after NP-AMT, a rapid regression of the external inflammatory signs, progressive clearing of the membrane, and a closed corneal epithelium were noted in the right eye. However, hypopyon was detected in the left eye (Figure 2). Repeat cultures of the corneal scrapings were negative. An ultrasound of this eye showed no vitreous infiltration. Because of suspected sterile hypopyon iritis, our patient was administered 100 mg hydrocortisone and 2.0 g ceftriaxon intravenously. Subsequently, the hypopyon resolved within three days. In the second week, systemic steroid use was tapered, and the use of antibiotic eye drops was ended. In the fifth week, our patient was caught trying to steal a bottle of proparacaine. The psychiatry clinic was consulted for further investigation and treatment. Because of poor compliance our patient was re-hospitalized and kept under close surveillance.\n\nFigure 2 After nonpreserved amniotic membrane transplantation, hypopyon was detected in the left eye.\n\nAt two months, our patient had no pain and no epithelial defects in the right eye (Figure 3). He had impending corneal perforation in the left eye. The visual acuity in the right eye was finger counting at a distance of four meters with residual corneal scarring, and in the left eye, it was limited to finger counting at a distance of one meter. Our patient was referred to the eye bank for penetrating keratoplasty, which was required to treat corneal perforation in his left eye (Figure 4).\n\nFigure 3 In the final examination, the patient had no pain and no epithelial defect in the right eye.\n\nFigure 4 In the final examination, he had impending corneal perforation in the left eye.\n\nDiscussion\nTopical anesthetic abuse is a serious disorder, which involves persistent epithelial defects, corneal stromal ring infiltrates, anterior segment inflammation, disproportionate pain, visual loss, and a history of psychoactive substance abuse [1-3]. Rosenwasser et al. determined poor visual acuity in six patients [3]. Another study demonstrated that all topical anesthetics caused a reduction in the rate of epithelial healing in an animal model [4]. Management of this disorder depends on the discontinuation of the anesthetic agent, which is very difficult for the patients because of psychoactive substance abuse. Topical anesthetic abuse occurs mostly in patients with access to medication, for example nurses and pharmacists [2,3]. Similarly, our patient was a health care worker. Since patient compliance to conservative approaches was poor, we chose to perform NP-AMT in our patient.\n\nThis surgery has been successfully performed many times at our institution, and no post-operative intra-ocular inflammation has been encountered to date [5]. Hypopyon occurred rarely after amniotic membrane transplantation for ocular surface disorders [6]. Most types of anterior uveitis are sterile inflammatory reactions [7]. A hypopyon was determined in our patient's left eye. An ultrasound of this eye showed no vitreous infiltration. In light of these findings, our patient's condition was considered to be a case of sterile inflammation, and additional intravenous steroid use was preferred. Then, the hypopyon resolved within three days.\n\nClinical evidence indicates that amniotic membrane cells do not express histocompatibility (HLA) antigens A, B, C, or DR. Although the amniotic membrane preparation, the surgical procedure applied, and the surgeon were the same, hypopyon occurred in one eye after NP-AMT. Contrary to what has been suggested in the literature [6], we used amniotic membrane from different donors. This may account for local immunoreaction after NP-AMT.\n\nThe outcome of topical anesthetic abuse cases is poor because of continued drug use after keratitis commences [1,3]. This is because the attending physician may not suspect drug abuse and/or dishonesty on the part of the patient. Anesthetic abusers frequently continue to self-administer anesthetic agents, often covertly, even when informed of the consequences of their actions. Thus, long-term anatomical and functional results are very poor. Despite NP-AMT, in our patient, the right eye healed with residual corneal scarring, and the left eye required a penetrating keratoplasty.\n\nPsychiatric consultation is extremely helpful and should be considered in the management of these patients. We recommend that the patients be hospitalized and treated under close supervision. It is important to identify and treat patients who abuse topical anesthetics before permanent vision loss develops.\n\nConclusions\nIt is important to identify and treat patients who abuse topical anesthetics before permanent vision loss ensues. In addition, close medical supervision and psychiatric consultation should be considered. As a final option, NP-AMT may be considered in relieving pain and improving corneal surface in resistant anesthetic agent abusers. However, the efficiency of NP-AMT cannot be determined based on this single case alone. Further studies, which will investigate the changes after NP-AMT, compare its clinical outcomes, and evaluate safety and efficacy of NP-AMT to treat anesthetic abuse keratopathy, are needed.\n\nAbbreviations\nNP-AMT: nonpreserved amniotic membrane transplantation.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nAAA and MB were major contributors in writing the manuscript and reviewed the patient's notes. EMS drafted and revised the manuscript critically for important intellectual content. KS collected the psychiatric data, observed the patient closely. All the authors read and approved the final manuscript.\n==== Refs\nPharmakakis NM Katsimpris JM Melachrinou MP Koliopoulos JX Corneal complications following abuse of topical anesthetics Eur J Ophthalmol 2002 12 373 378 12474918 \nVarga JH Rubinfeld RS Wolf TC Topical anesthetic abuse ring keratitis: report of four cases Cornea 1997 16 424 429 9220240 \nRosenwasser GO Holland S Pflugfelder SC Topical anesthetic abuse Ophthalmology 1990 97 967 972 2402423 \nSmith RB Everett WG Physiology and pharmacology of local anesthetic agents Int Ophthalmol Clin 1973 13 35 60 4202608 \nUcakhan OO Koklu G Firat E Nonpreserved human amniotic membrane transplantation in acute and chronic chemical eye injuries Cornea 2002 21 169 172 10.1097/00003226-200203000-00008 11862088 \nSrinivasan R T SS Gupta A Kaliaperumal S Hypopyon iritis after primary fresh amniotic membrane transplantation Cornea 2007 26 1275 1276 10.1097/ICO.0b013e31814b8b94 18043192 \nAmerican Academy of Ophthalmology Clinical approach to uveitis 2005 Intraocular inflammation and uveitis. San Francisco, Leo 106\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "4()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "262",
"pmc": null,
"pmid": "20698973",
"pubdate": "2010-08-10",
"publication_types": "D016428:Journal Article",
"references": "4202608;9220240;2402423;12474918;11862088;18043192",
"title": "Nonpreserved amniotic membrane transplantation for bilateral toxic keratopathy caused by topical anesthetic abuse: a case report.",
"title_normalized": "nonpreserved amniotic membrane transplantation for bilateral toxic keratopathy caused by topical anesthetic abuse a case report"
} | [
{
"companynumb": "ALCN2011TR004544",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPARACAINE HYDROCHLORIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Calcium channel blocker overdose is usually very fatal and challenging to manage. The patients are usually asymptomatic on admission, but deteriorate very rapidly. Currently, there is no specific antidote, and the treatment is supportive requiring high level of critical care, and may necessitate extracorporeal membrane oxygenation. The use of high-dose insulin is reported to help stabilize the blood pressure and wean off inotropes. The recommendations for supportive treatment in patients with calcium channel blocker overdose are based upon low-quality evidence reports including case series and animal studies. We present the case of a 55-year-old male with a history of atrial fibrillation who was admitted to the hospital 30 min after intentionally ingesting 80 tablets of 180 mg extended release verapamil. On admission, the patient was asymptomatic, but electrocardiogram (ECG) showed a complete heart block which necessitated a transcutaneous pacing, followed by transvenous pacemaker placement. Rapid deterioration of the patient's hemodynamic status led to the patient getting intubated and was started on pressors as well as high-dose insulin. Despite all the aggressive measures, the patient died in less than 24 h after being admitted. We report this case to provide a brief review of the treatment options available at this time, because to date, there is no specific antidote for such overdose, and it remains very fatal despite the amount of supportive care provided.",
"affiliations": "Richmond University Medical Center, Staten Island, NY, USA.;Richmond University Medical Center, Staten Island, NY, USA.;Richmond University Medical Center, Staten Island, NY, USA.;Richmond University Medical Center, Staten Island, NY, USA.;Richmond University Medical Center, Staten Island, NY, USA.;Richmond University Medical Center, Staten Island, NY, USA.;Richmond University Medical Center, Staten Island, NY, USA.",
"authors": "Atemnkeng|Francis|F|;Shabani|Jawad|J|;Chen|Lu|L|;Gala|Bhavesh|B|;Ramalho|Jonathan|J|;Diaz|Keith|K|;Nfonoyim|Jay|J|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.14740/jmc3763",
"fulltext": "\n==== Front\nJ Med Cases\nJ Med Cases\nElmer Press\nJournal of Medical Cases\n1923-4155\n1923-4163\nElmer Press\n\n10.14740/jmc3763\nCase Report\nA Fatal Case of Massive Verapamil Overdose: An Overview of the Treatment Options\nA Fatal Case of Verapamil Overdose\nAtemnkeng Francis ab\nShabani Jawad a\nChen Lu a\nGala Bhavesh a\nRamalho Jonathan a\nDiaz Keith a\nNfonoyim Jay a\na Richmond University Medical Center, Staten Island, NY, USA\nb Corresponding Author: Francis Atemnkeng, Richmond University Medical Center, Staten Island, NY, USA. Email: fatemnkeng@rumcsi.org\n9 2021\n25 8 2021\n12 9 373376\n30 7 2021\n13 8 2021\nCopyright 2021, Atemnkeng et al.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nCalcium channel blocker overdose is usually very fatal and challenging to manage. The patients are usually asymptomatic on admission, but deteriorate very rapidly. Currently, there is no specific antidote, and the treatment is supportive requiring high level of critical care, and may necessitate extracorporeal membrane oxygenation. The use of high-dose insulin is reported to help stabilize the blood pressure and wean off inotropes. The recommendations for supportive treatment in patients with calcium channel blocker overdose are based upon low-quality evidence reports including case series and animal studies. We present the case of a 55-year-old male with a history of atrial fibrillation who was admitted to the hospital 30 min after intentionally ingesting 80 tablets of 180 mg extended release verapamil. On admission, the patient was asymptomatic, but electrocardiogram (ECG) showed a complete heart block which necessitated a transcutaneous pacing, followed by transvenous pacemaker placement. Rapid deterioration of the patient’s hemodynamic status led to the patient getting intubated and was started on pressors as well as high-dose insulin. Despite all the aggressive measures, the patient died in less than 24 h after being admitted. We report this case to provide a brief review of the treatment options available at this time, because to date, there is no specific antidote for such overdose, and it remains very fatal despite the amount of supportive care provided.\n\nCalcium channel blocker overdose\nVerapamil overdose\nAntidote\nAtrioventricular dissociation\nHigh-dose insulin\n==== Body\npmcIntroduction\n\nCalcium channel blocker overdose is very fatal and challenging to manage with a mortality of approximately 38% [1]. According to the latest 2019 National Poison Data System (NPDS) Annual Report published by The American Association of Poison Control Centers, calcium channel blockers, alone or in combination with other substances, are listed as the sixth leading cause of fatal drug-related toxicities [2]. Patients may present to the hospital asymptomatic, but deteriorate very rapidly. Ingesting more than 5 - 10 times the usual dose may lead to signs and symptoms such as drowsiness, hypotension, bradycardia and respiratory and heart failures [3]. Currently, there is no antidote for calcium channel blocker overdose, and treatment options are supported by very low-quality evidence including case series and animal studies [4-6]. The treatment is usually supportive and options include gastric lavage, intravenous (IV) calcium, glucagon, catecholamines, and high-dose insulin. Patients might also get severe heart blocks requiring transvenous pacemaker. For severely poisoned patients, extracorporeal membrane oxygenation (ECMO) may be a necessity if available in the hospital [7-10]. We present a fatal case of massive, intentional sustained-release verapamil overdose despite optimal supportive treatment. This case highlights the quick deterioration of such patients, the lack of potential reversal of outcomes, and the need for novel treatments such as antidotes.\n\nCase Report\n\nInvestigations\n\nA 55-year-old male with a history of hypertension, atrial fibrillation, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, major depressive disorder, pulmonary embolism and upper gastrointestinal bleed presented to the emergency department (ED) 30 min after he intentionally ingested 80 tablets of 180 mg sustained-release verapamil. At the time of presentation, the patient endorsed suicidal ideation, headache, dizziness and mild shortness of breath. He denied chest pain, palpitations, abdominal pain, nausea and vomiting. When the patient arrived in the ED, he was alert and oriented to person, place and time, and in no apparent distress. His blood pressure was 126/80 mm Hg, with a heart rate of 93 beats/min (bpm). The lungs were clear to auscultation bilaterally, heart sounds were regular with no murmurs.\n\nDiagnosis\n\nElectrocardiogram (ECG) showed a third degree heart block with narrow complex ventricular escape rhythm (Fig. 1); chest X-ray was unremarkable. Laboratory studies on admission showed a blood glucose of 172 mg/dL, corrected calcium of 9.2 mg/dL, hypomagnesemia (1.6 mg/dL) and low-normal levels of potassium (3.6 mmol/L).\n\nFigure 1 ECG when patient arrived in the emergency department. It showed atrioventricular dissociation with accelerated junctional rhythm with occasional premature ventricular complexes. P waves (red arrows) were not in accordance with QRS complexes (yellow arrows). ECG: electrocardiogram.\n\nTreatment\n\nAn urgent cardiology consult was called, and the patient was immediately placed on telemetry monitoring while a transcutaneous pacemaker along with a trial of atropine were attempted without resolution of the heart block. The patient was administered IV fluids and electrolyte repletion. An immediate consult was placed with the Regional Poison Control Center as well, and they recommended 50 g of activated charcoal which was administered, and to start whole bowel irrigation with polyethylene glycol.\n\nIn the meantime, the patient was transferred to the cardiac intensive care unit (CCU) and was started on IV calcium gluconate. About 1 h after the patient was transferred to CCU, he quickly became hypotensive and bradycardic with a respiratory rate in the 40s and an oxygen saturation level of 92% on 4 L of oxygen through nasal cannula. Due to his inability to protect his airway, the decision was made to intubate the patient. A right internal jugular vein transvenous pacemaker was placed, as well as a left internal jugular vein central line for IV access; and he was started on norepinephrine and dopamine drips. For more optimal blood pressure control, an arterial line was placed.\n\nA repeat finger stick blood glucose was 275 mg/dL, most likely due to the verapamil overdose. The patient was started on insulin with a loading dose of 1 U/kg, with a total of 172 units given as IV push, followed by a continuous drip at a dose of 0.5 U/kg/h, with a total of 86 U/h (see blood glucose measurements in Fig. 2).\n\nFigure 2 Evolution of blood glucose during admission and after starting high dose insulin.\n\nDespite receiving norepinephrine at a rate of 40 µg/min and dopamine at a rate of 20 µg/kg/min, the patient’s mean arterial pressure was persistently less than 65 mm Hg; thus vasopressin drip was added at a rate of 0.03 units/min (see blood pressure measurements in Fig. 3). The oxygen saturation recorded was ranging between 70% and 80% on assist-control mode of ventilation set at rate of 18 breaths/min, tidal volume of 500 mL/breath, fraction of inspired oxygen (FiO2) of 100% and a positive end-expiratory pressure (PEEP) of 10 cm H2O.\n\nFigure 3 Evolution of blood pressure during the course of admission.\n\nFollow-up and outcomes\n\nThe patient was considered for ECMO at a nearby specialized center but he was deemed as a poor candidate due to being very unstable for transfer. Bedside echocardiography was performed, which showed adequate ejection fraction and no obvious regional wall motion abnormalities. His refractory shock was consistently unchanged despite addition of phenylephrine and the patient subsequently sustained cardiopulmonary arrest after about 22 h since admission, without return of spontaneous circulation.\n\nDiscussion\n\nThe potential toxicity of calcium channel blockers is often underappreciated, and currently, there are no antidotes present. The non-dihydropyridine group such as verapamil selectively blocks the L-type calcium channels in the myocardium, which are responsible for myocardial contractility, vascular smooth muscle contraction, as well as conducting and pacemaker cells [11]. Verapamil toxicity will therefore cause peripheral vasodilation, decreased cardiac contractility and bradycardia. Our patient who ingested a massive dose of verapamil (14,400 mg) subsequently became hypotensive due to the decreased contractility and the vasodilatory effects of the medication, as well as developing an atrioventricular dissociation as seen on the ECG. Verapamil is highly protein bound, with clearance through the liver. The extended release form, as consumed by our patient prolongs the effects and renders the absorption unpredictable due to its high volume of distribution. Most of the time, the patients are usually asymptomatic on arrival, but can deteriorate very rapidly, therefore requiring frequent reassessment.\n\nPresently, there is no antidote for calcium channel blocker overdose, and current treatment options are based upon limited evidence from case series and animal studies [4]. These treatment options are mainly supportive, until the medication reaches a safe level in the blood stream. The first step to treatment is to consult a poison control center and report the case. Orogastric lavage is usually recommended in patients who present within 1 - 2 h following ingestion of greater than 5 - 10 times the standard dose. Activated charcoal should also be administered regardless if the patients are asymptomatic. Our patient, who initially did not have any symptoms, received activated charcoal and whole bowel irrigation as recommended by poison control. The presence of atrioventricular dissociation with ventricular escape rhythm present on the ECG upon admission probably represented the possibility that a large quantity of the verapamil had already been absorbed, or the patient had ingested it longer than the 30 min prior, contrary to which he informed us. Despite the activated charcoal and the continuous bowel irrigation, our patient deteriorated rapidly and became hypotensive, bradycardic and developed respiratory failure which required intubation, transvenous pacemaker placement and the use of vasopressors.\n\nPatients who develop severe symptoms require simultaneous interventions including stabilization of airway, IV boluses of isotonic crystalloid, IV calcium, glucagon, high-dose insulin and glucose, vasopressors, and sometimes ECMO as last resort [6]. The choice of vasopressors will require a direct-acting agent with positive inotropy, chronotropy and vasoconstrictive effects such as norepinephrine, and to be titrated upwards with a goal mean arterial blood pressure of 65 mm Hg or higher. Despite initiating these treatment options on our patient as well as starting norepinephrine, a dose of 40 µg/min did not raise the mean arterial pressure above 65 mm Hg, so dopamine was added. The use of high-dose insulin has also been shown to have positive inotropic effects in animal models and case reports [8]. Despite starting our patient on high-dose insulin therapy, the patient still had refractory hypotension, leading to the addition of a third vasopressor and eventually a fourth. Attempts were made to transfer the patient to a center capable of performing ECMO, but due to the patient being very unstable, the transfer could not be initiated. The dangerous combination of hypotension and bradycardia can be profound and refractory, even to maximal treatment. Despite all the therapeutic interventions, the patient died in less than 24 h of admission. This case highlights the fatality of calcium channel blocker overdose and the lack of an antidote, with treatment options based upon case series and animal studies.\n\nConclusions\n\nCalcium channel blocker overdose is very fatal with a mortality of 38%, and symptoms can be refractory despite maximal treatment. Currently, there is no antidote and treatment options are based upon weak evidence from case series and animal studies. Further research is needed to obtain a cure, and to acquire stronger evidence for supportive treatment options.\n\nNone to declare.\n\nFinancial Disclosure\n\nNone to declare.\n\nConflict of Interest\n\nThe authors report no conflict of interest.\n\nInformed Consent\n\nNot applicable.\n\nAuthor Contributions\n\nF. Atemnkeng collected the data, guided the literature search, wrote the manuscript, and is the research guarantor. J. Shabani, L. Chen, J. Ramalho, B. Gala, and K. Diaz helped with the data collection and writing of the article. J. Nfonoyim reviewed and supervised the study.\n\nData Availability\n\nThe authors declare that data supporting the findings of this study are available within the article.\n==== Refs\nReferences\n\n1 Watson WA Litovitz TL Rodgers GC Jr Klein-Schwartz W Youniss J Rose SR Borys D et al 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System Am J Emerg Med 2003 21 5 353 421 10.1016/s0735-6757(03)00088-3 14523881\n2 Gummin DD Mowry JB Beuhler MC Spyker DA Brooks DE Dibert KW Rivers LJ et al 2019 annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 37th annual report Clin Toxicol (Phila) 2020 58 12 1360 1541 10.1080/15563650.2020.1834219 33305966\n3 Lindeman E Alebring J Johansson A Ahlner J Kugelberg FC Nordmark Grass J The unknown known: non-cardiogenic pulmonary edema in amlodipine poisoning, a cohort study Clin Toxicol (Phila) 2020 58 11 1042 1049 10.1080/15563650.2020.1725034 32114860\n4 St-Onge M Dube PA Gosselin S Guimont C Godwin J Archambault PM Chauny JM et al Treatment for calcium channel blocker poisoning: a systematic review Clin Toxicol (Phila) 2014 52 9 926 944 10.3109/15563650.2014.965827 25283255\n5 Ashraf M Chaudhary K Nelson J Thompson W Massive overdose of sustained-release verapamil: a case report and review of literature Am J Med Sci 1995 310 6 258 263 7503108\n6 Hofer CA Smith JK Tenholder MF Verapamil intoxication: a literature review of overdoses and discussion of therapeutic options Am J Med 1993 95 4 431 438 10.1016/0002-9343(93)90314-f 8213877\n7 Thanacoody R Caravati EM Troutman B Hojer J Benson B Hoppu K Erdman A et al Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients Clin Toxicol (Phila) 2015 53 1 5 12 10.3109/15563650.2014.989326 25511637\n8 Kline JA Tomaszewski CA Schroeder JD Raymond RM Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine J Pharmacol Exp Ther 1993 267 2 744 750 8246150\n9 Boyer EW Shannon M Treatment of calcium-channel-blocker intoxication with insulin infusion N Engl J Med 2001 344 22 1721 1722 10.1056/NEJM200105313442215 11386285\n10 Durward A Guerguerian AM Lefebvre M Shemie SD Massive diltiazem overdose treated with extracorporeal membrane oxygenation Pediatr Crit Care Med 2003 4 3 372 376 10.1097/01.PCC.0000074273.50306.F5 12831424\n11 Katz AM Cardiac ion channels N Engl J Med 1993 328 17 1244 1251 10.1056/NEJM199304293281707 7681934\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1923-4155",
"issue": "12(9)",
"journal": "Journal of medical cases",
"keywords": "Antidote; Atrioventricular dissociation; Calcium channel blocker overdose; High-dose insulin; Verapamil overdose",
"medline_ta": "J Med Cases",
"mesh_terms": null,
"nlm_unique_id": "101551824",
"other_id": null,
"pages": "373-376",
"pmc": null,
"pmid": "34527109",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "33305966;25511637;11386285;14523881;12831424;25283255;7503108;32114860;7681934;8213877;8246150",
"title": "A Fatal Case of Massive Verapamil Overdose: An Overview of the Treatment Options.",
"title_normalized": "a fatal case of massive verapamil overdose an overview of the treatment options"
} | [
{
"companynumb": "US-RECRO GAINESVILLE LLC-REPH-2021-000015",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"... |
{
"abstract": "OBJECTIVE\nTo investigate plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), an established marker of cardiac function, in patients with chronic hepatitis C during interferon-based antiviral therapy.\n\n\nMETHODS\nUsing a sandwich immunoassay, plasma levels of NT-proBNP were determined in 48 patients with chronic hepatitis C at baseline, wk 24 and 48 during antiviral therapy and at wk 72 during follow-up.\n\n\nRESULTS\nPlasma NT-proBNP concentrations were significantly increased (P<0.05) at wk 24, 48 and 72 compared to the baseline values. NT-proBNP concentrations at baseline and wk 24 were closely correlated (r = 0.8; P<0.001). At wk 24, 7 (14.6%) patients had NT-proBNP concentrations above 200 ng/L compared to 1 (2%) patient at baseline (P = 0.059). Six of these 7 patients had been treated with high-dose IFN-alpha induction therapy. In multiple regression analysis, NT-proBNP was not related to other clinical parameters, biochemical parameters of liver disease or virus load and response to therapy.\n\n\nCONCLUSIONS\nElevated levels of NT-proBNP during and after interferon-based antiviral therapy of chronic hepatitis C may indicate the presence of cardiac dysfunction, which may contribute to the clinical symptoms observed in patients during therapy. Plasma levels of NT-proBNP may be used as a diagnostic tool and for guiding therapy in patients during interferon-based antiviral therapy.",
"affiliations": "Internal Medicine II, Saarland University Hospital, Kirrberger Strasse, 66421 Homburg/Saar, Germany. dr_bojunga@web.de",
"authors": "Bojunga|Jorg|J|;Sarrazin|Christoph|C|;Hess|Georg|G|;Zeuzem|Stefan|S|",
"chemical_list": "D000998:Antiviral Agents; D015415:Biomarkers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010446:Peptide Fragments; D011994:Recombinant Proteins; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v12.i36.5875",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "12(36)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D015415:Biomarkers; D005260:Female; D006331:Heart Diseases; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012044:Regression Analysis",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5875-7",
"pmc": null,
"pmid": "17007056",
"pubdate": "2006-09-28",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "11738297;11492984;11788208;11796549;12020489;12417542;14633912;14768714;14960742;15314719;15477431;1704826;8097802;7719376;16462543;10577444;10791374;11742939",
"title": "Elevated plasma levels of N-terminal pro-brain natriuretic peptide in patients with chronic hepatitis C during interferon-based antiviral therapy.",
"title_normalized": "elevated plasma levels of n terminal pro brain natriuretic peptide in patients with chronic hepatitis c during interferon based antiviral therapy"
} | [
{
"companynumb": "DE-ROCHE-1449674",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INTERFERON ALFA-2A"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate whether intravenous lipid (IL) intake is associated with the development of parenteral nutrition-associated cholestasis (PNAC) in infants younger than 32 weeks gestational age (GA).\n\n\nMETHODS\nA retrospective matched case-control study (1:1) was performed including infants younger than 32 weeks GA admitted to the neonatal intensive care unit within 48 hours after birth. Infants with a chromosomal disorder, TORCH infection (toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes, human immunodeficiency virus, and parvovirus), metabolic disorder, and/or surgical abnormality of the hepatobiliary system were excluded. Infants with PNAC (direct bilirubin 2 mg/dL or higher) comprised the case group, while infants without PNAC comprised the control group. Duration of parenteral nutrition, intravenous fluid intake on the day of development of PNAC, and GA were used as matching criteria.\n\n\nRESULTS\nA total of 46 subjects were studied. Daily average intravenous dextrose (ID) intake was significantly higher in infants with PNAC compared with infants without PNAC (12.72 ± 2.5 g/kg/d and 10.64 ± 2.1 g/kg/d, respectively, P = .004). On comparison of receiver operating characteristic curves, the area under the curve for ID intake (0.74) was significantly higher (P = .01) compared with the area under the curve for IL intake (0.59) and intravenous protein (IP) intake (0.52). On logistic regression, daily ID intake was associated with PNAC (odds ratio 1.7; 95% CI, 1.04-2.9, P = .03) after controlling for daily IP and IL intake.\n\n\nCONCLUSIONS\nID intake may be associated with the development of PNAC in premature infants. Our findings suggest that limiting ID intake may be more useful than limiting IL intake in reducing the incidence of PNAC in premature infants.",
"affiliations": "Department of Pediatrics, Division of Neonatology.;Biostatistics, Golisano Children's Hospital at Strong, University of Rochester Medical Center, Rochester, New York, USA.;Department of Pediatrics, Division of Neonatology Sanjiv_Amin@urmc.rochester.edu.",
"authors": "Gupta|Kunal|K|;Wang|Hongyue|H|;Amin|Sanjiv B|SB|",
"chemical_list": "D004044:Dietary Proteins; D005217:Fat Emulsions, Intravenous; D005947:Glucose",
"country": "United States",
"delete": false,
"doi": "10.1177/0148607114555161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-6071",
"issue": "40(3)",
"journal": "JPEN. Journal of parenteral and enteral nutrition",
"keywords": "life cycle; lipids; neonates; nutrition; nutrition, liver disease; parenteral nutrition; research and diseases",
"medline_ta": "JPEN J Parenter Enteral Nutr",
"mesh_terms": "D061605:Administration, Intravenous; D016022:Case-Control Studies; D002779:Cholestasis; D004044:Dietary Proteins; D002149:Energy Intake; D005217:Fat Emulsions, Intravenous; D005260:Female; D005865:Gestational Age; D005947:Glucose; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007363:Intensive Care Units, Neonatal; D016015:Logistic Models; D008297:Male; D010288:Parenteral Nutrition; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "7804134",
"other_id": null,
"pages": "335-41",
"pmc": null,
"pmid": "25316680",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Parenteral Nutrition-Associated Cholestasis in Premature Infants: Role of Macronutrients.",
"title_normalized": "parenteral nutrition associated cholestasis in premature infants role of macronutrients"
} | [
{
"companynumb": "US-BAXTER-2016BAX019094",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EGG PHOSPHOLIPIDS\\GLYCERIN\\SOYBEAN OIL"
},
"d... |
{
"abstract": "We sequenced the mitochondrial genome from a 40-year-old woman with myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications. Histological and biochemical features of mitochondrial respiratory chain dysfunction were present. Direct sequencing showed a novel heteroplasmic mutation at nucleotide 5513 in the MT-TW gene that encodes tRNATrp. Restriction Fragment Length Polymorphism analysis confirmed that about 80% of muscle mtDNA harboured the mutation while it was present in minor percentages in mtDNA from other tissues. The mutation is predicted to disrupt a highly conserved base pair within the aminoacyl acceptor stem of the tRNA. This is the 17° mutation in MT-TW gene and expands the known causes of late-onset mitochondrial diseases.",
"affiliations": "Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Bracci 2, 53100, Siena, Italy. Electronic address: cardaioli@unisi.it.;Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Bracci 2, 53100, Siena, Italy.;Perugia Hospital, Neurophysiopathology Unit, Azienda Ospedaliera di Perugia, S. Andrea delle Fratte, 06156 Perugia, Italy.;Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Bracci 2, 53100, Siena, Italy.;Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.;Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.;Department of Translational Research & The New Technologies in Medicine & Surgery, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.;Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Bracci 2, 53100, Siena, Italy.;Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.;Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Bracci 2, 53100, Siena, Italy.",
"authors": "Cardaioli|Elena|E|;Mignarri|Andrea|A|;Cantisani|Teresa Anna|TA|;Malandrini|Alessandro|A|;Nesti|Claudia|C|;Rubegni|Anna|A|;Funel|Niccola|N|;Federico|Antonio|A|;Santorelli|Filippo Maria|FM|;Dotti|Maria Teresa|MT|",
"chemical_list": "D012364:RNA, Transfer, Trp",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbrc.2018.04.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-291X",
"issue": "500(2)",
"journal": "Biochemical and biophysical research communications",
"keywords": "MT-TW gene; Mitochondrial disease; New mutation; mtDNA; tRNA(Trp)",
"medline_ta": "Biochem Biophys Res Commun",
"mesh_terms": "D000328:Adult; D001483:Base Sequence; D004831:Epilepsies, Myoclonic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D056784:Leukoencephalopathies; D009154:Mutation; D012364:RNA, Transfer, Trp; D012174:Retinitis Pigmentosa; D017422:Sequence Analysis, DNA; D014057:Tomography, X-Ray Computed; D061205:Vascular Calcification",
"nlm_unique_id": "0372516",
"other_id": null,
"pages": "158-162",
"pmc": null,
"pmid": "29625105",
"pubdate": "2018-06-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications associated with a novel m.5513G>A mutation in the MT-TW gene.",
"title_normalized": "myoclonus epilepsy retinitis pigmentosa leukoencephalopathy and cerebral calcifications associated with a novel m 5513g a mutation in the mt tw gene"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1036899",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcomes are not well understood. We investigated the association between comorbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months.\n\n\n\nA multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the Drug-Induced Liver Injury Network prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson Comorbidity Index-patients with scores higher than 2 were considered to have significant comorbidities.\n\n\n\nSix-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio, 5.4; 95% confidence interval [CI], 2.1-13.8), Model for End-Stage Liver Disease score (odds ratio, 1.11; 95% CI, 1.04-1.17), and serum level of albumin at presentation (odds ratio, 0.39; 95% CI, 0.2-0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months, with c-statistic values of 0.89 (95% CI, 0.86-0.94) in the discovery cohort and 0.91 (95% CI, 0.83-0.99) in the validation cohort. We developed a web-based calculator for use in the clinic to determine risk of death within 6 months for patients with suspected DILI.\n\n\n\nWe developed and validated a model based on comorbidity burden, Model for End-Stage Liver Disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.",
"affiliations": "Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana.;Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.;Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana.;Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana.;Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina.;Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina.;Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana.;Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.;Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.;Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana. Electronic address: nchalasa@iu.edu.",
"authors": "Ghabril|Marwan|M|;Gu|Jiezhun|J|;Yoder|Lindsay|L|;Corbito|Laura|L|;Ringel|Amit|A|;Beyer|Christian D|CD|;Vuppalanchi|Raj|R|;Barnhart|Huiman|H|;Hayashi|Paul H|PH|;Chalasani|Naga|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2019.07.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "157(5)",
"journal": "Gastroenterology",
"keywords": "CCI; DILIN Prospective Study; MELD",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000328:Adult; D000368:Aged; D002423:Cause of Death; D056486:Chemical and Drug Induced Liver Injury; D015897:Comorbidity; D005260:Female; D006304:Health Status; D006305:Health Status Indicators; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "1245-1252.e3",
"pmc": null,
"pmid": "31302142",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D023361:Validation Study",
"references": "22134841;26346867;28543844;25754159;19132805;3558716;24681128;29124524;26351192;19750427;27655101;16201109;18955056;25043597;27787358;24935270;30227404;29306044;28762375;28061757",
"title": "Development and Validation of a Model Consisting of Comorbidity Burden to Calculate Risk of Death Within 6 Months for Patients With Suspected Drug-Induced Liver Injury.",
"title_normalized": "development and validation of a model consisting of comorbidity burden to calculate risk of death within 6 months for patients with suspected drug induced liver injury"
} | [
{
"companynumb": "US-ZYDUS-044505",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "A 43-year-old woman, whose pregnancy was complicated by the presence of a large single solid intra-abdominal fetal mass, was referred from the private sector into our fetal maternal unit at the Corniche Hospital, Abu Dhabi at 36 weeks postmenstrual age.Investigations subsequently confirmed that this mass was a congenital hepatoblastoma, one of the very rare embryonic tumours. The baby had chemotherapy and surgical excision of the tumour. Fifteen months later, the alpha feto-protein levels remain normal and follow-on MRI scans do not show recurrence or any residual disease.To our knowledge, this is the first case of congenital hepatoblastoma in the United Arab Emirates (UAE). In the UAE, the interphase between private health insurance schemes and medical (public and private) care within a growing health economy enhances access to unique services such as cancer treatments within specialised centres.",
"affiliations": "Neonatal Unit, Al Corniche Hospital, Abu Dhabi, United Arab Emirates.;Paediatric Surgery, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.;Feto-Maternal Medicine, Al Corniche Hospital, Abu Dhabi, United Arab Emirates.;Neonatal Unit, Al Corniche Hospital, Abu Dhabi, United Arab Emirates.",
"authors": "Ofoegbu|Bibian Nwanyioma|BN|http://orcid.org/0000-0001-5799-3902;Abdel Salam|Seif El Eslam|SEE|;Diehl|Werner Gerhard|WG|;Ghosn|Latifeh|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223344",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepbmjcrbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2017-22334410.1136/bcr-2017-223344Rare Disease15061523Case ReportCongenital hepatoblastoma in a growing health economy http://orcid.org/0000-0001-5799-3902Ofoegbu Bibian Nwanyioma 1Abdel Salam Seif El Eslam 2Diehl Werner Gerhard 3Ghosn Latifeh 1\n1 \nNeonatal Unit, Al Corniche Hospital, Abu Dhabi, United Arab Emirates\n\n2 \nPaediatric Surgery, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates\n\n3 \nFeto-Maternal Medicine, Al Corniche Hospital, Abu Dhabi, United Arab Emirates\nCorrespondence to Dr Bibian Nwanyioma Ofoegbu, bibiano@seha.ae2019 20 3 2019 20 3 2019 12 3 e22334428 2 2019 © BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/A 43-year-old woman, whose pregnancy was complicated by the presence of a large single solid intra-abdominal fetal mass, was referred from the private sector into our fetal maternal unit at the Corniche Hospital, Abu Dhabi at 36 weeks postmenstrual age.\n\nInvestigations subsequently confirmed that this mass was a congenital hepatoblastoma, one of the very rare embryonic tumours. The baby had chemotherapy and surgical excision of the tumour. Fifteen months later, the alpha feto-protein levels remain normal and follow-on MRI scans do not show recurrence or any residual disease.\n\nTo our knowledge, this is the first case of congenital hepatoblastoma in the United Arab Emirates (UAE). In the UAE, the interphase between private health insurance schemes and medical (public and private) care within a growing health economy enhances access to unique services such as cancer treatments within specialised centres.\n\npaediatric oncologymaterno-fetal medicineneonatal and paediatric intensive carepaediatric surgeryspecial-featureunlocked\n==== Body\nBackground\nWe believe this case is important because it’s the first case of congenital hepatoblastoma to be reported from the United Arab Emirates (UAE). The management reflects the changing dynamics in the healthcare infrastructure in the Emirates with availability of highly specialised treatments within the country guided by international protocols and thereby reducing the dependence on external health systems.\n\nCase presentation\nA 43-year-old, Gravida 6 Para 3, woman was referred to our fetal-maternal team at 36 weeks of gestation because the fetus was noted to have an unusual large intra-abdominal mass. She had diet controlled gestational diabetes and rheumatoid arthritis controlled with hydroxyquinone. Parents are non-consanguineous.\n\nThe antenatal ultrasound scan showed the presence of a huge echogenic abdominal mass (7.8×7.2×7.7 cm). The abdominal circumference was 35.7 cm (>97.7 centile for 36+4 weeks postmenstrual age). There was no evidence of significant arteriovenous shunting. Fetal arterial and venous Doppler’s and fetal echocardiography were normal. There was no evidence of hydrops fetalis. Pulmonary fields, brain and placenta appeared sonographically normal. Delivery at 39 weeks was planned as there was no impact of this mass on fetal well-being.\n\nA female child weighing 3440 g (50th centile) with occipital-frontal circumference of 34 cm (50th centile) was born following elective caesarean section at 39 weeks. Apgar’s were 9 and 10 in 1 and 5 min, respectively. The presence of a large abdominal mass was evident immediately after birth. She did not require any respiratory support but had bile stained gastric aspirate/vomiting due to a mass pressure effect on the bowel which resulted in delays in establishing enteral feeds. CT of abdomen and pelvis was obtained within a few days after birth which identified a highly vascular mass measuring 8.6×7.1×7.8 cm that appeared to be of hepatic origin.\n\nDifferential diagnosis\nNeuroblastoma, nephroblastoma, vascular tumours and rhabdoid tumours were considered as possible differentials antenatally. It was difficult to ascertain and assign the origin on antenatal ultrasound due to the gestational age at which mother presented to our fetal maternal unit.\n\nInvestigations\nAlpha feto-protein (AFP) measured over 68 000 IU/L on day 8 of life. It was serially monitored during the treatments. Normal AFP level would be expected to be between 20 and 30 IU/L within a few weeks after birth.\n\nOn day 12 of life, laparoscopic tumour biopsy was obtained which was positive for Hep-par 1 and AFP. These results (received a week later) confirmed that the mass was a hepatoblastoma (epithelial type with a fetal pattern).\n\nPre-chemotherapy CT of the chest revealed no evidence of metastasis. The tumour was a PRETEXT II (V and P negative).1\n\nTreatment\nHepatoblastoma was confirmed on day 19 of life. Chemotherapy was commenced on day 24 of life after baseline investigations which included cardiac echocardiography and audiology screen were completed.\n\nThe Children’s Oncology Group Protocol called AHEP0731 was applied. This consists of cisplatin, 5-fluoruracil, vincristine and doxorubicin delivered every 21 days over six cycles. The tumour was excised at 14 weeks postnatal age after the second cycle of chemotherapy.\n\nFollowing the second course of chemotherapy, CT showed a reduction of the tumour size to 6.4×6.2×5.5 cm and a corresponding fall in the AFP levels from just over 68 000–2900 IU/L. The tumour was staged as POST-TEXT II (V and P negative) at this time point.\n\nComplete surgical excision of the tumour was undertaken at 14 weeks’ postnatal age following which the AFP levels fell further to 303 IU/L.\n\nOutcome and follow-up\nShe was discharged home after the third course of chemotherapy and then electively readmitted for subsequent courses.\n\nPost chemotherapy morbidities that occurred after the first cycle included profound neutropenia (associated with fever on two occasions). She also developed vincristine-induced polyneuropathy involving the median nerves, peroneal nerve and sensory nerves of the upper limbs. She lost gross motor skills and developed an unsafe swallow. Vincristine was thereafter given at 50% of the dose in subsequent courses of chemotherapy. The neuropathy gradually resolved allowing the safe resumption of oral feeding 3 months after chemotherapy had been initiated.\n\nThere was no evidence of disease on serial MRI scans of the liver following the surgical resection. At the age of 19 months (12 months after the last course of chemotherapy) the AFP remains normal. Follow-up, which will include regular monitoring of AFP levels, will be for at least the next 5 years.\n\nDiscussion\nThe UAE is a young country that is growing and developing its infrastructure in several domains including Paediatric Oncology. This is supported by investments in fetal–maternal expertise, neonatal intensive care and cancer treatments across the Emirates. The case described is, to our knowledge, the first reported case of congenital hepatoblastoma in the UAE.\n\nHepatoblastoma is the the most common primary paediatric hepatic malignant tumour (although comparatively, they are one of the very rare paediatric solid tumours) with a reported frequency of 1–11.2 per million children under the age of 15 years.2 Most commonly, they arise from the right lobe of the liver.3 They may be associated Beckwith-Wiedemann syndrome and familial adenomatous polyposis.3\n\nAntenatal diagnosis of intra-abdominal tumours and hepatoblastoma has been reported previously.4 However, antenatal ultrasound diagnosis of congenital abdominal tumours is difficult and assigning their origin, especially at late gestational ages, is very challenging. Comprehensive Doppler studies and additional three-dimensional ultrasound techniques may help in this task, in order to prepare and optimise delivery. Fetal MRI in the third trimester may help to determine size and relation of the tumour to neighbouring organs, if specialised image interpretation is available.4 In general, the presence of fetal abdominal tumour does not affect time and mode of delivery; standard obstetric antenatal and intra-partum care are warranted. However, cases need to be individualised, since excessive tumour growth may lead to significantly increased abdominal circumference that could, in a vaginal delivery, increase the risk of tumour rupture and increase the chances of dystocia.4 Elective caesarean section may be preferred for tumours diagnosed in the antenatal period as suggested by Trobaugh-Lotrario et al\n5 following their review of a large series of their cases.5\n\nWithin the UAE, Standardised Cancer treatment protocols are used for treating children with cancer6 within a highly specialised multi-disciplinary setting. Treatment of hepatoblastoma depends on the staging which consists of chemotherapy and surgery in the stable patient.\n\nThis report highlights the importance and role of an evolving interphase between private and public healthcare and private insurance schemes. This relationship facilitates and promotes multidisciplinary team-working in the UAE, allows the application of expertise to make the diagnosis of such rare conditions and gives access to appropriate treatments in order to achieve good clinical outcomes.\n\nPatient’s perspective\n“Very happy especially, that as not from this country, my baby have treatment and is now good. Thank you”\n\nLearning points\nFirst reported case of congenital hepatoblastoma from the United Arab Emirates to our knowledge.\n\nThe importance of multidisciplinary teams-—fetal maternal, neonatology, paediatric surgery, oncology and parents working in partnership to deliver care.\n\nThe interphase between health insurance schemes and private and public-sector healthcare should be seamless—allowing all individuals access to specialised services.\n\nThe evolving health infrastructure in the Middle East allows access to specialised treatments within the county therefore reducing physical dependence on external systems.\n\nWe acknowledge Dr Naser Al Zein, Paediatric Oncologist, Sheikh Kalifa Medical City, Abu Dhabi, who as part of the multi-disciplinary team, supervised the application of the chemotherapy protocol and its monitoring.\n\nContributors: BNO prepared the manuscript with support from SEEAS, WGD and LG did the literature review. All authors have reviewed and agreed upon the manuscript content.\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\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nPatient consent for publication: Obtained.\n==== Refs\nReferences\n1 \nTowbin AJ , Meyers RL , Woodley H , et al \n2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT) . Pediatr Radiol \n2018 ;48 :536 –54 . 10.1007/s00247-018-4078-z \n29427028 \n2 \nSpector LG , Birch J \nThe epidemiology of hepatoblastoma . Pediatr Blood Cancer \n2012 ;59 :776 –9 . The epidemiology of hepatoblastoma \n10.1002/pbc.24215 \n22692949 \n3 \nIsaacs H \nFetal and neonatal hepatic tumors . J Pediatr Surg \n2007 ;42 :1797 –803 . 10.1016/j.jpedsurg.2007.07.047 \n18022426 \n4 \nShih JC , Tsao PN , Huang SF , et al \nAntenatal diagnosis of congenital hepatoblastoma in utero . Ultrasound Obstet Gynecol \n2000 ;16 :94 –7 . 10.1046/j.1469-0705.2000.00168.x \n11084976 \n5 \nTrobaugh-Lotrario AD , Chaiyachati BH , Meyers RL , et al \nOutcomes for patients with congenital hepatoblastoma . Pediatr Blood Cancer \n2013 ;60 :1817 –25 . 10.1002/pbc.24655 \n23798361 \n6 \nChildren’s oncology Group . https://www.childrensoncologygroup.org/ (last accessed 10 Oct 2017 )\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "12(3)",
"journal": "BMJ case reports",
"keywords": "materno-fetal medicine; neonatal and paediatric intensive care; paediatric oncology; paediatric surgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005865:Gestational Age; D018197:Hepatoblastoma; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008113:Liver Neoplasms; D011247:Pregnancy; D016216:Ultrasonography, Prenatal; D014479:United Arab Emirates",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30898949",
"pubdate": "2019-03-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11084976;18022426;22692949;23798361;29427028",
"title": "Congenital hepatoblastoma in a growing health economy.",
"title_normalized": "congenital hepatoblastoma in a growing health economy"
} | [
{
"companynumb": "AE-PFIZER INC-2019165177",
"fulfillexpeditecriteria": "1",
"occurcountry": "AE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "The effects of long-term use of opioid analgesics on the hypothalamic-pituitary-adrenal axis are not well recognized. We report a 41-year-old woman on chronic opioid therapy hospitalized for cardiovascular collapse following a right stellate ganglion nerve block. She developed severe hypotension after the procedure. Morning cortisol was low. The results from the cosyntropin test were consistent with secondary adrenal insufficiency. Her secondary adrenal insufficiency was likely due to long-term use of opioid analgesics for pain in the absence of other etiologies.",
"affiliations": "Department of Family and Community Medicine, Texas Tech University Health Science CenterLubbockTexas.;Department of Internal Medicine and Clinical Research Institute, Texas Tech University Health Science CenterLubbockTexas.",
"authors": "Ali|Emad S|ES|0000-0002-6852-2564;Peiris|Alan N|AN|0000-0001-9323-7557",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08998280.2019.1600180",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-8280",
"issue": "32(3)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": "Adrenal insufficiency; hypothalamic-pituitary-adrenal axis; opioids",
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "417-418",
"pmc": null,
"pmid": "31384206",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "15836666;20961018;25098712;25827960;29109870;30485501;30855285;6128489;6263025",
"title": "Secondary adrenal insufficiency induced by long-term use of opioid analgesics.",
"title_normalized": "secondary adrenal insufficiency induced by long term use of opioid analgesics"
} | [
{
"companynumb": "US-MALLINCKRODT-T201906756",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": "3",
... |
{
"abstract": "The unexpected transmission of donor-derived infection through organ transplantation is a rare event with current donor screening practices. In this case report we describe a probable donor-derived transmission of Herpes Simplex Virus (HSV)-2 via deceased donor kidney transplantation resulting in HSV hepatitis in the recipient. This manifested as acute liver failure which resolved with appropriate anti-viral therapy. Following recovery from the acute liver insult, the patient developed fibrotic liver morphology and portal hypertension, an unusual departure from the typical course.",
"affiliations": "Department of Surgery, Duke University, Durham, North Carolina.;Department of Surgery, Duke University, Durham, North Carolina.;Department of Surgery, Duke University, Durham, North Carolina.;Department of Medicine, Duke University, Durham, North Carolina.;Department of Medicine, Duke University, Durham, North Carolina.;Department of Surgery, Duke University, Durham, North Carolina.",
"authors": "Shaw|Brian I|BI|https://orcid.org/0000-0002-2317-6549;Nanavati|Aditya J|AJ|;Taylor|Vanessa|V|;Miller|Rachel A|RA|;Kappus|Matthew|M|;Barbas|Andrew S|AS|https://orcid.org/0000-0003-3476-2313",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": null,
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000212:Acyclovir; D000328:Adult; D064591:Allografts; D000998:Antiviral Agents; D001706:Biopsy; D005260:Female; D006525:Hepatitis, Viral, Human; D006561:Herpes Simplex; D018258:Herpesvirus 2, Human; D006801:Humans; D006975:Hypertension, Portal; D007668:Kidney; D016030:Kidney Transplantation; D008099:Liver; D008103:Liver Cirrhosis; D017114:Liver Failure, Acute; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13029",
"pmc": null,
"pmid": "30431215",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Donor derived HSV hepatitis in a kidney transplant recipient leading to liver fibrosis and portal hypertension.",
"title_normalized": "donor derived hsv hepatitis in a kidney transplant recipient leading to liver fibrosis and portal hypertension"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP001967",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "Simultaneous kidney pancreas transplantation (SKP) is a common procedure for the patient with long-term type 1 diabetes mellitus (DM) with terminal renal failure. It is unusual to consider the pancreas from a deceased donor who died after an acute intoxication with oral antidiabetic agent (OAA), which would suggest an abnormal functionality of the organ and preclude the potential use of the graft. We present a case of a successful pancreatic transplantation from a donor who died of acute cerebral edema secondary to severe hypoglycemia induced by OAA acute intoxication.",
"affiliations": "Sección de Donación y Coordinación de Trasplantes, Barcelona, Spain. Electronic address: crodri@clinic.ub.es.;Unidad de Diabetes, Servicio de Endocrinología y Nutición, Barcelona, Spain.;Cirugía Hepato-Bilio-Pancreática y Trasplante de Hígado y Páncreas, Barcelona, Spain.;Sección de Donación y Coordinación de Trasplantes, Barcelona, Spain.;Sección de Donación y Coordinación de Trasplantes, Barcelona, Spain.;Sección de Donación y Coordinación de Trasplantes, Barcelona, Spain.;Cirugía Hepato-Bilio-Pancreática y Trasplante de Hígado y Páncreas, Barcelona, Spain.;Cirugía Hepato-Bilio-Pancreática y Trasplante de Hígado y Páncreas, Barcelona, Spain.;Unidad de Trasplante Renal, Barcelona, Spain.;Cirugía Hepato-Bilio-Pancreática y Trasplante de Hígado y Páncreas, Barcelona, Spain.;Sección de Donación y Coordinación de Trasplantes, Barcelona, Spain.",
"authors": "Rodríguez-Villar|C|C|;Conget|I|I|;Ferrer-Fàbrega|J|J|;Paredes|D|D|;Ruíz|A|A|;Roque|R|R|;Rull|R|R|;López-Boado|M|M|;Ricart|M J|MJ|;Garcia|R|R|;Adalia|R|R|",
"chemical_list": "D007004:Hypoglycemic Agents; D005905:Glyburide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D003922:Diabetes Mellitus, Type 1; D003928:Diabetic Nephropathies; D062787:Drug Overdose; D005260:Female; D005905:Glyburide; D006801:Humans; D007004:Hypoglycemic Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D013405:Suicide; D014019:Tissue Donors; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2404-6",
"pmc": null,
"pmid": "26518941",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Pancreas Transplantation From a Deceased Donor Intoxicated With Oral Antidiabetic Agent: A Case Report.",
"title_normalized": "successful pancreas transplantation from a deceased donor intoxicated with oral antidiabetic agent a case report"
} | [
{
"companynumb": "ES-JNJFOC-20151117121",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": null,
"... |
{
"abstract": "Some typical and atypical Rett syndrome patients lack known genetic mutations. Mutations in the P/Q type calcium channel CACNA1A have been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia 2, and spinocerebellar ataxia 6, but not Rett syndrome. Patient Description: The authors describe a female patient with developmental regression and a de novo, likely pathogenic mutation in CACNA1A who meets 3 of 4 main criteria (stereotypic hand movements, loss of purposeful hand movements, gait disturbance), and 6 of 11 supportive criteria (impaired sleep, abnormal tone, vasomotor disturbance, scoliosis, growth retardation, and screaming spells) for atypical Rett syndrome. Furthermore, she resembles the early seizure variant of Rett syndrome. Previously, 3 children with similar CACNA1A mutations have been reported, but a Rett syndrome phenotype has not been described.\n\n\n\nCACNA1A mutations should be considered in children presenting with an atypical Rett syndrome phenotype, specifically, the early seizure variant.",
"affiliations": "1 Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;1 Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;1 Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;1 Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.",
"authors": "Epperson|Madison V|MV|;Haws|Michael E|ME|;Standridge|Shannon M|SM|;Gilbert|Donald L|DL|",
"chemical_list": "C105656:CACNA1A protein, human; D015220:Calcium Channels",
"country": "United States",
"delete": false,
"doi": "10.1177/0883073818754987",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "33(4)",
"journal": "Journal of child neurology",
"keywords": "epilepsy; epileptic encephalopathy; genetics",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D015220:Calcium Channels; D005260:Female; D006801:Humans; D020125:Mutation, Missense; D010641:Phenotype; D015518:Rett Syndrome",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "286-289",
"pmc": null,
"pmid": "29366381",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "28007990;24681721;27476654;22249839;6638958;21154482;25735478;19561590;20491871;27682832;27776117",
"title": "An Atypical Rett Syndrome Phenotype Due to a Novel Missense Mutation in CACNA1A.",
"title_normalized": "an atypical rett syndrome phenotype due to a novel missense mutation in cacna1a"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US12130",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": "3",
... |
{
"abstract": "Acinetobacter baumannii is an important cause of healthcare-associated infections, and is particularly problematic among patients who undergo organ transplantation. We describe a case of fulminant sepsis caused by carbapenem-resistant A. baumannii harboring the blaOXA-23 carbapenemase gene and belonging to international clone II. This isolate led to the death of a patient 6 days after simultaneous kidney-pancreas transplantation. Autopsy findings revealed acute mitral valve endocarditis, myocarditis, splenic and renal emboli, peritonitis, and pneumonia. This case highlights the severe nature of certain A. baumannii infections and the vulnerability of transplanted patients to the increasingly intractable \"high-risk\" clones of multidrug-resistant organisms.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.",
"authors": "Patel|G|G|;Perez|F|F|;Hujer|A M|AM|;Rudin|S D|SD|;Augustine|J J|JJ|;Jacobs|G H|GH|;Jacobs|M R|MR|;Bonomo|R A|RA|",
"chemical_list": "D001426:Bacterial Proteins; D015780:Carbapenems; D001618:beta-Lactamases; C063912:carbapenemase",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12351",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Acinetobacter baumannii; carbapenem resistance; endocarditis; simultaneous kidney-pancreas transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D016470:Bacteremia; D001426:Bacterial Proteins; D015780:Carbapenems; D003922:Diabetes Mellitus, Type 1; D024881:Drug Resistance, Bacterial; D004697:Endocarditis, Bacterial; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D011183:Postoperative Complications; D001618:beta-Lactamases",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "289-96",
"pmc": null,
"pmid": "25661804",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "24131374;12725359;24982065;22676635;18039798;24597542;25378635;23917322;16040625;24670166;21918019;21555763;19735384;24041466;19523312;22168176;19638006;24449752;24342636;22869261;20334552;18582814;23566148;18625687;23504089;19521868;21839276;22996302;17000742;23599308;11477528;25091170;1600019;23127486;23237530;20513702;22511922;21353436;25181313;23464995;17883360;19783325;18354105;23616495;23285002;17646423;18094380;23221186;24662709;20607268;23464996",
"title": "Fulminant endocarditis and disseminated infection caused by carbapenem-resistant Acinetobacter baumannii in a renal-pancreas transplant recipient.",
"title_normalized": "fulminant endocarditis and disseminated infection caused by carbapenem resistant acinetobacter baumannii in a renal pancreas transplant recipient"
} | [
{
"companynumb": "US-TEVA-562352USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nPrognosis in limited disease small-cell lung cancer (SCLC) after concurrent chemoradiotherapy is poor. While some studies show better survival after multimodality treatment including surgery, other trials failed to prove a surgery-related survival benefit. Therefore, this study investigated survival in stage IA-IIIB SCLC following surgery combined with chemotherapy and/or thoracic radiotherapy.\n\n\nMETHODS\nWe retrospectively reviewed all stage IA-IIIB SCLC patients without supraclavicular lymph node involvement at a single institution between January 1999 and August 2016 after multimodality treatment with curative intent. This comprised surgery consisting of primary tumor resection and systematic lymph node dissection combined with chemotherapy, chemoradiotherapy, or thoracic radiotherapy. Survival was determined using the Kaplan-Meier method, and differences were compared using log-rank tests. The risk of locoregional relapse was calculated.\n\n\nRESULTS\nA total of 47 patients (29 men, 18 women; mean age: 62 years) were included. Thirty-day mortality was 0%. Overall median survival was 56 months, and 2-, 3-, 5-, and 10-year survival rates were 69, 54, 46, and 30%, respectively. The only significant prognostic factor (p = 0.006) was R0 resection (n = 40) increasing median survival to 64 versus 17 months in case of technical inoperability (n = 5). The risk of locoregional relapse was 2.5% (n = 1) after R0 resection.\n\n\nCONCLUSIONS\nMultimodality treatment including surgery was safe and led to considerable survival. R0 resection was the only factor extending survival. It could be achieved in most patients and was associated with a low risk of locoregional relapse. Prospective randomized controlled studies are needed to define best practice in stage IA-IIIB SCLC.",
"affiliations": "Department of Thoracic Surgery, HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Hessen, Germany.;Department of Thoracic Surgery, HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Hessen, Germany.;Department of Thoracic Surgery, HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Hessen, Germany.",
"authors": "Weckler|Barbara Christine|BC|;Baldes|Natalie|N|;Schirren|Joachim|J|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0038-1667145",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0171-6425",
"issue": "67(4)",
"journal": "The Thoracic and cardiovascular surgeon",
"keywords": null,
"medline_ta": "Thorac Cardiovasc Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D059186:Chemoradiotherapy, Adjuvant; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008197:Lymph Node Excision; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011013:Pneumonectomy; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D012307:Risk Factors; D055752:Small Cell Lung Carcinoma; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "7903387",
"other_id": null,
"pages": "291-298",
"pmc": null,
"pmid": "30092600",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Survival following Multimodality Treatment Including Surgery for Stage IA-IIIB Small-Cell Lung Cancer.",
"title_normalized": "survival following multimodality treatment including surgery for stage ia iiib small cell lung cancer"
} | [
{
"companynumb": "DE-JNJFOC-20190700009",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Antiseizure prophylaxis is required during busulfan administration for hematopoietic stem cell transplantation. However, antiseizure agents such as benzodiazepines and phenytoin may produce adverse effects through interaction with other drugs. We retrospectively assessed the prophylactic efficacy and safety of levetiracetam and clonazepam against busulfan-induced seizures between 2013 and 2018. Thirty patients (after 2015) received levetiracetam, and 13 patients (before 2015) received clonazepam in this study. Levetiracetam was well-tolerated and had a significantly lower frequency of adverse effects, such as somnolence, compared with clonazepam, although two patients in the levetiracetam group experienced seizures. Levetiracetam is a feasible option for preventing busulfan-induced seizures.",
"affiliations": "Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Department of Pharmaceuticals, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyoto, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan. katom-tky@umin.ac.jp.",
"authors": "Tsujimoto|Shin-Ichi|SI|;Shirai|Ryota|R|;Utano|Tomoyuki|T|;Osumi|Tomoo|T|;Matsumoto|Kana|K|;Shioda|Yoko|Y|;Kiyotani|Chikako|C|;Uchiyama|Toru|T|;Deguchi|Takao|T|;Terashima|Keita|K|;Tomizawa|Daisuke|D|;Matsumoto|Kimikazu|K|;Kato|Motohiro|M|http://orcid.org/0000-0001-5145-1774",
"chemical_list": "D000077287:Levetiracetam; D002998:Clonazepam; D002066:Busulfan",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-019-02795-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "111(3)",
"journal": "International journal of hematology",
"keywords": "Busulfan-induced seizure; Clonazepam; Levetiracetam",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000293:Adolescent; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D002998:Clonazepam; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D012189:Retrospective Studies; D012640:Seizures; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "463-466",
"pmc": null,
"pmid": "31863341",
"pubdate": "2020-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "8269597;2591002;25672602;1606085;23208313;23575621;22378696;27745925;26271192;29143423;20677921;31201644;19025431;26053959;30083882",
"title": "Comparison of clonazepam and levetiracetam in children for prevention of busulfan-induced seizure in hematopoietic stem cell transplantation.",
"title_normalized": "comparison of clonazepam and levetiracetam in children for prevention of busulfan induced seizure in hematopoietic stem cell transplantation"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-243090",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"d... |
{
"abstract": "Although autologous stem cell transplantation or melphalan-based chemotherapy has significantly improved the prognosis of POEMS syndrome, a few patients will relapse or be refractory to primary therapy, and there is a lack of studies regarding these patients. In this study, we used low-dose lenalidomide (10 mg daily) and dexamethasone (40 mg, once weekly) to treat twelve patients with relapsed (n = 8) or refractory (n = 4) POEMS syndrome. After a median follow-up time of 20 months, the overall hematologic response rate was 77% with 44% having a complete response. Eight (67%) patients had neurological response, and the median overall neuropathy limitation scale score was reduced from 3 (range, 1-9) to 2 (range, 0-6). Serum vascular endothelial growth factor response rate was 91% and 46% of patients had normal serum VEGF levels. One patient had progression of the disease 3 months after the end of treatment and subsequently died from the disease. Therefore, the estimated 2 year overall survival and progression-free survival were 92%. The low-dose lenalidomide and dexamethasone regimen was well tolerated, with no treatment-related death or any grade 3 or 4 toxicity. In conclusion, low-dose lenalidomide plus dexamethasone therapy is an effective and safe regimen for patients with relapsed or refractory POEMS syndrome.",
"affiliations": "Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.",
"authors": "Cai|Qian-Qian|QQ|;Wang|Chen|C|;Cao|Xin-Xin|XX|;Cai|Hao|H|;Zhou|Dao-Bin|DB|;Li|Jian|J|",
"chemical_list": "D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12492",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "95(4)",
"journal": "European journal of haematology",
"keywords": "POEMS syndrome; lenalidomide; relapsed or refractory; vascular endothelial growth factor",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003907:Dexamethasone; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D016878:POEMS Syndrome; D012008:Recurrence; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "325-30",
"pmc": null,
"pmid": "25401269",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of low-dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome.",
"title_normalized": "efficacy and safety of low dose lenalidomide plus dexamethasone in patients with relapsed or refractory poems syndrome"
} | [
{
"companynumb": "CN-CELGENE-CHN-2014120278",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Calciphylaxis is a rare and often fatal condition mostly associated with end-stage renal disease. The pathophysiology remains elusive and treatment options are scarce. We present a rare case of severe calciphylaxis after kidney transplantation in a patient with persistent hyperparathyroidism.\n\n\nMETHODS\nA 78-year-old man with a history of end-stage renal disease developed edema and ulcerations on both lower limbs 14 months after kidney transplantation while receiving an mammalian target of rapamycin inhibitor to manage polyoma virus-associated nephropathy. Skin biopsies taken from the ulcerations confirmed calciphylaxis. A multimodal treatment regimen combining medical (calcium-free phosphate binders, cinacalcet, paricalcitol, sodium thiosulfate, antibiotic treatment) and surgical treatments (debridement and autologous skin transplantation) ultimately resulted in successful wound healing.\n\n\nCONCLUSIONS\nWe describe a case of severe calciphylaxis in a nonuremic patient after kidney transplantation. Rapid diagnosis by skin biopsy and an aggressive multimodal therapy regimen followed by long-term oral sodium thiosulfate treatment were crucial factors for a favorable outcome.",
"affiliations": "Renal Division, University Medical Center Freiburg, Freiburg, Germany.;Renal Division, University Medical Center Freiburg, Freiburg, Germany.;Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.;Renal Division, University Medical Center Freiburg, Freiburg, Germany.;Renal Division, University Medical Center Freiburg, Freiburg, Germany.;Renal Division, University Medical Center Freiburg, Freiburg, Germany.;Renal Division, University Medical Center Freiburg, Freiburg, Germany.; Center for Biological Signaling Studies (BIOSS), Freiburg, Germany.;Renal Division, University Medical Center Freiburg, Freiburg, Germany.",
"authors": "Welte|Thomas|T|;Arnold|Frederic|F|;Technau-Hafsi|Kristin|K|;Neumann-Haefelin|Elke|E|;Wobser|Rika|R|;Zschiedrich|Stefan|S|;Walz|Gerd|G|;Kramer-Zucker|Albrecht|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/TXD.0000000000000582",
"fulltext": "\n==== Front\nTransplant DirectTXDTransplantation Direct2373-8731Lippincott Williams & Wilkins TXD5005910.1097/TXD.000000000000058200002Kidney TransplantationSuccessful Management of Calciphylaxis in a Kidney Transplant Patient: Case Report Welte Thomas MD1Arnold Frederic MD1Technau-Hafsi Kristin MD2Neumann-Haefelin Elke MD1Wobser Rika MD1Zschiedrich Stefan MD1Walz Gerd MD13Kramer-Zucker Albrecht MD11 Renal Division, University Medical Center Freiburg, Freiburg, Germany.2 Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.3 Center for Biological Signaling Studies (BIOSS), Freiburg, Germany.Correspondence: Albrecht Kramer-Zucker, Department Innere Medizin, Universitätsklinikum Freiburg, Klinik für Nephrologie und Allgemeinmedizin, Hugstetter Straße 55, 79106 Freiburg, Germany. (albrecht.kramer-zucker@uniklinik-freiburg.de).4 2016 17 3 2016 2 4 e705 12 2015 17 1 2016 9 2 2016 Copyright © 2016 The Authors. Transplantation Direct. Published by Wolters Kluwer Health, Inc.2016The Authors. Transplantation Direct. Published by Wolters Kluwer Health, Inc.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.Introduction\nCalciphylaxis is a rare and often fatal condition mostly associated with end-stage renal disease. The pathophysiology remains elusive and treatment options are scarce. We present a rare case of severe calciphylaxis after kidney transplantation in a patient with persistent hyperparathyroidism.\n\nCase description\nA 78-year-old man with a history of end-stage renal disease developed edema and ulcerations on both lower limbs 14 months after kidney transplantation while receiving an mammalian target of rapamycin inhibitor to manage polyoma virus-associated nephropathy. Skin biopsies taken from the ulcerations confirmed calciphylaxis. A multimodal treatment regimen combining medical (calcium-free phosphate binders, cinacalcet, paricalcitol, sodium thiosulfate, antibiotic treatment) and surgical treatments (debridement and autologous skin transplantation) ultimately resulted in successful wound healing.\n\nDiscussion\nWe describe a case of severe calciphylaxis in a nonuremic patient after kidney transplantation. Rapid diagnosis by skin biopsy and an aggressive multimodal therapy regimen followed by long-term oral sodium thiosulfate treatment were crucial factors for a favorable outcome.\n\nOPEN-ACCESSTRUE\n==== Body\nCalciphylaxis or calcific uremic arteriolopathy is a rare (1-4% of the population with end-stage renal disease [ESRD]) and life-threatening clinical condition with a fatal progression in the majority of cases.1 The details of the underlying pathogenesis are still poorly understood.2 Characteristic calcification of small-sized and medium-sized arterioles is considered to be the major trigger for intense septal panniculitis, thrombotic vaso-occlusion, and the subsequent pathognomonic subcutaneous necrosis. The syndrome is usually diagnosed in patients suffering from ESRD receiving renal replacement therapy.1 Established risk factors include an elevated serum phosphate levels, hyperparathyroidism (HPT), coagulopathies, the use of vitamin K antagonists, hypoalbuminemia, diabetes mellitus, obesity (body mass index > 30), treatment with corticosteroids and female gender.3 However, calciphylaxis can also occur in patients without ESRD, so-called nonuremic calciphylaxis.4-6 We continue to use the term calciphylaxis instead of calcific uremic arteriolopathy to also refer to the disorder in non-ESRD patients.\n\nRecommended therapeutic approaches for calciphylaxis are heterogeneous, and there is no standardized treatment regimen. Treatment attempts mainly focus on wound and pain management, normalization of elevated calcium and phosphate levels by hemodialysis and medication, pharmacological or surgical reduction of elevated parathyroid hormone (PTH) levels, and (off-label) administration of sodium thiosulfate (STS). Sodium thiosulfate is supposed to prevent and reduce the critical calcium phosphate precipitation in small vessels.7-9\n\nHere, we report the successful management of nonuremic calciphylaxis in a patient after kidney transplantation and present a possible blueprint for an effective therapeutic approach.\n\nCASE DESCRIPTION\nA 78-year-old man was admitted to our nephrology center with fever and painful ulcerations on both legs in December 2014, 14 months after kidney transplantation. The ulcerations developed without trauma 2 months before admission.\n\nThe patient had a history of ESRD due to mesangioproliferative glomerulonephritis diagnosed in 2001. Peritoneal dialysis had been performed for 5 years preceding postmortem kidney transplantation in October 2013. There had been longstanding severe secondary HPT before transplantation (laboratory results 2011-2013: ionized calcium, 1.25 to 1.35 mmol/L, reference range, 1.0-1.3 mmol/l; phosphate, 1.8-2.1 mmol/L, reference range, 0.81-1.45 mmol/l; PTH, 590-740 pg/mL, reference range, 15-65 pg/mL). Furthermore, the patient was treated with vitamin K antagonists due to a heterozygous factor II mutation with venous thromboembolism. The patient was maintained on usual immunosuppressive triple therapy with tacrolimus, mycophenolate, and prednisone. Estimated glomerular filtration rate (MDRD) was 48 mL/min per 1.73 m2. Because of biopsy-proven polyoma virus-associated nephropathy, the mTOR inhibitor everolimus was introduced instead of mycophenolate. Under this regimen, polyoma virus load decreased from more than 10 million copies/mL to less than 10 thousand copies/mL and estimated glomerular filtration rate (GFR) (MDRD) stabilized at around 42 mL/min per 1.73 m2 with tacrolimus and everolimus trough levels of 2 to 4 ng/mL in whole blood. There was no posttransplantation diabetes mellitus.\n\nDuring the course of treatment, persisting edema of the lower limbs developed and initially was considered a side effect of everolimus. Treatment with mTOR inhibitor was discontinued, leading to a dual immunosuppressive regimen with tacrolimus trough levels between 3 to 5 ng/mL and prednisone 10 mg per day. Despite discontinuation of everolimus, indurations and ulcerations of the skin formed.\n\nPhysical examination revealed extensive gangrenous ulcerations on both lower legs (Figure 1A). Wound swabs taken from the lesions grew Staphylococcus dysgalactiae, Staphylococcus aureus, Klebsiella oxytoca, and Stenotrophomonas maltophilia. Initial blood tests showed deranged serum levels of PTH (428 pg/mL), total calcium (2.29 mmol/L), ionized calcium 1.26 mmol/L, and phosphate slightly off range (1.6 mmol/L) as well as an elevation of white blood cell (27 800 cells/μL; reference range, 3500-10 500 cells/μL) and C-reactive protein (280 mg/L; reference range, <3 mg/L). There were no symptoms or signs of peripheral artery occlusive disease. Biopsies from the skin lesions were taken. The samples showed pathognomonic calcium deposits in the small dermal arterioles, confirming the diagnosis of calciphylaxis (Figures 2A-C).\n\nFIGURE 1 Skin manifestation of calciphylaxis on the right lower leg. At admission (A), 1 day after surgical debridement (B), 1 day after autologous skin graft transplantation (C), and 7 months after autologous skin graft transplantation (D).\n\nFIGURE 2 Histology of the left lower leg. A, Ischemic necrosis of skin and subcutis. B, C, Intimal proliferation of small vessels with luminal narrowing. Calcification of the media of small vessels in the panniculus with fibroplasia of the intima. A, 25 × H&E, (B) 400 × H&E, (C) 200 × von Kossa staining. H&E, hematoxylin-eosin.\n\nWe established a multimodal treatment regimen.10 Wounds were surgically debrided and vacuum-assisted closure therapy was applied. Antibiotic treatment was guided by clinical evaluation, microbiological results of wound swabs, and laboratory results (piperacillin/tazobactam, ceftriaxone, meropenem, piperacillin/tazobactam, levofloxacin, linezolid, and cotrimoxazole were applied sequentially over several weeks). Opioid analgesics were given according to the pain service team. Calcium-free phosphate binders (sevelamer carbonate) and cinacalcet (60-90 mg per day) were given to lower the levels of PTH below 250 pg/mL. Paricalcitol (1 μg per day) was included in the regimen having shown benefits in calciphylaxis in previous reports.11,12 The vitamin K antagonist (phenprocoumon) was replaced by a factor Xa antagonist (rivaroxaban) and vitamin K was supplemented regularly. To dissolve tissue calcium deposition, off-label intravenous STS was administered (GFR-adjusted dose: 12.5 g, thrice per week12) carefully monitoring the acid-base balance. Sodium bicarbonate was given orally to keep bicarbonate levels within normal range (measured values, 21-26 mmol/L), thus avoiding metabolic acidosis. Sodium thiosulfate treatment was well tolerated without any obvious adverse effects.\n\nHyperbaric oxygen therapy as a supportive treatment option for calciphylaxis was considered but dismissed by the patient due to claustrophobia.\n\nThis multimodal pharmacological approach in combination with optimal wound care and antibiotic treatment led to pain control and eventually arrested ulceration growth. To improve wound healing after debridement, plastic reconstruction with autologous skin graft transplant was performed (Figures 1B-D). Intravenous STS was administered regularly over a period of 6 months until formation of granulation tissue of the ulcer floor was achieved. Under this treatment regimen, transplant renal function deteriorated, and polyoma virus-associated nephropathy was still present on kidney biopsy. Eventually, estimated GFR (MDRD) stabilized at 30 mL/min per 1.73 m2, with a low polyoma viral load of 500 copies/mL.\n\nFor consolidation, we switched to oral STS treatment (600 mg thrice daily13,14; capsules provided by our hospital pharmacy), and weekly clinical follow-ups were scheduled. Follow-up blood tests showed normalized total calcium (2.2-2.3 mmol/L), phosphate (1.0-1.2 mmol/L), and PTH levels (150-250 pg/mL). Oral STS treatment was applied for 3 additional months until complete wound healing was accomplished. Medication with cinacalcet and paricalcitol is also continued because the patient declined parathyroidectomy, the benefit of which is debatable.3,15\n\nDISCUSSION\nWe describe the management of a case of nonuremic calciphylaxis after kidney transplantation despite normal graft function. Details of our successful multimodal regimen are highlighted, providing a possible blueprint for an effective treatment. Although typically associated with ESRD, there are some reports of calciphylaxis after kidney transplantation.16-18 Although most case reports describe calciphylaxis either shortly or many years after kidney transplantation, implicating aftermath of ESRD or deteriorating graft function, our case illustrates that calciphylaxis must be considered even when graft function is normal.\n\nIn this case, individual risk factors included ESRD before kidney transplantation, secondary/tertiary HPT resulting in elevated calcium and phosphate levels, coagulopathy with venous thromboembolism, and anticoagulation using vitamin K antagonists.\n\nOur case demonstrates the vital importance of both early diagnosis by skin biopsy and aggressive multimodal therapy.3 Treatment should focus on optimal wound care (including management of peripheral artery occlusive disease if present), analgesia, antibiotic treatment if necessary, normalization of sodium, and phosphate levels as well as PTH levels by medication or surgical intervention.\n\nTo dissolve calcium phosphate deposits and to prevent further deposition, off-label medication with STS has been described as beneficial in several case reports and should be considered.7,8 In this case, STS was initially given intravenously to achieve high serum levels and effectively stop ulceration growth. Intralesional STS application might also be an effective alternative for localized calciphylaxis.19 As a convenient maintenance therapy for our kidney transplant patient, we later switched to oral STS treatment as described above.13\n\nIn our case, Paricalcitol was chosen as an active vitamin D agent to circumvent cinacalcet-associated hypocalcemia and to prevent further microvascular calcification.11,20\n\nAdministration of bisphosphonates is thought to prevent arterial calcification and has been reported to be beneficial in calciphylaxis.21-24 The same could be true for denosumab.25 Both substances were not used in our patient because calcium levels were on the low side.\n\nAlso, administration of hyperbaric oxygen has been reported in successful treatment of calciphylaxis.26,27 Especially in patients with failure of multimodal therapy, hyperbaric oxygen treatment could be a further option with only rare serious side effects. There might even be a synergism combining STS and hyperbaric oxygen therapy.26,28\n\nPathophysiologically, the calcification of the arterioles seems to trigger the subcutaneous septal panniculitis with thrombotic vaso-occlusion and subsequent necrosis, this provides the rationale for treatment with low-dose tissue plasminogen activator, which might be considered.29\n\nIn conclusion, an early multidisciplinary therapeutic approach is mandatory for successful management of calciphylaxis for which our case report is suggesting a practical outline. The diverse treatment options demonstrate that the management of this rare condition should be taken over by a specialized facility. Even after kidney transplantation, and in the absence of ESRD, calciphylaxis must be considered in a given context by health care providers to allow early treatment and achieve a favorable outcome for the patient.\n\n17 March 2016.\n\nE.N.H. and G.W. are funded by the Deutsche Forschungsgemeinschaft (DFG).\n\nThe authors declare no conflicts of interest.\n\nT.W. and F.A. gave equal contribution.\n\nT.W., F.A., and A.K.Z. wrote the first draft of the article. K.T.H. performed the histological examination of the lesion. E.N.H., R.W., S.Z., and G.W. participated in patient diagnosis and treatment and critically reviewed and edited the manuscript. All authors read and approved the final article.\n==== Refs\nREFERENCES\n1 \nAngelis M Wong LL Myers SA \nCalciphylaxis in patients on hemodialysis: a prevalence study . \nSurgery . \n1997 ;\n122 :\n1083 –\n1090 .9426423 \n2 \nDominguez A \nCalciphylaxis: controversies in pathogenesis, diagnosis and treatment . UT Southwestern Medical Center Web site. https://cme.utsouthwestern.edu/sites/cme.utsouthwestern.edu/files/em1508d_082115_protocol_dominguez.pdf. Published August 20, 2015. (Accessed on October 1, 2015) .\n3 \nNigwekar SU Kroshinsky D Nazarian RM \nCalciphylaxis: risk factors, diagnosis, and treatment . \nAm J Kidney Dis . \n2015 ;\n66 :\n133 –\n146 .25960299 \n4 \nNigwekar SU Wolf M Sterns RH \nCalciphylaxis from nonuremic causes: a systematic review . \nClin J Am Soc Nephrol . \n2008 ;\n3 :\n1139 –\n1143 .18417747 \n5 \nAlmafragi A Vandorpe J Dujardin K \nCalciphylaxis in a cardiac patient without renal disease . \nActa Cardiol . \n2009 ;\n64 :\n91 –\n93 .19317304 \n6 \nCouto FM Chen H Blank RD \nCalciphylaxis in the absence of end-stage renal disease . \nEndocr Pract . \n2006 ;\n12 :\n12406 –\n12410 .\n7 \nSchlieper G Brandenburg V Ketteler M \nSodium thiosulfate in the treatment of calcific uremic arteriolopathy . \nNat Rev Nephrol . \n2009 ;\n5 :\n539 –\n543 .19701230 \n8 \nNigwekar SU Brunelli SM Meade D \nSodium thiosulfate therapy for calcific uremic arteriolopathy . \nClin J Am Soc Nephrol . \n2013 ;\n8 :\n1162 –\n1170 .23520041 \n9 \nCicone JS Petronis JB Embert CD \nSuccessful treatment of calciphylaxis with intravenous sodium thiosulfate . \nAm J Kidney Dis . \n2004 ;\n43 :\n1104 –\n1108 .15168392 \n10 \nBaldwin C Farah M Leung M \nMulti-intervention management of calciphylaxis: a report of 7 cases . \nAm J Kidney Dis . \n2011 ;\n58 :\n988 –\n991 .21872378 \n11 \nKakagia D Kriki P Thodis E \nCalcific uremic arteriolopathy treated with cinacalcet, paricalcitol, and autologous growth factors . \nJ Cutan Med Surg . \n2011 ;\n15 :\n121 –\n124 .21477562 \n12 \nSantos PW Hartle EJ Quarles DL \nCalciphylaxis (calcific uremic arteriolopathy) . In: UpToDate , \nGoldfarb S \n(ED). UpToDate , \nWaltham MA \n(Accessed on September 23, 2015).\n13 \nAlBugami MM Wilson JA Clarke JR \nOral sodium thiosulfate as maintenance therapy for calcific uremic arteriolopathy: a case series . \nAm J Nephrol . \n2013 ;\n37 :\n104 –\n109 .23363879 \n14 \nMusso CG Enz P Vidal F \nOral sodium thiosulfate solution as a secondary preventive treatment for calciphylaxis in dialysis patients . \nSaudi J Kidney Dis Transpl . \n2008 ;\n19 :\n820 –\n821 .18711307 \n15 \nWeenig RH Sewell LD Davis MD \nCalciphylaxis: natural history, risk factor analysis, and outcome . \nJ Am Acad Dermatol . \n2007 ;\n56 :\n569 –\n579 .17141359 \n16 \nAlikadic N Kovac D Krasna M \nReview of calciphylaxis and treatment of a severe case after kidney transplantation with iloprost in combination with hyperbaric oxygen and cultured autologous fibrin-based skin substitutes . \nClin Transplant . \n2009 ;\n23 :\n968 –\n974 .19712088 \n17 \nHanvesakul R Silva MA Hejmadi R \nCalciphylaxis following kidney transplantation: a case report . \nJ Med Case Rep . \n2009 ;\n3 :\n9297 .20062786 \n18 \nVanbelleghem H Terryn W Van Leuven L \nA dramatic case of calciphylaxis 20 years after kidney transplantation . \nNephrol Dial Transplant . \n2004 ;\n19 :\n3183 –\n3185 .15575010 \n19 \nStrazzula L Nigwekar SU Steele D \nIntralesional sodium thiosulfate for the treatment of calciphylaxis . \nJAMA Dermatol . \n2013 ;\n149 :\n946 –\n949 .23760631 \n20 \nVargemezis V Liakopoulos V Kriki P \nPivotal role of paricalcitol in the treatment of calcific uremic arteriolopathy in the presence of a parathyroid adenoma . \nAm J Kidney Dis . \n2010 ;\n55 :\n144 –\n147 .19481317 \n21 \nRaymond CB Wazny LD Sood AR \nSodium thiosulfate, bisphosphonates, and cinacalcet for calciphylaxis . \nCANNT J . \n2009 ;\n19 :\n25 –\n27 ; quiz 28–29 .20136032 \n22 \nHanafusa T Yamaguchi Y Tani M \nIntractable wounds caused by calcific uremic arteriolopathy treated with bisphosphonates . \nJ Am Acad Dermatol . \n2007 ;\n57 :\n1021 –\n1025 .18021849 \n23 \nPrice PA Faus SA Williamson MK \nBisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption . \nArterioscler Thromb Vasc Biol . \n2001 ;\n21 :\n817 –\n824 .11348880 \n24 \nTorregrosa JV Durán CE Barros X \nSuccessful treatment of calcific uraemic arteriolopathy with bisphosphonates . \nNefrologia . \n2012 ;\n32 :\n329 –\n334 .22592420 \n25 \nHelas S Goettsch C Schoppet M \nInhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice . \nAm J Pathol . \n2009 ;\n175 :\n473 –\n478 .19590040 \n26 \nAn J Devaney B Ooi KY \nHyperbaric oxygen in the treatment of calciphylaxis: a case series and literature review . \nNephrology (Carlton) . \n2015 ;\n20 :\n444 –\n450 .25707425 \n27 \nVassa N Twardowski ZJ Campbell J \nHyperbaric oxygen therapy in calciphylaxis-induced skin necrosis in a peritoneal dialysis patient . \nAm J Kidney Dis . \n1994 ;\n23 :\n878 –\n881 .8203373 \n28 \nRogers NM Coates PTH \nCalcific uremic arteriolopathy—the argument for hyperbaric oxygen and sodium thiosulfate . \nSemin Dial . \n2010 ;\n23 :\n38 –\n42 .20331817 \n29 \nel-Azhary RA Arthur AK Davis MDP \nRetrospective analysis of tissue plasminogen activator as an adjuvant treatment for calciphylaxis . \nJAMA Dermatol . \n2013 ;\n149 :\n63 –\n67 .23324758\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2373-8731",
"issue": "2(4)",
"journal": "Transplantation direct",
"keywords": null,
"medline_ta": "Transplant Direct",
"mesh_terms": null,
"nlm_unique_id": "101651609",
"other_id": null,
"pages": "e70",
"pmc": null,
"pmid": "27500261",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": "15168392;9426423;21872378;17141359;21477562;18021849;18417747;19590040;8203373;23520041;23324758;16901796;22592420;23760631;18711307;25960299;25707425;20062786;19317304;20136032;15575010;19712088;23363879;19481317;11348880;19701230;20331817",
"title": "Successful Management of Calciphylaxis in a Kidney Transplant Patient: Case Report.",
"title_normalized": "successful management of calciphylaxis in a kidney transplant patient case report"
} | [
{
"companynumb": "DE-ACCORD-043375",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThe optimal therapeutic regimen for chemotherapy-refractory and node-positive small-cell lung cancer (SCLC) is criticizable for the lack of evidence.\nA patient with locally advanced SCLC was insensitive to the first-line chemotherapy of etoposide, irinotecan, and cisplatin.\nThe patient was diagnosed as SCLC with mediastinal lymph node metastasis by pathological staining.\n\n\nMETHODS\nSalvage pneumonectomy and systematic lymph node dissection combined with oral apatinib and mediastinal radiotherapy were performed for him.\n\n\nRESULTS\nThe patient survived for more than 2 years without recurrence after the operation and adjuvant therapy.\n\n\nCONCLUSIONS\nFor patients with chemotherapy-resistant but resectable SCLC, a timely resection combined with postoperative radiotherapy and apatinib might be effective.",
"affiliations": "Department of General Surgery, Xuzhou Infectious Disease Hospital, Xuzhou, China Department of Thoracic Surgery Department of Oncology, Xuzhou Central Hospital Affiliated to Southeast University, Xuzhou, China.",
"authors": "Pan|Yong|Y|;Kong|Feng-Wei|FW|;Wang|Heng|H|;Wang|Xiang|X|;Zhang|Hui|H|;Wu|Wen-Bin|WB|;Zhang|Miao|M|",
"chemical_list": "D011725:Pyridines; C553458:apatinib",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000008922",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health MD-D-17-0560610.1097/MD.0000000000008922089225700Research ArticleClinical Case ReportA recurrence-free survivor with chemotherapy-refractory small cell lung cancer after pneumonectomy A case report and review of the literaturePan Yong MDaKong Feng-Wei MDaWang Heng MD, PhDbWang Xiang MDcZhang Hui MDbWu Wen-Bin MD, PhDbZhang Miao MDb∗NA. a Department of General Surgery, Xuzhou Infectious Disease Hospital, Xuzhou, Chinab Department of Thoracic Surgeryc Department of Oncology, Xuzhou Central Hospital Affiliated to Southeast University, Xuzhou, China.∗ Correspondence: Miao Zhang, Department of Thoracic Surgery, Xuzhou Central Hospital Affiliated to Southeast University, Xuzhou, China (e-mail: zhangmiaodr@163.com).11 2017 27 11 2017 96 47 e892214 9 2017 3 11 2017 7 11 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nThe optimal therapeutic regimen for chemotherapy-refractory and node-positive small-cell lung cancer (SCLC) is criticizable for the lack of evidence.\n\nPatient concerns:\nA patient with locally advanced SCLC was insensitive to the first-line chemotherapy of etoposide, irinotecan, and cisplatin.\n\nDiagnoses:\nThe patient was diagnosed as SCLC with mediastinal lymph node metastasis by pathological staining.\n\nInterventions:\nSalvage pneumonectomy and systematic lymph node dissection combined with oral apatinib and mediastinal radiotherapy were performed for him.\n\nOutcomes:\nThe patient survived for more than 2 years without recurrence after the operation and adjuvant therapy.\n\nLessons:\nFor patients with chemotherapy-resistant but resectable SCLC, a timely resection combined with postoperative radiotherapy and apatinib might be effective.\n\nKeywords\napatinibsalvage surgerysmall cell lung cancer (SCLC)targeted therapyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nSmall cell lung cancer (SCLC) is characterized by rapid metastasis and widespread dissemination. The therapeutic regimen of SCLC has not changed significantly in the past several decades. Although it is sensitive to initial chemo-radiotherapy, long-term survivors are rare. The 5-year survival rate of these patients remains low (<7%), and most patients survive only for 1 year or less after diagnosis.[1] Surgery (lobectomy and systemic lymph node dissection) could only be considered for strictly selected patients with cT1-2N0M0 SCLC,[2,3] which is associated with improved long-term survival as compared to concurrent chemoradiotherapy. To date, no definitive regimen has been established for patients with chemotherapy-refractory SCLC. The role of aggressive surgery and targeted therapy has not been approved for the lack of evidence, despite the poor efficacy of the other treatment options. Meanwhile, the patients would take the risk of accelerated metastasis and worse prognosis of this devastating disease after surgery. However, it is reported that surgery may be actually underused for patients with early stage SCLC.[4] Adjuvant radiotherapy followed by prophylactic cranial irradiation (PCI) might be effective for node-positive patients. There are still no approved targeted drugs for SCLC. Apatinib, an antiangiogenesis agent targeting vascular endothelial growth factor receptor-2 (VEGFR-2), demonstrates satisfactory efficacy in advanced nonsmall cell lung cancer (NSCLC) patients.[5]\n\nHerein, a locally advanced SCLC patient who was resistant to the first-line chemotherapy was presented for discussion. To the best of our knowledge, this is the first report of salvage surgery combined with apatinib for stage IIIA SCLC, who gained recurrence-free survival for more than 2 years after surgery.\n\n2 Case presentation\nA 54-year-old, male coal miner without smoking or drinking history was admitted to our hospital on May 9, 2015. His major complaint was discontinuous irritating cough, without hemoptysis, fever, or significant loss of weight. His family history indicated nothing abnormal. Physical examination showed respiratory harshness, without palpable supraclavicular lymph nodes. Related examinations were carried out step by step for differential diagnosis, such as pneumonia, tuberculosis, silicosis, and lung cancer. The laboratory tests including white blood cell count, cytokeratin 19 fragment (CYFRA 21-1), squamous cell carcinoma (SCC), neuron specific enolase (NSE), and carcinoembryonic antigen (CEA) were in normal range. His chest computed tomography (CT) revealed a central-type pulmonary mass measuring 2.0 cm × 2.0 cm in size and enlarged mediastinal lymph nodes, which involved the right middle and lower lobes (Fig. 1A). The tumor invaded the main bronchus but > 2 cm away from the carina. Fine-needle biopsy under bronchoscopy revealed the pathological diagnosis of SCLC. Biopsy of the lymph nodes by endobronchial ultrasound for staging was avoided, with the aim to diminish iatrogenic tumor dissemination.\n\nFigure 1 (A) CT scan on June 5, 2015 showed progressed central-type lung cancer after the first cycle chemotherapy using etoposide. (B) The tumor enlarged after the second cycle of etoposide. (C) The tumor progressed after the third cycle of chemotherapy using irinotecan. (D) Pathological staining of a tumor section indicated SCLC, by H-E staining (×200), on August 7, 2015. CT = computed tomography, SCLC = small-cell lung cancer.\n\nThen the patient was clinically staged as IIIA (cT2N2M0), and he was not a candidate for surgery according to the updated guideline.[3] But the patient showed progressive disease (PD) after two cycles of chemotherapy using etoposide (100 mg/day, for 4 days) and cisplatin (75 mg/m2 of body surface area) (EP), followed by one cycle of irinotecan (60 mg/m2 of body surface area, on day 1 and day 8) and cisplatin (75 mg/m2 of body surface area) (IP), as indicated morphologically in CT (Fig. 1B and C). Although peripheral pneumonia could not be excluded, the patient showed normal temperature without productive cough. Based on the above findings, he was considered to be chemotherapy refractory. After a second multidisciplinary consultation by thoracic surgeons and oncologists, salvage surgery combined with oral apatinib was considered to be the only choice for this rapidly aggravated disease. The patient probably loses the chance of single-stage radical resection after another neoadjuvant therapy. It was approved by Ethical Committee of our hospital.\n\nFurther abdomen CT, enhanced cranial magnetic resonance image (MRI), and bone emission computed tomography (ECT) excluded distant metastasis. Positron emission tomography was not carried out, because it was not covered by his health insurance. After his informed consent, pneumonectomy with mediastinal lymph node dissection was performed on August 7, 2015, strictly in accordance with the principles of oncological surgery.\n\nThe postoperative recovery was mainly uneventful, and the patient was discharged 16 days after surgery. Postoperative pathological staining of the specimen confirmed the diagnosis of SCLC (Fig. 1D), with positive expression of thyroid transcription factor 1, synaptophysin, chromogranin A and neural cell adhesion molecule. Besides, the lymph nodes in stations of 4, 7, and 10 were tumor involved. The resection margin was tumor free. Then the patient was pathologically staged as IIIA (pT2N2M0).\n\nOne month after the surgery, adjuvant chemoradiotherapy and targeted therapy were carried out simultaneously. His therapeutic regimen was illustrated in Fig. 2. First, oral apatinib 425 mg once daily was administered for 3 months, and then it was discontinued because of persistent moderate anemia, fatigue, hand-foot syndrome, oral ulcerative mucositis, and hypertension. Three cycles of second-line chemotherapy using gemcitabine (1000 mg/m2 over 30 minutes, on day 1 and day 8, every 21 days) and cisplatin (75 mg/m2, every 21 days) (GP) were administered. Subsequently, the patient received mediastinal radiotherapy with a total dose of 50 Gy (2 Gy per day and 5 days/week), and 10 mg of nedaplatin on the first day was given as a radiosensitizer.\n\nFigure 2 The schematic illustration of therapeutic regimen of the patient. EP = etoposide and cisplatin, GP = gemcitabine and cisplatin, IP = irinotecan and cisplatin, RT = radiotherapy.\n\nThe patient refused prophylactic cranial irradiation (PCI) because of his compromised quality of life. During the follow-up, his serum tumor markers of CYFRA 21–1, SCC, NSE, and CEA were in normal range. He survived without local recurrence or distant metastasis for more than 2 years after the surgery up to now.\n\n3 Discussion\nThe median survival time of patients with extensive stage SCLC is 9.4 to 12.8 months, and the 2-year survival rate is 5.2% to 19.5%.[6] Resistance-to-conventional therapy and high-recurrence rate are ascribed to the heterogeneous genetic structure of SCLC.[7] Benefit from second-line chemotherapy in SCLC patients is limited. Moreover, treatment for SCLC patients who are resistant to platinum-based chemotherapy is not yet elucidated. New therapeutic targets have emerged, but no significant improvement has been demonstrated thus far for SCLC.[8] Due to the dismal prognosis of SCLC, novel effective treatments are urgently needed. As for this case, several issues might contribute to his long-term, recurrence-free survival.\n\nFirst, many studies on antiangiogenesis agents for SCLC are ongoing.[9] However, the role of angiogenesis inhibitors for SCLC is controversial. A meta-analysis indicates that adding angiogenesis inhibitors to chemotherapy does not improve the progression-free survival (PFS), overall survival, objective response rate, or 1-year PFS of SCLC patients.[10] Besides, maintenance with targeted therapy fails to improve the survival of patients with limited or extensive-stage SCLC.[11] Specifically, 7.5 mg/kg bevacizumab after induction chemotherapy does not improve the oncological outcomes in extensive-stage SCLC patients.[12] The addition of rilotumumab or ganitumab to etoposide and carboplatin/cisplatin does not indicate improved benefit for extensive-stage SCLC.[13] Comprehensive genomic analysis of SCLC might be a choice to identify patients who could benefit from targeted therapy.[14,15]\n\nSecond, in addition to concurrent chemoradiotherapy, aggressive surgery is beneficial to potentially curable limited-stage SCLC.[16] Besides, an accurate staging is critical before surgery. Multidisciplinary therapies make more patients eligible for surgical resection. The assessment of circulating tumor cells in SCLC patients seems to be a precise method to detect tumor dissemination, which is potentially helpful in selection of patients who are suitable for surgery.[17] However, the evidence from currently available randomized controlled trials does not support surgical resection for limited-stage SCLC as compared with chemoradiotherapy alone.[18] Indications of salvage surgery include locally progressive and recurrent tumors,[19] nevertheless, it might be technically more difficult with higher morbidity.[20]\n\nIt is noteworthy that the standard therapy for locally advanced chemotherapy-refractory SCLC is radiotherapy. Gemcitabine could be recommended for patients who have relapsed in 6 months after primary therapy,[3] which has modest activity in previously treated SCLC patients.[21] Pneumonectomy should not be recommended as first treatment. Besides, after refractory to platinum-based chemotherapy, cisplatin, or nedaplatin should not be recommended in the third line treatment. Apatinib has not been approved as second- or third-line therapy for SCLC in the NCCN guideline. As for this presented case, radical resection of the tumor and postoperative radiotherapy might affect more than oral apatinib on the recurrence-free survival of this patient, but the role of apatinib in SCLC worth further research.\n\n4 Conclusion\nTimely salvage surgery combined with radiotherapy and apatinib might be effective for patients with chemotherapy-refractory SCLC. However, high-quality studies regarding the exact efficacy of antiangiogenic agent and surgery are necessary.\n\nAbbreviations: CEA = carcinoembryonic antigen, CYFRA 21–1 = cytokeratin 19 fragment, ECT = emission computed tomography, EP = etoposide and cisplatin, GP = gemcitabine and cisplatin, IP = irinotecan and cisplatin, MDR = multidrug resistance, NSE = neuron specific enolase, PCI = prophylactic cranial irradiation, PD = progressive disease, PFS = progression-free survival, RT = radiotherapy, SCC = squamous cell carcinoma, SCLC = small-cell lung cancer, VEGFR-2 = vascular endothelial growth factor receptor-2.\n\nYP and F-WK are the co-first authors.\n\nMZ, F-WK, and HW planned the article and contributed to the discussion and review. YP, XW, HZ, and W-BW participated in data collection and writing the article.\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nThis study is supported by Jiangsu Province Innovative and Entrepreneurial Talent Introduction Plan (Wenbin Wu, 2016), and Xuzhou City Science and Technology Project (No. KC16SH102).\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Byers LA Rudin CM \nSmall cell lung cancer: where do we go from here? \nCancer \n2015 ;121 :664 –72 .25336398 \n[2] Rudin CM Ismaila N Hann CL \nTreatment of small-cell lung cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline . J Clin Oncol \n2015 ;33 :4106 –11 .26351333 \n[3] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: small cell lung cancer, Version 3.2017. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed May 23, 2017 .\n[4] Yang CJ Chan DY Shah SA \nLong-term survival after surgery compared with concurrent chemoradiation for node-negative small cell lung cancer . Ann Surg \n2017 ;doi: 10.1097/SLA.0000000000002287 .\n[5] Ding L Li QJ You KY \nThe use of apatinib in treating nonsmall-cell lung cancer: case report and review of literature . Medicine (Baltimore) \n2016 ;95 :e3598 .27196461 \n[6] Asai N Ohkuni Y Kaneko N \nRelapsed small cell lung cancer: treatment options and latest developments . Ther Adv Med Oncol \n2014 ;6 :69 –82 .24587832 \n[7] Kahnert K Kauffmann-Guerrero D Huber RM \nSCLC-state of the art and what does the future have in store? \nClin Lung Cancer \n2016 ;17 :325 –33 .27397481 \n[8] Koinis F Kotsakis A Georgoulias V \nSmall cell lung cancer (SCLC): no treatment advances in recent years . Transl Lung Cancer Res \n2016 ;5 :39 –50 .26958492 \n[9] Schneider BJ Kalemkerian GP \nPersonalized therapy of small cell lung cancer . Adv Exp Med Biol \n2016 ;890 :149 –74 .26703804 \n[10] Li Q Wu T Jing L \nAngiogenesis inhibitors for the treatment of small cell lung cancer (SCLC): a meta-analysis of 7 randomized controlled trials . Medicine (Baltimore) \n2017 ;96 :e6412 .28353568 \n[11] Roviello G Zanotti L Cappelletti MR \nNo advantage in survival with targeted therapies as maintenance in patients with limited and extensive-stage small cell lung cancer: a literature-based meta-analysis of randomized trials . Clin Lung Cancer \n2016 ;17 :334 –40 .27346522 \n[12] Pujol JL Lavole A Quoix E \nRandomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trial† . Ann Oncol \n2015 ;26 :908 –14 .25688059 \n[13] Glisson B Besse B Dols MC \nA randomized, placebo-controlled, phase 1b/2 study of rilotumumab or ganitumab in combination with platinum-based chemotherapy as first-line treatment for extensive-stage small-cell lung cancer . Clin Lung Cancer \n2017 ;18 :615.e8 –25.e8 .28601388 \n[14] Umemura S Tsuchihara K Goto K \nGenomic profiling of small-cell lung cancer: the era of targeted therapies . Jpn J Clin Oncol \n2015 ;45 :513 –9 .25670763 \n[15] Santarpia M Daffina MG Karachaliou N \nTargeted drugs in small-cell lung cancer . Transl Lung Cancer Res \n2016 ;5 :51 –70 .26958493 \n[16] Almquist D Mosalpuria K Ganti AK \nMultimodality therapy for limited-stage small-cell lung cancer . J Oncol Pract \n2016 ;12 :111 –7 .26869647 \n[17] Hamilton G Rath B Ulsperger E \nA review of the role of surgery for small cell lung cancer and the potential prognostic value of enumeration of circulating tumor cells . Eur J Surg Oncol \n2016 ;42 :1296 –302 .27402116 \n[18] Barnes H See K Barnett S \nSurgery for limited-stage small-cell lung cancer . Cochrane Database Syst Rev \n2017 ;4 :CD011917 .28429473 \n[19] Van Breussegem A Hendriks JM Lauwers P \nSalvage surgery after high-dose radiotherapy . J Thorac Dis \n2017 ;9 (suppl 3) :S193 –200 .28446984 \n[20] Uramoto H \nCurrent topics on salvage thoracic surgery in patients with primary lung cancer . Ann Thorac Cardiovasc Surg \n2016 ;22 :65 –8 .26948299 \n[21] Masters GA Declerck L Blanke C \nPhase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597 . J Clin Oncol \n2003 ;21 :1550 –5 .12697880\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "96(47)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D006801:Humans; D008175:Lung Neoplasms; D008197:Lymph Node Excision; D008198:Lymph Nodes; D008297:Male; D008482:Mediastinum; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011013:Pneumonectomy; D011725:Pyridines; D018714:Radiotherapy, Adjuvant; D016879:Salvage Therapy; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e8922",
"pmc": null,
"pmid": "29382030",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A recurrence-free survivor with chemotherapy-refractory small cell lung cancer after pneumonectomy: A case report and review of the literature.",
"title_normalized": "a recurrence free survivor with chemotherapy refractory small cell lung cancer after pneumonectomy a case report and review of the literature"
} | [
{
"companynumb": "CN-ACCORD-062394",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "We report the case of a 60-year-old man who was receiving immunosuppressive therapy for a bilateral lung transplant and presented with a crusted, violaceous plaque on the left hand. Based on histopathology and microbiological culture the patient was diagnosed with infection by Alternaria species. Treatment with itraconazole led to complete resolution of the skin lesion. Forty months later he developed four reddish, nodular, skin lesions on the left leg. Analysis of a biopsy from one of these lesions using histopathologic and molecular techniques identified a mold that shared 98% homology with a strain of Alternaria triticina. Alternaria species belong to a group of dematiaceous fungi that cause opportunistic infections in humans. The incidence of these infections is increasing, mainly in transplant centers. To the best of our knowledge, this is the first reported case of a human infection caused by A. triticina.",
"affiliations": "Departamento de Anatomía Patológica, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria e IFIMAV, Santander, Spain.;Servicio de Dermatología, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain.;Servicio de Microbiología, Hospital Universitario Marqués de Valdecilla, Santander, Spain.;Departamento de Anatomía Patológica, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria e IFIMAV, Santander, Spain. Electronic address: apavbj@humv.es.",
"authors": "González-Vela|M C|MC|;Armesto|S|S|;Unda-Villafuerte|F|F|;Val-Bernal|J F|JF|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-7310",
"issue": "105(8)",
"journal": "Actas dermo-sifiliograficas",
"keywords": "Alternaria triticina; Alternariosis cutánea; Cutaneous alternariosis; Feohifomicosis; Organ transplantation; Phaehyphomycoses; Trasplante de órganos",
"medline_ta": "Actas Dermosifiliogr",
"mesh_terms": "D060487:Alternariosis; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications",
"nlm_unique_id": "0373062",
"other_id": null,
"pages": "e51-4",
"pmc": null,
"pmid": "24440281",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous infection with Alternaria triticina in a Bilateral lung transplant recipient.",
"title_normalized": "cutaneous infection with alternaria triticina in a bilateral lung transplant recipient"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-102362",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "BACKGROUND\nPrimary immune thrombocytopenia is a severe bleeding disorder. About 50-85% of patients achieve initial remission from first-line therapies, but optimal second-line treatment remains a challenge. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haemopoiesis, making it a possible treatment option. We aimed to evaluate the efficacy and safety of ATRA plus danazol versus danazol in non-splenectomised patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia.\n\n\nMETHODS\nWe did a multicentre, randomised, open-label, phase 2 study of adult patients (≥18 years) with primary immune thrombocytopenia from five different tertiary medical centres in China. Those eligible were non-splenectomised, resistant to corticosteroid treatment or relapsed, and had a platelet count less than 30 × 109 per L. Masked statisticians used simple randomisation to assign patients (1:1) to receive oral ATRA (10 mg twice daily) plus oral danazol (200 mg twice daily) or oral danazol monotherapy (200 mg twice daily) for 16 weeks. Neither clinicians nor patients were masked to group assignments. All patients were assessed every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. The primary endpoint was 12-month sustained response defined as platelet count of 30 × 109 per L or more and at least a doubling of baseline platelet count (partial response), or a platelet count of 100 × 109 per L or more (complete response) and the absence of bleeding without rescue medication at the 12-month follow-up. All randomly allocated patients, except for those who withdrew consent, were included in the modified intention-to-treat population and efficacy assessment, and all patients who received at least one dose of the study agents were included in the safety analysis. Study enrolment was stopped early because the trial results crossed the interim analysis efficacy boundary for sustained response. This trial is registered with ClinicalTrials.gov, number NCT01667263.\n\n\nRESULTS\nFrom June 1, 2012, to July 1, 2016, we screened 130 patients for eligibility; 34 were excluded and 96 were randomly assigned. 93 patients were included in the modified intention-to-treat analysis: 45 in the ATRA plus danazol group and 48 in the danazol group. At the 12-month follow-up, sustained response was achieved more frequently in patients receiving ATRA plus danazol than in those receiving danazol monotherapy (28 [62%] of 45 vs 12 [25%] of 48; odds ratio 4·94, 95% CI 2·03-12·02, p=0·00037). Only two grade 3 adverse events were reported: one (2%) patient receiving ATRA plus danazol with dry skin, and one (2%) patient receiving danazol monotherapy with liver injury. There was no grade 4 or worse adverse event or treatment-related death in either group.\n\n\nCONCLUSIONS\nPatients with primary immune thrombocytopenia given ATRA plus danazol had a rapid and sustained response compared with danazol monotherapy. This finding suggests that ATRA represents a promising candidate for patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia.\n\n\nBACKGROUND\nNational Natural Science Foundation of China, Beijing Natural Science Foundation, Beijing Municipal Science and Technology Commission, and the National Key Research and Development Program of China.",
"affiliations": "Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Department of Haematology, Beijing Hospital, National Centre of Gerontology, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Department of Haematology, Beijing Hospital, National Centre of Gerontology, Beijing, China.;Department of Haematology, Qilu Hospital, Shandong University, Jinan, China.;Department of Haematology, Qilu Hospital, Shandong University, Jinan, China.;Department of Haematology, PLA Navy General Hospital, Beijing, China.;Department of Haematology, Beijing Tongren Hospital, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China.;Peking University People's Hospital, Peking University Institute of Haematology, Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Collaborative Innovation Centre of Haematology, Peking University, Beijing, China. Electronic address: zhangxh100@sina.com.",
"authors": "Feng|Fei-Er|FE|;Feng|Ru|R|;Wang|Min|M|;Zhang|Jia-Min|JM|;Jiang|Hao|H|;Jiang|Qian|Q|;Lu|Jin|J|;Liu|Hui|H|;Peng|Jun|J|;Hou|Ming|M|;Shen|Jian-Liang|JL|;Wang|Jing-Wen|JW|;Xu|Lan-Ping|LP|;Liu|Kai-Yan|KY|;Huang|Xiao-Jun|XJ|;Zhang|Xiao-Hui|XH|",
"chemical_list": "D014212:Tretinoin; D003613:Danazol",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(17)30170-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3026",
"issue": "4(10)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000328:Adult; D003613:Danazol; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D019233:Retreatment; D016896:Treatment Outcome; D014212:Tretinoin; D055815:Young Adult",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e487-e496",
"pmc": null,
"pmid": "28917657",
"pubdate": "2017-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial.",
"title_normalized": "oral all trans retinoic acid plus danazol versus danazol as second line treatment in adults with primary immune thrombocytopenia a multicentre randomised open label phase 2 trial"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1071678",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
... |
{
"abstract": "Evading tumor-mediated immunosuppression through antibodies to immune checkpoints has shown clinical benefit in patients with select solid tumors. There is a heterogeneity of responses in patients receiving immunotherapy, including pseudoprogression in which the tumor burden increases initially before decreasing to reach disease control. The characteristics and basis of pseudoprogression, however, remains poorly understood. We hereby report a case of microsatellite instability (MSI)-high metastatic colorectal cancer treated with combination of OX40 agonist and programmed death ligand-1 (PD-L1) antagonist that demonstrated pseudoprogression reaching 163% increase from baseline tumor burden. Tumor regression was subsequently observed and patient has remained in stable disease. Despite the substantial radiological progression, the symptomatic improvement reported by the patient led us to the decision of treatment continuation based on the suspicion of pseudoprogression, illustrating the importance of clinical evaluation in medical decision making while managing patients on immunotherapy. Additionally, the patient's MSI-high status contributes to his good, maintained response to PD-L1 blockade. Our case provides a frame of reference for fluctuation in tumor burden associated with pseudoprogression. Here we also evaluate the incidence and scale of pseudoprogression across solid tumor types.",
"affiliations": "Developmental Therapeutics Program of the Division of Hematology Oncology, Northwestern University, Chicago, Illinois, USA.;Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Developmental Therapeutics Program of the Division of Hematology Oncology, Northwestern University, Chicago, Illinois, USA.;Developmental Therapeutics Program of the Division of Hematology Oncology, Northwestern University, Chicago, Illinois, USA.;Developmental Therapeutics Program of the Division of Hematology Oncology, Northwestern University, Chicago, Illinois, USA.",
"authors": "Chae|Young Kwang|YK|;Wang|Si|S|;Nimeiri|Halla|H|;Kalyan|Aparna|A|;Giles|Francis J|FJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.18361",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 1836110.18632/oncotarget.18361Case ReportPseudoprogression in microsatellite instability-high colorectal cancer during treatment with combination T cell mediated immunotherapy: a case report and literature review Chae Young Kwang 123Wang Si 2Nimeiri Halla 123Kalyan Aparna 123Giles Francis J. 1231 Developmental Therapeutics Program of the Division of Hematology Oncology, Northwestern University, Chicago, Illinois, USA2 Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA3 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USACorrespondence to:Young Kwang Chae,young.chae@northwestern.edu22 8 2017 3 6 2017 8 34 57889 57897 28 12 2016 23 5 2017 Copyright: © 2017 Chae et al.2017This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.Evading tumor-mediated immunosuppression through antibodies to immune checkpoints has shown clinical benefit in patients with select solid tumors. There is a heterogeneity of responses in patients receiving immunotherapy, including pseudoprogression in which the tumor burden increases initially before decreasing to reach disease control. The characteristics and basis of pseudoprogression, however, remains poorly understood. We hereby report a case of microsatellite instability (MSI)-high metastatic colorectal cancer treated with combination of OX40 agonist and programmed death ligand-1 (PD-L1) antagonist that demonstrated pseudoprogression reaching 163% increase from baseline tumor burden. Tumor regression was subsequently observed and patient has remained in stable disease. Despite the substantial radiological progression, the symptomatic improvement reported by the patient led us to the decision of treatment continuation based on the suspicion of pseudoprogression, illustrating the importance of clinical evaluation in medical decision making while managing patients on immunotherapy. Additionally, the patient's MSI-high status contributes to his good, maintained response to PD-L1 blockade. Our case provides a frame of reference for fluctuation in tumor burden associated with pseudoprogression. Here we also evaluate the incidence and scale of pseudoprogression across solid tumor types.\n\nimmune checkpoint inhibitorsmetastatic colorectal cancerimmune-related responseanti-programmed death ligand-1 antibodypseudoprogression\n==== Body\nINTRODUCTION\nImmunotherapy that restores antitumor response within the host is rising as a promising treatment option for cancer patients. As a part of the immune checkpoint system, the programmed death (PD) -1/PD ligand-1 (PD-L1) pathway is a critical mechanism which the tumor cells utilize to escape from immune destruction. Blockade of the PD-1/PD-L1 pathway through antibodies to PD-1 has demonstrated encouraging potential in treating advanced solid tumors [1]. During treatments of immune checkpoint inhibitors such as antibodies against PD-1 or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), tumor responses were observed and assessed using Response Evaluation Criteria in Solid Tumors (RECIST) [2]. Some patients, however, experience immune-related responses such as initial tumor growth or appearance of new lesions followed by reduction in tumor burden. For example, in a subgroup of melanoma patients treated with ipilimumab, an anti-CTLA-4 monoclonal antibody, lesion enlargement preceded a decrease in tumor burden. The biopsy of the enlarged lesions revealed inflammatory cell infiltrates or necrosis [3]. This pattern of delayed clinical responses, or pseudoprogression, is recognized by clinicians and researchers as unconventional and characterized by tumor regression occurring or being maintained in the presence of new lesions or after initial radiological evidence of progressive disease (PD) determined by RECIST [4–6].\n\nSuch findings of pseudoprogression are not unique to immune-targeted treatments. They have been first described with tyrosine kinase inhibitors such as imatinib that result in tumor enlargement with decreased tumor density. Size-based RECIST is inadequate in recognizing change in tumor density as a parameter for treatment response, hence prompting the development of Choi criteria [7]. Similarly, response to bevacizumab, an antiangiogenic agent, may not be adequately assessed by RECIST because changes in tumor morphology on computed tomography (CT) were shown to be more significantly related to overall survival than tumor size [8]. With immunotherapeutics on the rise, pseudoprogression poses a challenge to clinicians who wish to accurately evaluate the clinical efficacy of these novel agents. The frequency, depth, developmental patterns, and predisposing factors of pseudoprogression still remain largely unknown to date. To further characterize pseudoprogression, increased reporting of this unconventional pattern of response in ongoing trials with immunotherapeutics will be beneficial.\n\nWe present the case of a 61-year-old male with metastatic adenocarcinoma of the colon treated with OX40 agonist and PD-L1 antagonist, who experienced initial increase in size and number of tumor lesions with subsequent tumor regression. We will also provide a brief literature review of the frequency and scale of pseudoprogression during treatment with FDA-approved and additional immune checkpoint inhibitors.\n\nCASE PRESENTATION\nThe patient first presented with microcytic anemia and guaiac-positive stool during routine physician visit. Colonoscopy revealed a proximal lesion of the cecum that was biopsied and positive for adenocarcinoma. Two months later he underwent a laparoscopic assisted right hemicolectomy, with surgical pathology revealing well-differentiated, low-grade adenocarcinoma with no lymph node involvement (staged T2N0). There were also histologic features suggestive of MSI including mild to moderate intratumoral lymphocytic response, moderate peritumor lymphocytic response and <5% mucinous tumor component. In follow-up CT local recurrence was noted at the anastomotic site as well as new perirenal nodules. Four months after surgery, the patient complained of abdominal pain with radiation to the back. He then underwent transverse/descending colon cancer resection with biopsy demonstrating poorly-differentiated, high-grade adenocarcinoma with lymph-vascular invasion (staged T3N1b). Two of 19 lymph nodes were found to be positive for disease. Immunohistochemistry of the tumor specimen demonstrated loss of MLH1 and PMS2, and retention of MSH2 and MSH6. Further analysis revealed negative MLH1 hypermethylation but heterozygous mutation in KRAS codon 13. Subsequent imaging revealed peri-nephric mass, hepatic lesions and mesenteric lymph node involvement. The patient later underwent comprehensive genomic profiling with next generation sequencing (Table 1).\n\nTable 1 Mutations detected in the patient and their functional implication status\nDisease relevant gene\tAlteration identified\tPossible functional implication a\t\nKRAS\tG13D\tYes\t\nTET2\tK95fs*18, N439fs*4\tYes\t\nBRCA2\tK1691fs*15\tYes\t\nCEBPA\tH24fs*84\tYes\t\nCTNNB1\tS45F\tYes\t\nFBXW7\tL234fs*5\tYes\t\nTP53\tP222L\tYes\t\nARID1A\tP224fs*8\tYes\t\nASXL1\tG645fs*12\tYes\t\nCDH1\tA634fs*29\tYes\t\nMLH1\tV612fs*2\tYes\t\nNOTCH2\tS1419fs*8\tYes\t\nALK\tE310D\tNo\t\nARID2\tR1679Q\tNo\t\nATR\tP315T\tNo\t\nBARD1\tP358_S364del\tNo\t\nCTNNA1\tR540H\tNo\t\nESR1\tR269C\tNo\t\nFGFR3\tK403fs*93\tNo\t\nIL7R\tI121fs*1\tNo\t\nIRF4\tK302E\tNo\t\nIRS2\tN21del, P1225L\tNo\t\nJAK1\tP861fs*4\tNo\t\nJAK2\tV984M\tNo\t\nKDM6A\tR621C\tNo\t\nMLL2\tP565L\tNo\t\nMYC\tG301D\tNo\t\nMYCN\tP237L\tNo\t\nNF1\tR1870W\tNo\t\nNOTCH1\tH196R\tNo\t\nNTRK3\tM452V\tNo\t\nPIK3CG\tL91M\tNo\t\nPIK3R1\tI292N, K593E\tNo\t\nPTCH1\tE44del\tNo\t\nRB1\tR910Q\tNo\t\nRUNX1T1\tR336H\tNo\t\nSETD2\tL2486M\tNo\t\nSPEN\tI2469V, P255del\tNo\t\nTGFBR2\tT230M\tNo\t\na Functional implication status was reported as part of the patient's genomic profile from Foundation Medicine.\n\nThe patient underwent 7 cycles of folinic acid with fluorouracil and oxaliplatin plus bevacizumab following surgery and discontinued due to neuropathy. Post-chemotherapy CT scan revealed 50% shrinkage of liver lesion and persistence of peri-nephric mass. He was subsequently transitioned to folinic acid with fluorouracil and irinotecan plus bevacizumab for one month. A right radical nephrectomy was performed two months later to remove the right retroperitoneal mass and resect the small bowel and omental flap. Surgical pathology returned with grade III infiltrating colonic adenocarcinoma with areas of necrosis in the retroperitoneal mass of the right kidney (8.0 × 7.2 × 5.2 cm) and a firm red mucosal segment of the small bowel (3.8 × 3.0 cm) adherent to the mass. New baseline CT scan two months after operation revealed no evidence of disease in chest, abdomen or pelvis. The patient was subsequently initiated on adjuvant chemotherapy of capecitabine plus oxaliplatin and developed increasing sciatica pain after 3 cycles. CT revealed recurrence in right psoas muscle and possible liver lesion metastases. He then underwent palliative radiotherapy for right psoas mass followed by 6 cycles of folinic acid with fluorouracil and irinotecan plus aflibercept, but experienced intolerance with diarrhea and fatigue. His carcinoembryonic antigen level was within normal limit at the beginning of this last round of chemotherapy (2.7 ng/mL).\n\nThe patient was enrolled in a clinical trial in year 2 with combination treatment of OX40 agonist and PD-L1 antagonist administered every two weeks. Major findings from baseline magnetic resonance imaging (MRI) scan included right hepatic lobe surface metastasis (1.8 × 1.0 cm) and mesenteric metastasis (2.0 × 1.4 cm) (Figure 1a and 1b). Lactate dehydrogenase (LDH) level was normal prior to treatment (201 unit/L) and raised slowly once treatment started. LDH level was abnormally high at week seven and nine (242 unit/L and 258 unit/L respectively). Follow-up MRI at week ten demonstrated enlarged right hepatic lobe surface metastasis (2.2 × 2.4 cm) and mesenteric metastasis (4.3 × 3.7 cm), along with numerous new liver metastases and new periportal lymphadenopathy (2.2 × 1.7 cm) (Figure 1). One of the new metastases in the caudate lobe measured to be 2.0 × 1.9 cm (Figure 2). An increase of 163% from baseline tumor burden was observed (Figure 2). Despite the radiological progression, the patient was doing well with no new complaints. Intriguingly he reported improvement in abdominal and back pain with most lab parameters being reasonably within limits. After discussion with the patient, the decision was made to continue on current treatment in suspicion of pseudoprogression. In following weeks, LDH level dropped to be within normal limits (ranging from 144 - 181 unit/L). Subsequent MRI at week 18 showed an excellent response with shrunken right hepatic lobe surface metastasis (1.7 × 1.2 cm) and mesenteric metastasis (1.4 × 2.1 cm) (Figure 1a and 1b). The previously seen periportal lymph node was resolved with central necrosis (0.8 × 0.9 cm) (Figure 1c). The caudate lobe mass decreased to 0.2 × 0.3 cm (Figure 2). MRI at week 34 continued to reveal slight decrease of tumor burden and the patient continued to report feeling well to date (liver metastasis 1.7 × 0.7 cm, mesenteric metastasis 1.5 × 1.2 cm, lymph node undetectable) (Figure 2).\n\nFigure 1 Tumor response to combined OX-40 agonist and PD-L1 antagonist regimen\na. The right hepatic lobe surface metastasis (white arrow) was significantly increased in size at week 10, measuring 2.2 × 2.4 cm compared with 1.8 × 1.0 cm on baseline. At week 18, the lesion shrunk to 1.7 × 1.2 cm. b. The mesenteric metastasis (white arrow) grew from 2.0 × 1.4 cm at baseline to 4.3 × 3.7 cm at week 10, and subsequently decreased to 1.4 × 2.1 cm at week 18. c. A new periportal lymph node (white arrow) was detected at week 10 that measured to be 2.2 × 1.7 cm and subsequently became 0.8 × 0.9 cm with central necrosis at week 18.\n\nFigure 2 Change in tumor burden under combined treatment of OX40 agonist and PD-L1 antagonist over time\nThe diameters of new and existing lesions were measured in millimeters every eight to ten weeks. Blue blocks denote baseline lesions. Orange blocks are new metastatic lesions, and yellow are new lymphadenopathy. * The periportal lymph node detected at week ten was not included in overall tumor burden at week 18 because it decreased to less than 10mm.\n\nTable 2 Unconventional response rates and magnitude of increase in tumor burden from baseline for CTLA-4, PD-1 and PD-L1 inhibitors across solid tumors\nAgent\tMechanism of action\tTrial\tCancer Type\tNo. of Evaluable Patients\tNo. of unconventional Responses\tUnconventional Response Rate (%)\tMaximum increase from baseline tumor burden (%) a\tPrimary Tumor response criteria\t\nIpilimumab\tAnti-CTLA-4 monoclonal antibody\tWolchok et al (2009) [4]\tMelanoma\t227\t22\t9.7\t113\tirRC\t\nO’Day et al (2010) [16]\tMelanoma\t155\t12\t7.7\tNot reported\tirRC\t\nTremelimumab\tAnti-CTLA-4 monoclonal antibody\tRibas et al (2012) [17]\tMelanoma\t36\t1\t2.8\tNot reported\tRECIST 1.0\t\nCalabro et al (2015) [18]\tMesothelioma\t29\t2\t6.9\tNot reported\tirRC\t\nPembrolizumab\tAnti-PD-1 monoclonal antibody\tRibas et al (2015) [19]\tMelanoma\t360\t57\t15.8\tNot reported\tRECIST 1.1\t\nHodi et al (2016) [13]\tMelanoma\t327\t24\t7.3\t80\tRECIST 1.1\t\nSeiwert et al (2016) [20]\tHead and neck squamous cell carcinoma\t56\t1\t1.8\tNot reported\tRECIST 1.1\t\nNivolumab\tAnti-PD-1 monoclonal antibody\tHodi et al (2014) [6]\tMelanoma\t107\t4\t3.7\tNot reported\tRECIST 1.0\t\nRobert et al (2015) [21]\tMelanoma\t206\t17\t8.3\t63\tRECIST 1.1\t\nWeber et al (2015) [5]\tMelanoma\t120\t10\t8.3\t25\tRECIST 1.1\t\nGettinger et al (2016)[9]\tNon-small-cell lung cancer\t52\t3\t5.8\t20\tRECIST 1.1\t\nAtezolizumab\tAnti-PD-L1 monoclonal antibody\tPowles et al (2014) [22]\tUrothelial carcinoma\t67\t1\t1.5\t10 b\tRECIST 1.1\t\nMcDermott et al (2016) [23]\tRenal cell carcinoma\t70\t4\t5.7\t80\tirRC and RECIST 1.1\t\nRosenberg et al (2016) [24]\tUrothelial carcinoma\t310\t20\t6.5\t95\tirRC and RECIST 1.1\t\nDurvalumab\tAnti-PD-L1 monoclonal antibody\tMassard et al (2016) [25]\tUrothelial carcinoma\t42\t3\t7.1\t75\tRECIST 1.1\t\nAvelumab\tAnti-PD-L1 monoclonal antibody\tKaufman et al (2016)[26]\tMerkel cell carcinoma\t65\t1\t1.5\t60\tRECIST 1.1\t\nUnconventional response is defined as tumor regression occurring or being maintained in the presence of new lesions or after initial radiological evidence of tumor growth.\n\na Changes in tumor burden were estimated from published spider plots. The published graphs, from which the percent increase in this column was estimated, were based on unidimensional tumor measurements, except the ones in Wolchok et al [4].\n\nb This patient who initially responded to treatment later presented with new lesions that were consistent with pseudoprogression with a biopsy of extensive necrosis. The maximum increase in tumor burden was estimated from the tumor assessment prior to appearance of new lesions instead of from baseline.\n\nDISCUSSION\nTo our knowledge, a scale of pseudoprogression that reached 163% increase from baseline as demonstrated in our case has not been reported previously. Our patient was found to have substantial radiological progression soon after he was administered a combination of OX40 agonist and PD-L1 inhibitor. Appearance of new lesions and enlargement of target lesions, leading to 163% increase from baseline in overall tumor burden, would have been characterized as disease progression according to RECIST (Figure 2). Per the immune-related response criteria (irRC), this patient would have also been characterized as disease progression (irPD), but confirmation requires a repeat scan within four weeks. The patient, however, had improving clinical presentation that mismatched with the radiological evidence of disease. The disconnection between clinical and radiological presentations thus raised the suspicion of pseudoprogression. Subsequent scans demonstrated a steady trend of decline in tumor burden, confirming previous findings as pseudoprogression and rejecting the previous assessment of irPD. The patient has remained in stable disease to date per irRC.\n\nThis case is unique for two reasons. First, it shows extraordinary scale of pseudoprogression, with 163% of tumor growth from baseline. In addition to the substantial enlargement of target lesions, the size of new liver metastases when they first appeared was also notable. The mass in the caudate lobe initially presented as a considerable lesion with its dimensions being 2.0 × 1.9 cm, contributing considerably to the increase in overall tumor burden at the time. This is unusual for new lesions because they typically first appear small before growing into larger ones. The magnitude of maximum increase in tumor burden associated with pseudoprogression reported previously ranges from 20% - 113% (Table 2) [4, 9]. Our case contributes to further elucidating pseudoprogression by serving as a reference point for the extent of tumor growth. Second, even with substantial increase in tumor burden including the emergence of new large lesions, the symptomatic improvement experienced by the patient is a key reason why we continued the treatment regimen. Recently hyperprogressive disease was observed in a small subset of patients treated with anti-PD-1/PD-L1 monotherapy, which is associated with older patients (> 65 years old) and slower growing tumors at baseline [10]. It is difficult to differentiate pseudoprogression from hyperprogression based on radiological evidence alone when they first emerge. Treating physicians therefore need to rely on other aspects of the clinical data to evaluate tumor response. In our case, the patient's pain almost disappeared and fatigue resolved with increased overall level of energy. Had the dramatic radiological change been real disease progression or hyperprogression, the patient's condition would have probably deteriorated instead. This demonstrates that in addition to radiologic criteria, clinical evaluation is also a critical part of medical decision making regarding patients on immune checkpoint inhibitors.\n\nNot only is the scale of “tumor flare” significant in this case, but the degree of tumor shrinkage following the flare within eight weeks is also worth noting. One of the new lesions, a periportal lymph node, measured to be 2.2 × 1.7 cm at week ten after treatment but subsequently shrunk to 0.8 × 0.9 cm with central necrosis evident on MRI at week 18 (Figure 1c and Figure 2). The lymph node was so small that it was not included in future calculation of tumor burden. Similarly, one of the target lesions at baseline, the mesenteric metastasis, doubled both of its dimensions at the first scan post-treatment and decreased to a size smaller than baseline eight weeks later (Figure 1b). The relatively fast and major reduction in tumor size provides a frame of reference regarding how much fluctuation in tumor burden can be expected in pseudoprogression.\n\nChange in LDH level reasonably correlates with the change in overall tumor burden in this case. A rise of LDH level to being abnormally high was observed around the same time when pseudoprogression was detected. The decline of LDH level back to normal range also paralleled the shrinkage of tumor time wise. It is not clear at this point how to interpret the relationship of LDH level and radiological progression observed in this case, but it may be clinically relevant to study the role of LDH in differentiating pseudoprogression and real progression in the setting of immune-targeted treatment.\n\nAnother notable feature of our patient is that his MSI status is high, which may explain his excellent response to treatment of immune checkpoint inhibitors compared to chemotherapy. His tumor specimen demonstrated loss of MLH1 and PMS2 and retention of MSH2 and MSH6, indicating loss of normal DNA mismatch repair function within the tumor. The patient also had a lot of somatic mutations evident from the genetic profiling report (Table 1). All information points to very high MSI status and indicates the deficiency of tumors at mismatch repair. Le et al. found that the mismatch repair-deficit tumors respond better to PD-1 blockade than mismatch repair-proficient tumors regardless of tumor type [11]. This may be explained by the fact that the mismatch repair-deficient tumors create a microenvironment full of immune checkpoint ligands including PD-1, PD-L1 and CTLA-4 to evade tumor elimination [12]. Given the high MSI status of our patient, it is not surprising to see him responding well to a treatment involving PD-L1 antagonist. It is worth to investigate, however, whether having MSI-high status would likely cause more pseudoprogression as compared to MSI-stable cancer.\n\nPseudoprogression with immune checkpoint inhibitors has been observed in previous reports and would have been misclassified as progressive disease according to size-based WHO or RECIST criteria, therefore prompting the development of irRC [4]. Applying irRC, it was found that 9.7% of melanoma patients (22 of 227 patients) treated with ipilimumab demonstrated pseudoprogression that would have been prematurely classified as PD by WHO criteria [4]. Similarly, 7.3% of patients (24 of 327) who received pembrolizumab (anti-PD-1 antibody) for treatment of advanced melanoma experienced early or delayed pseudoprogression, including tumor regression and stable disease despite new lesion development, as well as temporary increase in the size of target lesions [13]. One study reported that 3.7% of metastatic melanoma patients (4 of 107 patients) treated with nivolumab (anti-PD-1 antibody) had unconventional response patterns suggestive of pseudoprogression [6]. During treatments of solid tumors with antibodies against CTLA-4, PD-1 or PD-L1, mean incidence of unconventional immune-related responses, or pseudoprogression is 6.3% (range 1.5 - 15.8%) (Table 2). PD-1 inhibitors appear to have a higher rate of pseudoprogression (mean 7.3%, range 1.8 - 15.8%) than anti-CTLA-4 and anti-PD-L1 agents (mean 6.8% and 4.5%, range 2.8 - 9.7% and 1.5 - 7.1% respectively). In addition, although the report of the degree of pseudoprogression in combined immunotherapy is limited, it was observed that 7.7% of patients (4 of 52 patients) with advanced melanoma receiving nivolumab plus ipilimumab had immune-related partial response or stable disease [14]. Our case report contributes to further delineating the frequency of such atypical response pattern in dual immunotherapy, but more clinical data is needed to fully understand this phenomenon. Regardless of whether immunotherapeutic agents are used alone or in combination, it is evident that solely relying on conventional criteria such as RECIST runs into the risk of inadequately evaluating the tumor response to immune checkpoint inhibitors for a small subgroup of patients.\n\nAlthough pseudoprogression is becoming increasingly recognized by clinicians and researchers, the basis of this phenomenon is still not fully understood. Evidence such as biopsy that revealed inflammatory cell infiltrates and necrosis in the enlarged lesions supports the idea that pseudoprogression may be “tumor inflammation” instead and clinical response may be delayed [3, 15]. Because current imaging technique cannot differentiate pseudoprogression from real disease progression, clinicians should take extra caution when evaluating each patient's response to immunotherapeutic agents. The goal is to avoid either premature withdrawal of the treatment or prolonging ineffective treatment. Due to a paucity of information on pseudoprogression, currently there is no means to predict whether a patient will demonstrate pseudoprogression when treated with immune checkpoint inhibitors. Further studies are needed to help delineate the characteristics of patients who experienced pseudoprogression. With this information, clinicians will be more prepared when managing patients with a high possibility of encountering pseudoprogression on immunotherapy. It remains unknown whether patients who experienced pseudoprogression remain in disease control longer than those who did not. A meta-analysis regarding the long term response is ongoing by our research team currently.\n\nAs immune checkpoint inhibitors, especially anti-PD-1 and anti-PD-L1 agents, become more widely used by clinicians, the task of appropriately evaluating tumor response remains a challenge in patient management. Multiple studies using antibodies against CTLA-4, PD-1 and PD-L1 provide the basis of evaluating the incidence and scale of pseudoprogression across a variety of solid tumors [4–6, 9, 13, 16–26] (Table 2). Our case, however, is the first to demonstrate pseudoprogression during combinational treatment of PD-L1 inhibitor and OX40 agonist in MSI-high metastatic colorectal adenocarcinoma. It also represents a much larger tumor burden increase (163% from the baseline) than what has been previously published (113%) [4]. Further research is needed to delineate the basis of pseudoprogression in the usage of immune checkpoint inhibitors, differentiate pseudoprogression from real progression, as well as characterizing predisposing factors of pseudoprogression.\n\nCONFLICTS OF INTEREST\n\nWe report no potential conflict of interest.\n==== Refs\nREFERENCES\n1 Pedoeem A Azoulay-Alfaguter I Strazza M Silverman GJ Mor A Programmed death-1 pathway in cancer and autoimmunity Clin Immunol 2014 153 145 52 10.1016/j.clim.2014.04.010 24780173 \n2 Chiou VL Burotto M Pseudoprogression and Immune-Related Response in Solid Tumors J Clin Oncol 2015 33 3541 3 10.1200/jco.2015.61.6870 26261262 \n3 Di Giacomo AM Danielli R Guidoboni M Calabro L Carlucci D Miracco C Volterrani L Mazzei MA Biagioli M Altomonte M Maio M Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases Cancer Immunol Immunother 2009 58 1297 306 10.1007/s00262-008-0642-y 19139884 \n4 Wolchok JD Hoos A O’Day S Weber JS Hamid O Lebbe C Maio M Binder M Bohnsack O Nichol G Humphrey R Hodi FS Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria Clin Cancer Res 2009 15 7412 20 10.1158/1078-0432.ccr-09-1624 19934295 \n5 Weber JS D’Angelo SP Minor D Hodi FS Gutzmer R Neyns B Hoeller C Khushalani NI Miller WH Jr Lao CD Linette GP Thomas L Lorigan P Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial The Lancet Oncology 2015 16 375 84 10.1016/S1470-2045(15)70076-8 25795410 \n6 Hodi FS Sznol M Kluger HM McDermott DF Carvajal RD Lawrence DP Topalian SL Atkins MB Powderly JD Sharfman WH Puzanov I Smith DC Leming PD Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial J Clin Oncol 2014 32 \n7 Choi H Charnsangavej C Faria SC Macapinlac HA Burgess MA Patel SR Chen LL Podoloff DA Benjamin RS Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria J Clin Oncol 2007 25 1753 9 10.1200/jco.2006.07.3049 17470865 \n8 Chun YS Vauthey JN Boonsirikamchai P Maru DM Kopetz S Palavecino M Curley SA Abdalla EK Kaur H Charnsangavej C Loyer EM Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases JAMA 2009 302 2338 44 10.1001/jama.2009.1755 19952320 \n9 Gettinger S Rizvi NA Chow LQ Borghaei H Brahmer J Ready N Gerber DE Shepherd FA Antonia S Goldman JW Juergens RA Laurie SA Nathan FE Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer J Clin Oncol 2016 34 2980 7 10.1200/jco.2016.66.9929 27354485 \n10 Champiat S Dercle L Ammari S Massard C Hollebecque A Postel-Vinay S Chaput N Eggermont A Marabelle A Soria JC Ferte C Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1 Clin Cancer Res 2016 23 1920 1928 10.1158/1078-0432.ccr-16-1741 27827313 \n11 Le DT Uram JN Wang H Bartlett BR Kemberling H Eyring AD Skora AD Luber BS Azad NS Laheru D Biedrzycki B Donehower RC Zaheer A PD-1 Blockade in Tumors with Mismatch-Repair Deficiency N Engl J Med 2015 372 2509 20 10.1056/NEJMoa1500596 26028255 \n12 Llosa NJ Cruise M Tam A Wicks EC Hechenbleikner EM Taube JM Blosser RL Fan H Wang H Luber BS Zhang M Papadopoulos N Kinzler KW The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints Cancer Discov 2015 5 43 51 10.1158/2159-8290.cd-14-0863 25358689 \n13 Hodi FS Hwu WJ Kefford R Weber JS Daud A Hamid O Patnaik A Ribas A Robert C Gangadhar TC Joshua AM Hersey P Dronca R Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab J Clin Oncol 2016 34 1510 7 10.1200/jco.2015.64.0391 26951310 \n14 Wolchok JD Kluger H Callahan MK Postow MA Rizvi NA Lesokhin AM Segal NH Ariyan CE Gordon RA Reed K Burke MM Caldwell A Kronenberg SA Nivolumab plus ipilimumab in advanced melanoma N Engl J Med 2013 369 122 33 10.1056/NEJMoa1302369 23724867 \n15 de Velasco G Krajewski KM Albiges L Awad MM Bellmunt J Hodi FS Choueiri TK Radiologic Heterogeneity in Responses to Anti-PD-1/PD-L1 Therapy in Metastatic Renal Cell Carcinoma Cancer Immunol Res 2016 4 12 7 10.1158/2326-6066.cir-15-0197 26589768 \n16 O’Day SJ Maio M Chiarion-Sileni V Gajewski TF Pehamberger H Bondarenko IN Queirolo P Lundgren L Mikhailov S Roman L Verschraegen C Humphrey R Ibrahim R Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study Ann Oncol 2010 21 1712 7 10.1093/annonc/mdq013 20147741 \n17 Ribas A Chesney JA Gordon MS Abernethy AP Logan TF Lawson DH Chmielowksi B Glaspy JA Lewis K Huang B Wang E Hsyu PH Gomez-Navarro J Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion J Transl Med 2012 10 236 10.1186/1479-5876-10-236 23171508 \n18 Calabrò L Morra A Fonsatti E Cutaia O Fazio C Annesi D Lenoci M Amato G Danielli R Altomonte M Giannarelli D Di Giacomo AM Maio M Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study The Lancet Respiratory Medicine 2015 3 301 9 10.1016/S2213-2600(15)00092-2 25819643 \n19 Ribas A Wolchok JD Robert C Kefford R Hamid O Daud A Hwu WJ Weber JS Joshua AM Gangadhar TC Patnaik A Hersey P Dronca R P0116 Updated clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in 411 patients with melanoma Eur J Cancer 2015 51 e24 10.1016/j.ejca.2015.06.072 \n20 Seiwert TY Burtness B Mehra R Weiss J Berger R Eder JP Heath K McClanahan T Lunceford J Gause C Cheng JD Chow LQ Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial The Lancet Oncology 2016 17 956 65 10.1016/S1470-2045(16)30066-3 27247226 \n21 Robert C Long GV Brady B Dutriaux C Maio M Mortier L Hassel JC Rutkowski P McNeil C Kalinka-Warzocha E Savage KJ Hernberg MM Lebbé C Nivolumab in Previously Untreated Melanoma without BRAF Mutation N Engl J Med 2015 372 320 30 10.1056/NEJMoa1412082 25399552 \n22 Powles T Eder JP Fine GD Braiteh FS Loriot Y Cruz C Bellmunt J Burris HA Petrylak DP Teng SL Shen X Boyd Z Hegde PS MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer Nature 2014 515 558 62 10.1038/nature13904 25428503 \n23 McDermott DF Sosman JA Sznol M Massard C Gordon MS Hamid O Powderly JD Infante JR Fassò M Wang YV Zou W Hegde PS Fine GD Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study J Clin Oncol 2016 34 833 42 10.1200/jco.2015.63.7421 26755520 \n24 Rosenberg JE Hoffman-Censits J Powles T van der Heijden MS Balar AV Necchi A Dawson N O’Donnell PH Balmanoukian A Loriot Y Srinivas S Retz MM Grivas P Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial The Lancet 2016 387 1909 20 10.1016/S0140-6736(16)00561-4 \n25 Massard C Gordon MS Sharma S Rafii S Wainberg ZA Luke J Curiel TJ Colon-Otero G Hamid O Sanborn RE O’Donnell PH Drakaki A Tan W Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer J Clin Oncol 2016 34 3119 25 10.1200/jco.2016.67.9761 27269937 \n26 Kaufman HL Russell J Hamid O Bhatia S Terheyden P D’Angelo SP Shih KC Lebbé C Linette GP Milella M Brownell I Lewis KD Lorch JH Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial The Lancet Oncology 10.1016/S1470-2045(16)30364-3\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(34)",
"journal": "Oncotarget",
"keywords": "anti-programmed death ligand-1 antibody; immune checkpoint inhibitors; immune-related response; metastatic colorectal cancer; pseudoprogression",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "57889-57897",
"pmc": null,
"pmid": "28915720",
"pubdate": "2017-08-22",
"publication_types": "D016428:Journal Article",
"references": "25819643;23724867;26952546;26589768;27247226;19934295;27827313;27269937;25358689;27592805;25399552;26755520;25795410;23171508;24780173;25428503;19139884;19952320;27354485;20147741;17470865;26261262;26028255;26951310",
"title": "Pseudoprogression in microsatellite instability-high colorectal cancer during treatment with combination T cell mediated immunotherapy: a case report and literature review.",
"title_normalized": "pseudoprogression in microsatellite instability high colorectal cancer during treatment with combination t cell mediated immunotherapy a case report and literature review"
} | [
{
"companynumb": "US-CIPLA LTD.-2017US18076",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Raynaud's of the tongue following radiation alone or chemoradiotherapy (CRT) is a rare occurrence. The present study reports a case where typical symptoms and signs of Raynaud's phenomenon involving the tongue occurred ~18 months following CRT treatment in a 53-year-old female, who was a smoker prior to CRT with stage T2N2cM0 local-regional advanced stage IV oropharyngeal cancer. The patient was treated using cisplatin chemotherapy and intensity-modulated radiation with a dose of 70 Gray (Gy). The intermittent episodes of painful discoloration of the tongue were exacerbated due to the cold and emotional stress. No definite clinical or laboratory evidence of connective tissue disorder was identified. To the best of our knowledge, this is the first reported case of Raynaud's of the tongue following CRT without primary Raynaud's of the digits. The possible pathogenesis involving vascular and neural mechanism is discussed in the case report.",
"affiliations": "Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA.;Department of Radiation Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.",
"authors": "Mittal|Amit|A|;Mittal|Bharat B|BB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2016.1103",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "6(2)",
"journal": "Molecular and clinical oncology",
"keywords": "Raynaud's; chemotherapy; oropharynx; radiation; tongue",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "187-188",
"pmc": null,
"pmid": "28357090",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "22335764;20092952;1119826;6168223;22939802;23457400;22782008;12697923;8712862;2456930",
"title": "Raynaud's of the tongue following chemoradiation for squamous cell carcinoma of the oropharynx.",
"title_normalized": "raynaud s of the tongue following chemoradiation for squamous cell carcinoma of the oropharynx"
} | [
{
"companynumb": "US-TEVA-748037USA",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "1",
"druga... |
{
"abstract": "Chylous ascites is rarely observed in patients undergoing peritoneal dialysis Here, we present the occurrence of chyloperitoneum in a peritoneal dialysis patient disappeared immediately after discontinuation of calcium-antagonist.",
"affiliations": "Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.;Nephrology and Dialysis Unit, \"Pugliese-Ciaccio\" Hospital of Catanzaro, Italy.",
"authors": "Nicotera|Ramona|R|;Chiarella|Salvatore|S|;Placida|Giordano|G|;De Paola|Luciano|L|;D'Onofrio|Giuseppina|G|;Panzino|Maria Teresa|MT|;Panzino|Antonio|A|;Mileti|Salvatore|S|;Pinciaroli|Angela Rosa|AR|;Coppolino|Giuseppe|G|",
"chemical_list": "D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C060343:lercanidipine",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "35(4)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": "Chylous ascites; calcium-antagonist; chyloperitoneum ",
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D002121:Calcium Channel Blockers; D002915:Chylous Ascites; D004095:Dihydropyridines; D005260:Female; D006801:Humans; D008875:Middle Aged; D010531:Peritoneal Dialysis, Continuous Ambulatory",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30035445",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Possible role of Lercanidipine in Chiloperitoneum occurrence in CAPD: a case-report.",
"title_normalized": "possible role of lercanidipine in chiloperitoneum occurrence in capd a case report"
} | [
{
"companynumb": "IT-ACCORD-155494",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nDigoxin is a cardiac glycoside that is frequently prescribed in atrial fibrillation and heart failure. Symptoms such as nausea, hyperkalaemia, cardiac arrhythmias and cardiac arrest are seen in digoxin toxicity. The treatment focuses on reduction of digoxin absorption, prevention of hypokalaemia and hyperkalaemia, treatment of symptoms and, in severe toxicity, administration of digoxin antibodies.\n\n\nMETHODS\nA 73-year-old man with a history of extensive cardiac disease was seen 45 minutes after ingesting 20 mg of digoxin. The patient developed ventricular fibrillation within 3 hours of ingestion, before arrival of the digoxin antibodies. The patient passed away despite resuscitation and administration of an insufficient amount of digoxin antibodies.\n\n\nCONCLUSIONS\nThe national supply of digoxin antibodies in the Netherlands proved to be too limited for the treatment of a patient with severe digoxin toxicity. An increase in the supply, and central storage, of digoxin antibodies could promote faster administration of an adequate amount of the antibodies. Timely transportation to an extra corporeal membrane oxygenation centre should also be considered.",
"affiliations": "Tergooi, Hilversum.",
"authors": "van Rhee|K P|KP|;van Bentum|R|R|;van Keulen|K|K|;Kuypers|M I|MI|;Haak|M B|MB|",
"chemical_list": "D004077:Digoxin",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "161()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000368:Aged; D001145:Arrhythmias, Cardiac; D001281:Atrial Fibrillation; D004077:Digoxin; D017809:Fatal Outcome; D006323:Heart Arrest; D006801:Humans; D008297:Male; D009426:Netherlands; D014693:Ventricular Fibrillation",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "D839",
"pmc": null,
"pmid": "28224871",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A patient with severe digoxin toxicity.",
"title_normalized": "a patient with severe digoxin toxicity"
} | [
{
"companynumb": "NL-MYLANLABS-2017M1024537",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nAtLaS was a single-arm pilot study that demonstrated promising efficacy and safety of treatment simplification to a dual regimen with atazanavir/ritonavir + lamivudine in virologically suppressed HIV-positive patients. Here, we report data from the 144 week follow-up.\n\n\nMETHODS\nAt baseline, patients treated with a three-drug atazanavir/ritonavir-based regimen were switched to 300/100 mg of atazanavir/ritonavir plus 300 mg of lamivudine once daily. Major clinical events, laboratory parameters, neurocognitive performance, bone composition and body fat distribution were monitored. Treatment failure was defined as a discontinuation/switch of the regimen or virological failure (HIV-RNA >50 copies/mL in two consecutive determinations or a single level above 1000 copies/mL).\n\n\nRESULTS\nAfter 144 weeks, 9/40 (22.5%) treatment failures occurred, including two virological failures (Weeks 48 and 53, without resistance). A significant increase in the CD4 count was observed at Week 96 (+124 cells/mm(3); P = 0.002) and Week 144 (+94 cells/mm(3); P = 0.008). After 144 weeks, a significant increase in total cholesterol (+25 mg/dL; P = 0.001), HDL cholesterol (+6 mg/dL; P = 0.024) and LDL cholesterol (+12 mg/dL; P = 0.008) was observed, without any change in triglyceride levels, total cholesterol/HDL ratio or LDL/HDL ratio. A significant increase in the estimated glomerular filtration rate (+25 mL/min/1.73 m(2); P < 0.001) and lumbar spine T-score and Z-score (+0.2, P = 0.011; and +0.35, P = 0.001, respectively) and a decrease in trunk fat (-1.898 g; P = 0.005) were also observed. Neurocognitive function did not decline over time. Concerning safety, 10 moderate to severe adverse events were recorded in eight patients; overall seven cases of renal colic (possibly treatment related) were observed, leading to a discontinuation of treatment in two patients.\n\n\nCONCLUSIONS\nData from the 144 week follow-up suggested good long-term efficacy of the simplification strategy that was investigated, with rare virological failure and a potential for improvement of the CD4 count, renal function and bone mineral density. This strategy warrants further investigation in a randomized trial.",
"affiliations": "Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy massifab@alice.it.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Infectious Diseases Unit, Siena University Hospital, Siena, Italy.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.",
"authors": "Mondi|A|A|;Fabbiani|M|M|;Ciccarelli|N|N|;Colafigli|M|M|;D'Avino|A|A|;Borghetti|A|A|;Gagliardini|R|R|;Cauda|R|R|;De Luca|A|A|;Di Giambenedetto|S|S|",
"chemical_list": "D019380:Anti-HIV Agents; D019259:Lamivudine; D000069446:Atazanavir Sulfate; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkv037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "70(6)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": "antiviral; combined antiretroviral therapy; dual therapy",
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate; D018791:CD4 Lymphocyte Count; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D019438:Ritonavir; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "1843-9",
"pmc": null,
"pmid": "25885326",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression: 144 week follow-up of the AtLaS pilot study.",
"title_normalized": "efficacy and safety of treatment simplification to atazanavir ritonavir lamivudine in hiv infected patients with virological suppression 144 week follow up of the atlas pilot study"
} | [
{
"companynumb": "IT-CIPLA LTD.-2016IT02282",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Small bowel angioedema induced by angiotensin converting enzyme (ACE) inhibitors is a rare and often-unrecog- nized condition that presents with transient abdominal pain, nausea and vomiting. We report a case diagnosed in a 36 year-old female. Ultrasound and CT showed segmental small bowel wall thickening and straightening associated with marked submucosal edema and ascites. Laboratory tests only revealed mild leukocytosis. The patient improved spontaneously.",
"affiliations": "Hospital Infante D. Pedro - Centro Hospitalar de Baixo Vouga, Aveir, Portugal. mluisaooc@yahoo.com",
"authors": "Coelho|M L|ML|;Amaral|R|R|;Curvo-Semedo|L|L|;Caseiro-Alves|F|F|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D003287:Contrast Media",
"country": "Belgium",
"delete": false,
"doi": "10.5334/jbr-btr.84",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0302-7430",
"issue": "97(4)",
"journal": "JBR-BTR : organe de la Societe royale belge de radiologie (SRBR) = orgaan van de Koninklijke Belgische Vereniging voor Radiologie (KBVR)",
"keywords": null,
"medline_ta": "JBR-BTR",
"mesh_terms": "D000328:Adult; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D003287:Contrast Media; D003937:Diagnosis, Differential; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D007421:Intestine, Small; D011856:Radiographic Image Enhancement; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "100888280",
"other_id": null,
"pages": "239-41",
"pmc": null,
"pmid": "25603633",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Small bowel angioedema induced by angiotensin converting enzyme (ACE) inhibitor: US and CT findings.",
"title_normalized": "small bowel angioedema induced by angiotensin converting enzyme ace inhibitor us and ct findings"
} | [
{
"companynumb": "PT-RANBAXY-2015R1-93991",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENALAPRIL"
},
"drugadditional": "1",
... |
{
"abstract": "The objective was to describe the frequency, mode of presentation and characteristics of epilepsy in children with congenital hemiparesis (CH). It is a etrospective, descriptive and multicenter study, based on the collection of data from the clinical records of patients from 0 to 19 years with CH secondary to perinatal infarction in different centers of the community of Catalonia. A total of 310 children were included (55% males and 45% females), from a total of 13 centers in Catalonia. Average age of onset of the crises was 2 ± 1 year. Epilepsy was present in 29.5% (n = 76), among which the most frequent vascular subtype was arterial presumed perinatal ischemic stroke (51.3%), followed by neonatal arterial ischemic stroke (18.4%), periventricular venous infarction (15.8%), neonatal hemorrhagic stroke (10.5%) and neonatal cerebral sinovenous thrombosis (3.9%). Semiology of the most frequent seizures was motor focal in 82%, followed by focal motor with secondary bilateralization in 23%, focal discognitive in 13.5%, generalized by 2% and spasms in 6.5%. The 67.3% were controlled with monotherapy and the drugs used were valproate, levetiracetam or carbamazepine. The antecedent of electrical status during sleep was identified in 3 patients, all associated with extensive lesions that included the thalamus. Of the total number of children with epilepsy, 35% began with neonatal seizu res in the first 3 days of life. The 30% of children with perinatal stroke and CH present a risk of epilepsy during childhood. Children with ischemic strock have the highest risk, so they will require a follow-up aimed at detecting prematurely the epilepsy and start a treatment.",
"affiliations": "Servicio de Neuropediatría Hospital Sant Joan de Déu, Barcelona, España. E-mail: danielarevillaorias@hotmail.com.;Servicio de Neuropediatría Hospital Sant Joan de Déu, Barcelona, España.;Servicio de Neuropediatría Hospital Sant Joan de Déu, Barcelona, España.;Servicio de Neuropediatría, Hospital Valle de Hebron, Barcelona, España.;Neuropediatría, Hospital Parc Tauli, Barcelona, España.;Servicio de Neuropediatría Hospital Sant Joan de Déu, Barcelona, España.",
"authors": "Revilla Orías|M Daniela|MD|;Alonso|Xenia|X|;Campistol|Jaume|J|;Macaya|Alfons|A|;Escofet|Conchita|C|;Fons|Carmen|C|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D000077287:Levetiracetam; D014635:Valproic Acid",
"country": "Argentina",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7680",
"issue": "79 Suppl 3()",
"journal": "Medicina",
"keywords": "congenital hemiparesis; epilepsy; perinatal infarction",
"medline_ta": "Medicina (B Aires)",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002220:Carbamazepine; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000077287:Levetiracetam; D008297:Male; D010291:Paresis; D012189:Retrospective Studies; D012307:Risk Factors; D012640:Seizures; D013030:Spain; D020521:Stroke; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "0204271",
"other_id": null,
"pages": "6-9",
"pmc": null,
"pmid": "31603835",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Epilepsy in children with congenital hemiparesis secondary to perinatal ictus.",
"title_normalized": "epilepsy in children with congenital hemiparesis secondary to perinatal ictus"
} | [
{
"companynumb": "ES-PFIZER INC-2020114196",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "Oxaliplatin causes a wider variety of immediate hypersensitivity reactions than do other platin-based chemotherapeutics. Some resemble type 1 reactions that respond to desensitization. Others are atypical, possibly mast cell-independent cytokine release reactions refractory to desensitization. Given this variability, clinicians need an evidence-based strategy to personalize therapy for oxaliplatin-hypersensitive patients.\n\n\n\nTo develop a data-driven algorithm to optimize treatment of oxaliplatin-hypersensitive patients.\n\n\n\nWe retrospectively analyzed the baseline clinical characteristics, biomarkers, and reactions of 48 oxaliplatin-hypersensitive patients who received a total of 266 oxaliplatin desensitizations.\n\n\n\nWe characterized 4 endophenotypes: type 1, cytokine release, mixed, and either. A mean 40-fold increase in serum concentration of IL-6 helped define the cytokine release endophenotype. Younger patients were more likely to have a cytokine release endophenotype, whereas older patients were more likely to have a type 1 reaction. Skin testing was not informative for determining endophenotype or risk of reaction during desensitization, and did not associate with initial or desensitization grade of reaction. Patients with a history of atopy and an initial type 1 reaction responded to desensitization with antihistamine premedications, whereas nonatopic patients with the same initial reaction phenotype were more likely to convert to a cytokine release or mixed reaction during desensitization. We combined these reaction patterns with biomarker data and desensitization outcomes to construct an algorithm that helps tailor desensitization protocol design to meet individual patient needs.\n\n\n\nEndophenotyping oxaliplatin hypersensitivity reactions may help forecast desensitization outcomes and personalize treatment plans.",
"affiliations": "Division of Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.;The Ohio State University College of Medicine, Columbus, Ohio.;Division of Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.;Department of Adult Immunology-Allergy, Florence Nightingale Hospitals, Kadıkoy Medicine Center, Istanbul, Turkey.;Division of Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Electronic address: dsloane@bwh.harvard.edu.;Division of Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.",
"authors": "Silver|Jared|J|;Garcia-Neuer|Marlene|M|;Lynch|Donna-Marie|DM|;Pasaoglu|Gülden|G|;Sloane|David E|DE|;Castells|Marianna|M|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2020.02.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "8(5)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Colorectal cancer; Desensitization; Endophenotype; Hypersensitivity; Oxaliplatin",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000970:Antineoplastic Agents; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D006801:Humans; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012189:Retrospective Studies",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "1668-1680.e2",
"pmc": null,
"pmid": "32112926",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Endophenotyping Oxaliplatin Hypersensitivity: Personalizing Desensitization to the Atypical Platin.",
"title_normalized": "endophenotyping oxaliplatin hypersensitivity personalizing desensitization to the atypical platin"
} | [
{
"companynumb": "US-TEVA-2020-US-1510029",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo identify determinants of adverse outcomes in acute retinal necrosis (ARN), presenting characteristics and incidence rates of vision loss and ocular complications in a cohort of polymerase chain reaction (PCR)-positive eyes were analyzed.\n\n\nMETHODS\nRetrospective observational cohort study.\n\n\nMETHODS\nForty-one eyes of 36 patients with clinically diagnosed ARN, PCR-positive for herpes simplex virus or varicella zoster virus and evaluated between January 2002 and June 2013, were included. Main outcome measures included incidence rates of vision loss and retinal detachment (RD).\n\n\nRESULTS\nPresenting visual acuity was generally poor (20/50 to >20/200 in 27%; 20/200 or worse in 56%). The incidence rate of ≤20/200 was 0.66/eye-year (EY), (95% confidence interval [CI], 0.32/EY to 1.22/EY); the rate of light perception or no light perception vision was 0.07/EY (95% CI, 0.02/EY to 0.16/EY). During follow-up, 59% of eyes developed at least 1 RD (rate = 0.40/EY, 95% CI, 0.19/EY to 0.58/EY). Eyes with retinitis involving ≥25% of the retina at presentation detached at nearly 12 times the rate, as compared to those with <25% retinal involvement (0.70/EY vs 0.06/EY; P = .001). Development of an RD was the greatest determinant of adverse visual outcomes, with 4% of eyes, that had experienced at least 1 RD, achieving a best-corrected visual acuity of ≥20/40 compared to 53% of eyes that never detached (P = .0003).\n\n\nCONCLUSIONS\nPoor outcomes in ARN were common in this cohort. RD confers the greatest risk of incident vision loss, and once 25% or more of the retina is involved the risk of RD and visual loss increases significantly.",
"affiliations": "Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Veterans Affairs Boston Healthcare System, Jamaica Plain, Massachusetts. Electronic address: njbutler@gmail.com.;The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.;The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.;The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.;The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.;The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.;The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.",
"authors": "Butler|Nicholas J|NJ|;Moradi|Ahmadreza|A|;Salek|Sherveen S|SS|;Burkholder|Bryn M|BM|;Leung|Theresa G|TG|;Dunn|James P|JP|;Thorne|Jennifer E|JE|",
"chemical_list": "D004279:DNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajo.2017.05.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "179()",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004279:DNA, Viral; D015828:Eye Infections, Viral; D005260:Female; D005500:Follow-Up Studies; D006561:Herpes Simplex; D006563:Herpes Zoster Ophthalmicus; D014645:Herpesvirus 3, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D015882:Retinal Necrosis Syndrome, Acute; D012189:Retrospective Studies; D014792:Visual Acuity; D055815:Young Adult",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "179-189",
"pmc": null,
"pmid": "28501392",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Acute Retinal Necrosis: Presenting Characteristics and Clinical Outcomes in a Cohort of Polymerase Chain Reaction-Positive Patients.",
"title_normalized": "acute retinal necrosis presenting characteristics and clinical outcomes in a cohort of polymerase chain reaction positive patients"
} | [
{
"companynumb": "US-ALLERGAN-1728538US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": null... |
{
"abstract": "Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required.\n\n\nCONCLUSIONS\nThis report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms.",
"affiliations": "Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Clovis Oncology, San Francisco, California.;Stanford Cancer Institute, Stanford University, Stanford, California.;Stanford Cancer Institute, Stanford University, Stanford, California.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Clovis Oncology, San Francisco, California.;Massachusetts General Hospital, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Clovis Oncology, San Francisco, California.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. lvsequist@partners.org.",
"authors": "Piotrowska|Zofia|Z|;Niederst|Matthew J|MJ|;Karlovich|Chris A|CA|;Wakelee|Heather A|HA|;Neal|Joel W|JW|;Mino-Kenudson|Mari|M|;Fulton|Linnea|L|;Hata|Aaron N|AN|;Lockerman|Elizabeth L|EL|;Kalsy|Anuj|A|;Digumarthy|Subba|S|;Muzikansky|Alona|A|;Raponi|Mitch|M|;Garcia|Angel R|AR|;Mulvey|Hillary E|HE|;Parks|Melissa K|MK|;DiCecca|Richard H|RH|;Dias-Santagata|Dora|D|;Iafrate|A John|AJ|;Shaw|Alice T|AT|;Allen|Andrew R|AR|;Engelman|Jeffrey A|JA|;Sequist|Lecia V|LV|",
"chemical_list": "D000178:Acrylamides; D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000589977:rociletinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "United States",
"delete": false,
"doi": "10.1158/2159-8290.CD-15-0399",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2159-8274",
"issue": "5(7)",
"journal": "Cancer discovery",
"keywords": null,
"medline_ta": "Cancer Discov",
"mesh_terms": "D000178:Acrylamides; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D008175:Lung Neoplasms; D009154:Mutation; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "101561693",
"other_id": null,
"pages": "713-22",
"pmc": null,
"pmid": "25934077",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "16258065;18588508;17463250;18458038;25923549;25758528;25589191;25394791;25384085;25301631;25301630;24142049;23470965;24065147;24101047;25923550;19097774;20118985;20432502;21062933;21430269;21670455;22189618;22397650;22722830;22980976",
"title": "Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.",
"title_normalized": "heterogeneity underlies the emergence of egfrt790 wild type clones following treatment of t790m positive cancers with a third generation egfr inhibitor"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-48847GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"d... |
{
"abstract": "OBJECTIVE\nTo describe rare but important cerebrovascular complications of giant cell arteritis (GCA).\n\n\nMETHODS\nWe report a 59-year-old man who initially presented with vasculitis of the lower extremities. While on steroids, he developed strokes in multiple vascular territories. The conventional angiogram showed stenosis of bilateral carotid and vertebral vessels as they entered the dura. Temporal artery biopsy confirmed GCA. He began cyclophosphamide treatment, which stabilized his clinical course; however, this was switched to tocilizumab by an outside rheumatologist. Two months later, the patient had progression of vessel stenosis and suffered additional strokes. Despite interventions to augment cerebral perfusion, the infarctions continued to expand and the patient passed away.\n\n\nCONCLUSIONS\nThis case highlights several important features of strokes in GCA: the predilection for the dural entry point of cerebral blood vessels, the progression of disease despite steroids, and the need to quickly escalate treatment in these cases. As seen in our patient, however, this disease carries high morbidity and mortality and patients often have poor outcomes despite aggressive immunosuppression.",
"affiliations": "Department of Neurology, Mayo Clinic, Rochester, MN.",
"authors": "Cox|Benjamin C|BC|;Fulgham|Jimmy R|JR|;Klaas|James P|JP|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000237",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "24(4)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D018450:Disease Progression; D013700:Giant Cell Arteritis; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D020521:Stroke",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "139-141",
"pmc": null,
"pmid": "31246724",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent Stroke in Giant Cell Arteritis Despite Immunotherapy.",
"title_normalized": "recurrent stroke in giant cell arteritis despite immunotherapy"
} | [
{
"companynumb": "PHHY2019US181249",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "A 14-year-old female, presenting sudden and progressive holocraneal headache along with incoercible vomiting arrived to emergency room. Acute confusional state and meningoencephalitis syndrome where identified. Brain computed tomography-scan with normal results was performed. Lumbar puncture with crystal-clear cerebrospinal fluid was obtained: low glucose, elevated proteins and cell-count of 15/mm. China-Ink and Criptococcus neoformans culture both positive. Viral, lupus-anticoagulant, and HIV tests negative. Fluconazole 200 mg/kg/day, amphotericin-B 0.7 mg/kg/day, dexamethasone 1 mg/kg/day were prescribed. 48-h later evolved to cerebral edema, multiple-organ-failure and death. Hereby we present a Cryptococcus spp. infection case report, addressing the public health challenge and vulnerability of immunocompromised patients in Mexico.",
"affiliations": "Clínica de Enfermedad Cerebro Vascular; Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México; México.;Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México; México.;Departamento de Enseñanza, Hospital Psiquiátrico de Tampico, Tampico, Tamps.; Ciudad de México. México.;Departamento de Investigación Clínica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México. México.",
"authors": "Becerra-Pedraza|Luis Cuitláhuac|LC|;Martínez-Piña|Daniel Arturo|DA|;Calles-Carmona|Génesis Rocío|GR|;San-Juan|Daniel|D|",
"chemical_list": null,
"country": "Mexico",
"delete": false,
"doi": "10.24875/GMM.17002676",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-3813",
"issue": "153(7)",
"journal": "Gaceta medica de Mexico",
"keywords": "Cerebral cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; Headache; Immunocompetent; Meningoencefalic syndrome; Multiple organ failure",
"medline_ta": "Gac Med Mex",
"mesh_terms": "D000293:Adolescent; D020314:Central Nervous System Fungal Infections; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007121:Immunocompetence; D016921:Meningitis, Fungal; D008590:Meningoencephalitis; D008800:Mexico",
"nlm_unique_id": "0010333",
"other_id": null,
"pages": "911-914",
"pmc": null,
"pmid": "29414953",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Paciente inmunocompetente con criptococosis cerebral: reporte de un caso.",
"title_normalized": "paciente inmunocompetente con criptococosis cerebral reporte de un caso"
} | [
{
"companynumb": "MX-INFO-000586",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Immune thrombocytopenia can have several causes including the use of certain drugs. Thrombocytopenia has been documented as a rare adverse effect of some nonsteroidal antiinflammatory drugs (NSAIDs) including diclofenac, naproxen, and ibuprofen. However, only one previously documented case of meloxicam-associated thrombocytopenia has been reported in the literature. We describe an 84-year-old woman who developed a case of immune-mediated thrombocytopenia that was attributed to meloxicam therapy. The patient's platelet count decreased from a baseline of 267 × 10(3) /mm(3) to 2 × 10(3) /mm(3) 1 week after she received her first lifetime dose of meloxicam. She also experienced black stools and bruising that coincided with the meloxicam administration. The almost immediate onset of thrombocytopenia and symptoms after initiation of meloxicam, as well as the marked reduction in her platelet count, suggest an idiosyncratic reaction. According to the Hill criteria for assessing causality of adverse drug events, it is plausible that this reaction was due to meloxicam. Health care providers should be aware of the possibility of thrombocytopenia secondary to NSAID therapy including meloxicam. Immune thrombocytopenia can be life threatening if it is not identified and treated promptly. A thorough medication history is particularly important when patients present with unusual symptoms, with a focus on those drugs that have been recently initiated. Although thrombocytopenia is a rare adverse effect of NSAID therapy, it should be considered a potential cause in patients receiving these drugs who have signs and symptoms consistent with this blood dyscrasia.",
"affiliations": "Department of Pharmacy Practice, Temple University School of Pharmacy, Philadelphia, Pennsylvania.",
"authors": "Ranieri|Melissa M|MM|;Bradley|Elizabeth F|EF|;Simon|Allison B|AB|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D013843:Thiazines; D013844:Thiazoles; D000077239:Meloxicam",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1372",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "34(2)",
"journal": "Pharmacotherapy",
"keywords": "drug-induced; immune thrombocytopenia; meloxicam; nonsteroidal antiinflammatory drugs; thrombocytopenia",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005260:Female; D006801:Humans; D000077239:Meloxicam; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D013843:Thiazines; D013844:Thiazoles",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e14-7",
"pmc": null,
"pmid": "24214337",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Meloxicam-induced thrombocytopenia.",
"title_normalized": "meloxicam induced thrombocytopenia"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP016672",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELOXICAM"
},
"drugadditional"... |
{
"abstract": "Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been associated with serious urinary tract infections (UTIs) including pyelonephritis and urosepsis. The Food and Drug Administration (FDA) issued a label change to include this warning in December 2015 due to a small number of cases (n = 19) reported to the FDA Adverse Event Reporting System. Details of these cases are limited and none involved empagliflozin. To date, there has been no published literature comprehensively describing serious UTIs attributed to empagliflozin. We describe a case of septic shock due to Serratia marcescens pyelonephritis and bacteremia that required intensive care unit admission in a well-controlled, type 2 diabetic patient who had begun taking empagliflozin 2 months prior. The patient was treated successfully with intravenous antibiotics followed by oral ciprofloxacin. After discontinuation of empagliflozin and completion of antibiotic therapy, no subsequent UTIs were documented in the following 4 months.",
"affiliations": "1 Department of Pharmacy, Upstate University Hospital, Syracuse, NY, USA.;2 University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA.;3 Department of Pharmacy, Upstate University Hospital, Syracuse, NY, USA.",
"authors": "Kufel|Wesley D|WD|;Scrimenti|Ali|A|;Steele|Jeffrey M|JM|",
"chemical_list": "D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C570240:empagliflozin",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190016679760",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "30(6)",
"journal": "Journal of pharmacy practice",
"keywords": "empagliflozin; pyelonephritis; sodium–glucose cotransporter 2 inhibitor; urinary tract infection",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000368:Aged; D016470:Bacteremia; D001559:Benzhydryl Compounds; D003924:Diabetes Mellitus, Type 2; D005960:Glucosides; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D011704:Pyelonephritis; D016868:Serratia Infections; D012706:Serratia marcescens; D012772:Shock, Septic",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "672-675",
"pmc": null,
"pmid": "27876693",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Septic Shock Due to Serratia marcescens Pyelonephritis and Bacteremia in a Patient Receiving Empagliflozin.",
"title_normalized": "a case of septic shock due to serratia marcescens pyelonephritis and bacteremia in a patient receiving empagliflozin"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-081869",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationrout... |
{
"abstract": "Epithelioid sarcoma (ES) is an uncommon soft tissue neoplasm first described in 1970. It is a unique soft tissue neoplasm of adolescents and younger adults which usually presents as a subcutaneous and deep dermal mass in the distal portions of the extremities. The proximal-type variant of this rare soft tissue neoplasm was only recently reported. The proximal form typically arise in proximal extremities and in the deep parts of pelvis, perineum and genital tract. The proximal type variant has distinct histological characteristics and aggressive clinical course as compared to the distal ES. Inactivation of INI1 has been reported in both distal and proximal variants and can help to make the diagnosis. Furthermore, the proximal variant has a possible association with malignant rhabdoid neoplasm. We describe here a case of primary pleural ES of the proximal type and highlight its diagnostic and therapeutic challenges.",
"affiliations": "Section of Hematology/Oncology, Department of Medicine, West Virginia University School of Medicine, Morgantown, WV, USA.;Department of Medicine, West Virginia University School of Medicine, Morgantown, WV, USA.;Section of Molecular Pathology, Department of Pathology, West Virginia University School of Medicine, Morgantown, WV, USA.;Section of Molecular Pathology, Department of Pathology, West Virginia University School of Medicine, Morgantown, WV, USA.;Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA, USA.",
"authors": "Ahmad|Zeeshan|Z|;Stanazai|Qasim|Q|;Wright|Staphanie|S|;Smolkin|Matthew|M|;Ma|Patrick C|PC|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/tlcr.2019.09.16",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2218-6751",
"issue": "8(5)",
"journal": "Translational lung cancer research",
"keywords": "Epithelioid sarcoma (ES); primary pleural; proximal type; rare sarcoma",
"medline_ta": "Transl Lung Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "101646875",
"other_id": null,
"pages": "700-705",
"pmc": null,
"pmid": "31737506",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "11454997;15899790;19141382;9042279;18327208;16353216;5476785;12796375;27045049;27800093;19415960;12445750;24457248;23627453;23677068;10452506;19033866;23204785",
"title": "Primary pleural epithelioid sarcoma of the proximal type: a diagnostic and therapeutic challenge.",
"title_normalized": "primary pleural epithelioid sarcoma of the proximal type a diagnostic and therapeutic challenge"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-00037",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MESNA"
},
"drugad... |
{
"abstract": "Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use.\n\n\n\nWe did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed.\n\n\n\nBetween Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2·05, 95% CI 1·18-3·56; p=0·0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay.\n\n\n\nPlatelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice.\n\n\n\nThe Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health.",
"affiliations": "Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands.;Université Lille, Inserm U1171, Degenerative and Vascular Cognitive Disorders, CHU Lille, Department of Neurology, Lille, France.;Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.;Department of Neurology, Groene Hart Ziekenhuis, Gouda, Netherlands.;Sanquin Bloodbank, Amsterdam, Netherlands.;Sanquin Bloodbank, Amsterdam, Netherlands.;Department of Radiology, Academic Medical Centre, Amsterdam, Netherlands.;Department of Radiology, Academic Medical Centre, Amsterdam, Netherlands.;Department of Radiology, Academic Medical Centre, Amsterdam, Netherlands; Department of Biomedical Engineering and Physics, Academic Medical Centre, Amsterdam, Netherlands.;Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands.;Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands.;Clinical Research Unit, Academic Medical Centre, Amsterdam, Netherlands.;Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands. Electronic address: y.b.roos@amc.uva.nl.",
"authors": "Baharoglu|M Irem|MI|;Cordonnier|Charlotte|C|;Al-Shahi Salman|Rustam|R|;de Gans|Koen|K|;Koopman|Maria M|MM|;Brand|Anneke|A|;Majoie|Charles B|CB|;Beenen|Ludo F|LF|;Marquering|Henk A|HA|;Vermeulen|Marinus|M|;Nederkoorn|Paul J|PJ|;de Haan|Rob J|RJ|;Roos|Yvo B|YB|;|||",
"chemical_list": "D010975:Platelet Aggregation Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(16)30392-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "387(10038)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002543:Cerebral Hemorrhage; D005060:Europe; D005260:Female; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D017713:Platelet Transfusion; D020521:Stroke; D016896:Treatment Outcome",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "2605-2613",
"pmc": null,
"pmid": "27178479",
"pubdate": "2016-06-25",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial.",
"title_normalized": "platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy patch a randomised open label phase 3 trial"
} | [
{
"companynumb": "NL-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-56810BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPYRIDAMOLE"
},
... |
{
"abstract": "Heart transplant recipients represent a particularly vulnerable patient population to the novel coronavirus disease 2019 (COVID-19) due to chronic immunosuppression and high rates of comorbidities. Currently, data are limited and evidence to guide management of heart transplant recipients with COVID-19 is sparse. In this case report, we provide a summary of the current literature as well as an in-depth analysis of our clinical decision-making.\nA 67-year-old female who underwent cardiac transplantation 1 year prior was found to have acute hypoxic respiratory failure due to COVID-19. Her immunosuppressant medications were modulated with discontinuation of mycophenolate and titration of tacrolimus troughs with a goal of 6-10 ng/dL. She was administered supportive treatment including convalescent plasma, remdesivir, and dexamethasone, in addition to antibiotic treatment that resulted in resolution of her symptoms within a matter of days despite her precarious disposition.\nThis case demonstrates that it can be safe and efficacious to modulate immunosuppressant medications in cardiac transplant recipients in accordance with recommendations made by the International Society of Heart and Lung Transplantation. This case additionally demonstrates that aspects of the current literature regarding the management of COVID-19 can be safely extrapolated to cardiac transplant recipients. Providing supportive care with dexamethasone, remdesivir, and convalescent plasma as indicated can be beneficial in cardiac transplant recipients; although, the current literature regarding convalescent plasma and remdesivir is conflicting.",
"affiliations": "Department of Cardiology, University of Nevada, Las Vegas, 1800 W Charleston Blvd, Las Vegas, NV 89102, USA.;Department of Cardiology, University of Nevada, Las Vegas, 1800 W Charleston Blvd, Las Vegas, NV 89102, USA.;Department of Cardiology, University of California, San Diego Health, 200 West Arbor Drive, San Diego, CA 92103, USA.;Department of Cardiology, University of Nevada, Las Vegas, 1800 W Charleston Blvd, Las Vegas, NV 89102, USA.",
"authors": "Schreiber|Ariyon|A|https://orcid.org/0000-0003-2947-1095;Elango|Kalaimani|K|https://orcid.org/0000-0003-1562-2411;Hong|Kimberly|K|https://orcid.org/0000-0003-3293-138X;Ahsan|Chowdhury|C|https://orcid.org/0000-0001-5269-8488",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab217",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n34189399\n10.1093/ehjcr/ytab217\nytab217\nCase Report\nAcademicSubjects/MED00200\nCardiac transplant recipient with COVID-19 induced acute hypoxic respiratory failure: a case report\nhttps://orcid.org/0000-0003-2947-1095\nSchreiber Ariyon 1\nhttps://orcid.org/0000-0003-1562-2411\nElango Kalaimani 1\nhttps://orcid.org/0000-0003-3293-138X\nHong Kimberly 2\nhttps://orcid.org/0000-0001-5269-8488\nAhsan Chowdhury 1\n1 Department of Cardiology, University of Nevada, Las Vegas, 1800 W Charleston Blvd, Las Vegas, NV 89102, USA\n2 Department of Cardiology, University of California, San Diego Health, 200 West Arbor Drive, San Diego, CA 92103, USA\nPellicori Pierpaolo Handling Editor\nRusso Domitilla Editor\nCosmi Deborah Editor\nNgo Linh Editor\nAhmed Nida Editor\nThe first two authors Ariyon Schreiber and Kalaimani Elango shared co-first authorship and contributed equally to the study.\n\nCorresponding author. Tel: +1 714 309 5603, Email: ariyon.schreiber@unlv.edu\n6 2021\n26 6 2021\n26 6 2021\n5 6 ytab21712 5 2021\n30 9 2020\n10 11 2020\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nHeart transplant recipients represent a particularly vulnerable patient population to the novel coronavirus disease 2019 (COVID-19) due to chronic immunosuppression and high rates of comorbidities. Currently, data are limited and evidence to guide management of heart transplant recipients with COVID-19 is sparse. In this case report, we provide a summary of the current literature as well as an in-depth analysis of our clinical decision-making.\n\nCase summary\n\nA 67-year-old female who underwent cardiac transplantation 1 year prior was found to have acute hypoxic respiratory failure due to COVID-19. Her immunosuppressant medications were modulated with discontinuation of mycophenolate and titration of tacrolimus troughs with a goal of 6–10 ng/dL. She was administered supportive treatment including convalescent plasma, remdesivir, and dexamethasone, in addition to antibiotic treatment that resulted in resolution of her symptoms within a matter of days despite her precarious disposition.\n\nDiscussion\n\nThis case demonstrates that it can be safe and efficacious to modulate immunosuppressant medications in cardiac transplant recipients in accordance with recommendations made by the International Society of Heart and Lung Transplantation. This case additionally demonstrates that aspects of the current literature regarding the management of COVID-19 can be safely extrapolated to cardiac transplant recipients. Providing supportive care with dexamethasone, remdesivir, and convalescent plasma as indicated can be beneficial in cardiac transplant recipients; although, the current literature regarding convalescent plasma and remdesivir is conflicting.\n\nCOVID-19\nCardiac transplantation\nImmunosuppressant medications\nCase report\n==== Body\nLearning points\n\nModifying immunosuppressant agents in line with recommendations made by International Society of Heart and Lung Transplantation can be safe and efficacious.\n\nDue to the lack of data regarding management of coronavirus disease 2019 infection in cardiac transplant patients, cautious extrapolation of the current literature may be made.\n\nProviding supportive care with dexamethasone, remdesivir, antibiotic therapy, and convalescent plasma as indicated can be beneficial in cardiac transplant recipients; although, the current literature regarding convalescent plasma is conflicting.\n\nIntroduction\n\nHeart transplant recipients represent a particularly vulnerable patient population to coronavirus disease 2019 (COVID-19) because of chronic immunosuppression and high rates of comorbidities.1,2 Due to impaired immune defences from both underlying disease and treatment, immunocompromised patients with viral respiratory infections are at increased risk of more severe infection and increased rates of bacterial and fungal superinfection compared with their immunocompetent counterparts.3 Data regarding mortality in solid organ transplant patients and concomitant COVID-19 infection have been found to be similar to the general population; however, data are conflicting.4–6 Here, we provide a case report and discussion of a patient who previously underwent a cardiac transplantation and was found to be in acute hypoxic respiratory failure due to COVID-19.\n\nTimeline\n\n6 days prior to admission\tPatient began experiencing symptoms of coronavirus disease 2019 (COVID-19) infection\t\n4 days prior to admission\tPatient found to be COVID-19 positive\t\nHospital Day 1\tPatient having worsening symptoms of COVID-19 infection, requiring oxygen and hospitalization. Patient started on Intravascular fluids as well as supportive management for COVID-19 including convalescent plasma\t\nHospital Day 2\tPatient started on remdesivir. Her immunosuppressant regimen was adjusted in line with the International Society of Heart and Lung Transplantation\t\nHospital Day 6\tPatient clinically improving significantly not requiring oxygen\t\nHospital Day 7\tPatient was safely discharged home with instructions to continue isolation and follow-up with her primary and transplant physician to discuss the possibility of restarting her home immunosuppressant regimen\t\n\nCase presentation\n\nA 67-year-old female with a prior history of cardiac transplant 1 year prior, on an immunosuppressant regimen, presented to University Medical Center (UMC) with worsening shortness of breath. Her symptoms of fever, headaches, and myalgias had started 6 days prior. Two days later, she was seen in clinic and diagnosed with COVID-19. At that time, she was paucisymptomatic and was sent home with over the counter medications. Her immunosuppressive regimen included mycophenolate 250 mg twice daily and tacrolimus 9 mg daily. On the day of admission to UMC, her symptoms of cough and dyspnoea worsened acutely. Her dyspnoea had become so severe that she was unable to walk around her home or take care of her activities of daily living.\n\nIn the emergency room, she was found to be dyspnoeic at rest requiring 4–5 L per minute nasal cannula to maintain saturations >90%. Her physical exam was unremarkable other than ‘mildly distant heart sounds, and globally diminished breath sounds, no rales, or wheezing noted’.\n\nLabs were drawn that demonstrated leukopenia (2.7 k/mm3), lymphocytopenia (absolute lymphocyte count 0.72 k/mm3), and elevated creatinine (1.67 mg/dL). Furthermore, she was found to have elevated inflammatory markers (Table 1). Since the D-dimer was mildly elevated (0.62 mg/L), she was started on a prophylactic dose of enoxaparin 40 mg twice daily. Repeat testing confirmed COVID-19 infection. Troponins were negative. Brain natriuretic peptide (BNP) was elevated 136 pg/mL. Blood and respiratory cultures were drawn that demonstrated no growth throughout her admission.\n\nTable 1 Laboratory tests throughout admission\n\nLaboratory findings\tReference\tDay 1\tDay 3\tDay 5\tDay 6\t\nFerritin (ng/mL)\t7.0–271\t207\t225\t161\t139\t\nD-dimer (mg/L)\t<0.49\t0.41\t0.62 (H)\t0.52 (H)\t0.61 (H)\t\nC-reactive protein (mg/L)\t<3\t68.4(H)\t20.2(H)\t—\t3.1 (H)\t\nLactate dehydrogenase (U/L)\t125–243\t426 (H)\t437(H)\t—\t320 (H)\t\nProcalcitonin (ng/mL)\t<0.04\t0.06 (H)\t—\t—\t<0.04\t\nTroponin I (ng/mL)\t0.02–0.04\t<0.006\t—\t—\t—\t\nCreatinine (mg/dL)\t0.55–1.30\t1.67 (H)\t1.25\t1.18\t1.17\t\nB-type natriuretic peptide (pg/mL)\t<99\t136 (H)\t—\t—\t—\t\n\nChest X-ray demonstrated new increased density in the right lower lung concerning for infiltrate as well as central vascular prominence (Figure 1). A chest computed tomography (CT) was ordered to evaluate her developing COVID-19 pneumonia (Figure 2). Chest CT demonstrated diffuse peripheral and lower lung predominant ground-glass opacities, with some underlying septal thickening. Transthoracic echocardiogram demonstrated a normal left ventricular ejection fraction 55–60% and normal right ventricular systolic function.\n\nFigure 1 Left is from hospital admission Day 1 and right is from hospital admission Day 6 on completing course of treatment.\n\nFigure 2 (A) Computed tomography scan mid-thorax; (B) computed tomography scan of mid-thorax; (C) computed tomography scan base of thorax.\n\nShe was admitted to the coronary care unit because of her history of heart transplant and concern for progression of her acute hypoxic respiratory failure given her COVID-19 status. The case was discussed with infectious disease who initially held remdesivir given her elevated creatinine. She was instead given convalescent plasma, dexamethasone, and started on empiric antibiotics for possible community-acquired pneumonia. Clinically she appeared dehydrated; maintenance fluids were thus administered and resulted in improvement of her renal function back to baseline. The very next day, she was started on a course of remdesivir for 5 days.\n\nMycophenolate mofetil was stopped in line with recommendations from the International Society of Heart and Lung Transplantation (ISHLT). Initial tacrolimus trough level was found to be supratherapeutic (12.5 ng/mL), so it was initially held as well. Throughout the course of her admission, her renal function improved and her tacrolimus levels were adjusted to goal target of 6–10 ng/mL. Her leukopenia resolved; however, she continued to have a persistent lymphocytopenia consistent with her COVID-19 infection. Inflammatory markers trended downwards (Table 1).\n\nShe completed her courses of remdesivir and empiric antibiotics, and was weaned from oxygen completely. Repeat chest X-ray demonstrated significant improvement (Figure 1). She was discharged home with instructions to complete 20 days of isolation per recommendations by infectious disease. She was additionally instructed to follow-up with her primary care and transplant physicians to discuss restarting her home regimen of mycophenolate mofetil. She was discharged with dexamethasone 6 mg daily and tacrolimus extended release 8 mg daily.\n\nDiscussion\n\nHerein, we report a case of an immunosuppressed heart transplant recipient who was found to be in acute hypoxic respiratory failure due to a COVID-19 infection. Due to her worsening clinical picture, she was started on a number of supportive measures in addition to titration of her immunosuppressant medications to help enhance her recovery. The case highlights a possible treatment strategy for patients with COVID-19 in the setting of an immunocompromised transplant recipient.\n\nIt is not uncommon to adjust immunosuppressant medications in the setting of viral infections.7 According to the guidance by the ISHLT, at this time there is no evidence to guide decisions regarding the use of COVID-19 strategies specifically in patients with thoracic transplant.8 A specific treatment for COVID-19 remains unavailable; therefore, the initial clinical management is based on supportive care including antibiotic therapy, oxygen supply, pausing of mycophenolate as described in ‘Guidance for cardiothoracic transplant and ventricular assist device centers regarding the SARS CoV-2 pandemic by the ISHLT’, and transition from sirolimus to tacrolimus; though specific data are lacking at this time.9,10\n\nResults of a systematic review of SARS-CoV-1 highlights two in vitro studies that showed a potential benefit to tacrolimus by demonstrating that cell lines treated with tacrolimus inhibited viral replication of SARS-CoV-1 and resulted in a reduction of viral titres to undetectable levels.11 Tacrolimus has been found to not only inhibit lymphocyte activation, but to also effectively down-regulate the infiltration of inflammatory cells, which may be beneficial in the treatment of COVID-19.12,13 Mycophenolate, on the other hand, has been associated with more viral load and even fatal disease in in vivo studies.14 Additionally, mycophenolate has a number of drug–drug interactions that may complicate recovery.\n\nDue to the lack of evidence to guide decision-making regarding the use of SARS-CoV-2 treatment strategies in patients with thoracic transplant, the ISHLT recommends careful extrapolation of current published data to help guide treatment in heart transplant recipients with concomitant SARS-CoV-2 infection. In accordance, we carefully extrapolated recommendations from the COVID-19 Guidelines Recommendation Panel of the National Institute of Health, providing our patient with a number of supportive measures including dexamethasone and remdesivir. Although we administered remdesivir, the World Health Organization has recently issued a conditional recommendation against its use in hospitalized patients, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients. At the time of treatment, the COVID-19 Guidelines Panel was recommending for the use of convalescent plasma. Although we administered convalescent plasma, the COVID-19 guidelines panel recently updated their guidelines regarding convalescent plasma recommending against its use. Additionally, we adjusted her immunosuppressive medications in accordance with ISHLT’s recommendations allowing her to mount an inflammatory response without triggering significant inflammatory storm or acute rejection. Additionally, our patient’s D-dimer was elevated throughout her admission; however, she was not started on therapeutic anticoagulation because it was felt that the risks outweighed the benefit given her mild elevation in D-dimer. Instead, she was started on prophylactic enoxaparin 40 mg twice daily. Because of the prognostic role troponin and BNP play in COVID-19, these laboratories were drawn, however, were found to be unremarkable and only mildly elevated.15 These measures led to her clinical improvement and ultimately a positive outcome despite her precarious disposition.\n\nIn conclusion, more literature is required to determine if modulating immunosuppressant medications, as aligned with ISHLT’s recommendations, in heart transplant recipients experiencing acute hypoxic respiratory failure due to COVID-19 is safe and efficacious.\n\nLead author biography\n\nAriyon Schreiber performed his undergraduate education at the University of California, San Diego in Biochemistry and Cell Biology. He attended medical school in Michigan at Oakland University-William Beaumont School of Medicine. Currently, he is training in internal medicine at the University of Nevada, Las Vegas. His current research interests include COVID-19 and cardiovascular disease.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSupplementary Material\n\nytab217_Supplementary_Data Click here for additional data file.\n\nAcknowledgements\n\nThe authors thank Dr. Yassin Naga, Dr. Christopher Nguyen, Dr. Brooke Lentz, Dr. Matthew Klinka, Dr. Jimmy Diep, and Jacky Schreiber.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n==== Refs\nReferences\n\n1 Latif F , FarrMA, ClerkinKJ, HabalMV, TakedaK, NakaY et al Characteristics and outcomes of recipients of heart transplant with coronavirus disease 2019. JAMA Cardiol 2020;5 :e202159.\n2 Singhvi A , BarghashM, LalaA, MitterSS, ParikhA, OliverosE et al Challenges in heart transplantation during COVID-19: a single-center experience. J Heart Lung Transplant 2020;39 :894–903.32891266\n3 Manuel O , EstabrookM; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019;33 :e13511.30817023\n4 Rinaldi M , BartolettiM, BussiniL, PancaldiL, PascaleR, ComaiG et al COVID-19 in solid organ transplant recipients: no difference in survival compared to general population. Transpl Infect Dis 2021;23 :e13421.32779808\n5 Miarons M , Larrosa-GarcíaM, García-GarcíaS, Los-ArcosI, MoresoF, BerasteguiC et al ; on behalf of the Vall d’Hebron COVID-19 Working Group. COVID-19 in solid organ transplantation: a matched retrospective cohort study and evaluation of immunosuppression management. Transplantation 2021;105 :138–150.32941394\n6 Kates OS , HaydelBM, FlormanSS, RanaMM, ChaudhryZS, RameshMS et al COVID-19 in solid organ transplant: a multi-center cohort study. Clin Infect Dis 2020;ciaa1097. doi:10.1093/cid/ciaa1097.32766815\n7 Kotton CN , KumarD, CaliendoAM, HuprikarS, ChouS, Danziger-IsakovL et al ; The Transplantation Society International CMV Consensus Group. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102 :900–931.29596116\n8 Lee H , MantellBS, RichmondME, LawSP, ZuckermanWA, AddonizioLJ et al Varying presentations of COVID-19 in young heart transplant recipients: a case series. Pediatr Transplant 2020;24 :e13780.32542914\n9 Mathies D , RauschningD, WagnerU, MuellerF, MaibaumM, BinnemannC et al A case of SARS-CoV-2 pneumonia with successful antiviral therapy in a 77-year-old man with a heart transplant. Am J Transplant 2020;20 :1925–1929.32319218\n10 Aslam S , GrossiP, TeutebergJ, AdlerE, FarreroM, FrigerioM et al Guidance for Cardiothoracic Transplant and Ventricular Assist Device Centers Regarding the SARS CoV-2 Pandemic. International Society of Heart & Lung Transplantation. 2020.\n11 Russell B , MossC, GeorgeG, SantaolallaA, CopeA, PapaS et al Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. Ecancermedicalscience 2020;14 :1022.32256705\n12 Kobashigawa JA , MillerLW, RussellSD, EwaldGA, ZuckerMJ, GoldbergLR et al ; the Study Investigators. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant 2006;6 :1377–1386.16686761\n13 Pereira R , MedeirosYS, FrödeTS. Antiinflammatory effects of tacrolimus in a mouse model of pleurisy. Transpl Immunol 2006;16 :105–111.16860713\n14 Allison AC , EuguiEM. Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation. Transplant Proc 1994;26 :3205–3210.7998117\n15 Arcari L , LucianiM, CacciottiL, MusumeciMB, SpuntarelliV, PistellaE et al Incidence and determinants of high-sensitivity troponin and natriuretic peptides elevation at admission in hospitalized COVID-19 pneumonia patients. Intern Emerg Med 2020;15 :1467–1476.32986136\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(6)",
"journal": "European heart journal. Case reports",
"keywords": "COVID-19; Cardiac transplantation; Case report; Immunosuppressant medications",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytab217",
"pmc": null,
"pmid": "34189399",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "7998117;32941394;32402056;16686761;32891266;32256705;16860713;32986136;32779808;30817023;29596116;32319218;32542914;32766815",
"title": "Cardiac transplant recipient with COVID-19 induced acute hypoxic respiratory failure: a case report.",
"title_normalized": "cardiac transplant recipient with covid 19 induced acute hypoxic respiratory failure a case report"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK067014",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditiona... |
{
"abstract": "Immunotherapy is an effective treatment option for gynecological malignancies. Radiologists dealing with gynecological patients undergoing treatment with immune checkpoint inhibitors should be aware of unconventional immune-related imaging features for the evaluation of tumor response and immune-related adverse events. In this paper, immune checkpoint inhibitors used for gynecological malignancies and their mechanisms of action are briefly presented. In the second part, patterns of pseudoprogression are illustrated, and different forms of immune-related adverse events are discussed.",
"affiliations": "UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. benedetta.gui@policlinicogemelli.it.;Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy.;UOC Ginecologia Oncologica, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Istituto di Ginecologia e Ostetricia, Università Cattolica del Sacro Cuore, Rome, Italy.;UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;UOC Ginecologia Oncologica, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.",
"authors": "Russo|Luca|L|0000-0002-0495-7462;Avesani|Giacomo|G|0000-0001-9926-760X;Gui|Benedetta|B|0000-0002-5130-2100;Trombadori|Charlotte Marguerite Lucille|CML|0000-0002-1238-9688;Salutari|Vanda|V|0000-0002-9420-7146;Perri|Maria Teresa|MT|0000-0002-0222-656X;Di Paola|Valerio|V|0000-0003-0422-4792;Rodolfino|Elena|E|0000-0002-9382-6252;Scambia|Giovanni|G|0000-0003-2758-1063;Manfredi|Riccardo|R|0000-0003-4428-4554",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "Korea (South)",
"delete": false,
"doi": "10.3348/kjr.2020.1299",
"fulltext": "\n==== Front\nKorean J Radiol\nKorean J Radiol\nKJR\nKorean Journal of Radiology\n1229-6929\n2005-8330\nThe Korean Society of Radiology\n\n34047505\n10.3348/kjr.2020.1299\nGenitourinary Imaging\nReview Article\nImmunotherapy-Related Imaging Findings in Patients with Gynecological Malignancies: What Radiologists Need to Know\nhttps://orcid.org/0000-0002-0495-7462\nRusso Luca 1\nhttps://orcid.org/0000-0001-9926-760X\nAvesani Giacomo 1\nhttps://orcid.org/0000-0002-5130-2100\nGui Benedetta 1\nhttps://orcid.org/0000-0002-1238-9688\nTrombadori Charlotte Marguerite Lucille 2\nhttps://orcid.org/0000-0002-9420-7146\nSalutari Vanda 3\nhttps://orcid.org/0000-0002-0222-656X\nPerri Maria Teresa 4\nhttps://orcid.org/0000-0003-0422-4792\nDi Paola Valerio 1\nhttps://orcid.org/0000-0002-9382-6252\nRodolfino Elena 1\nhttps://orcid.org/0000-0003-2758-1063\nScambia Giovanni 34\nhttps://orcid.org/0000-0003-4428-4554\nManfredi Riccardo 12\n1 UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.\n2 Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy.\n3 UOC Ginecologia Oncologica, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.\n4 Istituto di Ginecologia e Ostetricia, Università Cattolica del Sacro Cuore, Rome, Italy.\nCorresponding author: Benedetta Gui, MD. UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy. benedetta.gui@policlinicogemelli.it\n8 2021\n20 5 2021\n22 8 13101322\n14 8 2020\n26 1 2021\n05 3 2021\nCopyright © 2021 The Korean Society of Radiology\n2021\nThe Korean Society of Radiology\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nImmunotherapy is an effective treatment option for gynecological malignancies. Radiologists dealing with gynecological patients undergoing treatment with immune checkpoint inhibitors should be aware of unconventional immune-related imaging features for the evaluation of tumor response and immune-related adverse events. In this paper, immune checkpoint inhibitors used for gynecological malignancies and their mechanisms of action are briefly presented. In the second part, patterns of pseudoprogression are illustrated, and different forms of immune-related adverse events are discussed.\n\nCheckpoint inhibitors\nPseudoprogression\nAdverse drug event\nGynaecological oncology\n==== Body\nINTRODUCTION\n\nGynecological malignancies, such as cervical, endometrial, and ovarian cancers, are common. In 2012, cervical cancer was the fourth most frequently diagnosed cancer in female, with 527600 new cases [1]. Instead, for endometrial and ovarian cancers, 319600 and 239000 new cases were registered, respectively [2]. An increase in the prevalence of ovarian cancer is expected by 2035, which accounts for 371000 (+ 55%) new cases and 254000 (+ 67%) new deaths [2].\n\nAn increase in incidence and mortality must be addressed as an unmet medical need for gynecological patients. Despite advances in surgery, radiation, and chemotherapy, the prognosis for advanced stages of gynecological disease remains poor [34].\n\nDuring the last decade, immunotherapy has revolutionized the field of oncology and has assumed an important role as a standard treatment for several malignancies. The use of immunotherapy has rapidly increased for solid tumor treatment because of its satisfactory results in clinical trials. In 2011, an immune checkpoint inhibitor (ICI) was first approved for the treatment of metastatic melanoma [5]. Since then, ICIs have provided a successful therapeutic option for several solid tumors, including renal cell carcinoma, non-small cell lung cancer (NSCLC), non-Hodgkin's lymphoma, urothelial carcinoma, and hepatocellular carcinoma [6789]. In this scenario, immunotherapy was thought to be valuable for gynecological malignancies; therefore, several clinical trials have been initiated in recent years [1011].\n\nIn 2019, pembrolizumab (an anti-programmed cell death protein [PD]-1 agent), in combination with lenvatinib, was approved by the Food and Drug Administration (FDA) for the treatment of advanced endometrial cancer [12]. Currently, several other randomized controlled trials of ICIs are ongoing in Europe (ClinicalTrials.gov Identifier: NCT03737643; NCT03786081; NCT04199104).\n\nGiven the growing use of ICIs in gynecologic oncology, radiologists need to develop an increased understanding of imaging findings related to ICIs in daily clinical practice beyond the setting of treatment response evaluation for clinical trials.\n\nThis review aims to provide an overview of the most leveraged immunotherapy mechanisms for gynecological cancer and a practical guide for its action during routine follow-up using diagnostic imaging. In particular, we focused on the evaluation of pseudoprogression tumor response patterns (included in the Response Evaluation Criteria in Solid Tumors [iRECIST]) and the imaging findings of the immune-related adverse events (irAEs), which require a prompt diagnosis to establish a specific treatment [13].\n\nMechanisms of Action of Immune Checkpoint Inhibitors\n\nThe importance of intact immune surveillance in controlling the outgrowth of neoplastic transformations has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissues and a favorable prognosis for various malignancies. In particular, the presence of CD8+ T cells and the CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) ratio correlates with improved prognosis and long-term survival of patients with solid malignancies, such as ovarian, colorectal, and pancreatic cancer, hepatocellular carcinoma, malignant melanoma, and renal cell carcinoma [14].\n\nVarious cancer immunotherapy methods, including cancer-specific and non-specific immune stimulants, have been developed. For gynecological malignancies, the most frequently used immunotherapeutic agents are ICIs, as shown in Table 1.\n\nICIs represent an emerging class of non-specific immunotherapy drugs that interfere with immune checkpoint pathways for T-cells [15]. ICIs have been designed to improve anti-cancer immunity. Their targets are molecules that act as checkpoints for balancing immune response regulation. Under physiological conditions, immune checkpoints are fundamental to maintaining self-tolerance and preventing immune over-activation and host-tissue damage. However, tumor cells take advantage of the mechanisms of host immune system recognition. The goal of an ICI is to reduce immune checkpoint activity to enhance anti-cancer immunity and induce a targeted immune response against cancer cells.\n\nThe most relevant immune checkpoints are targets of ICIs: cytotoxic T lymphocyte-associated Protein-4 (CTLA-4), PD-1, and programmed death ligand 1 (PD-L1). CTLA-4 and PD-1 belong to the same CD28 family of T-cell receptors and act as negative regulators of immune responses; hence, the suppression of their activity leads to immune system activation and the mounting of the immune response (Fig. 1) [10]. PD-L1 is a ligand of PD-1 expressed by tumor cells.\n\nPD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1, which is expressed on the cell surface of activated T-cells under healthy conditions, is to downregulate unwanted or excessive immune responses, including autoimmune reactions [16]. PD-1 is a transmembrane receptor normally expressed on the surface of activated T-cells, Tregs, activated B cells, and natural killer cells. PD-L1 is expressed in different tissues and cancer cells. Anti-PD-1 and anti-PD-L1 antibodies act during the effector phase of the T-cell response [17]. During this phase, PD-1 binds to PD-L1, resulting in T-cell downregulation [18]. In a tumor environment, tumor cells expressing PD-L1 can bind PD-1 receptors of T-cells, inducing T-cell immune tolerance, energy, and apoptosis, which leads to the downregulation of the host immune response [19].\n\nMonoclonal antibodies directed against PD-1 or PD-L1 have been demonstrated to reverse and/or prevent tumor-associated T-cell exhaustion, which promotes the activation of tumor detection and destruction [20].\n\nSeveral immunohistological studies have demonstrated elevated expression levels of PD-1 and PD-L1 in gynecological malignancies, with estimated expression rates of PD-1 of 75.2% in endometrial cancer, 66.9% in epithelial ovarian cancer, and 63.1% in cervical cancer [19]. The estimated PD-L1 expression level was between 67% and 100% in endometrial cancer [10]. PD-L1 expression may represent an actionable target, but it does not directly translate into treatment response, as studies have shown that it is important to highlight that treatment responses may also occur regardless of tumor PD-L1 status [14].\n\nThere is a strong theoretical rationale for adopting immunotherapy in ovarian cancer: the tumor presents with a high PD-L1 expression, an elevated number of TILs, and a neo-antigen load, particularly when harboring homologous recombination deficiency or microsatellite instability-high (MSI-H) [21].\n\nNevertheless, no immunotherapy agent has been approved so far for ovarian cancer because of the disappointing results of clinical trials [2223]. However, several phase III studies are ongoing to clarify the role of immunotherapy in ovarian cancer (ClinicalTrials.gov NCT03737643; NCT03740165).\n\nRegarding cervical cancer, there is a strong rationale for immunotherapy due to the role of the tumor immune environment in cervical HPV-associated tumors. In addition, the tumor tissues of HPV-associated cancers show high PD-1 expressing CD8+ T cells [24]. Pembrolizumab monotherapy demonstrated a long-lasting antitumor activity and manageable safety in patients with advanced cervical cancer. At ASCO in 2016, the preliminary results of the KEYNOTE-028 study on cervical cancer patients were as follows: 17% objective responses and OS of 9 months were reported for pembrolizumab monotherapy in a population of 24 advanced/recurrent cervical cancer patients pre-treated with platinum-based chemotherapy (96%), radiotherapy (92%), and bevacizumab (42%); 38% of the patients received pembrolizumab at least as 4th line chemotherapy [25]. A subsequent phase 2 study, KEYNOTE-158, enrolled 98 patients with pre-treated advanced cervical cancers who received pembrolizumab as a single agent. The overall response rate (ORR) was 13.3%; three patients had CR and 10 patients had PR [26]. Based on these results with pembrolizumab, the US FDA granted an accelerated approval of pembrolizumab for patients with advanced PD-L1-positive cervical cancer who experienced progression during or after chemotherapy.\n\nRecently, the results of a phase 1/2 study evaluating nivolumab 240 mg every 2 weeks for vulvar, vaginal, and cervical tumors were published. The cervical cancer patients demonstrated promising clinical activity with a good toxicity profile (ORR 26.3%; progression-free survival 5.5 months) [27].\n\nIn endometrial cancer cells, PD-L1 and PD-L2 are considerably overexpressed, which represents the highest expression among gynecologic cancers as well as tumor-infiltrating CD4+ and CD8+ T cells [28]. In addition, some endometrial cancer subtypes (e.g., POLE mutant/hypermutated and MSI-H) express a high tumor mutational burden; therefore, they are highly immunogenic [29].\n\nApproximately 20–30% of patients with endometrial cancer have MSI-H disease and are eligible for checkpoint inhibitor monotherapy. The GARNET trial (ClinicalTrials.gov NCT02715284) demonstrated promising response rates of 42% with dostarlimab (a PD-1 inhibitor) in patients with recurrent or advanced endometrial cancer who had progression during or after platinum-based chemotherapy and had MSI-H tumors [30].\n\nPembrolizumab provides long-lasting responses in patients with MSI-H cancers and is approved in the US and Japan for the treatment of MSI-H advanced solid tumors. Recently, the combination of pembrolizumab and lenvatinib has been approved by the FDA for advanced endometrial carcinoma without MSI-H or mismatch repair-deficient disease [12]. In a recently published trial, lenvatinib plus pembrolizumab showed promising antitumor activity regardless of MSI status in patients with advanced endometrial carcinoma who had experienced disease progression after prior systemic therapy [31].\n\nTumor Response Evaluation and Pseudoprogression (RECIST and iRECIST)\n\nRECIST represents a set of guidelines for tumor response evaluation, and they were first published in 2000 and revised in 2009 as RECIST 1.1 [32]. They represent standard criteria for clinical trial evaluation of tumor response after therapy, but they are not always efficient for patients treated with immunotherapy. Immunotherapy may result in an initial apparent tumor burden increase, which is related to the immune response to tumors rather than cancer cell growth [33]. However, after an initial increase in the total tumor burden or the appearance of new lesions, a patient may experience a response or a reduction in the total tumor burden [34]. This phenomenon is called pseudoprogression and is mainly due to inflammatory cell infiltration and swelling as a result of enhanced immunity against cancer cells. Therefore, radiologists who perform imaging studies of gynecologic cancer patients undergoing ICI treatment should be familiar with these response patterns and the concept of pseudoprogression.\n\nPseudoprogression occurs in 9.7% of patients treated with an anti-CTLA-4 agent (ipilimumab) and 0.6–7% of patients with melanoma or NSCLC who are treated with anti-PD-1 agents, such as nivolumab or pembrolizumab [35363738].\n\nPseudoprogression may occur at any time from the onset of therapy till after the discontinuation of treatment, but it is more common within the first 12 weeks of treatment (Fig. 2) [39]. It is more frequent in younger patients, probably because their immune system provides higher reactivity [38].\n\nAccording to RECIST 1.1, stable disease is defined as < 20% increase and < 30% reduction in the sum of target lesions, partial response as ≥ 30% reduction in the sum of target lesions, and progressive disease (PD) as ≥ 20% increase in the sum of target lesions and eventual new lesions from the nadir [32].\n\nHowever, RECIST v1.1 fails to identify atypical patterns of tumor response associated with immunotherapy, known as pseudoprogression. Pseudoprogression is defined as an initial increase in tumor size followed by a reduction in tumor burden or an initial reduction in tumor size with the appearance of new lesions, which subsequently regress (Table 2).\n\nIn this context, several modified response criteria have been proposed, including immune-related response criteria, immune-related RECIST, immune-modified RECIST, and immune RECIST [133335].\n\nThe RECIST group proposed iRECIST, which is a modified criterion for immunotherapy [13]. In the case of tumor progression (“PD”), iRECIST incorporated the term “unconfirmed progressive disease (iUPD)” to facilitate the differentiation of true tumor progression from pseudoprogression, whereby the initially unconfirmed PD is confirmed during follow-up after 4–8 weeks for reassessment before it can be called PD.\n\niUPD is characterized by:\n\n- ≥ 20% increase in tumor volume from the nadir\n\n- A non-target lesion progression\n\n- The appearance of new lesions\n\nPD is confirmed after 4–8 weeks in cases with the following:\n\n- Target lesions increase in size by ≥ 5 mm.\n\n- Significant increase in non-target lesions previously classified as iUPD\n\n- New lesion increase by ≥ 5 mm or an increase in the number of new lesions\n\nCurrently, RECIST 1.1 remains the standard for tumor response evaluation in clinical practice. iRECIST is valuable for immunotherapy response evaluation during ICI clinical trials (Table 2) [40].\n\nImmune-Related Adverse Events (irAEs)\n\nImmunotherapy enhances immune activity and may be responsible for the dysregulation of immune homeostasis in other organs, leading to specific toxicities defined as irAEs. The global incidence of irAEs in patients treated with anti-PD-1/PD-L1 agents was reported to be approximately 27% in a meta-analysis conducted in 2017 [41]. The incidence of severe irAEs has been reported to be 6%. The incidence of irAEs was 8.25% with nivolumab, 5.10% with pembrolizumab, and 5.28% with atezolizumab [41]. irAEs usually occur at the onset of therapy; nonetheless, they can occur at any time, even after treatment cessation [42]. The management of irAEs generally requires the discontinuation of immunotherapy and steroid administration. IrAEs involve several organs and tissues, with a wide range of imaging findings [43]. The most common irAEs are fatigue, diarrhea, pruritus, rash, and colitis followed by pneumonitis and hepatitis (Fig. 3) [34]. Some adverse events may be asymptomatic and can only be detected during imaging studies. Radiologists should be familiar with imaging features suggestive of irAEs, as they can occur in up to 17% of patients receiving immunotherapy [33]. Some of these irAEs are life-threatening and require prompt recognition because radiological findings may precede clinical manifestations [44].\n\nPneumonitis\n\nPneumonitis is one of the most frequent irAEs, especially in patients receiving ICIs in combination, and it occurs in approximately 5% of patients treated with anti-PD-1/PD-L1 agents [45]. Despite the restricted availability of data on ICIs as a result of their recent introduction, different CT patterns for ICI-related pneumonitis have been described [46].\n\nOrganizing pneumonia (OP) is the most frequent presentation of ICI-therapy-related pneumonitis in the largest cohort currently available, to our knowledge [47]. OP manifests as patchy bilateral consolidative or ground-glass opacities or a combination of both, with peribronchovascular or subpleural distribution and predominant involvement of the lower lobes (Fig. 4). Air bronchograms are usually observed for opacities [46]. A possible marker for OP is a round consolidative opacity surrounding a central ground-glass area observed as a reversed halo or atoll sign [48]. The nodular presentation can include small nodules, mostly in a peribronchovascular distribution, to mass-like nodules with spiculated margins mimicking a malignancy [49]. Differential diagnoses for ICI-related OP include cryptogenic pneumonia, COVID-19 pneumonia [50], and other infections (such as invasive aspergillosis). Clinical and laboratory findings are required to differentiate these conditions from OP [46].\n\nNon-specific interstitial pneumonia (NSIP) is the second most common presentation of ICI-related pneumonitis (Fig. 5). NSIP presents with bilateral and symmetric ground-glass and reticular opacities with lower lobe predominance [46]. A specific finding is subpleural sparing of the posterior lower lobes [49], which also allows its differentiation from infections.\n\nHypersensitivity pneumonitis (HP) is less common in patients with ICI-related pneumonitis. Imaging findings are the same as those for HP observed in other conditions, and they include diffuse or upper lobe prevalent centrilobular ground-glass nodules and, sometimes, air trapping [45]. Clinical and anamnestic findings can help distinguish ICI-related HP from HP associated with allergen exposure [46].\n\nAcute interstitial pneumonia (AIP)-acute respiratory distress syndrome (ARDS) is uncommon in ICI-related pneumonitis, but it manifests with a severe clinical presentation. AIP-ARDS features include geographic or diffuse ground-glass or consolidative opacities involving most of the lungs. Lobular sparing areas can be visualized; interlobular septal thickening and a crazy-paving pattern may also be observed [47].\n\nBronchiolitis is rare and, consequently, not well-described. Typically, bronchiolitis manifests as an area of centrilobular nodularity, often with a tree-in-bud arrangement. Wall thickening of the adjacent bronchi is frequently observed. Focal consolidative and ground-glass opacities are infrequently associated findings [51].\n\nSarcoid-Like Reaction\n\nA sarcoid-like reaction includes hilar and mediastinal lymphadenopathy and is usually associated with pulmonary granulomatosis. It occurs in 5–7% of patients treated with ipilimumab (anti-CTLA-4); to our knowledge, sarcoid-like reactions are very rare, with only a few case reports available in the literature; however, sarcoid-like reactions should be kept in mind in newly developing mediastinal and hilar adenopathy in the appropriate clinical setting. In these cases, this reaction should be recognized as an immunologic reaction rather than a sign of disease progression [525354]. Imaging features on CT include hilar and mediastinal lymphadenopathy associated with pulmonary peri-lymphatic nodules with a predominance in the upper lobes [46]. Hilar and mediastinal lymphadenopathies may appear hypermetabolic on PET/CT and mimic nodal metastases.\n\nEnteritis and Colitis\n\nICI-related colitis or enteritis are among the most prevalent and potentially severe irAEs (Figs. 6, 7). A recent meta-analysis reported an incidence of 0.3–1.1% in patients treated with anti-PD-1/PD-L1 agents [55]. ICI-related colitis usually occurs within 6-18 weeks after the initiation of therapy [56]. On CT, an inflammatory pattern is detectable as wall thickening, mucosal enhancement, air-fluid levels, perivisceral stranding, and mesenteric hyperemia. Perforation is an uncommon complication requiring early identification for prompt treatment [57]. Two different patterns of ICI-related colitis are described: 1) diffuse and 2) segmental colitis. Diffuse colitis is reported to be more frequent (75% of cases) and is characterized by mild and diffuse wall thickening with or without colonic distension and mesenteric vessel engorgement. Segmental colitis is associated with diverticulosis (SCAD) and has been observed in 25% of cases. An SCAD pattern includes moderate wall thickening and localized perivisceral inflammation in a large bowel segment in which diverticulosis is present [43]. Colitis should be correctly identified and reported because different treatment options are indicated: 1) steroids for diffuse colitis and 2) steroids and antibiotics for segmental colitis [57].\n\nPancreatitis\n\nICI-related pancreatitis is a rare complication with an incidence of 1–4% [58], and it can be clinically silent with an asymptomatic serum lipase/amylase increase or present with typical clinical symptoms of acute pancreatitis (Fig. 8). The biological and physio-pathological aspects of ICI pancreatitis are still unknown; ICI-related pancreatitis seems to be more common in patients with other associated adverse events [59]. Some studies have shown that immunotherapy-related pancreatitis is occult on imaging; however, imaging could play a potential role in the diagnosis, severity assessment, and recognition of possible complications. Contrast-enhanced CT provides a global assessment of the disease, and MRI plays a supplementary role [60].\n\nOn imaging, ICI-related pancreatitis presents with characteristics similar to those of traditional interstitial edematous pancreatitis and generally appears in several forms:\n\n- On CT, it appears as a pancreatic enlargement and focal or segmental hypo-enhancement, which is surrounded by fat stranding. Necrosis is rare in ICI-related pancreatitis [59].\n\n- On MRI, the edematous regions appear relatively hypointense relative to the liver on pre-contrast T1-weighted fat-suppressed images and slightly hyperintense relative to the liver on T2-weighted images, and a restriction of the signal on diffusion-weighted images can be observed [61].\n\n- On PET/CT, increased fluorodeoxyglucose (FDG) uptake throughout the pancreas is observed [62].\n\nDifferential diagnoses, including autoimmune pancreatitis [63] and pancreatic metastases [64], represent a potential imaging pitfall for radiologists because depicting and interpreting the features described above is crucial to guiding correct patient management.\n\nHepatitis\n\nHepatitis is a rare irAE, with incidence rates varying from 1% to 3% [65]. ICI-induced hepatitis can present with an asymptomatic increase in aspartate aminotransferase, alanine aminotransferase, and bilirubin serum levels. Hepatitis generally occurs within the first two months after treatment onset [64]. The diagnosis is based on laboratory results, and imaging does not play a primary role. Trans-abdominal ultrasound (US) can show focal or global structural changes in the liver parenchyma with heterogeneous echogenicity. Imaging features that can be underlined on CT and MRI are hepatomegaly, heterogeneous parenchymal enhancement with low attenuation areas, periportal edema, lymphadenopathy, and ascites [66].\n\nCholangitis and Cholecystitis\n\nSome ICI-related cholangitis cases have been reported in the literature as rare and serious irAEs in metastatic lung cancer patients treated with nivolumab [67]. On imaging, ICI-related cholangitis shows dilation, wall thickening, and hypervascularity of the intra- and extrahepatic bile ducts. Signs of cholecystitis can coexist with pericholecystic fluid collections (Fig. 9).\n\nNeuromuscular irAEs\n\nICI-related myositis is the most common neuromuscular complication [68]. In a large study, the incidence of myositis was 0.7% with both anti-CTLA-4 and anti-PD-1/PD-L1 agents [69]. Neuromuscular complications of ICI therapy are the most frequent neurological manifestations, with myasthenia gravis being characterized as the most common PD-1 inhibitor-associated neuromuscular complication [3839]. ICI-therapy-induced Guillain-Barré syndrome is another severe irAE of the peripheral nervous system. Its clinical presentation is characterized by diffuse and bilateral myalgia, possibly involving several muscle groups. On MRI, STIR sequences show hyperintense muscle signals representing inflammatory edema and necrotic changes observed on muscle biopsy [68]. ICI-related myositis is infrequently associated with myasthenia gravis [70].\n\nThyroiditis, Hypophysitis, Adrenalitis\n\nEndocrine involvement is common in patients receiving anti-CTLA-4 and anti-PD-L1 antibodies, with incidence rates varying from 5% to 10% [64]. Endocrine dysfunctions include thyroiditis, hypophysitis, and adrenalitis, and patients are generally symptomatic. Hypophysitis is identifiable on CT as an enlargement of the pituitary gland, but the gold standard is MRI, which shows diffuse and symmetric enlargement with homogeneous contrast enhancement [71]. Thyroid gland involvement has been demonstrated in patients treated with nivolumab [72] manifesting clinical symptoms of hypo- or hyperthyroidism. Thyroid involvement occurs more frequently in female [73]. The gold standard for detecting thyroiditis is US, and images show heterogeneous echogenicity and marked hypervascularity on Doppler analysis. Thyroiditis can be demonstrated with 18FDG-PET examination because thyroiditis shows an intense, diffuse radiotracer uptake into the thyroid gland. Adrenalitis should be suspected if bilateral adrenal gland enlargement with nodularity is observed on CT after ICI treatment initiation. Differential diagnoses include adrenal metastases [64].\n\nCONCLUSION\n\nICIs are becoming promising treatments for cancer and gynecological tumors; their use is expected to yield favorable overall and progression-free survival. Radiologists need to be familiar with the peculiarities of immunotherapy agents.\n\nThe iRECIST application is currently limited to some clinical trials, but all radiologists caring for gynecological patients who observe an apparent disease progression before regression should be aware of pseudoprogression tumor response patterns during follow-up scans. Moreover, irAEs can occur during immunotherapy treatment, and radiologists should identify and report adverse events to guide patient management. Since irAEs can mostly occur at any time during treatment, the differential diagnoses should always be considered, and multidisciplinary collaboration is required to ensure appropriate diagnosis and optimal management.\n\nIn conclusion, radiologists should promptly identify atypical tumor response patterns and common adverse events associated with ICIs. In this context, radiologic signs, such as thyroiditis, myositis, and colitis, of more frequent ICI-related gynecological cancers should be considered.\n\nFig. 1 Mechanisms of action of CTLA-4 and PD-1.\n\nCTLA-4 binds CD80/86 expressed on antigen-presenting cell, inhibiting T cell. PD-1 binds PD-L1, expressed on tumor cell, resulting in suppression of immune response. APC = antigen-presenting cell, CD = cluster of differentiation, CTLA-4 = cytotoxic T-limphocyte antigen 4, MHC = major histocompatibility complex, PD-1 = programmed cell death protein 1, PD-L1 = programmed cell death protein 1 ligand, TCR = T-cell receptor\n\nFig. 2 iRECIST criteria for evaluation of a 51-year-old female with ovarian cancer treated with pembrolizumab (anti PD-1).\n\nA, D. Baseline CT shows two peritoneal subglissonian metastases (arrows; T1: 17 mm; T2: 10 mm). B, E. On a 3-month follow-up, both lesions enlarged with an increase of 27% of the target lesions leading to an iUPD according to iRECIST. C, F. After 8 weeks, both lesions decreased in size, compared to baseline examination (−33%). iRECIST = included in the Response Evaluation Criteria in Solid Tumors, iUPD = unconfirmed progressive disease, PD-1 = programmed cell death protein 1, PR = partial response\n\nFig. 3 Most common immune-related adverse events in female.\n\nFig. 4 Pneumonitis with an organizing pneumonia pattern.\n\n57-year-old female with cervival cancer in treatment with atezolizumab showing mild dyspnea.\n\nA. Follow-up CT scan performed 5 weeks after atezolizumab initiation shows bilateral lower lobes consolidative opacities. B. CT scan performed 4 weeks after atezolizumab interruption and corticosteroids administration shows pneumonitis resolution with residual subpleural reticular opacities.\n\nFig. 5 Pneumonitis with a NSIP pattern.\n\n72 year-old female with ovarian cancer in treatment with durvalumab showing no significant respiratory symptoms\n\nA. Follow-up CT scan performed 6 weeks after durvalumab initiation shows bilateral confluent ground-glass and reticular opacities with subpleural sparing (arrows). B. CT scan performed 4 weeks after durvalumab interruption and corticosteroids administration shows partial resolution of NSIP. NSIP = non-specific interstitial pneumonia\n\nFig. 6 Colitis.\n\n58-year-old female with ovarian cancer presenting at emergency department with abdominal pain and diarrhea, 10 weeks after Pembrolizumab initiation.\n\nA, B. Coronal (A) and axial (B) contrast-enhanced abdominal CT show wall thickening of the descending colon (arrows) and surrounding fat stranding (arrowheads). C, D. Coronal (C) and axial (D) contrast-enhanced CT image, acquired 6 weeks after pembrolizumab interruption and corticosteroids administration shows normal appearance of descending colon (arrows).\n\nFig. 7 Enteritis.\n\n73-year-old female with endometrial cancer in treatment performing follow-up CT and pelvis MRI.\n\nA. Follow-up CT scan performed 15 weeks after Pembrolizumab initiation shows wall thickening of an ileal loop (arrow). B. Axial fast spin echo T2-weighted images shows wall thickening and mild hyperintensity of submucosal layer (arrow), representing oedema. C. Axial T1-weighted fat-sat post-gadolinium images better show stratified pattern of the ileal wall thickening with mucosal enhancement (arrow) and low-intensity submucosal oedema.\n\nFig. 8 Pancreatitis.\n\n66-year-old female with cervix cancer presenting at emergency department with right abdominal pain, 10 weeks after Atezolizumab initiation.\n\nA. Contrast-enhanced CT scan shows pancreatic head enlargement associated to focal hypo-enhancement (arrow). B. Axial T1-weighted fat-sat images clearly show focal hypointensity on pancreatic head (arrow). C. Diffusion-weighted images shows significant diffusion restriction in the pancreatic head. D. CT scan performed 6 weeks after treatment interruption and corticosteroids administration shows normal appearence of the pancreas.\n\nFig. 9 Cholecystitis.\n\n71-year-old female with ovarian cancer presenting at emergency department with right upper abdominal pain, 12 weeks after pembrolizumab initiation. Coronal-reconstructed abdominal CT scan shows mucosal enhancement (arrow) and pericholecistic fluid collection (arrowhead).\n\nTable 1 A List of Currently Most Studied Immune Checkpoint Inhibitors in Gynecological Malignancies\n\nImmune Checkpoint Inhibitor\tMolecular Target\tGynecological Malignancies\t\nPembrolizumab\tPD-1\tEndometrial, ovarian and cervical cancer\t\nCemiplimab\tPD-1\tCervical cancer\t\nNivolumab\tPD-1\tOvarian cancer\t\nDurvalumab\tPD-L1\tOvarian cancer\t\nAvelumab\tPD-L1\tEndometrial and ovarian cancer\t\nAtezolizumab\tPD-L1\tCervical cancer\t\nThey are usually administered in combination to standard chemotherapy or other experimental agents. PD-L1 = programmed cell death protein 1 ligand, PD-1 = programmed cell death protein 1\n\nTable 2 Comparison of Tumor Response Evaluation Criteria: RECIST 1.1 and iRECIST\n\nType of Criteria\tMeasurement\tTarget Lesions (No.)\tSD Criteria (Sum of Target Lesions)\tPR Criteria (Sum of Target Lesions)\tPD Criteria (Sum of Target Lesions)\tPD Confirmation\tNew Lesion\t\nRECIST 1.1 (2009) [32]\tUnidimensional (LA, SA for nodes)\t5 (max 2/organ): LA ≥ 10 mm; nodes (SA ≥ 15 mm)\t< 20% increase and < 30% reduction\t≥ 30% reduction\tPD: ≥ 20% increase\tNot required\tDefines PD\t\niRECIST (2017) [13]\tUnidimensional (LA, SA for nodes)\t5 (max 2/organ): LA ≥ 10 mm); nodes (SA ≥ 15 mm)\t< 20% increase and < 30% reduction\t≥ 30% reduction\tiUPD: ≥ 20% increase\tScan after 4–8 weeks\tDefines iUPD, PD confirmation necessary\t\niRECIST = included in the RECIST, iUPD = unconfirmed progressive disease, LA = long axis, PD = progressive disease, PR = partial response, RECIST = Response Evaluation Criteria in Solid Tumors, SA = short axis, SD = stable disease\n\nConflicts of Interest: The authors have no potential conflicts of interest to disclose.\n\nAuthor Contributions: Conceptualization: Riccardo Manfredi, Luca Russo.\n\nData curation: Valerio Di Paola.\n\nInvestigation: Charlotte Marguerite Lucille Trombadori, Maria Teresa Perri.\n\nMethodology: Benedetta Gui.\n\nProject administration: Vanda Salutari.\n\nSupervision: Giovanni Scambia.\n\nVisualization: Elena Rodolfino.\n\nWriting—original draft: Luca Russo, Charlotte Marguerite Lucille Trombadori, Vanda Salutari.\n\nWriting—review & editing: Benedetta Gui, Giacomo Avesani.\n==== Refs\n1 Bhatla N Aoki D Sharma DN Sankaranarayanan R Cancer of the cervix uteri Int J Gynaecol Obstet 2018 143 Suppl 2 22 36 30306584\n2 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 2015 136 E359 E386 25220842\n3 Mihor A Tomsic S Zagar T Lokar K Zadnik V Socioeconomic inequalities in cancer incidence in Europe: a comprehensive review of population-based epidemiological studies Radiol Oncol 2020 54 1 13 32074075\n4 Siegel RL Miller KD Jemal A Cancer statistics, 2018 CA Cancer J Clin 2018 68 7 30 29313949\n5 Hodi FS O'Day SJ McDermott DF Weber RW Sosman JA Haanen JB Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 2010 363 711 723 20525992\n6 Massari F Di Nunno V Ciccarese C Graham J Porta C Comito F Adjuvant therapy in renal cell carcinoma Cancer Treat Rev 2017 60 152 157 28992528\n7 Pishko A Nasta SD The role of novel immunotherapies in non-Hodgkin lymphoma Transl Cancer Res 2017 6 93 103 28955654\n8 Ramos JD Yu EY Immuno-oncology in urothelial carcinoma: who or what will ultimately sit on the iron throne? Immunotherapy 2017 9 951 954 28971748\n9 Lee HW Cho KJ Park JY Current status and future direction of immunotherapy in hepatocellular carcinoma: what do the data suggest Immune Netw 2020 20 e11 32158599\n10 Grywalska E Sobstyl M Putowski L Roliński J Current possibilities of gynecologic cancer treatment with the use of immune checkpoint inhibitors Int J Mol Sci 2019 20 4705\n11 Lynam S Lugade AA Odunsi K Immunotherapy for gynecologic cancer: current applications and future directions Clin Obstet Gynecol 2020 63 48 63 31833846\n12 Green AK Feinberg J Makker V A review of immune checkpoint blockade therapy in endometrial cancer Am Soc Clin Oncol Educ Book 2020 40 1 7\n13 Seymour L Bogaerts J Perrone A Ford R Schwartz LH Mandrekar S iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics Lancet Oncol 2017 18 e143 e152 28271869\n14 Disis ML Taylor MH Kelly K Beck JT Gordon M Moore KM Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial JAMA Oncol 2019 5 393 401 30676622\n15 Shih K Arkenau HT Infante JR Clinical impact of checkpoint inhibitors as novel cancer therapies Drugs 2014 74 1993 2013 25344022\n16 Greenwald RJ Freeman GJ Sharpe AH The B7 family revisited Annu Rev Immunol 2005 23 515 548 15771580\n17 Wang DH Guo L Wu XH Checkpoint inhibitors in immunotherapy of ovarian cancer Tumour Biol 2015 36 33 39 25409618\n18 Pedoeem A Azoulay-Alfaguter I Strazza M Silverman GJ Mor A Programmed death-1 pathway in cancer and autoimmunity Clin Immunol 2014 153 145 152 24780173\n19 Eskander RN Tewari KS Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer Clin Ther 2015 37 20 38 25592089\n20 Liu YL Zamarin D Combination immune checkpoint blockade strategies to maximize immune response in gynecological cancers Curr Oncol Rep 2018 20 94 30421009\n21 Hamanishi J Mandai M Iwasaki M Okazaki T Tanaka Y Yamaguchi K Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer Proc Natl Acad Sci U S A 2007 104 3360 3365 17360651\n22 Matulonis UA Shapira-Frommer R Santin AD Lisyanskaya AS Pignata S Vergote I Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study Ann Oncol 2019 30 1080 1087 31046082\n23 Ledermann JA Colombo N Oza AM Fujiwara K Birrer MJ Randall LM Avelumab in combination with and/or following chemotherapy vs chemotherapy alone in patients with previously untreated epithelial ovarian cancer: results from the phase 3 javelin ovarian 100 trial Gynecol Oncol 2020 159 13 14 32771275\n24 Ribas A Tumor immunotherapy directed at PD-1 N Engl J Med 2012 366 2517 2519 22658126\n25 Frenel JS Le Tourneau C O'Neil B Ott PA Piha-Paul SA Gomez-Roca C Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1–positive cervical cancer: results from the phase Ib KEYNOTE-028 trial J Clin Oncol 2017 35 4035 4041 29095678\n26 Chung HC Ros W Delord JP Perets R Italiano A Shapira-Frommer R Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study J Clin Oncol 2019 37 1470 1478 30943124\n27 Naumann RW Hollebecque A Meyer T Devlin MJ Oaknin A Kerger J Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial J Clin Oncol 2019 37 2825 2834 31487218\n28 Herzog TJ Arguello D Reddy SK Gatalica Z PD-1, PD-L1 expression in 1599 gynecological cancers: implications for immunotherapy Gynecol Oncol 2015 137 204 205\n29 Gargiulo P Della Pepa C Berardi S Califano D Scala S Buonaguro L Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: new candidates for checkpoint blockade immunotherapy? Cancer Treat Rev 2016 48 61 68 27362548\n30 Kasherman L Ahrari S Lheureux S Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer Future Oncol 2021 17 877 892 33251877\n31 Makker V Taylor MH Aghajanian C Oaknin A Mier J Cohn AL Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer J Clin Oncol 2020 38 2981 2992 32167863\n32 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 19097774\n33 Wolchok JD Hoos A O'Day S Weber JS Hamid O Lebbé C Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria Clin Cancer Res 2009 15 7412 7420 19934295\n34 Dromain C Beigelman C Pozzessere C Duran R Digklia A Imaging of tumour response to immunotherapy Eur Radiol Exp 2020 4 2 31900689\n35 Hodi FS Hwu WJ Kefford R Weber JS Daud A Hamid O Evaluation of immune-related response criteria and RECIST v1. 1 in patients with advanced melanoma treated with pembrolizumab J Clin Oncol 2016 34 1510 1517 26951310\n36 Katz SI Hammer M Bagley SJ Aggarwal C Bauml JM Thompson JC Radiologic pseudoprogression during anti–PD-1 therapy for advanced non–small cell lung cancer J Thorac Oncol 2018 13 978 986 29738824\n37 Nishino M Dahlberg SE Adeni AE Lydon CA Hatabu H Jänne PA Tumor response dynamics of advanced non-small cell lung cancer patients treated with PD-1 inhibitors: imaging markers for treatment outcome Clin Cancer Res 2017 23 5737 5744 28679767\n38 Nishino M Giobbie-Hurder A Manos MP Bailey N Buchbinder EI Ott PA Immune-related tumor response dynamics in melanoma patients treated with pembrolizumab: identifying markers for clinical outcome and treatment decisions Clin Cancer Res 2017 23 4671 4679 28592629\n39 Thust SC van den Bent MJ Smits M Pseudoprogression of brain tumors J Magn Reson Imaging 2018 48 571 589\n40 Kataoka Y Hirano K Which criteria should we use to evaluate the efficacy of immune-checkpoint inhibitors Ann Transl Med 2018 6 222 30023385\n41 Wang PF Chen Y Song SY Wang TJ Ji WJ Li SW Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis Front Pharmacol 2017 8 730 29093678\n42 Postow MA Sidlow R Hellmann MD Immune-related adverse events associated with immune checkpoint blockade N Engl J Med 2018 378 158 168 29320654\n43 Nishino M Hatabu H Hodi FS Imaging of cancer immunotherapy: current approaches and future directions Radiology 2019 290 9 22 30457485\n44 Martins F Sofiya L Sykiotis GP Lamine F Maillard M Fraga M Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance Nat Rev Clin Oncol 2019 16 563 580 31092901\n45 Naidoo J Wang X Woo KM Iyriboz T Halpenny D Cunningham J Pneumonitis in patients treated with anti–programmed death-1/programmed death ligand 1 therapy J Clin Oncol 2017 35 709 717 27646942\n46 Kalisz KR Ramaiya NH Laukamp KR Gupta A Immune checkpoint inhibitor therapy–related pneumonitis: patterns and management Radiographics 2019 39 1923 1937 31584861\n47 Nishino M Ramaiya NH Awad MM Sholl LM Maattala JA Taibi M PD-1 inhibitor–related pneumonitis in advanced cancer patients: radiographic patterns and clinical course Clin Cancer Res 2016 22 6051 6060 27535979\n48 Fragkou P Souli M Theochari M Kontopoulou C Loukides S Koumarianou A A case of organizing pneumonia (OP) associated with pembrolizumab Drug Target Insights 2016 10 9 12\n49 Ferguson EC Berkowitz EA Lung CT: part 2, the interstitial pneumonias--clinical, histologic, and CT manifestations AJR Am J Roentgenol 2012 199 W464 W476 22997396\n50 Larici AR Cicchetti G Marano R Merlino B Elia L Calandriello L Multimodality imaging of COVID-19 pneumonia: from diagnosis to follow-up. A comprehensive review Eur J Radiol 2020 131 109217 32861174\n51 Delaunay M Cadranel J Lusque A Meyer N Gounant V Moro-Sibilot D Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients Eur Respir J 2017 50 1700050 28798088\n52 Montaudié H Pradelli J Passeron T Lacour JP Leroy S Pulmonary sarcoid-like granulomatosis induced by nivolumab Br J Dermatol 2017 176 1060 1063 27291635\n53 Hiraki T Hatanaka M Arimura A Kawahira H Kirishima M Kitazono I Granulomatous/sarcoid-like reactions in the setting of programmed cell death-1 inhibition: a potential mimic of disease recurrence J Cutan Pathol 2020 47 154 160 31437317\n54 Nishino M Sholl LM Awad MM Hatabu H Armand P Hodi FS Sarcoid-like granulomatosis of the lung related to immune-checkpoint inhibitors: distinct clinical and imaging features of a unique immune-related adverse event Cancer Immunol Res 2018 6 630 635 29622582\n55 Baxi S Yang A Gennarelli RL Khan N Wang Z Boyce L Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis BMJ 2018 360 k793 29540345\n56 Eigentler TK Hassel JC Berking C Aberle J Bachmann O Grünwald V Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy Cancer Treat Rev 2016 45 7 18 26922661\n57 Hofmann L Forschner A Loquai C Goldinger SM Zimmer L Ugurel S Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy Eur J Cancer 2016 60 190 209 27085692\n58 Abu-Sbeih H Tang T Lu Y Thirumurthi S Altan M Jazaeri AA Clinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury J Immunother Cancer 2019 7 31 30728076\n59 Porcu M Solinas C Migali C Battaglia A Schena M Mannelli L Immune checkpoint inhibitor-induced pancreatic injury: imaging findings and literature review Target Oncol 2020 15 25 35 31925647\n60 Manikkavasakar S AlObaidy M Busireddy KK Ramalho M Nilmini V Alagiyawanna M Magnetic resonance imaging of pancreatitis: an update World J Gastroenterol 2014 20 14760 14777 25356038\n61 Barral M Taouli B Guiu B Koh DM Luciani A Manfredi R Diffusion-weighted MR imaging of the pancreas: current status and recommendations Radiology 2015 274 45 63 25531479\n62 Alabed YZ Aghayev A Sakellis C Van den Abbeele AD Pancreatitis secondary to anti–programmed death receptor 1 immunotherapy diagnosed by FDG PET/CT Clin Nucl Med 2015 40 e528 e529 26284765\n63 Manfredi R Frulloni L Mantovani W Bonatti M Graziani R Pozzi Mucelli R Autoimmune pancreatitis: pancreatic and extrapancreatic MR imaging-MR cholangiopancreatography findings at diagnosis, after steroid therapy, and at recurrence Radiology 2011 260 428 436 21613442\n64 Furtado VF Melamud K Hassan K Rohatgi S Buch K Imaging manifestations of immune-related adverse effects in checkpoint inhibitor therapies: a primer for the radiologist Clin Imaging 2020 63 35 49 32120311\n65 Mizuno K Ito T Ishigami M Ishizu Y Kuzuya T Honda T Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies J Gastroenterol 2020 55 653 661 32124082\n66 Alessandrino F Sahu S Nishino M Adeni AE Tirumani SH Shinagare AB Frequency and imaging features of abdominal immune-related adverse events in metastatic lung cancer patients treated with PD-1 inhibitor Abdom Radiol (NY) 2019 44 1917 1927 30790009\n67 Izumi H Kodani M Kurai J Takeda K Okazaki R Yamane K Nivolumab-induced cholangitis in patients with non-small cell lung cancer: case series and a review of literature Mol Clin Oncol 2019 11 439 446 31616560\n68 Psimaras D Neuromuscular complications of immune checkpoint inhibitors Presse Med 2018 47 e253 e259 30413332\n69 Liewluck T Kao JC Mauermann ML PD-1 inhibitor-associated myopathies: emerging immune-mediated myopathies J Immunother 2018 41 208 211 29200081\n70 Kao JC Brickshawana A Liewluck T Neuromuscular complications of programmed cell death-1 (PD-1) inhibitors Curr Neurol Neurosci Rep 2018 18 63 30078154\n71 Mekki A Dercle L Lichtenstein P Marabelle A Michot JM Lambotte O Detection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1 Eur J Cancer 2018 96 91 104 29698933\n72 Yamauchi I Yasoda A Matsumoto S Sakamori Y Kim YH Nomura M Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab PLoS One 2019 14 e0216954 31086392\n73 Byun DJ Wolchok JD Rosenberg LM Girotra M Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies Nat Rev Endocrinol 2017 13 195 207 28106152\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1229-6929",
"issue": "22(8)",
"journal": "Korean journal of radiology",
"keywords": "Adverse drug event; Checkpoint inhibitors; Gynaecological oncology; Pseudoprogression",
"medline_ta": "Korean J Radiol",
"mesh_terms": "D003952:Diagnostic Imaging; D005260:Female; D005833:Genital Neoplasms, Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D009369:Neoplasms; D000072177:Radiologists",
"nlm_unique_id": "100956096",
"other_id": null,
"pages": "1310-1322",
"pmc": null,
"pmid": "34047505",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "28992528;28798088;26922661;27535979;31584861;32120311;29698933;29095678;32861174;31925647;29622582;30413332;19097774;31046082;31547532;33251877;28106152;25592089;25220842;32158599;32074075;20525992;28971748;31437317;24780173;31833846;31900689;27362548;29738824;29313949;30421009;29540345;25531479;32124082;22997396;30457485;30728076;30306584;32167863;25344022;30023385;26284765;15771580;30676622;27257369;29734497;26951310;27085692;31092901;28679767;28592629;30078154;19934295;30943124;28271869;29320654;32213091;29093678;30790009;17360651;31086392;25356038;27646942;21613442;31616560;29200081;22658126;25409618;28955654;31487218;27291635",
"title": "Immunotherapy-Related Imaging Findings in Patients with Gynecological Malignancies: What Radiologists Need to Know.",
"title_normalized": "immunotherapy related imaging findings in patients with gynecological malignancies what radiologists need to know"
} | [
{
"companynumb": "IT-009507513-2111ITA009384",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAnabolic-androgenic steroid (AAS) use and testosterone therapy have been well established risk factors for the creation of a pro-thrombotic state, and to precipitate formation of thromboemboli in individuals already predisposed to thrombosis.\n\n\nMETHODS\nHere, we present the case of an amateur bodybuilder, with a negative thrombophilia workup, who experienced primary renal infarction while using the AAS trenbolone acetate and testosterone, as well as a subsequent renal infarction while anticoagulated with apixaban.\n\n\nCONCLUSIONS\nThe development of subsequent infarctions in an anticoagulated patient with discontinued recreational steroid use poses a unique situation and challenges the current understanding of a thrombophilic state associated with steroids. The lifetime prevalence of anabolic steroid use is estimated to be 1% in the male population in the United States which is significant.\n\n\nCONCLUSIONS\nFurther understanding and recommendations of appropriate anticoagulant should be further elucidated to appropriately medically manage patients from this confounding social and medical history.",
"affiliations": "Pinnacle Health System, Department of Internal Medicine, Harrisburg, PA, United States.;Pinnacle Health System, Department of General Surgery, Harrisburg, PA, United States.;Pinnacle Health System, Department of Internal Medicine, Harrisburg, PA, United States.;Pinnacle Health System, Department of Internal Medicine, Harrisburg, PA, United States.;Pinnacle Health System, Department of Internal Medicine, Harrisburg, PA, United States.;Pinnacle Health System, Department of Internal Medicine, Harrisburg, PA, United States.",
"authors": "Colburn|Shaun|S|;Childers|W Kurtis|WK|;Chacon|Alex|A|;Swailes|Alexa|A|;Ahmed|Fauzan M|FM|;Sahi|Rajinder|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.amsu.2017.01.015",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)Ann Med Surg (Lond)Annals of Medicine and Surgery2049-0801Elsevier S2049-0801(17)30016-X10.1016/j.amsu.2017.01.015Case ReportThe cost of seeking an edge: Recurrent renal infarction in setting of recreational use of anabolic steroids Colburn Shaun scolburn@pinnaclehealth.orga∗Childers W. Kurtis bChacon Alex aSwailes Alexa aAhmed Fauzan M. aSahi Rajinder aa Pinnacle Health System, Department of Internal Medicine, Harrisburg, PA, United Statesb Pinnacle Health System, Department of General Surgery, Harrisburg, PA, United States∗ Corresponding author. Department of Internal Medicine, 205 S. Front Street, Brady Building, Suite 3C, Harrisburg, PA 17101, United States.Department of Internal Medicine205 S. Front StreetBrady BuildingSuite 3CHarrisburgPA17101United States scolburn@pinnaclehealth.org12 1 2017 2 2017 12 1 2017 14 25 28 4 8 2016 10 1 2017 10 1 2017 © 2017 The Author(s)2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nAnabolic-androgenic steroid (AAS) use and testosterone therapy have been well established risk factors for the creation of a pro-thrombotic state, and to precipitate formation of thromboemboli in individuals already predisposed to thrombosis.\n\nCase report\nHere, we present the case of an amateur bodybuilder, with a negative thrombophilia workup, who experienced primary renal infarction while using the AAS trenbolone acetate and testosterone, as well as a subsequent renal infarction while anticoagulated with apixaban.\n\nDiscussion\nThe development of subsequent infarctions in an anticoagulated patient with discontinued recreational steroid use poses a unique situation and challenges the current understanding of a thrombophilic state associated with steroids. The lifetime prevalence of anabolic steroid use is estimated to be 1% in the male population in the United States which is significant.\n\nConclusion\nFurther understanding and recommendations of appropriate anticoagulant should be further elucidated to appropriately medically manage patients from this confounding social and medical history.\n\nHighlights\n• Consideration of earlier CT study with contrast.\n\n• Thorough history taking including gym supplements.\n\n• The use of NOACs.\n\n• The need for further understanding of how anabolic steroids affect coagulation.\n\n• Educating patients using anabolic steroids regarding the risks of continued use.\n\n\n\nKeywords\nRenal infarctionSteroidsAnabolicRenal artery thrombus\n==== Body\n1 Introduction\nRecreational anabolic-androgenic steroid (AAS) use have been highlighted in media with the overwhelming use in professional and amateur bodybuilders. Muscular hypertrophy proceeds with the desired effects, however, multiple medical side effects ensue – impotence, severe acne, gynecomastia, atrophy of testicles, increased agitation, liver and kidney dysfunction. One of the side effects includes coagulopathy from a multifactorial pathophysiology. In a multifactorial proposed mechanism, AAS induce thrombosis through increased platelet activity, increased production of coagulation factors, increased LDL and decreased HDL cholesterol, and increased inflammation as measured by C-reactive protein [1], [2]. Furthermore, testosterone therapy has been shown to promote a state of increased viscosity due to similar effects on HDL cholesterol metabolism and increases in hematocrit [3].\n\n2 Case report\nA 43-year-old male with a past medical history of obsessive compulsive disorder (OCD) and prior appendectomy presented to the emergency department reporting 2 days of left flank pain described as severe, sudden onset, sharp, constant, and without radiation. At the time of presentation, he denied fever, chills, dysuria, hematuria, change in urinary frequency, or changes in his bowel movements. He worked as a financial advisor and his only reported medication was escitalopram 20mg. During initial evaluation, he had an abdominal exam which revealed a soft and non-tender abdomen, no guarding or rebound elicited, no discoloration, no costovertebral angle tenderness, and no genitourinary abnormality. Urine analysis was unremarkable and urine electrolytes were not ordered. Blood work displayed a hemoglobin of 17.4 gm/dL, hematocrit of 49.5%, platelets of 186 K/μL, and creatinine of 1.7mg/dL (baseline <1.2mg/dL). A non-contrast CT was performed, which revealed no change in the renal parenchyma, and no evidence of nephrolithiasis. The patient was hemodynamically stable overnight with no signs of infection, and was sent home with opioid analgesics. His acute kidney injury was attributed to poor hydration in the setting of pain. The documentation did not reveal what the likely cause of the pain was.\n\nThe following day, the patient returned to the emergency department due to non-resolution of his pain. No changes in urination were mentioned. He underwent a contrast CT, which indicated a new, wedge-shaped hypodensity in the superolateral pole of the left kidney, measuring 5.2 × 2.5cm with adjacent fat stranding (Fig. 1). Additionally, the anterior segmental branch of the left renal artery demonstrated dilatation to 7mm with severe luminal narrowing due to occlusion by hypodense material. Serum creatinine was measured to be 1.7mg/dL again. At this time, the patient was diagnosed with left renal parenchymal infarct and acute kidney injury (AKI). He was admitted and started on a continuous heparin drip for anticoagulation.\n\nFurther work-up during that hospitalization included a transthoracic echocardiogram, which showed no evidence of thrombus or vegetations as potential etiologies for embolization. Extensive hypercoagulable workup was ordered: Factor II mutation - normal; Antithrombin III deficiency - 96% activity (normal 80–120); Factor V Leiden - normal; Cryoglobulin - none detected, ANA - negative; Lupus Anticoagulant – none detected; Anti-Cardiolipin IgG <14 (negative is < 14); Anti-Cardiolipin IgM < 12 (negative <12); Total Complement – 56U/mL (31–60); Complement C4 - 22mg/dL (12–38); Complement C3 – 78.2mg/dL (59–152); Homocysteine levels 8 μmol/L (normal 5–16). Normal ranges are mentioned above in parentheses. None of these disorders were detected. A lipid panel revealed a total cholesterol of 126mg/dL, LDL 65.8mg/dL, VLDL 15mg/dL, HDL 45mg/dL, and triglycerides of 76mg/dL. CRP was 3.57mg/L.\n\nUpon further questioning, the patient revealed that he had been using both testosterone and the injectable anabolic steroid, trenbolone acetate, intermittently over a period of 5 years, with last use 2 weeks prior to initial admission. Consistent with anabolic steroid use, his testosterone level was 14ng/dL, DHEA-S 124 mg/dL, 17b estradiol <20 pg/mL.\n\nAs the patient's renal function and flank pain showed consistent improvement, the patient was started on apixaban and discharged home on hospital day 3.\n\nFour days post discharge, this patient presented again to the emergency department with recurrence of severe left flank pain radiating to the left lower quadrant and groin with associated nausea. The patient again denied gross hematuria, dysuria, fever, or chills. Follow-up CT with contrast was ordered, at which time a new renal infarct was detected at the inferior pole of the left kidney (Fig. 2). The patient was again placed on a continuous heparin drip for anticoagulation. Doppler imaging revealed <60% stenosis of left renal artery with reduced flow to the superior pole. The renal vein was patent. Follow-up radioisotope renography (MAG3 scan) estimated differential renal function of 33% on the left and 67% on the right (Fig. 3). A urine drug screen was negative for all substances except opiates, which he had been prescribed.\n\nThe patient experienced gradual improvement in pain and renal function. On hospital day 3, enoxaparin was started as a bridge to therapeutic INR on warfarin. He was discharged on hospital day 4, following stabilization of creatinine (∼1.3mg/dL) and acceptable pain control. Extensive counseling was provided regarding the risk of devastating thromboembolic events with continued use of anabolic steroids.\n\n3 Discussion\nThe lifetime prevalence of anabolic steroid use is estimated to be 1% in the male population in the United States [4]. The breadth of complications from these agents, as well as the treatment algorithms for managing complications, are not well characterized. In this case, we cared for a 43 year old male with no predisposing pro-coagulable conditions who had been chronically using anabolic steroids, trenbelone acetate and testosterone, for recreational body building purposes. He subsequently experienced 2 renal infarcts, the second of which occurred while on anticoagulation with apixaban. As this patient's anabolic steroid use was not discovered until his second hospitalization, the diagnosis of renal infarction was delayed until day 4 of flank pain.\n\nThere has been one recent case of renal infarct secondary to anabolic steroid use in which diagnosis was delayed due to non-disclosure of this key aspect of the patient's history, and another in which a young male taking trenbolone acetate (the same anabolic agent our patient used) was not diagnosed with myocardial infarction until 3 days after initial presentation with epigastric pain [5], [6]. These occurrences, with delayed diagnoses, highlight the importance of asking all patients, especially young, athletic men, about workout supplements as well as anabolic steroid use at both preventive visits and when presenting with acute-onset pain.\n\nA critical confounding component in this patient's diagnosis was the unremarkable non-contrast abdominal CT conducted on initial presentation. Given his acute kidney injury at the time of presentation, CT with contrast was deferred due to the risk of further contrast-induced renal injury. We propose that in patients using supplements known to promote a hypercoagulable state, the acute onset of severe pain consistent with ischemia warrants the consideration of a CT with contrast to further evaluate potential for thrombosis.\n\nIdeal anticoagulation regimens for patients using AAS and suffering thrombotic events have not been established. While novel oral anticoagulants (NOACs) have shown great clinical utility in other thrombophilic states, their use in preventing further renal artery thrombosis has not been established. In a case series describing patients suffering thrombotic events while on testosterone therapy, the majority of patients were found to have concurrent thrombophilic or hypofibrinolytic syndromes [7]. Of note, those that continued use of testosterone therapy despite experiencing thrombotic events, 16% proceeded to have a recurrent thrombosis, and 9% experienced a third thrombotic event.\n\n4 Conclusion\nWith the increasing prevalence and use of anabolic steroids and testosterone, the spectrum of side effects must be understood and recognized. AAS and testosterone act as a pro-thrombotic and pro-coagulant, respectively, through a multifactorial mechanism. When used simultaneously, the risk for the development of thrombus and subsequent thromboemboli increases exponentially. As demonstrated previously, the continued use of steroids increases the risk of recurrent thrombosis. Our patient presents a unique situation of recurrent infarction of the kidney despite NOAC use. Though a thorough history of knowledge of AAS and steroid use would prevent a delay in diagnosis, this does not undermine the lack of knowledge and treatment strategies these unique patients present. Further data and mechanistic investigation of possible combination anti-platelet and NOAC medications needs to be explored to treat and prevent further thrombosis in patients in a pro-coagulation state due to AAS and steroid use [8].\n\nEthical approval\nN/A.\n\nSources of funding\nNone.\n\nConflicts of interest\nNone.\n\nAuthor contribution\nShaun Colburn: writing, literature search, review and editing.\n\nW. Kurtis Childers: writing, literature search, review and editing.\n\nAlex Chacon: writing, literature search.\n\nAlexa Swaiels: writing, literature search.\n\nFauzan M Ahmed: writing, literature search.\n\nRajinder Sahi: editing.\n\nTrial registry number – ISRCTN\nN/A.\n\nGuarantor\nShaun Colburn.\n\nResearch registration unique identifying number (UIN)\nN/A.\n\nFig. 1 Computed tomography scan of the abdomen with contrast indicating a new, wedge-shaped hypodensity in the superolateral pole of the left kidney (see arrow). Measuring 5.2 cm × 2.5 cm.\n\nFig. 1Fig. 2 Computed tomography scan of the abdomen with contrast revealed a new area of infarction at the inferior pole of the left kidney (indicated by the arrow).\n\nFig. 2Fig. 3 Radioisotope renography (MAG3 scan) revealed significant decreased in renal function of 33% on the left and 67% on the right. The time activity curves (indicated by the stars) reveal normal, brisk uptake and washout activity from the right kidney but are visibly reduced for the left kidney. The purple line represents the right kidney and the turquoise dashed line represents the left kidney.\n\nFig. 3\n==== Refs\nReferences\n1 Turillazzi E. Perilli G. Di Paolo M. Neri M. Riezzo I. Fineschi V. Side effects of AAS abuse: an overview Mini Rev. Med. Chem. 11 2011 374 389 21443513 \n2 Severo C. Ribeiro J. Umpierre D. Da Silveira A. Padilha M. De Aquino Neto F. Stein R. Increased atherothrombotic markers and endothelial dysfunction in steroid users Eur. J. Prev. Cardiol. 20 2 2012 195 201 22345686 \n3 Fernandez-Balsells M. Murad M. Lane M. Lampropulos J.F. Albuquerque F. Mullan R.J. Agrwal N. Elamin M. Gallegos-Orozco J. Wang A. Erwin P. Bhasin S. Montori V. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis J. Clin. Endocrinol. Metab. 95 6 2010 2560 2575 20525906 \n4 Dawson R. Drugs in sport-the role of the physician J. Endocrinol. 170 1 2001 55 61 11431137 \n5 Ammatuna E. Nijziel M. Polycythemia and renal infarction in a bodybuilder Q. J. Med. 107 2014 661 \n6 Shahsavari nia K. Rahmani F. Ebrahimi Bakhtavar F. Hashemi Aghdam Y. Balafar M. A young man with myocardial infection due to trenbolone acetate; a case report Emergency 2 1 2014 43 45 26495342 \n7 Glueck C. Prince M. Patel N. Patel J. Shah P. Mehta N. Wang P. Thrombophilia in 67 patients with thrombotic events after starting testosterone therapy Clin. Appl. Thromb. Hemost. 22 6 2016 Sep 548 553 26620418 \n8 Agha R.A. Fowler A.J. Saetta A. Barai I. Rajmohan S. Orgill DP and the SCARE Group. The SCARE Statement: consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 186 27613565\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2049-0801",
"issue": "14()",
"journal": "Annals of medicine and surgery (2012)",
"keywords": "Anabolic; Renal artery thrombus; Renal infarction; Steroids",
"medline_ta": "Ann Med Surg (Lond)",
"mesh_terms": null,
"nlm_unique_id": "101616869",
"other_id": null,
"pages": "25-28",
"pmc": null,
"pmid": "28127424",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports",
"references": "26495342;21443513;26620418;20525906;27613565;11431137;22345686",
"title": "The cost of seeking an edge: Recurrent renal infarction in setting of recreational use of anabolic steroids.",
"title_normalized": "the cost of seeking an edge recurrent renal infarction in setting of recreational use of anabolic steroids"
} | [
{
"companynumb": "US-ABBVIE-17P-163-1945966-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nSubstance use disorders are a key concern among US veterans. Substance use disorder pharmacotherapies with support for effectiveness are limited. Buprenorphine/naloxone (Suboxone) is an effective opioid replacement treatment option for opioid use disorder when used as part of a comprehensive treatment program. In June 2011, the Veterans Affairs San Diego Healthcare System began using a group format to prescribe buprenorphine/naloxone. This study aimed at examining outcomes of retention rates and percentage opioid negative urine samples. Results were compared for veteran patients seen in group versus individual formats.\n\n\nMETHODS\nThis retrospective chart review included data from 32 patients who were prescribed buprenorphine/naloxone between a 3-year window (ie, January 1, 2010, and December 31, 2012).\n\n\nRESULTS\nOverall results were 46% retention in treatment after 1 year, and 94% of opioid urine samples were negative. More patients seen in group were retained in treatment at 1 year compared with those seen individually (69% vs 27%, respectively; P < 0.03).\n\n\nCONCLUSIONS\nThis study found that veterans prescribed buprenorphine/naloxone in a group setting as part of a drug and alcohol treatment program were retained in treatment longer than veterans prescribed this medication individually. Because of inherent limitations in the study design, no causality can be determined; however, given the results found here, group medication management of buprenorphine/naloxone should be explored further.",
"affiliations": "From the Veterans Affairs San Diego Healthcare System (RB, CP, JL, SG, SR), San Diego, CA; University of California San Diego School of Pharmacy (RB, JL), San Diego; and Department of Psychiatry (CP, SG, SR), University of California San Diego School of Medicine.",
"authors": "Berger|Reisel|R|;Pulido|Carmen|C|;Lacro|Jonathan|J|;Groban|Stephen|S|;Robinson|Shannon|S|",
"chemical_list": "D009292:Narcotic Antagonists; D009270:Naloxone; D002047:Buprenorphine",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "8(6)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D002047:Buprenorphine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011615:Psychotherapy, Group; D012189:Retrospective Studies; D016896:Treatment Outcome; D014728:Veterans",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "415-20",
"pmc": null,
"pmid": "25275875",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Group medication management for buprenorphine/naloxone in opioid-dependent veterans.",
"title_normalized": "group medication management for buprenorphine naloxone in opioid dependent veterans"
} | [
{
"companynumb": "US-RB PHARMACEUTICALS LIMITED-RB-74396-2014",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLO... |
{
"abstract": "To describe a case of traumatic hyphema in a patient with severe hemophilia A.\nWe present a case of a 16-year-old boy with severe hemophilia A who presented to our ophthalmology department with total hyphema and elevated intraocular pressure 3 days after a history of blunt ocular trauma on his right eye. Due to the persistent intraocular pressure elevation and total hyphema despite medical intervention, an early anterior chamber washout was performed with the replacement of factor VIII preoperatively and postoperatively. Re-bleeding or any other complications were not experienced during surgery or postoperatively. At the first postoperative week, 20/20 visual acuity and a normal intraocular pressure without antiglaucoma medication was retained and remained stable during the 6-month follow-up.\nIn such cases with hemophilia A, traumatic hyphema, and intraocular pressure elevation despite medical intervention, an early surgical clot removal under intense factor VIII replacement could be performed. In the early postoperative period, factor replacement should be resumed in order to avoid re-bleeding.",
"affiliations": "Department of Ophthalmology, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey.;Department of Ophthalmology, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey.;Department of Paediatric Haematology, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey.;Department of Ophthalmology, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey.;Department of Paediatric Haematology, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey.",
"authors": "Belviranli|Selman|S|https://orcid.org/0000-0003-0272-7345;Ozkagnici|Ahmet|A|;Tokgoz|Huseyin|H|;Bitirgen|Gulfidan|G|;Caliskan|Umran|U|",
"chemical_list": "D003029:Coagulants; D005169:Factor VIII",
"country": "United States",
"delete": false,
"doi": "10.1177/1120672119856515",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "31(2)",
"journal": "European journal of ophthalmology",
"keywords": "Trauma; childhood glaucoma; genetic disease/congenital abnormalities; glaucoma; ocular trauma (includes shaken baby); pediatric ophthalmology",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000293:Adolescent; D000867:Anterior Chamber; D003029:Coagulants; D005131:Eye Injuries; D005169:Factor VIII; D006467:Hemophilia A; D006801:Humans; D006988:Hyphema; D007429:Intraocular Pressure; D008297:Male; D014792:Visual Acuity; D014949:Wounds, Nonpenetrating",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "NP106-NP108",
"pmc": null,
"pmid": "31187640",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Traumatic hyphema in a patient with severe hemophilia A: Clinical features and management.",
"title_normalized": "traumatic hyphema in a patient with severe hemophilia a clinical features and management"
} | [
{
"companynumb": "TR-B.BRAUN MEDICAL INC.-2114236",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MANNITOL"
},
"drugadditional": null,
... |
{
"abstract": "The long-term cardiac complications of radio(chemo)therapy for Hodgkin lymphoma include coronary artery disease, cardiac arrhythmias, valvular disease, pericardial disease, cardiomyopathy and heart failure. The extent of myocardial damage after radiotherapy is dependent on the dose, the volume and the technique of chest irradiation. Also, patient-specific factors, such as the age of the patient at the time of treatment and the presence of classical cardiac risk factors are supposed to be important. The relative risk of cardiovascular events is estimated to be 2 to 7 times higher than the general population. The patient's clinical picture can vary from asymptomatic to an acute presentation of end-stage coronary artery or valvular disease.",
"affiliations": null,
"authors": "Everaert|Bert R|BR|;Van den Heuvel|Paul|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/ac.69.2.3017304",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5385",
"issue": "69(2)",
"journal": "Acta cardiologica",
"keywords": null,
"medline_ta": "Acta Cardiol",
"mesh_terms": "D000328:Adult; D001022:Aortic Valve Insufficiency; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D054059:Coronary Occlusion; D023921:Coronary Stenosis; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D006321:Heart; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006689:Hodgkin Disease; D006801:Humans; D008944:Mitral Valve Insufficiency; D018714:Radiotherapy, Adjuvant; D012307:Risk Factors; D013616:Tachycardia, Sinus; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0370570",
"other_id": null,
"pages": "200-2",
"pmc": null,
"pmid": "24783474",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Radiation therapy for Hodgkin lymphoma.",
"title_normalized": "radiation therapy for hodgkin lymphoma"
} | [
{
"companynumb": "BE-JNJFOC-20150305210",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nRecent studies have shown that QT interval prolongation is associated with disease severity and predicts mortality in systemic inflammatory diseases, particularly rheumatoid arthritis. Systemic pro-inflammatory cytokines released from synovial tissues in rheumatoid arthritis, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, could have direct effects on cardiac electrophysiology, particularly changes in the expression and function of potassium and calcium channels, resulting in QT interval prolongation on surface electrocardiogram (ECG) and an increased predisposition to develop lethal ventricular arrhythmias. However, reports on torsade de pointes (TdP) due to acquired long QT syndrome in patients with polymyalgia rheumatica (PMR) are limited.\nAn 85-year-old Japanese woman with active PMR developed first syncope.\n\n\nMETHODS\nFrequent premature atrial contractions (PACs) with multiple patterns of aberrant conduction, QT interval prolongation, and morphological T-U wave variability followed by TdP were documented. PACs were the first beat of TdP.\n\n\nMETHODS\nAmiodarone, together with magnesium and potassium, was intravenously administered. However, TdP resulted in a ventricular arrhythmic storm, for which sedation with mechanical ventilatory support, temporary overdrive cardiac pacing, and intravenous landiolol administration in addition to multiple direct current shocks were effective.\n\n\nRESULTS\nApproximately 2 years later, the patient was treated with amiodarone, propranolol, and prednisolone. She did not undergo implantable cardioverter-defibrillator implantation and was quite well, with no recurrence of ventricular tachyarrhythmia.\n\n\nCONCLUSIONS\nIL-6 hyperproduction in inflamed tissues has been widely confirmed in PMR. Frequent PACs with various patterns of aberrant conduction, QT interval prolongation, and morphological T-U wave variability followed by TdP, for which IL-6-mediated enhancement of L-type Ca2+ current and inhibition of the rapid component of the delayed rectifier K+ current are the most likely mechanisms, were documented in an elderly Japanese woman with PMR. ECG may be recorded once in patients with active PMR even when these patients do not complain of palpitation or syncope. If QT interval prolongation or arrhythmia, including even PACs, is observed, follow-up ECG may be warranted, particularly for patients with some risk factors for QT prolongation that could lead to TdP, such as advanced age, female sex, hypopotassemia, and polypharmacy.",
"affiliations": "Department of Community Emergency Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.;Department of Cardiology, Yawatahama City General Hospital, Ehime, Japan.;Department of Community Emergency Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.;Department of Cardiology, Yawatahama City General Hospital, Ehime, Japan.;Department of Cardiology, Yawatahama City General Hospital, Ehime, Japan.;Department of Cardiology, Yawatahama City General Hospital, Ehime, Japan.;Department of Community Emergency Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.;Department of Medical Engineering, Yawatahama City General Hospital, Ehime, Japan.;Department of Medical Engineering, Yawatahama City General Hospital, Ehime, Japan.;Department of Medical Engineering, Yawatahama City General Hospital, Ehime, Japan.;Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Ehime, Japan.;Higuchi Internal Medicine Clinic, Ehime, Japan.",
"authors": "Takahashi|Koji|K|0000-0003-3826-3941;Yamashita|Mina|M|;Sakaue|Tomoki|T|;Enomoto|Daijiro|D|;Uemura|Shigeki|S|;Okura|Takafumi|T|;Ikeda|Shuntaro|S|;Takemoto|Masafumi|M|;Utsunomiya|Yutaka|Y|;Hyodo|Takashi|T|;Ochi|Masayuki|M|;Higuchi|Satoshi|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000027286",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-04154\n10.1097/MD.0000000000027286\n27286\n3400\nResearch Article\nClinical Case Report\nPremature atrial contractions with multiple patterns of aberrant conduction followed by torsade de pointes in a patient with polymyalgia rheumatica\nA case report\nhttp://orcid.org/0000-0003-3826-3941\nTakahashi Koji MD, PhD a b ∗\nYamashita Mina MD b\nSakaue Tomoki MD, PhD a b\nEnomoto Daijiro MD, PhD b\nUemura Shigeki MD b\nOkura Takafumi MD, PhD b\nIkeda Shuntaro MD, PhD a b\nTakemoto Masafumi ME c\nUtsunomiya Yutaka ME c\nHyodo Takashi ME c\nOchi Masayuki MD, PhD d\nHiguchi Satoshi MD e\nSaranathan. Maya\na Department of Community Emergency Medicine, Ehime University Graduate School of Medicine, Ehime, Japan\nb Department of Cardiology, Yawatahama City General Hospital, Ehime, Japan\nc Department of Medical Engineering, Yawatahama City General Hospital, Ehime, Japan\nd Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Ehime, Japan\ne Higuchi Internal Medicine Clinic, Ehime, Japan.\n∗ Correspondence: Koji Takahashi, Department of Cardiology, Yawatahama City General Hospital, 1-638 Ohira, Yawatahama, Ehime 796-8502, Japan (e-mail: michitokitatsumasa@gmail.com).\n17 9 2021\n17 9 2021\n100 37 e2728614 6 2021\n18 8 2021\n2 9 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nRecent studies have shown that QT interval prolongation is associated with disease severity and predicts mortality in systemic inflammatory diseases, particularly rheumatoid arthritis. Systemic pro-inflammatory cytokines released from synovial tissues in rheumatoid arthritis, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, could have direct effects on cardiac electrophysiology, particularly changes in the expression and function of potassium and calcium channels, resulting in QT interval prolongation on surface electrocardiogram (ECG) and an increased predisposition to develop lethal ventricular arrhythmias. However, reports on torsade de pointes (TdP) due to acquired long QT syndrome in patients with polymyalgia rheumatica (PMR) are limited.\n\nPatient concerns:\n\nAn 85-year-old Japanese woman with active PMR developed first syncope.\n\nDiagnosis:\n\nFrequent premature atrial contractions (PACs) with multiple patterns of aberrant conduction, QT interval prolongation, and morphological T-U wave variability followed by TdP were documented. PACs were the first beat of TdP.\n\nInterventions:\n\nAmiodarone, together with magnesium and potassium, was intravenously administered. However, TdP resulted in a ventricular arrhythmic storm, for which sedation with mechanical ventilatory support, temporary overdrive cardiac pacing, and intravenous landiolol administration in addition to multiple direct current shocks were effective.\n\nOutcomes:\n\nApproximately 2 years later, the patient was treated with amiodarone, propranolol, and prednisolone. She did not undergo implantable cardioverter-defibrillator implantation and was quite well, with no recurrence of ventricular tachyarrhythmia.\n\nLessons:\n\nIL-6 hyperproduction in inflamed tissues has been widely confirmed in PMR. Frequent PACs with various patterns of aberrant conduction, QT interval prolongation, and morphological T-U wave variability followed by TdP, for which IL-6-mediated enhancement of L-type Ca2+ current and inhibition of the rapid component of the delayed rectifier K+ current are the most likely mechanisms, were documented in an elderly Japanese woman with PMR. ECG may be recorded once in patients with active PMR even when these patients do not complain of palpitation or syncope. If QT interval prolongation or arrhythmia, including even PACs, is observed, follow-up ECG may be warranted, particularly for patients with some risk factors for QT prolongation that could lead to TdP, such as advanced age, female sex, hypopotassemia, and polypharmacy.\n\nKeywords\n\nβ-blocker\nelectrical storm\ninterleukin-6\npolymyalgia rheumatica\npremature atrial contraction\ntorsade de pointes\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nPremature atrial contractions (PACs) are common in all ages and increase with age.[1] PACs are commonly idiopathic in the setting of a structurally normal heart, and the structural causes of PACs include various heart diseases. Medical pathologies associated with increased PACs include hypertension, diabetes mellitus, chronic obstructive pulmonary disorder, infection, and inflammation.[1,2] Many PACs are considered benign electrophysiological phenomena, and prognosis is generally dependent on the underlying cause of the PACs and the presence of structural cardiac disease, although PACs originating in the pulmonary veins are initiators of most atrial fibrillations and have been shown to be associated with a greater risk of ischemic stroke development.[3]\n\nRecent studies have shown that the QT interval prolongation is associated with disease severity and inflammatory markers, and predicts mortality in systemic inflammatory diseases, particularly rheumatoid arthritis.[4] Systemic pro-inflammatory cytokines released from synovial tissues in rheumatoid arthritis, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, could have direct effects on cardiac electrophysiology, particularly changes in the expression and function of potassium and calcium channels, resulting in a prolonged effect on the cardiomyocyte action potential duration and thereby affecting the QT interval prolongation on surface electrocardiogram (ECG) and an increased predisposition to develop lethal ventricular arrhythmias. However, reports on torsade de pointes (TdP) due to acquired long QT syndrome (LQTS) in patients with polymyalgia rheumatica (PMR), which is a common, chronic, systemic rheumatic inflammatory disease that affects adults older than 50 years,[5] are limited.[6]\n\nWe encountered a case of active PMR in which frequent PACs with multiple patterns of aberrant conduction (such as right bundle branch block [RBBB], left anterior fascicular block [LAFB], left septal fascicular block [LSFB], or left posterior fascicular block [LPFB]), QT interval prolongation, and morphological T-U wave variability followed by TdP polymorphic ventricular tachycardia that led to an electrical storm were documented.[7–9] PACs were the first beat of TdP. Informed consent was obtained from the patient for the publication of this case report and accompanying images.\n\n2 Case presentation\n\nAn 85-year-old Japanese woman was transferred by ambulance to Yawatahama City General Hospital because of transient loss of consciousness. She had no history of smoking or alcohol consumption. Her medical history included long-standing hypertension, dyslipidemia, bronchial asthma, chronic renal disorder, hyperuricemia, and silent cerebral infarction, but she had no angina pectoris. She had been prescribed oral valsartan (40 mg/day), amlodipine besylate (7.5 mg/day), trichlormethiazide (1 mg/day), atorvastatin calcium hydrate (5 mg/day), and cilostazol (200 mg/day) at another clinic. Dry powder inhalers containing budesonide and formoterol fumarate dihydrate (2 puffs/day) were also prescribed. She underwent bilateral total knee arthroplasty for osteoarthritis at 10 years prior. Her ECG recorded in the clinic at 1 year prior revealed slight QT interval prolongation and multiple PACs without aberrant conduction (Fig. 1).\n\nFigure 1 An electrocardiogram (ECG) recorded in another clinic at 1 yr before admission. The ECG shows sinus rhythm and multiple premature atrial contractions (PACs) with no aberrant conduction. The coupling interval between the PAC and the preceding sinus beat is not fixed. The heart rate-corrected QT intervals, calculated using the Bazett formula to adjust the measured QT interval for cycle length by dividing the observed uncorrected QT interval by the square root of the R-R interval, are 470 ms.\n\nAt 7 days prior, she visited the Department of Neurology and the Department of Surgery at Yawatahama City General Hospital because of headache and stiffness in the neck and bilateral shoulders lasting for several weeks. At that time, her temperature was 37.6°C; pulse rate, 57 beats/minute with bigeminal rhythm; systemic blood pressure, 150/55 mm Hg; and oxygen saturation on room air measured using a pulse oximeter, 96%. Her blood tests revealed marked inflammatory response (C-reactive protein, 20.84 mg/dL; erythrocyte sedimentation rate, 99 mm/hour), microcytic hypochromic anemia with hemoglobin concentration of 9.8 g/dL, and renal dysfunction with an estimated glomerular filtration rate of 15 mL/minute/1.73 m2. The serum potassium concentration was 4.4 mEq/L. ECG revealed sinus rhythm and atrial bigeminy. Some PACs had incomplete or complete RBBB and RBBB-like QRS configuration, which may be due to aberrant conduction (Fig. 2). The echocardiogram showed a normal left ventricular ejection fraction of 64%, a slightly dilated left ventricle with an end-diastolic dimension of 48.3 mm, a slightly dilated left atrium with a volume of 58.1 mL/m2, and a normal interventricular septal wall thickness of 7.8 mm. Moderate aortic valvular stenosis with a maximum aortic jet velocity of 3.6 m/second, mean transvalvular pressure gradient of 25 mm Hg, or continuity equation valve area of 1.0 cm2 assessed by Doppler echocardiography was observed. Oral acetaminophen (1500 mg/day) was administered. Thereafter, the patient was diagnosed with PMR, and acetaminophen was replaced with prednisolone (20 mg/day).\n\nFigure 2 An electrocardiogram (ECG) recorded at 7 d before admission. The ECG shows sinus rhythm and atrial bigeminy. The coupling interval, defined as the interval between a premature atrial contraction (PAC) and a preceding sinus beat, is almost fixed at 450 ms. The P-wave duration is 90 ms in sinus beats and 100 ms in PACs. The PR duration is 140 ms for sinus beats and 110 ms for PACs. Some PACs have aberrant conduction of incomplete (the 4th beat) or complete right bundle branch block (RBBB) (the 12th and 16th beats) and left posterior fascicular block morphology. The QRS-ST-T morphology in the remaining PACs is also slightly different from that in sinus beats, indicating mild aberrant conduction; a slight shift of the QRS axis in the frontal plane and rsr's’ pattern in lead V1 together with an increase in the depth of s-waves in the left precordial leads are seen in the 2nd, 6th, 8th, and 10th beats, though to reflect incomplete RBBB-like morphology with disappearance of “incomplete” left anterior fascicular block. In PACs, the QT interval and the Tpeak–Tend interval are approximately 370 and 110 ms, respectively, but T-waves merge with U-waves in some PACs (the 12th, 14th, and 16th beats).\n\nIn the emergency room, her temperature was 36.5°C, pulse rate was 51 beats/minute, systemic blood pressure was 161/52 mm Hg, respiratory rate was 18 breaths/minute, and oxygen saturation was 100% at a flow rate of 3 L/minute over an oxygen mask. On auscultation, there was a systolic ejection murmur of grade 4/6, but with no rales in the lung fields. The liver was palpable with a two-finger breadth along the right midclavicular line below the costal margin. Mild pretibial edema was observed.\n\nThe blood tests revealed a high-sensitivity cardiac troponin I level of 12.7 pg/mL, which was below the reference range (≤16.0 pg/mL), but a brain natriuretic peptide level of 293.1 pg/mL, over the reference range (≤18.4 pg/mL). Her C-reactive protein level decreased to 3.02 mg/dL. The serum potassium concentration was 4.1 mEq/L, and magnesium concentration was not measured. A chest radiograph obtained with the patient in the supine position did not show pulmonary congestion. The ECG revealed sinus rhythm and atrial bigeminy with alternating RBBB morphology and non-RBBB morphology (Fig. 3). The echocardiogram showed no remarkable changes in findings that were recorded at 7 days prior.\n\nFigure 3 Electrocardiogram (ECG) recorded at admission. The ECG shows sinus rhythm and atrial bigeminy. The coupling interval between a premature atrial contraction (PAC) and a preceding sinus beat is almost fixed at 460 ms. The P-wave duration is 95 ms in sinus beats and 90 ms in PACs. The PR duration is 145 ms in sinus beats and 160 ms in PACs, together with PR-segment depression in PACs. All PACs have aberrant conduction. In the 2nd, 6th, 10th, and 14th beats, complete right bundle branch block plus left posterior fascicular block (LPFB) morphology is seen together with the increased height of the R-waves in lead V2 compared to that in sinus beats suggestive of “incomplete” or “complete” left septal fascicular block (LSFB). In the 8th and 12th beats, left anterior fascicular block (LAFB) and LPFB morphologies are observed, respectively. A slight shift of the QRS axis in the frontal plane and the increased height of the R-waves in lead V2 compared to that in sinus beats, thought to reflect the disappearance of “incomplete” LAFB and appearance of “incomplete” LSFB, are seen in the 4th and 16th beats. In PACs, morphological T-U wave variability is observed, and QT (QU) intervals are fluctuated. The longest QT (QU) interval and the Tpeak–Tend interval are over 500 and 200 ms, respectively, although the end of the T-waves is difficult to determine because T-waves merge with U-waves in some PACs.\n\nNon-sustained TdP ventricular tachycardia was documented in the emergency room; thus, intravenous administration of amiodarone hydrochloride, together with magnesium and potassium, was started at a dose of 50 mg/hour without initial loading infusions of 125 mg over the first 10 minutes. Approximately 6 hours after starting intravenous administration of amiodarone hydrochloride, non-sustained TdP continued (Fig. 4). Thus, intravenous administration of amiodarone hydrochloride was stopped, and nifekalant hydrochloride was intravenously administered at 20 mg over the first 3 minutes, followed by 500 mg over the next 24 hours. However, multiple sustained ventricular tachycardias or ventricular flutter with hemodynamic collapse requiring direct current shocks to resuscitate developed. The patient was diagnosed with a ventricular electrical storm. First, deep sedation to alleviate the sympathetic overdrive by achieving Richmond Agitation and Sedation Scale values below −2 with the use of one-shot intravenous administration of thiopental sodium followed by continuous intravenous administration of dexmedetomidine hydrochloride, along with mechanical ventilation after orotracheal intubation, was performed. Second, temporary overdrive cardiac pacing was performed. Subsequently, the ventricular tachyarrhythmia disappeared. However, non-sustained ventricular tachycardia was documented at the time of stopping temporary pacing on the 2nd hospital day. Intravenous administration of nifekalant hydrochloride was discontinued, and intravenous administration of amiodarone hydrochloride was resumed at a maintenance dose of 600 mg/day. Moreover, intravenous administration of landiolol hydrochloride was started at 1.5 μg/kg/minute and increased by 1.5 μg/kg/minute every 30 minutes to a maximum of 10 μg/kg/minute without recurrence of ventricular tachyarrhythmia even after stopping cardiac pacing.\n\nFigure 4 Rhythm strips of continuous electrocardiograms from bedside cardiac monitors recorded at approximately 1 h after admission. A bigeminal rhythm due to sinus beats and premature atrial contractions (PACs), including non-conducted PACs (black arrowheads), is observed. The QRS-ST configuration of PACs, arising from the nadir of giant T-U waves (black arrows), followed by a bizarre premature ventricular beat falling atop the T-wave, shows a massive ST-segment elevation thought to be caused by a transmural conduction block (asterisks). Additionally, five sets of torsade de pointes (TdP) non-sustained ventricular tachycardias are observed. There are two initiation patterns of TdP events with or without the QRS complex of the first TdP beat arising from giant negative T-U waves (black arrows). All TdP events are initiated with a short–long–short R–R cycle sequence and spontaneously terminated. PACs are the first beat of TdP. The coupling interval, defined as the interval between the first beat of TdP and the preceding sinus beat (double-headed green arrows), is over 500 ms, suggesting “true” TdP. The double-headed orange arrows and double-headed red arrows indicate the short–long–short R–R cycle sequence and TdP, respectively. Blue arrowheads indicate the conducted PACs. During sinus rhythm with non-conducted PACs in a pattern of atrial bigeminy, the QT, and heart rate-corrected QT (QTc) intervals of sinus beats are 600 and 550 ms, respectively. The QTc was calculated using the Bazett formula to adjust the measured QT interval for cycle length by dividing the observed uncorrected QT interval by the square root of the R–R interval.\n\nOn the 6th hospital day, 30 mg/day propranolol hydrochloride was administered via a nasogastric tube, and the dose of landiolol hydrochloride was initially reduced from 10 μg/kg/minute to 7 μg/kg/minute, then from 7 μg/kg/minute to 5 μg/kg/minute, and subsequently by 1 μg/kg/minute increments every 24 hours. The patient ultimately stopped landiolol hydrochloride treatment without recurrent ventricular extrasystoles. On the 8th hospital day, amiodarone hydrochloride was continued with a dose reduction from 600 mg/day administered intravenously to 200 mg/day administered via a nasogastric tube. On the 9th hospital day, the patient was weaned off the mechanical ventilator and extubated after stopping intravenous administration of dexmedetomidine hydrochloride.\n\nCardiac catheterization was performed on the 17th day of hospitalization. She had a cardiac index of 3.90 L/minute/m2 and a mean pulmonary capillary wedge pressure of 13 mm Hg. Coronary angiography revealed a narrowing without thrombi in the proximal left circumflex coronary artery (Fig. 5). The instantaneous wave-free ratio obtained with the use of a coronary-pressure guidewire was 0.84; thus, the patient was diagnosed with silent myocardial ischemia. An intravascular ultrasonography-guided everolimus-eluting platinum chromium coronary stent was successfully deployed to the lesion without residual stenosis. Diagnostic genetic testing for LQTS revealed a p.Ala283Val missense variant in KCNQ1.\n\nFigure 5 Coronary angiograms. Coronary angiograms reveal severe narrowing without thrombi or washout delay of the contrast medium at the posterolateral branch of the left circumflex coronary artery (LC) (panels B and C), but no significant stenosis is found in the right coronary artery or left anterior descending coronary artery (panels A–C). A coronary stent is successfully deployed to the lesion without residual stenosis (panel D). Arrowheads indicate severe stenosis of the LC.\n\nApproximately 2 years later, the patient was treated with amiodarone (50 mg/day), propranolol (30 mg/day), and prednisolone (10 mg/day). She did not undergo implantable cardioverter-defibrillator implantation and was quite well, with no recurrence of ventricular tachyarrhythmia.\n\n3 Discussion\n\nThe points of this case report are as follows:\n\n(i) frequent PACs with various patterns of aberrant conduction, QT interval prolongation, and morphological T-U wave variability were observed;\n\n(ii) TdP was induced by PAC but not premature ventricular contraction; and\n\n(iii) TdP occurrence could be associated with the disease activity of PMR.\n\nThe most noticeable ECG finding in our patient was frequent PACs with various QRS-ST-T configurations thought to be RBBB, LAFB, LSFB, LPFB, or a combination of these blocks (Fig. 3).[7,8] In general, these morphological changes in PACs may be due to aberrant ventricular conduction. If a PAC occurs while the atrioventricular node and His-Purkinje system are still refractory, the conducted beat will become aberrant. As the refractory period of the right bundle is slightly longer than that of the left bundle, the aberrantly conducted beat typically shows an RBBB morphology. In 1976, Kulbertus et al reported that multiple patterns of aberrant ventricular conduction were induced in several patients after the introduction of PACs through a transvenous electrode catheter.[10] In our patient, PACs with multiple patterns of aberrant conduction, including LAFB alone, RBBB plus LPFB, RBBB plus LPFB and LSFB, were spontaneously documented and were not by an experiment. Moreover, Kulbertus et al also pointed out that some patterns of aberrant conduction could not be readily classified into the usual categories of intraventricular conduction defects,[10–12] despite being obviously different in shape from the control (Figs. 2 and 3). The degree of aberrancy seemed to worsen for only a week (Figs. 2 and 3). The coupling intervals between PACs and preceding sinus beats were fixed even on admission, indicating unifocal PACs, and were almost the same as those at 7 days prior. Thus, these morphological changes in QRS-ST-T configurations in PACs could be unlikely due to Ashman's phenomenon as a physiological aberration and have a pathologic nature because the conduction disturbance does not comply with the “aberrancy rule.” While PACs as an initiation of ventricular tachyarrhythmia are uncommon, the atrial impulse propagates through the atrioventricular node and into the cardiac ventricles; such atrial impulse can induce ventricular tachyarrhythmia.[13,14]\n\nIn our patient, frequent PACs were documented at 1 year prior to TdP occurrence. Thus, we failed to establish any of the abovementioned triggering factors for PACs.[1,2] However, frequent PACs with QT interval prolongation, prolonged Tpeak–Tend interval, and morphological T-U wave variability reflecting the spatial dispersion of ventricular repolarization used as non-invasive markers for predicting the risk of malignant cardiac arrhythmias were thought to result from active inflammation due to PMR (Fig. 3).[9,15] Nonetheless, accurate QT interval assessment appeared to be difficult because almost all heartbeats showed sinus rhythm with PACs in a pattern of atrial bigeminy. In general, extra systoles and the beat directly following an extra systole should not be included in QT interval measurement.[16] In PMR, the role of circulating IL-6, mainly produced in inflamed tissues, appears dominant, and IL-6 hyperproduction has been widely confirmed. Circulating IL-6 prolongs the action potential duration by enhancing L-type Ca2+ current (ICa,L), which causes phase 2 early afterdepolarization.[17] Moreover, IL-6 inhibits the rapid component of the delayed rectifier K+ current (Ikr), prolonging the action potential duration and QT interval.[18] Although serum IL-6 levels were not measured, IL-6-mediated enhancement of ICa,L and inhibition of IKr are the most likely mechanisms for QT interval prolongation and morphological T-U wave variability in our patient, leading to TdP. Moreover, most patients with acquired LQTS have one or more risk factors, such as advanced age, female sex, hypopotassemia, latent congenital LQTS, and polypharmacy.[19] In our elderly female patient, the QT interval was slightly prolonged at 1 year prior (Fig. 1), and diagnostic genetic testing for LQTS revealed the p.Ala283Val missense variant in KCNQ1. Nevertheless, we consider that this is a variant of uncertain significance because there is insufficient information to support a more definitive classification of this variant at this time. On the contrary, cilostazol, which was prescribed at another clinic, is a selective phosphodiesterase type III inhibitor that has a likely mechanism for QT interval prolongation resulting from ICa,L-mediated action potential prolongation.[20]\n\nIn our patient, all TdP events had a short–long–short sequence preceding TdP. In these TdP events, the main mechanism underlying QT interval prolongation was likely IKr blockade.[21] Furthermore, the coupling interval, defined as the interval between the first beat of TdP and the preceding sinus beat, was over 500 millisecond, suggesting “true” TdP related to QT interval prolongation[22]; however, there were two initiation patterns of TdP events (Fig. 4). In the third and fifth TdP events, the QRS complex of the first TdP beat arose from giant negative T-U waves[19,23]; conversely, in the first, second, and fourth TdP events, it did not. The latter might be a short-coupled variant of TdP with a coupling interval of approximately 300 millisecond to the preceding PAC, considering the difficulty in determination by ECG monitoring only. If so, these TdP events signify Purkinje-related ventricular tachyarrhythmias.[24] Purkinje cells differ from ventricular myocytes with respect to electrical membrane properties, ionic currents, and ion-channel expression, with the former being more arrhythmogenic than the latter.[25] The most notable difference lies in Ca2+ handling; distinct proarrhythmic Ca2+-mediated mechanisms can lead to the ectopic afterdepolarization of Purkinje cells related to a highly prevalent triggered activity. In our patient, the PR duration in PACs on admission was longer than that at 7 days prior, irrespective of the absence of an interval change in P-wave duration (Figs. 2 and 3). This indicates a conduction abnormality in the atrioventricular node and His-Purkinje network, resulting in a preferential anterograde block, allowing retrograde conduction only.[25] Aberrant excitation patterns can also lead to a unidirectional block, which predisposes to re-entry formation. IL-6-mediated enhancement of ICa,L and inhibition of IKr in PMR, as well as that of ventricular myocytes, also prolong the action potential duration of Purkinje cells. Even in LQTS, Purkinje tissues are thought to be an important trigger of TdP.[26]\n\nA ventricular electrical storm, which is a state of cardiac electrical instability, is a life-threatening syndrome characterized by clustering of recurrent episodes of ventricular tachyarrhythmia within a relatively short period of time.[27,28] Acute management is aimed at reducing the burden of ventricular tachyarrhythmias and improving survival.[29] Triggers for electrical storms, such as myocardial ischemia as shown in our patient, acute heart failure, electrolyte disorders, hypoxia, and drug-related arrhythmogenicity, have to be screened for and immediately corrected,[30] although a trigger is identified only in 10% to 15% of patients.[28] An anti-arrhythmic drug regimen of β-blockers, amiodarone, sotalol, lidocaine, or quinidine should be considered in the acute phase to suppress further ventricular tachyarrhythmias. These drugs may be sequentially administered or a selection of them may be combined, if needed, with caution owing to the risk of potential proarrhythmia. In our patient, sustained ventricular tachyarrhythmias developed after intravenous administration of nifekalant hydrochloride (an IKr-selective blocking agent), which was switched from amiodarone hydrochloride, and might be due to the proarrhythmic reaction of these drugs.[31] Hendriks and Szili-Torok recommend that the first step in the treatment of electrical storm is the administration of β-blockers, which play a fundamental role in the management of electrical storms by blocking the sympathetic system.[29] Furthermore, they mentioned that propranolol, a lipophilic unselective β-blocker, was more effective in suppressing ventricular tachyarrhythmias than metoprolol and amiodarone. In our patient, landiolol hydrochloride, an ultra-short-acting β1-superselective β-adrenergic blocker, was considered highly effective, although we prescribed propranolol hydrochloride in the subacute to chronic phase. If we administered a β-adrenergic blocker to the patient before sustained ventricular tachycardia developed, an electrical storm might not occur. Moreover, calcium channel blockers, such as verapamil, might be effective in suppressing ICa,L via IL-6 hyperproduction in patients with PMR. Verapamil has been reported to be effective against some types of acquired LQTS.[32] When a ventricular electrical storm remains intractable despite aggressive anti-arrhythmic therapies, deep sedation must be considered, along with mechanical ventilation.[33] High-rate pacing for pause-dependent TdP, such as LQTS-related TdP as shown in our patient, would be effective, and administration of β-blockers or calcium channel blockers under temporary pacing would be preferable to prevent pauses that trigger TdP.[19,21] We considered that ventricular tachyarrhythmias could be suppressed by drug therapy; hence, implantation of an implantable cardioverter-defibrillator as the first-line treatment option for secondary prevention against sudden cardiac death was not required in our patient.\n\nIn conclusion, frequent PACs with various patterns of aberrant conduction, QT interval prolongation, and morphological T-U wave variability, for which IL-6-mediated enhancement of ICa,L and inhibition of IKr are the most likely mechanisms, were the first beats of TdP in an elderly Japanese woman with PMR. Irrespective of an intravenous administration of anti-arrhythmic drugs together with magnesium and potassium, TdP resulted in a ventricular arrhythmic storm. PACs in our patient might be “malignant” ectopies, which masquerade as “benign” beats, leading to lethal ventricular tachyarrhythmia. ECG may be recorded once in patients with active PMR even when these patients do not complain of palpitation or syncope. If QT interval prolongation or arrhythmia, including even PACs, is observed, follow-up ECG may be warranted, particularly for patients with some risk factors for QT prolongation that could lead to TdP, such as advanced age, female sex, hypopotassemia, latent congenital LQTS, underlying structural heart diseases, impairment in hepatic drug metabolism, and polypharmacy. Further studies involving larger case numbers are necessary to clarify the relationship between the QT interval and disease activity in patients with PMR.\n\nAcknowledgments\n\nThe authors thank Editage (www.editage.com) for English language editing.\n\nAuthor contributions\n\nConceptualization: Koji Takahashi.\n\nData curation: Koji Takahashi, Mina Yamashita, Tomoki Sakaue, Daijiro Enomoto, Masayuki Ochi.\n\nInvestigation: Koji Takahashi.\n\nMethodology: Koji Takahashi.\n\nResources: Masafumi Takemoto, Yutaka Utsunomiya, Takashi Hyodo, Masayuki Ochi, Satoshi Higuchi.\n\nSupervision: Koji Takahashi, Shigeki Uemura, Takafumi Okura, Shuntaro Ikeda.\n\nVisualization: Koji Takahashi.\n\nWriting – original draft: Koji Takahashi, Takafumi Okura, Shuntaro Ikeda.\n\nWriting – review & editing: Koji Takahashi, Takafumi Okura, Shuntaro Ikeda.\n\nAbbreviations: ECG = electrocardiogram, ICa,L = L-type Ca2+ current, Ikr = rapid component of the delayed rectifier K+ current, IL = interleukin, LAFB = left anterior fascicular block, LPFB = left posterior fascicular block, LQTS = long QT syndrome, LSFB = left septal fascicular block, PAC = premature atrial contraction, PMR = polymyalgia rheumatica, RBBB = right bundle branch block, TdP = torsade de pointes.\n\nHow to cite this article: Takahashi K, Yamashita M, Sakaue T, Enomoto D, Uemura S, Okura T, Ikeda S, Takemoto M, Utsunomiya Y, Hyodo T, Ochi M, Higuchi S. Premature atrial contractions with multiple patterns of aberrant conduction followed by torsade de pointes in a patient with polymyalgia rheumatica: A case report. Medicine. 2021;100:37(e27286).\n\nThe authors have no funding and conflicts of interest to disclose.\n\nAll authors attest that this case report is in compliance with regulations by the human study committees of the authors’ institutions and with the Food and Drug Administration guidelines, including patient consent, where appropriate.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n\n[1] Conen D Adam M Roche F . Premature atrial contractions in the general population: frequency and risk factors. Circulation 2012;126 :2302–8.23048073\n[2] Rao PB Singh N Ramalingam B . Dexmedetomidine-induced atrial premature complex. Ann Card Anaesth 2016;19 :347–50.27052083\n[3] Haïssaguerre M Jaïs P Shah DC . Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339 :659–66.9725923\n[4] Lazzerini PE Capecchi PL Laghi-Pasini F . Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis. Eur Heart J 2017;38 :1717–27.27252448\n[5] Matteson EL Dejaco C . Polymyalgia rheumatica. Ann Intern Med 2017;166 :ITC65–80.28460395\n[6] Lazzerini PE Bertolozzi I Acampa M Fulceri R Laghi-Pasini F Capecchi PL . Torsades de pointes in patients with polymyalgia rheumatica. Curr Pharm Des 2018;24 :323–40.29332573\n[7] Surawicz B Childers R Deal BJ . AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part III: intraventricular conduction disturbances: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol 2009;53 :976–81.19281930\n[8] Pérez Riera AR Ferreira C Ferreira Filho C . Electrovectorcardiographic diagnosis of left septal fascicular block: anatomic and clinical considerations. Ann Noninvasive Electrocardiol 2011;16 :196–207.21496172\n[9] Kurokawa S Niwano S Kiryu M . Importance of morphological changes in T-U waves during bepridil therapy as a predictor of ventricular arrhythmic event. Circ J 2010;74 :876–84.20354335\n[10] Kulbertus HE de Laval-Rutten F Casters P . Vectorcardiographic study of aberrant conduction anterior displacement of QRS: another form of intraventricular block. Br Heart J 1976;38 :549–57.1275985\n[11] Kodama K Hamada M Hiwada K . Transient leftward QRS axis shift during treadmill exercise testing or percutaneous transluminal coronary angioplasty is a highly specific marker of proximal left anterior descending coronary artery disease. Am J Cardiol 1997;79 :1530–4.9185649\n[12] Takahashi K Sakaue T Yamashita M . Variant angina with spontaneously documented ischemia- and tachycardia-induced “lambda” waves. Intern Med 2021;60 :1409–15.33952813\n[13] Bekheit S Turitto G Fontaine J el-Sherif N . Initiation of ventricular fibrillation by supraventricular beats in patients with acute myocardial infarction. Br Heart J 1988;59 :190–5.2449233\n[14] Kawano H Matsumoto Y Arakawa S Satoh O Hayano M . Premature atrial contraction induces torsades de pointes in a patient of Takotsubo cardiomyopathy with QT prolongation. Intern Med 2010;49 :1767–73.20720356\n[15] Antzelevitch C Burashnikov A . Overview of basic mechanisms of cardiac arrhythmia. Card Electrophysiol Clin 2011;3 :23–45.21892379\n[16] Postema PG Wilde AA . The measurement of the QT interval. Curr Cardiol Rev 2014;10 :287–94.24827793\n[17] Alvarez-Rodríguez L Lopez-Hoyos M Mata C . Circulating cytokines in active polymyalgia rheumatica. Ann Rheum Dis 2010;69 :263–9.19254903\n[18] Aromolaran AS Srivastava U Alí A . Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation. PLoS One 2018;13 :e0208321.30521586\n[19] Takahashi K Yamashita M Sakaue T . Suppression of amiodarone-induced torsade de pointes by landiolol in a patient with atrial fibrillation-mediated cardiomyopathy. Ann Noninvasive Electrocardiol 2021;e12842 Online ahead of print.33755267\n[20] Shimizu W Aiba T Antzelevitch C . Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias. Long QT syndrome and Brugada syndrome. Curr Pharm Des 2005;11 :1561–72.15892662\n[21] Tan HL Bardai A Shimizu W . Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation 2006;114 :2096–103.17088455\n[22] Rosso R Hochstadt A Viskin D . Polymorphic ventricular tachycardia, ischaemic ventricular fibrillation, and torsade de pointes: importance of the QT and the coupling interval in the differential diagnosis. Eur Heart J 2021;ehab138 Online ahead of print).33693589\n[23] Kirchhof P Franz MR Bardai A Wilde AM . Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation. J Am Coll Cardiol 2009;54 :143–9.19573731\n[24] Nogami A . Purkinje-related arrhythmias part ii: polymorphic ventricular tachycardia and ventricular fibrillation. Pacing Clin Electrophysiol 2011;34 :1034–49.21671950\n[25] Haissaguerre M Vigmond E Stuyvers B Hocini M Bernus O . Ventricular arrhythmias and the His-Purkinje system. Nat Rev Cardiol 2016;13 :155–66.26727298\n[26] Haïssaguerre M Extramiana F Hocini M . Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes. Circulation 2003;108 :925–8.12925452\n[27] Maruyama M . Management of electrical storm: the mechanism matters. J Arrhythm 2014;30 :242–9.\n[28] Sagone A . Electrical storm: incidence, prognosis and therapy. J Atr Fibrillation 2015;8 :1150.27957218\n[29] Hendriks AA Szili-Torok T . Editor's choice – the treatment of electrical storm: an educational review. Eur Heart J Acute Cardiovasc Care 2018;7 :478–83.30035628\n[30] Haegeli LM Della Bella P Brunckhorst CB . Management of a patient with electrical storm: role of epicardial catheter ablation. Circulation 2016;133 :672–6.26884622\n[31] Tagami T Matsui H Ishinokami S . Amiodarone or nifekalant upon hospital arrival for refractory ventricular fibrillation after out-of-hospital cardiac arrest. Resuscitation 2016;109 :127–32.27568110\n[32] Aiba T Shimizu W Inagaki M . Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil. J Am Coll Cardiol 2005;45 :300–7.15653031\n[33] Kowlgi GN Cha YM . Management of ventricular electrical storm: a contemporary appraisal. Europace 2020;22 :1768–80.32984880\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "100(37)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000369:Aged, 80 and over; D018880:Atrial Premature Complexes; D000075224:Cardiac Conduction System Disease; D017023:Coronary Angiography; D004562:Electrocardiography; D005260:Female; D006801:Humans; D011111:Polymyalgia Rheumatica; D013575:Syncope; D016171:Torsades de Pointes",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e27286",
"pmc": null,
"pmid": "34664888",
"pubdate": "2021-09-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19573731;30521586;21671950;32984880;30035628;33755267;15653031;27568110;9725923;1275985;29332573;20720356;28460395;9185649;33952813;33693589;23048073;26727298;2449233;19281930;17088455;21496172;15892662;19254903;27052083;27957218;24827793;27252448;26884622;20354335;21892379;12925452",
"title": "Premature atrial contractions with multiple patterns of aberrant conduction followed by torsade de pointes in a patient with polymyalgia rheumatica: A case report.",
"title_normalized": "premature atrial contractions with multiple patterns of aberrant conduction followed by torsade de pointes in a patient with polymyalgia rheumatica a case report"
} | [
{
"companynumb": "JP-TEVA-2022-JP-1997436",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CILOSTAZOL"
},
"drugadditional": "3",
... |
{
"abstract": "Gingival hypertrophy (GH) is a well-known physical manifestation due to inflammatory conditions, pregnancy, vitamin C deficiency, systemic diseases like leukemia, Wegners granulomatosis, and various drugs like anticonvulsants, immunosuppresant, and calcium channel blockers (CCBs).We present here a case of a 45-year-old woman, who has been taking Amlodipine 10mg once a day together with Atenelol 50mg per day for one and half years, and has subsequently developed gum hypertrophy. This manifestation was reversed after stopping of Amlodipine. Though this case presentation is described in literature, we hereby present it in a pictorial form, to sensitize the treating physician toward it.",
"affiliations": "Senior Resident, Department of Medicine, University College of Medical Sciences & Guru Teg Bahadur Hospital (University of Delhi), Delhi110095, India. Electronic address: drlaxmikantucms@gmail.com.;Assistant Professor, Department of Medicine, University College of Medical Sciences & Guru Teg Bahadur Hospital (University of Delhi), Delhi110095, India.",
"authors": "Tomar|L R|LR|;Aggarwal|A|A|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-4832",
"issue": "67(5)",
"journal": "Indian heart journal",
"keywords": "Amlodipine; Calcium channel blocker; Gingival hypertrophy",
"medline_ta": "Indian Heart J",
"mesh_terms": "D017311:Amlodipine; D002121:Calcium Channel Blockers; D003951:Diagnostic Errors; D005260:Female; D005881:Gingiva; D005886:Gingival Hypertrophy; D006801:Humans; D006973:Hypertension; D008875:Middle Aged",
"nlm_unique_id": "0374675",
"other_id": null,
"pages": "491-2",
"pmc": null,
"pmid": "26432745",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23431239;10052772;9249639;12147940;9526908",
"title": "Missing diagnosis: gingival hypertrophy due to amlodipine.",
"title_normalized": "missing diagnosis gingival hypertrophy due to amlodipine"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2015-03428",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nIt was studied the clinical management and the medical outcomes of 6 pregnancies in 5 women affected by Beta Thalassemia major, based on last guidelines and pharmacological treatments.\n\n\nBACKGROUND\nPaediatric Department and Department of Obstetrics and Gynaecology of the University of Catania.\n\n\nMETHODS\nThese patients were taken among a group of 116 women affected by beta-thalassemia major divided into three subgroups, according to the characteristics of their menstrual cycle: 1) women with primitive amenorrhoea, 2) women with secondary amenorrhoea and 3) women with normal menstruation. Only one woman, affected by primitive amenorrhoea, needed the induction of ovulation. An accurate and detailed pre-pregnancy assessment was effected before each conception. This was constituted by a series of essays, including checks for diabetes and hypothyroidism, for B and C hepatitis and for blood group antibodies. Moreover were evaluated: cardiac function, rubella immunity and transaminases. Other pregnancy monitoring, and cares during labour and delivery were effected according to usual obstetrics practice.\n\n\nRESULTS\nAll the women were in labour when they were 38 week pregnant, and the outcome were six healthy babies born at term. There were no complications related to the pregnancy and to the immediate outcome after delivery.\n\n\nCONCLUSIONS\nThe improvements of current treatments, especially in the management of iron deposits, the prolongation of survival rate, will result in a continuous increase of pregnancies in thalassemic women. Pregnancy is now a real possibility for women affected by such disease. Although numerous complications can occur, vigilant monitoring by both experienced obstetricians and hematologists can lead to successful pregnancy outcomes (Tab. 1, Fig. 1, Ref. 16).",
"affiliations": null,
"authors": "Gulino|F A|FA|;Vitale|S G|SG|;Fauzia|M|M|;Cianci|S|S|;Pafumi|C|C|;Palumbo|M A|MA|",
"chemical_list": null,
"country": "Slovakia",
"delete": false,
"doi": "10.4149/bll_2013_109",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-9248",
"issue": "114(9)",
"journal": "Bratislavske lekarske listy",
"keywords": null,
"medline_ta": "Bratisl Lek Listy",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D055815:Young Adult; D017086:beta-Thalassemia",
"nlm_unique_id": "0065324",
"other_id": null,
"pages": "523-5",
"pmc": null,
"pmid": "24020709",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Beta-Thalassemia major and pregnancy.",
"title_normalized": "beta thalassemia major and pregnancy"
} | [
{
"companynumb": "PHHY2017FR091164",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEFEROXAMINE MESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "Cryptococcal meningitis (CM) contributes significantly to high early mortality in the setting of advanced HIV. In resource poor settings, the current HIV disease management approach is focused on commencing antiretroviral therapy (ART) on the same day of HIV diagnosis ('Test and Treat'). The HIV program in Nigeria does not currently provide CrAg screening for patients with newly diagnosed and advanced HIV disease. We report a case of severe cryptococcal meningitis presenting following the commencement of ART. There is clear benefit in the early commencement of ART among HIV infected patients and to prevent patients lost to follow-up as aimed with the 'Test & Treat' approach. However, this approach needs to be balanced against the risk of IRIS and its associated morbidity and mortality when those patients are not being properly evaluated for opportunistic infections being present without overt symptoms.",
"affiliations": "Infectious Disease Unit, Department of Medicine, Lagos University Teaching Hospital, Lagos, Nigeria.;Department of Medicine, Federal Medical Center, Ebute-Metta, Lagos, Nigeria.;Department of Medical Microbiology and Parasitology, Lagos University Teaching Hospital, Lagos, Nigeria.;Department of Medicine, Ahmadu Bello University, Zaria, Nigeria.;MRC Center for Medical Mycology, Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, UK.;College of Medicine, University of Lagos, Lagos, Nigeria.",
"authors": "Akase|Iorhen E|IE|;Olowoyo|Olamide|O|;Oladele|Rita O|RO|;Obiako|Reginald O|RO|;Warris|Adilia|A|;Akanmu|Sulaimon A|SA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2019.04.003",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30023-510.1016/j.mmcr.2019.04.003Case ReportCryptococcal meningitis after ART: Need for proper baseline evaluation in the era of ‘Test & Treat’ Akase Iorhen E. akasephraim@yahoo.coma∗Olowoyo Olamide bOladele Rita O. cdObiako Reginald O. efWarris Adilia gAkanmu Sulaimon A. dha Infectious Disease Unit, Department of Medicine, Lagos University Teaching Hospital, Lagos, Nigeriab Department of Medicine, Federal Medical Center, Ebute-Metta, Lagos, Nigeriac Department of Medical Microbiology and Parasitology, Lagos University Teaching Hospital, Lagos, Nigeriad College of Medicine, University of Lagos, Lagos, Nigeriae Department of Medicine, Ahmadu Bello University, Zaria, Nigeriaf Neurology Unit, Ahmadu Bello University Teaching Hospital, Zaria, Nigeriag MRC Center for Medical Mycology, Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, UKh Department of Haematology and Blood Transfusion, Lagos University Teaching Hospital, Lagos, Nigeria∗ Corresponding author. akasephraim@yahoo.com16 4 2019 6 2019 16 4 2019 24 58 60 25 2 2019 28 3 2019 11 4 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cryptococcal meningitis (CM) contributes significantly to high early mortality in the setting of advanced HIV. In resource poor settings, the current HIV disease management approach is focused on commencing antiretroviral therapy (ART) on the same day of HIV diagnosis (‘Test and Treat’). The HIV program in Nigeria does not currently provide CrAg screening for patients with newly diagnosed and advanced HIV disease. We report a case of severe cryptococcal meningitis presenting following the commencement of ART. There is clear benefit in the early commencement of ART among HIV infected patients and to prevent patients lost to follow-up as aimed with the ‘Test & Treat’ approach. However, this approach needs to be balanced against the risk of IRIS and its associated morbidity and mortality when those patients are not being properly evaluated for opportunistic infections being present without overt symptoms.\n\nKeywords\nCryptococcal meningitisHIVIRISNigeriaTest and Treat\n==== Body\n1 Introduction\nCryptococcal meningitis (CM) contributes significantly to high early mortality in the setting of advanced HIV [1,2] with 10–20% of HIV associated deaths in Africa attributable to cryptococcosis [3]. It is estimated that Cryptococcus spp. is the causative organism in up to 63% of meningitis cases among adults in Sub-Saharan Africa [3,4]. The global prevalence of asymptomatic cryptococcal antigenaemia is 6% [5], but various studies in Nigeria have shown a higher prevalence of cryptococcal antigenaemia among HIV patients ranging from 2.3 to 13.1% [6,7]. The true incidence of CM in Nigeria is not known, however, a study by Gomerep et al. conducted among HIV patients presenting with features of meningitis found that 36% of confirmed cases were due to cryptococcal infection [8].\n\nThere is clear evidence to show that early commencement of antiretroviral therapy (ART) in HIV patients improves outcomes [9], and reduces the incidence of AIDS defining illnesses (including cryptococcosis) especially in Western countries [10]. The reduction of cryptococcal infections in the setting of HIV within Sub-Saharan countries has been less remarkable due to the high burden of HIV infection coupled with late presentation of advanced disease, and low ART coverage [11]. The situation is further compounded by high rates of poverty, sub-standard living conditions and weak, over-burdened and poorly funded health systems [12]. In resource poor settings, the current approach is focused on commencing ART on the same day of HIV diagnosis [13]. This is in the bid to reduce the progression of HIV infection and overcome the high rates of loss to follow up due to long laboratory turnaround times delaying the diagnosis commonly encountered in these settings.\n\nThe point of care cryptococcal antigen (CrAg) lateral flow assay has been proven to be a cost effective tool in the detection of cryptococcal antigenaemia allowing pre-emptive therapy in HIV infected patients with severe immunosuppression [14]. In spite of this, the HIV program in Nigeria does not provide CrAg screening in patients with newly diagnosed and advanced HIV. Consequently, newly diagnosed HIV patients are being commenced on ART on the same day of diagnosis without proper evaluation for infections like cryptococcosis, putting them at risk of life-threatening immune reconstitution inflammatory syndrome (IRIS) [15].\n\nWe report a case of severe cryptococcal meningitis presenting following the commencement of ART on the day a diagnosis of HIV was made.\n\n2 Case\nA 52 year old business man, presented with 4 weeks history of fever and headache, and a 1 week history of impaired vision.\n\nInitially been treated for malaria, but with a poor response, he presented at the peripheral hospital where he tested positive for HIV-1 antibodies and was commenced on ART consisting of tenofovir, lamivudine and efavirenz (TDF/3TC/EFV) the same day. Consequently, his headache become worse and he developed visual disturbances, for which a referral was made to our facility. At presentation (day 0), he had low grade fever with no history of drenching sweats, significant weight loss, anorexia and headaches associated with projectile vomiting. He was noticed to have become increasingly restless requiring restraint at home, and had complained of double and blurred vision with subsequent visual loss. There was no history of seizures, no differential limb weakness, and no history of preceding behavioral changes. There was no history of cough, and review of other systems was essentially normal. He was not previously known to be hypertensive or diabetic, and had a history of occasional alcohol use, however no previous tobacco use.\n\nOn examination he had a slightly elevated temperature (37.7 °C), an elevated blood pressure (170/134 mmHg) with a heart rate of 82/min. Pallor, neck stiffness and a positive Kernig's sign, and a marked restlessness was noticed. His Glasgow Coma Score was 12 (E-4, V-3, M-5). There was photophobia, sluggishly reactive unequal pupils, with a right lateral rectus palsy as well as asymmetrical right-sided facial weakness affecting the lower part of the face, corresponding to a left upper motor neuron type facial nerve palsy, but was moving all limbs. Fundoscopy showed papilloedema.\n\nBlood cryptococcal antigen (CrAg) test (LFA) was positive. Brain MRI was reported normal, and a lumbar puncture was performed. The opening pressure was high as revealed by forceful jet of cerebrospinal fluid (CSF) (we had no access to manometers), slightly turbid, non-bloody CSF which did not form strands on standing. Qualitative CSF CrAg test was positive; however, we were unable to carry out quantitative measurement of serum and CSF CrAg due to unavailability of this test modality in our center. Gram stain revealed scanty pus cells with no organisms seen, pleocytosis with 3680 lymphocytes/μL but nil neutrophils, elevated CSF protein of 1.07 g/L, CSF glucose of 2.2 mmol/L (blood glucose 6.0 mmol/L), and CSF culture growing Cryptococcus neoformans. The CSF gene Xpert test for tuberculous meningitis was negative. HIV viral load of 1807 copies/mL (after 2 weeks on ART).\n\nDue to initial unavailability of amphotericin B and flucytosine, he was commenced on monotherapy with intravenous fluconazole 1200mg daily in 3 divided doses (day 1). Amphotericin B was eventually procured after 8 days of monotherapy with fluconazole, and he then received a combination of amphotericin B (0.7 mg/kg/day) and fluconazole (1200mg day in 3 divided doses) for another 2 weeks (day 9 to day 25). He underwent daily therapeutic lumbar punctures for the initial four days of admission, each time draining about 15 mL of CSF with satisfactory clinical response.\n\nHe received consolidation treatment (from day 26 onwards) consisting of 800mg fluconazole orally per day in 2 divided doses for 8 weeks, and is currently receiving maintenance phase treatment with 200mg of oral fluconazole once daily. The patient has made sustained clinical progress (day 165), with resolution of symptoms and reduction of the blood pressure. He however has residual blindness, and the facial nerve palsy is yet to completely resolve (see Figs. 1 and 2). He is still on follow up at our clinic.Fig. 1 Forehead wrinkling and eyelid symmetry was preserved in the patient, but he had asymmetry of the lower part of the face when he was asked to smile and bare his teeth, corresponding to a left upper motor neuron facial nerve palsy. This was still observable after completion of induction therapy with amphotericin B and fluconazole for 2 weeks.\n\nFig. 1Fig. 2 Forehead wrinkling and eyelid symmetry was preserved in the patient, but an asymmetry of the lower part of the face was observed when he was asked to smile and bare his teeth, corresponding to a left upper motor neuron facial nerve palsy, still observed at 8 weeks since start of induction treatment (amphotericin B and fluconazole 1200 mg/d) followed by consolidation treatment with oral fluconazole (800 mg/d).\n\nFig. 2\n\n3 Discussion\nThis case highlights the drawback of the ‘Test & Treat’ approach; the low level of awareness/index for suspicion for cryptococcal meningitis among clinicians, the lack of a coordinated screening program for asymptomatic cryptococcal infection among newly diagnosed HIV patients and poor access to recommended antifungal medication.\n\nThe ‘Test & Treat’ approach, which is a public health algorithm, has clearly shown benefit in overcoming delay, reducing loss to follow-up commonly observed among newly diagnosed HIV-infected patients, and reversing the progressive immunosuppression and development of new opportunistic illnesses associated with HIV infection. The major drawback of the approach, especially where the implementation is not holistic, is the development of life-threatening IRIS. In Nigeria, the delay in the availability of CD4 cell counts during initial evaluation means that patients with very low CD4+ T cell counts also commence ART on the same day of treatment without the requisite evaluations/screening tests that could be lifesaving.\n\nThis case also highlights the low level of awareness and low index of suspicion among clinicians providing HIV care in Nigeria. Even though the symptoms of headache and fever were prominent when the patient initially presented to the initial hospital, those were not properly evaluated prior to commencing ART. As such, his presentation was likely a case of cryptococcal meningitis IRIS as evidenced by the observed clinical deterioration after commencement of ART, the lymphocytosis and elevated protein in the CSF [15].\n\nCurrent guidelines recommend screening all HIV infected patients with CD4 cell counts <100 cells/mm3 using CrAg LFA kits [16], which have been found to be highly sensitive and specific, and cost effective in reducing the mortality of cryptococcal disease in HIV infected patients, not to mention the added benefit of preventing the occurrence of unmasking IRIS among those starting ART. The COAT trial has clearly demonstrated the benefit of starting ART 4–6 weeks after the use of antifungals in patients with cryptococcal meningitis [17].\n\nPresently, there is no provision to routinely screen for cryptococcosis among HIV patients with advanced HIV disease in Nigeria. Where CrAg testing is available, patients pay for the tests out of pocket. In most cases however, they get prescribed low dose oral fluconazole or ART straight away. The WHO guidelines for the care of patients with advanced HIV provides for the evaluation for opportunistic infections prior to the start of ART [18]. This is geared towards reducing the mortality associated with the occurrence of IRIS in the setting of immune recovery [15]. Among patients who present with symptoms of headache and fever, the availability of CrAg tests has simplified the procedure for evaluating HIV infected patients at risk of cryptococcal infection [19]. Patients identified with asymptomatic cryptococcal antigenaemia are pre-emptively treated with oral fluconazole. Even though primary prophylaxis with low dose oral fluconazole among HIV may reduce mortality from cryptococcosis in patients without meningitis [1], there are unintended consequences, including increasing resistance of isolates to fluconazole and high costs [20].\n\nThere is therefore an urgent need to proactively institute routine screening for the detection of asymptomatic cryptococcal antigenaemia among at risk HIV infected patients who are receiving care within the Nigerian HIV treatment program. This should be implemented along with provision of point of care test kits for measurement of baseline CD4 cell counts to better identify at risk patients. Lastly, more effort is needed to increase the awareness of the Nigerian clinician about the risk and complications of cryptococcal meningitis in HIV.\n\nIn conclusion, there is clear benefit in the early commencement of ART among HIV infected patients and to prevent patients lost to follow-up as aimed with the ‘Test & Treat’ approach. Nevertheless, this approach needs to be balanced against the risk of IRIS and its associated morbidity and mortality when those patients are not being properly evaluated for opportunistic infections being present without overt symptoms. The ‘Test & Treat’ approach needs to be optimized with point-of-care screening tests being implemented to treat asymptomatic cryptococcal infections in newly diagnosed HIV infected patients.\n\nConflict of interest\nThere are none.\n==== Refs\nReferences\n1 Post F.A. Szubert A.J. Prendergast A.J. Johnston V. Lyall H. Fitzgerald F. Causes and timing of mortality and morbidity among late presenters starting antiretroviral therapy in the REALITY trial Clin. Infect. Dis. 66 suppl_2 2018 S132 S139 29514234 \n2 Bisson G.P. Ramchandani R. Miyahara S. Mngqibisa R. Matoga M. Ngongondo M. Risk factors for early mortality on antiretroviral therapy in advanced HIV-infected adults AIDS 31 16 2017 2217 2225 28742529 \n3 Park B.J. Wannemuehler K.A. Marston B.J. Govender N. Pappas P.G. Chiller T.M. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS AIDS 23 4 2009 525 530 19182676 \n4 Jarvis J.N. Meintjes G. Williams A. Brown Y. Crede T. Harrison T.S. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases BMC Infect. Dis. 10 2010 67 20230635 \n5 Rajasingham R. Smith R.M. Park B.J. Jarvis J.N. Govender N.P. Chiller T.M. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis Lancet Infect. Dis. 17 8 2017 873 881 28483415 \n6 Ezeanolue E.E. Nwizu C. Greene G.S. Amusu O. Chukwuka C. Ndembi N. Brief report: geographical variation in prevalence of cryptococcal antigenemia among HIV-infected, treatment-naive patients in Nigeria: a multicenter cross-sectional study J. Acquir. Immune Defic. Syndr. 73 1 2016 117 121 27144527 \n7 Chukwuanukwu R. Manafa P. Iloghalu E. Onyenekwe C. Ifeanyichukwu M. Mbamalu C. Cryptococcus Neoformans Antigenemia in HIV Positive Pregnant Women Attending a PMTCT Clinic in South-East Nigeria 2013 \n8 Gomerep S.S. Idoko J.A. Ladep N.G. Ugoya S.O. Obaseki D. Agbaji O.A. Frequency of cryptococcal meningitis in HIV-1 infected patients in north central Nigeria Niger. J. Med. 19 4 2010 395 399 21526627 \n9 Group I.S.S. Lundgren J.D. Babiker A.G. Gordin F. Emery S. Grund B. Initiation of antiretroviral therapy in early asymptomatic HIV infection N. Engl. J. Med. 373 9 2015 795 807 26192873 \n10 Lortholary O. Poizat G. Zeller V. Neuville S. Boibieux A. Alvarez M. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy AIDS 20 17 2006 2183 2191 17086058 \n11 Jarvis J.N. Harrison T.S. Forgotten but not gone: HIV-associated cryptococcal meningitis Lancet Infect. Dis. 16 7 2016 756 758 26971080 \n12 Siedner M.J. Ng C.K. Bassett I.V. Katz I.T. Bangsberg D.R. Tsai A.C. Trends in CD4 count at presentation to care and treatment initiation in sub-Saharan Africa, 2002-2013: a meta-analysis Clin. Infect. Dis. 60 7 2015 1120 1127 25516189 \n13 Koenig S.P. Dorvil N. Devieux J.G. Hedt-Gauthier B.L. Riviere C. Faustin M. Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: a randomized unblinded trial PLoS Med. 14 7 2017 e1002357 \n14 Jarvis J.N. Harrison T.S. Lawn S.D. Meintjes G. Wood R. Cleary S. Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa PLoS One 8 7 2013 e69288 \n15 Franco-Paredes C. Chastain D.B. Rodriguez-Morales A.J. Marcos L.A. Cryptococcal meningoencephalitis in HIV/AIDS: when to start antiretroviral therapy? Ann. Clin. Microbiol. Antimicrob. 16 1 2017 9 28264683 \n16 (WHO) WHO Guidelines for the Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-Infected Adults, Adolescents and Children: Supplement to the 2016 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection 2018 Available from: http://apps.who.int/iris/bitstream/handle/10665/260399/9789241550277-eng.pdf?sequence=1 \n17 Boulware D.R. Meya D.B. Muzoora C. Rolfes M.A. Huppler Hullsiek K. Musubire A. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis N. Engl. J. Med. 370 26 2014 2487 2498 24963568 \n18 (WHO) WHO Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy 2017 Available from: https://www.who.int/hiv/pub/guidelines/advanced-HIV-disease/en/ \n19 Jarvis J.N. Percival A. Bauman S. Pelfrey J. Meintjes G. Williams G.N. Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis Clin. Infect. Dis. 53 10 2011 1019 1023 21940419 \n20 Bongomin F. Oladele R.O. Gago S. Moore C.B. Richardson M.D. A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species Mycoses 61 5 2018 290 297 29377368\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "24()",
"journal": "Medical mycology case reports",
"keywords": "Cryptococcal meningitis; HIV; IRIS; Nigeria; Test and Treat",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "58-60",
"pmc": null,
"pmid": "31049279",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "17086058;19182676;20230635;21526627;21940419;23894442;24963568;25516189;26192873;26971080;27144527;28264683;28483415;28742529;28742880;29377368;29514234",
"title": "Cryptococcal meningitis after ART: Need for proper baseline evaluation in the era of 'Test & Treat'.",
"title_normalized": "cryptococcal meningitis after art need for proper baseline evaluation in the era of test treat"
} | [
{
"companynumb": "NG-HETERO CORPORATE-HET2019NG00720",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EFAVIRENZ\\LAMIVUDINE\\TENOFOVIR DISOPROXIL FUMARATE"
... |
{
"abstract": "Aripiprazole, a partial dopamine agonist has been reported to help reduce symptoms of tardive dyskinesia (TD). In a prospective, open label study of a series of cases, we examined the effectiveness of aripiprazole in reducing TD symptoms. Six clinically stable patients with schizophrenia or Schizoaffective disorder and a moderate to severe TD participated in this study. They were systematically cross-titrated from their current medication to aripiprazole and maintained for 16 weeks. The mean extra pyramidal symptom score measured by Abnormal Involuntary Movement Scale (AIMS) improved from a baseline score of 15.8 to final score of 5 (paired t-test; P=0.0009). The severity of psychiatric symptoms remained unchanged. This study supports our hypothesis that clinically stable patients with moderate tardive dyskinesia who are under treatment with other first- or second-generation antipsychotics may benefit from switching to aripiprazole with a reduction of TD symptoms but with out any significant benefit in psychiatric symptoms. The results need to be viewed with caution and not considered as indicative of a viable treatment option for TD as this is an open label study, and a small sample size.",
"affiliations": "Wayne State University School of Medicine, Detroit, MI, USA.",
"authors": "Rajarethinam|Rajaprabhakaran|R|;Dziuba|John|J|;Manji|Suzanne|S|;Pizzuti|Albert|A|;Lachover|Leonard|L|;Keshavan|Matcheri|M|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; C011825:fluphenazine depot; D006220:Haloperidol; D018967:Risperidone; D005476:Fluphenazine",
"country": "England",
"delete": false,
"doi": "10.1080/15622970902995612",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1562-2975",
"issue": "10(4 Pt 2)",
"journal": "The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry",
"keywords": null,
"medline_ta": "World J Biol Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced; D005260:Female; D005476:Fluphenazine; D005500:Follow-Up Studies; D006220:Haloperidol; D006801:Humans; D008297:Male; D008875:Middle Aged; D009460:Neurologic Examination; D010879:Piperazines; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders; D015363:Quinolones; D018967:Risperidone; D012559:Schizophrenia",
"nlm_unique_id": "101120023",
"other_id": null,
"pages": "416-9",
"pmc": null,
"pmid": "19492247",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Use of aripiprazole in tardive dyskinesia: an open label study of six cases.",
"title_normalized": "use of aripiprazole in tardive dyskinesia an open label study of six cases"
} | [
{
"companynumb": "US-JNJFOC-20130608922",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Studies in EGFR+ non-small cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM) comparing survival rates and gene mutation detection with matched cerebrospinal fluid (CSF) and plasma are relatively scarce. We evaluated gene mutations, treatment strategies, and clinical outcomes in EGFR+ NSCLC patients with LM.\n\n\n\nWe retrospectively reviewed gene mutation status in the CSF and plasma of 32 EGFR+ NSCLC patients with LM for prognostic significance.\n\n\n\nThe rate of LM disease control was significantly higher in patients that switched EGFR-tyrosine kinase inhibitor (TKI) treatments, initiated EGFR-TKIs, or received high-dose EGFR-TKI treatment than those who continued their current EGFR-TKI treatment, received chemotherapy, or were not administered antitumor treatment (24/24, 100.0% vs. 1/8, 12.5%; P = 0.000). Overall survival was 27.0 months (95% confidence interval [CI] 19.0-37.5), median survival after LM was 7.0 months (95% CI 5.0-11.0), and median survival before LM was 17.0 months (95% CI 12-25.5). Median survival after LM was significantly shorter in patients with \"worse\" status (n = 7) than in those with \"improved/stable\" status (n = 25; 4.2 [95% CI 2.2-6.1] vs. 33.7 [95% CI 25.5-41.8] months, HR 10.114, 95% CI 0.29-1.37; P = 0.008).\n\n\n\nEGFR-TKIs should be the priority course of treatment in EGFR+ NSCLC patients after a diagnosis of LM. Liquid biopsy in both plasma and CSF, as well as dynamic detection, play important roles in the direction of treatment for such patients.",
"affiliations": "Department of Comprehensive Oncology, State Key Laboratory of Molecular Oncolgy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.",
"authors": "Li|Ning|N|0000-0002-7285-246X;Liu|Yutao|Y|;Duan|Jianchun|J|0000-0003-1479-2304;Yang|Boyan|B|;Bai|Hua|H|;Sun|Rui|R|;Yu|Lei|L|;Wang|Jie|J|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.13123",
"fulltext": "\n==== Front\nThorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 10.1111/1759-7714.13123TCA13123Original ArticleOriginal ArticlesPrognostic significance of molecular characteristics of cerebrospinal fluid for non‐small cell lung cancer patients with leptomeningeal metastasis Prognostic significance of CSF in LMN. Li et al.Li Ning https://orcid.org/0000-0002-7285-246Xmzbgd_0@sina.com \n1\nLiu Yutao \n2\nDuan Jianchun https://orcid.org/0000-0003-1479-2304\n2\nYang Boyan \n3\nBai Hua \n2\nSun Rui \n3\nYu Lei \n3\nWang Jie zlhuxi@163.com \n2\n\n1 \nDepartment of Comprehensive Oncology, State Key Laboratory of Molecular Oncolgy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\nChinese Academy of Medical Sciences & Peking Union Medical College\nBeijing\nChina\n\n2 \nState Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\nChinese Academy of Medical Sciences & Peking Union Medical College\nBeijing\nChina\n\n3 \nDepartment of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital\nChinese Academy of Medical Sciences & Peking Union Medical College\nBeijing\nChina\n* Correspondence\n\nJie Wang, Department of Medical Oncology, State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 nanli, Panjiayuan, Chaoyang District, Beijing 100021, China.\n\nTel: +86 10 8778 8524\n\nFax: +86 10 8778 8524\n\nEmail: zlhuxi@163.com\n\nNing Li, State Key Laboratory of Molecular Oncology, Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China\n\nTel: +86 139 1122 8723\n\nFax: +86 10 8778 8527\n\nEmail: mzbgd_0@sina.com\n10 7 2019 8 2019 10 8 10.1111/tca.v10.81673 1682 07 4 2019 22 5 2019 27 5 2019 © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background\nStudies in EGFR+ non‐small cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM) comparing survival rates and gene mutation detection with matched cerebrospinal fluid (CSF) and plasma are relatively scarce. We evaluated gene mutations, treatment strategies, and clinical outcomes in EGFR+ NSCLC patients with LM.\n\nMethods\nWe retrospectively reviewed gene mutation status in the CSF and plasma of 32 EGFR+ NSCLC patients with LM for prognostic significance.\n\nResults\nThe rate of LM disease control was significantly higher in patients that switched EGFR‐tyrosine kinase inhibitor (TKI) treatments, initiated EGFR‐TKIs, or received high‐dose EGFR‐TKI treatment than those who continued their current EGFR‐TKI treatment, received chemotherapy, or were not administered antitumor treatment (24/24, 100.0% vs. 1/8, 12.5%; P = 0.000). Overall survival was 27.0 months (95% confidence interval [CI] 19.0–37.5), median survival after LM was 7.0 months (95% CI 5.0–11.0), and median survival before LM was 17.0 months (95% CI 12–25.5). Median survival after LM was significantly shorter in patients with “worse” status (n = 7) than in those with “improved/stable” status (n = 25; 4.2 [95% CI 2.2–6.1] vs. 33.7 [95% CI 25.5–41.8] months, HR 10.114, 95% CI 0.29–1.37; P = 0.008).\n\nConclusions\nEGFR‐TKIs should be the priority course of treatment in EGFR+ NSCLC patients after a diagnosis of LM. Liquid biopsy in both plasma and CSF, as well as dynamic detection, play important roles in the direction of treatment for such patients.\n\nEGFR mutationleptomeningeal metastasisliquid biopsynon‐small cell lung cancersurvival source-schema-version-number2.0component-idtca13123cover-dateAugust 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:01.08.2019\n==== Body\nIntroduction\nSeveral kinds of solid tumors, including malignant melanoma and lung, breast, and gastric cancer are accompanied by leptomeningeal metastasis (LM) at some stage during disease progression. Among these cancers, non‐small cell lung cancer (NSCLC) accounts for approximately 40–50% of cases that include LM.1, 2 In recent years, the incidence of LM in patients with NSCLC has increased, especially in EGFR+ NSCLC patients, and 9.0% of EGFR+ NSCLC patients were diagnosed with LM.3, 4, 5 Whole brain radiotherapy (WBRT), systemic chemotherapy, and intrathecal chemotherapy (ITCT) are the traditional treatment choices for NSCLC patients with LM. However, there is no consensus on the optimal treatment strategy, and the efficacies of these treatments for LM patients remain unsatisfactory. Presently, LM is still closely associated with a poor prognosis and rapid deterioration in clinical situations. Therefore, the goal of LM treatment is to improve or stabilize neurological symptoms, which can improve quality of life and lead to improved survival rates.\n\nAn increasing number of reports have shown that NSCLC patients with EGFR gene mutations (EGFR+) tend to have more central nervous system (CNS) metastases, including both brain and leptomeningeal metastases after using of EGFR‐tyrosine kinase inhibitors (TKIs) in association with theuse of EGFR‐tyrosine kinase inhibitors (TKIs). There are several potential reasons for this phenomenon. Firstly, the survival of EGFR+ NSCLC patients has been significantly prolonged.6 Secondly, first (i.e. gefitinib) and second‐generation (afatinib) EGFR‐TKIs have poor penetration across the blood–brain barrier (BBB). The percentage of penetration ranges from 0.69% to 1.3%, which may provide a good opportunity for tumor cell growth in the CNS.7 Thirdly, as the treatment duration increases, the likelihood of the development of several secondary resistance mechanisms to EGFR‐TKIs also increases.8, 9, 10 Based on these considerations, the treatment options for EGFR+ NSCLC patients with LM generally include an intial high‐dose of first or second‐generation EGFR‐TKIs, or a switch to a different EGFR‐TKI.\n\n\nEGFR mutations can be detected by analyzing circulating tumor DNA (ctDNA) in both plasma and cerebrospinal fluid (CSF), which provides an alternative to tumor biopsies for further study. With the widespread use of third generation EGFR‐TKIs, data on LM in NSCLC patients with EGFR+ is relatively scarce. We retrospectively assessed the diagnosis, treatment modes, and survival status of EGFR+ NSCLC patients with LM that had been enrolled in our hospital. We determined their gene mutation status by analyzing ctDNA extracted from peripheral blood, CSF, and tumor tissue samples.\n\nMethods\nPatient population\nIn this retrospective study, EGFR+ NSCLC patients diagnosed with advanced‐stage (stage IV) NSCLC between January 2016 and November 2018 were reviewed for diagnosis of LM. All LM patients needed to be diagnosed by magnetic resonance imaging (MRI) and/or by the detection of malignant cells in the CSF by cytopathological diagnosis. In the event that only atypical and/or suspicious cells were found in the CSF, patients were not diagnosed with LM.\n\nAll patients signed informed consent to participate in this study and gave permission to use their peripheral blood and CSF. The ethical committee of the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College approved the protocol.\n\n\nEGFR mutation detection\nWe ascertained the EGFR mutation status of patients in the following regions: EGFR driver mutations (exon 18 alteration, exon 19 deletion, exon 21 L858Arg, HER2 alterations), EGFR resistance mutations (exon 20 Thr790Met, exon 20‐C797s), or mutations in tumor suppressor genes of plasma and CSF ctDNA. EGFR mutation status was determined for all patients by analyzing ctDNA exracted from tumor samples and/or CSF. Paired CSF and plasma samples were collected at the same time from the majority of patients. Approximately 10 mL of CSF was collected by lumbar puncture for cytology examination and gene detection by amplified refractory mutation system (ARMS) or next‐generation sequencing (NGS). Additionally, 8 mL of plasma was collected for super AMRS or NGS analysis concurrently with the collection of CSF.\n\nStatistical analysis\nFollow‐up continued until January 2019. The duration of investigation was calculated from the initial diagnosis of LM until death or the last date of follow‐up, with a minimum follow‐up period for statistical analysis set at one month. The primary outcome measurement was disease control of LM, which was evaluated using the following criteria: improved/stable, defined as clinical symptom improvement or maintaining a consistent state, and/or enhanced computed tomography (CT) or MRI examination showing decreased or stable lesion state; worse, defined as a worsening of clinical symptoms or observation of increased lesions on enhanced CT or MRI examination according to European Association of Neuro‐Oncology–European Society for Medical Oncology (EANO–ESMO) Clinical Practice Guidelines.11 Extracranial lesions that appeared to be LM were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and were defined as confirmed complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) four weeks after LM diagnosis. Secondary outcomes were overall survival (OS), and survival duration before and after LM diagnosis. OS was defined as the duration from the diagnosis of lung cancer until the date of death or last follow‐up. Survival duration before LM was calculated from the diagnosis of lung cancer until LM diagnosis. Survival duration after LM was calculated from the date of LM diagnosis to the date of death.\n\nComparisons of categorical and continuous variables were performed using the χ2 test and independent t‐test, respectively. Survival analyses were performed according to the Kaplan–Meier method and tested for significance with the log‐rank test. Comparisons between subgroups were made using a Cox proportional hazards model and Wald 95% confidence intervals (CIs), where appropriate. Statistical analyses were performed using SPSS version 19.\n\nResults\nCharacteristics of leptomeningeal metastasis (LM) in non‐small cell lung cancer (NSCLC) patients\nThe medical records of 32 patients with a diagnosis of EGFR+ advanced‐stage NSCLC with LM were reviewed. LM was diagnosed by both MRI and CSF cytology in 20 patients (62.5%), only by CSF cytology in 10 patients (31.3%), and only by MRI in two patients (6.3%) (Table 1).\n\nTable 1 Clinical characteristics of patients with LM from NSCLC\n\nCharacteristics\t\nn = 32\t\nP\n\t\nGender (male/female)\t\t\t\nMale\t17\t\t\nFemale\t15\t\t\nMedian age, year (range)\t\t\t\n< 60\t22\t\t\n≥ 60\t10\t\t\nHistopathology\t\t\t\nAdenocarcinoma\t30\t\t\nUnspecified non‐small cell carcinoma\t2\t\t\nMedian time from cancer diagnosis to LM, months\t\t0.046\t\n< 12\t12\t\t\n≥ 12\t20\t\t\nYes\t28\t0.000\t\nNo\t4\t\t\nECOG PS\t\n0–2\t28\t0.000\t\n3–4\t4\t\t\nExtracranial SD/PR\t\nYes\t25\t0.000\t\nNo\t7\t\t\nECOG PS, Eastern Cooperative Oncology Group performance status; LM, leptomeningeal metastasis; NSCLC, non‐small cell lung cancer; PR, partial response; SD, stable disease.\n\nThe median time from NSCLC diagnosis to LM diagnosis with EGFR+ was 17.0 months (95% CI 12.0–25.5, range: 0–88), and there were significant differences in duration between patients diagnosed within 12 and over 12 months. (20/32, 62.5%; P = 0.046). A total of 28 patients had brain metastasis (BM) before LM or at the same time as LM diagnosis (87.5%, P = 0.000). Eastern Cooperative Oncology Group performance status (ECOG PS) was evaluated at the time of LM diagnosis. The ECOG PS of 28 patients was 0–2 (87.5%; P = 0.000), and 25 patients were assessed with SD/PR of extracranial tumors (78.1%; P = 0.000) (Table 1).\n\n\nEGFR mutation status in histopathology, cerebrospinal fluid, and plasma DNA\nTwenty‐nine patients (90.6%) underwent EGFR mutation analysis and histopathology before initial treatment: 12 (41.4%) had exon 19 deletions, 15 (51.7%) had exon 21 L858R, 1 (3.4%) had an exon 20 insertion, and 1 patient (3.4%) had an ERBB2 alteration (Fig 1).\n\nFigure 1 Treatment status and EGFR mutations in histopathology, cerebrospinal fluid (CSF), and plasma DNA. *Patient died. Afa, afatinib; Eri, erlotinib; Gef, gefitinib; Ico, icotinib; m, months; Osi, osimertinib. () Patients with EGFR driver mutations and/or T790M negative in plasma but positive in CSF. () Patients with EGFR driver mutations and/or T790M positive in both plasma and CSF. () Patients with EGFR driver mutations and/or T790M positive in plasma but negative in CSF. () Patients with EGFR driver mutations and T790M negative in both plasma and CSF. () Patients with EGFR driver mutations and T790M unknown in plasma. () From cancer diagnosis to LM diagnosis (m) and () After LM diagnosis (m).\n\nAll 32 patients underwent identical EGFR driver mutation detection analysis on ctDNA extracted from the CSF after LM diagnosis: 20 (62.5%) were tested by ARMS, and 12 were tested by NGS. The results revealed: 13 patients (37.5%) had exon 21 L858R mutations; 8 (25.0%) had exon 19 deletions; 6 (18.8%) had wild‐type EGFR; 1 (3.1%) had a T790M mutation; 1 (3.1%) had an exon 19 deletion and T790M mutation; 1 (3.1%) had an exon 20‐C797S mutation and exon 19 deletion; 1 (3.1%) had an exon 20‐770 alteration; and 1 patient (3.1%) had an exon 18 alteration (Fig 1).\n\nAmong the 12 patients whose mutations were detected by NGS in CSF, 2 (16.7%) had T790M mutations, 6 (50.0%) had TP53 alterations, and 7 (58.3%) had EGFR driver mutations (Table 2).\n\nTable 2 Gene mutation status detected by NGS in CSF\n\nGene mutation\t\nn\n\tPercentage\t\n\nEGFR exon 19 + TP53\n\t1\t8.30%\t\n\nEGFR exon 20–797s + exon 19\t1\t8.30%\t\n\nEGFR exon 20–770 + TP53\n\t1\t8.30%\t\n\nEGFR exon 21 L858R + TP53\n\t2\t16.70%\t\n\nEGFR exon 19 + T790M + TP53\n\t1\t8.30%\t\nT790M\t1\t8.30%\t\n\nEGFR exon 19\t1\t8.30%\t\n\nEGFR exon 21\t2\t16.70%\t\n\nTP53\n\t1\t8.30%\t\n\nEGFR exon 18\t1\t8.30%\t\nCSF, cerebrospinal fluid; NSG, next generation sequencing.\n\nAnalysis of EGFR mutations via ARMS versus NGS in CSF showed different results. The detection rate of EGFR T790M and exon 20 mutations was significantly higher by NGS than by ARMS (2/12, 16.7% vs. 0/20, 0.0%, P = 0.133; 2/12, 16.7% vs. 0/20, 0.0%, P = 0.133, respectively).\n\nAmong the 32 patients, 29 underwent mutation analysis after LM diagnosis in plasma paired with CSF. Their results were as follows: 16 patients (16/29, 55.2%) had wild‐type EGFR; 4 (4/29, 13.8%) had EGFR exon 19 deletions; 3 (3/29, 10.3%) had EGFR exon 21 L858R mutations; 2 (2/29, 6.9%) had HER2 alterations; 2 (2/29, 6.9%) had EGFR T790M mutations; 1 (1/29, 3.4%) had ROS‐1 alterations; and 1 patient (1/29, 3.4%) had EGFR exon 21 L858R and T790M mutations (Fig 1).\n\nIn summary, 11 patients showed EGFR driver mutations and ROS‐1 in plasma, while 24 patients showed EGFR driver mutations in CSF (11/29 vs. 24/32; P = 0.003). No mutations were detected in the plasma and CSF of 16 and 6 patients, respectively (16/29 vs. 6/32; P = 0.005) (Fig 2).\n\nFigure 2 Positive detection among plasma, cerebrospinal fluid (CSF), and tissue.*P = 0.003 EGFR driver mutations and ROS‐1 plasma versus CSF. **P = 0.005 wild plasma versus CSF. ctDNA, circulating tumor DNA. () Tissue (n = 29), () Plasma (n = 29), and () CSF (n = 32).\n\nTreatment of EGFR‐mutated NSCLC patients with LM\nAt the time of LM diagnosis, 27 patients (84.4%) were treated using a specfic EGFR‐TKI. Five different regimens were used during follow‐up treatment for LM according to the personal and specific conditions of each patient: EGFR‐TKIs, chemotherapy, WBRT, ITCT, and TMZ. EGFR‐TKI treatment included: continuation of current EGFR‐TKI treatment, initiation of EGFR‐TKI treatment, switching from one EGFR‐TKI treatment to another, and high‐dose EGFR‐TKI treatment (Table 3). There was a significant difference in the rate of LM disease control between patients that switched EGFR‐TKI treatments, intiated EGFR‐TKI treatment, or received high‐dose EGFR‐TKI treatment and those that continued with their current EGFR‐TKI treatment, received chemotherapy, or were not administered antitumor treatment (24/24, 100.0% vs. 1/8, 12.5%; P = 0.000) (Table 3). Among this group, 21 patients (21/32, 65.6%) were treated with combined ITCT (Table 4), 1 patient (3.1%) with TMZ, and 1 patient (3.1%) with radiotherapy. Subgroup analysis of the rate of LM disease control indicated no significant difference between patients administered third‐generation EGFR‐TKIs with or without ITCT (8/9, 88.9% vs. 10/10, 100.0%, respectively; P = 0.474) (Table 5).\n\nTable 3 Treatment in EGFR‐mutated NSCLC patients with LM\n\nTreatment before LM\t\tTreatment after LM\tDisease control of LM after 1 month (n)\t\n(Targeted therapy or chemotherapy)\t\nn\n\t(Targeted therapy or chemotherapy)\tWorse\tImproved/Stable\t\nChemotherapy\t1\tOsimertinib\t0\t1\t\nNo treatment\t4\tOsimertinib\t0\t1\t\n\t\tChemotherapy\t1\t1\t\n\t\tNo treatment\t1\t0\t\nGefitinib or icotinib\t17\tChemotherapy\t1\t0\t\nGefitinib\t1\t0\t\n\t\tErlotinib\t0\t3\t\n\t\tAfatinib\t0\t1\t\n\t\tOsimertinib\t0\t11\t\nErlotinib\t6\tDoubled erlotinib\t0\t1\t\n\t\tOsimertinib\t0\t5\t\nAfatinib\t1\tAfatinib\t1\t0\t\nOsimertinib\t3\tOsimertinib\t1\t0\t\n\t\tOsimertinib and gefitinib\t0\t1\t\n\t\tNo treatment\t1\t0\t\nLM, leptomeningeal metastasis; NSCLC, non‐small cell lung cancer.\n\nTable 4 Response of LM treated by ITCT or not\n\nCombined with ITCT\t\nn\n\tImproved/Stable\t\nP\n\t\nYes\t21\t(16/21) 76.2%\t0.078\t\nNo\t11\t(11/11) 100%\t\t\nITCT, intrathecal chemotherapy; LM, leptomeningeal metastasis.\n\nTable 5 Response of LM after EGFR‐TKI with or without ITCT\n\n\t\tSystemic treatment after LM\t\nResponse\t\tEGFR‐TKIs1st\n\tEGFR‐TKI2nd\n\tEGFR‐TKI3rd\n\tChemotherapy\tNo treatment\t\nN\n\t\nP\n\t\nImproved/Stable\tNo ITCT\t0\t1\t10\t0\t0\t25\t0.000\t\nITCT\t5\t0\t8\t1\t0\t\nWorse\tNo ITCT\t0\t0\t0\t0\t0\t7\t\nITCT\t1\t1\t1\t1\t3\t\nITCT, intrathecal chemotherapy; LM, leptomeningeal metastasis; TKI, tyrosine kinase inhibitor.\n\nThere was a significant difference in the rate of LM disease control between patients with EGFR driver and/or T790M‐positive mutations and those without EGFR driver mutations or T790M‐negative (9/10, 90.0% vs. 0/2, 0.0%, respectively; P = 0.007) (Table 6).\n\nTable 6 Response of LM according to different gene mutations in CSF\n\nResponse\t\nn\n\tImproved/Stable\tWorse\t\nP\n\t\nGene mutations by NGS\t\n\nEGFR driver mutations and/or T790M\t\nPositive\t10\t9\t1\t0.007\t\nNegative\t2\t0\t2\t\nTumor‐suppressor gene mutations\t\nPositive\t6\t5\t1\t0.505\t\nNegative\t6\t4\t2\t\n\nEGFR driver mutations by ARMS\t\n\nEGFR exon 19\t6\t5\t1\t0.966\t\n\nEGFR exon 21\t9\t7\t2\t\nWild\t5\t4\t1\t\nARMS, amplified refractory mutation system; CSF, cerebrospinal fluid; LM, leptomeningeal metastasis; NSG, next‐generation sequencing.\n\nSurvival and response of EGFR‐mutated NSCLC patients with LM\nSeven (7/32, 21.9%) of the EGFR+ NSCLC patients with LM died before their follow‐up appointments and the one‐year survival rate was 59.4% (19/32). The OS of all 32 patients was 27.0 months (95% CI 19.0–37.5) (Fig 3).\n\nFigure 3 Kaplan–Meier curves of (a) overall survival (OS) in EGFR‐mutated non‐small cell lung cancer patients with leptomeningeal metastases (LM); (b) survival duration before LM according to EGFR driver mutations and/or T790M in plasma (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.29–1.37; P = 0.211), () Plasma positive and () plasma negative; (c) survival duration before LM according to EGFR driver mutations and/or T790M in plasma using first‐generation EGFR‐tyrosine kinase inhibitors (HR 2.41, 95% CI 0.87–6.70; P = 0.078), () Plasma positive and () plasma negative; and (d) survival duration after LM diagnosis according to LM disease control status (HR 10.114, 95% CI 0.29–1.37; P = 0.008), () Improved/stable and () worse.\n\nThe median survival duration before LM in all 32 patients was 17.0 months (95% CI 12–25.5): 15.0 months (95% CI 4.0–27.0) in 9 patients with EGFR driver and/or T790M positive mutations in both plasma and CSF; 20.5 months (95% CI 12.0–48.0) in 14 patients with EGFR driver mutations and/or T790M negative in plasma but positive in CSF; 20.0 months (95% CI 6.0–30.0) in 3 patients with EGFR driver and/or T790M positive mutations in plasma but negative in CSF; and 18.0 months (95% CI 0.0–27.0) in 3 patients with EGFR driver mutations and T790M negative in both plasma and CSF. The median survival duration in 17 patients with EGFR driver mutations and/or T790M negative in plasma was longer than in 12 patients with EGFR driver and/or T790M positive mutations in plasma (18.0 [95% CI 12.0–27.0] vs. 16.0 months [95% CI 7.0–26.5]; HR 0.63, 95% CI 0.29–1.37; P = 0.211) (Fig 3b, Table 7). Subgroup analysis of patients who acquired resistance to first‐generation EGFR‐TKIs revealed that median survival in 14 patients with EGFR driver mutations and/or T790M negative in plasma was longer compared to 7 patients with EGFR driver and/or T790M positive mutations in plasma (24.0 [95% CI 5.7–42.3] vs. 15.0 months [95% CI 7.3–22.7]; HR 2.41, 95% CI 0.87–6.70; P = 0.078) (Fig 3c).\n\nTable 7 Systemic treatment before LM according to EGFR status in plasma\n\n\tSystemic treatment before LM\t\nEGFR and/or T790M\tEGFR‐TKIs1st\n\tEGFR‐TKI2nd\n\tEGFR‐TKI3rd\n\tChemotherapy\tNo treatment\t\nn\n\t\nP\n\t\nPositive\t7\t1\t3\t0\t1\t12\t0.083\t\nNegative\t14\t0\t0\t3\t0\t17\t\nLM, leptomeningeal metastasis; TKI, tyrosine kinase inhibitor.\n\nThe median survival duration after LM of all 32 patients was 7.0 months (95% CI 5.0–11.0): 11.4 months (95% CI 5.5–20.6) in 9 patients with EGFR driver and/or T790M positive mutations in both plasma and CSF; 7.2 months (95% CI 4.1–11.0) in 14 patients with EGFR driver mutations and/or T790M negative in plasma but positive in CSF; 4.5 months (95% CI 1.5–10.0) in 3 patients with EGFR driver and/or T790M positive mutations in plasma but negative in CSF; and 14.0 months (95% CI 7.0–18.0; P = 0.477) in 3 patients with EGFR driver mutations and T790M negative in both plasma and CSF.\n\nCompared to patients with improved/stable LM (n = 25), the median survival duration after LM was significantly shorter in patients with worse LM (n = 7;33.7 [95% CI 25.5–41.8] vs. 4.2 months [95% CI 2.2–6.1]; HR 10.114, 95% CI 0.29–1.37; P = 0.008) (Fig 3d).\n\nDiscussion\nWe monitored a group of EGFR+ NSCLC patients with LM and assessed the status of their varied EGFR mutations in paired plasma and CSF samples. Our results showed that EGFR+ NSCLC patients with LM had better response rates when they switched EGFR‐TKI treatments or received high‐dose EGFR‐TKI treatment after LM diagnosis. Our results also revealed that more mutated genes were found in CSF samples, and to some extent there were differences in the gene mutation status among tissues, plasma, and CSF. This result demonstrates the importance of detecting gene mutations in both CSF and plasma by NGS after LM diagnosis.\n\nIn previous studies, researchers reported that NSCLC patients not administered systemic chemotherapy, chemotherapy, or EGFR‐TKI treatment as a basic option after LM diagnosis only survived three months.12, 13 Kuiper et al. reported a survival duration after LM diagnosis of only 3.1 months in EGFR+ patients, as third‐generation EGFR‐TKIs, such as osimertinib, were not available for clinical treatment at the time.4 In our study, the median survival after a diagnosis of LM in the EGFR+ group was 7.0 months, which included patients who received high doses of first‐generation EGFR‐TKIs or switched EGFR‐TKI treatment (i.e. from first‐generation to second or third‐generation EGFR‐TKIs). Because EGFR+ patients had higher ECOG PS scores at the time of LM diagnosis, patients with unspecific symptoms, such as headaches and dizziness, need to have their LM status taken into consideration.\n\nBecause of the BBB, the concentrations of available first and second‐generation EGFR‐TKIs in CSF, such as gefitinib, erlotinib, and afatinib, are considerably lower compared to the concentration in extracranial lesions.7 When the extracranial concentration of EGFR‐TKIs is increased, a higher concentration in the CSF can be achieved, which can have a positive therapeutic effect.14 Under this treatment strategy, drug toxicity needs to be monitored and deemed acceptable. Reports have shown that this treatment strategy for EGFR+ NSCLC patients with LM has produced various results.15, 16 Kuiper et al. reported that 12 EGFR+ NSCLC patients with LM treated with high dose first‐generation EGFR‐TKIs after LM diagnosis achieved survival after LM of only 2.4 months.4\n\n\nAfatinib is a second generation EGFR‐TKI. A recent study showed that if patients experienced disease progression after treatment of standard doses of erlotinib or gefitinib, 66% of them could achieve disease control when they switched to afatinib.17 In our study, one patient exhibited CNS disease control with afatinib after switching from gefitinib and achieved survival of 12 months. In addition, the third‐generation EGFR‐TKI osimertinib is reported to be active in the CNS.18, 19, 20 In this retrospective study, the LM disease control of all 19 patients was either improved or stable after switching from gefitinib or erlotinib to osimertinib, regardless of whether the T790M mutation was negative or positive. Patients that switched EGFR‐TKI treatments, intiated EGFR‐TKI treatment, or received high‐dose EGFR‐TKI treatment had better LM disease control status. Furthermore, in our study, improved and stable LM disease control status was predictive of better clinical outcomes.\n\nIn recent years, ITCT has been a traditional treatment choice for NSCLC patients with LM, but evidence of its efficacy is limited. In a sample of 105 NSCLC patients with LM, ITCT use resulted in OS of only 3.0 months. Furthermore, varying symptoms, such as headaches, altered mental state, and cauda equine, showed relatively low response rates, ranging from 42% to < 10%, and negative conversion of CSF cytology could not prolong OS. In our study, only 16 out of 21 patients administered ITCT achieved disease control (76.2%, n = 16), whereas all 11 patients not administered ITCT achieved disease control, which could be associated with the small sample size. Third generation EGFR‐TKIs combined with ITCT did not achieve a higher rate of LM disease control compared to third genenration EGFR‐TKIs alone. Unfortunately, there are no satisfactory survival results available related to ITCT.\n\nRadiotherapy is another traditional treatment after a diagnosis of LM; however, there is a lack of evidence of the efficacy of radiotherapy in NSCLC patients with LM, and the toxicity associated with whole cerebrospinal radiotherapy can cause high mortality. In a report of 125 patients with LM, no difference in survival was observed between patients treated with or without WBRT.13 In our study, this treatment strategy could not be incorporated into the analyses because only one patient was administered radiotherapy after an LM diagnosis. Some reasons for the low use of radiotherapy in our study stem from the inconclusive efficacy of radiotherapy for LM, and the fact that some of the patients were administered radiotherapy for brain metastasis prior to LM diagnosis.\n\nIn our study, SD or PR was achieved in more extracranial tumors than in a previous study of unselected NSCLC patients with LM which reported that PD was associated with extracranial tumors. It is possible that extracranial tumors and LM arise from different mechanisms.21 Because of the BBB, CSF circulation is isolated from the blood circulation system, which may be one of the reasons why gene mutations in CSF are different to those in plasma. In our study, only 9.4% of patients had paired plasma and CSF samples (n = 3) with gene mutations in common. In 12 patients diagnosed by NGS, more types of gene mutations in CSF were associated with both secondary resistance genes and suppressors, in addition to other EGFR driver mutations. Therefore, detecting genomic alterations in CSF directly, especially by NGS, is a feasible method to represent the genetic status of intercranial lesions. Similarly, ctDNA in plasma provides an alternative to tumor samples for EGFR mutation analysis, and plasma gene mutations showed greater advantages than solid tumor cells for revealing the genetic landscape of primary and metastatic lesions, which are relatively limited. In the BENEFIT clinical trial, EGFR mutations reappeared in ctDNA with plasma samples when the disease progressed in 46% (56/123) of patients.22 In our study, 37.9% (11/29) of patients had EGFR driver mutations and ROS‐1 in plasma when LM appeared, which is relatively low compared to the results of the BENEFIT analysis. However, in our study, more patients had EGFR driver mutations in CSF and more without EGFR driver mutations in plasma when LM was diagnosed, which is relatively high compared to the BENEFIT results. Therefore, LM might have a different mechanism from extracranial progression, and further studies need to be conducted to verify this possibility. Gene mutation status in an individual patient can be spatiotemporally heterogeneous, and in this case, it is necessary to detect multiple lesions simultaneously. The median survival duration before LM of 17 patients with EGFR driver mutations and/or T790M negative in plasma was 18.0 months, which was longer than in patients found to be T790M mutation positive in plasma. Subgroup analysis indicated that the median survival before LM of patients with EGFR driver mutations and/or T790M mutation negative in plasma and administered first‐generation EGFR‐TKIs was 24.0 months, which was longer than that when found positive in plasma. This result suggests that patients without gene mutations in plasma could have longer survival before LM, although the difference between subgroups was not significant. A similar result was observed in the BENEFIT study.22\n\n\nAcquired resistance to EGFR‐TKIs is a common clinical problem, and the T790M mutation has been confirmed by several studies to be one of the most important biomarkers of acquired resistance.10 In our study, T790M was identified in two patients (2/12, 16.7%) in CSF by NGS, which is a lower rate than previously reported.23 However, none of the patients (0/20, 0%) had T790M in CSF when assessed by ARMS, which may be related to the technology used. The current standard treatment for T790M‐mediated resistance after confirmation of disease progression is third‐generation EGFR‐TKIs, such as osimertinib. In our study, the rate of disease control in patients (9/10, 90.0%) with EGFR driver mutations and/or T790M was significantly higher than in patients (0/2, 0%) without EGFR driver mutations and T790M. However, acquired resistance to osimertinib was also observed, and the molecular mechanisms of resistance (such as EGFR‐C797S, BRAF‐V600E, METamp, and ERBB2amp) are not yet fully understood. In our study, one patient developed an EGFR‐C797S resistance mutation in CSF accompanied with an EGFR exon 19 deletion (1/12, 8.3%) after osimertinib treatment. Therefore, NGS with more advanced, targeted, ultra‐deep sequencing in CSF, which could more effectively monitor the gene mutation status and provide clinicians more opportunities to adjust EGFR‐TKI therapy for patients after acquired resistance to classic EGFR‐TKIs is needed.\n\n\nTP53 is a common tumor‐suppressor gene and is more highly expressed in patients whose disease transforms to SCLC (82%), which is another factor for EGFR‐TKI resistance in lung adenocarcinoma.24 In our study, TP53 (6/12, 50%) was uniquely identified in CSF ctDNA, but there was no significant difference in disease control between patients with or without TP53. This result suggests that TP53 may play a role in the progression of LM, but larger sample size studies are required to further explore this possibility.\n\nIn our study, three patients had re‐biopsies after presenting with clinical deterioration in the CNS. One patient was administered eight ITCT treatments and systemic treatment for five months, and after clinical deterioration in the CNS was observed, re‐biopsy detected alterations of ALK, ROS‐1, EGFR exon 20 insertions, and BRAF in the CSF. After taking alectinib for one month, the LM symptoms in the CNS improved. Another patient was found to have L858R in both CSF and plasma when diagnosed with LM, and achieved disease control for 14 months until clinical deterioration in CNS was observed. Re‐biopsy revealed EGFR L858R and MET alterations in the CSF. Another patient with EGFR exon 19 deletion in plasma and EGFR exon 19 deletion and exon 20 insertion‐C797S in CSF when diagnosed with LM achieved disease control for seven months until the appearance of clinical deterioration in CNS. Re‐biopsy detected coexisting EGFR exon 19 deletion, EGFR exon 20 insertion‐C797S, MET, BRAF, KRAS, and EGFRamp in the CSF. These results collectively suggest that it is important to re‐biopsy in clinical practice after disease progression in order to find any new mutations and alter therapeutic strategies.\n\nOur study has several limitations. First, the study was retrospective with a small sample size, particularly regarding the use of NGS. Second, the rate of dynamic monitoring of ctDNA in CSF and plasma during treatment after LM was low. We plan to investigate the efficacy of EGFR‐TKIs in prospective trials based on EGFR mutations detected by other methods, such as NGS, and concentrate on dynamic detection.\n\nIn conclusion, we describe a cohort of EGFR+ NSCLC patients with LM. The median survival duration after diagnosis of LM was 7.0 months. EGFR‐TKIs should be considered priority treatment, as they are associated with superior survival in NSCLC patients after a diagnosis of LM. Tissue and liquid biopsies from multiple sites, as well as dynamic detection by NGS, play important roles in determining treatment strategies for EGFR+ NSCLC patients with LM.\n\nDisclosure\nNo authors report any conflict of interest.\n==== Refs\nReferences\n1 \n\nWaki \nF \n, \nAndo \nM \n, \nTakashima \nA \n\net al\nPrognostic factors and clinical outcomes in patients with leptomeningeal metastasis from solid tumors . J Neurooncol \n2009 ; 93 : 205212.\n2 \n\nClarke \nJL \n, \nPerez \nHR \n, \nJacks \nLM \n. Leptomeningeal metastases in the MRI era . Neurology \n2010 ; 74 : 1449 –54 .20439847 \n3 \n\nEichler \nAF \n, \nKahle \nKT \n, \nWang \nDL \n\net al\nEGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer . J Neurooncol \n2010 ; 12 : 1193 –9 .\n4 \n\nKuiper \nJL \n, \nHendriks \nLE \n, \nvan der Wekken \nAJ \n\net al\nTreatment and survival of patients with EGFR‐mutated non‐small cell lung cancer and leptomeningeal metastasis: A retrospective cohort analysis . Lung Cancer \n2015 ; 89 : 255 –61 .26117231 \n5 \n\nLee \nSJ \n, \nLee \nJI \n, \nNam \nDH \n\net al\nLeptomeningeal carcinomatosis in non‐small‐cell lung cancer patients: Impact on survival and correlated prognostic factors . J Thorac Oncol \n2013 ; 8 : 185 –91 .23328548 \n6 \n\nMok \nTS \n, \nWu \nY‐L \n, \nAhn \nM‐J \n\net al\nOsimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer . N Engl J Med \n2017 ; 376 : 629 –40 .27959700 \n7 \n\nTan \nCS \n, \nCho \nBC \n, \nSoo \nRA \n. Treatment options for EGFR mutant NSCLC with CNS involvement‐can patients BLOOM with the use of next generation EGFR TKIs? \nLung Cancer \n2017 ; 108 : 29 –37 .28625644 \n8 \n\nThress \nKS \n, \nPaweletz \nCP \n, \nFelip \nE \n\net al\nAcquired EGFR C797S mutation mediates resistance to AZD9291 in non‐small cell lung cancer harboring EGFR T790M . Nat Med \n2015 ; 21 : 560 –2 .25939061 \n9 \n\nNiederst \nMJ \n, \nHu \nH \n, \nMulvey \nHE \n\net al\nThe allelic context of the C797S mutation acquired upon treatment with third‐generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies . Clin Cancer Res \n2015 ; 21 : 3924 –33 .25964297 \n10 \n\nHata \nA \n, \nKatakami \nN \n, \nYoshioka \nH \n\net al\nSpatiotemporal T790M heterogeneity in individual patients with EGFR‐mutant non‐small‐cell lung cancer after acquired resistance to EGFR‐TKI . J Thorac Oncol \n2015 ; 10 : 1553 –9 .26309190 \n11 \n\nLe Rhun \nE \n, \nWeller \nM \n, \nBrandsma \nD \n\net al\nEANO–ESMO clinical practice guidelines for diagnosis, treatment and follow‐up of patients with leptomeningeal metastasis from solid tumours . Ann Oncol \n2017 ; 28 : 84 –99 .\n12 \n\nGwak \nHS \n, \nJoo \nJ \n, \nKim \nS \n\net al\nAnalysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non‐small‐cell lung cancer . J Thorac Oncol \n2013 ; 8 : 599 –605 .23422833 \n13 \n\nMorris \nPG \n, \nReiner \nAS \n, \nSzenberg \nOR \n\net al\nLeptomeningeal metastasis from non‐small cell lung cancer: Survival and the impact of whole brain radiotherapy . J Thorac Oncol \n2012 ; 7 : 382 –5 .22089116 \n14 \n\nClarke \nJL \n, \nPao \nW \n, \nWu \nN \n, \nMiller \nVA \n, \nLassman \nAB \n. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer . J Neurooncol \n2010 ; 99 : 283 –6 .20146086 \n15 \n\nKuiper \nJL \n, \nSmit \nEF \n. High‐dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases‐one with a remarkable thoracic response as well . Lung Cancer \n2013 ; 80 : 102 –5 .23375403 \n16 \n\nJackman \nD \n, \nMach \nS \n, \nHeng \nJC \n\net al\nPulsed dosing of erlotinib for central nervous system (CNS) progression in EGFR‐mutant non‐small cell lung cancer (NSCLC) . J Clin Oncol \n2013 ; 31 : suppl): Abstract 8116.\n17 \n\nHoffknecht \nP \n, \nTufman \nA \n, \nWehler \nT \n\net al\nAfatinib Compassionate Use Consortium (ACUCP). Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)‐pretreated non‐small cell lung cancer patients with brain metastases or leptomeningeal disease . J Thorac Oncol \n2015 ; 10 : 156 –63 .25247337 \n18 \n\nCross \nDA \n, \nAshton \nSE \n, \nGhiorghiu \nS \n\net al\nAZD9291, an irreversible EGFR TKI, overcomes T790M‐mediated resistance to EGFR inhibitors in lung cancer . Cancer Discov \n2014 ; 4 : 1046 –61 .24893891 \n19 \n\nBallard \nP \n, \nYates \nJW \n, \nYang \nZ \n\net al\nPreclinical comparison of osimertinib with other EGFR‐TKIs in EGFR‐mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity . Clin Cancer Res \n2016 ; 22 : 5130 –40 .27435396 \n20 \n\nYang \nJC‐H \n, \nKim \nD‐W \n, \nKim \nS‐W \n\net al\nOsimertinib activity in patients (pts) with leptomeningeal (LM) disease from non‐small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study . J Clin Oncol \n2016 ; 34 : Suppl): Abstract 9002.\n21 Li N, Yu L, Yang B. Clinical features and prognostic factors of lung spiepr132 cancer‐inducedspiepr132 leptomeningeal metastasis. Oncol Prog\n2016 ; 14 : 59–63.\n22 \n\nWang \nZ \n, \nCheng \nY \n, \nAn \nT \n\net al\nDetection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first‐line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): A phase 2, single‐arm, multicentre clinical trial . Lancet Respir Med \n2018 ; 6 : 681 –90 .30017884 \n23 \n\nLi \nYS \n, \nJiang \nBY \n, \nYang \nJJ \n\net al\nUnique genetic profiles from cerebrospinal fluid cell‐free DNA in leptomeningeal metastases of EGFR‐mutant non‐small cell lung cancer: A new medium of liquid biopsy . Ann Oncol \n2018 ; 29 : 945 –52 .29346604 \n24 \n\nLee \nJK \n, \nLee \nJ \n, \nKim \nS \n\net al\nClonal history and genetic predictors of transformation into small‐cell carcinomas from lung adenocarcinomas . J Clin Oncol \n2017 ; 35 : 3065 –74 .28498782\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1759-7706",
"issue": "10(8)",
"journal": "Thoracic cancer",
"keywords": "EGFR mutation; leptomeningeal metastasis; liquid biopsy; non-small cell lung cancer; survival",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D002555:Cerebrospinal Fluid; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D055756:Meningeal Carcinomatosis; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "1673-1682",
"pmc": null,
"pmid": "31368671",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": "19043775;20146086;20439847;20627894;22089116;23328548;23375403;23422833;24893891;25247337;25939061;25964297;26117231;26309190;27435396;27959700;28498782;28625644;28881917;29346604;30017884",
"title": "Prognostic significance of molecular characteristics of cerebrospinal fluid for non-small cell lung cancer patients with leptomeningeal metastasis.",
"title_normalized": "prognostic significance of molecular characteristics of cerebrospinal fluid for non small cell lung cancer patients with leptomeningeal metastasis"
} | [
{
"companynumb": "CN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-035300",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "Zoledronic acid has been used for prevention of osteolytic and osteoblastic bone metastasis. This case report illustrates an undesirable consequence from prolonged usage of zoledronic acid in bone metastasis prevention. Periprosthetic acetabular fracture in a patient treated with zoledronic acid for 7 years was reported. The clinical presentation, radiographic and pathological results were described. This is a rare complication after total hip arthroplasty which should not be ignored especially in patients who received long term bisphosphonate.",
"affiliations": "Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.",
"authors": "Tantavisut|Saran|S|;Tanavalee|Aree|A|;Thanakit|Voranuch|V|;Ngarmukos|Srihatach|S|;Wilairatana|Vajara|V|;Wangroongsub|Yongsak|Y|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "Korea (South)",
"delete": false,
"doi": "10.4055/cios.2014.6.3.358",
"fulltext": "\n==== Front\nClin Orthop SurgClin Orthop SurgCIOSClinics in Orthopedic Surgery2005-291X2005-4408The Korean Orthopaedic Association 10.4055/cios.2014.6.3.358Case ReportSpontaneous Acetabular Periprosthetic Fracture in a Patient Continuously Having Zoledronic Acid Tantavisut Saran MDTanavalee Aree MDThanakit Voranuch MD*Ngarmukos Srihatach MDWilairatana Vajara MDWangroongsub Yongsak MDDepartment of Orthopaedics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.* Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.\nCorrespondence to: Aree Tanavalee, MD. Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, 1873 Rama IV Road, Bangkok 10330, Thailand. Tel: +66-2-256-4212, Fax: +66-2-256-4625, areetana@hotmail.com9 2014 05 8 2014 6 3 358 360 07 2 2011 02 7 2011 Copyright © 2014 by The Korean Orthopaedic Association2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Zoledronic acid has been used for prevention of osteolytic and osteoblastic bone metastasis. This case report illustrates an undesirable consequence from prolonged usage of zoledronic acid in bone metastasis prevention. Periprosthetic acetabular fracture in a patient treated with zoledronic acid for 7 years was reported. The clinical presentation, radiographic and pathological results were described. This is a rare complication after total hip arthroplasty which should not be ignored especially in patients who received long term bisphosphonate.\n\nHip arthroplastyFractureLooseningZoledronic acidBisphosphonate\n==== Body\nZoledronic acid has been used for prevention of osteolytic and osteoblastic bone metastases.1) Additionally, Bobyn et al.2) demonstrated that bisphosphonates improved cementless implant fixation by enhancing osteointegration. However, a long-term usage of bisphosphonates has been reported to relate with atypical fracture in subtrochanteric area.3,4) To our knowledge, the periprosthetic acetabular fracture in association with the use of bisphosphonate has never been reported. We report a case of periprosthetic acetabular fracture in a patient having continuous zoledronic acid.\n\nCASE REPORT\nA 75-year-old Asian woman was presented at our department in 2009, with a sudden right groin pain and a limp. She had the history of right breast cancer and was treated with simple mastectomy 15 years ago. She started her continuous course of 4-mg intravenous zoledronic acid therapy for every 6 weeks since 2002 when she was 68 years old. She developed progressive right hip pain due to primary osteoarthritis and underwent cementless total hip arthroplasty (THA) in late 2007. The preoperative radiograph showed reactive lateral cortex thickening at subtrochanteric area (Fig. 1). Zoledronic acid course was cessated 3 months before the surgery and restarted again at 6 weeks after a THA. At the surgery, a specimen biopsy was taken around the right hip. The histological finding of the specimens and bones showed no evidence of malignant cells. The immediate postoperative radiograph is demonstrated in Fig. 2. Following the THA, she had pain-free and improved clinical functions with well-aligned implant position shown on the radiograph. In 2009, following a long day of walking, she developed a sudden right groin pain and a limp. The radiograph and computerized tomography demonstrated a complete transverse acetabular fracture of the superomedial ilium with migration of acetabular component (Fig. 3). A revision total hip surgery was performed. Intraoperatively, the acetabular component was easily removed with no evidence of bone ingrowth while the femoral component was well-fixed. The gross appearance of the acetabulum was yellowish without any abnormal space occupying soft tissue. The specimen from the periacetabular bone revealed necrosis of hematopoietic marrow, fat with various calcifications, and diffuse lack of osteocytes as osteonecrosis (Fig. 4).\n\nDISCUSSION\nPeriprosthetic fracture of acetabulum is an uncommon complication after a THA.5) According to few of the previous studies, the causes of a postoperative fracture were related to unidentified intraoperative fracture,6) severe osteolysis,7) trauma,8) and stress fracture.9) We considered that the periprosthetic acetabular fracture in this study was associated with zoledronic acid, due to 2 reasons. Firstly, the cortical thickening was observed in the lateral (tension) side of the subtrochanteric area, on a preoperative radiograph (Fig. 1). This is a specific prefracture radiographic pattern resulting from a long-term use of bisphosphonate.10) It can relatively indicates that the patient had sufficient dosage or length of time on bisphosphonate administration to cause systemic negative effects. Secondly, the specimen collected from the periprosthetic acetabular fracture site presented an unusual pathological result (Fig. 4).\n\nWe believe that following the cementless fixation of the acetabular component, the stability was dependent on mechanical fit and screw augmentation, while the biological fixation has not been developed. The acetabulum failed due to the chronic stress from repetitive workload with daily activities. A spontaneous fracture can indicate an extreme inhibition of bone turnover following a long-term therapy of zoledronic acid. However, atypical fracture in subtrochanteric area did not occur in this case, because the application of femoral prosthesis bypassed the subtrochanteric area.\n\nZoledronic acid has been reported to have potential role of inducing osteointegration in cementless prosthesis.2) However, the findings in this case were discordant with those reported studies. These findings may indicate that zoledronic acid did not enhance cementless fixation or the doses administered in this case was not proper to induce osteointegration.\n\nThis case report informs the surgeons that a prolonged use of zoledronic for prevention of bone metastasis can cause periprosthetic acetabular fracture. The cessation of bisphosphonate, application of anabolic agent, and a period of delay before weight bearing may reduce the incidence of such complication. However, further study is needed to clarify these issues.\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Preoperative radiograph showing the lateral cortex thickening in the subtrochanteric area and osteoarthritic change of the hip.\n\nFig. 2 Immediate postoperative radiograph.\n\nFig. 3 Radiograph (A) and computer tomography scan (B) taken before the revision surgery showing transverse fracture of the acetabulum and loosened acetabular component.\n\nFig. 4 Photomicrograph of the bone from the acetabular fragment at the time of the revision arthroplasty showing complete absence of osteoclastic and osteoblastic activity.\n==== Refs\n1 Coleman RE Seaman JJ The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases Semin Oncol 2001 28 2 Suppl 6 11 16 11346860 \n2 Bobyn JD Hacking SA Krygier JJ Harvey EJ Little DG Tanzer M Zoledronic acid causes enhancement of bone growth into porous implants J Bone Joint Surg Br 2005 87 3 416 420 15773657 \n3 Wernecke G Namdari S DiCarlo EF Schneider R Lane J Case report of spontaneous, nonspinal fractures in a multiple myeloma patient on long-term pamidronate and zoledronic acid HSS J 2008 4 2 123 127 18815855 \n4 Lenart BA Neviaser AS Lyman S Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study Osteoporos Int 2009 20 8 1353 1362 19066707 \n5 McElfresh EC Coventry MB Femoral and pelvic fractures after total hip arthroplasty J Bone Joint Surg Am 1974 56 3 483 492 4822511 \n6 Sharkey PF Hozack WJ Callaghan JJ Acetabular fracture associated with cementless acetabular component insertion: a report of 13 cases J Arthroplasty 1999 14 4 426 431 10428222 \n7 Sanchez-Sotelo J McGrory BJ Berry DJ Acute periprosthetic fracture of the acetabulum associated with osteolytic pelvic lesions: a report of 3 cases J Arthroplasty 2000 15 1 126 130 10654474 \n8 Gelalis ID Politis AN Arnaoutoglou CM Georgakopoulos N Mitsiou D Xenakis TA Traumatic periprosthetic acetabular fracture treated by acute one-stage revision arthroplasty: a case report and review of the literature Injury 2010 41 4 421 424 19896125 \n9 Andrews P Barrack RL Harris WH Stress fracture of the medial wall of the acetabulum adjacent to a cementless acetabular component J Arthroplasty 2002 17 1 117 120 11805938 \n10 Cermak K Shumelinsky F Alexiou J Gebhart MJ Case reports: subtrochanteric femoral stress fractures after prolonged alendronate therapy Clin Orthop Relat Res 2010 468 7 1991 1996 20020334\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2005-291X",
"issue": "6(3)",
"journal": "Clinics in orthopedic surgery",
"keywords": "Bisphosphonate; Fracture; Hip arthroplasty; Loosening; Zoledronic acid",
"medline_ta": "Clin Orthop Surg",
"mesh_terms": "D000077:Acetabulum; D000368:Aged; D019644:Arthroplasty, Replacement, Hip; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D016723:Bone Remodeling; D001943:Breast Neoplasms; D004164:Diphosphonates; D005260:Female; D005598:Fractures, Spontaneous; D006622:Hip Prosthesis; D006801:Humans; D007093:Imidazoles; D015207:Osteoarthritis, Hip; D057068:Periprosthetic Fractures; D011475:Prosthesis Failure; D012086:Reoperation; D000077211:Zoledronic Acid",
"nlm_unique_id": "101505087",
"other_id": null,
"pages": "358-60",
"pmc": null,
"pmid": "25177464",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18815855;19896125;11346860;4822511;19066707;11805938;10654474;15773657;10428222;20020334",
"title": "Spontaneous acetabular periprosthetic fracture in a patient continuously having zoledronic acid.",
"title_normalized": "spontaneous acetabular periprosthetic fracture in a patient continuously having zoledronic acid"
} | [
{
"companynumb": "TH-ACTAVIS-2015-10956",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIs thin endometrium unresponsive to standard treatments expandable by intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF)?\n\n\nCONCLUSIONS\nThis cohort study is supportive of the effectiveness of G-CSF in expanding chronically unresponsive endometria.\n\n\nBACKGROUND\nIn a previous small case series, we reported the successful off-label use of G-CSF in four consecutive patients, who had previously failed to expand their endometria beyond 6.9 mm with the use of standard treatments.\n\n\nMETHODS\nIn a prospective observational cohort pilot study over 18 months, we described 21 consecutive infertile women with endometria <7 mm on the day of hCG administration in their first IVF cycles at our center. All previous cycles using traditional treatments with estradiol, sildenafil citrate (Viagra™) and/or beta-blockers had been unsuccessful. G-CSF (Nupogen™) was administered per intrauterine catheter by slow infusion before noon on the day of hCG administration. If the endometrium had not reached at least a 7-mm within 48h, a second infusion was given following oocyte retrieval. Primary and secondary main outcomes were an increase in endometrial thickness and clinical pregnancy, respectively. Endometrial thickness was assessed by vaginal ultrasound at the most expanded area of the endometrial stripe.\nThis study was uncontrolled, each patient serving as her own control in a prospective evaluation of endometrial thickness. The mean ± SD age of the cohort was 40.5 ± 6.6 years, gravidity was 1.8 ± 2.1 (range 0-7) and parity was 0.4 ± 1.1 (range 0-4); 76.2% of women had, based on age-specific FSH and anti-Müllerian hormone, an objective diagnosis of diminished ovarian reserve and had failed 2.0 ± 2.1 prior IVF cycles elsewhere.\n\n\nRESULTS\nWith 5.2 ± 1.9 days between G-CSF perfusions and embryo transfers, endometrial thickness increased from 6.4 ± 1.4 to 9.3 ± 2.1 mm (P < 0.001). The Δ in change was 2.9 ± 2.0 mm, and did not vary between conception and non-conception cycles. A 19.1% ongoing clinical pregnancy rate was observed, excluding one ectopic pregnancy.\n\n\nCONCLUSIONS\nSmall sample size (but a highly selected patient population) in an uncontrolled cohort study and in unselected first IVF cycles at our center.\n\n\nCONCLUSIONS\nThis pilot study supports the utility of G-CSF in the treatment of chronically thin endometrium and suggests that such treatment will, in very adversely affected patients, result in low but very reasonable clinical pregnancy rates.\n\n\nBACKGROUND\nThis work was supported by the Foundation for Reproductive Medicine, New York, New York, USA, a not-for-profit research foundation and intramural grants from the Center for Human Reproduction (CHR)-New York. N.G. and D.H.B. are members of the board of the Foundation for Reproductive Medicine. N.G. is owner of CHR-New York, where the study was conducted. N.G. and D.H.B. have been recipients of research awards, travel grants and speaker honoraria from various pharmaceutical and medical device companies. None of these companies was, however, in any way associated with the materials and the manuscript presented here. N.G. and D.H.B. are listed as co-inventors on a number of awarded and still pending U.S. patents, none related to the materials presented here. N.G. is on the board of a medically related company, not in any way associated with the data presented here.",
"affiliations": "The Center for Human Reproduction, New York and the Foundation for Reproductive Medicine, New York, NY 10021, USA. ngleicher@thechr.com",
"authors": "Gleicher|N|N|;Kim|A|A|;Michaeli|T|T|;Lee|H-J|HJ|;Shohat-Tal|A|A|;Lazzaroni|E|E|;Barad|D H|DH|",
"chemical_list": "D005300:Fertility Agents, Female; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1093/humrep/des370",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1161",
"issue": "28(1)",
"journal": "Human reproduction (Oxford, England)",
"keywords": null,
"medline_ta": "Hum Reprod",
"mesh_terms": "D000282:Administration, Intravaginal; D000328:Adult; D015331:Cohort Studies; D016903:Drug Monitoring; D004351:Drug Resistance; D004717:Endometrium; D005260:Female; D005300:Fertility Agents, Female; D005307:Fertilization in Vitro; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007247:Infertility, Female; D007263:Infusions, Parenteral; D008875:Middle Aged; D009519:New York City; D010062:Ovulation Induction; D010865:Pilot Projects; D011247:Pregnancy; D018873:Pregnancy Rate; D016649:Primary Ovarian Insufficiency; D011446:Prospective Studies; D011994:Recombinant Proteins; D014591:Uterine Diseases",
"nlm_unique_id": "8701199",
"other_id": null,
"pages": "172-7",
"pmc": null,
"pmid": "23081869",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A pilot cohort study of granulocyte colony-stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies.",
"title_normalized": "a pilot cohort study of granulocyte colony stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies"
} | [
{
"companynumb": "US-AMGEN-USASP2018184086",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GONADOTROPHIN, CHORIONIC"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nTo study the efficacy and safety of sorafenib combined with low dose cytarabine for treating patients with FLT3(+) relapsed and refractory acute myeloid leukemia (FLT3(+) RR-AML).\n\n\nMETHODS\nSeven patients with FLT3(+) RR-AML were treated with sorafenib and low dose cytarabine. The curative rate and adverse effects were observed in these patients.\n\n\nRESULTS\nOut of 7 RR-AML patients after treatment, 5 patients achieved complete remission (CR), 2 patients achieved partial remission (PR), and the overall response rate (ORR) after one course of therapy was 100%. No severe bleeding, nausea, vomiting and other side effects were found in these patients.\n\n\nCONCLUSIONS\nSorafenib combined with low dose cytarabine can effectively induce the remission of FLT3(+) RR-AML patients, and is worth for further clinical trails to verify its safty and efficiency.",
"affiliations": "Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China.;Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China.;Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China.;Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China.;Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China.;Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China.;Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China. E-mail: wubingyi@aliyun.com.",
"authors": "Liu|Xiao-Shu|XS|;Long|Hui|H|;Huang|Yu-Xian|YX|;Xu|Jian-Hui|JH|;Zhu|Jun-Yu|JY|;DU|Qing-Feng|QF|;Wu|Bing-Yi|BY|",
"chemical_list": "D010671:Phenylurea Compounds; D003561:Cytarabine; D009536:Niacinamide; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3",
"country": "China",
"delete": false,
"doi": "10.7534/j.issn.1009-2137.2016.02.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1009-2137",
"issue": "24(2)",
"journal": "Zhongguo shi yan xue ye xue za zhi",
"keywords": null,
"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D003561:Cytarabine; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D009536:Niacinamide; D010671:Phenylurea Compounds; D012008:Recurrence; D012074:Remission Induction; D000077157:Sorafenib; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "101084424",
"other_id": null,
"pages": "394-8",
"pmc": null,
"pmid": "27150998",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Efficacy of Sorafenib Combined with Low Dose Cytarabine for Treating Patients with FLT3+ Relapsed and Refractory Acute Myeloid Leukemia.",
"title_normalized": "clinical efficacy of sorafenib combined with low dose cytarabine for treating patients with flt3 relapsed and refractory acute myeloid leukemia"
} | [
{
"companynumb": "CN-BAYER-2016-106402",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nPremature pubarche is associated with conditions such as virilizing congenital adrenal hyperplasia, androgen-secreting tumors, and exogenous exposure to androgen products. We describe the clinical and hormonal features of a series of children who were referred to endocrine evaluation due to premature pubarche.\n\n\nMETHODS\nThis is a retrospective case series study of 14 children with premature pubarche and/or virilization. Five were unintentionally exposed to testosterone gel (parental use). Nine patients were intensely exposed to diaper rash prevention creams. Clinical and laboratory data were revised.\n\n\nRESULTS\nModerate to severe virilization was detected in the 5 patients (2 boys and 3 girls) who were exposed to testosterone gel. These patients had pubic hair development associated with clitoromegaly (3/3), penile enlargement (2/2), and accelerated growth (5/5). Testosterone levels were elevated in 4/5 patients associated with normal prepubertal gonadotropin levels and adrenal androgen precursors. The 9 children who were intensely exposed to diaper rash prevention creams had mild pubarche (intermediate hair) without any other clinical manifestation of pubertal development. Three of them exhibited pubic hair thinning after cream withdrawal.\n\n\nCONCLUSIONS\nUnintentional topical androgen exposure or the intense use of diaper rash prevention cream should be ruled out in children with precocious pubarche and/or virilization signs to avoid misdiagnosis and expendable investigation.",
"affiliations": "Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, carolinaramos50@hotmail.com.;Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.;Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.;Departamento de Pediatria Universidade Federal de Santa Catarina, Florianópolis, Brazil.;Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.;Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.;Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.;Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.",
"authors": "Ramos|Carolina de Oliveira|CO|;Macedo|Delanie Bulcão|DB|;Bachega|Tania Aparecida Sartori Sanchez|TASS|;Nascimento|Marilza Leal|ML|;Madureira|Guiomar|G|;Latronico|Ana Claudia|AC|;Brito|Vinicius Nahime|VN|;de Mendonca|Berenice Bilharinho|BB|",
"chemical_list": "D013739:Testosterone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000495664",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1663-2818",
"issue": "91(6)",
"journal": "Hormone research in paediatrics",
"keywords": "Androgens; Diaper rash prevention cream; Premature pubarche; Pubarche; Testosterone gel",
"medline_ta": "Horm Res Paediatr",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D003963:Diaper Rash; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011629:Puberty, Precocious; D012189:Retrospective Studies; D063465:Skin Cream; D013739:Testosterone; D014770:Virilism",
"nlm_unique_id": "101525157",
"other_id": null,
"pages": "411-415",
"pmc": null,
"pmid": "30677757",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Premature Pubarche due to Exogenous Testosterone Gel or Intense Diaper Rash Prevention Cream Use: A Case Series.",
"title_normalized": "premature pubarche due to exogenous testosterone gel or intense diaper rash prevention cream use a case series"
} | [
{
"companynumb": "BR-UPSHER-SMITH LABORATORIES, LLC-2019USL00868",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TESTOSTERONE"
},
"drugad... |
{
"abstract": "An infant of 2 months presented with absence of the femoral pulses, albeit with no signs of cardiac failure. The mother was known to have ingested Valproate during pregnancy. Echocardiography showed the aortic arch to be interrupted between the left common carotid and left subclavian arteries, so-called type B interruption, in the setting of an intact ventricular septum. Angiography, and multislice computed tomography, revealed the descending aorta to be supplied by a collateral artery originating from the right subclavian artery. Corrective surgery was successfully performed, but revealed an atretic segment of the arch at the site of interruption of flow.",
"affiliations": "Département de Cardiologie (Pédiatrique), Hôpital de la Timone, Boulevard Jean Moulin, Marseille, France.",
"authors": "Bonello|Béatrice|B|;Ghez|Olivier|O|;Fraisse|Alain|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1017/S1047951107001655",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "18(1)",
"journal": "Cardiology in the young",
"keywords": null,
"medline_ta": "Cardiol Young",
"mesh_terms": "D000792:Angiography; D001013:Aorta, Thoracic; D003937:Diagnosis, Differential; D018618:Echocardiography, Doppler, Color; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D013348:Subclavian Artery; D014057:Tomography, X-Ray Computed; D054079:Vascular Malformations; D014656:Vascular Surgical Procedures",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "105-7",
"pmc": null,
"pmid": "18093355",
"pubdate": "2008-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atresia of the aortic arch, with a collateral artery from the right subclavian artery supplying the descending aorta.",
"title_normalized": "atresia of the aortic arch with a collateral artery from the right subclavian artery supplying the descending aorta"
} | [
{
"companynumb": "FR-ABBVIE-17P-056-2033220-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALPROATE SODIUM"
},
"drugadditional": nul... |
{
"abstract": "Pain and emotional distress are relevant risk factors as clinicians assess for aberrant opioid-associated behavior and provide adequate and responsible pain relief to patients who engage in behaviors that may be interpreted as drug seeking in nature. The present case illustrates how undertreated pain and treatment-related anxiety affected the opioid use of a young adult with cancer. Because these risk factors were identified during the initial consult, the treatment team was able to implement a multimodal and multidisciplinary treatment approach that provided the patient with better analgesia and coping skills for anxiety.",
"affiliations": "1 Department of Psychology, University of Mississippi , University, Mississippi.;3 Department of Psychology, St. Jude Children's Research Hospital , Memphis, Tennessee.;4 Division of Anesthesiology, Department of Pediatric Medicine, St. Jude Children's Research Hospital , Memphis, Tennessee.",
"authors": "Peck|Kelly R|KR|;Harman|Jennifer L|JL|;Anghelescu|Doralina L|DL|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.1089/jayao.2018.0093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2156-5333",
"issue": "8(2)",
"journal": "Journal of adolescent and young adult oncology",
"keywords": "anxiety; opioids; pain management; palliative care; pediatric",
"medline_ta": "J Adolesc Young Adult Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D001859:Bone Neoplasms; D000072716:Cancer Pain; D003131:Combined Modality Therapy; D011307:Drug Prescriptions; D006801:Humans; D015994:Incidence; D008297:Male; D009293:Opioid-Related Disorders; D059408:Pain Management; D011379:Prognosis; D012512:Sarcoma, Ewing; D055815:Young Adult",
"nlm_unique_id": "101543508",
"other_id": null,
"pages": "221-224",
"pmc": null,
"pmid": "30335554",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Provision of Adequate Pain Management to a Young Adult Oncology Patient Presenting with Aberrant Opioid-Associated Behavior: A Case Study.",
"title_normalized": "provision of adequate pain management to a young adult oncology patient presenting with aberrant opioid associated behavior a case study"
} | [
{
"companynumb": "US-PURDUE-GBR-2019-0066453",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "Extranodal non-Hodgkin lymphomas (NHLs) arising in soft tissue is rare. This study describes a rare case of chemo-resistant large B-cell NHL of skeletal muscle, characterized by voluminous swelling in the thigh which responded well to radiotherapy. In this patient, recurrent NHL showed refractoriness to various chemotherapy regimens and was treated with radiation therapy repeatedly with excellent local response and no evidence of disease for 18 months. Most of the published literature describes surgery or chemotherapy as treatment for NHL soft tissue. This is the first case report describing the durable response with radiation without in-field recurrence in chemo-resistant large B-cell NHL skeletal muscle.",
"affiliations": "Department of Radiation Oncology, Apollo Speciality Hospital, Chennai, Tamil Nadu, India.;Department of Radiation Oncology, Apollo Speciality Hospital, Chennai, Tamil Nadu, India.;Department of Radiation Oncology, Apollo Speciality Hospital, Chennai, Tamil Nadu, India.;Department of Medical Oncology, Apollo Speciality Hospital, Chennai, Tamil Nadu, India.;Department of Radiation Oncology, Apollo Speciality Hospital, Chennai, Tamil Nadu, India.",
"authors": "Balasundaram|Subathira|S|;Ramadas|Rathnadevi|R|;Stumpf|Janos|J|;Thirumalairaj|Raja|R|;Perumal|Karthikeyan|K|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.174531",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "13(3)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D013848:Thigh",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "589-592",
"pmc": null,
"pmid": "28862233",
"pubdate": "2017",
"publication_types": "D016422:Letter",
"references": null,
"title": "Radiation treatment for chemotherapy-resistant non-Hodgkin's lymphoma in the left thigh.",
"title_normalized": "radiation treatment for chemotherapy resistant non hodgkin s lymphoma in the left thigh"
} | [
{
"companynumb": "IN-GLENMARK PHARMACEUTICALS-2017GMK029094",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nNon-steroidal anti-inflammatory drugs (NSAIDs) frequently cause adverse drug reactions. Many studies have shown that drugs which selectively inhibit the cyclooxygenase-2 enzyme (COX-2) are safe alternatives in the majority of patients. However, hypersensitivity reactions to COX-2 inhibitors have been published. Hardly any data are available regarding the safety of alternatives in case of COX-2 inhibitor hypersensitivity. We aimed to investigate the tolerance to COX-2 inhibitors in patients with non-selective NSAID hypersensitivity. Furthermore, in COX-2 hypersensitive patients tolerance of a second COX-2 inhibitor was investigated.\n\n\nMETHODS\nWe retrospectively analyzed 91 patients with proven non-selective NSAID hypersensitivity that underwent oral challenges with a COX-2 inhibitor. Patients with intolerance to the first challenged COX-2 inhibitor received a second challenge with a different COX-2 inhibitor.\n\n\nRESULTS\n19 out of 91 (21%) patients had a positive reaction to the first oral challenge with a COX-2 inhibitor. 14 of them underwent a second challenge with a different COX-2 inhibitor and 12 (86%) did not react.\n\n\nCONCLUSIONS\nA relatively high percentage (21%) of the non-selective NSAID hypersensitive patients did not tolerate a COX-2 inhibitor and oral challenge is advised prior to prescription of a COX-2 inhibitor. For the majority of patients reacting to a COX-2 inhibitor an alternative can be found.",
"affiliations": "Department of Dermatology/Allergology, University Medical Centre Utrecht, Heidelberglaan 100, G 02,124, Utrecht 3584 CX, The Netherlands. h.rockmann@umcutrecht.nl.",
"authors": "Malskat|Wendy Sj|WS|;Knulst|André C|AC|;Bruijnzeel-Koomen|Carla Afm|CA|;Röckmann|Heike|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/2045-7022-3-20",
"fulltext": "\n==== Front\nClin Transl AllergyClin Transl AllergyClinical and Translational Allergy2045-7022BioMed Central 2045-7022-3-202379989810.1186/2045-7022-3-20ResearchTolerance to alternative cyclooxygenase-2 inhibitors in nonsteroidal anti-inflammatory drug hypersensitive patients Malskat Wendy SJ 12w.malskat@erasmusmc.nlKnulst André C 1a.c.knulst@umcutrecht.nlBruijnzeel-Koomen Carla AFM 1c.bruijnzeel@umcutrecht.nlRöckmann Heike 1h.rockmann@umcutrecht.nl1 Department of Dermatology/Allergology, University Medical Centre Utrecht, Heidelberglaan 100, G 02.124, Utrecht 3584 CX, The Netherlands2 Current Address: Department of Dermatology, Erasmus Medical Centre, Rotterdam, The Netherlands2013 24 6 2013 3 20 20 15 2 2013 9 6 2013 Copyright © 2013 Malskat et al.; licensee BioMed Central Ltd.2013Malskat et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nNon-steroidal anti-inflammatory drugs (NSAIDs) frequently cause adverse drug reactions. Many studies have shown that drugs which selectively inhibit the cyclooxygenase-2 enzyme (COX-2) are safe alternatives in the majority of patients. However, hypersensitivity reactions to COX-2 inhibitors have been published. Hardly any data are available regarding the safety of alternatives in case of COX-2 inhibitor hypersensitivity. We aimed to investigate the tolerance to COX-2 inhibitors in patients with non-selective NSAID hypersensitivity. Furthermore, in COX-2 hypersensitive patients tolerance of a second COX-2 inhibitor was investigated.\n\nMethods\nWe retrospectively analyzed 91 patients with proven non-selective NSAID hypersensitivity that underwent oral challenges with a COX-2 inhibitor. Patients with intolerance to the first challenged COX-2 inhibitor received a second challenge with a different COX-2 inhibitor.\n\nResults\n19 out of 91 (21%) patients had a positive reaction to the first oral challenge with a COX-2 inhibitor. 14 of them underwent a second challenge with a different COX-2 inhibitor and 12 (86%) did not react.\n\nConclusions\nA relatively high percentage (21%) of the non-selective NSAID hypersensitive patients did not tolerate a COX-2 inhibitor and oral challenge is advised prior to prescription of a COX-2 inhibitor. For the majority of patients reacting to a COX-2 inhibitor an alternative can be found.\n\nCOX-2Drug hypersensitivityNonsteroidal anti-inflammatory drugsOral provocation\n==== Body\nBackground\nNSAIDs (non-steroidal anti-inflammatory drugs) are the most universally used analgesics and are responsible for about 21-35% of all drug hypersensitivity reactions [1-3]. Symptoms vary from cutaneous (urticaria and/or angioedema) and respiratory (rhinitis and/or dyspnea) to anaphylactic shock. The frequency of NSAID hypersensitivity might be higher in patients with chronic spontaneous urticaria, asthma [4-6] and mastocytosis [7]. The majority of reactions (about 75%) are not caused by immunological mechanisms (IgE or T-cell mediated), but by pharmacological inhibition of the cyclooxygenase-(COX) pathway [8]. This is supported by the clinical observation that many NSAID hypersensitive patients react to various NSAIDs of unrelated structure [5,6,9-11]. There are at least 2 isoforms of COX; the constitutively expressed COX-1 enzyme takes part in fundamental mechanisms of homeostasis, whereas the inducible COX-2 enzyme mediates inflammation. The therapeutic effects of NSAIDs are thought to be mainly related to the inhibition of COX-2, whereas COX-1 inhibition seems to be more responsible for the adverse effects [6,10]. For that reason selective COX-2 inhibitors have been developed.\n\nTherapeutic options to diagnose NSAID hypersensitivity are still limited. Oral drug challenge (preferably placebo controlled) is the gold standard in diagnosing NSAID hypersensitivity [12,13].\n\nSeveral studies have shown (partial) tolerability of COX-2 inhibitors in patients with hypersensitivity to non-selective NSAID and/or aspirin sensitive asthma [14-16]. Weberstock et al. [15] reviewed 84 studies, 13 of them described double-blind COX-2 inhibitor challenges. Of the 3304 patients described, 119 (3.6%) had hypersensitivity to COX-2 inhibitors, consisting of urticaria, angioedema and/or rhinorrhea. Therefore, NSAIDs that selectively inhibit COX-2 are assumed to be a safe alternative in the majority of non-selective NSAID hypersensitive patients. A recent review by Asero [17] described a wide variation in the percentage of COX-2 inhibitor hypersensitivity up to 33%. Recently, Dona et al. [18] described a high percentage of COX-2 inhibitor hypersensitivity (25%) in patients with hypersensitivity to multiple non-selective NSAIDs and paracetamol. In the same study, patients hypersensitive to multiple non-selective NSAIDs, but tolerant to paracetamol showed only 6% of COX-2 inhibitor hypersensitivity.\n\nSo far, tolerance of an alternative COX-2 inhibitor in COX-2 hypersensitive patients has been hardly investigated. A case-report of 2 patients with hypersensitivity to numerous non-selective NSAIDs and a selective COX-2 inhibitor, described tolerance to a second COX-2 inhibitor, celecoxib and etoricoxib respectively [19]. Quinones Estevez [20] described a case series of 8 patients with hypersensitivity to non-selective NSAIDs and selective COX-2 inhibitors. Three of 5 patients that were challenged tolerated an alternative COX-2 inhibitor; celecoxib or etoricoxib. A study comparing tolerance to different COX-2 inhibitors (n = 37) (nimesulide, meloxicam and rofecoxib) showed tolerance to meloxicam in 8 of 11 patients hypersensitive to nimesulide. The majority of nimesulide hypersensitive patients (10/11) tolerated rofecoxib [21].\n\nThe aim of this study was to assess the tolerance of a first and, in case of intolerance, a second COX-2 inhibitor in patients with hypersensitivity to non-selective NSAIDs in a larger population.\n\nMethods\nSelection of patients\nAll patients (n = 91) with proven non-selective NSAID hypersensitivity and oral challenge to a selective COX-2 inhibitor at the outpatient clinic of Allergology of the University Medical Center Utrecht, from September 2002 until April 2012, were analyzed. NSAID hypersensitivity was diagnosed, based on either a convincing unequivocal patient history (n = 69), or a positive oral challenge with the suspicious drug (n = 22). Challenge protocols are shown in Table 1. The criteria for a convincing patient history [22] were: 1. a time interval of a few minutes up to a maximum of 5 hours between intake of the drug and start of symptoms, 2. objective signs of urticaria, angioedema, rhinitis, dyspnea and/or anaphylactic shock (systolic BP <90 mm Hg or a >30 mm Hg drop). We analyzed if patients had two or more reactions to the same or distinct NSAID(s), reported either by challenge or by history. We also analyzed usage and intolerance of paracetamol after reaction to the culprit drug documented in patient history.\n\nTable 1 Challenge protocols of culprit NSAIDs\n\n \tDiclofenac\tIbuprofen\tAspirin\tNaproxen\tPropyfenazon\t\nAdministration\toral\toral\toral\toral\toral\t\nDose 1 (mg)\t0.1\t0.1\t10\t0.1\t1\t\nDose 2 (mg); time interval (min)\t1; 30\t1; 30\t44; 30\t1; 30\t5; 30\t\nDose 3 (mg); time interval (min)\t10; 30\t10; 30\t117; 60\t10; 30\t25; 30\t\nDose 4 (mg); time interval (min)\t25; 60\t50; 30\t312; 60\t50; 30\t100; 60\t\nDose 5 (mg); time interval (min)\t50; 60\t100; 60\t500; 120\t125; 30\t250; 60\t\nDose 6 (mg); time interval (min)\tNA\t200; 60\tNA\t250; 60\tNA\t\nLegend:Min, minutes; NA, not applicable; (Since this study the dosages have been revised and the dosage of 0.1 mg is removed.)\n\nStudy design\nSex, age, suspected NSAID(s) and co-morbidity data were obtained, using patient files and, where necessary, telephone calls to complete and confirm the data. The clinical reaction patterns, the challenge with the culprit drug and the outcome of challenge with COX-2 inhibitor were assessed based on differentiated organ involvement: cutaneous (urticaria and/or angioedema), respiratory (rhinitis and/or dyspnea) or anaphylactic shock. The Medical Ethics Review Committee (METC) of UMC Utrecht agreed to the study (METC-protocol number 12-438).\n\nCOX-2 inhibitor challenges\nAt first COX-2 inhibitor challenges were performed with rofecoxib, until it was withdrawn from the market in 2003 (dosages: 1, 6.25, and 12.5 mg; interval 60 minutes). After 2003, celecoxib was preferentially used for a first challenge (dosages: 0.1, 1, 10, 20 mg at 30 minutes intervals and 50 and 100 mg at 60 minutes intervals). Etoricoxib was preferentially used for a second challenge (dosages: 0.1, 1, 5, 10 mg at 30 minutes intervals and 30 and 60 mg at 60 minutes intervals). The time interval between different oral challenges was 6–12 weeks.\n\nThe challenges were performed in a clinical setting, equipped for resuscitation and monitoring of vital signs. Appearance of symptoms was closely monitored. A challenge test was considered to be positive when objective symptoms occurred, e.g. itching and erythema, urticaria, angioedema, rhinoconjunctivitis, dyspnea, hypotension or anaphylactic shock. If objective symptoms were present, the challenge was stopped and the symptoms were treated with antihistamines or prednisone. None of the patients required treatment with epinephrine.\n\nStatistical analysis\nNumeric results were expressed as mean ± standard deviation (SD). Nominal variables were expressed as percentage of the patients. The Statistical Package for Social Sciences (SPSS) for Windows Version 15.0 was used to analyze the data.\n\nResults\nPatient characteristics\n91 patients with a diagnosis of non-selective NSAID hypersensitivity were challenged with a first COX-2 inhibitor. The demographic and clinical characterizations of the study group, as well as the drugs suspected to cause a hypersensitivity reaction are shown in Table 2 and 3. Diagnosis of NSAID hypersensitivity was confirmed by oral challenge with the culprit drug in 22 patients. In 69 patients, the history was highly suggestive and no oral challenges were performed. 44 (of 69) patients (63%) reported repeated reactions to the same culprit drug. Of the 22 patients with a single reaction and without challenge to the culprit drug 11 patients (50%) experienced anaphylactic reactions. In 3 patients information about repeated reactionswas missing.\n\nTable 2 Demographic and clinical features of the study group\n\nVariable\tPatients (n = 91)\t\nSex (male/female) n (%)\t23/68 (25/75%)\t\nAge (years) (mean ± SD)\t51.9 ± 13.3\t\nReaction to 1 NSAID n (%)\t71 (78%)\t\nReaction to various NSAIDs n (%)\t20 (22%)\t\nReaction to paracetamol1\t17 (18%)\t\nCo-morbid disorders n (%)\t \t\n- Chronic spontaneous urticaria\t11 (12%)\t\n- Asthma\t9 (10%)\t\nDiagnosed non-selective NSAID hypersensitivity n (%)\t \t\n- Patient history; repeated reaction to the same culprit drug\t44 (48%)\t\n- Patient history; no/unknown repeated reaction to the same culprit drug\t25 (28%)\t\n- Oral challenge with the culprit drug\t22 (24%)\t\n1by patient history.\n\nTable 3 Type of reaction to the suspected drugs according to patient history\n\nSpecific drug\tType of reaction\t\nUrticaria1\tAngioedema2\tRespiratory3\tAnaphylaxis4\tTotal n (%)\t\nDiclofenac\t6\t4\t10\t22\t42 (46%)\t\nIbuprofen\t2\t5\t4\t4\t15 (16%)\t\nNaproxen\t1\t3\t2\t2\t8 (9%)\t\nAspirin\t0\t2\t2\t0\t4 (4%)\t\nPropyfenazon\t0\t1\t1\t0\t2 (2%)\t\nVarious NSAIDs\t6\t8\t2\t4\t20 (22%)\t\nTotal\t15 (16%)\t23 (25%)\t21 (23%)\t32 (35%)\t91 (100%)\t\n1Presence of urticaria (without angioedema).\n\n2Presence of angioedema (with or without urticaria).\n\n3Presence of respiratory symptoms (rhinitis, dyspnea) (additional to urticaria and/or angioedema).\n\n4Presence of hypotension <90 mmHg or >30 mmHg drop (additional to urticaria and/or angioedema).\n\nOf the 91 patients, 9 (10%) suffered from concomitant chronic asthma and 11 patients (12%) from concomitant chronic spontaneous urticaria unrelated to the intake of NSAIDs. The majority of the patients (n = 71; 78%) reported a reaction to one NSAID, while 22% (n = 20) reacted to several (2 or 3) non-selective NSAIDs. Paracetamol was tolerated in 70 patients (79%) following reaction to a NSAID. Information on paracetamol tolerance was missing in 4 patients. The most frequently involved drug was diclofenac in 42 patients (46%). Anaphylactic shock was the most frequent reaction type reported in 32 subjects (35%), followed by angioedema in 23 subjects (25%). None of the patients suffered from aspirin sensitive asthma.\n\nFirst COX-2 inhibitor challenges\nIn 77 patients (85%) celecoxib was given and in 13 patients (14%) rofecoxib. Etoricoxib was used in the first challenge in only one patient. 19 patients (21%) had a positive challenge to one of these COX-2 inhibitors. Characteristics and symptoms of patients with a positive first challenge are presented in Table 4 and 5. Three of these COX-2 hypersensitive patients suffered from concomitant chronic spontaneous urticaria but were free of urticarial symptoms for 6 weeks or more, before oral challenge with the COX-2 inhibitor. In 14 of 19 patients (74%) diagnosis of non selective NSAID hypersensitivity was confirmed by challenge or repeated reaction to the culprit NSAID. Eight of the 19 patients (42%) with a positive challenge to a COX-2 inhibitor had a history of hypersensitivity to multiple non-selective NSAIDs. Four patients were intolerant to paracetamol. Ten patients (16%) with unknown status of hypersensitivity to multiple non-selective NSAIDs, reacted to a COX-2 inhibitor.\n\nTable 4 Demographic and clinical features of patients with positive first COX-2 inhibitor challenge\n\nVariable\tPatients (n = 19)\t\nSex (male/female) n (%)\t4/15 (21/79%)\t\nAge (years) (mean ± SD)\t53.2 ± 10.9\t\nReaction to 1 NSAID n (%)\t12 (63%)\t\nReaction to various NSAIDs n (%)\t7 (37%)\t\nReaction to paracetamol1\t4 (21%)\t\nCo-morbid disorders n (%)\t \t\n- Chronic spontaneous urticaria\t3 (16%)\t\n- Asthma\t4 (21%)\t\nDiagnosed non-selective NSAID hypersensitivity n (%)\t \t\n- Patient history; repeated reaction to the same culprit drug\t11 (58%)\t\n- Patient history; no/unknown repeated reaction to the same culprit drug\t3 (15%)\t\n- Oral challenge with the culprit drug\t5 (26%)\t\n1By patient history.\n\nTable 5 Clinical features and results of patients with positive first COX-2 inhibitor challenge\n\nPatient no.\tSex/age\tCo-morbid disorders\tCulprit drug\tParacetamol intolerance\tType of reaction\tManner of diagnosis\tReaction to oral COX-2 inhibitor challenges\t\nFirst\tSecond\t\nDrug Reaction\tDrug Reaction\t\n1\tF/55\tAs\tdiclofenac\tno\tU/A/Ana\tPH; repRX\trofecoxib\tU/D\tnd\t \t\n2\tM/78\tNS\tdiclofenac\tno\tA/D/Ana\tC\trofecoxib\tU\tnd\t \t\n3\tF/65\tAs\tmultiple\tno\tU\tPH; repRX\tcelecoxib\tU\trofecoxib\tNeg\t\n4\tF/55\tNS\tdiclofenac\tno\tU/Ana\tC\trofecoxib\tA\tcelecoxib\tNeg\t\n5\tF/46\tNS\tnaproxen\tno\tA\tPH\trofecoxib\tA\tcelecoxib\tNeg\t\n6\tM/36\tNS\tmultiple\tyes\tU/A\tPH; repRX\tcelecoxib\tU\tnd\t \t\n7\tF/35\tNS\tmultiple\tno\tU/A\tC\tetoricoxib\tU/A\tcelecoxib\tNeg\t\n8\tF/51\tAs\tdiclofenac\tno\tA/D\tPH; repRX\tcelecoxib\tU/An/D/A\tnd\t \t\n9\tF/56\tNS\tmultiple\tyes\tA\tC, repRX\tcelecoxib\tA\trofecoxib\tNeg\t\n10\tF/50\tNS\tnaproxen\tno\tU/Ana\tPH; repRX\tcelecoxib\tA\tetoricoxib\tNeg\t\n11\tF/59\tNS\tnaproxen\tno\tU/A\tPH; repRX\tcelecoxib\tA\tetoricoxib\tNeg\t\n12\tF/46\tNS\tdiclofenac\tno\tU/A/D/Ana\tPH\tcelecoxib\tA\tetoricoxib\tNeg\t\n13\tF/62\tU\tmultiple\tyes\tU/A\tPH; repRX\tcelecoxib\tU\tnd\t \t\n14\tM/40\tU\tibuprofen\tyes\tU/A\tPH; repRX\tcelecoxib\tU/D\tetoricoxib\tU/D\t\n15\tF/66\tNS\tdiclofenac\tno\tU/A/D/Ana\tPH; repRX\tcelecoxib\tU/A\tetoricoxib\tNeg\t\n16\tF/63\tNS\tmultiple\tno\tU/A/ D\tPH; repRX\tcelecoxib\tU/A\tetoricoxib\tNeg\t\n17\tF/53\tNS\tdiclofenac\tno\tU\tC\tcelecoxib\tU/A\tetoricoxib\tU/A/D\t\n18\tF/46\tA/U\tmultiple\tno\tU/A\tPH; repRX\tcelecoxib\tA\tetoricoxib\tNeg\t\n19\tM49\tNS\tdiclofenac\tno\tU/A\tPH\tcelecoxib\tU/A\tetoricoxib\tNeg\t\nLegend: F, female; M, male; NS, none specific; As, asthma; U, urticaria; A, angioedema (without weals); Ana, anaphylactic shock; D, dyspnea; PH, patient history; repRx, repeated reaction to the same drug; C, challenge test; nd, not done; Neg, negative reaction. 2 patients with a positive challenge to a second COX-2 inhibitor are highlighted in bold.\n\nSecond COX-2 inhibitor challenges\n14 out of 19 patients with a positive first challenge to a COX-2 inhibitor underwent a second challenge test with a different COX-2 inhibitor (9 etoricoxib, 3 celecoxib and 2 rofecoxib), while 5 patients declined. The second provocation was positive in only 2 patients. Both patients presented with urticaria, generalized itch and dyspnoea following challenge with etoricoxib. One of them had a history of hypersensitivity reactions to the non-selective NSAIDs ibuprofen and naproxen together with a past history of chronic spontaneous urticaria, but not with asthma. The second patient had a history of hypersensitivity reactions to diclofenac, without chronic spontaneous urticaria or asthma.\n\nDiscussion\nIn this retrospective study a relative high percentage of 21% COX-2 hypersensitivity was found in patients with non-selective NSAID hypersensitivity. However, in COX-2 hypersensitive patient’s tolerance to another COX-2 inhibitor was found in the majority (86%) of patients.\n\nThere is a large variation (0% to 33%) in the percentage of COX-2 inhibitor hypersensitivity in patients with NSAID hypersensitivity (17). Most studies describe low percentages [15,21,23-37]. One study associated a high percentages (25%) of hypersensitivity to etoricoxib with paracetamol intolerance (compared to 6% in multiple NSAID hypersensitivity without paracetamol intolerance) [18]. In contrast, COX-2 inhibitor hypersensitivity was not associated with paracetamol hypersensitivity in our patient population.\n\nDifferences in study design may explain the variability in the different studies. Many studies did not perform oral challenges to confirm non selective NSAID hypersensitivity [21,24,26,27,29,34,35,38]. This may have induced a higher percentage of incorrect diagnosis of non selective NSAID hypersensitivity, especially since some studies included patients with a long time interval, up to 72 hours, between intake of the culprit non selective NSAID and onset of symptoms [26,29,33]. Incorrect diagnosis of non selective NSAID hypersensitivity may consequently lead to a lower estimate of the percentage of COX-2 inhibitor hypersensitivity. The majority of patients in our study were also included based on a suggestive history. However, we used strict criteria: only patients with objective symptoms and within 5 hours after intake were included. Furthermore, 53 (58%) patients had re-intake of the same culprit drug followed by a similar hypersensitivity reaction, which strongly supports the diagnosis. 44 patients with a repeated reaction did not underwent a challenge with the culprit drug. In addition, the percentages of COX-2 hypersensitivity did not differ between the patients diagnosed by careful history only versus those in which the diagnosis was confirmed by challenge.\n\nProvocation with COX-2 inhibitors was open and not placebo controlled. However, the challenges were only considered positive if the patient developed objective symptoms, in agreement with other studies [21,36]. Since we performed this study, the challenged drug dosages have been revised; the lowest dosage of 0.1 mg has appeared to be unnecessary and has been removed from the protocol.\n\nAnother important factor that might influence the rate of COX-2 inhibitor hypersensitivity is patient selection. Patients in our population who previously reacted to numerous non-selective NSAIDs had a higher rate (38%) of reaction to COX-2 inhibitors than patients who reacted to only one NSAID (16%). This is in line with Dona et al., analyzing patients with multiple NSAID hypersensitivity, showing a generally high percentage of hypersensitivity to etoricoxib [18]. Multiple NSAID reactivity was not known in all patients. Therefore, the current classification of EAACI/ENDA group [11] could not be applied to subdivide the study population.\n\nAnother important factor could be the specific culprit drug, since acetylsalicylic acid (ASA) was the most frequently reported culprit drug in many other studies (21 - 100%) [14,21,23,25-27,29,30,33-36,39],[40]. In our study population, diclofenac, ibuprofen and naproxen represented the most common culprit drugs with 46% , 15% and 9% , respectively. Only 4 patients (4%) reported a hypersensitivity reaction to ASA only. None of them showed a reaction to a COX-2 inhibitor. Further studies are needed to investigate the relation between the specific culprit drug in non-selective NSAID hypersensitive patients and hypersensitivity to COX-2 inhibitors.\n\nThe frequency of chronic spontaneous urticaria (12%) in our study group was comparable with previous literature (2.7-11%) [21,23,29,41] and cannot explain the high percentage of COX- hypersensitivity. The frequency of asthma in our study population was rather low, compared to the literature [14,21,23,27,29,39]. Specific studies are needed to investigate whether hypersensitivity to COX-2 inhibitors is dependent on these factors.\n\nInterestingly, a second COX-2 inhibitor was tolerated in the majority of challenged patients (86%). Of the patients with a second COX-2 inhibitor challenge, six had a history of reactions to multiple NSAIDs. However, five of them tolerated the challenge with a second COX-2 inhibitor. This shows that patients who react to a particular COX-2 inhibitor, may be tolerant to another one. This was also described in two small case-series [19,42]. Cimbollek et al. described two patients with multiple NSAID hypersensitivity reacting to one COX-2 inhibitor but tolerating another. Quinones-Estevez described 8 patients with multiple NSAID hypersensitivity of which five were challenged with both celecoxib and etoricoxib. Three patients reacted to only one of the drugs, while two to both. In our study, etoricoxib was mainly used as a secondly challenged alternative COX-2 inhibitor, known to have a much higher COX-2 selectivity than celecoxib [43]. This might explain the higher percentage of tolerance to etoricoxib. However, advantage of etoricoxib over celecoxib was not observed in case-series [19,20] or a recent review analyzing COX-2 inhibitor hypersensitivity [17].\n\nOur results in a large group of patients with NSAID hypersensitivity and reaction to a specific COX-2 inhibitor show that an alternative COX-2 inhibitor can be tolerated.Challenge with a second COX-2 inhibitor can be recommended in these patients. So far, there seems no preference which COX-2 inhibitor, celecoxib or etoricoxib, should be challenged first and which second.\n\nConclusions\nIn most patients with non-selective NSAID hypersensitivity COX-2 inhibitors were safe. However, given the relatively high percentage (21%) of positive challenges, it is necessary to perform an oral challenge prior to prescription. In case of hypersensitivity to a COX-2 inhibitor, second challenges with a different COX-2 inhibitor can provide an alternative. Further studies are needed to define risk factors for COX-2 inhibitor hypersensitivity in patients with non-selective NSAID hypersensitivity.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nWM wrote the first version of the manuscript. WM and HR were involved in collection and interpretation of the data. HR, CB and AK contributed to the preparation and critical revision of the manuscript. All authors approved the final version of the manuscript.\n==== Refs\nGomes E Cardoso MF Praca F Gomes L Marino E Demoly P Self-reported drug allergy in a general adult Portuguese population Clin Exp Allergy 2004 34 1597 1601 10.1111/j.1365-2222.2004.02070.x 15479276 \nFaich GA Adverse-drug-reaction monitoring N Engl J Med 1986 314 1589 1592 10.1056/NEJM198606123142427 3713757 \nDona I Blanca-Lopez N Torres MJ Garcia-Campos J Garcia-Nunez I Gomez F Salas M Rondon C Canto MG Blanca M Drug hypersensitivity reactions: response patterns, drug involved, and temporal variations in a large series of patients J Investig Allergol Clin Immunol 2012 22 363 371 23101312 \nSzczeklik A Adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs Ann Allergy 1987 59 113 118 3318575 \nStevenson DD Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs J Allergy Clin Immunol 1984 74 617 622 10.1016/0091-6749(84)90115-5 6436354 \nNamazy JA Simon RA Sensitivity to nonsteroidal anti-inflammatory drugs Ann Allergy Asthma Immunol 2002 89 542 550 605 10.1016/S1081-1206(10)62099-6 12487218 \nMastalerz L Setkowicz M Sanak M Szczeklik A Hypersensitivity to aspirin: common eicosanoid alterations in urticaria and asthma J Allergy Clin Immunol 2004 113 771 775 10.1016/j.jaci.2003.12.323 15100686 \nDona I Blanca-Lopez N Cornejo-Garcia JA Torres MJ Laguna JJ Fernandez J Rosado A Rondon C Campo P Agundez JA Blanca M Canto G Characteristics of subjects experiencing hypersensitivity to non-steroidal anti-inflammatory drugs: patterns of response Clin Exp Allergy 2011 41 86 95 10.1111/j.1365-2222.2010.03651.x 21155908 \nSzczeklik A Stevenson DD Aspirin-induced asthma: advances in pathogenesis and management J Allergy Clin Immunol 1999 104 5 13 10.1016/S0091-6749(99)70106-5 10400832 \nSzczeklik A Gryglewski RJ Czerniawska-Mysik G Clinical patterns of hypersensitivity to nonsteroidal anti-inflammatory drugs and their pathogenesis J Allergy Clin Immunol 1977 60 276 284 10.1016/0091-6749(77)90106-3 410857 \nKowalski ML Makowska JS Blanca M Bavbek S Bochenek G Bousquet J Bousquet P Celik G Demoly P Gomes ER Nizankowska-Mogilnicka E Romano A Sanchez-Borges M Sanz M Torres MJ De Weck A Szczeklik A Brockow K Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA* Allergy 2011 66 818 829 10.1111/j.1398-9995.2011.02557.x 21631520 \nMacy E Bernstein JA Castells MC Gawchik SM Lee TH Settipane RA Simon RA Wald J Woessner KM Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper Ann Allergy Asthma Immunol 2007 98 172 174 10.1016/S1081-1206(10)60692-8 17304886 \nNizankowska-Mogilnicka E Bochenek G Mastalerz L Swierczynska M Picado C Scadding G Kowalski ML Setkowicz M Ring J Brockow K Bachert C Wohrl S Dahlen B Szczeklik A EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity Allergy 2007 62 1111 1118 10.1111/j.1398-9995.2007.01409.x 17521312 \nWoessner KM Simon RA Stevenson DD The safety of celecoxib in patients with aspirin-sensitive asthma Arthritis Rheum 2002 46 2201 2206 10.1002/art.10426 12209526 \nWeberschock TB Muller SM Boehncke S Boehncke WH Tolerance to coxibs in patients with intolerance to non-steroidal anti-inflammatory drugs (NSAIDs): a systematic structured review of the literature Arch Dermatol Res 2007 299 169 175 10.1007/s00403-007-0757-6 17492455 \nMartin-Garcia C Hinojosa M Berges P Camacho E Garcia-Rodriguez R Alfaya T Iscar A Safety of a cyclooxygenase-2 inhibitor in patients with aspirin-sensitive asthma Chest 2002 121 1812 1817 10.1378/chest.121.6.1812 12065343 \nAsero R Cutaneous hypersensitivity to multiple NSAIDs: never take tolerance to selective COX-2 inhibitors (COXIBs) for granted! Eur Ann Allergy Clin Immunol 2013 45 3 6 23678553 \nDona I Blanca-Lopez N Jagemann LR Torres MJ Rondon C Campo P Gomez AI Fernandez J Laguna JJ Rosado A Blanca M Canto G Response to a selective COX-2 inhibitor in patients with urticaria/angioedema induced by nonsteroidal anti-inflammatory drugs Allergy 2011 66 1428 1433 10.1111/j.1398-9995.2011.02684.x 21834936 \nCimbollek S Quiralte J Avila R COX-2 inhibitors in patients with sensitivity to nonselective NSAIDs N Engl J Med 2009 361 2197 2198 10.1056/NEJMc0907208 19940308 \nQuinones Estevez MD Are selective COX-2 inhibitors a safe option in patients with intolerance to nonsteroidal antiinflammatory drugs? J Investig Allergol Clin Immunol 2009 19 328 330 19639736 \nBavbek S Celik G Ozer F Mungan D Misirligil Z Safety of selective COX-2 inhibitors in aspirin/nonsteroidal anti-inflammatory drug-intolerant patients: comparison of nimesulide, meloxicam, and rofecoxib J Asthma 2004 41 67 75 10.1081/JAS-120026063 15046380 \nAsero R Bavbek S Blanca M Blanca-Lopez N Cortellini G Nizankowska-Mogilnicka E Quaratino D Romano A Sanchez-Borges M Torres-Jaen MJ Clinical management of patients with a history of urticaria/angioedema induced by multiple NSAIDs: an expert panel review Int Arch Allergy Immunol 2013 160 126 133 10.1159/000342424 23018315 \nBavbek S Celik G Pasaoglu G Misirligil Z Rofecoxib, as a safe alternative for acetyl salicylic acid/nonsteroidal anti-inflammatory drug-intolerant patients J Investig Allergol Clin Immunol 2006 16 57 62 16599250 \nNettis E Di PR Ferrannini A Tursi A Tolerability of rofecoxib in patients with cutaneous adverse reactions to nonsteroidal anti-inflammatory drugs Ann Allergy Asthma Immunol 2002 88 331 334 10.1016/S1081-1206(10)62017-0 11926629 \nPacor ML Di Lorenzo G Biasi D Barbagallo M Corrocher R Safety of rofecoxib in subjects with a history of adverse cutaneous reactions to aspirin and/or non-steroidal anti-inflammatory drugs Clin Exp Allergy 2002 32 397 400 10.1046/j.1365-2222.2002.01260.x 11940070 \nPerrone MR Artesani MC Viola M Gaeta F Caringi M Quaratino D Romano A Tolerability of rofecoxib in patients with adverse reactions to nonsteroidal anti-inflammatory drugs: a study of 216 patients and literature review Int Arch Allergy Immunol 2003 132 82 86 10.1159/000073268 14555862 \nAhlbach S Usadel KH Kaufmann R Boehncke WH [The selective cyclooxygenase-2 inhibitor celecoxib is a safe alternative in patients with pseudo-allergic reactions to nonsteroidal anti-inflammatory drugs]Der selektive Cyclooxygenase-2-Inhibitor Celecoxib ist ein sicheres Ausweichpraparat bei Intoleranz gegenuber nichtsteroidalen Antiphlogistika Med Klin (Munich) 2003 98 242 244 10.1007/s00063-003-1251-3 12721666 \nAsero R Etoricoxib challenge in patients with chronic urticaria with NSAID intolerance Clin Exp Dermatol 2007 32 661 663 10.1111/j.1365-2230.2007.02464.x 17953635 \nCelik G Pasaoglu G Bavbek S Abadoglu O Dursun B Mungan D Misirligil Z Tolerability of selective cyclooxygenase inhibitor, celecoxib, in patients with analgesic intolerance J Asthma 2005 42 127 131 10.1081/JAS-51326 15871445 \nGarcia-Rodriguez RM Hinojosa M Camacho-Garrido E Berges Gimeno P Martin Garcia C Celecoxib, safe in NSAID intolerance Allergy 2002 57 1085 1086 10.1034/j.1398-9995.2002.23836_7.x 12359017 \nNettis E Colanardi MC Ferrannini A Vacca A Tursi A Short-term tolerability of etoricoxib in patients with cutaneous hypersensitivity reactions to nonsteroidal anti-inflammatory drugs Ann Allergy Asthma Immunol 2005 95 438 442 10.1016/S1081-1206(10)61169-6 16312166 \nQuercia O Emiliani F Foschi FG Stefanini GF Safety of etoricoxib in patients with reactions to NSAIDs J Investig Allergol Clin Immunol 2008 18 163 167 18564626 \nRoll A Wuthrich B Schmid-Grendelmeier P Hofbauer G Ballmer-Weber BK Tolerance to celecoxib in patients with a history of adverse reactions to nonsteroidal anti-inflammatory drugs Swiss Med Wkly 2006 136 684 690 17183430 \nSanchez-Borges M Caballero-Fonseca F Capriles-Hulett A Safety of etoricoxib, a new cyclooxygenase 2 inhibitor, in patients with nonsteroidal anti-inflammatory drug-induced urticaria and angioedema Ann Allergy Asthma Immunol 2005 95 154 158 10.1016/S1081-1206(10)61205-7 16136765 \nViola M Quaratino D Gaeta F Caringi M Valluzzi R Caruso C Volpetti S Romano A Celecoxib tolerability in patients with hypersensitivity (mainly cutaneous reactions) to nonsteroidal anti-inflammatory drugs Int Arch Allergy Immunol 2005 137 145 150 10.1159/000085794 15897671 \nViola M Quaratino D Gaeta F Caruso C Valluzzi R Romano A Etoricoxib tolerability in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs Int Arch Allergy Immunol 2007 143 103 108 10.1159/000098658 17228166 \nTrombetta D Imbesi S Vita G Isola S Minciullo PL Saija A Gangemi S Possible link between history of hypersensitivity to a specific non-steroidal anti-inflammatory drug (NSAID) and positive results following challenge test to alternative NSAIDS Arzneimittelforschung 2009 59 410 414 19813464 \nSanchez-Borges M Caballero-Fonseca F Capriles-Hulett A Tolerance of nonsteroidal anti-inflammatory drug-sensitive patients to the highly specific cyclooxygenase 2 inhibitors rofecoxib and valdecoxib Ann Allergy Asthma Immunol 2005 94 34 38 10.1016/S1081-1206(10)61282-3 15702813 \nWoessner KM Simon RA Stevenson DD Safety of high-dose rofecoxib in patients with aspirin-exacerbated respiratory disease Ann Allergy Asthma Immunol 2004 93 339 344 10.1016/S1081-1206(10)61392-0 15521369 \nSanchez-Borges M Capriles-Hulett A Caballero-Fonseca F Adverse reactions to selective cyclooxygenase-2 inhibitors (coxibs) Am J Ther 2004 11 494 500 10.1097/01.mjt.0000125121.35422.b4 15543091 \nIsik SR Karakaya G Celikel S Demir AU Kalyoncu AF Association between asthma, rhinitis and NSAID hypersensitivity in chronic urticaria patients and prevalence rates Int Arch Allergy Immunol 2009 150 299 306 10.1159/000222683 19494528 \nEstevez MDQ Are selective Cox-2 inhibitors a safe option in patients with intolerance to nonsteroidal antiinflammatory drugs? J Investig Allergol Clin Immunol 2009 19 328 330 19639736 \nWarner TD Mitchell JA Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic FASEB J 2004 18 790 804 10.1096/fj.03-0645rev 15117884\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7022",
"issue": "3(1)",
"journal": "Clinical and translational allergy",
"keywords": null,
"medline_ta": "Clin Transl Allergy",
"mesh_terms": null,
"nlm_unique_id": "101576043",
"other_id": null,
"pages": "20",
"pmc": null,
"pmid": "23799898",
"pubdate": "2013-06-24",
"publication_types": "D016428:Journal Article",
"references": "11926629;17304886;17183430;23018315;16312166;14555862;23101312;16599250;15117884;15479276;21834936;17492455;15702813;3713757;15046380;18564626;19494528;15897671;12721666;12065343;12359017;19813464;17228166;16136765;12487218;19940308;17521312;15871445;11940070;21631520;15543091;15521369;21155908;15100686;17953635;12209526;6436354;3318575;410857;23678553;19639736;10400832",
"title": "Tolerance to alternative cyclooxygenase-2 inhibitors in nonsteroidal anti-inflammatory drug hypersensitive patients.",
"title_normalized": "tolerance to alternative cyclooxygenase 2 inhibitors in nonsteroidal anti inflammatory drug hypersensitive patients"
} | [
{
"companynumb": "NL-DEPOMED, INC.-NL-2017DEP000453",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3",... |
{
"abstract": "Denosumab is often used in men with advanced prostate cancer to prevent skeletal-related events, but can be associated with severe hypocalcaemia. Our objective was to review the pathophysiology, identify risk factors and provide recommendations for prevention and management of denosumab-associated hypocalcaemia.\n\n\n\nWe reviewed the literature regarding denosumab-associated severe hypocalcaemia, defined as necessitating hospitalization for intravenous calcium treatment, in the context of prostate cancer.\n\n\n\nMen with prostate cancer with severe denosumab-associated hypocalcemia.\n\n\n\nWe identified 20 men with prostate cancer with severe denosumab-associated hypocalcemia, including the present case. Median age (range) was 70 years (45-86). All had skeletal metastases and presented with symptomatic hypocalcemia 16 days (4-35) after the initial (n = 18) or second (n = 2) denosumab treatment, with a serum total calcium of 1.36 mmol/L (1.13-1.91). The key risk factor was presence of active osteoblastic metastases, evidenced by elevated serum alkaline phosphatase, 838 U/L (58-2620) and supportive imaging. Other risk factors reported in some men included vitamin D deficiency (<50 nmol/L), 25-OH vitamin D 44 nmol/L (22-81), renal impairment, serum creatinine 103 μmol/L (62-1131) and hypomagnesaemia, 0.82 mmol/L (0.29-1.20). Men received intravenous calcium infusions for 16 days (1-90), and median total intravenous elemental calcium requirements were 3.17 g (0.47-26.65).\n\n\n\nDenosumab treatment in men with metastatic prostate cancer can be associated with life-threatening hypocalcaemia requiring prolonged hospitalization for intravenous calcium treatment. Modifiable risk factors should be corrected before denosumab administration. In men with active osteoblastic metastases, consideration should be given to delay denosumab treatment until underlying disease activity is controlled, and/or be administered with close monitoring and proactive treatment with calcium and calcitriol.",
"affiliations": "Department of Endocrinology, Austin Health, Melbourne, Vic., Australia.;Department of General Medicine, Royal Melbourne Hospital, Melbourne, Vic., Australia.;Department of Oncology, Austin Health, Melbourne, Vic., Australia.;Department of Endocrinology, Austin Health, Melbourne, Vic., Australia.;Department of Endocrinology, Austin Health, Melbourne, Vic., Australia.;Department of Endocrinology, Austin Health, Melbourne, Vic., Australia.;Department of Oncology, Austin Health, Melbourne, Vic., Australia.;Department of Endocrinology, Austin Health, Melbourne, Vic., Australia.",
"authors": "Lau|Lik-Hui|LH|0000-0002-9323-5655;Cliff|Edward R S|ERS|;Wong|Vanessa|V|;Wong|Henry|H|;Torkamani|Niloufar|N|;Eer|Audrey|A|;Weickhardt|Andrew|A|;Grossmann|Mathis|M|0000-0001-8261-3457",
"chemical_list": "D050071:Bone Density Conservation Agents; D014807:Vitamin D; D000069448:Denosumab; D002118:Calcium",
"country": "England",
"delete": false,
"doi": "10.1111/cen.14169",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-0664",
"issue": "92(6)",
"journal": "Clinical endocrinology",
"keywords": "consumption hypocalcaemia; denosumab; hypocalcaemia; pathophysiology; prostate cancer; risk factors; treatment",
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D002118:Calcium; D000069448:Denosumab; D006801:Humans; D006996:Hypocalcemia; D008297:Male; D011471:Prostatic Neoplasms; D014807:Vitamin D",
"nlm_unique_id": "0346653",
"other_id": null,
"pages": "495-502",
"pmc": null,
"pmid": "32017154",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypocalcaemia following denosumab in prostate cancer: A clinical review.",
"title_normalized": "hypocalcaemia following denosumab in prostate cancer a clinical review"
} | [
{
"companynumb": "AU-AMGEN-AUSSP2019213878",
"fulfillexpeditecriteria": "2",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nParadoxical reaction in tuberculosis (TB) is defined as the reappearance of general symptoms, aggravation of pre-existing diseases, or appearance of new lesions despite adequate anti-TB therapy. It may result from the hyperactivity of the immune response, resulting in an intense inflammation. There are few cases of vertebral TB reported as paradoxical reaction, mainly among immunocompetents patients.\nWe describe a male immunocompetent patient with confirmed pulmonary and meningeal TB. He was readmitted after 60 days of adequate treatment, with vertebral TB and paravertebral abscess, despite clinical improvement of the other locations. We defined as an uncommon case of a paradoxical reaction, confirmed by nuclear magnetic resonance and molecular rapid test for TB.\n\n\nMETHODS\nMycobacterium tuberculosis (MTB) was detected in cerebrospinal fluid by molecular rapid test (Gene Xpert MTB/ rifampicina method). Sputum research and culture were positive for the same agent. Lumbosacral spine nuclear magnetic resonance revealed bone destruction from T8 to T11, and a paravertebral collection was found. Gene Xpert MTB/rifampicina and culture were positive for M tuberculosis in the drained material of the paravertebral abscess.\n\n\nMETHODS\nThe paravertebral abscess was drainage by tomography-guided. Treatment with 4 anti-TB drugs was extended for 60 days and 2 anti-TB drugs was maintained for 10 months. There was a complete clinical improvement.\n\n\nRESULTS\nAfter draining the paravertebral abscess, the patient progressively improved and was discharged for outpatient follow-up. He was on antituberculous drugs for 1 year; subsequently, complete resolution of the infection was reported.\n\n\nCONCLUSIONS\nParadoxical reaction may be a difficult diagnosis in immunocompetent patient. Vertebral TB as a paradoxical reaction is an uncommon presentation. Therapeutic failure or resistance to treatment should be ruled out to confirm the diagnosis of paradoxical reaction.",
"affiliations": "Graduate Program in Infectious and Parasitic Diseases of Federal University of Mato Grosso do Sul.;Regional Hospital of Mato Grosso do Sul.;Regional Hospital of Mato Grosso do Sul.;Regional Hospital of Mato Grosso do Sul.;Graduate Program in Infectious and Parasitic Diseases of Federal University of Mato Grosso do Sul.;Graduate Program in Infectious and Parasitic Diseases of Federal University of Mato Grosso do Sul.;Maria Aparecida Pedrossian University Hospital.;Maria Aparecida Pedrossian University Hospital.;School of Medicine at Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.;School of Medicine at Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.;School of Medicine at Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.",
"authors": "Volpe-Chaves|Cláudia Elizabeth|CE|0000-0002-3004-2039;Lacerda|Mara Luci Gonçalves Galiz|MLGG|;Castilho|Suse Barbosa|SB|;Fonseca|Simone Sousa Oliveira|SSO|;Saad|Bruna Abdul Ahad|BAA|;Franciscato|Caroline|C|;Tibana|Tiago Kojun|TK|;Nunes|Thiago Franchi|TF|;Venturini|James|J|;Oliveira|Sandra Maria do Valle Leone de|SMDVL|;Paniago|Anamaria Mello Miranda|AMM|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000020012",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32481268\nMD-D-19-08445\n10.1097/MD.0000000000020012\n20012\n4900\nResearch Article\nClinical Case Report\nVertebral tuberculosis as a paradoxical reaction to the treatment of pulmonary and meningeal tuberculosis in an immunocompetent patient\nA case reportVolpe-Chaves Cláudia Elizabeth Mscabc∗ Lacerda Mara Luci Gonçalves Galiz Espb Castilho Suse Barbosa Espb Fonseca Simone Sousa Oliveira Mscb Saad Bruna Abdul Ahad Espab Franciscato Caroline Mscac Tibana Tiago Kojun Espc Nunes Thiago Franchi PhDc Venturini James PhDd de Oliveira Sandra Maria do Valle Leone PhDd Paniago Anamaria Mello Miranda PhDd Saranathan. Maya a Graduate Program in Infectious and Parasitic Diseases of Federal University of Mato Grosso do Sul\nb Regional Hospital of Mato Grosso do Sul\nc Maria Aparecida Pedrossian University Hospital\nd School of Medicine at Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.\n∗ Correspondence: Cláudia Elizabeth Volpe-Chaves, Av. Engenheiro Luthero Lopes, n.36 – Bairro Aero Rancho V, Campo Grande, MS, Brazil, CEP 79.084-180 (e-mail: claudiavolpe70@hotmail.com).\n22 5 2020 \n22 5 2020 \n99 21 e2001229 10 2019 05 2 2020 26 3 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nParadoxical reaction in tuberculosis (TB) is defined as the reappearance of general symptoms, aggravation of pre-existing diseases, or appearance of new lesions despite adequate anti-TB therapy. It may result from the hyperactivity of the immune response, resulting in an intense inflammation. There are few cases of vertebral TB reported as paradoxical reaction, mainly among immunocompetents patients.\n\nPatient concerns:\nWe describe a male immunocompetent patient with confirmed pulmonary and meningeal TB. He was readmitted after 60 days of adequate treatment, with vertebral TB and paravertebral abscess, despite clinical improvement of the other locations. We defined as an uncommon case of a paradoxical reaction, confirmed by nuclear magnetic resonance and molecular rapid test for TB.\n\nDiagnosis:\nMycobacterium tuberculosis (MTB) was detected in cerebrospinal fluid by molecular rapid test (Gene Xpert MTB/ rifampicina method). Sputum research and culture were positive for the same agent. Lumbosacral spine nuclear magnetic resonance revealed bone destruction from T8 to T11, and a paravertebral collection was found. Gene Xpert MTB/rifampicina and culture were positive for M tuberculosis in the drained material of the paravertebral abscess.\n\nInterventions:\nThe paravertebral abscess was drainage by tomography-guided. Treatment with 4 anti-TB drugs was extended for 60 days and 2 anti-TB drugs was maintained for 10 months. There was a complete clinical improvement.\n\nOutcome:\nAfter draining the paravertebral abscess, the patient progressively improved and was discharged for outpatient follow-up. He was on antituberculous drugs for 1 year; subsequently, complete resolution of the infection was reported.\n\nConclusion:\nParadoxical reaction may be a difficult diagnosis in immunocompetent patient. Vertebral TB as a paradoxical reaction is an uncommon presentation. Therapeutic failure or resistance to treatment should be ruled out to confirm the diagnosis of paradoxical reaction.\n\nKeywords\nextrapulmonary tuberculosismeningeal tuberculosisparadoxical reactionPott's diseaseTuberculosisvertebral tuberculosisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nParadoxical reaction in patients with tuberculosis (TB) is defined as the reappearance of general symptoms, aggravation of pre-existing diseases, or appearance of new lesions after an initial improvement, without a visible cause, at least 2 weeks from the start of treatment. It may result from the disinhibition of anti-TB cell-mediated immunity, resulting in an increased intensity of inflammation.[1] High antigenic load and inflammation may act in association with pathogenesis and involve T-helper-1-induced immune response in the presence of multibacillary disease and immunodeficiency.[2] With the control of TB, improved cellular immunity would be accompanied by an uncontrolled inflammatory reaction that exceeds the target involving specific adaptive immunity and innate immunity. Anemia, lymphopenia, hypoalbuminemia, and extrapulmonary localization can be risk factors in these patients.[3]\n\nPott's disease as a paradoxical reaction has been rarely reported, and the thoracic and lumbar spine are the most frequently described sites.[3,4]\n\nIn this study we describe a male immunocompetent patient with an uncommon case of vertebral TB as paradoxical reaction in confirmed pulmonary and meningeal TB despite adequate anti-TB therapy.\n\n2 Case report\nA 39-year-old male patient was admitted to the emergency room with anorexia, weakness, dry cough, weight loss and daily fever. He had a history of alcoholism. He presented normal laboratory tests, and his serologic test results were negative for HIV. Chest X-ray showed alveolar-interstitial consolidations in the upper lobes, with a suspected pulmonary TB (PTB).\n\nDuring hospitalization, the patient had headache, mental confusion, stiff neck, and a positive Brudzinski sign. Skull computed tomography (CT) was normal, and the cerebrospinal fluid puncture presented 343 leukocytes/mm3; 95% lymphomononuclear cells; 5% polymorphonuclear cells; glucose, 25 mg/dL; protein, 435.6 mg/dL. Mycobacterium tuberculosis (MTB) without rifampicin (RIF) resistance was detected in cerebrospinal fluid by molecular rapid test (Gene Xpert MTB/RIF method). Sputum research and culture were positive for the same agent with sensitivity to the anti TB agents used, confirming the diagnosis of PTB and meningeal TB.\n\nFour oral tablets (once daily) of 150-mg RIF, 75-mg isoniazid, 400-mg pyrazinamide, and 275-mg ethambutol, and 4-mg dexamethasone IV 6 /6 h (0.3 mg/kg/d) were administered and maintained until hospital discharge. The patient showed clinical improvement and was discharged on the 16th day of hospitalization. Prednisone was prescribed with doses reduction to suspension, with a total treatment time of <8 weeks, as observed in medical records.\n\nOn the 60th day of regular treatment with anti-TB drugs, although the patient reported improvements in pulmonary and meningeal manifestations, he returned to the hospital with fever and abdominal and lumbar pain. However, skull and chest CT and lumbar puncture evidenced no signs of disease activity.\n\nLumbosacral spine nuclear magnetic resonance revealed a signal alteration and a heterogeneous enhancement by contrast medium from T8 to T11, with reduction of the vertebral bodies’ height of T10 and T11 and collapse of the respective intervertebral space. A paravertebral collection was found, located adjacent to the vertebral bodies from T8 to T11, mainly on the right, measuring 7.0 × 4.8 × 3.0 cm, with an estimated volume of approximately 50 mL (Fig. 1).\n\nFigure 1 Lumbosacral spine nuclear magnetic resonance (NMR) of (A) the sagittal section and (B) the axial section. The NMR shows the extensive vertebral involvement of T8 to T11 (red arrow) and paravertebral abscess (yellow arrow). NMR = nuclear magnetic resonance.\n\nTreatment with 4 anti-TB drugs was maintained, and morphine was prescribed due to severe pain. Tomography-guided abscess drainage was performed. Direct BAAR screening in the drained material was negative, but the Gene Xpert MTB/RIF and culture were positive for M tuberculosis with RIF sensitivity.\n\nAfter this procedure, the patient showed clinical improvement and reduction of fever. The drain was removed after 10 days and a new control image revealed abscess reduction. The patient was discharged, and he received anti-TB drugs for 12 months from the date of abscess drainage. There was a complete clinical improvement, and the patient is under follow-up with a programmed neurosurgery for repairing a fracture by bone TB sequelae.\n\n3 Discussion\nHerein, we described an uncommon presentation of PTB and meningeal TB in an apparently immunocompetent patient. Upon completion of 60 days of effective anti-TB drug treatment with a marked improvement in pulmonary and meningeal focus, he developed vertebral TB and paravertebral abscess, both characteristics of a paradoxical reaction (PR).[5]\n\nTB is classified into PTB, which includes cases of pulmonary impairment, pulmonary with extrapulmonary, laryngeal and concomitant miliary disease, as observed in our case, and extrapulmonary TB (EPTB), which involves any organs other than the lungs.[6]\n\nRisk factors for PTB and EPTB are common, especially in patients with acquired immunodeficiency virus (HIV), diabetes, and malnutrition. Alcoholism seems to increase the risk for extrapulmonary locations, as observed in our report. Long-term corticosteroid and/or other immunosuppressive drugs were ruled out in our case. However, other causes, such as hereditary defects in cell-mediated immunity, were not investigated.[7]\n\nCentral nervous system involvement by M tuberculosis affects 0.5% to 2% of TB patients,[8] with meningitis being the most severe form. In immunocompetent patients, TB meningitis constitutes 5% to 6% of EPTB cases and has a high morbidity and mortality rate,[9] differing from the clinical improvement of our patient. Due to this severe form and in addition to the anti-TB therapy, corticotherapy was introduced, which is widely recommended in the literature.[10]\n\nOsteoarticular TB accounts for 10% to 35% of extrapulmonary locations, and extension to adjacent soft tissues with cold abscess formation is commonly observed.[7,11] The abscess formation is a strong indication for a potential diagnosis of TB,[12] as it happened in our report.\n\nThe development of Pott's disease accounts for 40% to 50% of cases and it occurs due to hematogenous dissemination of the Batson venous plexus TB bacillus, secondary to an extravertebral source.[12,13]\n\nPR was first described in non-HIV patients in 1954, after anti-TB drugs were introduced. [2] It is estimated to be present in 2% to 30% of immunocompetents patients,[2,3] being more frequent in patients with extrapulmonary locations.[2] PR is usually seen in patients with HIV, also called immune reconstitution syndrome, and it is poorly studied in immunocompetent patients.[3,8,14]\n\nThe PR usually observed in HIV-positive patients appears after starting HAART and is triggered by an excessive inflammatory response in the context of immune reconstitution.[15] This immunity is not protective and, as a consequence, the existing disease may worsen or new lesions may appear.[16] In HIV-negative patients showing PR to anti TB treatment (ATT), occurs as a result of ATT-induced disinhibition of cell-mediated immunity combined with the release of mycobacterial cell wall antigens during lysis of the microorganism.[17]\n\nOur patient had no signs or symptoms of vertebral disease at admission that indicated MRI or thoracolumbar spine computed tomography. The emergence of new symptoms and new lesions despite adequate therapy after an initial clinical improvement, defined a PR in this case.\n\nFor the confirmed diagnosis of PR, we need to rule out differential diagnoses, such as inadequate anti TB therapy, and this item were ruled out in our report.[14]\n\nThe median time to onset of PR is 3 months after initiation of the anti-TB treatment in non-HIV-infected patients. In our report, this period was 2 months. Overall mortality in patients with PR has been estimated at 3%.[2]\n\nIn CNS infections, PR can occur in up to 52% of patients and has been reported as an important prognostic factor in young patients.[5] Pott's disease as a paradoxical reaction has been rarely reported, and the thoracic and lumbar spine are the most frequently described sites,[3,4] as noted in our report.\n\nPR must be differentiated from therapeutic failure, and the anti-TB replacement is not indicated.[3] In our report, we ruled out therapeutic failure based on the patient's report of regular use of therapy as well as on improvement in the signs and symptoms of pulmonary and meningeal TB diagnosed initially. In addition, the sputum culture described was sensitive to all anti TB agents. The patient responded satisfactorily with the same drugs for the treatment of spinal TB as for the PR.\n\nIn PR, the main interventions are related to complications, such as the need for surgical intervention and residual functional deficit.[4,14] In our report, the first phase of TB treatment was extended for 60 days, and the use of corticosteroids—despite being considered[4] —was not necessary.\n\nThe treatment of PR can be based on clinical and surgical interventions, and the use of steroids can be considered.[18]\n\nCorticosteroids have been recommended in patients with tuberculous meningitis, especially for non-HIV patients,[10,19] as used in our report, but there was a description of early reduction and suspension after hospital discharge. As PR is related to an intensification of the inflammatory response, we believe that this factor may have contributed to its manifestation soon after its suspension.\n\nWe report a rare case of vertebral TB as a PR in an immunocompetent patient. This diagnosis should be part of the clinical follow-up, especially in patients with extrapulmonary locations for TB, which may have a major impact on the patient's prognosis.\n\nAcknowledgments\nThe authors are grateful for the support of the Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES).\n\nAuthor contributions\nData curation: Cláudia Elizabeth Volpe-Chaves, Mara Luci Gonçalves Galiz Lacerda, Suse Barbosa Castilho, Simone Sousa Oliveira Fonseca.\n\nMethodology: Cláudia Elizabeth Volpe-Chaves, Mara Luci Gonçalves Galiz, Suse Barbosa Castilho, Simone Sousa Oliveira Fonseca, Bruna Abdul Ahad Saad, Caroline Franciscato, Tiago Kojun Tibana.\n\nSupervision: Thiago Franchi Nunes, James Venturini, Sandra Maria do Valle Leone de Oliveira, Anamaria Mello Miranda Paniago.\n\nWriting – original draft: Cláudia Elizabeth Volpe-Chaves, Mara Luci Gonçalves Galiz, Suse Barbosa Castilho, Caroline Franciscato, Simone Sousa Oliveira Fonseca, Bruna Abdul Ahad Saad, Tiago Kojun Tibana.\n\nWriting – review and editing: Cláudia Elizabeth Volpe-Chaves, Thiago Franchi Nunes, James Venturini, Sandra Maria do Valle Leone de Oliveira, Anamaria Mello Miranda Paniago.\n\nAbbreviations: MTB = Mycobacterium tuberculosis, PTB = pulmonary tuberculosis, RIF = rifampicina, TB = tuberculosis.\n\nHow to cite this article: Volpe-Chaves CE, Lacerda ML, Castilho SB, Fonseca SS, Saad BA, Franciscato C, Tibana TK, Nunes TF, Venturini J, Oliveira SM, Paniago AM. Vertebral tuberculosis as a paradoxical reaction to the treatment of pulmonary and meningeal tuberculosis in an immunocompetent patient – a case report. Medicine. 2020;99:21(e20012).\n\nThis study was financed in part by the Fundação Universidade Federal de Mato Grosso do Sul – UFMS/MEC – Brazil.\n\nPatient has provided informed consent for publication of the case.\n\nThe authors have no conflicts of interest to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n[1] Ghali MGZ Srinivasan VM Kim J \nSpinal intramedullary tuberculosis with concurrent supra and infratentorial intracranial disease in a 9 month old boy: case report and review of the literature\n. World Neurosurg \n2017 ;106 :37 –45\n.28532916 \n[2] Lanzafame M Vento S \nTuberculosis-immune reconstitution inflammatory syndrome\n. J Clin Tuberc Other Mycobact Dis \n2016 ;3 :6 –9\n.31723680 \n[3] Bacha S Khemiri M Racil H \nParadoxical reaction following antituberculosis therapy in immunocompetent patient\n. Revue de Pneumologie Clinique \n2016 ;72 :367 –72\n.27776947 \n[4] Im JH Baek JH Kwon HY \nParadoxical reaction of tuberculous vertebral osteomyelitis: a case series\n. Infect Dis \n2015 ;47 :271 –4\n.\n[5] Liu Y Wang Z Yao G \nParadoxical reaction in HIV-negative TBM patients with spinal involvement\n. Int J Infect Dis \n2019 ;79 :104 –8\n.30529369 \n[6] World Health Organization-WHO . Definitions and reporting framework for tuberculosis-2013 revision (updated December 2014)\n. WHO Publications \n2013 ;1 –47\n.\n[7] Verma R Patil TB Lalla R \nDisseminated tuberculosis manifesting as pulmonary, meningeal and spinal tuberculosis in an immunocompetent patient\n. BMJ Case Rep \n2012 ;1 –3\n.\n[8] Tekin R Kacar E Çevic FC \nIntracranial and intramedullary tuberculoma with intravertebral abscess manifestation under anti-tuberculous treatment: a case report\n. Clin Neurol Neurosurg \n2013 ;115 :1858 –60\n.23481899 \n[9] Ranganath S Wilson B Narasimhan A \nDisseminated tuberculosis in an immunocompetent patient\n. Cent Eur J Med \n2014 ;9 :144 –7\n.\n[10] World Health Organization . (2017). Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update. World Health Organization. https://apps.who.int/iris/handle/10665/255052 .\n[11] Ketata W Rekik WK Ayadi H \nLes tuberculosis extrapulmonaires\n. Rev Pneumol Clin \n2014 ;449 :1 –0\n.\n[12] Maurya VK Sharma P Ravikumar R \nTubercular spondylitis: a review of MRI findings in 80 cases\n. Med J Armed Forces \n2016 ;74 :11 –7\n.\n[13] Gehlot PS Chaturvedi S Kashyap R \nPott's Spine: retrospective analysis of MRI scans of 70 cases\n. J Clin Diagn Res \n2012 ;6 :1534 –8\n.23285449 \n[14] Cheng VCC Ho PL Lee RA \nClinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients\n. Eur J Clin Microbiol Infect Dis \n2002 ;21 :803 –9\n.12461590 \n[15] Lipman M Breen R \nImmune reconstitution inflammatory syndrome in HIV\n. Curr Opin Infect Dis \n2006 ;19 :20 –5\n.16374213 \n[16] Breen RAM Smith CJ Bettinson H \nParadoxical reactions during tuberculosis treatment in patients with and without HIV co-infection\n. Thorax \n2004 ;59 :704 –7\n.15282393 \n[17] Velivela K Rajesh A \nParadoxical response in spinal tuberculosis: lessons learnt\n. J Neurosci Rural Pract \n2016 ;7 :206 –9\n.27114649 \n[18] Cheng VCC Yam WC Woo PCY \nRisk factors for development of paradoxical response during antituberculosis therapy in HIV-Negative Patients\n. Eur J Clin Microbiol Infect Dis \n2003 ;22 :597 –602\n.14508660 \n[19] Prasad K Singh MB Ryan H \nCorticosteroids for managing tuberculous meningitis\n. Cochrane Database Syst Rev \n2016 ;4 :1 –64\n.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(21)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D006801:Humans; D007121:Immunocompetence; D008279:Magnetic Resonance Imaging; D008297:Male; D009169:Mycobacterium tuberculosis; D012447:Sacrum; D014390:Tuberculosis, Meningeal; D014397:Tuberculosis, Pulmonary; D014399:Tuberculosis, Spinal",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e20012",
"pmc": null,
"pmid": "32481268",
"pubdate": "2020-05-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vertebral tuberculosis as a paradoxical reaction to the treatment of pulmonary and meningeal tuberculosis in an immunocompetent patient: A case report.",
"title_normalized": "vertebral tuberculosis as a paradoxical reaction to the treatment of pulmonary and meningeal tuberculosis in an immunocompetent patient a case report"
} | [
{
"companynumb": "BR-FRESENIUS KABI-FK202007240",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Dystonic storm or status dystonicus is a life-threatening hyperkinetic movement disorder with biochemical alterations due to the excessive muscle contractions. The medical management can require pediatric intensive care unit admission and a combination of medications while the underlying trigger is managed. Severe cases may require general anesthesia and paralytic agents with intubation and may relapse when these drugs are weaned. Deep brain stimulation of the globus pallidum has been reported to terminate dystonic storm in several pediatric cases. We present a 10-year-old boy with a de novo GNAO1 mutation-induced dystonic storm who required a 2-month pediatric intensive care unit admission and remained refractory to all medical treatments. Deep brain stimulation was performed under general anesthetic without complication. His dyskinetic movements stopped with initiation of stimulation. He was discharged from the pediatric intensive care unit after 4 days. We present prospectively evaluated changes in dystonia symptoms and quality of life for a patient with GNAO1 mutation treated with deep brain stimulation.",
"affiliations": "1 Department of Surgery, Section of Neurosurgery, University of Manitoba, Winnipeg, Canada.;2 Faculty of Medicine, University of British Columbia, Vancouver, Canada.;3 Centre for Molecular Medicine and Therapeutics, Vancouver, Canada.;7 Department of Pediatrics, BC Children's Hospital Research Institute, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.;4 BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.;10 Division of Neurosurgery, Department of Surgery, University of British Columbia, Vancouver, Canada.",
"authors": "Honey|C Michael|CM|;Malhotra|Armaan K|AK|;Tarailo-Graovac|Maja|M|;van Karnebeek|Clara D M|CDM|;Horvath|Gabriella|G|;Sulistyanto|Adi|A|",
"chemical_list": "C584143:GNAO1 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go",
"country": "United States",
"delete": false,
"doi": "10.1177/0883073818756134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "33(6)",
"journal": "Journal of child neurology",
"keywords": "GNAO1 mutation; deep brain stimulation; status dystonicus",
"medline_ta": "J Child Neurol",
"mesh_terms": "D002648:Child; D003422:Critical Care; D046690:Deep Brain Stimulation; D020821:Dystonic Disorders; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D005917:Globus Pallidus; D006801:Humans; D008297:Male; D009154:Mutation",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "413-416",
"pmc": null,
"pmid": "29661126",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "GNAO1 Mutation-Induced Pediatric Dystonic Storm Rescue With Pallidal Deep Brain Stimulation.",
"title_normalized": "gnao1 mutation induced pediatric dystonic storm rescue with pallidal deep brain stimulation"
} | [
{
"companynumb": "CA-BAUSCH-BL-2018-014634",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "To describe a case of peripheral ulcerative keratitis in the setting of autoimmune hepatitis and possible overlap syndrome with primary sclerosing cholangitis.\nA 48-year-old African American female with autoimmune hepatitis with possible overlap syndrome with primary sclerosing cholangitis presented with tearing, irritation, and injection of the left eye that was determined to be peripheral ulcerative keratitis. The patient was treated with topical and systemic steroids, immunosuppressant drugs (azathioprine and mycophenolate mofetil), a biologic (rituximab), and surgery (conjunctival resection), and the peripheral ulcerative keratitis epithelialized but ultimately led to corneal perforation.\nIn this unique case, a patient with peripheral ulcerative keratitis who underwent treatment ultimately had a corneal perforation. This case may suggest a possible relationship between autoimmune hepatitis and peripheral ulcerative keratitis.",
"affiliations": "Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.;Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.;Department of Ophthalmology, Rutgers New Jersey Medical School, Newark, NJ, USA.",
"authors": "Eshraghi|Hamoon|H|0000-0002-5103-1435;Mahtabfar|Aria|A|0000-0002-4026-7821;Dastjerdi|Mohammad H|MH|0000-0002-4768-883X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/3939413",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2017/3939413Case ReportA Case of Peripheral Ulcerative Keratitis Associated with Autoimmune Hepatitis http://orcid.org/0000-0002-5103-1435Eshraghi Hamoon \n1\nhttp://orcid.org/0000-0002-4026-7821Mahtabfar Aria \n1\nhttp://orcid.org/0000-0002-4768-883XDastjerdi Mohammad H. mhd45@njms.rutgers.edu\n2\n\n1Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA\n2Department of Ophthalmology, Rutgers New Jersey Medical School, Newark, NJ, USAAcademic Editor: Guillaume Geri\n\n2017 9 10 2017 2017 393941320 7 2017 7 9 2017 24 9 2017 Copyright © 2017 Hamoon Eshraghi et al.2017This 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.Purpose\n To describe a case of peripheral ulcerative keratitis in the setting of autoimmune hepatitis and possible overlap syndrome with primary sclerosing cholangitis. \n\nCase Report\n A 48-year-old African American female with autoimmune hepatitis with possible overlap syndrome with primary sclerosing cholangitis presented with tearing, irritation, and injection of the left eye that was determined to be peripheral ulcerative keratitis. The patient was treated with topical and systemic steroids, immunosuppressant drugs (azathioprine and mycophenolate mofetil), a biologic (rituximab), and surgery (conjunctival resection), and the peripheral ulcerative keratitis epithelialized but ultimately led to corneal perforation. \n\nConclusion\n In this unique case, a patient with peripheral ulcerative keratitis who underwent treatment ultimately had a corneal perforation. This case may suggest a possible relationship between autoimmune hepatitis and peripheral ulcerative keratitis.\n==== Body\n1. Background\nPeripheral ulcerative keratitis (PUK) is an autoimmune condition believed to involve complement system activation via immune complexes in the peripheral cornea. The end result is a localized inflammatory response, leading to the enzymatic destruction of local cellular architecture; in particular, neutrophils and macrophages release collagenase and other proteases that destroy the corneal stroma [1]. The characteristic lesion is a crescent-shaped stromal inflammation of the juxtalimbal cornea. The etiology of PUK has not been completely ascertained, but consensus has centered on an autoimmune response to a localized antigen. Given the inflammatory nature of the disease, PUK is often associated with other autoimmune conditions including rheumatoid arthritis and lupus. There have been cases of association between peripheral corneal ulcers and Mooren's ulcer and viral hepatitis [2, 3]. However, there have been no cases in the literature of a presentation of PUK in the setting of autoimmune hepatitis or primary sclerosing cholangitis (PSC).\n\nAutoimmune hepatitis is an autoimmune disorder characterized by inflammation of the liver that is often asymptomatic or can present with nonspecific symptoms such as fatigue, jaundice, abdominal pain, and even acute liver failure. The condition is more common among females and is often associated with serological markers such as anti-nuclear antibody and anti-smooth muscle antibody. The condition often has clinical characteristics that overlap with either PSC or primary biliary cholangitis (PBC), often known as overlap syndrome. We report a case of PUK in the setting of autoimmune hepatitis with possible overlap syndrome with PSC.\n\n2. Case Report\nA 48-year-old African American woman with a past medical history of autoimmune hepatitis and possible overlap syndrome with primary sclerosing cholangitis status post multiple stent placements and endoscopic retrograde cholangiopancreatography (ERCP) presented with tearing, redness, and irritation of the left eye. She was diagnosed with autoimmune hepatitis for over ten years before the visual symptoms began and was on a low-dose steroid maintenance treatment for the condition. She had strictures that extended to her intrahepatics with accompanying cholangitis. Histological examination confirmed hepatitis, and laboratory values confirmed a cholestatic liver enzyme profile. She also was positive for anti-nuclear and anti-smooth muscle antibodies and negative for hepatitis B and C. Visual acuity was 20/20 in the right eye and 20/40 in the left eye, and the intraocular pressures (IOPs) were 21 and 19 mmHg, respectively. Slit lamp exam showed a crescent-shaped left peripheral corneal ulcer measuring 4.5 × 0.5 mm extended from 5 to 6:30 o'clock with about 50% thinning and no anterior chamber reaction. The adjacent sclera was also inflamed with injected and edematous conjunctiva. The remainder of the eye exam was unremarkable. The patient had previously been on 10 mg of oral prednisone for prior medical history but was started on topical prednisolone acetate 1% eye drop four times daily. Prophylactic topical antibiotic eye drops, moxifloxacin, and oral doxycycline 100 mg twice daily along with preservative artificial tears were also started.\n\nOver the next 6 weeks, there was continued worsening of the ulcer. One week after initial presentation, the patient returned with no improvement. Three weeks later, the ulcer base became widened and deepened with significant thinning of about 70%. At this time, the patient was started on azathioprine 150 mg and prednisone 60 mg daily by her rheumatologist. One month later, there was continued worsening of the ulcer extending to the 3 o'clock position with about 70–80% thinning (Figure 1()). Moreover, her right eye also showed a small area of ulceration along the limbus at the 2 o'clock position. Because of lack of progress and concern of poor medication compliance, the patient was admitted to the hospital for intravenous methylprednisolone and rituximab treatment by her rheumatologist.\n\nWhile the right eye ulcer started epithelialization, the left eye showed no improvement. The patient underwent conjunctival resection in the area of ulcer in the left eye with application of fibrin glue and a bandage contact lens. Meanwhile, the patient finished a course of 1000 mg rituximab infusion along with intravenous methylprednisolone sodium succinate, 1 gram daily for 3 days, and discharged on mycophenolate mofetil and a tapering dose of oral prednisone. A month after the procedure, the ulceration in the left eye had epithelialized to about 2 or 3 clock hours, and within a subsequent month, the lesion had healed entirely with residual thinning. Visual acuities were 20/20 OD and 20/30 OS.\n\nThe patient was monitored on a monthly basis afterwards. After five months, the patient presented with 20/100 vision in the left eye. Examination showed a small linear corneal perforation near the limbus with iris prolapse at the site of previous ulcer in the left eye. The perforation was repaired with direct closure. The patient was discharged on mycophenolate mofetil. A month after the surgery, the corneal perforation had healed with superficial neovascularization, and there was a small area of iridocorneal adhesion. In a three-month follow-up visit, uncorrected visual acuity in the left eye was 20/100 that was corrected to 20/40. The intraocular pressure was measured to be 16 mmHg. There were no signs of recurrent inflammation or ulceration.\n\n3. Conclusions\nThe autoimmune nature of PUK has led to a strong association with various autoimmune diseases. In fact, collagen vascular diseases are associated with over half of all PUK cases [4]. The dysregulated T helper cell type 1 and 2 (Th-1 and Th-2) pathways in PUK are parallel to those in other autoimmune diseases. Specifically, the reported upregulation of T-box expressed in T cells (T-bet) and self-antigen recognition in autoimmune hepatitis create a plausible etiology leading to PUK [5]. Immune complex deposition is also considered a mechanism leading to activation of the complement cascade. Antibodies associated with autoimmune hepatitis, including anti-nuclear antibody, anti-smooth muscle antibody, and peripheral anti-neutrophil cytoplasmic antibody, are involved in immune complex deposition, which may lead to activation of the complement cascade and/or promotion of T helper response. In other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, documented associations have been established with PUK, albeit with a poor understanding of the underlying mechanism of the disease [6]. There is a clear crossover between the etiology of autoimmunity involved in autoimmune hepatitis and PUK. Although various case reports associate Mooren's ulcer with hepatitis C viral infection [3], corneal complications have rarely been reported in autoimmune hepatitis. In our search of the literature, there were no prior presentations of PUK in the setting of autoimmune hepatitis, despite having similar pathophysiology.\n\nBecause of the often-asymptomatic presentation of autoimmune hepatitis, and diagnosis necessitating liver biopsy, an underreporting phenomenon may be present [7]. The current case is the first example of peripheral ulcerative keratitis associated with autoimmune hepatitis. If later studies establish a stronger association, future cases may necessitate an examination for autoimmune hepatitis in patients who present with PUK.\n\nAbbreviations\nPUKPeripheral ulcerative keratitis\n\nPSCPrimary sclerosing cholangitis\n\nPBCPrimary biliary cholangitis\n\nERCPEndoscopic retrograde cholangiopancreatography\n\nIOPIntraocular pressure\n\nODRight eye\n\nOSLeft eye\n\nTh-1T helper cell type 1\n\nTh-2T helper cell type 2\n\nT-betT-box expressed in T cells.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nAuthors' Contributions\nHamoon Eshraghi and Aria Mahtabfar were major contributors in writing the case report. Mohammad H. Dastjerdi examined the patient, interpreted the patient data, and provided the image. All authors read, edited, and approved the case report.\n\nFigure 1 Left eye photo 6 weeks after initial presentation which shows peripheral corneal ulcer extended from 3 to 6:30 o'clock position with about 70–80% stromal thinning.\n==== Refs\n1 Yagci A. Update on peripheral ulcerative keratitis Clinical Ophthalmology 2012 6 Auckland, New Zealand 747 754 10.2147/opth.s24947 2-s2.0-84863447937 22654502 \n2 Wei D. W. Pagnoux C. Chan C. C. Peripheral ulcerative keratitis secondary to chronic hepatitis B infection Cornea 2017 36 4 515 517 10.1097/ico.0000000000001087 2-s2.0-84995741137 27861312 \n3 Wilson S. E. Lee W. M. Murakami C. Weng J. Moninger G. A. Mooren-type hepatitis C virus-associated corneal ulceration Ophthalmology 1994 101 4 736 745 10.1016/s0161-6420(94)31291-7 7512254 \n4 Tauber J. Sainz de la Maza M. Hoang-Xuan T. Foster C. S. An analysis of therapeutic decision making regarding immunosuppressive chemotherapy for peripheral ulcerative keratitis Cornea 1990 9 1 66 73 10.1097/00003226-199001000-00013 2297997 \n5 Behfarjam F. Sanati M. H. Nasseri Moghaddam S. Ataei M. Nikfam S. Jadali Z. Role of Th1/Th2 cells and related cytokines in autoimmune hepatitis Turkish Journal of Gastroenterology 2017 28 2 110 114 10.5152/tjg.2017.17501 28119269 \n6 Messmer E. M. Foster C. S. Vasculitic peripheral ulcerative keratitis Survey of Ophthalmology 1999 43 5 379 396 10.1016/s0039-6257(98)00051-4 2-s2.0-0032914322 10340557 \n7 Gatselis N. K. Zachou K. Koukoulis G. K. Dalekos G. N. Autoimmune hepatitis, one disease with many faces: etiopathogenetic, clinico-laboratory and histological characteristics World Journal of Gastroenterology 2015 21 1 60 83 10.3748/wjg.v21.i1.60 2-s2.0-84920897099 25574080\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2017()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "3939413",
"pmc": null,
"pmid": "29129978",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "28119269;25574080;2297997;27861312;7512254;22654502;10340557",
"title": "A Case of Peripheral Ulcerative Keratitis Associated with Autoimmune Hepatitis.",
"title_normalized": "a case of peripheral ulcerative keratitis associated with autoimmune hepatitis"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2018US-191079",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dr... |
{
"abstract": "BACKGROUND\nThe diffuse alveolar hemorrhage (DAH) syndrome is a life-threatening pulmonary complication related to systemic vasculitides, posthematopoietic stem cell transplantation, drugs, or toxins. Once DAH develops, the mortality rate is as high as 50% to 80%. Initial treatment consists of high-dose steroids and supportive measures, including mechanical ventilation. We present a case series of 6 patients treated with intrapulmonary recombinant factor VIIa (rFVIIa) to treat refractory DAH.\n\n\nMETHODS\nSix patients with DAH were treated with intrapulmonary instillation of rFVIIa. Doses were divided equally between the right and the left lungs. Doses were 30, 50, or 60 mcg/kg and frequencies varied from a single administration to repeated doses on subsequent days on the basis of the clinical response. All patients received high-dose steroids, and 4 also received an aminocaproic acid infusion.\n\n\nRESULTS\nIntrapulmonary rVFIIa treated DAH effectively in 5 of 6 patients. Doses used were smaller and less frequent than those described previously.\n\n\nCONCLUSIONS\nIntrapulmonary factor VII is an effective adjunctive treatment for DAH. We achieved treatment success with both smaller and less frequent doses than those described previously. This may be a good therapeutic option for DAH, particularly when standard therapies have failed or bleeding is immediately life threatening. It is possible that intrapulmonary rFVIIa could save costs, while improving the intensive care unit length of stay. Further prospective studies are needed to assess the optimal dose and frequency for adequate therapeutic efficacy.",
"affiliations": "Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Indiana University School of Medicine, Indianapolis, IN.",
"authors": "Baker|Mary S|MS|;Diab|Khalil J|KJ|;Carlos|W Graham|WG|;Mathur|Praveen|P|",
"chemical_list": "D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa; D015119:Aminocaproic Acid",
"country": "United States",
"delete": false,
"doi": "10.1097/LBR.0000000000000286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1948-8270",
"issue": "23(3)",
"journal": "Journal of bronchology & interventional pulmonology",
"keywords": null,
"medline_ta": "J Bronchology Interv Pulmonol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015119:Aminocaproic Acid; D004359:Drug Therapy, Combination; D015942:Factor VIIa; D017809:Fatal Outcome; D005260:Female; D006470:Hemorrhage; D006801:Humans; D007322:Instillation, Drug; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011650:Pulmonary Alveoli; D011994:Recombinant Proteins; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101496866",
"other_id": null,
"pages": "255-8",
"pmc": null,
"pmid": "27261934",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intrapulmonary Recombinant Factor VII as an Effective Treatment for Diffuse Alveolar Hemorrhage: A Case Series.",
"title_normalized": "intrapulmonary recombinant factor vii as an effective treatment for diffuse alveolar hemorrhage a case series"
} | [
{
"companynumb": "US-ACCORD-043804",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe effect of antipyretic therapy on mortality in patients with sepsis remains undetermined. The present study aimed to investigate the role of antipyretic therapy in ICU patients with sepsis by using a large clinical database.\n\n\nMETHODS\nThe multiparameter intelligent monitoring in intensive care II (MIMIC- II) database was employed for the study. Adult patients with sepsis were included for analysis. Antipyretic therapy included antipyretic medication and external cooling. Multivariable model with interaction terms were employed to explore the association of antipyretic therapy and mortality risk.\n\n\nRESULTS\nA total of 15,268 patients fulfilled inclusion criteria and were included in the study. In multivariable model by treating temperature as a continuous variable, there was significant interaction between antipyretic therapy and the maximum temperature (Tmax). While antipyretic therapy had no significant effect on mortality in low temperature quintiles, antipyretic therapy was associated with increased risk of death in the quintile with body temperature >39°C (OR: 1.29, 95% CI: 1.04-1.61).\n\n\nCONCLUSIONS\nOur study shows that there is no beneficial effect on reducing mortality risk with the use of antipyretic therapy in ICU patients with sepsis. External cooling may even be harmful in patients with sepsis.",
"affiliations": "Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, Zhejiang, P. R. China.;Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, Zhejiang, P. R. China.;Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, Zhejiang, P. R. China.",
"authors": "Zhang|Zhongheng|Z|;Chen|Lin|L|;Ni|Hongying|H|",
"chemical_list": "D058633:Antipyretics",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0121919",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2582261410.1371/journal.pone.0121919PONE-D-14-52650Research ArticleAntipyretic Therapy in Critically Ill Patients with Sepsis: An Interaction with Body Temperature Antipyretic Therapy in Critically Ill PatientsZhang Zhongheng *Chen Lin Ni Hongying \nDepartment of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, Zhejiang, P. R. China\nAzevedo Luciano Cesar Pontes Academic Editor\nHospital Sirio-Libanes, BRAZIL\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: ZZ. Performed the experiments: LC. Analyzed the data: ZZ LC. Contributed reagents/materials/analysis tools: ZZ. Wrote the paper: HN ZZ.\n\n* E-mail: zh_zhang1984@hotmail.com30 3 2015 2015 10 3 e012191923 11 2014 6 2 2015 © 2015 Zhang et al2015Zhang et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background and Objective\nThe effect of antipyretic therapy on mortality in patients with sepsis remains undetermined. The present study aimed to investigate the role of antipyretic therapy in ICU patients with sepsis by using a large clinical database.\n\nMethods\nThe multiparameter intelligent monitoring in intensive care II (MIMIC- II) database was employed for the study. Adult patients with sepsis were included for analysis. Antipyretic therapy included antipyretic medication and external cooling. Multivariable model with interaction terms were employed to explore the association of antipyretic therapy and mortality risk.\n\nMain Results\nA total of 15,268 patients fulfilled inclusion criteria and were included in the study. In multivariable model by treating temperature as a continuous variable, there was significant interaction between antipyretic therapy and the maximum temperature (Tmax). While antipyretic therapy had no significant effect on mortality in low temperature quintiles, antipyretic therapy was associated with increased risk of death in the quintile with body temperature >39°C (OR: 1.29, 95% CI: 1.04–1.61).\n\nConclusion\nOur study shows that there is no beneficial effect on reducing mortality risk with the use of antipyretic therapy in ICU patients with sepsis. External cooling may even be harmful in patients with sepsis.\n\nThe study was funded by the science and technology foundation of Jinhua city (approval No. 2013-3-008)(http://www.zjjhst.gov.cn/kjzw/Default.aspx) HN received funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll MIMIC-2 files are available from the mimic-2 database. It is a open access database. the URL is https://mimic.physionet.org/. my access number is: (certification number: 1132877).Data Availability\nAll MIMIC-2 files are available from the mimic-2 database. It is a open access database. the URL is https://mimic.physionet.org/. my access number is: (certification number: 1132877).\n==== Body\nIntroduction\nSepsis is among the most important causes of morbidity and mortality in the intensive care unit. It is estimated that about 5% deaths are directly attributable to sepsis [1]. Depending on different severities of illness varying from sepsis, severe sepsis and septic shock, patients with sepsis show mortality rates ranging from 10% to 40% [2,3]. Diagnostic criteria of sepsis are easy to fulfill, requiring only the confirmation of systematic inflammatory response syndrome (SIRS) and documented or suspected infection [4]. Because sepsis continues to be a great threat to human health, the surviving sepsis campaign has made tremendous efforts to reduce its morbidity and mortality. Strategies such as early goal directed therapy, low tidal volume ventilation, early use of appropriate antibiotics have shown some beneficial effects on sepsis patients. However, the improvement is only minimal and the mortality rate of sepsis remains high. Therefore, new studies begin to focus on other novel medications or strategies for the improvement of medical care for patients with sepsis [5].\n\nFever is the cardinal symptom of sepsis, and is the most important reason for hospital visit. Most physicians will prescribe antipyretic therapy to patients with sepsis, aiming to relieve the symptom of fever. They believe that fever increases metabolic rate via sympathetic activation, making the imbalance between oxygen demand and supply even more severe [6]. This is particularly true in patients with septic shock requiring extracorporeal life support. In this regard, antipyretic therapy is thought to be beneficial for sepsis patients. However, opponents contend that fever is a natural response of human body to microorganism infection and may help to inhibit the growth of microorganism. Therefore, they usually withhold antipyretics when fever is caused by infection, as is the case in sepsis [7–9].\n\nInvestigations on antipyretic therapy have never waned from the very beginning of 1990s [10–13]. Both observational studies and randomized controlled trials (RCT) have been conducted but their results are conflicting. The problem is attributable to variations in study populations, designs, and protocols for performing antipyretic therapy. For instance, body temperature is a continuous variable and the effect of antipyretic therapy on mortality may be altered by different levels body temperature. In other words, there could be an interaction between body temperature and mortality. However, the inclusion of interaction terms substantially increases the degree of freedom in the multivariable model. For most of previous studies, this could not be done due to small sample size (e.g. the sample size cannot support too many degrees of freedom, otherwise, the problem of overfitting arises). The present study utilized a large clinical database to allow for models with complexity. Fractional polynomials and interaction terms were explored after the main effect model was determined. We hypothesized that the effect of antipyretic therapy on mortality would be modified by body temperature.\n\nMaterials and Methods\nClinical database\nThe multiparameter intelligent monitoring in intensive care II (MIMIC- II) database was employed for the study. MIMIC- II was a freely available database comprising more than 30,000 ICU patients. Patients’ information on demographics, laboratory findings, imaging study, vital signs and progress notes were available [14]. The institutional review boards of the Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA) approved the establishment of the database. De-identification was performed to ensure patients’ confidentiality. Our access to the database was approved after completion of the national institute of health (NIH) web-based training course named “Protecting Human Research Participants” by the author Z.Z. (certification number: 1132877).\n\nSubject selection\nAdult patients meeting the criteria of sepsis were included for analysis. The diagnosis of sepsis was adapted from that defined in Surviving sepsis Campaign [4]. SIRS was defined as fulfilling two or more of the following criteria within 24 hours after ICU admission: 1) fever (>38.3°C) or hypothermia (<36°C); 2) tachycardia (>90/min); 3) leukocytosis (WBC count>12000/μL) or leukopenia (WBC count<4000/μL); 4) tachypnea (>20/min). If there were multiple measurements within 24 hours, the one most likely to meet the criteria was adopted (e.g. highest or lowest temperature, highest heart rate). Infection was defined as documented or suspected. Infection was defined if one of the following criteria was fulfilled 1) ICD9 contains the term “infection” or “pneumonia”; 2) microbiological culture was positive. Data management was performed by using the software Stata 13.1 (College Station, Texas 77845 USA). The code for the selection of sepsis patients is shown in supplemental file (S1 Appendix).\n\nData extraction\nAntipyretic therapy consisted of antipyretic medication and external cooling. The former included drugs such as acetaminophen, ibuprofen, naproxen, valtaren, ketoprofen, nimesulide, diclofenac. The latter included blanket cooling and ice pack. Structural query language (SQL) to extract external cooling was:\n\n select*fromcharteventswhereitemid=134ORitemid=7281 All measurements of body temperature recorded during ICU stay were extracted. A total of 1,164,474 measurements were obtained. Other variables including initial lactate [15], sequential organ failure assessment (SOFA), simplified acute physiology score (SAPSⅠ), age at ICU admission, gender and ICU type were extracted. There were four types of ICU: medical ICU (MICU), SICU (surgical ICU), coronary care unit (CCU) and cardiac surgery recovery unit (CSRU).\n\nICU mortality was used as the study endpoint. It was defined as the status of a subject at ICU discharge (dead vs. alive). It was a solid outcome that was not subject to bias.\n\nDefinitions of body temperature\nBecause temperatures were measured repeatedly for each subject, some definitions of temperature were adopted to accommodate the magnitude and duration of temperature. The measurement of temperature recorded in the database was not standardized but could be measured via rectum, oral cavity, axilla or tympanic membrane. The measurement site was not recorded in the database. Temperature load was defined as the difference between actual temperature area and normal temperature area (Fig. 1). We acknowledged that there were circadian changes in body temperature and it was difficult to simply define a cutoff point [16–18]. However, we defined fever as body temperature>37.2°C, which was recommended in the classic medical textbook Harrison’s internal medicine [19]. Temperature values at each measurement time were connected with the time as the horizontal axis. Actual temperature area was the area under the actual temperature line, and normal temperature area was the area under normal temperature (37.2°C). If the temperature load was less than or equal to zero, it was defined as no temperature load (coded as 0 for the variable). The calculation was performed for each time where temperature was measured. Maximum temperature (Tmax) was defined as the highest temperature during ICU stay.\n\n10.1371/journal.pone.0121919.g001Fig 1 Definition of temperature load.\nThe shaded area indicates normal temperature. The blue non-shaded area is temperature exceeding 37.2°C, termed temperature load.\n\nMissing data management\nVariables with missing data were common in the MIMIC-Ⅱ database. If the percentage of missing observations was less than 5%, we replace the missing variable with mode or mean value of that variable. If a variable had more than 30% observations missing, we used dummy variable to recode the missing observations. In the dataset, we found that 40% of the lactate values were missing. We coded missing lactate value as 2, and assigned 0 and 1 for normal lactate and hyperlactatemia, respectively. If missing values accounted for 5%–30%, multiple imputation technique was performed for further estimation [20].\n\nStatistical analysis\nVariables were expressed as mean±standard deviation (SD) or median and 95% confidence interval (CI) as appropriate. Bivariate analysis was performed to compare the difference between survivors and non-survivors.\n\nMultivariable regression model was established by treating temperature as continuous variable. Both SASP-I and SOFA represented the severity of illness and only SOFA was included in the model. Another reason by doing so was that SOFA did not incorporate age as a component. Since we had already included age in the model, incorporation of scores with age may increase the risk of collinearity. All other covariates were included into the multivariable regression model. The model incorporated the maximum body temperature (Tmax) as a continuous variable. Fractional polynomials method was employed to explore the linearity of continuous variables such as age and Tmax [21]. Closed test procedure was used to examine whether the model with higher power terms performed better than the linear model. If there was no statistical significance at p = 0.05 level, the linear model was adopted for the principal of parsimony. Interactions between antipyretic therapy and body temperature were explored to examine whether the effect of antipyretic therapy on mortality differs at different levels of body temperature. If there was statistically significant interaction, odds ratios of antipyretic therapy would be reported at different levels of body temperature.\n\nAll statistical analyses were performed by using Stata 13.1 (College Station, Texas 77845 USA). Statistical significance was considered at p<0.05.\n\nResults\nA total of 32,319 adult ICU patients were identified in the MIMIC-Ⅱ database, including 15,268 patients meeting the criteria of sepsis. There were significant differences in many variables between survivors and non-survivors (Table 1). Survivors were younger than non-survivors (64.0±20.4 vs 69.6±16.2 years, p<0.001). Patients with hyperlactatemia were more likely to die than those with normal or missing values (p<0.001). Patients in MICU were associated with increased risk of death (50.98% vs. 42.96%, p<0.001), whereas those in CSRU were less likely to die (20.92% vs. 29.73%, p<0.001). As expected, non-survivors showed significantly higher SOFA (9.95±4.51 vs. 5.88±3.77, p<0.001) and SAPS-Ⅰ(19.21±5.54 vs. 14.11±5.12, p<0.001) scores. Fever was associated with increased risk of death, irrespective of how it was measured (within 24 hours after ICU admission, during ICU stay and temperature load). Antipyretic therapy was associated with increased risk of death (17.71% vs. 11.49%, p<0.001). However, there was no effect of the use of antipyretic medications (6.63% vs. 7.46%, p = 0.198).\n\n10.1371/journal.pone.0121919.t001Table 1 Comparison of clinical characteristics between ICU survivors and non-survivors.\nVariables\tOverall (n = 15268)\tSurvivors (n = 13538)\tNon-survivors (n = 1730)\tp\t\nAge (years)\t64.6±20.0\t64.0±20.4\t69.6±16.2\t<0.001\t\nGender (male vs)\t8175 (53.54)\t7240 (53.48)\t935 (54.05)\t0.656\t\nLactate\t\t\t\t<0.001\t\nNormal (<2mmol/l)\t4842 (31.71)\t4246 (31.36)\t596 (34.45)\t\t\nHyperlactamia (>2 mmol/l)\t4336 (28.40)\t3429 (25.33)\t907 (52.43)\t\t\nMissing values\t6090 (39.89)\t5863 (43.31)\t227 (13.12)\t\t\nCare unit\t\t\t\t<0.001\t\nMICU\t6,698 (43.87)\t5,816 (42.96)\t882 (50.98)\t\t\nSICU\t1,050 (6.88)\t973 (7.19)\t77 (4.45)\t\t\nCCU\t3,133 (20.52)\t2,724 (20.12)\t409 (23.64)\t\t\nCSRU\t4,387 (28.73)\t4,025 (29.73)\t362 (20.92)\t\t\nSOFA\t6.34±4.07\t5.88±3.77\t9.95±4.51\t<0.001\t\nSAPS-Ⅰ\t14.67±5.41\t14.11±5.12\t19.21±5.54\t<0.001\t\nFever in 24 hours\t9287 (60.83)\t8028 (59.30)\t1259 (72.77)\t<0.001\t\nFever during ICU stay\t11433 (74.88)\t10036 (74.13)\t1397 (80.75)\t<0.001\t\nTemperature load (°C×hr)\t32.01 (30.77, 33.26)\t30.26 (28.95, 31.56)\t45.75 (41.79, 49.70)\t<0.001\t\nAntipyretic therapy of any method\t1852 (12.13)\t1555 (11.49)\t297 (17.17)\t<0.001\t\nAntipyretic medication\t1027 (6.73)\t898 (6.63)\t129 (7.46)\t0.198\t\nExternal cooling\t1006 (6.59)\t794 (5.86)\t212 (12.25)\t<0.001\t\nAbbreviations: MICU, medical intensive care unit; SICU, surgical intensive care unit; CCU, coronary care unit; CSRU, Cardiac Surgery Recovery Unit\n\nIn the regression model Tmax was incorporated into the model as a continuous variable (Table 2). There was significant interaction between Tmax and antipyretic therapy. When there was no antipyretic therapy (coded as 0), Tmax was significantly associated with mortality risk (OR: 1.15, 95% CI: 1.07–1.23). The mortality risk slope was steeper in antipyretic therapy group than non-antipyretic group (Fig. 2). We further categorized temperature into quintiles and the result showed that the effect of antipyretic therapy had no significant effect on mortality in the four lower quintiles, while antipyretic therapy was associated with increased risk of death in the quintile with body temperature>39°C (OR: 1.29, 95% CI: 1.04–1.61, Table 3). When temperature load was incorporated into the model, antipyretic therapy remained to have adverse effect on mortality (OR: 1.355, 95% CI: 1.153–1.593). However, temperature load was not associated with mortality outcome in this model (Table 4).\n\n10.1371/journal.pone.0121919.g002Fig 2 The relationship between probability of death and Tmax.\nThe Probability of death increased with increasing Tmax, and the slope was altered by the use of antipyretic therapy.\n\n10.1371/journal.pone.0121919.t002Table 2 Adjustment for the effect of antipyretic therapy for patients with sepsis by treating temperature as continuous variable (maximum body temperature during ICU stay).\nOdds Ratio\tOdds ratio\tLower limit of 95% CI\tUpper limit of 95% CI\tP\t\nAge\t1.02\t1.01\t1.02\t<0.001\t\nSOFA\t1.22\t1.20\t1.24\t<0.001\t\nSex\t1.12\t1.003\t1.251\t0.044\t\nCare unit (MICU as the reference)\t\nSICU\t0.70\t0.54\t0.90\t0.006\t\nCCU\t0.96\t0.83\t1.10\t0.524\t\nCSRU\t0.46\t0.40\t0.53\t<0.001\t\nLactate (normal as the reference)\t\nHyperlactamia (>2 mmol/l)\t1.30\t1.15\t1.48\t<0.001\t\nMissing values\t0.47\t0.40\t0.56\t<0.001\t\nMaximum temperature during ICU stay (with each 1°C increase) ¶\n\t1.15\t1.07\t1.23\t<0.001\t\nAntipyretic therapy\t.0000164\t1.98e-08\t.013631\t<0.001\t\nAntipyretic therapy×Tmax\n‡\n\t1.33\t1.12\t1.58\t<0.001\t\n¶ The main effect of Tmax (OR = 1.15) is exponentiation of the slope in the regression model when no antipyretic therapy was given (antipyretic therapy = 1).\n\n‡ The coefficient of the interaction term was the difference of the slope in groups with and without antipyretic therapy. An OR>1 indicates a positive coefficient and steeper slope of the antipyretic therapy group than non-antipyretic group.\n\n10.1371/journal.pone.0121919.t003Table 3 Effect of antipyretic therapy on mortality (expressed as odds ratio) at different degrees of body temperature.\nTemperature range (°C)\tOdds ratio¶\n\t95% CI\tP\t\n<37.2\t1.65\t0.77–3.53\t0.196\t\n37.2–37.7\t0.98\t0.50–1.90\t0.950\t\n37.7–38.2\t0.97\t0.52–1.82\t0.930\t\n38.2–39\t0.73\t0.51–1.04\t0.082\t\n>39\t1.29\t1.04–1.61\t0.020\t\n¶The odds ratios were obtained by fitting the main effect model without interaction terms.\n\n10.1371/journal.pone.0121919.t004Table 4 Adjustment for the effect of antipyretic therapy for patients with sepsis by using temperature load as continuous variable.\n\tOdds ratio\tLower limit of 95% CI\tUpper limit of 95% CI\tP\t\nAge\t1.016\t1.013\t1.019\t<0.001\t\nSOFA\t1.222\t1.205\t1.240\t<0.001\t\nSex\t1.098\t0.984\t1.226\t0.095\t\nCare unit (MICU as the reference)\t\nSICU\t0.686\t0.530\t0.888\t0.004\t\nCCU\t0.963\t0.839\t1.105\t0.590\t\nCSRU\t0.458\t0.399\t0.527\t<0.001\t\nLactate (normal as the reference)\t\nHyperlactamia (>2 mmol/l)\t1.303\t1.151\t1.474\t<0.001\t\nMissing values\t0.450\t0.381\t0.531\t<0.001\t\nAntipyretic therapy\t1.355\t1.153\t1.593\t<0.001\t\nTemperature load\t1.000\t0.999\t1.001\t0.904\t\nConstant term\t0.011\t0.008\t0.014\t<0.001\t\nAbbreviations: MICU, medical intensive care unit; SOFA: sequential organ failure assessment; SICU, surgical intensive care unit; CCU, coronary care unit; CSRU, Cardiac Surgery Recovery Unit.\n\nFurthermore, we restricted to external cooling in multivariable analysis (Table 5). Again there was no fractional polynomial term or interactions. External cooling was associated with increased risk of death (OR: 1.51, 95% CI: 1.23–1.84). The predictive margins of patients with and without external cooling are shown in Fig. 3. Some patients received both external cooling and antipyretic mediations. To exclude the influence of antipyretic mediations, we performed sensitivity analysis by restricting to those without antipyretic mediations and the model was refitted. There were 14,241 observations included into the model and the result showed that external cooling was still an independent risk factor for mortality risk (OR: 1.40, 95% CI: 1.12–1.74).\n\n10.1371/journal.pone.0121919.g003Fig 3 Probability of death increased with increasing Tmax.\nUse of external cooling significantly increased the risk of death, but there was no interaction between external cooling and Tmax.\n\n10.1371/journal.pone.0121919.t005Table 5 Adjustment for the effect of external cooling for patients with sepsis by treating temperature as continuous variable (maximum body temperature during ICU stay).\n\tOdds Ratio\tLower limit of 95% CI\tUpper limit of 95% CI\tP>z\t\nMaximum temperature (with each 1 degree increase)\t1.16\t1.09\t1.24\t<0.001\t\nExternal cooling\t1.51\t1.23\t1.84\t<0.001\t\nAge\t1.02\t1.01\t1.02\t<0.001\t\nSOFA\t1.22\t1.20\t1.24\t<0.001\t\nSex\t1.12\t1.01\t1.25\t0.040\t\nCare unit (MICU as the reference)\t\nSICU\t0.66\t0.51\t0.86\t0.002\t\nCCU\t0.95\t0.83\t1.09\t0.498\t\nCSRU\t0.46\t0.40\t0.53\t<0.001\t\nLactate (normal as the reference)\t\nHyperlactamia (>2 mmol/l)\t1.31\t1.15\t1.48\t<0.001\t\nMissing values\t0.48\t0.40\t0.56\t<0.001\t\nThe model contains no interaction terms.\n\nDiscussion\nThe study showed that antipyretic therapy, especially the external cooling, had adverse impact on mortality outcome in ICU patients with sepsis. The adverse effect was independent of the body temperature. When Tmax was incorporated into the model as continuous variable, there was significant interaction between body temperature and antipyretic therapy. In other words, the effect of antipyretic therapy on mortality risk could be modified by Tmax. We further explored the effect of antipyretic therapy on mortality in quintiles of Tmax and found that while the effect was not statistically significant in the quintile with Tmax<39°C, the adverse effect was significant at the quintile with Tmax>39°C. Interestingly, the adverse effect of antipyretic therapy was only true for external cooling, and the use of antipyretic medication showed neutral effect.\n\nOur finding supports the notion that elevated body temperature is a natural response to infection and it is beneficial to sepsis patients. The plausible reasons can be due to increased production of protective heat shock proteins, direct inhibition of microorganism growth, enhancement of antibiotic effectiveness and augmentation of immune function [8]. Although the adverse effects of hyperthermia such as increase in metabolic burden and oxygen consumption do exist, these effects may be outweighed by the beneficial effect in sepsis. For example, increased oxygen consumption may well be balanced by increasing oxygen supply in ICU. Several observational studies demonstrated that fever may confer protection against adverse outcome. In a study involving 612 patients with confirmed gram-negative bacteria, fever with 24 hours was shown to be protective against mortality risk [22]. In another study involving invasive candida infection, Leroy O and coworkers found that a body temperature >38.2°C at the onset of infection was an independent predictor of survival [23]. However, Laupland KB and colleagues[24] showed that fever was associated with increased mortality (20.3% vs. 12%, p < 0.0001), which was consistent with the result of the bivariate analysis in our study. The result was confirmed in multivariable regression model. Laupland’s study incorporated unselected ICU patients including those with trauma and brain injury, which may partly explain the difference. Several randomized controlled trails have been performed to explore the effect of antipyretic therapy on mortality. The results are conflicting. Only one study reported beneficial effect of antipyretic therapy on mortality risk [25], others reported either neutral or adverse effect [12,26–28]. These RCTs are of limited sample size, which are subject to sampling error.\n\nA novel finding in our study was that the effect of antipyretic therapy on mortality could be modified by Tmax. To further explore the interaction between antipyretic therapy and Tmax, we categorized Tmax into quintiles and found that the adverse effect of antipyretic therapy was only significant in the quintile with body temperature>39°C. It is probable that the beneficial effects of fever increase positively with temperature and only at relatively high temperatures the benefits outweigh the adverse effect of fever. Experimental studies have demonstrated that some protective heat shock proteins are produced at highest rate at high temperatures [29]. For instance, detectable Hsp70 protein expression required 24 h exposure at 38.5°C, 6h exposure at 39.5°C, and only 1h exposure at 41°C. These results support our finding that antipyretic therapy at higher temperature confers more adverse effects [30]. At lower temperature range, the beneficial effect may not be prominent and can be abolished by its adverse effect.\n\nOf note, our study showed that the adverse effect of antipyretic therapy was limited to external physical cooling, and there was no significant difference in the proportion of patients using antipyretic medicines between survivors and non-survivors. External cooling acts by lowering skin temperature considerably more than core temperature, resulting in cutaneous vasoconstriction and increase in blood pressure. Furthermore, external cooling usually leads to muscular shivering thereby increasing metabolic rate, energy expenditure and oxygen consumption. These effects act in concert to counteract the metabolic benefit of antipyretic therapy [31]. As a result, external cooling appears to have much greater adverse effect on clinical outcomes than drugs as shown in our study.\n\nThe study is retrospective in nature and bears some inherent limitations. First, Antipyretic medications may also be used for pain control. The study was based on data mining of electronic medical record and it was difficult to determine the reason why antipyretic medications were prescribed in most cases. However, we believed that the most important reason for the use of antipyretic medications were to control fever in sepsis patients. Second, the clinical outcome was short-term mortality and it was largely unknown whether antipyretic therapy could improve other long-term outcomes. This point should be kept in mind in interpreting our findings. Third, the anatomic source of infection was not included in our analysis because it was technically impossible to determine the source of infection. Our study was based on data mining of a critical care big data. Since the source of infection has been shown to be an important determinant of prognosis [32], it could be a confounding factor and our result should be interpreted with caution.\n\nIn conclusion, our study shows that there is no beneficial effect on reducing mortality risk with the use of antipyretic therapy in ICU patients with sepsis. External cooling may even be harmful. However, the findings in the study are hypothesis generating at best due to above-mentioned limitations. In order to assure future relevance of the results of this study, prospective studies must be conducted to examine the effect of antipyretic therapy on mortality in sepsis patients.\n\nSupporting Information\nS1 Appendix Stata code for extracting patients with diagnosis of sepsis.\n(DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nMcPherson D , Griffiths C , Williams M , Baker A , Klodawski E , et al (2013 ) Sepsis-associated mortality in England: an analysis of multiple cause of death data from 2001 to 2010 . BMJ Open \n3 .\n2 \nSerpa Neto A , Cardoso SO , Ong DS , Esposito DC , Pereira VG , et al (2013 ) The use of the pulse oximetric saturation/fraction of inspired oxygen ratio for risk stratification of patients with severe sepsis and septic shock . J Crit Care \n28 : 681 –686 . 10.1016/j.jcrc.2013.04.005 \n23726018 \n3 \nZhang Z , Zhang Z , Xue Y , Xu X , Ni H (2012 ) Prognostic value of B-type natriuretic peptide (BNP) and its potential role in guiding fluid therapy in critically ill septic patients . Scand J Trauma Resusc Emerg Med \n20 : 86 \n10.1186/1757-7241-20-86 \n23276277 \n4 \nDellinger RP , Levy MM , Rhodes A , Annane D , Gerlach H , et al (2013 ) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 . Crit Care Med \n41 : 580 –637 . 10.1097/CCM.0b013e31827e83af \n23353941 \n5 \nKarnad DR , Bhadade R , Verma PK , Moulick ND , Daga MK , et al (2014 ) Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study . Intensive Care Med \n40 : 830 –838 . 10.1007/s00134-014-3278-8 \n24737258 \n6 \nMohr NM , Doerschug KC (2013 ) Point: Should antipyretic therapy be given routinely to febrile patients in septic shock? Yes . Chest \n144 : 1096 –1098 ; discussion 1101–1093. 10.1378/chest.13-0916 \n24081339 \n7 \nDrewry AM , Hotchkiss RS (2013 ) Counterpoint: Should antipyretic therapy be given routinely to febrile patients in septic shock? No . Chest \n144 : 1098 –1101 ; discussion 1101–1093. 10.1378/chest.13-0918 \n24081340 \n8 \nLauney Y , Nesseler N , Malledant Y , Seguin P (2011 ) Clinical review: fever in septic ICU patients—friend or foe? \nCrit Care \n15 : 222 \n10.1186/cc10097 \n21672276 \n9 \nGreisman LA , Mackowiak PA (2002 ) Fever: beneficial and detrimental effects of antipyretics . Curr Opin Infect Dis \n15 : 241 –245 .\n12015457 \n10 \nMohr N , Skrupky L , Fuller B , Moy H , Alunday R , et al (2012 ) Early antipyretic exposure does not increase mortality in patients with gram-negative severe sepsis: a retrospective cohort study . Intern Emerg Med \n7 : 463 –470 .\n22926744 \n11 \nWang X , Liu D , Yang Y , Zhou X , Chai W , et al (2014 ) [The effect of body temperature control on organ function and prognosis in patients with refractory septic shock ]. Zhonghua Nei Ke Za Zhi \n53 : 293 –297 .\n24857304 \n12 \nBernard GR , Reines HD , Halushka PV , Higgins SB , Metz CA , et al (1991 ) Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition . Am Rev Respir Dis \n144 : 1095 –1101 .\n1952438 \n13 \nHaupt MT , Jastremski MS , Clemmer TP , Metz CA , Goris GB (1991 ) Effect of ibuprofen in patients with severe sepsis: a randomized, double-blind, multicenter study . The Ibuprofen Study Group. Crit Care Med \n19 : 1339 –1347 .\n1935150 \n14 \nSaeed M , Villarroel M , Reisner AT , Clifford G , Lehman LW , et al (2011 ) Multiparameter Intelligent Monitoring in Intensive Care II: a public-access intensive care unit database . Crit Care Med \n39 : 952 –960 . 10.1097/CCM.0b013e31820a92c6 \n21283005 \n15 \nZhang Z , Chen K , Ni H , Fan H (2014 ) Predictive value of lactate in unselected critically ill patients: an analysis using fractional polynomials . J Thorac Dis \n6 : 995 –1003 . 10.3978/j.issn.2072-1439.2014.07.01 \n25093098 \n16 \nSund-Levander M , Forsberg C , Wahren LK (2002 ) Normal oral, rectal, tympanic and axillary body temperature in adult men and women: a systematic literature review . Scand J Caring Sci \n16 : 122 –128 .\n12000664 \n17 \nSund-Levander M , Grodzinsky E (2009 ) Time for a change to assess and evaluate body temperature in clinical practice . Int J Nurs Pract \n15 : 241 –249 . 10.1111/j.1440-172X.2009.01756.x \n19703039 \n18 \nLaupland KB (2009 ) Fever in the critically ill medical patient . Crit Care Med \n37 : S273 –278 . 10.1097/CCM.0b013e3181aa6117 \n19535958 \n19 \nLongo DL , Fauci AS , Kasper DL , Hauser SL , Jameson JL , et al (2011 ) Part 2. Cardinal Manifestations and Presentation of Diseases\nHarrison's Principles of Internal Medicine . 18 ed. \nUSA : McGraw-Hill Companies, Inc. \n\n20 \nSchafer JL , Graham JW (2002 ) Missing data: Our view of the state of the art . Psychological Methods \n7 : 147 –177 .\n12090408 \n21 \nRoyston P , Ambler G , Sauerbrei W (1999 ) The use of fractional polynomials to model continuous risk variables in epidemiology . International Journal of Epidemiology \n28 : 964 –974 .\n10597998 \n22 \nKreger BE , Craven DE , McCabe WR (1980 ) Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients . Am J Med \n68 : 344 –355 .\n6987871 \n23 \nLeroy O , Gangneux JP , Montravers P , Mira JP , Gouin F , et al (2009 ) Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006) . Crit Care Med \n37 : 1612 –1618 . 10.1097/CCM.0b013e31819efac0 \n19325476 \n24 \nLaupland KB , Shahpori R , Kirkpatrick AW , Ross T , Gregson DB , et al (2008 ) Occurrence and outcome of fever in critically ill adults . Crit Care Med \n36 : 1531 –1535 . 10.1097/CCM.0b013e318170efd3 \n18434882 \n25 \nSchortgen F , Clabault K , Katsahian S , Devaquet J , Mercat A , et al (2012 ) Fever control using external cooling in septic shock: a randomized controlled trial . Am J Respir Crit Care Med \n185 : 1088 –1095 . 10.1164/rccm.201110-1820OC \n22366046 \n26 \nYang YL , Liu DW , Wang XT , Long Y , Zhou X , et al (2013 ) Body temperature control in patients with refractory septic shock: too much may be harmful . Chin Med J (Engl) \n126 : 1809 –1813 .\n23673091 \n27 \nMemiş D , Karamanlıoğlu B , Turan A , Koyuncu O , Pamukçu Z (2004 ) Effects of lornoxicam on the physiology of severe sepsis . Critical Care \n8 : R474 \n15566594 \n28 \nBernard GR , Wheeler AP , Russell JA , Schein R , Summer WR , et al (1997 ) The Effects of Ibuprofen on the Physiology and Survival of Patients with Sepsis . New England Journal of Medicine \n336 : 912 –918 .\n9070471 \n29 \nSingh IS , Hasday JD (2013 ) Fever, hyperthermia and the heat shock response . Int J Hyperthermia \n29 : 423 –435 . 10.3109/02656736.2013.808766 \n23863046 \n30 \nTulapurkar ME , Asiegbu BE , Singh IS , Hasday JD (2009 ) Hyperthermia in the febrile range induces HSP72 expression proportional to exposure temperature but not to HSF-1 DNA-binding activity in human lung epithelial A549 cells . Cell Stress Chaperones \n14 : 499 –508 . 10.1007/s12192-009-0103-3 \n19221897 \n31 \nAxelrod P (2000 ) External cooling in the management of fever . Clin Infect Dis \n31 \nSuppl 5 : S224 –229 .\n11113027 \n32 \nLeligdowicz A , Dodek PM , Norena M , Wong H , Kumar A , et al (2014 ) Association between source of infection and hospital mortality in patients who have septic shock . Am J Respir Crit Care Med \n189 : 1204 –1213 . 10.1164/rccm.201310-1875OC \n24635548\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(3)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058633:Antipyretics; D001831:Body Temperature; D003422:Critical Care; D016638:Critical Illness; D017679:Cryotherapy; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011336:Probability; D012307:Risk Factors; D018805:Sepsis",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0121919",
"pmc": null,
"pmid": "25822614",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24081339;6987871;12000664;19325476;24857304;9070471;23726018;1935150;22926744;12015457;10597998;24737258;19535958;21283005;24635548;25093098;1952438;15566594;23673091;24081340;23276277;12090408;19221897;23863046;22366046;21672276;18434882;19703039;23353941;23913771;11113027",
"title": "Antipyretic therapy in critically ill patients with sepsis: an interaction with body temperature.",
"title_normalized": "antipyretic therapy in critically ill patients with sepsis an interaction with body temperature"
} | [
{
"companynumb": "CN-JNJFOC-20150419346",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nBedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets.\n\n\nMETHODS\nA randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability.\n\n\nRESULTS\nThere was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.\n\n\nCONCLUSIONS\nThe bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.",
"affiliations": "Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.;TASK Applied Science, Cape Town, South Africa.;TASK Applied Science, Cape Town, South Africa.;TASK Applied Science, Cape Town, South Africa.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.;Department of Pediatrics, State University of New York Stony Brook, New York, USA.;Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesada, USA.;TASK Applied Science, Cape Town, South Africa.;Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.;Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.",
"authors": "Svensson|Elin M|EM|http://orcid.org/0000-0002-0093-6445;du Bois|Jeannine|J|;Kitshoff|Rene|R|;de Jager|Veronique R|VR|;Wiesner|Lubbe|L|;Norman|Jennifer|J|;Nachman|Sharon|S|;Smith|Betsy|B|;Diacon|Andreas H|AH|;Hesseling|Anneke C|AC|;Garcia-Prats|Anthony J|AJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13696",
"fulltext": "\n==== Front\nBr J Clin PharmacolBr J Clin Pharmacol10.1111/(ISSN)1365-2125BCPBritish Journal of Clinical Pharmacology0306-52511365-2125John Wiley and Sons Inc. Hoboken 10.1111/bcp.13696BCP13696MP-00312-18.R1Original ArticleOriginal ArticlesRelative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children Bioavailability of suspended bedaquilineE. M. Svensson et al.Svensson Elin M. http://orcid.org/0000-0002-0093-6445elin.svensson@farmbio.uu.se \n1\n\n2\n\n†\ndu Bois Jeannine \n3\n\n†\nKitshoff Rene \n3\nde Jager Veronique R. \n3\nWiesner Lubbe \n4\nNorman Jennifer \n4\nNachman Sharon \n5\nSmith Betsy \n6\nDiacon Andreas H. \n3\n\n7\nHesseling Anneke C. \n8\n\n‡\nGarcia‐Prats Anthony J. \n8\n\n‡\n\n1 \nDepartment of Pharmaceutical Biosciences\nUppsala University\nUppsala\nSweden\n\n2 \nDepartment of Pharmacy, Radboud Institute for Health Sciences\nRadboud University Medical Center\nNijmegen\nThe Netherlands\n\n3 \nTASK Applied Science\nCape Town\nSouth Africa\n\n4 \nDivision of Clinical Pharmacology, Department of Medicine\nUniversity of Cape Town\nCape Town\nSouth Africa\n\n5 \nDepartment of Pediatrics\nState University of New York Stony Brook\nNew York\nUSA\n\n6 \nDivision of AIDS\nNational Institute of Allergy and Infectious Diseases, National Institutes of Health\nBethesada\nUSA\n\n7 \nDivision of Medical Physiology, Faculty of Medicine and Health Sciences\nStellenbosch University\nSouth Africa\n\n8 \nDesmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences\nStellenbosch University\nCape Town\nSouth Africa\n* \nCorrespondence\n\nElin M. Svensson, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. Tel.: +46 708475571; Fax: +46 4714003;\n\nE‐mail: elin.svensson@farmbio.uu.se\n† Authors contributed equally, shared first authorship.\n\n‡ Authors contributed equally, shared senior authorship.\n\n10 8 2018 10 2018 10 8 2018 84 10 10.1111/bcp.v84.102384 2392 26 4 2018 15 6 2018 20 6 2018 © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Aims\nBedaquiline is an important novel drug for treatment of multidrug‐resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short‐term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets.\n\nMethods\nA randomized, open‐label, two‐period cross‐over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed‐effects modelling. A questionnaire was used to assess palatability and acceptability.\n\nResults\nThere was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94–108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.\n\nConclusions\nThe bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug‐resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.\n\nbedaquilinebioavailabilitypaediatric dosingpopulation PKsuspended tabletsNational Institute of Allergy and Infectious DiseasesUM1AI068616UM1AI068632UM1AI106716 source-schema-version-number2.0component-idbcp13696cover-dateOctober 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.7.1 mode:remove_FC converted:14.09.2018\n\n\nSvensson , E. M. \n, \ndu Bois , J. \n, \nKitshoff , R. \n, \nde Jager , V. R. \n, \nWiesner , L. \n, \nNorman , J. \n, \nNachman , S. \n, \nSmith , B. \n, \nDiacon , A. H. \n, \nHesseling , A. C. \n, and \nGarcia‐Prats , A. J. \n (2018 ) Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children . Br J Clin Pharmacol , 84 : 2384 –2392 . 10.1111/bcp.13696 .\n==== Body\nWhat is Already Known about this Subject\n\nThere is currently no paediatric formulation available of the novel antituberculosis drug bedaquiline\n\nImportant absorption properties such as the bioavailability can be altered if a drug formulation is manipulated to enable administration to children, for example through crushing or suspending the tablets\n\n\n\n\nWhat this Study Adds\n\nA precise estimate of the relative bioavailability of bedaquiline tablets suspended in water compared to when administered whole\n\nSupport for the use of suspended bedaquiline tablets as an option for treatment of multidrug‐resistant tuberculosis in children\n\n\n\n\nIntroduction\nBedaquiline, the first novel antituberculosis drug developed in decades, is increasingly used for treatment of multidrug‐resistant (MDR) tuberculosis (TB). Based on phase II trial data it received accelerated approval from the US Food and Drug Administration in 2012 and is included on the World Health Organization list of essential medicines. Bedaquiline is being rolled out for programmatic use globally 1. Janssen Pharmaceuticals has developed a paediatric dispersible formulation of bedaquiline and paediatric bedaquiline trials are now underway (Janssen C211, NCT02354014 and IMPAACT P1108, NCT02906007). However, considerably more time is needed for this formulation to become available for widespread routine care, limiting bedaquiline's immediate potential for use in young children.\n\nBedaquiline is a diarylquinoline that inhibits mycobacterial ATP‐synthase, resulting in potent antimycobacterial activity 2. The recommended adult dose is 400 mg daily for 2 weeks, then 200 mg thrice weekly for 22 weeks. In adults, the time to maximum bedaquiline serum concentrations is 4–6 h, with 2.0–2.4‐fold increased absorption when administered together with food 3. Absolute bioavailability, i.e. the fraction of the total dose administered which is absorbed to the systemic blood circulation, for bedaquiline is not known 4. Bedaquiline is primarily metabolized by CYP3A4 to M2 3. This leads to drug–drug interactions with several antiretroviral and anti‐TB compounds which induces or inhibits CYP3A4 5, 6, 7. Both bedaquiline and its M2 metabolite have cationic amphiphilic properties. They bind to phospholipids and accumulate in cells and tissues, resulting in long terminal elimination half‐lives (bedaquiline 164 days; M2 159 days) due to the slow release from tissues 3.\n\nBedaquiline 100 mg tablets are increasingly available for the treatment of adults with MDR TB, with global access improving rapidly 8, 9. These tablets could potentially be used for treatment of children. However, administration of these tablets to young children who cannot swallow tablets may require suspending or crushing the adult formulation. Such formulation manipulation for paediatric administration, which is commonly done for most second‐line TB drugs given in children, may affect the bioavailability 10. Characterizing the effect of suspending bedaquiline tablets on the bioavailability would inform the safe and effective use of this formulation in young children, potentially accelerating access to this much needed medication, given limited treatment options and availability of child‐friendly formulations in children.\n\nThe primary objective of this study was to evaluate the bioequivalence of bedaquiline tablets swallowed whole vs. suspended in water, based on the primary pharmacokinetic (PK) parameter affecting the extent of absorption, i.e. the bioavailability. Secondary objectives were to determine the impact of suspending the tablets on the time‐course of absorption, and to describe the palatability, acceptability and safety of whole vs. suspended bedaquiline.\n\nMethods\nStudy design and participants\nThis was a randomized, open‐label, two‐period cross‐over study. Healthy male and female adults were eligible if they were aged 18–55 years and weighed 40–90 kg. Exclusion criteria included a history or clinical evidence of any of the following: QT prolongation, dysrhythmia or other significant cardiac conditions; other serious comorbid illness including but not limited to liver disease, kidney disease, human immunodeficiency virus infection, hepatitis B or C infection, hypothyroidism; use of QT prolonging medications or CYP3A4 inducers or inhibitors; suspected or documented current active TB or recent household TB exposure. The study was conducted in Cape Town, South Africa, from November to December 2016.\n\nThe sample size, the length of the washout‐period and the number and timing of PK samples were selected with help of clinical trial simulations. These were conducted with stochastic simulation and re‐estimation procedures, using a published population model of bedaquiline and M2 PK developed on data from healthy volunteers 5. The designs evaluated included washout periods between 2 and 28 days long, and 11–17 samples per dosing occasion. One hundred virtual trials were simulated for each design, assuming no difference in absorption characteristics for whole and suspended tablets. Model parameters were re‐estimated including factors allowing for differences in bioavailability, and delay and rate of absorption, between whole and suspended tablets. Effects on distribution‐ and elimination‐related parameters were not evaluated as these cannot be affected by the drug formulation. The power to show bioequivalence under the suggested design given that the two forms are truly equal, were evaluated by calculating in how many of the 100 trials the 95% confidence interval of the factors describing a difference between whole and suspended tablets were fully contained within the bioequivalence criteria, defined as 80–125% of the expected value 11. The selected design (described below) was estimated to have an 87% power (95% confidence interval 80–94%) to fulfil the formal bioequivalence criteria for bioavailability.\n\nIntervention and randomization\nThe selected design included 24 participants who received a single dose of each treatment (formulation), with a washout period of 14 days between the two dosing occasions. Each bedaquiline tablet (Sirturo, Janssen Pharmaceuticals) contains 120.89 mg of bedaquiline fumarate drug substance, which is equivalent to 100 mg of bedaquiline. As tablets, 400 mg bedaquiline was administered as 4 × 100 mg tablets swallowed whole with 240 ml water. A bedaquiline suspension was prepared by adding 4 × 100 mg tablets to 30 ml clean water in a plastic dosing cup, using a metal spoon to stir and break up the tablets over 2 min. The suspension was administered within 5 min of adding the tablets to the water. An additional 20 ml of water was added to the dosing cup to rinse any residual medication from the cup and stirrer, and administered to the participant. Lastly, another 10 ml of water was added to the cup for a final rinse and then administered to the participant. All doses were administered within 30 min after a standardized breakfast consisting of approximately 670 kcal with at least 33% fat content.\n\nParticipants were randomized 1:1 to having bedaquiline administered as whole tablets at the first occasion, and then as tablets suspended in water on the second occasion, or the reverse. The randomization scheme was created using computer generated random numbers in a single block to ensure equal numbers of participants were assigned to each treatment sequence. Consecutively numbered, sealed, opaque envelopes were prepared by the study pharmacist and stored in a secure location at the site. After enrolment of a participant, the research pharmacist opened the next consecutively numbered envelope to determine the participant's allocation.\n\nData collection\nPharmacokinetic samples were drawn just before and at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48 and 336 h after each dose (the 336 h sample for the first occasion also serving as the predose sample for the second). Whole blood samples were drawn into EDTA‐containing tubes and immediately placed on ice. Samples were centrifuged at 1500–2000 g within 1 h, plasma was separated and stored at –80°C until bioanalysis was performed.\n\nAll treatment emergent laboratory and clinical adverse events were recorded by the study team, and assessed for attribution to the study medication and for severity using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, dated November 2014 by the site investigators. Twelve‐lead electrocardiograms were done at screening and on dosing days, just prior to the dose and at 4 h postdose. The QT interval was calculated using the Frederica correction and captured along with other clinically significant abnormalities. Safety laboratory monitoring included haematology, liver function tests and lactate.\n\nA palatability/acceptability questionnaire was administered to each participant within 1 h of each dose. The questionnaire utilized a five‐point facial hedonic scale to assess taste, smell, visual appearance, texture, size/volume and overall acceptability of both treatments.\n\nBioanalysis\nBedaquiline and M2 concentrations were determined using a validated liquid chromatography–tandem mass spectrometry assay developed in the Division of Clinical Pharmacology, University of Cape Town, South Africa, validated according to Food and Drug Administration and European Medicines Agency guidelines, as previously described 12 and further detailed in the online supplementary material. The assay was validated over the concentration range of 0.01–5 μg ml–1 for bedaquiline and 0.01–0.5 μg ml–1 for M2 (lower and upper limit of quantification). During sample analysis, the accuracies (% Nom) for bedaquiline were 102.6%, 102.0% and 99.3% at the high (4 μg ml–1), medium (2 μg ml–1) and low (0.024 μg ml–1) QC levels respectively with precision (% CV) <10% across all three levels. The accuracies for M2 were 99.1%, 99.3% and 96.7% at the high (0.40 μg ml–1), medium (0.20 μg ml–1) and low (0.024 μg ml–1) QC levels, respectively, with precision (% CV) <7%.\n\nPharmacokinetic analysis\nNonlinear mixed‐effects models, able to characterize both typical parameter values and distributions of random interindividual and interoccasion variability (IIV and IOV), as well as unexplained residual variability, were employed for the analysis. The previously developed population PK model utilized in the clinical trial simulations was used as a starting point 5. This model included three distribution compartments for bedaquiline and two for M2. Each bedaquiline dose was defined as a separate occasion. IIV and IOV were implemented with log‐normal distributions. A correlation between the residual errors for observations at the same time point was included. Concentration measurements below the limit of quantification were excluded from the analysis. Model selection was based on maximum likelihood ratio test (95% significance level) and goodness‐of‐fit plots, including visual predictive checks based on simulations from the final model (n = 1000). Secondary PK metrics (area under the concentration curve up to 48 and 336 h after dose, i.e. AUC0–48h and AUC0–336h, and time and magnitude of peak concentrations, i.e. Tmax and Cmax) were derived from the final model.\n\nData management, post processing of results and plotting were performed in R (R Foundation for Statistical Computing, Vienna, Austria) 13. The modelling and simulations were performed in NONMEM 7.3 (Icon Development Solutions, Ellicott City, MD, USA) 14, aided by PsN (Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden) and Pirana (Pirana Software & Consulting, San Francisco, CA, USA) 15. Parameter uncertainty was obtained from the covariance step in NONMEM. Additionally, log‐likelihood profiling (as implemented in PsN) was used to obtain nonparametric confidence intervals for the parameters describing potential effects of suspending tablets.\n\nEthics\nThis study was approved by the Pharma‐Ethics Independent Research Ethics Committee of South Africa (#141110730). All participants provided written informed consent. The trial was registered at http://clinicaltrials.gov with identifier NCT03032367.\n\nResults\nStudy participants and data\nAll 24 participants completed the study. A summary of the demographic characteristics can be found in Table 1. Study investigators noted that the tablets did suspend in this volume of water over 2 min, although some amount of stirring and breaking up the tablets with the spoon handle were required. Some visual particles usually remained, which were successfully suspended by the described rinses. There were 552 concentration observations each for bedaquiline and M2 available. All predose observations at the first sampling occasion as well as five postdose bedaquiline and 81 postdose M2 observations were below the limit of quantification. The average concentration of bedaquiline and M2 per nominal time point is shown in Figure S1.\n\nTable 1 Summary of the demographic characteristics of the study participants\n\nCharacteristics\tAll participants\tWhole tablets first\tSuspension first\t\nMedian (range)/n (%)\tMedian (range)/n (%)\tMedian (range)/n (%)\t\n\nn\n\t24\t12\t12\t\n\nWeight (kg)\n\t63.4 (45.6, 88.5)\t66.15 (45.6, 84.7)\t61.85 (53.3, 88.5)\t\n\nAge (years)\n\t23.5 (19, 37)\t22 (19, 26)\t24.5 (20, 37)\t\n\nFemale sex\n\t15 (62.5%)\t8 (66.7%)\t7 (58.3%)\t\n\nRace\n\t\t\t\t\n\nBlack\n\t21 (87.5%)\t11 (91.7%)\t10 (83.3%)\t\n\nMixed race\n\t3 (12.5%)\t1 (8.3%)\t2 (16.7%)\t\nPharmacokinetic analysis\nThe starting model generally described the data well, and only a few modifications were required. A 6‐h maximum limit for the mean absorption time (i.e. the typical time to when 90% of the dose is absorbed) was added to the flexible transit compartment model describing absorption, consistent with another recently published model of bedaquiline PK 16. The absorption model was simplified without a statistically significant loss of fit by making the rate of absorption from the last transit compartment the same as the rate of transfer between the transit compartments.\n\nThe difference in bioavailability between suspended and whole tablets was not statistically significant (P = 0.92). The nonparametric 95% confidence interval (CI) of the relative bioavailability of suspended bedaquiline tablets was 94–108% relative to that of whole bedaquiline tablets; hence the predefined bioequivalence criteria (80–125%) were fulfilled. IIV in bioavailability was not significantly different between whole and suspended tablets. The mean absorption time was slightly longer for suspended tablets, +23% (95% CI 2.1–48%, P = 0.03). In the final model, only the formulation effect on mean absorption time was included. Parameter estimates with uncertainty are reported in Table 2, and the NONMEM control stream detailing the parametrization is included in the online supplementary material. The fit of the model to the observed data per formulation and sequence are shown in Figure 1 and 2 for bedaquiline and M2, respectively. The typical PK profile after a single 400 mg dose bedaquiline administered either as whole or suspended tablets are demonstrated in Figure 3. Secondary PK metrics (AUC0–48h, AUC0–336h, Cmax and Tmax) are reported in Table 3 and Table S1 to facilitate comparison with other clinical studies.\n\nTable 2 Parameter estimates for the final model including uncertainty\n\nStructural parameters\tParameter value\tRelative standard error\t\n\nMAT (h)\t2.63\t5.0%\t\n\nNN\n\t4.00\t10.9%\t\n\nCL\nBDQ\n/F (l h\n–1\n)\n\t5.67\t10.1%\t\n\nV\nBDQ\n/F (l)\n\t130\t6.1%\t\n\nQ\nBDQ,1\n/F (l h\n–1\n)\n\t6.33\t9.6%\t\n\nVP\nBDQ,1\n/F (l)\n\t3020\t28.0%\t\n\nQ\nBDQ,2\n/F (l h\n–1\n)\n\t4.83\t15.5%\t\n\nVP\nBDQ,2\n/F (l)\n\t64.5\t13.1%\t\n\nCL\nM2\n/F/fm (l h\n–1\n)\n\t17.2\t11.8%\t\n\nV\nM2\n/F/fm (l)\n\t1380\t9.2%\t\n\nQ\nM2\n/F/fm (l h\n–1\n)\n\t126\t12.9%\t\n\nVP\nM2\n/F/fm (l)\n\t3450\t11.7%\t\n\nWeighting residual error samples 0‐6 h\n\t1.67\t5.6%\t\n\nEffect of suspending on MAT (%)\n\t23\t43.0%\t\n\nVariability between individuals and occasions\n\t\n\nIOV F\n\t9.1%\t23.8%\t\n\nIIV F\n\t22.6%\t12.8%\t\n\nIOV MAT\n\t66.3%\t9.4%\t\n\nIIV CL\nBDQ\n\t17.1%\t23.2%\t\n\nCorrelation IIV CL\nBDQ\n‐CLM2\n\t8.5%\t5.4%\t\n\nIIV CL\nM2\n\t20.5%\t23.4%\t\n\nIIV V\nBDQ\n\t28.3%\t15.5%\t\n\nIIV Q\nBDQ,1\n\t17.3%\t25.7%\t\n\nIIV V\nM2\n\t26.3%\t25.3%\t\n\nIIV VP\nM2\n\t22.3%\t35.6%\t\n\nResidual variability\n\t\t\t\n\nProportional error BDQ\n\t23.1%\t4.0%\t\n\nCorrelation error BDQ‐M2\n\t53.1%\t11.7%\t\n\nProportional error M2\n\t11.4%\t3.7%\t\nBDQ, bedaquiline; M2, metabolite M2; MAT, mean absorption time; NN, number of transit compartments; CL, clearance; V, volume of distribution central compartments; Q, intercompartmental clearance; VP, volume of distribution peripheral compartments; F, bioavailability; IOV, interoccasion variability; IIV, interindividual variability\n\nFigure 1 Visual predictive check showing the 5th, 50th and 95th percentiles (lines) of observed bedaquiline concentrations (open circles) over time after dose, per formulation (whole or suspended tablets) and dose. The shaded areas represent the 90% confidence intervals for the same percentiles calculated from model simulated data\n\nFigure 2 Visual predictive check showing the 5th, 50th and 95th percentiles (lines) of observed M2 concentrations (open circles) over time after dose, per formulation (whole or suspended tablets) and dose. The shaded areas represent the 90% confidence intervals for the same percentiles calculated from model simulated data\n\nFigure 3 Typical pharmacokinetic profile after a single 400 mg dose bedaquiline administered either as whole (solid line) or suspended (broken line) tablets, based on final model parameters\n\nTable 3 Summary of secondary PK metrics after two single doses of 400 mg bedaquiline administered 14 days apart. The numbers represent geometric mean and range of individual exposure estimates from the final model\n\n\tFirst dose, whole (n = 12)\tFirst dose, suspended (n = 12)\tSecond dose, whole (n = 12)\tSecond dose, suspended (n = 12)\t\n\nBedaquiline\n\t\n\nAUC\n0–48h\n(ng ml\n–1\n*h)\n\t31 900 (18 600, 51 600)\t32 900 (25 600, 43 800)\t35 900 (29 600, 49 100)\t34 700 (20 700, 54 000)\t\n\nAUC\n0–336h\n(ng ml\n–1\n*h)\n\t43 500 (24 900, 69 300)\t45 900 (34 300, 60 700)\t56 700 (44 600, 75 400)\t53 400 (31 100, 89 700)\t\n\nC\nmax\n(ng ml\n–1\n)\n\t2400 (1410, 3660)\t2260 (1750, 3280)\t2500 (2030, 3820)\t2460 (1490, 3910)\t\n\nT\nmax\n(h)\n\t4.3 (2.8, 5.6)\t4.9 (2.8, 6.9)\t4.1 (2.8,6.7)\t4.9 (3.3, 7.3)\t\n\nM2 metabolite\n\t\n\nAUC\n0–48h\n(ng ml\n–1\n*h)\n\t1650 (818, 3110)\t1780 (1270, 2580)\t2800 (1990, 4140)\t2520 (1360, 4380)\t\n\nAUC\n0–336h\n(ng ml\n–1\n*h)\n\t8450 (4520, 15 400)\t9340 (6480, 13 600)\t14 900 (10 400, 22 000)\t13 400 (7750, 22 300)\t\n\nC\nmax\n(ng ml\n–1\n)\n\t44.3 (22.0, 81.2)\t47.9 (33.4, 72.2)\t69.5 (50.7, 106)\t63.6 (33.9, 109)\t\n\nT\nmax\n(h)\n\t14.4 (10.1, 19.6)\t14.8 (11.4, 18.1)\t14.0 (10.9, 17.3)\t14.8 (11.0, 20.0)\t\nAUC, area under the concentration curve; Cmax, maximal concentration, Tmax, time of maximal concentration\n\nSafety, palatability and acceptability\nThere were no Grade 3 or 4 or serious treatment emergent adverse events, nor any treatment adverse events leading to withdrawal from the study. All adverse events and all potentially bedaquiline‐related treatment emergent adverse events are shown in Tables S2 and S3 by grade of severity. The most frequent event (n = 7) was mild or moderate headache. No participant had a QTcF >450 ms at any point during the study. No lactate levels >3 mmol l–1 were found. Table 4 shows results of the acceptability and palatability questionnaire by formulation (whole tablets vs. suspension). The large majority of participants (88–100%) were either neutral to or liked most aspects of the bedaquiline suspension palatability, such as taste, smell, texture. Twenty‐three of 24 participants (96%) reported the suspension to be acceptable overall.\n\nTable 4 Results of palatability and acceptability assessments in healthy adults receiving suspended vs. whole bedaquiline tablets (n = 24)\n\n\tWhole formulation\tSuspended formulation\t\n\tDislike very much or dislike\tNeutral, Like or Like very much\tDislike very much or dislike\tNeutral, Like or Like very much\t\n\nHow did you feel about the visual appeal of the formulation? (did the formulation look acceptable to you?)\n\t1 (4%)\t23 (96%)\t3 (13%)\t21 (88%)\t\n\nHow did you feel about the smell of the formulation?\n\t0 (0%)\t24 (100%)\t1 (4%)\t23 (96%)\t\n\nHow did you feel about the taste of the formulation?\n\t3 (13%)\t21 (88%)\t3 (13%)\t21 (88%)\t\n\nHow did you feel about the texture of the formulation? (how did the formulation feel in your mouth?)\n\t5 (21%)\t19 (79%)\t2 (8%)\t22 (92%)\t\n\nHow did you feel about the size/amount of the formulation (volume of liquid or size of tablet)?\n\t5 (21%)\t19 (79%)\t0 (0%)\t24 (100%)\t\n\nHow did you feel about the OVERALL acceptability of the formulation?\n\t0 (0%)\t24 (100%)\t1 (4%)\t23 (96%)\t\n\nIf a child is required to take this formulation, how do you think they would feel about the taste of the formulation?\n\t5 (21%)\t19 (79%)\t2 (8%)\t22 (92%)\t\n\nIf a child is required to take this formulation, how do you think they would feel about the size/amount of the formulation (volume of liquid or size of tablet)?\n\t6 (25%)\t18 (75%)\t1 (4%)\t23 (96%)\t\n\nIf a child is required to take this formulation, how do you think they would feel about the OVERALL acceptability?\n\t3 (13%)\t21 (88%)\t3 (13%)\t21 (88%)\t\nDiscussion\nThis study demonstrates that a 400 mg dose of bedaquiline given as 100 mg tablets suspended in a small volume of water had equivalent bioavailability to bedaquiline administered as 100 mg tablets swallowed whole. The suspended bedaquiline tablets were considered by the majority of participants to be palatable and acceptable.\n\nThe mean absorption time for suspended bedaquiline was found to typically be 23% longer. This translates to a delay in the time to peak bedaquiline concentrations from 4.3 to 5.2 h, and a decrease in typical maximal concentrations of 5%, but no change in the average concentration. Given that average rather than peak concentrations have been linked to bedaquiline efficacy 17, we do not expect the effect of suspending on mean absorption time to be clinically relevant. The bedaquiline exposures observed in this study (see Table 3) were somewhat lower compared to other studies in healthy volunteers with similar design and the same dose. Dooley et al. reported bedaquiline AUC0–336h of 58 200 (42 200–78 200) ng ml–1*h 18, and Winter et al. reported 67 200 (standard deviation 20 200) ng ml–1*h 19, while the median in this study was 44 000 ng ml–1*h. This might be explained by the larger proportion of black subjects included here (88%) compared to in the studies by Dooley and Winter (22% and 6%, respectively), since black race has been associated with higher bedaquiline clearance 16.\n\nOur findings have important implications for the clinical use of bedaquiline 100 mg tablets in young children, who will be unlikely to have access to paediatric bedaquiline formulations in routine care settings in the near future. Data on the safety and dosing of bedaquiline from paediatric trials across the age range (0–17 years) is expected to be available long before the paediatric formulation used in the studies is registered and widely available, as there are many barriers preventing access to TB medications in children 20, including the development, manufacturer, licensure, procurement and uptake of paediatric drug formulations. Given no other choice due to the lack of child friendly formulations, adult formulations manipulated either by splitting, crushing, dissolving or suspending are frequently used in paediatric TB care, especially for MDR‐TB 10. However, the impact of such manipulation on drug exposures or formulation acceptability is often unknown. Data from our study address these questions for bedaquiline and will facilitate the use of bedaquiline in children with the already widely available adult 100 mg tablets, once paediatric dosing and safety is established, and until the paediatric formulation becomes widely available in the field. It is reassuring that the vast majority of adults found the suspended tablets to be palatable and acceptable, a critical consideration for children's medication and adherence to long‐term treatment. Although children may have different perceptions of palatability and acceptability, the data suggest that poor palatability or acceptability are unlikely to be major barriers to use of suspended bedaquiline tablets in children.\n\nThe design of this study was supported by clinical trials simulations to ensure adequate statistical power. The data were analysed with a model‐based approach to handle the extremely long terminal half‐life of bedaquiline and M2 and expected carry‐over between the sampling occasions, avoiding the risk of bias associated with noncompartmental analysis in such cases 21. However, the final model has some limitations. Individual bedaquiline profiles showed a tendency towards having dual peaks. This is not accounted for in the structure of the final model, but simply handled by the larger residual error estimated for the absorption phase (first 6 h after dose). An expanded structural model including enterohepatic circulation linked to meal times was evaluated, but did not improve the model fit to the data. Furthermore, concentration observations below the limit of quantification were excluded in this analysis. For bedaquiline, the proportion of samples below limit of quantification was very low (<1%), hence the exclusion is not expected to impact our results. For M2, the proportion of samples below the limit of quantification was larger (15%) and 95% of occurred within the first 4 h after dose administration. This may have influenced the M2 parameter estimates. However, predictions from the final model at the time points of samples with below limit of quantification results were in 77 of 81 cases below two times the quantification limit, indicating a reasonable description also at low concentration levels.\n\nThis study demonstrating bioequivalence of 100 mg bedaquiline tablets suspended in water vs. swallowed whole will support the use of bedaquiline for MDR TB in children. Similar work would be beneficial for other novel TB medications in the future. While these data address an immediate gap in medication formulation availability for children, it should not result in delays or limit the development and availability of an affordable child‐friendly formulation of bedaquiline, preferably a palatable dispersible scored formulation. Equitable access to child‐friendly formulations of life‐saving medications must continue to be a priority for the TB community.\n\nCompeting Interests\nA.D., B.S., E.M.S., J.B., J.N., L.W., R.K., S.N., A.G.P. and V.R.J. have no competing interests to declare. A.C.H. chairs the IMPAACT P1108 study protocol (NCT02906007).\n\n\nThe authors thank the volunteers and staff that made the study possible and acknowledge Professor Mats O. Karlsson, Uppsala University, for valuable contribution in the process of designing this study. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Exchange and collaboration was facilitated by the Swedish Foundation for International Cooperation in Research and Higher Education, STINT, jointly with the South African National Research Foundation, NRF (grant number STINT: SA2015‐6259, NRF: 101575).\n\n\nSupporting information\n\nFigure S1 (a) Observed bedaquiline concentrations above the limit of quantification presented as average per nominal time‐point. The table below specifies the number of samples contributing to the average value per nominal time point. (b) Observed M2 concentrations above the limit of quantification presented as average per nominal time‐point. The table below specifies the number of samples contributing to the average value per nominal time point\n\n\nTable S1 Summary of secondary pharmacokinetic metrics after two single doses of 400 mg bedaquiline administered 14 days apart. The statistics are calculated from individual exposure estimates from the final model\n\n\nTable S2 Incidence of treatment emergent adverse events by system organ class, preferred term and maximum severity safety population\n\n\nTable S2 Incidence of potentially investigational medicinal product related treatment emergent adverse events by system organ class, preferred term and maximum severity\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nBorisov \nSE \n, \nDheda \nK \n, \nEnwerem \nM \n, \nLeyet \nRR \n, \nD'Ambrosio \nL \n, \nCentis \nR \n, et al\nBedaquiline (BQ)‐containing regimen at the programmatic level for MDR‐TB: preliminary results . Eur Respir J \n2017 ; 50 (Suppl. 61 ): OA4852.\n2 \n\nAndries \nK \n, \nVerhasselt \nP \n, \nGuillemont \nJ \n, \nGöhlmann \nHWH \n, \nNeefs \nJM \n, \nWinkler \nH \n, et al\nA Diarylquinoline drug active on the ATP synthase of mycobacterium tuberculosis . Science \n2005 ; 307 : 223 –227 .15591164 \n3 \n\nvan Heeswijk \nRPG \n, \nDannemann \nB \n, \nHoetelmans \nRMW \n. Bedaquiline: a review of human pharmacokinetics and drug–drug interactions . J Antimicrob Chemother \n2014 ; 69 : 2310 –2318 .24860154 \n4 \nFDA \n. Center for drug evaluation and research. Application number 204384Orig1s000 , Clinical Pharmacology and Biopharmaceutics review (s). Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/204384Orig1s000ClinPharmR.pdf (last accessed 24 July 2018).\n5 \n\nSvensson \nEM \n, \nAweeka \nF \n, \nPark \nJG \n, \nMarzan \nF \n, \nDooley \nKE \n, \nKarlsson \nMO \n. Model‐based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis . Antimicrob Agents Chemother \n2013 ; 57 : 2780 –2787 .23571542 \n6 \n\nSvensson \nEM \n, \nDooley \nKE \n, \nKarlsson \nMO \n. Impact of lopinavir–ritonavir or nevirapine on bedaquiline exposures and potential implications for patients with tuberculosis‐HIV coinfection . Antimicrob Agents Chemother \n2014 ; 58 : 6406 –6412 .25114140 \n7 \n\nSvensson \nEM \n, \nMurray \nS \n, \nKarlsson \nMO \n, \nDooley \nKE \n. Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti‐TB drug . J Antimicrob Chemother \n2015 ; 70 : 1106 –1114 .25535219 \n8 \nMedecins sans frontiers \n. TB briefing paper – an overview of MSF's programmatic use and clinical research with new TB treatment regimens , October 2016. Available at http://www.msf.org/sites/msf.org/files/tbbriefingpaper.pdf (last accessed 24 July 2018).\n9 \n\nCariem \nR \n, \nCox \nV \n, \nde Azevedo \nV \n, \nHughes \nJ \n, \nMohr \nE \n, \nDurán \nLT \n, et al\nThe experience of bedaquiline implementation at a decentralised clinic in South Africa . Public Health Action \n2016 ; 6 : 190 –192 .27695682 \n10 \n\nRichey \nRH \n, \nShah \nUU \n, \nPeak \nM \n, \nCraig \nJV \n, \nFord \nJL \n, \nBarker \nCE \n, et al\nManipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence . BMC Pediatr \n2013 ; 13 : 81 .23688279 \n11 \nFDA \n. Guidance for industry: bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA , December 2013 Available at https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm377465.pdf (last accessed 24 July 2018).\n12 \n\nPandie \nM \n, \nWiesner \nL \n, \nMcIlleron \nH \n, \nHughes \nJ \n, \nSiwendu \nS \n, \nConradie \nF \n, et al\nDrug–drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV‐infected patients with drug‐resistant TB . J Antimicrob Chemother \n2016 ; 71 : 1037 –1040 .26747099 \n13 \nR Core Team \n. R: A Language and Environment for Statistical Computing . Vienna, Austria: 2014. Available at: http://www.r-project.org (last accessed 24 July 2018).\n14 \n\nBeal \nS \n, \nSheiner \nLB \n, \nBoeckmann \nA \n, \nBauer \nRJ \n. NONMEM User's guides . (1989‐2013), Icon Development Solutions. Ellicott City, MD, USA; 2013 .\n15 \n\nKeizer \nRJ \n, \nKarlsson \nMO \n, \nHooker \nA \n. Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose . CPT Pharmacomet Syst Pharmacol \n2013 ; 2 : e50.\n16 \n\nSvensson \nEM \n, \nDosne \nAG \n, \nKarlsson \nMO \n. Population pharmacokinetics of bedaquiline and metabolite M2 in drug‐resistant tuberculosis patients – the effect of time‐varying weight and albumin . CPT Pharmacomet Syst Pharmacol \n2016 ; 5 : 682 –691 .\n17 \n\nSvensson \nEM \n, \nKarlsson \nMO \n. Modelling of mycobacterial load reveals bedaquiline's exposure–response relationship in patients with drug‐resistant TB . J Antimicrob Chemother \n2017 ; 72 : 3398 –3405 .28961790 \n18 \n\nDooley \nKE \n, \nPark \nJG \n, \nSwindells \nS \n, \nAllen \nR \n, \nHaas \nDW \n, \nCramer \nY \n, et al\nSafety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group study A5267 . J Acquir Immune Defic Syndr 1999 \n2012 ; 59 : 455 –462 .\n19 \n\nWinter \nH \n, \nEgizi \nE \n, \nMurray \nS \n, \nErondu \nN \n, \nGinsberg \nA \n, \nRouse \nDJ \n, et al\nEvaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampicin and a single dose of bedaquiline in healthy adult subjects . Antimicrob Agents Chemother \n2014 ; 59 : 1219 –1224 .25512422 \n20 \n\nSchaaf \nHS \n, \nGarcia‐Prats \nAJ \n, \nMcKenna \nL \n, \nSeddon \nJA \n. Challenges of using new and repurposed drugs for the treatment of multidrug‐resistant tuberculosis in children . Expert Rev Clin Pharmacol \n2017 ; 11 : 1 –12 .29224406 \n21 \n\nSvensson \nEM \n, \nAcharya \nC \n, \nClauson \nB \n, \nDooley \nKE \n, \nKarlsson \nMO \n. Pharmacokinetic interactions for drugs with a long half‐life—evidence for the need of model‐based analysis . AAPS J \n2015 ; 18 : 171 –179 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0306-5251",
"issue": null,
"journal": "British journal of clinical pharmacology",
"keywords": "bedaquiline; bioavailability; paediatric dosing; population PK; suspended tablets",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "7503323",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29952141",
"pubdate": "2018-06-27",
"publication_types": "D016428:Journal Article",
"references": "26747099;27863179;23571542;15591164;24860154;25114140;28961790;29952141;22126739;29280409;23688279;27695682;23836189;25535219;25512422;26463060",
"title": "Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.",
"title_normalized": "relative bioavailability of bedaquiline tablets suspended in water implications for dosing in children"
} | [
{
"companynumb": "SE-JNJFOC-20181034411",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEDAQUILINE FUMARATE"
},
"drugadditional": "3",
... |
{
"abstract": "Intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing papillary neoplasms of the pancreatic or biliary ductal system that exhibit variable cellular atypia and cause ductal dilation. There are few reported cases of IPMN arising from the biliary tree in the literature. It has a higher propensity to undergo malignant transformation compared to IPMN arising from the pancreatic duct. An 80-year-old male underwent cross-sectional tomography (CT) imaging of the abdomen for evaluation of prostate adenocarcinoma, which revealed an incidental 2.3 × 2.7 cm soft tissue mass centered at the porta hepatis with diffuse dilatation of the left intrahepatic biliary ductal system and mild prominence of the right intrahepatic ductal system. Endoscopic ultrasound showed 2 adjacent hilar masses involving the common hepatic duct and the left hepatic duct with protrusion of the tissue into the lumen of the duct and upstream ductal dilatation. Endoscopic retrograde cholangiopancreatography revealed a large filling defect in the common hepatic duct extending into the left hepatic duct. A large amount of clot and soft tissue with a fish-egg appearance was retrieved. The patient underwent left hepatic lobectomy, radical resection of the common hepatic duct with Roux-en-Y hepaticojejunostomy to the right hepatic duct. Histopathological examination of the resected specimen revealed intraductal papillary mucinous neoplasm with diffuse high-grade dysplasia. Follow-up CT scan of the abdomen 2 months after the surgery was negative for any masses.",
"affiliations": "Henry Ford Health System, Detroit, MI, USA.;Henry Ford Health System, Detroit, MI, USA.;Henry Ford Health System, Detroit, MI, USA.;Henry Ford Health System, Detroit, MI, USA.",
"authors": "Parekh|Ravish|R|;Krol|Gregory|G|;Piraka|Cyrus|C|;Batra|Surinder|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000450539",
"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000450539crg-0010-0743Single CaseA Rare Case of Intraductal Papillary Mucinous Neoplasm of the Biliary Duct in a Patient with Prostate Adenocarcinoma Parekh Ravish *Krol Gregory Piraka Cyrus Batra Surinder Henry Ford Health System, Detroit, MI, USA*Ravish Parekh, MD, Henry Ford Health System, 2799 West Grand Blvd. K-7, Detroit, MI 48202 (USA), E-Mail rparekh1@hfhs.orgSep-Dec 2016 13 12 2016 13 12 2016 10 3 743 748 1 7 2016 31 8 2016 Copyright © 2016 the Author(s)2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing papillary neoplasms of the pancreatic or biliary ductal system that exhibit variable cellular atypia and cause ductal dilation. There are few reported cases of IPMN arising from the biliary tree in the literature. It has a higher propensity to undergo malignant transformation compared to IPMN arising from the pancreatic duct. An 80-year-old male underwent cross-sectional tomography (CT) imaging of the abdomen for evaluation of prostate adenocarcinoma, which revealed an incidental 2.3 × 2.7 cm soft tissue mass centered at the porta hepatis with diffuse dilatation of the left intrahepatic biliary ductal system and mild prominence of the right intrahepatic ductal system. Endoscopic ultrasound showed 2 adjacent hilar masses involving the common hepatic duct and the left hepatic duct with protrusion of the tissue into the lumen of the duct and upstream ductal dilatation. Endoscopic retrograde cholangiopancreatography revealed a large filling defect in the common hepatic duct extending into the left hepatic duct. A large amount of clot and soft tissue with a fish-egg appearance was retrieved. The patient underwent left hepatic lobectomy, radical resection of the common hepatic duct with Roux-en-Y hepaticojejunostomy to the right hepatic duct. Histopathological examination of the resected specimen revealed intraductal papillary mucinous neoplasm with diffuse high-grade dysplasia. Follow-up CT scan of the abdomen 2 months after the surgery was negative for any masses.\n\nKeywords\nIntraductal papillary mucinous neoplasmBile ductMucinous neoplasm\n==== Body\nBackground\nIntraductal papillary mucinous neoplasms (IPMNs) are mucin-producing papillary neoplasms of the pancreatic or biliary ductal system that exhibit variable cellular atypia and cause ductal dilation. IPMN develops from epithelial cells and has malignant potential. It usually arises from the pancreatic duct [1]. IPMNs have been classified as main duct (MD) type or branch duct (BD) type based upon the anatomic involvement of the pancreatic duct. Patients with involvement of both the main and branch ducts are referred to as having mixed-type IPMN. The MD-IPMNs are histologically more aggressive than BD-IPMNs and more likely to harbor a malignancy [2]. The male-to-female ratio for MD-IPMN has varied in reports from 1.1 to 3: 1, and for BD-IPMN it has varied from 0.7 to 1.8: 1 [3]. The risk factors of IPMN include cigarette smoking [4], diabetes, family history of pancreatic adenocarcinoma [5], Peutz-Jeghers syndrome [6], familial adenomatous polyposis syndrome [7], or familial pancreatic carcinoma [8].\n\nThere are few reported cases of IPMN arising from the biliary tree in literature. It has a higher propensity to undergo malignant transformation compared to IPMN arising from the pancreatic duct [9, 10]. Surgery is the treatment of choice due to the higher propensity of malignancy [11]. Our patient was found to have an incidental biliary tract IPMN with high-grade dysplasia during the staging of newly diagnosed prostate adenocarcinoma.\n\nCase Presentation\nAn 80-year-old male was evaluated for an elevated prostate-specific antigen level, and a biopsy of the prostate gland revealed adenocarcinoma with a Gleason score 9. The patient accomplished cross-sectional tomography (CT) imaging of the abdomen, which revealed an incidental 2.3 × 2.7 cm soft tissue mass centered at the porta hepatis with diffuse dilatation of the left intrahepatic biliary ductal system and mild prominence of the right intrahepatic ductal system (Fig 1).\n\nOn physical examination, the head, eyes, ears, nose, and throat were normal. There was no jaundice. The abdomen was soft, nontender, and nondistended, no masses or free fluid were found, and bowel sounds were normal. Laboratory evaluation revealed normal liver enzymes, lipase, and amylase. Carbohydrate antigen (19–9) was 35.2 units/mL (normal value <35 units/mL). The patient accomplished endoscopic ultrasound and endoscopic retrograde cholangiopancreatography. Endoscopic ultrasound showed 2 adjacent hilar masses involving the common hepatic duct and left hepatic duct with protrusion of the tissue into the lumen of the duct and upstream ductal dilatation with parenchymal atrophy (Fig 2). Endoscopic retrograde cholangiopancreatography revealed a large filling defect in the common hepatic duct extending into the left hepatic duct. A large amount of clot and soft tissue with a fish-egg appearance was retrieved (Fig 3). Two pigtail biliary stents were placed into the left hepatic duct upstream from the soft tissue mass. The biopsy of the soft tissue mass revealed IPMN of the bile duct with diffuse high-grade dysplasia and intramucosal carcinoma.\n\nThe patient underwent left hepatic lobectomy, radical resection of the common hepatic duct with Roux-en-Y hepaticojejunostomy to the right hepatic duct. Histopathological examination of the resected specimen revealed IPMN with diffuse high-grade dysplasia (Fig 4). The surgical margins and lymph nodes were negative for carcinoma.\n\nThe postoperative course was complicated by intraabdominal abscesses and pneumonia, requiring intravenous antibiotics and CT-guided drainage. The patient was readmitted 2 weeks after discharge with worsening hypoxia and lung infiltrates. He was found to have eosinophilic pneumonitis secondary to the antibiotics daptomycin and meropenem that resolved with discontinuation of the medications.\n\nA follow-up CT scan of the abdomen 2 months after the surgery was negative for any masses. The patient feels well and remains asymptomatic 12 months after the surgery.\n\nDiscussion\nIntraductal papillary mucinous neoplasms (IPMNs) are intraductal, mucin-producing tumors arising from epithelial cells and have malignant potential. IPMN usually arises from the pancreatic duct. In the literature, there are few reported cases of IPMN arising from the biliary tree [9, 11, 12, 13, 14].\n\nIPMN of the bile duct is usually associated with higher levels of carbohydrate antigen 19–9 and carcinoembryonic antigen. It has a higher propensity to undergo malignant transformation compared to IPMN arising from the pancreatic duct [10, 11].\n\nIt produces large amounts of mucin, leading to mass effect and disturbances in the bile flow. It is associated with bile duct dilatation and rarely exhibits invasion of surrounding margins. The most common form of presentation is a benign neoplasm. In rare cases, bile duct dilatation is the only finding. It can lead to cyst formation or papillary proliferation and may have varying degrees of cellular atypia. The malignant potential rises with increasing size (>3 cm) [14, 15]. Multiple genetic mutations have been described [16].\n\nMost IPMNs of the biliary tree are benign and noninvasive; however, due to increasing size and malignant potential, surgical resection is the treatment of choice. The surgical treatment is based on the location of the IPMN. Various surgical treatments include resection of a liver lobe, hepaticojejunostomy, pancreaticoduodenectomy, and bile duct resection [10, 15]. The patients with benign neoplasms have a good long-term prognosis and survival.\n\nThere is no known association between prostate cancer and biliary duct IPMN in the literature. The diagnosis of IPMN in our patient was incidental and did not seem to be related to the patient's underlying prostate adenocarcinoma.\n\nConclusion\nBiliary tract IPMNs are rare but can potentially lead to malignant tumors. Surgery is the treatment of choice. Our patient's IPMN was 2.7 cm with high-grade dysplasia, which was successfully treated with surgical resection.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nFig. 1 Cross-sectional imaging showing the 23.7 × 27.6 mm mass at the porta hepatis.\n\nFig. 2 Endoscopic ultrasound showing the hilar mass with protrusion into the Iumen of the duct.\n\nFig. 3 Endoscopic retrograde cholangiopancreatography with removal of the soft tissue mass.\n\nFig. 4 Intraductal papillary neoplasm of the bile duct. Hematoxylin and eosin stain. Magnification ×200.\n==== Refs\nReferences\n1 Adsay V Mino-Kenudson M Furukawa T Basturk O Zamboni G Marchegiani G Pathologic evaluation and reporting of intraductal papillary mucinous neoplasms of the pancreas and other tumoral intraepithelial neoplasms of pancreatobiliary tract: recommendations of Verona consensus meeting Ann Surg 2016 263 162 177 25775066 \n2 Serikawa M Sasaki T Fujimoto Y Kuwahara K Chayama K Management of intraductal papillary-mucinous neoplasm of the pancreas: treatment strategy based on morphologic classification J Clin Gastroenterol 2006 40 856 862 17016145 \n3 Ingkakul T Warshaw AL Fernandez-Del Castillo C Epidemiology of intraductal papillary mucinous neoplasms of the pancreas: sex differences between 3 geographic regions Pancreas 2011 40 779 780 21673537 \n4 Fukushima N Mukai K Pancreatic neoplasms with abundant mucus production: emphasis on intraductal papillary-mucinous tumors and mucinous cystic tumors Adv Anat Pathol 1999 6 65 77 10331069 \n5 Capurso G Boccia S Salvia R Del Chiaro M Frulloni L Arcidiacono PG Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study Am J Gastroenterol 2013 108 1003 1009 23458848 \n6 Sato N Rosty C Jansen M Fukushima N Ueki T Yeo CJ STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas Am J Pathol 2001 159 2017 2022 11733352 \n7 Maire F Hammel P Terris B Olschwang S O'Toole D Sauvanet A Intraductal papillary and mucinous pancreatic tumour: a new extracolonic tumour in familial adenomatous polyposis Gut 2002 51 446 449 12171972 \n8 Poley JW Kluijt I Gouma DJ Harinck F Wagner A Aalfs C The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer Am J Gastroenterol 2009 104 2175 2181 19491823 \n9 Subhash R Valiyaveettil IA Natesh B Raji L Biliary tract intraductal papillary mucinous neoplasm: a brief report and review of literature Indian J Pathol Microbiol 2014 57 588 590 25308012 \n10 Minagawa N Sato N Mori Y Tamura T Higure A Yamaguchi K A comparison between intraductal papillary neoplasms of the biliary tract (BT-IPMNs) and intraductal papillary mucinous neoplasms of the pancreas (P-IPMNs) reveals distinct clinical manifestations and outcomes Eur J Surg Oncol 2013 39 554 558 23506840 \n11 Barton JG Barrett DA Maricevich MA Schnelldorfer T Wood CM Smyrk TC Intraductal papillary mucinous neoplasm of the biliary tract: a real disease? HPB (Oxford) 2009 11 684 691 20495637 \n12 Mo A Brat G Spolverato G Pawlik TM Intraductal papillary mucinous neoplasm of the liver: GI image J Gastrointest Surg 2015 19 792 794 25617079 \n13 Wang X Cai YQ Chen YH Liu XB Biliary tract intraductal papillary mucinous neoplasm: report of 19 cases World J Gastroenterol 2015 21 4261 4267 25892877 \n14 Rocha FG Lee H Katabi N DeMatteo RP Fong Y D'Angelica MI Intraductal papillary neoplasm of the bile duct: a biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas? Hepatology 2012 56 1352 1360 22504729 \n15 Jung G Park KM Lee SS Yu E Hong SM Kim J Long-term clinical outcome of the surgically resected intraductal papillary neoplasm of the bile duct J Hepatol 2012 57 787 793 22634127 \n16 Sclabas GM Barton JG Smyrk TC Barrett DA Khan S Kendrick ML Frequency of subtypes of biliary intraductal papillary mucinous neoplasm and their MUC1, MUC2, and DPC4 expression patterns differ from pancreatic intraductal papillary mucinous neoplasm J Am Coll Surg 2012 214 27 32 22112419\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "10(3)",
"journal": "Case reports in gastroenterology",
"keywords": "Bile duct; Intraductal papillary mucinous neoplasm; Mucinous neoplasm",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "743-748",
"pmc": null,
"pmid": "28100995",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "25617079;12171972;22504729;19491823;21673537;25308012;23458848;25892877;22634127;17016145;23506840;25775066;10331069;20495637;11733352;22112419",
"title": "A Rare Case of Intraductal Papillary Mucinous Neoplasm of the Biliary Duct in a Patient with Prostate Adenocarcinoma.",
"title_normalized": "a rare case of intraductal papillary mucinous neoplasm of the biliary duct in a patient with prostate adenocarcinoma"
} | [
{
"companynumb": "US-ACS-000817",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "1",
"drugadmin... |
{
"abstract": "BACKGROUND\nNo conventional surgical intervention has been shown to improve outcomes for patients with spontaneous intracerebral hemorrhage (ICH) compared with medical management.\n\n\nOBJECTIVE\nWe report the initial multicenter experience with a novel technique for the minimally invasive evacuation of ICH using the Penumbra Apollo system (Penumbra Inc, Alameda, California).\n\n\nMETHODS\nInstitutional databases were queried to perform a retrospective analysis of all patients who underwent ICH evacuation with the Apollo system from May 2014 to September 2014 at 4 centers (Medical University of South Carolina, Stony Brook University, University of California at San Diego, and Semmes-Murphy Clinic). Cases were performed either in the neurointerventional suite, operating room, or in a hybrid operating room/angiography suite.\n\n\nRESULTS\nTwenty-nine patients (15 female; mean age, 62 ± 12.6 years) underwent the minimally invasive evacuation of ICH. Six of these parenchymal hemorrhages had an additional intraventricular hemorrhage component. The mean volume of ICH was 45.4 ± 30.8 mL, which decreased to 21.8 ± 23.6 mL after evacuation (mean, 54.1 ± 39.1% reduction; P < .001). Two complications directly attributed to the evacuation attempt were encountered (6.9%). The mortality rate was 13.8% (n = 4).\n\n\nCONCLUSIONS\nMinimally invasive evacuation of ICH and intraventricular hemorrhage can be achieved with the Apollo system. Future work will be required to determine which subset of patients are most likely to benefit from this promising technology.",
"affiliations": "*Medical University of South Carolina, Department of Neurosciences, Division of Neurosurgery, Charleston, South Carolina; ‡Stony Brook University Medical Center, Department of Neurosurgery, Stony Brook, New York; §University of San Diego, Department of Neurosurgery, San Diego, California; ¶University of Tennessee, Department of Radiology, Memphis, Tennessee; ‖Medical University of South Carolina, Department of Radiology and Radiological Sciences, Charleston, South Carolina.",
"authors": "Spiotta|Alejandro M|AM|;Fiorella|David|D|;Vargas|Jan|J|;Khalessi|Alexander|A|;Hoit|Dan|D|;Arthur|Adam|A|;Lena|Jonathan|J|;Turk|Aquilla S|AS|;Chaudry|M Imran|MI|;Gutman|Frederick|F|;Davis|Raphael|R|;Chesler|David A|DA|;Turner|Raymond D|RD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1227/NEU.0000000000000698",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "11 Suppl 2()",
"journal": "Neurosurgery",
"keywords": null,
"medline_ta": "Neurosurgery",
"mesh_terms": "D000328:Adult; D000368:Aged; D002140:California; D002543:Cerebral Hemorrhage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "243-51; discussion 251",
"pmc": null,
"pmid": "25714520",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Initial multicenter technical experience with the Apollo device for minimally invasive intracerebral hematoma evacuation.",
"title_normalized": "initial multicenter technical experience with the apollo device for minimally invasive intracerebral hematoma evacuation"
} | [
{
"companynumb": "US-BAYER-2018-195295",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "To report clinical outcomes of temozolomide (TMZ)-based radio-chemotherapy and adjuvant chemotherapy in patients with aggressive/high-risk low-grade glioma (LGG).\n\n\n\nMedical records of patients defined as aggressive/high-risk LGG based on clinicoradiologic and/or histomorphologic features treated between 2009 and 2016 in an academic neuro-oncology unit with upfront postoperative radiotherapy at time of initial diagnosis with concurrent and adjuvant TMZ were reviewed, retrospectively.\n\n\n\nIn total, 64 patients with median age of 38 years at initial diagnosis were included. Histomorphologically, patients were classified into oligodendroglioma, mixed oligoastrocytoma, and astrocytoma. Molecular markers such as isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion were used to classify 37 of 64 (58%) patients into molecularly defined entities comprising oligodendroglioma (IDH-mutant with 1p/19q codeletion), IDH-mutant astrocytoma (immunohistochemistry or gene sequencing), and IDH-wild-type astrocytoma (gene sequencing). All 64 patients completed planned conventionally fractionated focal conformal radiotherapy (median dose 55.8 Gy) with concurrent TMZ. Fifty-nine patients received further adjuvant TMZ for a median of 12 cycles. Adjuvant TMZ was stopped prematurely in 6 (9%) patients due to toxicity or early disease progression. At a median follow-up of 56.7 months, 5-year Kaplan-Meier estimates of progression-free survival and overall survival for the study cohort were 74.6% and 84.3%, respectively. Five-year overall survival was 87.5%, 90.4%, and 71.9% for oligodendroglioma, mixed oligoastrocytoma, and astrocytoma, respectively (P = 0.42) Similar estimates for molecularly defined oligodendroglioma, IDH-mutant astrocytoma, and IDH-wild-type astrocytoma were 85.8%, 90%, and 66.7%, respectively (P = 0.87).\n\n\n\nUpfront TMZ-based concurrent radio-chemotherapy and adjuvant TMZ chemotherapy provides acceptable survival outcomes in aggressive/high-risk LGG with modest toxicity.",
"affiliations": "Department of Radiation Oncology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.;Department of Radiation Oncology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.;Department of Radiation Oncology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India. Electronic address: tejpalgupta@rediffmail.com.;Department of Clinical Research Secretariat, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.;Department of Neuro-surgical Oncology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.;Department of Pathology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.;Department of Medical Oncology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.;Department of Radiation Oncology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.;Department of Radiation Oncology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.;Department of Radiation Oncology, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India.",
"authors": "Anand|Sachith|S|;Chatterjee|Abhishek|A|;Gupta|Tejpal|T|;Panda|Pankaj|P|;Moiyadi|Aliasgar|A|;Epari|Sridhar|S|;Patil|Vijay|V|;Krishnatry|Rahul|R|;Goda|Jayant Sastri|JS|;Jalali|Rakesh|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2021.07.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "154()",
"journal": "World neurosurgery",
"keywords": "Adjuvant therapy; Diffuse glioma; Molecular markers; Risk-classification; Survival",
"medline_ta": "World Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "e176-e184",
"pmc": null,
"pmid": "34245877",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Upfront Therapy of Aggressive/High-Risk Low-Grade Glioma: Single-Institution Outcome Analysis of Temozolomide-Based Radio-Chemotherapy and Adjuvant Chemotherapy.",
"title_normalized": "upfront therapy of aggressive high risk low grade glioma single institution outcome analysis of temozolomide based radio chemotherapy and adjuvant chemotherapy"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-323765",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"dr... |
{
"abstract": "Kırık S, Güneş H, Yurttutan S, Sarışık N, Acıpayam C, Kırık Y. Hemophagocytic lymphohistiocytosis associated with oxcarbazepine. Turk J Pediatr 2019; 61: 297-300. Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening multisystem disorder. Reports of the disorder as a side effect of drugs are extremely rare. We report the case of a 3-year-old boy with a history of epileptic seizures in which oxcarbazepine was added to treatment for the last 35 days and dose had been increased. For 10 days he had a fever, hepatosplenomegaly, rash, edema and other systemic symptoms. He was diagnosed with HLH after bone marrow examination. Oxcarbazepine treatment was terminated after the intravenous immunoglobulin treatment. The next day, clinical and laboratory results had improved. This is the first HLH report of an association with oxcarbazepine. Bone marrow aspiration may be indicated to confirm the diagnosis when facing a patient with systemic symptoms after newly added antiepileptic drug treatment.",
"affiliations": "Departments of Pediatric Neurology, Kahramanmaras Sutcu Imam University, Faculty of Medicine, Kahramanmaras, Turkey.;Departments of Pediatrics, Kahramanmaras Sutcu Imam University, Faculty of Medicine, Kahramanmaras, Turkey.;Departments of Pediatrics, Kahramanmaras Sutcu Imam University, Faculty of Medicine, Kahramanmaras, Turkey.;Departments of Pediatrics, Kahramanmaras Sutcu Imam University, Faculty of Medicine, Kahramanmaras, Turkey.;Departments of Pediatrics, Kahramanmaras Sutcu Imam University, Faculty of Medicine, Kahramanmaras, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Necip Fazıl State Hospital, Kahramanmaras, Turkey.",
"authors": "Kırık|Serkan|S|;Güneş|Hatice|H|;Yurttutan|Sadık|S|;Sarışık|Nafiz|N|;Acıpayam|Can|C|;Kırık|Yasemin|Y|",
"chemical_list": "D000927:Anticonvulsants; D016756:Immunoglobulins, Intravenous; D000078330:Oxcarbazepine",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "61(2)",
"journal": "The Turkish journal of pediatrics",
"keywords": "epilepsy; hemophagocytic lymphohistiocytosis; oxcarbazepine",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000927:Anticonvulsants; D002675:Child, Preschool; D006801:Humans; D016756:Immunoglobulins, Intravenous; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D000078330:Oxcarbazepine; D012640:Seizures",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "297-300",
"pmc": null,
"pmid": "31951347",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Hemophagocytic lymphohistiocytosis associated with oxcarbazepine.",
"title_normalized": "hemophagocytic lymphohistiocytosis associated with oxcarbazepine"
} | [
{
"companynumb": "TR-AMNEAL PHARMACEUTICALS-2020-AMRX-01102",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
"drugadditi... |
{
"abstract": "We report a case of emergence delirium after a propofol-based sedation for a renal biopsy in a teenager patient who had received high-dose and long-term corticosteroid treatment. Corticosteroid treatment is proposed as a possible risk factor for emergence delirium, although controlled studies are needed to assess this relationship. Although treatment for emergence delirium has not been well established, as described with steroid-induced psychiatric symptoms, antipsychotics could be a good therapeutic option.",
"affiliations": "Department of Pediatrics, Hospital Vall d'Hebron, Barcelona, Spain.;Department of Pediatric Nephrology, Hospital Vall d'Hebron, Barcelona, Spain.;Department of Anesthesiology, Hospital Vall d'Hebron, Barcelona, Spain.;Department of Anesthesiology, Hospital Vall d'Hebron, Barcelona, Spain.;Department of Anesthesiology, Hospital Vall d'Hebron, Barcelona, Spain.",
"authors": "Esmel-Vilomara|Roger|R|0000-0003-4449-3217;Cruz|Alejandro|A|;Inoriza|Cristina|C|;Andreu|Eva|E|;Munar|Francisca|F|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0040-1709655",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2146-4626",
"issue": "9(4)",
"journal": "Journal of pediatric intensive care",
"keywords": "corticosteroid; emergence delirium; haloperidol",
"medline_ta": "J Pediatr Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "101592756",
"other_id": null,
"pages": "304-306",
"pmc": null,
"pmid": "33133750",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "15114210;22764363;22424158;29638141;25272344;30665281;28203739;27798810",
"title": "Emergence Delirium: Can Corticosteroids Contribute to It?",
"title_normalized": "emergence delirium can corticosteroids contribute to it"
} | [
{
"companynumb": "ES-PFIZER INC-2020472374",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe South African department of health recently introduced subdermal Implanon contraceptive implant with the aim to reduce teenage pregnancy and maternal mortality. First used in all public healthcare facilities across the country since early 2014, this method of contraception has been described as highly effective. However, some women have reported unbearable side effects, forcing them to remove the contraceptive implant early before its expiry date. Negligible emphasis has been placed on staff training and development to equip the nurses with new protocol and policies on Implanon.\n\n\nOBJECTIVE\nThe objective of this study was to explore experiences of women using Implanon as method of contraception at a selected primary healthcare facility in KwaZulu-Natal province of South Africa.\n\n\nMETHODS\nA qualitative, descriptive and exploratory study design was used. A purposive sampling technique was used and a sample of seven women aged between 15 and 50 years was selected for this study. Semi-structured interviews were used in the data collection process. The Tesch's method for data coding and data analysis was utilised. Necessary ethical measures were taken to ensure that the study is trustworthy. The study was conducted at Community Health Centre, KwaZulu-Natal between June 2017 and December 2018.\n\n\nRESULTS\nThe findings showed that some participants were still willing to continue using this method of contraception regardless of the unwanted side effects. Major side effects reported were heavy menstrual bleeding, pain and discomfort, weight loss, insomnia and decreased sexual interest, which resulted in most participants stopping the use of Implanon.\n\n\nCONCLUSIONS\nMost of the participants' experience unwanted side effects because of poor screening, counselling and support. There is a clear demand to develop a screening tool and facilitate training of healthcare workers when initiating the use of Implanon.",
"affiliations": "School of Nursing, Faculty of Health Sciences, Walter Sisulu University, Umthatha. lwandlenhlaka@gmail.com.",
"authors": "Mgobhozi|Lucky N|LN|;Mbeje|Pretty N|PN|;Mchunu|Gugu G|GG|",
"chemical_list": "D003271:Contraceptive Agents, Female; C044815:etonogestrel; D017135:Desogestrel",
"country": "South Africa",
"delete": false,
"doi": "10.4102/curationis.v44i1.2187",
"fulltext": "\n==== Front\nCurationis\nCurationis\nCUR\nCurationis\n0379-8577\n2223-6279\nAOSIS\n\nCUR-44-2187\n10.4102/curationis.v44i1.2187\nOriginal Research\nWomen’s experiences on the use of Implanon as a contraceptive method in a selected primary healthcare facility in KwaZulu-Natal\nhttps://orcid.org/0000-0002-3389-0420\nMgobhozi Lucky N. 1\nhttps://orcid.org/0000-0002-2704-8763\nMbeje Pretty N. 2\nhttps://orcid.org/0000-0001-8021-4129\nMchunu Gugu G. 3\n1 School of Nursing, Faculty of Health Sciences, Walter Sisulu University, Umthatha, South Africa\n2 School of Nursing and Public Health, Faculty of Health Sciences, University of KwaZulu-Natal, Durban, South Africa\n3 Faculty of Health Sciences, Durban University of Technology, Durban, South Africa\nCorresponding author: Lucky Mgobhozi, lwandlenhlaka@gmail.com\n08 11 2021\n2021\n44 1 218708 9 2020\n08 8 2021\n© 2021. The Authors\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee: AOSIS. This work is licensed under the Creative Commons Attribution License.\nBackground\n\nThe South African department of health recently introduced subdermal Implanon contraceptive implant with the aim to reduce teenage pregnancy and maternal mortality. First used in all public healthcare facilities across the country since early 2014, this method of contraception has been described as highly effective. However, some women have reported unbearable side effects, forcing them to remove the contraceptive implant early before its expiry date. Negligible emphasis has been placed on staff training and development to equip the nurses with new protocol and policies on Implanon.\n\nObjectives\n\nThe objective of this study was to explore experiences of women using Implanon as method of contraception at a selected primary healthcare facility in KwaZulu-Natal province of South Africa.\n\nMethods\n\nA qualitative, descriptive and exploratory study design was used. A purposive sampling technique was used and a sample of seven women aged between 15 and 50 years was selected for this study. Semi-structured interviews were used in the data collection process. The Tesch’s method for data coding and data analysis was utilised. Necessary ethical measures were taken to ensure that the study is trustworthy. The study was conducted at Community Health Centre, KwaZulu-Natal between June 2017 and December 2018.\n\nResults\n\nThe findings showed that some participants were still willing to continue using this method of contraception regardless of the unwanted side effects. Major side effects reported were heavy menstrual bleeding, pain and discomfort, weight loss, insomnia and decreased sexual interest, which resulted in most participants stopping the use of Implanon.\n\nConclusion\n\nMost of the participants’ experience unwanted side effects because of poor screening, counselling and support. There is a clear demand to develop a screening tool and facilitate training of healthcare workers when initiating the use of Implanon.\n\nImplanon\nImplanon users\nexperiences\nperceptions\nprimary healthcare\n==== Body\npmcBackground of the study\n\nEvery day, about 800 women die because of pregnancy and childbirth-related complications, with almost 99% of these cases occurring in developing countries (Alemayehu et al. 2015; Haddou 2014; WHO 2014). An estimated 200 million women in developing countries use contraceptive methods, but there are still barriers to access such services. Some of these barriers are transport challenges for most women who live in remote areas (UNFPA 2015). Kartz (2015) argued that in some instances, supply chains cut off remote rural areas where the poorest segment of low-income population resides. The prohibitive cost of contraceptives in many developing countries is a prominent contraceptive access barrier to women (Kartz 2015). The above-mentioned barriers mainly affect women who come from disadvantaged communities (Abiodum & Balogum 2009; Imo, Isiugo-Abanihe & Onabanjo 2013).\n\nIt has been argued that a large number of maternal deaths could be averted by following family planning, particularly long acting contraceptive methods. The efficacy of these methods lie in their ability to reduce visits to healthcare facilities. They are also highly effective and cheap. Implanon is one of the many such contraceptives that have been introduced. The contraceptive has been available since 2014 (South Africa; South African Department of Health 2015). The total uptake of Implanon estimated by the Department of Health for 2018 was 433 000 women, but the total demand was as high as 567 000 (Chola et al. 2019). However, such statistics indicate that women are in great need of long-lasting contraceptive method. Despite this high percentage of users, an increasing number of women have recently reported unwanted side effects in the past subsequent years it was introduced and decrease of almost 50% of insertion numbers after a year (Pleaner et al. 2017).\n\nImplanon is a birth control contraceptive implant – small flexible plastic rod, the size of a matchstick – inserted subdermally under the skin of the upper arm that releases small amounts of progestogen into the body for a period of three years (Patel 2014). It inhibits ovulation in the ovaries, thus causing changes to the cervical mucus so that spermatozoa does not reach the uterine cavity. Implanon consists of a single ethylene vinyl acetate copolymer rod that is 2 mm in diameter and 4 cm long (Gbolade 2010; Patel 2014; Spies et al. 2010).\n\nPatni et al. (2006) argued that Implanon’s failure result from potent-enzyme inducers known to have deleterious effects leading to intrauterine or ectopic pregnancy. However, two of these pregnancies were directly related to a concomitant use of rifampicin. Recent studies show that other drugs that have contributed to the failure of Implanon include: anti-epileptic drugs (phenytoin, phenobarbital, primidone), antibiotics (rifampicin, rifabutin), antifungal drugs (griseofulvin), protease inhibitors (lopinavir, atazanavir, amprenavir) and non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine). A research case report on the failure of Implanon on anti-tuberculous therapy by Gbolade (2010) established that drug interaction with hormonal contraceptives are challenging when steroid metabolism is stimulated. However, in the liver enzyme system cytochrome P450 plays a significant role in drug metabolism, and drugs that induce these enzymes cause increased elimination of contraceptive steroids, which adversely lead to reduced reliability and unplanned pregnancy. There are several factors that counteract effectiveness of Implanon in the body such as certain drugs used to treat epilepsy, tuberculosis and antiretroviral drugs, as also poor screening and lifestyle factors (alcohol consumption and sport).\n\nMukuka (2015) argued that some women in South Africa have experienced side effects of the Implanon device and are not convinced of this new contraceptive implant in terms of effectiveness. However, clinical evidence indicates that it is common for women to experience side effects for the first three months after insertion of this implant (Patel 2014). But there are still high numbers of women who experience side effects because of Implanon, forcing them to remove the implant before its expiry (Patel 2014; Sikosana 2015; UNFPA 2015). Another investigation by Sikosana (2015) revealed that some clinics have stopped providing Implanon contraceptive implant because there were many issues raised regarding its use, and some issues are still unclear between the healthcare providers and clients. Another challenge is that there has been little emphasis placed on staff training and development to equip the nurses with new protocol and policies on Implanon. The above-mentioned argument clearly supports the need for this study to be conducted because this is a fairly new contraceptive method and there seems to be gaps in the service provision.\n\nPatel (2014) conducted a study on contraceptives and personal responsibility in South Africa. It was revealed that the main issue with the Implanon implant is the change in bleeding patterns and this adverse effect is responsible for women discontinuing its use, especially if they were not adequately counselled. Whilst no pregnancies were reported in the study population, pregnancies reported were related to insertion issues. Implanon was found to be safe for use in obese and hypertensive women. Similarly, in a study conducted on experiences with Implanon in Southern Nigeria (Ojule, Oranu & Enyindah 2012) it was found that women who are currently on Implanon experienced unwanted side effects, such as vaginal spotting 60%, menorrhagia 13.3% and inter-menstrual bleeding 13.3%. Amongst the participants 51.8% of the clients changed from other contraceptive methods to Implanon. Other participants discontinued Implanon during the study period, whereas the continuation rate was 94.6% (participants who accepted Implanon). This also indicates client satisfaction, acceptance and continuation with Implanon.\n\nAim and objectives\n\nThis article aimed to explore describes the experiences and perceptions of women using Implanon at a selected primary healthcare facility in KwaZulu-Natal, South Africa.\n\nMethod\n\nA triangulation of convergence model was used where the researchers collected and analysed quantitative and qualitative data separately. The scope of this article is on the qualitative aspect of the study, which explored the experiences of the users.\n\nThe exploratory descriptive design using qualitative approach was employed to analyse qualitative data collection. This method was used to obtain experiences of women using Implanon contraceptive method.\n\nStudy participants and setting\n\nThe target population were all clients at the clinic who had inserted Implanon in the past 6 weeks, have been visiting the clinic for follow up, and individuals who had removed Implanon as a result of other problems.\n\nParticipants were sampled purposively based on their first-hand experience with Implanon use. Selected participants were clients who were being served by the clinic at the time of data collection. The sample size was determined by the saturation of the data, and data saturation was reached in the 12th day of data collection. Four participants were pretested but the results were not used in the main study; seven participants participated in this study.\n\nThe setting for the study was a community healthcare facility located in uMgungundlovu district of KwaZulu-Natal. Most of the clients who are seen at this community healthcare centre belong to the middle-income class and the majority is well educated (South African Department of Health 2014). However, this community healthcare centre was chosen because it has higher uptake of Implanon contraceptive and is located centrally in town. The clients who use these community healthcare centres generally come for minor and alignment consultation, integrated management of childhood illness, family planning, chronic illness, as well as other primary healthcare services. The data collection was performed in the family planning department focusing on Implanon users, who were coming for follow up consultation, and any other clients readily available at the clinic meeting the recruitment criteria.\n\nData collection\n\nThe data collection process took place after obtaining ethical approval and permission from the relevant authorities to conduct the study. On obtaining the ethical clearance, the researcher approached the management of the selected clinic situated at uMgungundlovu District to arrange for data collection process commencement. Data collection took place at a selected community healthcare centre in a Family Planning department. The data collection venue where interviews were conducted was also identified and suitable interview dates were confirmed. Data collection process was conducted over a period of 12 days until the data saturation was reached. Sample size was not pre-determined.\n\nThe researcher explained the purpose and the process of the data collection to the staff allocated at the family planning clinic on the day of the data collection. The researcher waited upon each client coming in for family planning services in the waiting area; specifically, those coming for consultation or review were asked to participate in this study. Then those women with Implanon were asked to follow the researcher into a consultation room, where data collection procedure took place. In the consultation room, everyone was provided with a chair and a table to sit at. Thereafter, all the women who met the recruitment criteria were briefed on the study and asked if they were willing to participate. Those who were willing were then asked to sign consent forms before they participated in the study.\n\nAn interview guide was used to obtain information from the willing participants for approximately 15–20 min. The interview guide contained semi-structured questions, with the researcher probing where necessary to obtain more clarity and in-depth information (Brink, Van der Walt & Van der Rensburg 2012). The main interview question for this study was ‘What is your experience with the use of Implanon contraceptive?’. Other questions were just probes seeking clarity from the participants. The pilot study of the interview guide was performed by researcher with four participants at the clinic before data collection. This was carried out to determine whether questions and directions were clear to the participants. There was no relationship between the researcher and the participants. Therefore, selection of participants was fair and free of offence or threats.\n\nPilot study\n\nIn this study, a pilot study was carried out with four participants prior to data collection. The results of the pilot study were not included in the main study. The pilot study showed the suitability of the instrument positively with no difficulties imposed on the participants. Participants were clear with the questions and probing or questions seeking clarity were asked.\n\nTrustworthiness\n\nTrustworthiness was ensured by following a certain criterion: credibility, transferability, dependability and confirmability (Brink et al. 2012; Polit & Beck 2008).\n\nCredibility\n\nTo ensure credibility, the researcher made notes and recorded interviews using audiotapes to make sure that information was thorough and correct. Interviewer was making notes during each interview and used audiotape to record the interviews after obtaining consent from the participants. Participants confirmed the information after transcription. This was done to ensure that the themes generated from the information obtained accurately represented the views of the participants.\n\nTransferability\n\nThe researcher ensured the trustworthiness of the findings by sharing the findings with all healthcare practitioners who did not participate in the study for constructive criticism.\n\nDependability\n\nData collection was performed on participants who had used Implanon for more than 6 weeks. All participants were able to share their experiences because they understood Implanon contraceptive. An audit trail was maintained by ensuring that raw information that was collected from each participant was kept safe for future reference.\n\nConfirmability\n\nConfirmability was based on the characteristics of data being dependable. Raw data were confirmed by the use of direct quotes from the raw data to eliminate subjectivity. Co-coder was utilised in the analysis.\n\nData analysis\n\nTesch’s method of eight steps in data analysis was adopted. In developing themes, the researcher was guided by the theoretical framework and research objectives. The following were investigated in order to answer the research questions:\n\nExperiences of women using Implanon\n\nPerceived barriers to the use of Implanon\n\nPerceived enablers to the use of Implanon\n\nThe following covers the theoretical framework guiding the study:\n\nCues of action\n\nEfficacy\n\nThe following section details the process of how data analysis was undertaken in this study.\n\nData were analysed according to Tesch’s eight steps of data analysis whereby the researcher carefully read through all the transcriptions, making notes of ideas that came to mind. The researcher selected one interview and read it to try to extract meaning from the information, writing down thoughts that would come to mind. Similar topics were arranged in groups, forming columns labelled: major topics, unique topics, and leftovers, respectively. The researcher found the most descriptive wording for the topics and converted them into categories.\n\nThere are five different stages, namely (1) familiarisation with the material, (2) formulation of emergent themes, (3) coding of different themes, (4) charting, cutting, pasting and rearrangement of data under different themes and (5) interpretation and explanation of findings.\n\nResults\n\nExperiences were either positive (enablers) or negative (barriers). The participant’s responses were categorised and sub-categorised into themes which are detailed as follows.\n\nParticipants’ demographics\n\nIn this study, four participants were used for pilot study and seven participants were interviewed for the actual study. The age range was between 15 and 50 years. There were three married participants whilst the rest were not married. Four of the participants were unemployed whilst the other three were employed. Five of the participants were Christian, one was Muslim and one belonged to the Zulu traditional religion. All the participants were women using Implanon contraceptive for family planning.\n\nPerceived enabling experiences\n\nMost participants were satisfied with using Implanon, others even complemented the positive staff attitude and assistance by nurses. Of note was that these participants reported unwanted side effects but nevertheless, they were happy with the method as they showed positivity (all citations hereafter are verbatim):\n\n‘I only came to the clinic because of side effects. Besides that, I was happy with having the implants on my body.’ (34 years, single, female)\n\n‘I had a very good experience with Implanon except during [the] menstrual period. I still want to use it even now.’ (46 years, married, female)\n\n‘I can advise others to use the implant. It worked very well and I had a good experience with it.’ (17 years, single, female)\n\nPositive staff attitude\n\nDespite the side effects, positive staff attitude surpassed it all. Participants were extremely pleased with nurse’s attitude and assistance when they visited the healthcare clinics for help:\n\n‘Nurses were very helpful to me, they explained everything before Implanon was inserted, and when I returned, they were willing to help. I am happy.’ (22 years, single, female)\n\n‘Staff attitude I saw in everyone today left me satisfied with Implanon.’ (29 years, married, female)\n\nExperiences perceived as barriers\n\nSome participants were reluctant to use this method of contraception because of the side effects. Some felt that Implanon worked well with other people whilst they were the only ones experiencing severe side effects. As such, the method was viewed as working differently on different people. These participants shared their negative experiences in relation to menstrual bleeding/periods:\n\n‘I was on menstrual periods continuously because of this new injection on my arm … and my weight dropped significantly since then.’ (50 years, married, female)\n\n‘In a day I changed maybe four to five sanitary pads when I had heavy menstrual bleeding …’ (25 years, single, female)\n\nIneffective treatment of symptoms\n\nParticipants indicated that they were forced to return to the clinic with the same problem of intermittent menstrual bleeding but there was no effective treatment as it usually stopped for a while after taking treatment from the clinic:\n\n‘I had continuous menstrual bleeding for the past 4 months, then last month it stopped after taking tablets from the clinic but it started again.’ (50 years, married, female)\n\n‘I was up and down to the clinic but they couldn’t help me … I was given contraceptive pills, they told me to drink yellow pills not red ones which I had to take once or twice a day.’ (25 years, Single, female)\n\n‘At another clinic they said discharge has nothing to do with the implant. But where I inserted the implant they said it’s common to have a discharge or headache.’ (34 years, single, female)\n\nUnexplained weight loss\n\nSome participants were very concerned about the unplanned weight loss after starting this method of contraception. This was viewed as a reason to remove the device:\n\n‘… when I came to the clinic another male nurse checked my weight and he observed that it had dropped too much and he advised me to have it removed at the hospital …’ (46 years, married, female)\n\n‘It was very painful and sad to be bleeding and losing weight every time, yet when you seek help you don’t get it …’ (22 years, single, female)\n\nDiscomfort and pains\n\nSome participants reported that they experienced headaches and body pains, which they believed were because of the use of the implant i:\n\n‘… I had headache, loss of weight, pains on my shoulders after having continuous menstrual bleeding for about a month.’ (34 years, single, female)\n\n‘I have been experiencing dizziness, loss of appetite, lower abdominal pain, acne, headache and sweating. Lastly, continuous menstrual periods. But they only gave me tablets for heavy bleeding and headache.’ (17 years, single, female)\n\nNeurological symptoms\n\nWhilst these symptoms were not directly linked to the method of contraception, participants believed these symptoms were effects of Implanon because it was confirmed by other users:\n\nMemory loss\n\nSome participants complained about memory loss and stated that:\n\n‘… this injection can make you forget things easily, you just become insane, for I was forgetting where I kept my money most of the time.’ (29 years, married, female)\n\n‘… I wasn’t aware until another girl from my church told me that she was forgetting the names of her colleagues at work. I have heard many reporting the same problem that the injection causes you to forget things whilst it is inside you.’ (25 years single, female)\n\nInsomnia\n\nSome participants complained that they could not sleep at night. This happened when they were experiencing other side effects and it happened without any clear reference as a cause:\n\n‘… at night I couldn’t sleep at all.’ (46 years, married, female)\n\n‘I also had loss of weight, memory loss; sweating and I couldn’t sleep well.’ (29 years, married, female)\n\nEffects on sex life\n\nParticipants also reported that they wanted no sexual contact whilst others reported lack of sexual desire with their partners after they have had the implant inserted on them. In most cases, they wanted no sexual intimacy:\n\n‘… I had no desire for sex at all ever since …’ (34 years, single, female)\n\n‘Most of the times I had no desire to have sex; it also started when I was using the implant.’ (17 years, single, female)\n\nMismanagement of side effects\n\nFor some participants the experience of visiting more than one health facility because of their side effects was more discouraging as they would get the same treatment over and over again without any relief of symptoms:\n\n‘I decided to visit the clinic regarding this menstrual period problem, and I was told it will go away after time. It’s just a side effect.’ (34 years, single, female)\n\n‘When I had this problem, I went to the other clinic where they told me they couldn’t take it out. They said I should go to Eastern Cape where I got the implant. I went back, some other day and another nurse gave me contraceptive tablets to stop vaginal bleeding … they told me to go to another clinic if I want to remove it.’ (50 years, married, female)\n\nSeverity of side effects\n\nAccording to some participants, the side effects were severe enough to get the device removed. However, the nurses at the clinics were not willing to remove it:\n\n‘I came back to the clinic to remove the implant and then they refused to remove it. They told me about the procedure they have to follow. They gave me tablets. I went back again then they told me I had quickly returned as I should have allowed treatment to work first until they remove it after 3 years.’ (22 years, single, female)\n\n‘I tried hard to get the implant removed, every clinic referring me to another. I learnt a lesson. I decided to remain patient until a solution was found.’ (29 years, married, female)\n\nStaff attitude\n\nThe nurses’ attitude when participants asked for help with removal of the device was a concern as healthcare workers either refused to remove the device or blamed them for wasting government’s resources:\n\n‘Nurses told me that I was wasting government money for this implant. They said it was very expensive. They also said if I go to private it’s too expensive. Why are you taking advantage over short period you have had it.’ (17 years, single, female)\n\n‘… they book three per day for removal but whenever we come for bookings we get very distant dates.’ (22 years, single, female)\n\nLack of support\n\nImplanon users revealed that they were not educated or counselled about the implant, they therefore ended up wanting to remove the Implanon too soon before its expiry. This is how they responded:\n\n‘I had an abortion in 2014, when a nurse called us all those who were there to use new implant. She didn’t explain to us how it worked and did not give us other information we were supposed to know.’ (22 years, single, female)\n\n‘Another thing happened, I got it very late that only HIV negative women are free to insert Implanon but it was not explained initially to me.’ (50 years, married, female)\n\n‘If it was wrong for me to use antibiotics and other medication they should have told me before because I didn’t know whether to take medicine or not.’ (34 years, single, female)\n\nMisconceptions and rumours from clients\n\nIt was found that various rumours and misconceptions were spread amongst the women using the implant. Some participants were told by their peers that it is possible to get pregnant whilst using the implant. This is how they responded:\n\n‘My friend told me that it is possible to be pregnant whilst using the implant because there were people she knew who fell pregnant whilst using the implant. She said it is possible to happen, really …’ (34 years, single, female)\n\n‘Yesterday, another friend of mine told me that it is possible to get pregnant whilst using the implant. Then, I asked her, how come I am not pregnant, because I am also using the implant. She responded that it differs from one person to another.’ (25 years, single, female)\n\nParter disapproval and violence against women\n\nAmongst the participants it was reported that some women experienced some violence and disapproval for using Implanon. It was found that women were forced to remove the implant and razors or needles were used whilst trying to remove the implant. This is how they responded:\n\n‘My husband was fine when I first told him that I am using the implant, suddenly his mind changed and told me that he won’t continue with lobola negotiations until I remove the implant. I then promised him to go to the clinic.’ (25 years, single, female)\n\n‘My partner didn’t want me to use the implant. He tried to remove it by using a razor to cut a small opening and he then used a needle to remove the implant. When the blood was coming out, I told him to stop because it might be dangerous and risky to remove it. I was so disappointed when I got a very far booking in August.’ (34 years, single, female)\n\nDissatisfaction with Implanon\n\nMost participants who were interviewed in this study reported they were dissatisfied with Implanon. The common reasons for their dissatisfaction were: side effects, failure and other potential risk suspected by users. This is how they responded:\n\n‘I won’t use it again; I don’t think it will be good for me … I am not satisfied at all with the implant because of the continuous menstrual bleeding. I won’t use it again; I don’t think it will be good for me.’ (22 years, single, female)\n\n‘It works differently with people. Some are not happy, others are happy, just like myself. It is a matter of choice; a person must choose what works for her.’ (29 years, married, female)\n\n‘At the beginning of the year 2016, I felt so sick at all times. I experienced fever, cough, vomiting after eating and dizziness. So I came to the clinic with the problem then the nurse at the clinic suggested for urine test. I was then checked and I found out that I was pregnant. I was surprised because I was using the implant. I will never use Implanon, because I got pregnant. Although I was told that I won’t get pregnant for the period of 3 years. This disappointed me.’ (50 years, married, female)\n\nDiscussion\n\nOverall, the experiences of the women suggest that better measures should be taken to deal with side effects as in most cases, women stopped using Implanon because of side effects. Others use Implanon because it lasts longer and the majority of women are extremely satisfied with the use of Implanon. Most of the participants were satisfied with the assistance they receive at from healthcare facilities. It was found that most women heard about Implanon from their peers and from clinics. Amongst the issues that they had the common side effects were: menstrual bleeding, weight gain, and loss of sex drive.\n\nThe results reveal that most women were commonly having side effects whilst they were using Implanon contraceptive device. The side effects experienced varied for each individual. Amongst these side effects those commonly reported were vaginal bleeding/period disturbances, loss of body weight, headache and pain, memory loss or disturbances, insomnia and loss of sex drive. One of the widely reported side effect was menstrual bleeding or periods in most cases. The study participants reported that whenever they reach the clinic with menstrual bleeding or period disturbance, they were given contraceptive pills, which were helping them temporarily with the symptom, but after the completion of treatment the bleeding restarted. A descriptive study was conducted on healthcare provider communicator style and patient comprehension of oral contraceptive use. It was reported that there was poor instruction from healthcare practitioners with use of oral contraceptive pill that contributed to lack of understanding in patients. As a result, patients had poor recall or lack of motivation further resulting in failure (Schrader & Schrader 2001). However, the study’s findings also revealed that there was no improvement in the subsequent bleeding patterns. This shows that menstrual bleeding is a common problem to all women who use the implant and is a significant challenge that can be modified through treatment. Again treatment works over a short period, therefore the problem is solved temporarily. Then, the need for long lasting treatment is required to tackle the side effects of Implanon within the 3-year period. Conversely, a qualitative study conducted in 2010 (Spies et al. 2010) found that women were concerned with potential side effects and problems stemming from using new contraceptives. However, they required more information about long-acting reversible contraceptives related to side effects, how they work, length of use and how they might affect their fertility.\n\nThe literature revealed that women were more concerned with side effects that were related to the use of contraceptives. At the initial phase when screening and counselling is provided women are not adequately educated about side effects as a result they end up discontinuing the implant before its duration lapses. This is linked with a finding presented by Patel in 2014, which revealed that within the first 3 months after insertion of the Implanon it is common to experience side effects but women with the issue of bleeding patterns and other adverse effects were discontinuing the implant as they were not adequately counselled.\n\nOther side effects reported were not so major in a way that could lead these women to remove the implant before its duration. The findings show that women were also experiencing other side effects such as weight loss, memory loss, loss of sex drive, headache and pains and insomnia. However, these side effects were not common with all participants hence they can be controlled and managed by adjustments with lifestyle. Therefore, the intervention requires properly taking history to identify other related causes that contribute to experiencing them. Similarly, a study conducted on women’s experiences with Implanon in South Nigeria revealed that most prevalent side effects experienced were vaginal spotting 60%, menorrhagia 13.3% and inter-menstrual bleeding 13.3% (Spies et al. 2010). However, there were other side effects reported but the bleeding disturbances contributed to 51.8% participants to change from Implanon to other contraceptives. Subsequently, there are various factors that are contraindicated to Implanon contraceptive, such as epilepsy, tuberculosis and antiretroviral drugs, poor screening and other lifestyle factors, such as substance abuse and alcohol consumption (Organon Laboratories Limited 2009). Therefore, the women may have not been sufficiently informed of other causes of pregnancy initially when they were introduced to Implanon.\n\nPatni et al. (2006) found that Implanon’s® failure was because of potent enzyme inducers known to have deleterious effects resulting in intrauterine or ectopic pregnancy. The effects of pregnancy were directly related to drug interference of antiepileptic drugs (phenytoin, phenobarbital), antibiotics (rifampicin), antifungal drugs, protease inhibitors (efavirenz, nevirapine). Woolrych and Hill (2005) conducted a study to identify common reason for unintended pregnancy on Implanon users. The study’s findings showed 218 cases of unintended pregnancy, where 45 had insufficient data to assess the reason for contraceptives failure and 46 women were determined to have been already pregnant before Implanon insertion. There were 127 cases that were remaining and in some cases there was a failure to insert the implant in 84 women (Bradley, Croft & Rustein 2011). The other 19 cases were linked to incorrect timing of insertion, three cases were because of expulsion of Implanon and there were eight cases of interaction with hepatic enzyme-inducing medicines. Thus, this evidence shows that majority of the women may patiently continue to use the implant if they experience no changes with bleeding patterns. Other side effects are therefore regarded as modifiable. Conversely, most side effects were found to be experienced continuously without disappearing, although clients are informed that it is common within the first 3 months. Effective counselling and screening may improve contraceptive continuation even though there may be side effects that client’s experience (Landry, Wei & Frost 2008).\n\nThe study’s findings show that some participants were treated violently or harshly by their husbands at home when they discovered that their wives were using this implant. It was reported that one participant was forced to remove the implant because her husband told her that he would not continue paying lobola at home until she bears a child for him. Despite the situation she had at home, the nurses at the clinic deferred her booking date for the implant removal, making her anxious and concerned. Another situation was when a participant reported that her husband tried to remove her implant with a razor and needle. This clearly revealed that women experienced potential domestic violence and lack of support at home. In the first analysis it was evidenced that 69.1% of women stated that they had informed their partners or husbands about their decision to use the implant, whilst 30.9% also responded that their partners were not aware that they were using it. Peel and Moreje (2013) argued that South African society, particularly in rural areas, is still male-dominated, and that women feel forced to prove their fertility. Kamal and Lim (2010) revealed that a husband’s approval of family planning is taken as a pivotal determinant of women’s contraceptive use.\n\nWilliams et al. (2008) reported that women experience limited autonomy, mobility and power related to household and fertility decision-making. The autonomy described by women is subversive and nested within a framework where they are not able to make overt decisions about their bodies, often manifested by covert contraceptives. According to one of the participant, some husbands feel that a wife should always listen to them and obey them. Kamal and Kim (2006) argued that men dominate decision-making regarding family size and their partner’s use of contraceptive methods, amongst a variety of traditions. It was found that men attempt to prevent women from using contraceptives. It was also evidenced that certain men even fight against women in trying to prevent them from visiting the clinic for family planning. In some instances, some men destroy clinic cards or contraceptives received from the clinic because they want to prove their fertility as the result of their actions (Williamson et al. 2009).\n\nLimitations\n\nThe study was conducted in one community healthcare clinic found in Pietermaritzburg in KwaZulu-Natal. Therefore, the research findings cannot be generalised to all community healthcare clinics in this province. Furthermore, the small sample size was also a possible limitation.\n\nImplications for future research\n\nA challenge for the future research must be on implementation of effective screening and training or retraining programme of all healthcare professionals especially in primary healthcare clinics to prevent high numbers of clients discontinuing Implanon contraceptive device. Furthermore, there is a great need to evaluate contraceptive policy and guidelines with a view to come up with long-acting contraceptive method in the health system. The study’s findings can be used by other researchers, health professionals, government and global authorities.\n\nRecommendations\n\nThese recommendations are proposed as interventions that will assist to improve standards in the service provision of Implanon contraceptive device. Therefore, these interventions were made based on the study’s findings in this research investigation:\n\nEffective screening and counselling still need to be strengthened strongly to prevent adverse outcome with Implanon use amongst women. This investigation found that most of the issues arising with Implanon could have been prevented initially if proper screening and counselling were performed such as: proper history taking and performing investigations required in screening and educating. In addition, women should be counselled about the side effects to be expected initially and should be informed about possible treatments to correct the side effects.\n\nAll healthcare practitioners and staff should always support those women coming to clinic subsequent to side effects. Staff must show empathy and should be non-judgemental with a professional attitude towards any client. It is the role of a nurse to listen attentively and communicate friendly with clients and suggest strategic ways to solve all issues raised by the clients. No clients should leave the health facility without receiving sufficient assistance.\n\nThe national health government should seek strategies that will stop uncontrollable side effects such as menstrual bleeding in clients. There should be a hierarchy when dealing with bleeding issues where the first line of option should be a general treatment and second line should be intense treatment thereafter implant should be removed especially those with constant heavy bleeding that does not subside. Problems could arise if clients could end up staying at home whilst bleeding profusely as they may be avoiding healthcare practitioners because of their attitude.\n\nThe need for spousal support should be explored broadly therefore clients must be encouraged to bring their partners when coming for contraceptives to create the awareness and support from spouse. Women should be advised to come with their partners when they have to decide on contraceptive method they want.\n\nBooking for removal of implant should not be scheduled very far in cases where clients are having negative experiences with the implant. At least clients should be free to remove the implant any day they want without any pressure to continue to use the implant.\n\nAll healthcare providers especially nurses working in primary healthcare facility should receive in-service training on the use of Implanon. This can help to achieve the one-stop shop strategy whereby the client should receive all relevant help, they came for in the clinic in one consultation room and from one healthcare provider. This will also allow the health staff to work as a team when dealing with various conditions and in solving side effects or issues brought forward by clients.\n\nEffective screening tools should be in place and developed specifically for Implanon to allow health care practitioners to easily adopt and understand the entire implant process.\n\nBody weight of all clients who used the implant should be strictly monitored, even in subsequent visits when they come with side effects. Healthcare workers should constantly monitor their weight.\n\nIt is essential at the initial phase before Implanon insertion that the clients are asked to specify all medication they are taking and further educate the clients as to which medications are contra-indicated with Implanon contraceptive method.\n\nAwareness campaigns should also be organised by coordinators to increase awareness and knowledge about the implant. School health teams, community health workers, nurses and other members should work to achieve awareness in library, schools, community and church.\n\nImperative research investigation should be conducted broadly to explore Implanon contraceptive method involving more health facilities and clients. Investigation should involve healthcare providers as to issues and experiences they might have regarding this new contraceptive method.\n\nConclusion\n\nThe National Department of Health must introduce a proper and effective screening tool and reinforce staff training to improve the uptake of Implanon. There is a need to revise guidelines in management of side effects of Implanon as a major intervention. Effective measures should be taken to strengthen partner support and awareness in the society.\n\nAcknowledgements\n\nThe authors would like to acknowledge the KwaZulu-Natal Department of Health and the women who participated in this study.\n\nCompeting interests\n\nThe authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.\n\nAuthors’ contributions\n\nL.N.M. conceived the study topic, performed the data collection and analyses, and wrote the first draft of the article; P.N.B. provided inputs and guidance throughout the study; M.G.G. overall supervised and facilitated the study and reviewed all versions of the article. All authors have approved this final manuscript.\n\nEthical considerations\n\nEthical approval was obtained from the University of KwaZulu-Natal Ethics Committee and the Department of Health (BE604/16).\n\nInformed consent was obtained from all the participants. Participants who were underage (less than 15 years) were excluded to participate in the study as per South African ethical guidelines for good practice (Naidoo 2012). Therefore, consent was obtained autonomously on the minor respondents above 15 years.\n\nTo ensure confidentiality of participants, no real names were used during the interviews, but pseudo names. Participants were also informed that they could withdraw from the study any time, without being prejudiced because participation in the study was voluntary.\n\nFunding information\n\nThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\n\nData availability\n\nData sharing is not applicable to this article as no new data were created or analysed in this study.\n\nDisclaimer\n\nThe views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors, and the Publisher/s.\n\nHow to cite this article: Mgobhozi, L.N., Mbeje, P.N. & Mchunu, G.G., 2021, ‘Women’s experiences on the use of Implanon as a contraceptive method in a selected primary healthcare facility in KwaZulu-Natal’, Curationis 44(1), a2187. https://doi.org/10.4102/curationis.v44i1.2187\n==== Refs\nReferences\n\nAbiodum, O. M. & Balogum, O.R., 2009, Sexual activity and contraceptive use among youth female students of tertiary education institutions in Ilorin, Nigeria. Contraception 79 , 146–149. 10.1016/j.contraception.2008.08.002 19135573\nAlemayehu, M., Kalayu, A., Desta, A., Gebremichael, H., Hagos, T. & Yebyo, H., 2015, ‘Rural women are more likely to use long acting contraceptive in Tigray region Northern Ethiopia: A comparative community–base cross section study’, BMC Women Healthy 15 , 71. 10.1186/s12905-015-0229-7\nBradley, S.E.K., Croft, T.N. & Rutstein, S.O., 2011, ‘The impact of contraceptive failure on unintended births and induced abortions: Estimates and strategies for reduction’, in I.C.F. Macro (ed.), DHS analytical studies, ICF Macro, Calverton, NY.\nBrink, H., Van der Walt, C. & Van der Rensburg, G., 2012, Fundamentals of research methodology for healthcare professional, 3rd edn., Juta, Lansdowne.\nChola, L., MacQuikan, K., Winch, A., Rapiti, R., Edoka, I., Kohli-Lynch, C. et al ., 2019, ‘Projecting the fiscal impact of South Africa’s contraceptive needs: Scaling up family planning posts 2020’, South African Medical Journal 109 (10 ), 756–760. 10.7196/SAMJ.2019.v109i10.13707 31635573\nGbolade, B.A., 2010, Failure of Implanon on antituberculous therapy, Dove Medical Press Limited, West Yorkshire.\nHaddou, L., 2014, ‘Global development maternal mortality down 45% Globally but 33 women an hour are still dying’, The Guardian, London, viewed 07 May 2014, from http://www.theguardian.com/.\nImo, C.K., Isiugo-Abanihe, U.C. & Onabanjo, O.D., 2013, Knowledge and use of contraceptives among Urban and rural women of Abia state, Nigeria, Ife Psychologia, Nigeria, viewed 06 June 2016, from http://www.questia.comflibrary/journal/Ip32922991301/knowledge-and-use-of-countraceptive-among-urban-and.\nKamal, N. & Lim, C., 2006, The influence of husbands on the contraceptive use of women in Nepal, viewed 08 July 2016, from http://pdfs.seminticscholar.org/28dl/d634779a9656c27bd3e54ea8a532c2ded295.pdf.\nKamal, N. & Lim, C., 2010, The influence of husbands on contraceptive use by Bangladeshi women, Health Policy and Planning 15 , 43–51. 10.1093/heapol/15.1.43\nKartz, B., 2015, ‘Human right why 222 million women can’t get the birth control they need-on World Contraceptive Day, we Look at the forces that prevent millions of women in developing countries from accessing contraceptive’, Women in the World Median, 26 September, The New Your Times.\nLandry, D.J., Wei, J. & Frost, J.J., 2008, ‘Public and private providers’ involvement in improving their patients’ contraceptive use’, Contraception 78 (1 ), 42–51. 10.1016/j.contraception.2008.03.009.18555817\nMukuka, C., 2015, Is the hormonal contraceptive Implanon right for you? Clicks, 25 August, viewed 12 July 2016, from https://clicks.co.za/health/article-view/is-the-hormonal-contraceptive-implanon-right-for-you.\nNaidoo, S., 2012, ‘Consent for children participating in research’, South African Medical Journal 102 (3 ), 201. 10.7196/SAMJ.5537\nOjule, J.D., Oranu, E.O. & Enyindah, C.E., 2012, ‘Experiences with Implanon in Southern Nigeria’, International Research Journal 3 (11 ), 710–714.\nOrganon Laboratories Limited, 2009, ‘Implanon 68 mg implant for subdermal use’, EMC Medicine Organization Online, 09 June, viewed 22 July 2016, from http://www.medicines.org.uk/emc/medicine/5382/SPC/Implanon+68mg+implant+for+subdermal+use/.\nPatel, M., 2014, ‘Contraception: Everyone’s responsibility’, South African Medical Journal 104 (9 ), 644. 10.7196/SAMJ.8764 26307790\nPatni, S., Ebden, P., Kevelighan, E. & Bibby, J., 2006, ‘Ectopic pregnancy with Implanon’, The Journal of Family Planning and Reproductive Health Care 32 (2 ), 115. 10.1783/147118906776276404 16824306\nPeel, N. & Morojele, N., 2013, ‘Factors associated with contraceptive use in a rural area in western cape province’, South African Medical Journal 103 (6 ), 406–412. 10.7196/SAMJ.6201 23725962\nPleaner, M., Morroni, C., Smit, J., Lince Deroche, N., Chersich, M., Mullick, S. et al ., 2017, ‘Lessons learnt from the introduction of the contraceptive implant in South Africa’, South African Medical Journal 107 (11 ), 933–938. 10.7196/SAMJ.2017.v107i11.12805 29399422\nPolit, F.D. & Beck, C.T., 2008, Nursing research. Generating and assessing evidence for nursing practice, 8th edn., JB Lippincott, Philadelphia, PA.\nSchrader, E.L. & Schrader, D.C., 2001, ‘Health care provider communicator style and patient comprehension of oral contraceptive use’, Journal of the American Academy of Nurse Practitioners 13 (2 ), 80–83. 10.1111/j.1745-7599.2001.tb00222.x 11930401\nSikosana, I., 2015, Birth control implant needs a shot in the arm: Poor training of nurses may have led to severe reactions to a new contraceptive device, viewed 12 September 2015, from http://bhekisisa.org/article/2015-05-21-birth-control-implant-needs-a-shot-in-the-arm.\nSouth African Department of Health, 2014, New contraceptive Implanon implant, Government News Agency, Government Printer, Pretoria.\nSouth African Department of health, 2015, Annual report. Maternal, child & women health and nutrition, Government Publishers, KwaZulu-Natal, p. 430, Report no: 2014/15 (vote 7).\nSpies, E.L., Askelson, N.M., Gelman, E. & Losch, M., 2010, ‘Young women’s knowledge, attitudes and behaviors related to long acting reversible contraceptive’, WHI 20 (6 ), 394–399. 10.1016/j.whi.2010.07.005 21050998\nUnited Nations Population (UNFPA), 2015, Trends in contraceptive use worldwide, viewed 16 June 2015, from http://www.unfpa.org.\nWilliams, W., Stepheson, R., Juvekar, S. & Andes, K., 2008, ‘Domestic violence and contraceptive use in a rural Indian village’, PubMed 10 , 1181–1198. 10.1177/1077801/208323793\nWilliamson, L.M., Parkes, A., Wight, D., Petticrew, M. & Hart, G.J., 2009, ‘Limits to modern contraceptive use among young women in developing countries: A systematic review of qualitative research’, Reproductive Health 6 , 3. 10.1186/1742-4755-6-3 19228420\nWoolrych, M.H. & Hill, R., 2005, ‘Unintended pregnancies with the etonogestrel implant (Implanon): A case series from post-marketing experience in Australia’, Elsevier Science Incorporate 60 , 1–8.\nWorld Health Organisation (WHO), 2014, Maternal mortality: Fact sheet, to improve maternal health, barriers that limit access to equality maternal health services must be identified and addressed at all levels of the health system, 6th edn., WHO, Geneva.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0379-8577",
"issue": "44(1)",
"journal": "Curationis",
"keywords": "Implanon; Implanon users; experiences; perceptions; primary healthcare",
"medline_ta": "Curationis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003267:Contraception; D003271:Contraceptive Agents, Female; D017135:Desogestrel; D005260:Female; D006801:Humans; D008875:Middle Aged; D011247:Pregnancy; D011320:Primary Health Care; D013019:South Africa; D055815:Young Adult",
"nlm_unique_id": "7901092",
"other_id": null,
"pages": "e1-e9",
"pmc": null,
"pmid": "34797106",
"pubdate": "2021-11-08",
"publication_types": "D016428:Journal Article",
"references": "18555817;15792651;21050998;19135573;26307790;19228420;16824306;22380888;10731234;11930401;18802213;23725962;29399422;26341405;31635573",
"title": "Women's experiences on the use of Implanon as a contraceptive method in a selected primary healthcare facility in KwaZulu-Natal.",
"title_normalized": "women s experiences on the use of implanon as a contraceptive method in a selected primary healthcare facility in kwazulu natal"
} | [
{
"companynumb": "ZA-ORGANON-O2112ZAF000546",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETONOGESTREL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nTAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly. In contrast to that in multicentric Castleman disease, interleukin-6 targeting strategies seem ineffective in some TAFRO syndrome cases; however, the optimal treatment remains unclear. Here, we report 2 cases of TAFRO syndrome, where 1 with cardiomyopathy, successfully treated with tacrolimus. This is the first case report of successful treatment with tacrolimus in TAFRO syndrome.\nBoth patients (cases 1 and 2) developed fever, anasarca, thrombocytopenia, renal dysfunction, and mild hepatosplenomegaly.\nIn both patients, lymph node pathology revealed mixed type Castleman disease-like features, and bone marrow showed reticulin myelofibrosis. TAFRO syndrome was diagnosed based on the patients' laboratory, clinical, and pathologic findings. In case 2, we observed a rare complication of cardiomyopathy with no evidence of takotsubo cardiomyopathy or viral myocarditis.\n\n\nRESULTS\nIn case 1, tocilizumab combined with glucocorticoids was ineffective and caused septic shock; additionally, cyclosporine A was discontinued because of hepatotoxicity. However, tacrolimus was effective in resolving TAFRO syndrome without any adverse events. In case 2, tacrolimus completely reversed TAFRO syndrome and was also effective in cardiomyopathy.\n\n\nCONCLUSIONS\nThis report suggests that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent. Our literature review shows that calcineurin inhibitors, including tacrolimus, may be effective in TAFRO syndrome. Since previous studies indicate a role of Th1 inflammation in TAFRO syndrome pathogenesis, tacrolimus may, therefore, be effective in treating TAFRO syndrome.",
"affiliations": "Department of Rheumatology and Clinical Immunology, Kobe University Hospital, Chuo-ku, Kobe, Japan.",
"authors": "Shirai|Taiichiro|T|;Onishi|Akira|A|;Waki|Daisuke|D|;Saegusa|Jun|J|;Morinobu|Akio|A|",
"chemical_list": "D065095:Calcineurin Inhibitors; D005938:Glucocorticoids; D015850:Interleukin-6; D016572:Cyclosporine; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000011045",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29879072MD-D-18-0117810.1097/MD.0000000000011045110453600Research ArticleClinical Case ReportSuccessful treatment with tacrolimus in TAFRO syndrome: two case reports and literature review Shirai Taiichiro MD∗Onishi Akira MD, PhDWaki Daisuke MDSaegusa Jun MD, PhDMorinobu Akio MD, PhDNA. Department of Rheumatology and Clinical Immunology, Kobe University Hospital, Chuo-ku, Kobe, Japan.∗ Correspondence: Taiichiro Shirai, Department of Rheumatology and Clinical Immunology, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan (e-mail: shirai@med.kobe-u.ac.jp).6 2018 18 6 2018 97 23 e1104516 2 2018 15 5 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nTAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly. In contrast to that in multicentric Castleman disease, interleukin-6 targeting strategies seem ineffective in some TAFRO syndrome cases; however, the optimal treatment remains unclear. Here, we report 2 cases of TAFRO syndrome, where 1 with cardiomyopathy, successfully treated with tacrolimus. This is the first case report of successful treatment with tacrolimus in TAFRO syndrome.\n\nPatient concerns:\nBoth patients (cases 1 and 2) developed fever, anasarca, thrombocytopenia, renal dysfunction, and mild hepatosplenomegaly.\n\nDiagnoses:\nIn both patients, lymph node pathology revealed mixed type Castleman disease-like features, and bone marrow showed reticulin myelofibrosis. TAFRO syndrome was diagnosed based on the patients’ laboratory, clinical, and pathologic findings. In case 2, we observed a rare complication of cardiomyopathy with no evidence of takotsubo cardiomyopathy or viral myocarditis.\n\nInterventions and outcomes:\nIn case 1, tocilizumab combined with glucocorticoids was ineffective and caused septic shock; additionally, cyclosporine A was discontinued because of hepatotoxicity. However, tacrolimus was effective in resolving TAFRO syndrome without any adverse events. In case 2, tacrolimus completely reversed TAFRO syndrome and was also effective in cardiomyopathy.\n\nLessons:\nThis report suggests that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent. Our literature review shows that calcineurin inhibitors, including tacrolimus, may be effective in TAFRO syndrome. Since previous studies indicate a role of Th1 inflammation in TAFRO syndrome pathogenesis, tacrolimus may, therefore, be effective in treating TAFRO syndrome.\n\nKeywords\ncalcineurin inhibitorscardiomyopathycyclosporine Amulticentric Castleman diseasetacrolimusTAFRO syndromeOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nTAFRO syndrome was first described in Japan in 2010 as a unique variant of multicentric Castleman disease (MCD) with an aggressive clinical course and comprised thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO).[1] MCD constitutes a heterogeneous group of lymphoproliferative disorders characterized by excessive systemic inflammatory features, including frequent fever, generalized peripheral lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia, and elevated levels of serum C-reactive protein (CRP), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF). These clinical manifestations of MCD are possibly driven by excessive proinflammatory hypercytokinemia, particularly in association with elevated levels of IL-6. On the contrary, MCD is strongly associated with human herpesvirus-8 (HHV-8), which infects B cells and expresses a viral homolog of IL-6; TAFRO syndrome is considered as a subgroup of HHV-8-negative MCD or idiopathic MCD group.[2]\n\nAlthough IL-6 levels in TAFRO syndrome are elevated, many of its features differ considerably from classical MCD features, including severe thrombocytopenia and absence of hypergammaglobulinemia,[3] which is difficult to explain owing to hyper-IL-6 syndrome because IL-6 overexpression typically results in thrombocytosis and hypergammaglobulinemia. In addition, IL-6 targeting strategies seem to be ineffective for some TAFRO syndrome cases, whereas they are highly effective for MCD (91% complete response rate).[4] These findings suggest that not only IL-6 but also other proinflammatory conditions may play roles in the pathogenesis of TAFRO syndrome.[5] Furthermore, the combination of glucocorticoids and tocilizumab, an anti-IL-6 receptor antibody, increases the risk of severe infections.[6] In terms of effectiveness and adverse events, IL-6-targeting agents may not be the best choice for TAFRO syndrome; however, the optimal treatment remains unclear.\n\nTo the best of our knowledge, this is the first report of 2 cases of TAFRO syndrome successfully treated with tacrolimus, where 1 with a rare complication of cardiomyopathy, which was also completely resolved after treatment. We also discuss the relationship between the action mechanism of tacrolimus and possible pathogenesis of TAFRO syndrome.\n\n2 Case reports\n2.1 Case 1\nA 68-year-old Japanese woman without medical history was admitted to our hospital with a 4-week history of abdominal distension and fever of 38.1°C. Physical examination revealed swollen cervical and axillary lymph nodes (<1 cm in diameter) and abdominal tenderness. Laboratory studies revealed anemia (hemoglobin, 7.3 g/dL); thrombocytopenia (38,000/μL); reduced immunoglobulin G (IgG, 770 mg/dL); elevated levels of alkaline phosphatase (ALP, 720 U/L), soluble interleukin-2 receptor (sIL-2R, 3060 U/mL), and CRP (2.7 mg/dL); and renal dysfunction (serum creatinine 1.6 mg/dL) with microhematuria. Test results for autoantibodies, including antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA); and viruses, including HHV-8 and human immunodeficiency virus (HIV), were negative. Computed tomography (CT) revealed systemic lymphadenopathy, bilateral pleural effusion, massive ascites, and hepatosplenomegaly. IL-6 and VEGF levels in serum (24 and 390 pg/mL, respectively) and in ascitic fluid (1800 and 63 pg/mL, respectively) were elevated. Cervical lymph node biopsy revealed atrophic germinal centers, expanded mantle zones, and proliferated high endothelial venules and small number of plasma cells in the interfollicular zones (Fig. 1A, B). Bone marrow biopsy revealed hyperplasia of megakaryocytes and reticulin fibrosis. These symptoms and histopathologic findings met the diagnostic criteria for TAFRO syndrome.[3,7]\n\nFigure 1 Histologic findings of the cervical lymph node. (A) Lymph node with proliferated high endothelial venules and small number of plasma cells in the interfollicular zone. Hematoxylin and eosin staining (40× magnification). (B) Atrophic germinal centers with enlarged nuclei of high endothelial cells and expanded mantle zones. Hematoxylin and eosin staining (100× magnification).\n\nInitial treatment with 60 mg/day (1 mg/kg/day) of oral prednisolone gradually improved renal dysfunction but failed to resolve thrombocytopenia and massive ascites, requiring frequent platelet transfusion, romiplostim administration, and ascites drainage (Fig. 2). Additional treatment with 8 mg/kg of tocilizumab failed to improve the symptoms; moreover, the patient developed septic shock from empyema caused by methicillin-sensitive Staphylococcus aureus, necessitating the discontinuation of tocilizumab. Additionally, 150 mg/day (2.5 mg/kg/day) of cyclosporine A had to be discontinued within a week because of hepatotoxicity. Referring to literature demonstrating the effectiveness of calcineurin inhibitor,[8,9] we administered 4 mg/day (0.07 mg/kg/day) of tacrolimus targeting 5 to 10 ng/mL of trough concentrations, after obtaining informed consent from the patient. Tacrolimus improved renal dysfunction and thrombocytopenia rapidly without requiring platelet transfusion or romiplostim administration. Abdominal distension gradually subsided without ascites drainage: CT showed complete ascites resolution 4 weeks after tacrolimus initiation, and glucocorticoids were tapered off rapidly. The patient has had an uneventful course without relapse for more than 3 years.\n\nFigure 2 Clinical course of case 1.\n\n2.2 Case 2\nA 17-year-old Japanese man without medical history was admitted to our hospital with a 4-week history of abdominal pain, nausea, and fever of 38.8°C. Physical examination revealed swollen axillary lymph nodes (<1 cm in diameter) and abdominal tenderness. Laboratory studies revealed anemia (hemoglobin, 6.7 g/dL); thrombocytopenia (68,000/μL); reduced IgG (810 mg/dL); elevated levels of ALP (870 U/L), sIL-2R (1250 U/mL), and CRP (23.0 mg/dL); and renal dysfunction (serum creatinine 1.6 mg/dL) with microhematuria. Test results for autoantibodies, including ANA and ANCA; and viruses, including HHV-8 and HIV, were negative. Electrocardiogram and echocardiography were normal. CT showed bilateral pleural effusion, ascites, and mild hepatosplenomegaly. Serum IL-6 and VEGF levels (70 and 730 pg/mL, respectively) and IL-6 and VEGF levels in the pleural effusion (370 and 88 pg/mL) and ascitic fluid (460 and 100 pg/mL) were elevated. Axillary lymph node biopsy revealed expanded mantle zones and proliferated high endothelial venules in atrophic germinal centers and interfollicular zones with small number of plasma cells. Bone marrow biopsy revealed normoplasia of megakaryocytes and reticulin fibrosis. The patient was diagnosed with TAFRO syndrome.[3,7]\n\nThe CRP level and fever improved spontaneously, but thrombocytopenia, creatinine level, pleural effusion, and ascites deteriorated (Fig. 3). Four weeks after admission, the patient suddenly developed cardiogenic shock without obvious causes; evidence of myocardial infarction, takotsubo cardiomyopathy, or viral myocarditis was not detected. Echocardiography revealed severe and diffuse hypokinesis of both ventricles (left ventricular ejection fraction, LVEF 20%) and moderate pericardial effusion (Fig. 4A). The brain natriuretic peptide (BNP) level was 1230 pg/mL (reference range, <18.4 pg/mL). We initiated methylprednisolone pulse therapy at 1000 mg/day for 3 consecutive days, followed by 60 mg/day (1 mg/kg/day) of oral prednisolone and 4 mg/day (0.07 mg/kg/day) of tacrolimus targeting 5 to 10 ng/mL of trough concentrations, with informed consent. One week after treatment initiation, repeat echocardiography revealed improved wall motion (LVEF 45%) and pericardial effusion. Four weeks later, serial echocardiography showed normal wall motion (LVEF 60%) without pericardial effusion (Fig. 4B), and a decrease in BNP level (8.0 pg/mL). Late gadolinium-enhanced cardiac magnetic resonance imaging showed no myocardial scarring. Thrombocytopenia, renal dysfunction, and anasarca had also improved since tacrolimus treatment initiation, and glucocorticoids were tapered off rapidly. The patient has had an uneventful course without relapse for more than 2 years.\n\nFigure 3 Clinical course of case 2.\n\nFigure 4 Clinical course of cardiomyopathy (echocardiography). (A) Severe and diffuse hypokinesis (LVEF 20%) and moderate pericardial effusion were detected. (B) Four weeks after treatment initiation, wall motion improved (LVEF 60%), and pericardial effusion disappeared. LVEF, left ventricular ejection fraction.\n\nThis case report did not involve any human trials, and ethical review board approval was not necessary. Written informed consent was obtained from both the patients (cases 1 and 2) for the publication of their clinical data.\n\n3 Discussion\nThis is the first case report of TAFRO syndrome successfully treated with tacrolimus. Although a standard treatment strategy for TAFRO syndrome is not yet established, our cases suggest that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent.\n\nFirst, tacrolimus was shown to be effective in our TAFRO syndrome cases. We reviewed the treatments of previous and current TAFRO syndrome cases to assess treatments and their responses; remission was defined as the absence of abnormalities on physical examinations and laboratory or imaging studies. Patients were treated with glucocorticoids alone or with combination therapy, including IL-6-targeting agents (tocilizumab, siltuximab); calcineurin inhibitors (tacrolimus, cyclosporine A); rituximab; and cytotoxic chemotherapy (Table 1). Treatment effectiveness greatly varied. Our literature review showed that calcineurin inhibitors, including tacrolimus, were effective for TAFRO syndrome, with 71% of patients attaining remission. Although the effectiveness of tacrolimus has not been compared with that of cyclosporine A, the superiority of tacrolimus over cyclosporine A has been extensively reported for kidney or liver transplant rejection, particularly in cases of glucocorticoid-resistant rejection.[10,11] While IL-6-targeting agents were frequently used for TAFRO syndrome, only 45% of patients attained remission.\n\nTable 1 Responses and adverse events associated with treatments of TAFRO syndrome.\n\nSecond, tacrolimus was safe in our TAFRO syndrome cases. Literature review revealed that the frequency of severe infections in patients treated with calcineurin inhibitors was low (Table 1). Hepatotoxicity was an adverse drug reaction of cyclosporine A in some cases, including case 1, which was successfully treated by replacing cyclosporine A with tacrolimus. In fact, hepatotoxicity occurs less frequently with tacrolimus than with cyclosporine A.[12] The frequency of severe infections, including septic shock, was high for treatment with tocilizumab, particularly in combination with high-dose glucocorticoids, as shown in case 1. In fact, in a survey of tocilizumab for rheumatoid arthritis, the most frequent adverse events were severe infections; the significant risk factor was identified as a glucocorticoid dosage of ≥5 mg/day (prednisolone equivalent).[6] In terms of safety, tacrolimus may be useful in treating TAFRO syndrome.\n\nThird, the mechanism of action of tacrolimus and possible pathogenesis of TAFRO syndrome indicate that tacrolimus may be a rational treatment choice. Tacrolimus suppresses Th1 cell responses and impairs transcription of IL-2 and several other proinflammatory cytokines.[13] In accordance with previous studies, we consider that Th1 inflammation may play a role in TAFRO syndrome pathogenesis. Increased IL-2 levels in the ascitic fluid in patients with TAFRO syndrome may suggest the contribution of endogenous IL-2 to disease pathogenesis.[14] Additionally, high serum levels of interferon-γ-induced protein 10 (IP-10) are strongly correlated with TAFRO syndrome but not classical MCD.[15] Overexpression of IP-10 is common in Th1-type inflammatory diseases and is critical for Th1-mediated immune responses.[16] Tacrolimus suppresses Th1-cell responses, which may be one of the underlying mechanisms for the effectiveness of tacrolimus in TAFRO syndrome. Notably, in case 1, treatment with tacrolimus was successful for tocilizumab-resistant TAFRO syndrome; cyclosporine A has also been shown to be effective in tocilizumab-resistant cases,[8,9] suggesting that in addition to IL-6, Th1 inflammation may play a role in TAFRO syndrome pathogenesis.\n\nFor case 2, we reported a complete reversal of cardiomyopathy, a rare complication of TAFRO syndrome, using tacrolimus and glucocorticoids. Few cases of TAFRO syndrome with cardiomyopathy have been reported,[17,18] one of which was refractory to tocilizumab, suggesting that some proinflammatory cytokines other than IL-6 may be involved.[17] In fact, in addition to IL-6, Th1 cytokines, such as IL-2 and tumor necrosis factor-α, have direct negative inotropic effect in a concentration-dependent, reversible manner, even after short-term exposure.[19] Tacrolimus may therefore be effective, although the exact mechanism of cardiomyopathy has been poorly understood.\n\nOur 2 cases suggested that tacrolimus is potentially effective and safe for TAFRO syndrome. However, with only 2 cases, it is early to conclude that tacrolimus is truly effective for TAFRO syndrome. The optimal treatment and precise pathogenesis of TAFRO syndrome remain unclear, and further research is needed to validate our findings and conclusions.\n\nAuthor contributions\nValidation: Daisuke Waki, Jun Saegusa, Akio Morinobu.\n\nWriting – original draft: Taiichiro Shirai.\n\nWriting – review & editing: Taiichiro Shirai, Akira Onishi.\n\nAbbreviations: ALP = alkaline phosphatase, ANA = antinuclear antibody, ANCA = antineutrophil cytoplasmic antibody, BNP = brain natriuretic peptide, CRP = C-reactive protein, CT = computed tomography, HHV-8 = human herpesvirus 8, HIV = human immunodeficiency virus, IgG = immunoglobulin G, IL-6 = interleukin-6, IP-10 = interferon-γ-induced protein 10, LVEF = left ventricular ejection fraction, MCD = multicentric Castleman disease, sIL-2R = soluble interleukin-2 receptor, TAFRO = thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly, VEGF = vascular endothelial growth factor.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Takai K Nikkuni K Momoi A \nThrombocytopenia with reticulin fibrosis accompanied by fever, anasarca and hepatosplenomegaly: a clinical report of five cases . J Clin Exp Hematop \n2013 ;53 :63 –8 .23801136 \n[2] Fajgenbaum DC Van Rhee F Nabel CS \nHHV-8-negative, idiopathic multicentric Castleman disease: Novel insights into biology, pathogenesis, and therapy . Blood \n2014 ;123 :2924 –33 .24622327 \n[3] Iwaki N Fajgenbaum DC Nabel CS \nClinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease . Am J Hematol \n2016 ;91 :220 –6 .26805758 \n[4] Liu AY Nabel CS Finkelman BS \nIdiopathic multicentric Castleman's disease: a systematic literature review . Lancet Haematol \n2016 ;3 :163 –75 .\n[5] Masaki Y Nakajima A Iwao H \nJapanese variant of multicentric Castleman's disease associated with serositis and thrombocytopenia – A report of two cases: Is TAFRO syndrome (Castleman-Kojima disease) a distinct clinicopathological entity? \nJ Clin Exp Hematop \n2013 ;53 :79 –85 .23801138 \n[6] Koike T Harigai M Inokuma S \nPostmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients . Ann Rheum Dis \n2011 ;70 :2148 –51 .21852254 \n[7] Masaki Y Kawabata H Takai K \nProposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, 2015 version . Int J Hematol \n2016 ;103 :686 –92 .27084250 \n[8] Yamaga Y Tokuyama K Kato T \nSuccessful treatment with cyclosporin a in tocilizumab-resistant TAFRO syndrome . Intern Med \n2016 ;55 :185 –90 .26781021 \n[9] Konishi Y Takahashi S Nishi K \nSuccessful treatment of TAFRO syndrome, a variant of multicentric Castleman's disease, with cyclosporine A: possible pathogenetic contribution of interleukin-2 . Tohoku J Exp Med \n2015 ;236 :289 –95 .26250536 \n[10] Webster AC Woodroffe RC Taylor RS \nTacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data . BMJ \n2005 ;331 :810 .16157605 \n[11] Haddad E Mcalister V Renouf E \nCyclosporin versus tacrolimus for liver transplanted patients . Cochrane Database Syst Rev \n2006 ;18 :CD005161 .\n[12] Grady JGO Hardy P Burroughs AK \nRandomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation: poststudy surveillance to 3 years . Am J Transpl \n2007 ;7 :137 –41 .\n[13] Med JJE Schreiber SL Crabtree GR \nThe mechanism of action of cyclosporin A and FK506 . Immunol Today \n1992 ;13 :1433 –9 .\n[14] Kubokawa I Yachie A Hayakawa A \nThe first report of adolescent TAFRO syndrome, a unique clinicopathologic variant of multicentric Castleman's disease . BMC Pediatr \n2014 ;14 :139 .24890946 \n[15] Iwaki N Gion Y Kondo E \nElevated serum interferon γ-induced protein 10 kDa is associated with TAFRO syndrome . Sci Rep \n2017 ;7 :42316 .28205564 \n[16] Dufour JH Dziejman M Liu MT \nIFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking . J Immunol \n2002 ;168 :3195 –204 .11907072 \n[17] Sumie H Koichiro O Hideaki T \nSuccessful treatment by rituximab in a patient with TAFRO syndrome with cardiomyopathy . Nihon Rinsho Meneki Gakkai Kaishi \n2016 ;39 :64 –71 .27181237 \n[18] Yasuda S Tanaka K Ichikawa A \nAggressive TAFRO syndrome with reversible cardiomyopathy successfully treated with combination chemotherapy . Int J Hematol \n2016 ;104 :512 –8 .27245076 \n[19] Finkel MS Oddis CV Jacob TD \nNegative inotropic effects of cytokines on the heart mediated by nitric oxide . Science \n1992 ;257 :387 –9 .1631560\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(23)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000293:Adolescent; D000368:Aged; D001853:Bone Marrow; D065095:Calcineurin Inhibitors; D009202:Cardiomyopathies; D005871:Castleman Disease; D016572:Cyclosporine; D004487:Edema; D005260:Female; D005334:Fever; D005355:Fibrosis; D005938:Glucocorticoids; D006529:Hepatomegaly; D006801:Humans; D015850:Interleukin-6; D008297:Male; D055728:Primary Myelofibrosis; D051437:Renal Insufficiency; D013163:Splenomegaly; D013577:Syndrome; D016559:Tacrolimus; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e11045",
"pmc": null,
"pmid": "29879072",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "27181237;27245076;1374612;27063975;23801138;21852254;28205564;11907072;24622327;27084250;24890946;23801136;17109723;26781021;17054241;1631560;26805758;16157605;26250536",
"title": "Successful treatment with tacrolimus in TAFRO syndrome: two case reports and literature review.",
"title_normalized": "successful treatment with tacrolimus in tafro syndrome two case reports and literature review"
} | [
{
"companynumb": "JP-TEVA-2018-JP-926288",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROMIPLOSTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Apixaban, an oral factor Xa inhibitor, has no commercially available assay to measure its activity and no specific antidote. To date, recommendations for managing bleeding associated with apixaban are based on studies with animal models and healthy volunteers (who do not have identified thrombogenic risk factors) and expert opinion. No clinical experience has been published in the literature. Ideally, apixaban would be reversed sufficiently to stop a perilous bleed without producing more thrombogenic risk than the patients' underlying risk factors. Three-factor prothrombin complex concentrate (PCC3) is the least thrombogenic among the suggested reversal agents. Fresh frozen plasma (FFP) is sometimes recommended to add to PCC3, but it adds considerable volume. We describe successful management of an active left gluteal arterial extravasation due to trauma and associated apixaban, in a patient with aortic stenosis and atrial fibrillation, by administration of PCC3 alone, without the added volume of FFP.",
"affiliations": "Marin General Hospital, Greenbrae, CA, USA School of Pharmacy, University of California, San Francisco, CA, USA denetclawt@pharmacy.ucsf.edu.;School of Pharmacy, University of California, San Francisco, CA, USA.;School of Pharmacy, University of California, San Francisco, CA, USA.;School of Pharmacy, University of California, San Francisco, CA, USA.;Marin General Hospital, Greenbrae, CA, USA.",
"authors": "Denetclaw|Tina Harrach|TH|;Tam|Jacqueline|J|;Arias|Victor|V|;Kim|Rachel|R|;Martin|Christopher|C|",
"chemical_list": "D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C025667:prothrombin complex concentrates; C522181:apixaban",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190015613231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "29(4)",
"journal": "Journal of pharmacy practice",
"keywords": "anticoagulation; cardiology; emergency medicine",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000369:Aged, 80 and over; D001779:Blood Coagulation Factors; D002081:Buttocks; D005119:Extravasation of Diagnostic and Therapeutic Materials; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D010949:Plasma; D011720:Pyrazoles; D011728:Pyridones",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "427-30",
"pmc": null,
"pmid": "26519251",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case Report: Apixaban-Associated Gluteal Artery Extravasation Reversed With PCC3 Without FFP.",
"title_normalized": "case report apixaban associated gluteal artery extravasation reversed with pcc3 without ffp"
} | [
{
"companynumb": "US-PFIZER INC-2016348456",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DILTIAZEM"
},
"drugadditional": null,
... |
{
"abstract": "Nine cases of diclofenac hypersensitivity recorded by the Allergy Vigilance Network in France from 2002 to 2012 were studied. Data from history, symptoms, skin tests, basophil activation tests, and oral challenge (OC) were recorded. Grade 3 severe anaphylactic reactions occurred in seven cases of nine. IgE-dependent anaphylaxis was confirmed in six cases: positive intradermal tests (n = 4), a syndromic reaction during skin tests (n = 1), and one case with grade 1 reaction and negative skin tests had an anaphylactic shock to the OC. A nonimmune reaction was suspected in one case. An IgE-dependent mechanism may be the predominant cause of adverse reactions to diclofenac. Allergy skin tests must be carried out sequentially at the recommended concentrations. BATs may be helpful because they can support the diagnosis of anaphylaxis. Given the risks of a direct challenge to diclofenac, OC to aspirin should be performed first to exclude a nonimmunologic hypersensitivity to NSAIDs. Tests for specific IgEs to most frequently used NSAIDs such as diclofenac and ibuprofen are urgently needed.",
"affiliations": "Allergy Department, Emile Durkheim Hospital, Epinal, France; Allergy Vigilance Network, Vandoeuvre les Nancy, France.",
"authors": "Picaud|J|J|;Beaudouin|E|E|;Renaudin|J M|JM|;Pirson|F|F|;Metz-Favre|C|C|;Dron-Gonzalvez|M|M|;Moneret-Vautrin|D A|DA|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D007073:Immunoglobulin E",
"country": "Denmark",
"delete": false,
"doi": "10.1111/all.12458",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-4538",
"issue": "69(10)",
"journal": "Allergy",
"keywords": "anaphylaxis; basophil; diclofenac; drug allergy; skin test",
"medline_ta": "Allergy",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D004342:Drug Hypersensitivity; D005260:Female; D005602:France; D006801:Humans; D007073:Immunoglobulin E; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "7804028",
"other_id": null,
"pages": "1420-3",
"pmc": null,
"pmid": "24931488",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anaphylaxis to diclofenac: nine cases reported to the Allergy Vigilance Network in France.",
"title_normalized": "anaphylaxis to diclofenac nine cases reported to the allergy vigilance network in france"
} | [
{
"companynumb": "PHHY2014FR145887",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": null,
"drug... |
{
"abstract": "Visual disturbance is a common complaint in patients with multiple myeloma, both at diagnosis and later in their course, and has a broad differential. Here, we report a novel cause of visual disturbance, namely retinal ischemia due to extramedullary plasmacytomas of the orbit. A 69 year-old male patient with known multiple myeloma presented with reduced vision in his left eye. The patient had been initially diagnosed with IgG myeloma 9 months earlier and multiples lines of medical therapy had been unsuccessful. Ophthalmology review was organised and fundoscopic examination showed evidence of retinal ischemia. Computed tomography of the orbits demonstrated multiple enhancing masses within both orbits, consistent with extramedullary plasmacytomas. The presence of retinal ischemia was thus attributed to mass effect on the orbital vessels. Extramedullary plasmacytomas within the orbit are a rare manifestation of multiple myeloma, but important to consider as a possible cause of visual disturbance.",
"affiliations": "Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: arian.lasocki@petermac.org.;Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.;Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia; Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.;Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia; Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.",
"authors": "Lasocki|Arian|A|;Furphy|Emma-Jane|EJ|;Westerman|David A|DA|;Harrison|Simon|S|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2020.01.052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "72()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Magnetic resonance imaging; Multiple myeloma; Plasmacytoma",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000368:Aged; D006801:Humans; D007511:Ischemia; D008297:Male; D009918:Orbital Neoplasms; D010954:Plasmacytoma; D012164:Retinal Diseases; D012171:Retinal Vessels; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "447-449",
"pmc": null,
"pmid": "31982273",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Retinal ischemia due to extramedullary plasmacytomas of the orbit.",
"title_normalized": "retinal ischemia due to extramedullary plasmacytomas of the orbit"
} | [
{
"companynumb": "AU-BAXTER-2020BAX021264",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Pupillary unrest in ambient light (PUAL), the normal pattern of pupil diameter fluctuation present in awake humans, has been proposed as a marker of central opioid effect. We report 2 cases in which PUAL identified the appropriate pain management for 2 patients, each with unique, challenging acute pain conditions. In both cases, PUAL accurately predicted opioid responsiveness, suggesting an effective, individualized analgesic approach for both patients.",
"affiliations": "From the Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California.;Department of Anesthesiology and Perioperative Medicine, Oregon Health Sciences University, Portland, Oregon.;From the Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California.",
"authors": "McKay|Rachel Eshima|RE|;Neice|Andrew E|AE|;Larson|Merlin D|MD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000710",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "10(10)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": null,
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "279-282",
"pmc": null,
"pmid": "29608463",
"pubdate": "2018-05-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pupillary Unrest in Ambient Light and Prediction of Opioid Responsiveness: Case Report on Its Utility in the Management of 2 Patients With Challenging Acute Pain Conditions.",
"title_normalized": "pupillary unrest in ambient light and prediction of opioid responsiveness case report on its utility in the management of 2 patients with challenging acute pain conditions"
} | [
{
"companynumb": "US-PFIZER INC-2019096056",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "The follow-up of eight patients who were alive and disease-free for at least 12 months following completion of therapy for small cell carcinoma of the lung (SCC) is presented. One patient is alive and well. Five patients (62%), including two with acute leukemia, died of second malignancies. One patient died with late recurrence of SCC, and one patient died of an unexplained neurologic degenerative disease with dementia. It is concluded that patients with apparent cure of SCC are at high risk for serious disorders including second malignancies.",
"affiliations": null,
"authors": "Volk|S A|SA|;Mansour|R F|RF|;Gandara|D R|DR|;Redmond|J|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/1097-0142(19840701)54:1<25::aid-cncr2820540106>3.0.co;2-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "54(1)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000368:Aged; D018288:Carcinoma, Small Cell; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D013997:Time Factors",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "25-7",
"pmc": null,
"pmid": "6326998",
"pubdate": "1984-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Morbidity in long-term survivors of small cell carcinoma of the lung.",
"title_normalized": "morbidity in long term survivors of small cell carcinoma of the lung"
} | [
{
"companynumb": "US-PFIZER INC-2019060088",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment opinion for advanced melanoma and non-small-cell lung cancer, as well as other cancerous entities. Immune checkpoint inhibitors such as anti-PD-1 antibody result in a unique side-effect profile, commonly described as immune-related adverse events (irAE). These irAE affect the skin, gastrointestinal tract, liver, endocrine system and other organ systems. We report two cases of oral lichenoid reaction showing multiple ulcers associated with nivolumab treatment. Both patients presented with multiple ulcers covered with fibrinous plaque over the entire oral mucosa, lips and tongue. Histopathological examination of ulceration showed epithelial necrosis and subepidermal clefts with dense band-like layers of lymphohistiocytic infiltrate within the upper dermis. Nivolumab was interrupted in both cases. Case 1 responded well to topical corticosteroids. Case 2 required oral corticosteroids, however, nivolumab could be restarted without recurrence of oral ulcers. We provide a comprehensive review of reported cases of lichenoid reaction showing multiple oral ulcers associated with anti-PD-1 therapy to date. Early recognition and management may improve treatment, avoid discontinuation of life-saving therapy and maintain quality of life in these patients.",
"affiliations": "Department of Dermatology, Kitasato University School of Medicine, Kanagawa, Japan.;Department of Dermatology, Kitasato University School of Medicine, Kanagawa, Japan.;Department of Dermatology, Kitasato University School of Medicine, Kanagawa, Japan.",
"authors": "Obara|Koya|K|http://orcid.org/0000-0002-5235-3161;Masuzawa|Mamiko|M|;Amoh|Yasuyuki|Y|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D005938:Glucocorticoids; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.14205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "45(5)",
"journal": "The Journal of dermatology",
"keywords": "anti-programmed death cell receptor-1; immune checkpoint inhibitor; immune-related adverse events; nivolumab; oral lichenoid reaction",
"medline_ta": "J Dermatol",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000284:Administration, Oral; D000287:Administration, Topical; D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001706:Biopsy; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D015994:Incidence; D017512:Lichenoid Eruptions; D008175:Lung Neoplasms; D008297:Male; D009055:Mouth; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor; D011788:Quality of Life; D012867:Skin; D016896:Treatment Outcome; D014456:Ulcer",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "587-591",
"pmc": null,
"pmid": "29352490",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Oral lichenoid reaction showing multiple ulcers associated with anti-programmed death cell receptor-1 treatment: A report of two cases and published work review.",
"title_normalized": "oral lichenoid reaction showing multiple ulcers associated with anti programmed death cell receptor 1 treatment a report of two cases and published work review"
} | [
{
"companynumb": "JP-STRIDES ARCOLAB LIMITED-2018SP008961",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MAGNESIUM OXIDE"
},
"drugaddit... |
{
"abstract": "Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%2. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease3-5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.",
"affiliations": "Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. JGao1@mdanderson.org.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. PadSharma@mdanderson.org.",
"authors": "Gao|Jianjun|J|http://orcid.org/0000-0001-6138-4472;Navai|Neema|N|;Alhalabi|Omar|O|http://orcid.org/0000-0002-9658-2206;Siefker-Radtke|Arlene|A|;Campbell|Matthew T|MT|http://orcid.org/0000-0003-1915-4491;Tidwell|Rebecca Slack|RS|http://orcid.org/0000-0003-3041-8582;Guo|Charles C|CC|;Kamat|Ashish M|AM|;Matin|Surena F|SF|;Araujo|John C|JC|;Shah|Amishi Y|AY|;Msaouel|Pavlos|P|;Corn|Paul|P|;Wang|Jianbo|J|;Papadopoulos|John N|JN|;Yadav|Shalini S|SS|;Blando|Jorge M|JM|;Duan|Fei|F|;Basu|Sreyashi|S|http://orcid.org/0000-0002-5028-3833;Liu|Wenbin|W|;Shen|Yu|Y|http://orcid.org/0000-0002-3899-7868;Zhang|Yuwei|Y|;Macaluso|Marc Daniel|MD|;Wang|Ying|Y|;Chen|Jianfeng|J|;Zhang|Jianhua|J|http://orcid.org/0000-0001-5412-9860;Futreal|Andrew|A|http://orcid.org/0000-0001-8663-2671;Dinney|Colin|C|;Allison|James P|JP|;Goswami|Sangeeta|S|;Sharma|Padmanee|P|http://orcid.org/0000-0003-4658-055X",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C000613593:durvalumab; D002945:Cisplatin; C520704:tremelimumab",
"country": "United States",
"delete": false,
"doi": "10.1038/s41591-020-1086-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-8956",
"issue": "26(12)",
"journal": "Nature medicine",
"keywords": null,
"medline_ta": "Nat Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D060908:CTLA-4 Antigen; D002277:Carcinoma; D002945:Cisplatin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D061026:Programmed Cell Death 1 Receptor; D012307:Risk Factors; D019459:Urothelium",
"nlm_unique_id": "9502015",
"other_id": null,
"pages": "1845-1851",
"pmc": null,
"pmid": "33046869",
"pubdate": "2020-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30343614;31686036;23911605;22914978;27530435;24821881;21502557;29742009;12944571;19517476;22189383;21555688;25096609;27733243;28817753;29268948;28212060;29217288;28967485;27939400;11600601;23724867;29562145;29077785;30851984;28803728;31636208;30926234;30150660;24777852;18818309;20460488;31942071;31942075;31942077;30297909;29658848;7746977;28663787;18989396;4836193;23396013;20601685;31240105;26825632;30510237;30341162;25242720",
"title": "Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.",
"title_normalized": "neoadjuvant pd l1 plus ctla 4 blockade in patients with cisplatin ineligible operable high risk urothelial carcinoma"
} | [
{
"companynumb": "2022A028141",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DURVALUMAB"
},
"drugadditional": "3",
"drugadmini... |
{
"abstract": "Postpneumonectomy syndrome involves mediastinal shift causing dynamic airway obstruction via compression of the main bronchus and distal trachea. A few case reports describe the development of ARDS in patients with postpneumonectomy syndrome. Reeb et al. (2017) describe the mortality of postpneumonectomy ARDS anywhere from 33% to 88%. One may encounter difficulty in intubation and ventilation as parameters based on ideal body weight may not apply. Prone positioning ventilation and ECMO have been successfully used in isolated cases. We present such a case and highlight challenges in management. A 70-year-old male Vietnam veteran with remote history of right pneumonectomy thirty years prior presented with fever, cough, and dyspnea. Physical exam was significant for T 36.3°C, BP 162/73, heart rate 145 BPM, RR 22 breaths/minute, ht. 1.72 m, and wt. 78 kg, with transmitted right lung sounds and rhonchi on the left. Labs showed WBC 23.92/nL and procalcitonin 0.84 ng/mL. CXR showed left infiltrate and opacification of right hemithorax with right mediastinal shift. EKG showed atrial fibrillation. He was started on broad spectrum antibiotics for pneumonia, but deteriorated, and was intubated for respiratory distress from ARDS. Vasopressors were initiated for shock. Given the history of pneumonectomy, he was initially ventilated with lower tidal volumes (320 mL). However, incremental changes were made to tidal volumes, and ETT was repositioned several times for hypoxia. Epoprostenol and cisatracurium were also initiated. Positional changes would lead to sudden desaturation; hence, prone positioning ventilation was not done. He was not considered for ECMO due to his pneumonectomy status. Unfortunately, his condition worsened progressively and he expired. The guidelines for ARDS are well established. However, postpneumonectomy patients are unique as seen in our patient. It is unclear whether an endobronchial tube advanced into the left bronchus could have helped difficult airway management resulting from suspected postpneumonectomy syndrome as suggested by CXR. Higher tidal volumes were also unsuccessful in alleviating hypoxia and led to persistently elevated plateau pressures and driving pressures as high as 23, which was inconsistent with our goal of lung protective ventilation. Few case reports describe the successful use of prone positioning ventilation or ECMO in postpneumonectomy patients with ARDS. Although not well studied, low tidal volumes supported with ECMO may have been a favorable strategy for our patient.",
"affiliations": "Department of Medicine, Overlook Medical Center, Summit, NJ 07901, USA.;Department of Medicine, Overlook Medical Center, Summit, NJ 07901, USA.;Department of Medicine, Overlook Medical Center, Summit, NJ 07901, USA.;Department of Medicine, Overlook Medical Center, Summit, NJ 07901, USA.;Department of Pulmonary Critical Care, Overlook Medical Center, Summit, NJ 07901, USA.",
"authors": "Purewal|Jaskaran K|JK|https://orcid.org/0000-0002-0098-8181;Sakul|N F N|NFN|https://orcid.org/0000-0002-2277-9970;Balabbigari|Nikhita R|NR|;Nenninger|Alberto|A|;Kotecha|Nisha|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/5476794",
"fulltext": "\n==== Front\nCase Rep Pulmonol\nCase Rep Pulmonol\nCRIPU\nCase Reports in Pulmonology\n2090-6846 2090-6854 Hindawi \n\n10.1155/2020/5476794\nCase Report\nOne Lung Soldier: A Ventilation Conundrum in a Postpneumonectomy Syndrome Complicated by Acute Respiratory Syndrome\nhttps://orcid.org/0000-0002-0098-8181Purewal Jaskaran K. jaskaran.purewal@gmail.com\n1\n https://orcid.org/0000-0002-2277-9970Sakul N. F. N. \n1\n Balabbigari Nikhita R. \n1\n Nenninger Alberto \n1\n Kotecha Nisha \n2\n \n1Department of Medicine, Overlook Medical Center, Summit, NJ 07901, USA\n\n2Department of Pulmonary Critical Care, Overlook Medical Center, Summit, NJ 07901, USA\nAcademic Editor: Tun-Chieh Chen\n\n\n2020 \n11 3 2020 \n2020 547679431 8 2019 23 1 2020 26 2 2020 Copyright © 2020 Jaskaran K. Purewal 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.Postpneumonectomy syndrome involves mediastinal shift causing dynamic airway obstruction via compression of the main bronchus and distal trachea. A few case reports describe the development of ARDS in patients with postpneumonectomy syndrome. Reeb et al. (2017) describe the mortality of postpneumonectomy ARDS anywhere from 33% to 88%. One may encounter difficulty in intubation and ventilation as parameters based on ideal body weight may not apply. Prone positioning ventilation and ECMO have been successfully used in isolated cases. We present such a case and highlight challenges in management. A 70-year-old male Vietnam veteran with remote history of right pneumonectomy thirty years prior presented with fever, cough, and dyspnea. Physical exam was significant for T 36.3°C, BP 162/73, heart rate 145 BPM, RR 22 breaths/minute, ht. 1.72 m, and wt. 78 kg, with transmitted right lung sounds and rhonchi on the left. Labs showed WBC 23.92/nL and procalcitonin 0.84 ng/mL. CXR showed left infiltrate and opacification of right hemithorax with right mediastinal shift. EKG showed atrial fibrillation. He was started on broad spectrum antibiotics for pneumonia, but deteriorated, and was intubated for respiratory distress from ARDS. Vasopressors were initiated for shock. Given the history of pneumonectomy, he was initially ventilated with lower tidal volumes (320 mL). However, incremental changes were made to tidal volumes, and ETT was repositioned several times for hypoxia. Epoprostenol and cisatracurium were also initiated. Positional changes would lead to sudden desaturation; hence, prone positioning ventilation was not done. He was not considered for ECMO due to his pneumonectomy status. Unfortunately, his condition worsened progressively and he expired. The guidelines for ARDS are well established. However, postpneumonectomy patients are unique as seen in our patient. It is unclear whether an endobronchial tube advanced into the left bronchus could have helped difficult airway management resulting from suspected postpneumonectomy syndrome as suggested by CXR. Higher tidal volumes were also unsuccessful in alleviating hypoxia and led to persistently elevated plateau pressures and driving pressures as high as 23, which was inconsistent with our goal of lung protective ventilation. Few case reports describe the successful use of prone positioning ventilation or ECMO in postpneumonectomy patients with ARDS. Although not well studied, low tidal volumes supported with ECMO may have been a favorable strategy for our patient.\n==== Body\n1. Introduction\nThe postpneumonectomy state is a unique entity with associated anatomical and physiological challenges. One such challenge is the postpneumonectomy syndrome, more commonly seen in patients with right pneumonectomies, which involves dynamic airway obstruction resulting from compression of the main bronchus and distal trachea by the vertebral column or aorta due to the rotation and right mediastinal shift. These patients pose particularly difficult challenges in ventilation due to the increased respiratory dead space and decreased venous return and are prone to shunting and development of pulmonary edema [1]. The management of ARDS in these patients is not well established but usually is conservative and often involves mechanical ventilation once it becomes necessary. Due to the unique anatomy and physiology, one may encounter difficulty in endotracheal tube positioning and selecting ventilation parameters. Studies regarding ventilator management in ARDS excluded patients with pneumonectomy. The usual lung protective ventilation parameters dependent on ideal body weight may not apply to patients with a single lung. But at the same time, the attempt to lower the tidal volume further may be impossible due to difficulty in oxygenation of such patients. Prone positioning ventilation and extracorporeal membrane oxygenation (ECMO) have been successfully used in isolated similar cases but have been generally reserved for postsurgical pneumonectomy patients who develop ARDS. In a small retrospective study by Reeb et al., the use of VV-ECMO in postpneumonectomy ARDS patients was studied and subsequently showed improved hospital survival [2]. We present a patient with remote history of pneumonectomy now admitted with ARDS and highlight unique challenges associated with its management.\n\n2. Case Presentation\nA 70-year-old male with hypertension and remote history of carcinoid tumor requiring right pneumonectomy thirty years prior presented with one week of generalized malaise, fever, nonproductive cough, and worsening dyspnea on exertion. He was in his usual state of health until one week prior to his presentation; overall, he was very healthy with good functional status with slightly decreased stamina. Initial physical exam was significant for temperature 36.3°C, BP 162/73, irregular heart rate 145 beats/minute, respiratory rate 22 breaths/minute, height 1.72 m, and weight 78 kg. He was a thin male with transmitted lung sounds on the right and significant rhonchi on the left. The remainder of the physical exam was otherwise within normal limits. Initial lab results showed leukocytosis (WBC 23.92/nL), positive procalcitonin (0.84 ng/mL), negative Legionella and S. pneumoniae urine antigen, negative respiratory viral panel, and mild respiratory alkalosis on ABG (7.49/39/69/24.6). EKG showed atrial fibrillation with rapid ventricular response. Initial CXR showed left-sided infiltrate with pleural effusion as well as complete opacification of the right hemithorax with right mediastinal shift (Figure 1). Overall, there was concern for severe sepsis due to multilobar community-acquired pneumonia. He was subsequently started on ceftriaxone and azithromycin and placed on high-flow nasal cannula. He was also started on a continuous infusion of diltiazem and received full-dose enoxaparin for anticoagulation in the setting of uncontrolled atrial fibrillation. He quickly converted to normal sinus rhythm within a few hours and was started on oral diltiazem. However, within four hours of hospital admission, his respiratory status quickly deteriorated and a rapid response was called for hypoxia and increased work of breathing. Oxygen requirements on high-flow nasal cannula had increased significantly, and while he was able to speak in full sentences, he was clearly anxious, air hungry, and using accessory muscles to breathe. ECHO showed normal left ventricular function with an ejection fraction of 55% and a sclerotic aortic valve without stenosis but was not significant for any cardiac shunt, such as patent foramen ovale. Repeat ABG showed worsening hypoxia with a PaO2 : FiO2 ratio of 71 mmHg. Repeat CXR showed worsening of the left-sided infiltrate (Figure 2). Further imaging with CT chest or even a bronchoscopy was needed to further qualify the worsening infiltrate as well as possible obstruction from postpneumonectomy syndrome; however, the patient was never hemodynamically stable for this. He required transfer to the intensive care unit and intubation for significant respiratory distress, with concern for developing ARDS and septic shock. Antibiotic coverage was broadened to vancomycin, piperacillin-tazobactam, and azithromycin; stress dose steroids and vasopressors were also initiated. Given the history of pneumonectomy, he was initially ventilated with low tidal volumes (320 mL). While the goal was to maintain lung protective ventilation, incremental changes were made to his tidal volume to maintain oxygenation but were not effective. Throughout his ICU course, oxygenation and ventilation proved to be difficult. In addition, his endotracheal tube was repositioned several times leading to temporary improvements in oxygenation (Figure 3). Epoprostenol and neuromuscular blockade were initiated for oxygenation and ventilator synchrony; however, they were only beneficial temporarily. Furthermore, peak and plateau pressures were consistently elevated, suggestive of an obstructive component, possibly from worsening edema from ARDS exacerbating his underlying postpneumonectomy state. While proning ventilation was considered, it was not done as even minimal changes in his position lead to sudden hemodynamic instability with desaturation and tachycardia. Furthermore, due to his remote history of pneumonectomy and clinical severity, he was not considered a good candidate for ECMO. Unfortunately, due to his progressively worsening clinical condition, which was also verified by the worsening chest X-ray (Figure 4), he was transitioned to comfort care measures and expired.\n\n3. Discussion\nARDS is a well-recognized clinical entity in an ICU setting, and its management involves treatment of the underlying etiology as well as ventilation management. Several guidelines and studies have been conducted to direct treatment and escalation of care to prone ventilation and ECMO. However, postpneumonectomy patients have particular anatomical and physiological changes that pose challenges in their management of ARDS as seen in our patient.\n\nPneumonectomies are indicated for numerous reasons including removal of malignancy or in a trauma setting. While uncommon, postpneumonectomy syndrome can occur within weeks or even years after removal of the lung. It is more commonly seen after right pneumonectomy, possibly due to the more severe anatomical changes. The postpneumonectomy syndrome results in airway obstruction due to rotation and mediastinal shift towards the pneumonectomy site. This results in eventual herniation and overinflation of the remaining lung and leads to central airway compression [3]. Patients will often present with stridor, worsening dyspnea, or recurrent pulmonary infections as a result. This was clearly seen in our patient. Imaging findings clearly described with relation to postpneumonectomy syndrome were clearly also illustrated in our patient's initial admitting chest X-ray (Figure 1). While he was asymptomatic from the clear anatomical changes noted on his imaging, infection and subsequent edema may have exacerbated his underlying postpneumonectomy state. In a study done in 2008, surgical correction of the syndrome with prostheses led to improved flow rates, decreased FVC, and correction of the hyperinflation, as well as an improved FEV1/FVC ratio. However, more than the changes noted on PFTs, patients experienced significant improvement in their symptoms [3]. It is clear that this syndrome causes airway compression, and thus, airway management may be difficult. Besides the difficulty in intubation from mechanical obstruction, the associated hypercapnia, hypoxia, increased respiratory dead space, and overall decreased venous return can contribute to ventilation problems, as was seen in our patient [1]. Initial airway management was difficult due to poor placement of the ETT (Figures 2 and 3). While a CT chest would have been ideal to visualize the extent this played in his ventilation problems, it was not feasible. A similar case was described in 2015, in which a patient underwent a left-sided pneumonectomy for a persistent mycobacterial infection and three months later became symptomatic. CT imaging in this patient showed significant obstruction of the bronchus intermedius and right lower bronchus. The case report also describes difficulty in oxygenating the patient, and eventually, the patient's endotracheal tube was then temporarily replaced with an endobronchial tube until surgery was viable. The authors additionally describe considering the use of an endobronchial stent but mention uncertainty in its efficacy or long-term risks [4]. In the anesthesia literature, mediastinal masses often create airway obstruction, which are managed with the use of endobronchial tubes [5]. Whether a single lumen endobronchial tube advanced up to the left bronchus could have been used to decompress the airway and overcome this obstruction to provide better ventilation remains unclear. Another potential concern was a possible platypnea-orthodeoxia syndrome caused by interatrial shunting after pneumonectomy [6]. However, this was highly unlikely as no intracardiac shunt was noted on ECHO, and furthermore, our patient was not symptomatic from this condition prior to presentation, even in the setting of his pneumonectomy done thirty years ago.\n\nSince the PROSEVA trial in 2013, early initiation of proning in patients with severe ARDS had an associated mortality benefit [7]. However, there is limited literature regarding postpneumonectomy patients affected with ARDS and the subsequent effect of proning. While prone ventilation was not an option for our patient due to hemodynamic instability, case reports have demonstrated significant improvement in similar patients [8, 9]. Furthermore, it is uncertain whether typical ventilation strategies used in ARDS management may be as effective due to a combination of the underlying pathophysiology of postpneumonectomy syndrome and ARDS. Initial ventilator settings were to maintain low tidal volumes and were adjusted based on the patient's pneumonectomy status; we still had difficulty maintaining adequate oxygenation despite adjustments and increases to the tidal volume. These increments in tidal volume led to persistently elevated plateau pressures > 30 and driving pressures as high as 23, which oppose the goal of lung protective ventilation. Low tidal volumes when supported with ECMO may have been a favorable strategy for our patient and allowed us to ventilate with a lower plateau and driving pressures. A small study done by Reeb et al. showed that the use of VV-ECMO in postpneumonectomy ARDS patients decreased the mortality from 80 to 50%. ECMO had allowed for greater lung protective strategies, decreased tidal volumes, adequate gas exchange, and overall better recovery of lung tissue [2]. ECMO was not considered in our patient but may have been beneficial and may have allowed for the use of improved lung protective strategies. While it is difficult in this particular set of patients, greater study is needed regarding ARDS management in postpneumonectomy patients.\n\n4. Conclusion\nFew case reports describe improved mortality with prone ventilation as well as ECMO in postpneumonectomy ARDS, which in hindsight may have been beneficial for our patient given the difficulties we had in managing our patient's ventilation. While this has not been well studied due to the unique nature of these disease states, it is important to keep in mind as a possibility for management in postpneumonectomy patients. Our case highlights how better guidelines with regard to treatment concerning single lung ventilation and a possible postpneumonectomy syndrome may have been life changing in his scenario.\n\nAbbreviations\nECMO:Extracorporeal membrane oxygenation\n\nARDS:Acute respiratory distress syndrome\n\nCXR:Chest X-ray\n\nEKG:Electrocardiogram\n\nABG:Arterial blood gas\n\nWBC:White blood cell\n\nFEV1:Forced expiratory volume\n\nFVC:Forced vital capacity\n\nPFTs:Pulmonary function tests\n\nETT:Endotracheal tube\n\nVV-ECMO:Venovenous extracorporeal membrane oxygenation.\n\nAdditional Points\n\nKey Points. Postpneumonectomy syndrome is a rare entity that leads to mechanical airway obstruction due to mediastinal shift, which can contribute to difficult airway management. The use of prone ventilation and ECMO have been used in isolated cases of postpneumonectomy ARDS, but their utility and subsequent effects are not well understood. Further study is needed on ventilation in patients with pneumonectomies.\n\nConflicts of Interest\nNo financial disclosures and no conflict of interest have been identified with any of the authors.\n\nFigure 1 Initial chest X-ray showing complete opacification of the right hemithorax from pneumonectomy. Right mediastinal shift present. Diffuse infiltrates noted in the left lung.\n\nFigure 2 Repeat chest X-ray done one day after admission. Patient noted to have worsening hypoxia and increased work of breathing and was subsequently intubated. Chest X-ray significant for worsening of the left-sided superior perihilar infiltrate.\n\nFigure 3 Chest X-ray done after advancement of the endotracheal tube, shown in the image to be projected toward the right side of the trachea. Persistent airspace disease noted in the left upper lobe.\n\nFigure 4 Chest X-ray showing significant worsening of the L-sided infiltrate, leading to complete opacification of the left lung.\n==== Refs\n1 Sharifpour M. Bittner E. A. Postpneumonectomy syndrome Anesthesiology 2014 121 6 p. 1334 10.1097/01.anes.0000435638.00429.ac 2-s2.0-84914125487 24047857 \n2 Reeb J. Olland A. Pottecher J. Extracorporeal membrane oxygenation for acute respiratory distress syndrome after pneumonectomy The Annals of Thoracic Surgery 2017 103 3 881 889 10.1016/j.athoracsur.2016.11.038 2-s2.0-85011394706 28168966 \n3 Shen K. R. Wain J. C. Wright C. D. Grillo H. C. Mathisen D. J. Postpneumonectomy syndrome: surgical management and long-term results The Journal of Thoracic and Cardiovascular Surgery 2008 135 6 1210 1219.e6 10.1016/j.jtcvs.2007.11.022 2-s2.0-44649174893 18544355 \n4 Karasaki T. Tanaka M. Life-threatening postpneumonectomy syndrome complicated with right aortic arch after left pneumonectomy Case Reports in Surgery 2015 2015 4 768067 10.1155/2015/768067 \n5 Harte B. Jaklitsch M. McKenna S. Body S. Use of a modified single-lumen endobronchial tube in severe tracheobronchial compression Anesthesiology 2002 96 2 510 511 10.1097/00000542-200202000-00042 2-s2.0-0036165963 11818789 \n6 Komatsu T. Bethune D. Platypnea orthodeoxia syndrome and bronchopleural fistula following right pneumonectomy: the first case of double misfortune following pneumonectomy International Journal of Surgery Case Reports 2011 2 4 47 48 10.1016/j.ijscr.2010.12.004 2-s2.0-79952624032 22096686 \n7 Guérin C. Reignier J. Richard J. Prone positioning in severe acute respiratory distress syndrome The New England Journal of Medicine 2013 368 23 2159 2168 10.1056/nejmoa1214103 2-s2.0-84878602907 23688302 \n8 Tatineni S. Sasikumar S. Shanbhag V. Prone position for management of refractory hypoxaemia in a patient with single lung Indian Journal Of Respiratory Care 2012 1 1 69 71 \n9 Cornejo R. Romero C. Goñi D. Ventilación en posición prono prolongada como alternativa en el tratamiento del síndrome de distrés respiratorio agudo grave posneumonectomía: caso clínico Revista Médica de Chile 2009 137 10 10.4067/s0034-98872009001000011\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6854",
"issue": "2020()",
"journal": "Case reports in pulmonology",
"keywords": null,
"medline_ta": "Case Rep Pulmonol",
"mesh_terms": null,
"nlm_unique_id": "101585355",
"other_id": null,
"pages": "5476794",
"pmc": null,
"pmid": "32231840",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "23688302;22096686;11818789;26106501;28168966;24047857;20011943;18544355",
"title": "One Lung Soldier: A Ventilation Conundrum in a Postpneumonectomy Syndrome Complicated by Acute Respiratory Syndrome.",
"title_normalized": "one lung soldier a ventilation conundrum in a postpneumonectomy syndrome complicated by acute respiratory syndrome"
} | [
{
"companynumb": "US-PFIZER INC-202101033259",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nDescribe the GETH haploidentical stem cell transplantation (haplo-HSCT) activity in non-malignant disease (NMDs).\n\n\nMETHODS\nWe retrospectively analyzed data from children with NMDs who underwent haplo-HSCT.\n\n\nRESULTS\nFrom January 2001 to December 2016, 26 pediatric patients underwent 31 haplo-HSCT through ex vivo T cell-depleted (TCD) graft platforms or post-transplantation cyclophosphamide (PT-Cy) at 7 Spanish centers. Five cases employed unmanipulated PT-Cy haplo-HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+ CD19+ depletion, TCRαβ+ CD19+ selection or naive CD45RA+ T-cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo-HSCT, and bone marrow was the source for one PT-Cy haplo-HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1-year cumulative incidence of graft failure was 27.4%. The 1-year III-IV acute graft-versus-host disease (GvHD) and 1-year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2-year overall survival was 44.9% for PIDs, and the 2-year graft-versus-host disease-free and relapse-free survival rate was 37.6% for the other NMDs. The transplantation-related mortality at day 100 was 30.8%.\n\n\nCONCLUSIONS\nAlthough these results are discouraging, improvements will come if procedures are centralized in centers of expertise.",
"affiliations": "La Paz University Hospital, Madrid, Spain.;La Paz University Hospital, Madrid, Spain.;Hospital Carlos Haya, Málaga, Spain.;Hospital Vall d'Hebron, Barcelona, Spain.;University of Santiago Clinical Hospital, Santiago de Compostela, Spain.;Virgen de la Arrixaca University Clinical Hospital, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.;Hospital Virgen del Rocio, Sevilla, Spain.;Hospital of Salamanca, Salamanca, Spain.;University of Santiago Clinical Hospital, Santiago de Compostela, Spain.;Virgen de la Arrixaca University Clinical Hospital, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.;La Paz University Hospital, Madrid, Spain.;La Paz University Hospital, Madrid, Spain.;La Paz University Hospital, Madrid, Spain.;Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.;Centro de Transfusión de la Comunidad de Madrid, Madrid, Spain.;Centro de Transfusión de la Comunidad de Madrid, Madrid, Spain.;La Paz University Hospital, Madrid, Spain.;Hospital Vall d'Hebron, Barcelona, Spain.;La Paz University Hospital, Madrid, Spain.",
"authors": "Torres Canizales|Juan|J|;Ferreras|Cristina|C|;Pascual|Antonia|A|;Alonso|Laura|L|https://orcid.org/0000-0002-7835-1594;Regueiro|Alexandra|A|https://orcid.org/0000-0003-3156-4784;Plaza|Mercedes|M|;Pérez Hurtado|José María|JM|;Benito|Ana|A|;Couselo|José M|JM|;Fuster|José L|JL|;Díaz-Almirón|Mariana|M|;Bueno|David|D|;Mozo|Yasmina|Y|;Gómez López|Alicia|A|;Vicario|José L|JL|;Balas|Antonio|A|;Sisinni|Luisa|L|;Díaz de Heredia|Cristina|C|;Pérez-Martínez|Antonio|A|https://orcid.org/0000-0002-6436-9195",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "106(2)",
"journal": "European journal of haematology",
"keywords": "T cell-depleted graft; haploidentical hematopoietic stem cell transplantation; high-dose post-transplantation cyclophosphamide; non-malignant diseases; pediatric",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000367:Age Factors; D002675:Child, Preschool; D019468:Disease Management; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007239:Infections; D008297:Male; D017063:Outcome Assessment, Health Care; D010372:Pediatrics; D010818:Practice Patterns, Physicians'; D011379:Prognosis; D012189:Retrospective Studies; D013030:Spain; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "196-204",
"pmc": null,
"pmid": "33084101",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Haploidentical transplantation in pediatric non-malignant diseases: A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation (GETH).",
"title_normalized": "haploidentical transplantation in pediatric non malignant diseases a retrospective analysis on behalf of the spanish group for hematopoietic transplantation geth"
} | [
{
"companynumb": "ES-VELOXIS PHARMACEUTICALS-2021VELES-000181",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"... |
{
"abstract": "Complicating disorders in various organs outside the intestinal tract are common in ulcerative colitis. This report deals with the occurrence of nephrotic syndrome in two patients with long-standing ulcerative colitis. In the patient studied in most detail, 2 episodes have taken place, the first developing into uremia. After colectomy had been performed, rapid improvement of renal function took place. The morphological changes in kidney biopsies were compatible with the presence of focal glomerular sclerosis. Activity in the complement system and a favorable response to steroid treatment indicate that humoral immune mechanisms are of pathogenetic importance with regard to the renal disease in these two patients. To our knowledge nephrotic syndrome has not previously been described as a complication to ulcerative colitis.",
"affiliations": null,
"authors": "Stokke|K T|KT|;Teisberg|P A|PA|;Myhre|E|E|;Hovig|T|T|;Flatmark|A|A|;Gjone|E|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5521",
"issue": "11(6)",
"journal": "Scandinavian journal of gastroenterology",
"keywords": null,
"medline_ta": "Scand J Gastroenterol",
"mesh_terms": "D000328:Adult; D003093:Colitis, Ulcerative; D006801:Humans; D007668:Kidney; D007677:Kidney Function Tests; D007678:Kidney Glomerulus; D008297:Male; D009404:Nephrotic Syndrome",
"nlm_unique_id": "0060105",
"other_id": null,
"pages": "571-6",
"pmc": null,
"pmid": "981960",
"pubdate": "1976",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nephrotic syndrome in ulcerative colitis.",
"title_normalized": "nephrotic syndrome in ulcerative colitis"
} | [
{
"companynumb": "NO-PFIZER INC-2021047390",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CORTISONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nRenal and obstetric outcomes in pregnancy after kidney transplantation in Singapore were last studied in 2002. A review of these outcomes in Singapore is now timely following advances in transplant and obstetric medicine. The aim was to evaluate the renal and obstetric outcomes in pregnancy after kidney transplantation in a Singapore tertiary center.\n\n\nMETHODS\nKidney transplant recipients who underwent pregnancy after transplantation at Singapore General Hospital between January 2001 and December 2012 were identified. Data on demographics, comorbidities and clinical outcomes were collected.\n\n\nRESULTS\nThere were 10 pregnancies identified in nine recipients. The median age of recipient at childbearing was 34.6 years (IQR, 32.8-36.8) and the median interval from transplantation to conception was 69 months (IQR, 38-97). There was no difference between the median pre-pregnancy estimated glomerular filtration rate (eGFR) (47.9 mL/min/1.73 m(2); IQR, 38.4-56.8) and median eGFR at time of last post-partum follow up (43.9 mL/min/1.73 m(2); IQR, 34.5-48.7, P = 0.549). Borderline allograft rejection occurred in one recipient (10.0%) 36 days after birth due to non-adherence to immunosuppressive medication, with subsequent allograft loss 37 months after birth. No mortalities were recorded during the study period. All the 10 pregnancies (100%) ended in singleton live births. Pre-eclampsia occurred in five pregnancies (50.0%), and there were seven (70.0%) preterm deliveries. The median gestational age was 35.4 weeks (IQR, 32.6-38.2) and the median birthweight was 2353 g (IQR, 1811-2648).\n\n\nCONCLUSIONS\nPost-transplantation pregnancies ended successfully with no significant worsening of allograft function, but they were associated with risks to both recipients and newborns.",
"affiliations": "Department of Renal Medicine, Singapore General Hospital, Singapore, Singapore.;Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.;Department of Obstetrics and Gynaecology, Singapore General Hospital, Singapore, Singapore.;Department of Obstetrics and Gynaecology, Singapore General Hospital, Singapore, Singapore.;Department of Renal Medicine, Singapore General Hospital, Singapore, Singapore.",
"authors": "Kwek|Jia Liang|JL|;Tey|Vanessa|V|;Yang|Liying|L|;Kanagalingam|Devendra|D|;Kee|Terence|T|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.12736",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "41(9)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "kidney transplantation; pregnancy; pregnancy complication; pregnancy outcome; renal outcome; transplantation",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D011225:Pre-Eclampsia; D011247:Pregnancy; D011256:Pregnancy Outcome; D012846:Singapore",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1337-44",
"pmc": null,
"pmid": "26017543",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Renal and obstetric outcomes in pregnancy after kidney transplantation: Twelve-year experience in a Singapore transplant center.",
"title_normalized": "renal and obstetric outcomes in pregnancy after kidney transplantation twelve year experience in a singapore transplant center"
} | [
{
"companynumb": "PHHY2015SG115059",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Pulmonary aspergillosis associated with cyanotic congenital heart disease is a rare condition, which is known to have a poor prognosis. We report a case of a 21-year-old woman with truncus arteriosus and major aortopulmonary collateral arteries who underwent primary Rastelli procedure after thoracoscopic lobectomy for the management of progressive pulmonary aspergillosis.",
"affiliations": "Department of Pediatrics, Kitami Red Cross Hospital, Kitami, Japan.;Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan.;Department of Cardiovascular Surgery, Kanagawa Children's Hospital, Yokohama, Japan.",
"authors": "Goto|Takeru|T|https://orcid.org/0000-0003-3977-5340;Takeda|Atsuhito|A|;Tachibana|Tsuyoshi|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1017/S1047951121000706",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "31(8)",
"journal": "Cardiology in the young",
"keywords": "Pulmonary aspergillosis; Rastelli surgery; lung lobectomy; major aortopulmonary collateral arteries; truncus arteriosus communis",
"medline_ta": "Cardiol Young",
"mesh_terms": "D000328:Adult; D003490:Cyanosis; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D011651:Pulmonary Artery; D055732:Pulmonary Aspergillosis; D014338:Truncus Arteriosus; D014339:Truncus Arteriosus, Persistent; D055815:Young Adult",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "1373-1375",
"pmc": null,
"pmid": "33682671",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful surgical management of cyanotic congenital heart disease complicated by pulmonary aspergillosis.",
"title_normalized": "successful surgical management of cyanotic congenital heart disease complicated by pulmonary aspergillosis"
} | [
{
"companynumb": "JP-SLATE RUN PHARMACEUTICALS-22JP001116",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditiona... |
{
"abstract": "Although intrathecal baclofen (ITB) therapy is an effective treatment for spasticity, it has several disadvantages and a risk of complications.\n\n\n\nWe present six pediatric patients who suffered from unusual mechanical failures of intrathecal baclofen pump systems.\n\n\n\nWith these case-vignettes, we provide a systematic approach on how to interpret the symptoms of ITB complications and an advice which further diagnostic and therapeutic steps to follow. We underline the seriousness of baclofen overdose, underdosing or withdrawal.",
"affiliations": "Division of Neuropediatrics, Hospital for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany. Janina.Gburek-Augustat@medizin.uni-leipzig.de.;Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.;Division of Neuropediatrics, Hospital for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany.;Pediatric Radiology, University Hospital Leipzig, Leipzig, Germany.;Pediatric Radiology, University Hospital Leipzig, Leipzig, Germany.;Pediatric Intensive Care Unit, Hospital for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany.;Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.;Division of Neuropediatrics, Hospital for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany.",
"authors": "Gburek-Augustat|Janina|J|;Krause|Matthias|M|;Bernhard|Matthias|M|;Sorge|Ina|I|;Gräfe|Daniel|D|;Siekmeyer|Manuela|M|;Nestler|Ulf|U|;Merkenschlager|Andreas|A|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-021-05154-3",
"fulltext": "\n==== Front\nChilds Nerv Syst\nChilds Nerv Syst\nChild's Nervous System\n0256-7040\n1433-0350\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33834279\n5154\n10.1007/s00381-021-05154-3\nOriginal Article\nUnusual mechanical failures of intrathecal baclofen pump systems: symptoms, signs, and trouble shooting\nGburek-Augustat Janina Janina.Gburek-Augustat@medizin.uni-leipzig.de\n\n1\nKrause Matthias M.Krause@medizin.uni-leipzig.de\n\n2\nBernhard Matthias Matthias.Bernhard@medizin.uni-leipzig.de\n\n1\nSorge Ina Ina.Sorge@medizin.leipzig.de\n\n3\nGräfe Daniel Daniel.Graefe@medizin.uni-leipzig.de\n\n3\nSiekmeyer Manuela Manuela.Siekmeyer@medizin.uni-leipzig.de\n\n4\nNestler Ulf Ulf.Nestler@medizin.uni-leipzig.de\n\n2\nMerkenschlager Andreas Andreas.Merkenschlager@medizin.uni-leipzig.de\n\n1\n1 grid.411339.d 0000 0000 8517 9062 Division of Neuropediatrics, Hospital for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany\n2 grid.411339.d 0000 0000 8517 9062 Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany\n3 grid.411339.d 0000 0000 8517 9062 Pediatric Radiology, University Hospital Leipzig, Leipzig, Germany\n4 grid.411339.d 0000 0000 8517 9062 Pediatric Intensive Care Unit, Hospital for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany\n8 4 2021\n8 4 2021\n2021\n37 8 25972604\n2 3 2021\n29 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nIntroduction\n\nAlthough intrathecal baclofen (ITB) therapy is an effective treatment for spasticity, it has several disadvantages and a risk of complications.\n\nMethods\n\nWe present six pediatric patients who suffered from unusual mechanical failures of intrathecal baclofen pump systems.\n\nResults\n\nWith these case-vignettes, we provide a systematic approach on how to interpret the symptoms of ITB complications and an advice which further diagnostic and therapeutic steps to follow. We underline the seriousness of baclofen overdose, underdosing or withdrawal.\n\nKeywords\n\nIntrathecal baclofen therapy\nBaclofen pump complication\nBaclofen withdrawal\nBaclofen overdose\nSpasticity\nCerebral palsy\nBisphosphonate therapy\nUniversität Leipzig (1039)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nReducing spasticity makes care easier, prevents secondary orthopedic problems and relieves pain. This improves the patient’s quality of life. Baclofen has an anti-spastic effect, but cerebral side effects often occur before therapeutic anti-spastic effects of oral administration are observed. To increase efficacy, intrathecal baclofen therapy (ITB) has been used to treat spasticity since the 1980s. ITB yields better reduction in spasticity at doses 1000 times lower than oral baclofen and minimizes adverse effects [1].\n\nThe indication for ITB treatment arises from the severity of spasticity and dystonia. Children with a gross motor function classification system (GMFCS) level IV or V benefit most. The treatment is palliative and constitutes a challenge with respect to the multimorbidity of the patients.\n\nThe baclofen pump is inserted subcutaneously in the lower abdomen and connected to a catheter as part of a surgical procedure. This catheter is placed under the skin and inserted into the intrathecal space at a lumbar level and then moved upwards. Placement of the tip of the intrathecal catheter has been suggested at the T1–T2 level for spastic quadriplegia, the T6–T10 level for spastic diplegia and in the midcervical region for dystonia [2]. The dose is adjusted individually, since in children there are no clear age-related or body weight-correlated recommendations [3]. Clinically, anti-spastic effects of continuous intrathecal dose changes occur with a 2–4-h delay [4]. A loss of efficacy in the long-term course in patients with a stable underlying disease (e.g. cerebral palsy) is seldomly observed [3].\n\nAlthough ITB is an effective treatment of spasticity, it suffers from several disadvantages. The pump reservoir must be refilled with baclofen regularly through an injection. In addition, the pump must be surgically exchanged about every 5–7 years for battery exhaustion. Furthermore physicians must be aware of potentially serious complications (Table 1). A withdrawal syndrome is the most common cause of a life-threatening event, but toxicity from overdose due to mechanical system malfunction has also to be beared in mind [5]. In children, ITB complications occur in about 24–30% of cases [6–8], and the complications can present challenges for clinicians, so a high index of suspicion is needed to make the correct diagnosis [9]. Table 1 Symptoms and therapy of baclofen-underdosing/withdrawal and overdosing\n\n\tUnderdosing/withdrawal\tOverdosing\t\nMild symptoms\tReturn of baseline spasticity, pruritus, irritability, agitation, temperature > 38 °C, labile blood pressure, tachycardia, headache, disorientation, hallucination\tWeakness (beginning in the lower limbs), tiredness to somnolence, listlessness, dizziness, constipation, urinary retention, nausea, vomiting, headache, drooling\t\nSevere symptoms\tExtreme CNS hyperexcitability, myoclonus, high fever (> 39 °C), altered mental status to coma, seizures, rhabdomyolysis, disseminated intravascular coagulation, multisystem organ failure, autonomic dysregulation to cardiac arrest, may advance to death when insufficiently treated\tMuscular hypotonia to functional decline, hypothermia, bradycardia, arterial hypotonia, altered mental status to coma, seizures, increase of slow-wave activity and epileptiform discharges in electroencephalography, respiratory suppression to respiratory arrest, may advance to death when insufficiently treated\t\nDifferential diagnosis\tPain, anxiety, infection/sepsis/meningitis, epilepsy, malignant hyperthermia, intracranial haemorrhage, neuroleptic-malignant or serotonin syndrome\tHypoglycemia, electrolyte imbalance, epilepsy, infection /sepsis /meningitis, intracranial haemorrhage\t\nTarget of treatment\tRestore intrathecal dose of baclofen used before underdosing as quick as possible\tRemove residual ITB solution from the pump, lumbar puncture to remove CSF and reduce baclofen concentration\t\nBridging emergency treatment\tSupportive care in an intensive care setting\n\nBaclofen p.o. (up to 150 mg/d)\n\nBenzodiazepine i.v. (1–2 mg/h continuously)\n\nPropofol i.v.\n\nDantrolen i.v. (to treat rhabdomyolysis)\n\nSymptomatic treatment (intravenous fluids)\n\nPlacement of an external lumbar catheter for administration of intrathecal baclofen\n\n\tSupportive care in an intensive care setting\n\nSymptomatic treatment (e.g. respiratory support)\n\nNo specific antidote available\n\nSeizure control according to guidelines\n\n(Physostigmine 0,02 mg/kg i.v. or i.m. can be considered)\n\n\t\n\nPatients and methods\n\nWe here describe six unusual mechanical ITB complications (Table 2), occurring in most of the patients after a long and successful treatment period, which obscured some of the hints to diagnosis and treatment of the failure (Tables 1 and 3). We use SynchroMed II pumps from Medtronic with corresponding Ascenda catheters. We applied a variable flow for patient case 6 and a fixed flow for all other patients. Table 2 Overview of cases with mechanical ITB complication\n\nCase\tLocalisation\tOnset after pump implantation\tSymptoms\tCause and findings\t\n1\tPump\t5 years\tSudden withdrawal symptoms.\tIntraoperatively a corroded, defective pump was found (Fig. 1)\t\n2\tConnection from pump to catheter\t5 years\tUnderdosing and indolent, nonreddened swelling in the abdominal area.\tConnector from the catheter to the pump was not tight and baclofen and cerebrospinal fluid was leaking (Fig. 2)\t\n3\tCatheter\t13 years\tUnderdosing\tCT showed catheter rupture (Fig. 3)\t\nCatheter and pump\tPronounced calcification of pump, catheter and surrounding tissue\tCalcification caused by treatment with bisphosphonates\t\n4\tCatheter\t1 month\tUnderdosing\tX-ray showed dislocation (Fig. 5)\t\nCatheter\t4 years\tUnderdosing\tX-ray fluoroscopy was assessed as inconspicuous, intraoperatively the catheter was found twisted (Fig. 6)\t\n5\tEpidural malpositioning of the catheter\tFrom the beginning\tFluctuating symptoms: alternation between under- und overdosing\tSpiral CT of the skull base and cranial spine after contrast medium application showed a faulty position of the tip of the tube system, which is placed epidurally (Fig. 7)\t\n6\tIntrathecal circulation problem\t7 years after implantation of the pump-catheter-system and immediately after replacement\tFluctuating symptoms: alternation between under- und overdosing\tRepositioning the catheter for high cervical baclofen delivery with high flow did improve the situation\t\n\nTable 3 Step-by-step procedure for suspected baclofen pump problems\n\nClinical symptoms (see Table 1)\t\nUnderdosing/withdrawal\tAlternating underdosing and overdosing\tOverdosing\t\nPossible causes\t\nIatrogenic mistake: baclofen concentration too low or running rate too low\tMechanical problem of the pump\tProblem with catheter\tMechanical problem of the pump\tMalposition of intrathecal catheter tip\tProblems with intrathecal baclofen distribution\tIatrogenic mistake: baclofen concentration too high or running rate too high\tMechanical problem of the pump\t\nTrouble shooting/diagnostic steps\t\nRead out the pump\t\nCheck the pump reservoir and refill the pump\t\nLaboratory tests: blood gas analysis, blood sugar, electrolytes, creatine kinase, creatinine, blood count, CRP, drug levels of anticonvulsants\t\nProgramme bolus\tX-ray of the pump\tX-ray of the catheter\tAll other causes should be excluded:\t-\tX-ray of the pump\t\n-\tX-ray of the pump before and after the bolus\tX-ray of the catheter\tEmpty catheter via side port and add contrast medium under fluoroscopy or CT-scan\tX-ray of pump and catheter\t\nEmpty catheter via side port and add contrast medium under fluoroscopy or CT-scan\tEmpty catheter via side port and add contrast medium under fluoroscopy or CT-scan\t\nExternal catheter in very high position with variation of flow\t\nIf still necessary, extended diagnostics can be considered:\n\nRadionuclide scintigraphy with serial sequential scanning after 24 h, 48 h, 72 h and/or MRI\n\n\t\nProblem-solving\t\nProblem solved by step “refilling”\tPump exchange\tCatheter exchange\tPump exchange\tChange position of the catheter\tIncrease baclofen flow and place catheter tip intrathecally in very high position\tProblem solved by step “refilling”\tPump exchange\t\n\nCase 1\n\nAt the age of 11 years, the boy suffered from a traffic accident with considerable brain trauma. He developed a severe residual syndrome with spasticity GMFCS V and apallic syndrome. With 12 years a baclofen pump was implanted with good effect on muscle tone. The pump was refilled regularly.\n\nFive years after baclofen pump implantation, for the first time a pump alarm arose. A few hours later, he presented at the emergency room because of high muscle tension, sweating and trembling. Creatine kinase was increased to 15.02 μkat/l (reference < 4.1). The suspected baclofen withdrawal symptoms were treated with oral baclofen, diazepam, continuous administration of analgesics and high-volume infusion therapy.\n\nIn search for the cause, an X-ray was taken, and because this was unremarkable, contrast medium was applied via the side port of the baclofen pump to test the catheter system. No contrast medium flow into the catheter system could be shown. In a subsequent computed tomography (CT), no leakage was demonstrated, neither. Disconnection of the catheter was not detectable, so pump replacement was indicated. During intraoperative evaluation, a corroded and thus no longer functional pump was found (Fig. 1), a very rare complication [10, 11]. A new pump was implanted and the symptoms resolved. Fig. 1 Case 1, photo of the corroded pump\n\nCase 2\n\nThe girl had fell victim to carbon monoxide poisoning at the age of 2 years. As a result, she developed spasticity GMFCS V and an apallic syndrome. A baclofen pump was implanted 1 month after the accident, and intrathecal baclofen therapy showed good effect on muscle tension. Five years later the patient was presented with a soft, indolent abdominal (Fig. 2). Spasticity had worsened in the previous weeks, so the baclofen dosage had been increased step by step. The swelling on the abdomen was punctured and serous fluid was collected. The fluid showed a high protein content (total protein 8.4 g/l) and no inflammatory cells, so it was interpreted as leakage out of the catheter. Surgical revision was performed, and the connector from the catheter to the pump was found to be loose. Baclofen was leaking from the proximal and cerebrospinal fluid from the distal part. The pump at the end of battery lifetime and the connector were replaced. Subsequently, a lower baclofen dosage was required to obtain sufficient treatment effects. Fig. 2 Case 2, photo of the abdomen shows subcutaneous bulging by dislocated catheter\n\nCase 3\n\nAt the age of three, the boy suffered from hypoxic brain damage and subsequent bilateral spasticity GMFCS V as result of a drowning accident. Four months later, a baclofen pump was implanted with good effect. During the longer course, the patient developed inactivity osteoporosis and experienced several bone fractures. With 12 years, treatment with bisphosophonates was therefore initiated.\n\nOverall, ITB was carried out in the patient for 13 years without any problems. Shortly before the planned explantation of the pump because of low battery charge, the patient’s spasticity worsened. A CT scan was performed under suspicion of catheter dysfunction which showed subdural contrast depots at two points and a subcutaneous catheter rupture (Fig. 3). Fig. 3 Case 3, CT shows catheter rupture: spiral CT of the spine after injection of the baclofen pump with 15 ml solutrast: evidence of a subcutaneous contrast medium extravasation as a sign of a tube rupture dorsal to L4 (long white arrow). In addition, most likely misalignment of the catheter tip with two subdural contrast agent deposits (short white arrows). Only minute amounts of contrast medium are displayed intrathecally\n\nFor that reason, both pump and catheter were explanted. Intraoperatively, it was recognized that the tissue around the pump was hardly movable, calcareous coating of the pump was noticed, and the entry point of the catheter into the spinal canal was found to be surrounded by chalky, strongly adherent tissue. The calcification was very unusual and was interpreted as an adverse side effect of the bisphosphonate therapy (Fig. 4). Fig. 4 Case 3, histological workup displays steps of heterotopic bone formation with fibrous mesenchymal tissue lying adjacent to calcifying areas and immature woven bone (Scalebar corresponds to 100 μM)\n\nSix days after replacement, wound dehiscence developed with purulent secretion. The patient suffered from fever and laboratory results showed leukocytosis and increased serum CRP values. Staphylococcus aureus was identified in local wound specimen and blood culture. Antibiotic treatment with cefotaxime and clindamycin was started. The new pump and the entire catheter system had to be completely removed.\n\nThe patient then developed pronounced withdrawal symptoms after the pump explantation: shakiness, sweating, agitation and increase in spasticity. He received high doses of oral baclofen, midazolam, clonidine and dronabinol to alleviate the withdrawal symptoms. The patient’s condition slowly improved, and a new pump system was reimplanted several months later uneventfully.\n\nCase 4\n\nFollowing peripartal varicella encephalitis associated with intracerebral haemorrhage, the newborn girl developed bilateral spastic cerebral palsy GMFCS V. At seven years ITB was started with an initially good response. The first complication occurred as soon as 1 month after pump implantation. An increase in spasticity and a higher frequency of crying periods were reported. By increasing the baclofen dose from 150 to 320 μg/d, no improvement of the symptoms could be achieved.\n\nX-ray demonstrated a dislocation of the intrathecal catheter (Fig. 5). The catheter was rolled up at the level of L3 and could be repositioned into the intrathecal space neurosurgically. Fig. 5 Case 4, lateral spine X-ray: the catheter is dislocated and a large part lies rolled up subcutaneously, so that it ends in the soft tissues between the lumbar spinous processes\n\nA long-term complication occurred 4 years later when spasticity and restlessness increased again. An X-ray was inconspicuous. Two months later, a discrepancy during pump filling was found. While 2.1 ml were supposed to be in the pump reservoir, 11 ml could be extracted. This showed a reduced extrusion of baclofen without programmed lowering of the flow rate. The catheter access port was punctured. Neither cerebrospinal fluid could be aspirated nor contrast agent injected. Surgical pump explantation revealed a coiled spinal catheter which had led to a functional closure of the catheter. Retrospectively, the detection of the once more subcutaneously twisted catheter on the X-ray images remains challenging (Fig. 6). Fig. 6 Case 4, X-ray fluoroscopy: after puncturing the access port of the pump, with correct needle position documented on the image, neither CSF can be aspirated nor contrast medium applied. The part of the tube system that is not covered by the pump is shown correctly, the tip of the catheter is projected at the level of the 6th thoracal vertebra (long white arrow). The short white arrows disclose the rolling up of the catheter\n\nCase 5\n\nThe patient presented with an Addison’s crisis and severe hypoglycemia as initial manifestation of X-linked adrenoleukodystrophy at the age of 4 years. He developed progressive leukodystrophy as typical feature of the underlying disease and bilateral basal ganglion necrosis which we interpreted as consequence of the severe Addison crisis. This resulted in a mixed picture of spastic and dystonic-dyskinetic movement disorder, initial GMFCS lay at III, decreasing to IV. One month after the neurological deterioration, baclofen pump was implanted.\n\nDifficulties with the intrathecal baclofen therapy started nearly immediately. The symptoms varied widely with intermittent weakness in the legs. This was interpreted as a sign of overdose. These symptoms alternated with phases of increased spasticity suggesting underdosing. The fluctuating symptoms led to frequent reprogramming of the baclofen pump rate. The dose varied between 25 and 510 μg/d. CT was performed because of the unstable treatment results and revealed an epidural position of the dislocated intrathecal catheter (Fig. 7). This incorrect positioning most likely resulted in the delivery of changing amounts of intrathecal baclofen which explained the fluctuating symptoms. After revision of the catheter, baclofen was effective at a dose of 350 μg/d. During follow-up the dose had to be increased only as the disease progressed. Fig. 7 Case 5, spiral CT of the skull base and the upper cervical spine after contrast medium application via the side port of the baclofen pump: The tube system was intact up to the intraspinal entry of the tube at the level of L4/L5, without evidence of leakage. Contrast medium distribution presents epidurally dorsal to the CSF space at C2 (long arrow), pushing between the dural sheets of the tentorium (short arrow). There is no evidence of intrathecal contrast medium\n\nCase 6\n\nPeriventricular leukomalacia because of preterm birth was the cause of bilateral spastic cerebral palsy GMFCS V in this patient. At seven years, the boy received a baclofen pump. ITB showed a good response until the baclofen pump was changed after 7 years when the battery was low. Three months after changing the pump, the patient developed a spastic crisis. X-ray was inconspicuous without signs of catheter interruption or leakage. A pump malfunction was assumed, and a replacement of the pump was planned. For short-term treatment of the withdrawal symptoms, an additional, external CSF catheter was placed to administer baclofen intrathecally which led to a rapid improvement. A new pump was implanted shortly afterwards and was connected to the remaining catheter system. However, during the following 5 months, problems persisted with increased intrathecal baclofen demand, interrupted by phases with signs of overdose as increased fatigue and somnolence. When analysing the difference between internal and external baclofen administration were twofold: the external catheter was positioned very high, and baclofen was more diluted leading doubled flow velocity. A rostral baclofen distribution problem has been discussed. For that reason a new spinal catheter was positioned to the level of C0/C1, and baclofen was thinned down to 1 mg/ml (compared to the standard dilution of 2 mg/ml) to allow for a reasonable intrathecal flow velocity delivered by the pump. This finally resulted in improvement and stabilisation of the previously unfavourable situation. Employing higher flow and extremely high catheter placement intraventricular placement could be avoided, what had been discussed as alternative solution.\n\nDiscussion\n\nAny change in the patient’s clinical state could be a warning sign of baclofen pump dysfunction.\n\nProblems with ITB can be divided into three categories: first, there are application errors. These include incorrect programming or filling of the pump with the wrong drug dilution or failure to recognize a pending battery change. Second, there are mechanical flow problems. Here it is important to identify the localization: Is it the pump itself that has a defect and either delivers too much, too little or no baclofen at all, is it the connection point pump to abdominal catheter or abdominal catheter to spinal catheter part, is it in the course of the catheter or is it the intrathecal positioning of the catheter? Third, there are infections, here beyond the scope of this manuscript.\n\nDepending on the dynamics of the onset and severity of the under- or overdosing symptoms, diagnostic and therapeutic steps should be initiated in a targeted manner. Symptom-related treatment should be initiated concomitant to the search for the underlying causes of malfunction (Tables 1 and 3).\n\nAn increase in spasticity may be a relative underdosing due to a therapeutic change in pump rate or because of an increased need with progressive worsening of the underlying disease. However, it is a warning sign, when spasticity suddenly deteriorates or when the dosage has been increased and the spasticity continues to worsen. At any level of the pump and catheter system, there might be the problem causing underdosing or withdrawal; therefore, each level must be checked step by step. Incorrect filling of the pump with low concentration of baclofen, lower dosage, a mechanical problem of the pump or failure to transport the drug out of the pump through the catheter into the intrathecal space due to dislocation, kinking, obstruction or malposition of the catheter tip, for example, can lead to a lack of baclofen at the site of action.\n\nOverdosing occurs less frequently and may occur as result of an iatrogenic mistake when filling of the pump was incorrect (high baclofen concentration) or the pump rate too high. Another reason might be that the pump itself has a mechanical problem and is transporting more baclofen solution than programmed. Catheter problems mostly result in too little baclofen arriving intrathecally; therefore this usually does not lead to overdosing but eventually to fluctuating treatment responses.\n\nIf there are fluctuating symptoms with an alternation of over- or underdosing, this may be due to pump dysfunction. However, a malpositioning of the catheter tip, similar to case 5, should also be considered, when varying amounts of baclofen arrive intrathecally. Changes in intrathecal baclofen distribution may also lead to fluctuating symptoms, even though the catheter tip is correctly located intrathecally. We report this in case 6. Other causes of pump or catheter complications were made unlikely in this case by extensive diagnostic workup. Without proof of a mechanical dysfunction, improving the situation can be tried in these cases by placing the catheter tip to the C0/C1 level, as an alternative to intraventricular placement in case of efficacy decline.\n\nChildren who are immobilized by chronic disease are at high risk of developing secondary osteoporosis. The probability of receiving ITB and concomitant treatment with bisphosphonates is therefore increased. The intraoperative findings in case 3 with a combination of ITB and bisphosphonates with pronounced calcifications were impressive and so far not observed by us in other patients. We assume this to be a side effect of the bisphosphonates. We also suspect that these calcifications of the tissue contributed to the subsequent infection of the pump pocket. We could not find any other similar case report in the literature.\n\nConclusion\n\nWe describe different causes of ITB failure, the resulting symptoms and signs, as well as an approach to trouble shooting.\n\nPatients with spasticity GMFCS level IV and V may benefit significantly from ITB. However, the benefit should also be balanced against the risk of potentially life-threatening complications.\n\nAbbreviations\n\nITB Intrathecal baclofen therapy\n\nGMFCS Gross motor function classification system\n\nCT Computed tomography\n\nAcknowledgements\n\nWe thank our patients and their families for their trust and cooperation. We thank Dr. med. Eisenlöffel, Department of Neuropathology, for providing us with the histological image.\n\nAuthor contribution\n\nDr. med. Janina Gburek-Augustat: Conception and writing of the manuscript. Data collection and analysis. Cared for the patients as pediatric neurologist.\n\nPD Dr. med. Matthias Krause: Revised the manuscript. Cared for the patients as pediatric neurosurgeon.\n\nDr. med. Matthias Bernhard: Revised the manuscript. Cared for the patients as pediatric neurologist.\n\nDr. med. Ina Sorge: Revised the manuscript. Responsible for radiological diagnostics, contribution of figures.\n\nDr. med. Daniel Gräfe: Revised the manuscript. Responsible for radiological diagnostics.\n\nDr. med. Manuela Siekmeyer: Revised the manuscript. Cared for the patients as pediatric intensive care physician.\n\nProf. Dr. med. Ulf Nestler: Revised the manuscript. Cared for the patients as neurosurgeon.\n\nProf. Dr. med. Andreas Merkenschlager: Idea and concept. Revision of the manuscript. Cared for the patients as pediatric neurologist.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nData Availability\n\nPatient findings, imaging and records are documented electronically in the in-house hospital data system of the University Hospital Leipzig.\n\nDeclarations\n\nEthics approval and Consent to participate\n\nThe patients were treated at the University Hospital Leipzig. Consent for treatment was given by the parents or caregivers and are in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki.\n\nConflicts of interest\n\nNone.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Mohammed I Hussain A Intrathecal baclofen withdrawal syndrome- a life-threatening complication of baclofen pump: a case report BMC Clin Pharmacol 2004 4 6 10.1186/1472-6904-4-6 15301690\n2. Albright AL Barry MJ Shafton DH Ferson SS Intrathecal baclofen for generalized dystonia Dev Med Child Neurol 2001 43 652 657 10.1017/s0012162201001190 11665821\n3. Voss W Gad D Mücke K-H Christen H-J Intrathekale Baclofentherapie: Palliativmaßnahme bei spastischen und dystonen Bewegungsstörungen Monatsschrift für Kinderheilkunde 2009 157 1 9 10.1007/s00112-009-2038-2\n4. Dressler D Berweck S Chatzikalfas A Ebke M Frank B Hesse S Huber M Krauss JK Mücke KH Nolte A Oelmann HD Schönle PW Schmutzler M Pickenbrock H Van der Ven C Veelken N Vogel M Vogt T Saberi FA Intrathecal baclofen therapy in Germany: proceedings of the IAB-interdisciplinary working group for movement disorders consensus meeting J Neural Transm (Vienna) 2015 122 11 1573 1579 10.1007/s00702-015-1425-1 26179478\n5. Tunali Y Hanimoglu H Tanriverdi T Hanci L Hanci M Intrathecal baclofen toxicity and deep coma in minutes J Spinal Cord Med 2006 29 3 237 239 10.1080/10790268.2006.11753880 16859228\n6. Winter G Beni-Adani L Ben-Pazi H Intrathecal baclofen therapy-practical approach: clinical benefits and complication management J Child Neurol 2018 33 11 734 741 10.1177/0883073818785074 30009656\n7. Motta F Antonello CE Analysis of complications in 430 consecutive pediatric patients treated with intrathecal baclofen therapy: 14-year experience J Neurosurg Pediatr 2014 13 3 301 306 10.3171/2013.11.PEDS13253 24404968\n8. Gooch JL Oberg WA Grams B Ward LA Walker ML Complications of intrathecal baclofen pumps in children Pediatr Neurosurg 2003 39 1 1 6 10.1159/000070870 12784068\n9. Woolf SM Baum CR Baclofen pumps: uses and complications Pediatr Emerg Care 2017 33 4 271 275 10.1097/PEC.0000000000001090 28353527\n10. Riordan J Murphy P Intrathecal pump: an abrupt intermittent pump failure Neuromodulation. 2015 18 5 433 435 10.1111/ner.12258 25382390\n11. Stetkarova I Brabec K Vasko P Mencl L Intrathecal baclofen in spinal spasticity: frequency and severity of withdrawal syndrome Pain Physician 2015 18 4 E633 E641 10.36076/ppj.2015/18/E 26218954\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0256-7040",
"issue": "37(8)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Baclofen overdose; Baclofen pump complication; Baclofen withdrawal; Bisphosphonate therapy; Cerebral palsy; Intrathecal baclofen therapy; Spasticity",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D001418:Baclofen; D002547:Cerebral Palsy; D002648:Child; D006801:Humans; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D009125:Muscle Relaxants, Central; D009128:Muscle Spasticity",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "2597-2604",
"pmc": null,
"pmid": "33834279",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26218954;12784068;11665821;16859228;28353527;15301690;25382390;24404968;30009656;26179478",
"title": "Unusual mechanical failures of intrathecal baclofen pump systems: symptoms, signs, and trouble shooting.",
"title_normalized": "unusual mechanical failures of intrathecal baclofen pump systems symptoms signs and trouble shooting"
} | [
{
"companynumb": "US-BEXIMCO-2021BEX00063",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": "4",
"... |
{
"abstract": "OBJECTIVE\nThere is a wide spectrum of clinical manifestations in children with anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis from two different health care settings.\n\n\nMETHODS\nWe describe our experience with 13 patients (median age, 7 years; range, 5 months to 19 years) presenting to tertiary referral centers in India and the United States.\n\n\nRESULTS\nInitial manifestations were neurological (seizures or movement disorders) in eight patients, and psychiatric (e.g., emotional lability and hallucination) in five patients. Symptoms during the clinical course included seizures in ten patients, movement disorders (dyskinesia and choreiform movements) in 11 patients, and behavioral changes (aggressiveness and insomnia) in ten patients. Concomitant infections (herpes simplex virus 1, tuberculous meningitis, and influenza A) were present in three patients. Analysis of the cerebrospinal fluid in all except two cases preceded by infection (herpes simplex virus encephalitis and tuberculous meningitis) was unremarkable. Treatment included intravenous immunoglobulin/methylprednisolone (11 patients), rituximab (eight patients), plasmapheresis (two patients), and cyclophosphamide (two patients). Six patients recovered completely. Two patients had mild residual neurological deficits, whereas four had severe residual neurological deficits. Two patients had profound autonomic instability, which was the cause of death for one of them. Two patients relapsed at two and six months after the initial recovery.\n\n\nCONCLUSIONS\nWe describe the differences and similarities of clinical presentation, test results, and response to treatment of children with anti-N-methyl-d-aspartate receptor encephalitis from India and the United States. Included is a description of one of the youngest patients with anti-N-methyl-d-aspartate receptor encephalitis (five months) and the first patient to be reported in association with tuberculous meningitis.",
"affiliations": "Saul R. Korey Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York. Electronic address: ajaygoenka2011@hotmail.com.;Santokba Durlabhji Memorial Hospital, Jaipur, Rajasthan, India.;Saul R. Korey Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.;Saul R. Korey Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.;Saul R. Korey Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.",
"authors": "Goenka|Ajay|A|;Jain|Vivek|V|;Nariai|Hiroki|H|;Spiro|Alfred|A|;Steinschneider|Mitchell|M|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.pediatrneurol.2017.03.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "72()",
"journal": "Pediatric neurology",
"keywords": "acute psychosis; autonomic instability; movement disorder; seizures",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000293:Adolescent; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006212:Hallucinations; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007194:India; D007223:Infant; D008297:Male; D008775:Methylprednisolone; D009069:Movement Disorders; D012640:Seizures; D007319:Sleep Initiation and Maintenance Disorders; D063189:Symptom Assessment; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "51-55",
"pmc": null,
"pmid": "28506503",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extended Clinical Spectrum of Anti-N-Methyl-d-Aspartate Receptor Encephalitis in Children: A Case Series.",
"title_normalized": "extended clinical spectrum of anti n methyl d aspartate receptor encephalitis in children a case series"
} | [
{
"companynumb": "US-PFIZER INC-2017230172",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nBupropion is a pharmacologic agent approved by the U.S. Food and Drug Administration as an antidepressant and to support smoking cessation. Because reduction of seizure threshold is a rare but serious side effect of bupropion, its use in patients with a known history of seizures is contraindicated. We report a patient without seizure risk factors who presented to the emergency department (ED) with new-onset seizures secondary to bupropion use.\n\n\nMETHODS\nA 66-year-old female presented to the ED by emergency medical services with altered mental status. She was determined to be postictal after a witnessed new-onset seizure 4 days after starting bupropion for smoking cessation. She had no personal or family history of seizure disorders, although her medication list raised suspicion that recent discontinuation of alprazolam may have contributed to a reduced seizure threshold. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: New-onset seizures secondary to bupropion use are less likely in patients with no personal or family history of seizure disorders. Emergency medicine clinicians should be aware, however, of the seizure risk associated with bupropion regardless of personal risk factors. Discontinuation of bupropion should be considered if determined to be a contributor to seizures.",
"affiliations": "Stritch School of Medicine, Loyola University, Chicago, Illinois.;Department of Emergency Medicine, Loyola University Medical Center, Chicago, Illinois.;Department of Emergency Medicine, Loyola University Medical Center, Chicago, Illinois; Department of Pharmacy, Loyola University Medical Center, Maywood, Illinois.",
"authors": "Saffaei|Donna|D|;Lovett|Shannon|S|;Rech|Megan A|MA|",
"chemical_list": "D016642:Bupropion",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2019.12.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "58(3)",
"journal": "The Journal of emergency medicine",
"keywords": "bupropion; new-onset seizure; smoking cessation",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000368:Aged; D016642:Bupropion; D005260:Female; D006801:Humans; D012640:Seizures; D016540:Smoking Cessation",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e145-e147",
"pmc": null,
"pmid": "32001124",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "New-Onset Seizure in Patient Medicated With Bupropion for Smoking Cessation: A Case Report.",
"title_normalized": "new onset seizure in patient medicated with bupropion for smoking cessation a case report"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-236900",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"druga... |
{
"abstract": "To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA).\n\n\n\nThis was a population-based case-malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995-2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies.\n\n\n\nThere were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73-2.33), isolated OC 1.45 (95% CI 0.80-2.63), isolated cleft palate 1.69 (95% CI 0.69-4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01-3.31) and 1.43 (95% CI 0.66-3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy.\n\n\n\nThe risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.",
"affiliations": "From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany. h.dolk@ulster.ac.uk.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.;From Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.",
"authors": "Dolk|Helen|H|;Wang|Hao|H|;Loane|Maria|M|;Morris|Joan|J|;Garne|Ester|E|;Addor|Marie-Claude|MC|;Arriola|Larraitz|L|;Bakker|Marian|M|;Barisic|Ingeborg|I|;Doray|Berenice|B|;Gatt|Miriam|M|;Kallen|Karin|K|;Khoshnood|Babak|B|;Klungsoyr|Kari|K|;Lahesmaa-Korpinen|Anna-Maria|AM|;Latos-Bielenska|Anna|A|;Mejnartowicz|Jan P|JP|;Nelen|Vera|V|;Neville|Amanda|A|;O'Mahony|Mary|M|;Pierini|Anna|A|;Rißmann|Anke|A|;Tucker|David|D|;Wellesley|Diana|D|;Wiesel|Awi|A|;de Jong-van den Berg|Lolkje T W|LT|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000002540",
"fulltext": "\n==== Front\nNeurologyNeurologyneurologyneurneurologyNEUROLOGYNeurology0028-38781526-632XLippincott Williams & Wilkins Hagerstown, MD 27053714NEUROLOGY201567390510.1212/WNL.00000000000025405361115228ArticleLamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies Dolk Helen DrPHScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\n(1) International Federation of Spina Bifida and Hydrocephalus, funding for travel to Annual Meeting 2015. (2) European Medicines Agency, funding for travel to meetings of European Network of Centres for Pharmacovigilance and Pharmacoepidemiology (3) MHRA. Funding for travel to meeting of Expert Group.\n\n\n\nEditorial Boards:\nEditorial Board of Rare.\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\n(1) GSK, funded Ulster University to conduct the study which is the subject of this paper.\n\n\n\nResearch Support, Government Entities:\n(1) EU DGSanco, funded Ulster University to co-ordinate EUROCAT: European Surveillance of Congenital Anomalies, which provided the database used for this study. Up to December 2014. (2) EU Framework 7, funded Ulster University to co-ordinate EUROmediCAT - Safety of Medication in pregnancy in relation to risk of congenital anomaly. 2011-2015. Funding not used for this study.\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nChest, Heart and Stroke (charity). Funding Ulster University to conduct a study of risk and protective factors for congenital heart disease.\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nWang Hao PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\n(1) commerical entity: My institution received funding from Glaxo Smith Kline, via Ulster University\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nLoane Maria PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\n(1) Glaxo Smith Kline (2009-2014)\n\n\n\nResearch Support, Government Entities:\n(1) EU DG Sanco Public Health Programme, Work Package leader, 2014 (2) ESRC, Co-investigator, 2013-2018 (3) EU Framework 7, Work Package leader, 2011-2015\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nMorris Joan PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nGarne Ester MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\n2009: GSK payment (< 1000 dollars) to my institution paid through University of Ulster\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nAddor Marie-Claude MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nfunds from GSK via ULSTER University for data\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nArriola Larraitz MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBakker Marian PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBarisic Ingeborg MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\n1) Shire Pharmaceuticals, funding for attending Hunter Syndrome Expert Meeting\n\n\n\nEditorial Boards:\nPaediatria Croatica, Editor in Chief 1999 -\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nThis study was sponsored by Glaxo Smith Kline. Funding was received via Ulster University, for data contributed to this study\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nDoray Berenice PhD, MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nGatt Miriam MScScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nGSK through University of Ulster provided research support.\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nKallen Karin Scientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nKhoshnood Babak MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nGSK Pharmaceutical company - Received funding for our registry for participation in, specifically for providing data, for the study.\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nKlungsoyr Kari PhD (DrMed)Scientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nLahesmaa-Korpinen Anna-Maria PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nLatos-Bielenska Anna Scientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nMejnartowicz Jan P. MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nPolpharma Trade Office, Warszawa, Poland: honorarium for lecture\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\n(1) Neurologia, Wydawnictwo Lekarskie PZWL, 2014 (2) Neurologia Kompendium, Wydawnictwo Lekarskie PZWL, 2015\n\n\n\nEmployment, Commercial Entity:\nFamily Practice No 1 in Lubon, Poland: Neurology Specialist 2012 - ongoing Alvamed Non-Public Health Care Facility in Poznan, Poland; Neurology Specialist; 2013 - ongoing\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\n(1) Foreign Affairs Hospital in Poznan, Poland, treating patients with epilepsy, 3%, 2008- ongoing (2) Family Practice No 1 in Lubon, Poland, treating patients with epilepsy, 5%, 2012 - ongoing\n\n\n\nResearch Support, Commercial Entities:\n(1) Glaxo Smith Kline - My institution received funds from Glaxo Smith Kline via Ulster University for data contributed to this and previous studies\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nNelen Vera MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nGSK funding for my institution received via Ulster University for data for the study\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nNeville Amanda BSc HonsScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nFunding to attend the EUROmediCAT meeting from CNR (Italian National Research Centre) Pisa. CNR is a governmental non profit research institute.\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nParticipation on 14 march 2015 Expert discussion Panel on Isotrentinoin for which I recieved a fee from Difa-Cooper a pharmaceutical company\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nConsultancy for 1 day with Difa Cooper a commericial entity. Consultancy with CNR national governmental research centre for EUROmediCAT meeting\n\n\n\nResearch Support, Government Entities:\nThe IMER registry which contributed data to the study is funded by the Emilia Romagna Health Authority. Grant number Delibera 1812/06 no. 2013/07\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nO'Mahony Mary MFPHMIScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nGlaxo Smith Kline provided funding, pre 2010, to cover the cost of work in contributing and verifying data, and commenting on progress and results for the original and follow up EUROCAT Lamotrigine studies to investigate a signal in the literature relating to facial cleft anomalies.\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nPierini Anna MScScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nGSK funded data via University of Ulster\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nRißmann Anke MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nMalformation Monitoring Centre Saxony-Anhalt is funded by Ministry of Labor and Social Affairs Saxony-Anhalt, Germany.\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nTucker David MPHScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nShare holder of GSK\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nWellesley Diana FRCPScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nWiesel Awi MScScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nGSK for case report of anti-epileptic exposure in newborns\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nUniversity of Mainz - until 2011\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nde Jong-van den Berg Lolkje T.W. PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFrom Ulster University (H.D., M.L.), Northern Ireland, UK; University of Groningen (H.W., L.T.W.d.J.-v.d.B.), the Netherlands; Barts and the London School of Medicine and Dentistry (J.M.), UK; Hospital Lillebaelt (E.G.), Kolding, Denmark; Registre Vaudois des Malformations (M.-C.A.), Lausanne, Switzerland; Public Health Division of Gipuzkoa (L.A.), Instituto BIO-Donostia, Basque Government, CIBER Epidemiología y Salud Pública-CIBERESP, Madrid, Spain; University Medical Centre Groningen (M.B.), the Netherlands; Children's University Hospital Zagreb (I.B.), Croatia; Registre des Malformations Congenitales D'Alsace (B.D.), University of Strasbourg, France; Department of Health Information and Research (M.G.), Malta; Swedish National Board of Health and Welfare (K. Kallen), Stockholm, Sweden; Institut National de la Sante et de la Recherche Medicale (B.K.), INSERM, Villejuif, France; Medical Birth Registry of Norway (K. Klungsoyr), Oslo; National Institute for Health & Welfare (A.-M.L.-K.), Helsinki, Finland; Poznan University of Medical Sciences (A.L.-B., J.P.M.), Poland; Provinciaal Instituut voor Hygiene (V.N.), Antwerp, Belgium; Center for Clinical and Epidemiological Research Ferrara (A.N.), Italy; Health Service Executive (M.O.), Kildare, Ireland; Institute of Clinical Physiology-National Research Council (IFC-CNR) (A.P.), Pisa, Italy; Otto-von-Guericke University Magdeburg (A.R.), Germany; Public Health Wales NHS Trust (D.T.), Congenital Anomaly Register and Information Service for Wales; Wessex Clinical Genetics Service (D.W.), Princess Anne Hospital, UK; and University Medical Center of Mainz Birth Registry Mainz Model (A.W.), Germany.Correspondence to Dr. Dolk: h.dolk@ulster.ac.ukGo to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by the authors.\n\n03 5 2016 03 5 2016 86 18 1716 1725 19 6 2015 26 1 2016 © 2016 American Academy of Neurology2016American Academy of NeurologyThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.Objective:\nTo test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA).\n\nMethods:\nThis was a population-based case–malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995–2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies.\n\nResults:\nThere were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73–2.33), isolated OC 1.45 (95% CI 0.80–2.63), isolated cleft palate 1.69 (95% CI 0.69–4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01–3.31) and 1.43 (95% CI 0.66–3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy.\n\nConclusions:\nThe risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.\n\nOPEN-ACCESSTRUE\n==== Body\nLamotrigine is commonly used for both epilepsy and bipolar disorder.1,2 Evidence of a good teratogenic safety profile relative to other antiepileptic drugs (AED), with an overall congenital anomaly (CA) risk close to background expectation in cohort studies,3–6 has encouraged use for women of childbearing age and pregnant women.1 However, there are concerns about pharmacokinetics and seizure risk in pregnancy5,7 and lamotrigine is not effective for some people with epilepsy.8 A warning about the specific risk of orofacial clefts (OC) is given in patient information (Medicines and Healthcare Products Regulatory Agency 2015), due to a signal from the North American AED registry of a 6-fold risk of OC, specifically cleft palate.9,10 A number of studies have been published since,6,11–13 none of which has produced further evidence to support an excess risk of this magnitude.\n\nEUROCAT is network of population-based CA registries.14 In 2008, we tested the signal of an increased risk of OC with lamotrigine monotherapy by analyzing data from 19 registries for the period 1995–2005.13 In an exploratory analysis, we found evidence of an excess risk of clubfoot, which could have been a chance finding and constituted a signal requiring confirmation in independent data.13 Our objective in this new study was to enlarge the study population in order to estimate more precisely the relative risk of OC, to follow-up the clubfoot signal, and to explore evidence of risk of other CA subgroups.\n\nMETHOD\nStudy design.\nCase-malformed control design to test OC and clubfoot signals.\n\nExploratory analysis comparing proportion of each CA subgroup between lamotrigine-exposed and non-AED-exposed.\n\n\n\nStudy population and registry data.\nThe EUROCAT central database contains anonymized, individual CA registrations, including livebirths, fetal deaths from 20 weeks' gestation, and terminations of pregnancy for fetal anomaly (TOPFA). One syndrome and up to 8 anomalies are coded by ICD-9/10 codes.15 Babies with only minor anomalies according to the EUROCAT list15 are excluded. Other variables include maternal age, maternal disease before and during pregnancy (ICD coded + text), and medications taken in the first trimester of pregnancy (Anatomical Therapeutic Chemical coded16).15 Information about maternal medication exposure is mainly obtained from medical records of pregnancy, and some registries also use maternal interviews after birth or prescription databases (table 1).17\n\nTable 1 Overview of participating registries: Region/country, source of medication exposure information, study years, total birth population covered, total major congenital malformation (MCM) registrations\n\nTwenty-one population-based registries participated—the 19 registries of the previous study,13 and Finland and Sweden, which as associate EUROCAT members transmitted data for this study. The study population comprised 10.1 million births from 1995 to 2011 (table 1), of which 6.3 million were an independent study population (table 1). One woman may have more than one baby in the study population.\n\nTOPFA were excluded in Norway and Sweden due to lacking medication exposure information. TOPFA in Emilia Romagna and Saxony-Anhalt were retained despite known exposure underascertainment.\n\nClassification of congenital anomalies.\nThere were 226,806 CA registrations in the study population, divided into nonchromosomal (n = 199,515, 88%) and chromosomal CA (n = 27,291, 12%). Nonchromosomal CA were classified into EUROCAT standard CA subgroups.15 One baby can be counted in more than one subgroup, but each baby is counted only once when subgroups are combined. OC cases were divided into isolated and multiply malformed (at least 2 major anomalies not part of a syndrome, sequence, or complex) according to Coding & Classification panel case review.18 Diagnoses of all lamotrigine-exposed registrations were also reviewed by the panel.\n\nExposure definition.\nRegistrations with maternal epilepsy or AED exposure were verified with registries. Exposures were classified as monotherapy or polytherapy (use of 2 or more AED types in the first trimester, concurrently or sequentially) and by type of AED (lamotrigine, any AED, any AED excluding valproic acid [VPA]). The category “any AED excluding VPA” was constructed due to established high teratogenicity of VPA. To avoid misclassification, we excluded mothers with epilepsy without recorded AED exposure (574 registrations, figure e-1 on the Neurology® Web site at Neurology.org).\n\nForty-three registrations of the 259 with lamotrigine exposure (22 mono, 21 poly, including 3 chromosomal registrations) were confirmed as exposed during pregnancy but could not be confirmed as first trimester exposures and were excluded in sensitivity analyses.\n\nCase and control definition and classification.\nOrofacial clefts.\nCases were babies with nonsyndromic OC. Cases were excluded where OC was part of a chromosomal, monogenic, or teratogenic syndrome or secondary to another primary anomaly (figure e-1). A subanalysis for cleft palate was performed since this was more strongly associated with lamotrigine in the original signal.10\n\nControls were babies with nonchromosomal major CA excluding OC.\n\nClubfoot.\nCases were babies with nonchromosomal clubfoot excluding spina bifida sequence (2% of all clubfoot) (figure e-1).\n\nControls were babies with nonchromosomal nonclubfoot major CA.\n\nLamotrigine monotherapy-exposed clubfoot cases were further classified as unilateral/bilateral, and the exclusion of positional talipes,15 a much more common minor anomaly, was verified. For comparison, diagnostic details and treatment type were provided for a random sample of 308 out of 1,429 clubfoot registrations in 16 registries (1995–2009): for each registry (excluding Finland, Sweden, Hainaut, Poland, and Strasbourg), a random 20 clubfoot registrations, or all clubfoot registrations if fewer than 20. Of the 308 sampled registrations, a questionnaire was filled in for 301. Thirteen cases (4.3%) were found not to have the major anomaly clubfoot (e.g., cases of positional talipes), leaving 288 for analysis.\n\nStatistical analysis.\nCrude odds ratios (ORs) were calculated first. WinBUGS was used to fit multinomial responses with a logistic link, including registries with no exposure to lamotrigine in either cases or controls, adjusting for registry. Noninformative priors were used and therefore the credible intervals are equivalent to confidence intervals (CIs). We also controlled for maternal age, treated as a categorical variable (<20, 20–24, 25–29, 30–34, and 35+ years of age). Due to the small numbers of exposures to lamotrigine, it was not possible to adjust simultaneously for both registry and maternal age. ORs adjusted for registry were a priori the outcome measure of choice due to the potential for confounding arising from differences in both CA prevalence and exposure prevalence among registries, and the lack of strong maternal age effects for most nonchromosomal anomalies.19 Modeling with Poisson regression produces almost identical results (not shown).\n\nFor the clubfoot analysis, ORs were calculated for the entire study population (table 1) and for the independent study population (table 1).\n\nAs it is not possible to estimate overall CA risk from a case-malformed control study as this would require information about nonmalformed babies, we also compared exposure to lamotrigine, and any AED, among all nonchromosomal CA combined to exposure among all chromosomal cases, assuming that exposure among chromosomal CA would represent population exposure. We calculated crude OR and OR adjusted for maternal age due to the strong relationship of maternal age to chromosomal anomalies.\n\nIn an exploratory proportional analysis, the number of babies with each nonchromosomal CA subgroup was calculated as a proportion of all babies with nonchromosomal CA, and was compared between the lamotrigine-exposed registrations and the non-AED-exposed registrations using Fisher exact test.\n\nIn a sensitivity analysis for OC, 6 OC cases (5 isolated, 1 multiply malformed) and 34 controls were excluded as lamotrigine monotherapy/polytherapy exposure was of uncertain timing during pregnancy. In a sensitivity analysis for clubfoot, 4 clubfoot cases (3 lamotrigine monotherapy, 1 lamotrigine polytherapy) including 1 case in the independent study population, and 36 controls, were excluded for the same reason.\n\nSensitivity analyses were also performed for the lamotrigine monotherapy analysis whereby clubfoot was excluded from the control group where cases were OC, and vice versa.\n\nFive-year analysis strategy and external advisory committee (EAC).\nThe study was performed over 5 years, with an interim analysis each year reviewed by an EAC consisting of a pediatrician specialized in teratology, a neurologist specialized in treatment of epilepsy in pregnancy, and a statistician. The EAC identified no concern that should lead to early publication of results. The report and comments received by the EAC and response to those comments from the research team were forwarded to GSK, who forwarded the report to the Medicines and Healthcare Products Regulatory Agency.\n\nStandard protocol approvals, registrations, and patient consents.\nThis study was approved by the Ulster University Ethics Committee. All contributing registries have their own ethics approval arrangements according to national laws.\n\nRESULTS\nAED exposure in the CA population.\nAED exposure was recorded in 6.0 per 1,000 registrations (table 2). AED monotherapy accounted for 80% of AED exposure (table 2); 43% of CA registrations with AED exposure had been exposed to VPA (table 2). Of the AED exposed, 79% (n = 1,073) had maternal epilepsy recorded; others had AED for other indications, or had missing data regarding indication.\n\nTable 2 AED exposure among registrations (per 1,000 registrations)\n\nTwelve percent of all AED-exposed CA registrations were exposed to lamotrigine monotherapy (table 2) and 7% to lamotrigine as part of polytherapy (table 2). Among lamotrigine monotherapy exposures, 77.1% were recorded with maternal epilepsy. The proportion of lamotrigine monotherapy exposures rose over time (table 2).\n\nAED-exposed registrations were similar in maternal age to unexposed registrations (29.2 vs 29.6 years), and lamotrigine-exposed registrations slightly younger (28.4 years).\n\nRegistrations included 89.4% livebirths, 1.3% stillbirths or late fetal deaths, and 9.3% TOPFA. The rate of AED exposure was 6.13 per 1,000 registrations among livebirths, 5.83 per 1,000 among fetal deaths, and 4.93 per 1,000 among TOPFA.\n\nOC.\nOC were significantly associated with AED exposure (All OC ORadj 1.34, 95% CI 1.11–1.62; all cleft palate ORadj 1.97, 1.54–2.52) with lower OR for isolated OC/cleft palate (table 3). ORs remained elevated after excluding VPA (table 3).\n\nTable 3 Orofacial cleft (OC) numbers and odds ratios (ORs) (95% confidence interval [CI]) for antiepileptic drug (AED) and lamotrigine exposure compared to no AED exposure among babies with nonchromosomal anomalies\n\nFor lamotrigine monotherapy, there were nonsignificant associations for all OC (ORadj 1.31, 95% CI 0.73–2.33) and for all cleft palate (ORadj 1.60, 95% CI 0.70–3.65) (table 3). The ORs for isolated OC/cleft palate were slightly higher but nonsignificant (table 3). The ORs for all OC/cleft palate with lamotrigine monotherapy were nonsignificantly higher than those for any AED monotherapy excluding VPA (table 3).\n\nIn the sensitivity analysis excluding uncertain timing of lamotrigine exposure, adjusted ORs were diluted (all OC: 1.22, 95% CI 0.63–2.34; isolated OC: 1.46, 95% CI 0.76–2.80; all cleft palate: 0.97, 95% CI 0.31–3.09; isolated cleft palate: 1.23, 95% CI 0.39–3.89).\n\nA sensitivity analysis excluded clubfoot from the controls: isolated OC OR 1.48 (0.74–2.69), all OC 1.33 (0.69–2.36), isolated cleft palate 1.70 (0.54–4.07), and all cleft palate 1.60 (0.58–3.60).\n\nDiagnostic review of lamotrigine monotherapy-exposed babies in the control group found 3 pairs of sibs where it is possible that the CA was genetically linked to the epilepsy of the mother: one pair with tuberous sclerosis, one with cleidocranial dysostosis (rarely linked with epilepsy), and one with lissencephaly. Exclusion of these cases from the controls in a sensitivity analysis hardly changed the OR for OC. There were no other sibpairs.\n\nClubfoot.\nThere was no excess of clubfoot with any AED exposure (ORadj 0.96, 95% CI 0.74–1.26) (table 4). With lamotrigine monotherapy exposure, there was a significant excess of clubfoot in the entire study population (ORadj 1.83, 95% CI 1.01–3.31), reduced and nonsignificant in the independent study population (ORadj 1.43, 95% CI 0.66–3.08) (table 4). Excluding lamotrigine of uncertain timing did not substantially change the estimates but the lower CI limit was below 1 (overall ORadj 1.60, 95% CI 0.81–3.15, independent study population ORadj 1.40, 95% CI 0.61–3.22). Excluding OC from the controls, OR estimates were nonsignificant: entire study population OR 1.88 (0.94–3.38), independent study population OR 1.52 (0.59–3.28).\n\nTable 4 Clubfoot numbers and odds ratios (OR, 95% confidence interval [CI]) with any antiepileptic drug (AED) and lamotrigine (monotherapy and polytherapy) exposure, in the entire study population (1995–2011) and the independent study populationa\n\nOf the 12 lamotrigine monoexposed clubfoot cases, 7 were bilateral and 11 were isolated, and all cases were confirmed as clubfoot (i.e., not positional talipes). This was similar to the profile in the random comparison sample of unexposed clubfoot (55.2% bilateral, 70.8% isolated, and 62.5% of liveborn cases treated with splints/casts/surgery).\n\nAll nonchromosomal CA combined compared with all chromosomal CA.\nThere were 147 lamotrigine monotherapy-exposed nonchromosomal CA and 10 lamotrigine monotherapy-exposed chromosomal controls, giving an OR of 1.77 (95% CI 0.93–3.37), adjusted for maternal age. The OR adjusted for maternal age for any AED was 2.25 (95% CI 1.78–2.85).\n\nExploratory analysis of CA subgroups.\nWe observed more cases of spina bifida than expected in the lamotrigine-exposed group, but only for polytherapy (table 5). We found a significant excess of respiratory anomalies for lamotrigine monotherapy (table 5). These cases were heterogeneous in diagnosis (table 5). They include 5 cases of stenosis of the upper airways.\n\nTable 5 Distributiona of anomaly subgroups by lamotrigine exposure status\n\nDISCUSSION\nThis study of lamotrigine exposure in early pregnancy more than doubled the size of the previous study population13 (from 3.8 to 10 million births) and added a period from 2006 onward when lamotrigine exposure was nearly 3 times more prevalent. Our estimate of the risk of OC relative to other anomalies is nonsignificant with an upper confidence limit of 2.3 and therefore does not support the 6-fold risk suggested by the North American AED cohort results.10 Our results concur with other studies published since the original signal,4,6,11,12 which do not find a large excess of OC or cleft palate. One of the reasons for the discrepancy with the original signal may be that our baseline population risk of OC is 1.4 per 1,000, rather than the 0.7 per 1,000 baseline estimated by the North American cohort,10 later revised upwards to 1.1 per 1,000.5 The size of the original OC signal may also have been a chance finding, or exacerbated by coexposures. Based on our European OC prevalence rate of 1.4 per 1,000, and an upper confidence limit of OR of 2.3, we estimate exposure to lamotrigine would result in OC in less than 1 in every 550 exposed babies.\n\nCleft palate is considered to be etiologically distinct from cleft lip with or without palate,20 although poor recording may lead to misclassification in some studies in the literature. In a previous EUROCAT study of VPA,21 we found an OR of 5.2 for cleft palate with no increased risk for cleft lip. A previous EUROCAT study of carbamazepine22 found no excess of cleft lip and a small nonsignificant OR of 1.3 for cleft palate,22 whereas an excess of cleft lip was reported in cohort studies in the literature.22 There is a strong signal in the literature for topiramate and OC, particularly cleft lip.5 We find a small excess risk of OC with any AED excluding VPA of borderline statistical significance (OR 1.33). However, due to the case-malformed control design, this would be diluted by inclusion of malformations associated with AED in the control group (such as spina bifida associated with carbamazepine22). The similarity with the point estimate of OR for lamotrigine (1.31) is therefore difficult to interpret. OC have long been found to be associated with anticonvulsant exposures of many types,23 and there is inconclusive evidence addressing hypotheses as to whether some types of epilepsy may be genetically linked to OC,23 whether anticonvulsant medication accentuates the underlying genetic tendency,23 or whether the medication effects are independent of epilepsy. Given this context, it is prudent to examine the baby of any woman with epilepsy carefully for cleft palate, which may not be externally visible, regardless of her medication.\n\nIn our previous study,13 we found a significant excess of clubfoot. We have now validated the recording of clubfoot as a major CA by EUROCAT registries. The only other evidence to support this association has been 3 cases in 802 exposed pregnancies reported by the International Lamotrigine Pregnancy Registry.4 We sought to confirm the signal13 in an independent dataset to exclude the possibility of it being a chance finding. We could not find statistically significant independent evidence of a clubfoot excess. However, the overall excess including the original signal remains statistically significant. We recommend that cohort studies also keep this anomaly under review using comparable diagnostic inclusion criteria. Clubfoot has been associated with exposure to various medications including selective serotonin reuptake inhibitors.24–26\n\nNo other CA were found to be associated with lamotrigine monotherapy. An excess of respiratory anomalies may be too heterogeneous to be interpreted as causally associated, and may be a chance finding due to the multiple comparisons performed, but due to differing interpretations among reviewers of these data we recommend other studies should follow-up stenosis of the upper airways.\n\nLimitations of case-malformed control studies are that without a nonmalformed control group it is not possible to estimate the overall CA risk associated with exposure and that estimated OR may be diluted if controls include CA associated with exposure. Cohort studies have found an overall CA rate associated with lamotrigine exposure similar to background expectation3–6 but do not have exact external comparators. We estimated the OR of nonchromosomal CA by comparing with chromosomal syndromes, assuming the latter to reflect population exposure. The OR, adjusted for maternal age, of 1.77 (95% CI 0.93–3.37), although not statistically significant and with a wide CI, is consistent with a small generalized excess of nonchromosomal CA, and thus an underestimation of our ORs for OC and clubfoot. However, the elevated OR may also reflect some underascertainment of lamotrigine exposure among TOPFA, which are more common in chromosomal syndromes.\n\nThe strengths of our study are the large sample size, population base, detailed and standardized diagnostic data on CA, and inclusion of TOPFA, which constitute a large proportion of some CA.27 Due to the rarity of OC and of lamotrigine exposure, the power to detect clinically significant associations remains limited and we therefore used the upper CI of the OR estimates for OC when estimating excess risk. Unlike most AED cohort studies, we have an internal comparator group. AED exposure was mainly prospectively ascertained, and the case-malformed control study design reduces recall and information bias. The AED exposure rate of 6.0 per 1,000 suggests good ascertainment, taking into account the expected population AED exposure rate of 3–5 per 1,0001 and the excess risk of CA among the AED exposed.21,22 We did not have information on dose, which would have been of interest given conflicting results concerning a dose-response effect for lamotrigine3–6,28 and therefore our results are relevant to average dose in the population.\n\nSupplementary Material\nData Supplement\n Supplemental data at Neurology.org\n\nACKNOWLEDGMENT\nThe authors thank the members of the External Advisory Committee (Dr. Jim Morrow, UK Epilepsy and Pregnancy Register; Dr. Christof Schaefer, Berlin Teratology Information Unit; Dr. David Prieto, London School of Hygiene and Tropical Medicine) for their comments each of 5 years on interim analysis reports; Prof. Christine Verellen-Dumoulin (Centre de Génétique Humaine Institut de Pathologie et de Génétique), Belgium, who contributed data to a previous paper on this subject, which were also included here; Prof. Elisa Calzolari, who contributed to the classification of cases for the study as member of the EUROCAT Coding & Classification Committee and made comments on earlier drafts; and Dr. Annukka Ritvanen for her involvement in contributing Finnish data and comments on earlier drafts.\n\nAUTHOR CONTRIBUTIONS\nProf. H. Dolk: drafting/revising the manuscript for content, study concept or design, analysis of interpretation of data, acquisition of data, statistical analysis, study supervision or coordination, obtaining funding. Dr. H. Wang: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data, statistical analysis. Dr. M. Loane: drafting/revising the manuscript for content, study concept or design, analysis of interpretation of data, statistical analysis, study supervision or coordination, obtaining funding, data management. Prof. J. Morris: drafting/revising the manuscript for content, analysis or interpretation of data, statistical analysis. Dr. E. Garne: drafting/revising the manuscript for content, study concept or design, analysis of interpretation of data, acquisition of data, classification of cases. Dr. M.-C. Addor: drafting/revising the manuscript for content, acquisition of data. Dr. L. Arriola: drafting/revising the manuscript for content, acquisition of data. Dr. M. Bakker: drafting/revising the manuscript for content, study concept or design, analysis or interpretation of data, acquisition of data. Prof. I. Barisic: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data. Dr. M. Gatt: drafting/revising the manuscript for content, acquisition of data. Dr. B. Doray: analysis or interpretation of data, acquisition of data. Prof. K. Kallen: drafting/revising the manuscript for content, study concept or design, analysis or interpretation of data, acquisition of data, obtaining funding, funding for the Swedish programme, independent from Glaxo. Dr. B. Khoshnood: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data, obtaining funding. Dr. K. Klungsoyr: drafting/revising the manuscript for content, acquisition of data. Dr. A.-M. Lahesmaa-Korpinen: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data. Dr. A. Latos-Bielenska: analysis or interpretation of data, acquisition of data, obtaining funding. Dr. J.P. Mejnartowicz: drafting/revising the manuscript for content, acquisition of data. Dr. V. Nelen: drafting/revising the manuscript for content, acquisition of data. Dr. A. Neville: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data. Dr. M. O'Mahony: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data. Dr. A. Pierini: drafting/revising the manuscript for content, study concept or design, analysis or interpretation of data, acquisition of data. Dr. A. Rissmann: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data. D. Tucker: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data. Dr. D. Wellesley: drafting/revising the manuscript for content, analysis or interpretation of data. Dr. A. Wiesel: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data. Prof. L.T.W. de Jong-van den Berg: drafting/revising the manuscript for content, study concept or design, analysis of interpretation of data, study supervision or coordination, obtaining funding.\n\nSTUDY FUNDING\nThe EUROCAT Central Database was funded by the EU Public Health Programme. Additional funding for this study was a grant from GlaxoSmithKline. GSK approved the protocol for this study prior to contract, but has not been involved in the conduct or management of the study, or analysis or interpretation of data or preparation of the paper. There were no other conflicts of interest. The External Advisory Committee had no direct or indirect financial relationship with GSK. This study was sponsored by GlaxoSmithKline.\n\nDISCLOSURE\nH. Dolk's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. H. Wang's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. M. Loane's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. J. Morris' institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. E. Garne's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. M.-C. Addor's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. L. Arriola's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. M. Bakker's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. I. Barisic's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. B. Doray reports no disclosures relevant to the manuscript. M. Gatt's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. K. Kallen reports no disclosures relevant to the manuscript. B. Khoshnood's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. K. Klungsoyr reports no disclosures relevant to the manuscript. A-M. Lahesmaa-Korpinen's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. A. Latos-Bielenska's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. J. Mejnartowicz's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. V. Nelen's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. A. Neville's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. M. O'Mahoney's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. A. Pierini's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. A. Rissmann's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. D. Tucker's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. David Tucker (Public Health Wales NHS Trust, UK) is a GSK shareholder since 2013. D. Wellesley reports no disclosures relevant to the manuscript. A. Wiesel's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. L. de Jong-van den Berg's institution received funding from GlaxoSmithKline, via Ulster University, for data or staff time contributed to this study. Go to Neurology.org for full disclosures.\n\nGLOSSARY\nAEDantiepileptic drug\n\nCAcongenital anomaly\n\nCIconfidence interval\n\nEACexternal advisory committee\n\nICD-9/10International Classification of Diseases–9/10\n\nOCorofacial cleft\n\nORodds ratio\n\nTOPFAtermination of pregnancy for fetal anomaly\n\nVPAvalproic acid\n==== Refs\nREFERENCES\n1. Charlton RA Garne E Wang H \nAntiepileptic drug prescribing before, during and after pregnancy: a study in 7 European regions . Pharmacoepidemiol Drug Saf \n2014 ;23 :22 –23 .\n2. Medicines and Healthcare Products Regulatory Agency (MHRA) Patient Information Leaflet . Lamotrigine . Available at: http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1404109838676.pdf. Accessed March 22, 2016 .\n3. Campbell E Kennedy F Russell A \nMalformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers . J Neurol Neurosurg Psychiatry \n2014 ;85 :1029 –1034 .24444855 \n4. Cunnington MC Weil JG Messenheimer JA Ferber S Yerby M Tennis P \nFinal results from 18 years of the international lamotrigine pregnancy registry . Neurology \n2011 ;76 :1817 –1823 .21606453 \n5. Hernandez-Diaz S Smith CR Shen A \nComparative safety of antiepileptic drugs during pregnancy . Neurology \n2012 ;78 :1692 –1699 .22551726 \n6. Tomson T Battino D Bonizzoni E \nDose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry . Lancet Neurol \n2011 ;10 :609 –617 .21652013 \n7. Tran TA Leppik IE Blesi K Sathanandan ST Remmel R \nLamotrigine clearance during pregnancy . Neurology \n2002 ;59 :251 –255 .12136066 \n8. Marson AG Appleton R Baker GA \nA randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs: the SANAD trial . Health Technol Assess \n2007 ;11 :iii–iv, ix–x, 1–134 .\n9. US Food and Drug Administration . FDA alert September 2006 . Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150637.htm. Accessed March 22, 2016 .\n10. Holmes LB Baldwin EJ Smith CR \nIncreased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy . Neurology \n2008 ;70 :2152 –2158 .18448870 \n11. Hunt SJ Craig JJ Morrow JI \nIncreased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy . Neurology \n2009 ;72 :1108 .19307550 \n12. Mølgaard-Nielsen D Hviid A \nNewer-generation antiepileptic drugs and the risk of major birth defects . JAMA \n2011 ;305 :1996 –2002 .21586715 \n13. Dolk H Jentink J Loane MA Morris JK de Jong-van den Berg LT ; EUROCAT Antiepileptic Drug Working Group . Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? \nNeurology \n2008 ;71 :714 –722 .18650491 \n14. Boyd P Barisic I Haeusler M Loane M Garne E Dolk H \nPaper 1: the EUROCAT network: organization and processes . Birth Defects Res A Clin Mol Teratol \n2011 ;91 :2 –15 .\n15. EUROCAT . EUROCAT Guide 1.3 and Reference Documents, Instructions for the Registration and Surveillance of Congenital Anomalies, September 2005 . Available at: http://www.eurocat.ulster.ac.uk/pdf/EUROCAT-Guide-1.3.pdf. Accessed April 3, 2015 .\n16. WHO Collaborating Centre for Drug Statistics Methodology . Anatomical Therapeutic Chemical Classification System . Available at: http://www.whocc.no/atc_ddd_index/. Accessed April 3, 2015 .\n17. EUROCAT . EUROCAT Special Report: Sources of Information of Medication Use in Pregnancy . EUROCAT Central Registry, University of Ulster ; 2014 \nAvailable at: http://www.eurocat-network.eu/content/Special-Report-Medication-Use-In-Pregnancy.pdf. Accessed April 3, 2015 .\n18. Garne E Dolk H Loane M \nPaper 5: surveillance of multiple congenital anomalies: implementation of a computer algorithm in European registers for classification of cases . Birth Defects Res A Clin Mol Teratol \n2011 ;91 :S44 –S50 .21384529 \n19. Loane M Dolk H Morris J ; EUROCAT Working Group . Maternal age-specific risk of non-chromosomal anomalies . BJOG \n2009 ;116 :1111 –1119 .19485989 \n20. FitzPatrick DR Raine PAM Boorman JG \nFacial clefts in the west of Scotland in the period 1980–1984: epidemiology and genetic diagnoses . J Med Genet \n1994 ;31 :126 –129 .8182717 \n21. Jentink J Loane MA Dolk H \nValproic acid monotherapy exposure in the first trimester of pregnancy and risk of specific birth defects . N Engl J Med \n2010b ;362 :2185 –2193 .20558369 \n22. Jentink J Dolk H Loane M Morris JK de Jong-van den Berg L ; for the EUROCAT Antiepileptic Drug Working Group . Carbamazepine monotherapy exposure in the first trimester of pregnancy and risk of specific birth defects . BMJ \n2010 ;341 :c6581 .21127116 \n23. Schardein JL. Chemically Induced Birth Defects . 3rd ed, New York: \nMarcel Dekker ; 2000 .\n24. Yazdy MM Michell AA Louik C Werler MM \nUse of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot . Epidemiology \n2014 ;25 :859 –865 .25171134 \n25. Wemakor A Casson K Garne E \nSelective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study . Eur J Epidemiol \n2015 ;30 :1187 –1198 .26148560 \n26. Werler MM Yazdy MM Kasser JR \nMedication use in pregnancy in relation to the risk of isolated clubfoot in offspring . Am J Epidemiol \n2014 ;180 :86 –93 .24824985 \n27. Garne E Dolk H Loane M Boyd P ; EUROCAT Working Group . EUROCAT website data on prenatal detection rates of congenital anomalies . J Med Screen \n2010 ;17 :97 –98 .20660439 \n28. Vajda FJ O'Brien TJ Lander CM Graham J Eadie MJ \nThe teratogenicity of the newer antiepileptic drugs: an update . Acta Neurol Scand \n2014 ;130 :234 –238 .25040242\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0028-3878",
"issue": "86(18)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D016022:Case-Control Studies; D002971:Cleft Lip; D002972:Cleft Palate; D004827:Epilepsy; D005060:Europe; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D016017:Odds Ratio; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First; D012042:Registries; D012306:Risk; D012680:Sensitivity and Specificity; D014227:Triazines",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "1716-25",
"pmc": null,
"pmid": "27053714",
"pubdate": "2016-05-03",
"publication_types": "D016428:Journal Article",
"references": "20660439;24824985;22551726;21652013;21606453;21586715;21384531;26148560;25171134;25040242;24444855;12136066;8182717;17903391;18448870;18650491;19307550;19485989;20558369;21127116;21384529",
"title": "Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies.",
"title_normalized": "lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies"
} | [
{
"companynumb": "GB-CIPLA LTD.-2016GB03934",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe Rumack-Matthew nomogram predicts the risk of hepatotoxicity following acute acetaminophen overdose based on a serum concentration obtained ≥ 4-hour post-ingestion. Some patients with low-risk concentrations at 4 hours may have subsequent values indicating increased risk (above the nomogram treatment line), especially if coingestants that slow gastrointestinal motility are involved. The treatment line currently used to identify low risk patients in the United States, Canada, and Australia begins at 150 mcg/mL (993 μmol/L) and intersects at 18.75 mcg/mL (124.1 μmol/L) 16 hours post-ingestion.\n\n\nOBJECTIVE\nTo determine the incidence of nomogram line crossing after acute overdose of acetaminophen combination products containing an opioid or antihistamine.\n\n\nMETHODS\nThis was a prospective cohort study of hospitalized patients reported to a regional poison center (RPC) after acute overdose of a combination product containing an opioid or antihistamine. If a 4-hour acetaminophen concentration was detectable but below the nomogram treatment line, the RPC recommended repeat concentrations. Patients were entered into the study if at least one subsequent concentration was available. During follow-up calls hospital providers were queried regarding clinical features, treatment, and indicators of liver injury.\n\n\nRESULTS\nOver a 4-year period 76 patients met entry criteria. 5/76 (6.6%) had measureable acetaminophen concentrations below the treatment line at or close to 4-hour post-ingestion followed by values above the line obtained at 6.5-12.5 hours. Four of the five were treated with acetylcysteine and none developed hepatotoxicity. Four of the five had clinical features reported to the RPC suggesting toxicity from the opioid or antihistamine component.\n\n\nCONCLUSIONS\nAfter acute overdose of acetaminophen combination products, patients with detectable but non-toxic 4-hour acetaminophen concentrations should have repeat concentrations obtained in a time frame that would allow providers to initiate acetylcysteine treatment, if needed, without undue delay.",
"affiliations": "a Nebraska Regional Poison Center , Omaha , NE , USA ;;b School of Pharmacy, University of Wyoming , Laramie , WY , USA ;;c College of Public Health, University of Nebraska Medical Center , Omaha , NE , USA.;a Nebraska Regional Poison Center , Omaha , NE , USA ;",
"authors": "Kirschner|Ronald I|RI|;Rozier|Christina M|CM|;Smith|Lynette M|LM|;Jacobitz|Kathy L|KL|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000931:Antidotes; D004338:Drug Combinations; D006633:Histamine Antagonists; D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2015.1110591",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "54(1)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Paracetamol; combination products; nomogram",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000293:Adolescent; D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000931:Antidotes; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D003661:Decision Support Techniques; D004338:Drug Combinations; D062787:Drug Overdose; D005260:Female; D006633:Histamine Antagonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D049451:Nomograms; D011039:Poison Control Centers; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "40-6",
"pmc": null,
"pmid": "26567585",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Nomogram line crossing after acetaminophen combination product overdose.",
"title_normalized": "nomogram line crossing after acetaminophen combination product overdose"
} | [
{
"companynumb": "US-PFIZER INC-2016007130",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Primary pulmonary artery masses are unusual entities that mimic pulmonary embolism (PE) in clinical presentation and on imaging studies. It is necessary to perform advanced diagnostic exams, such as transesophageal echocardiography (TEE) and cardiac magnetic resonance imaging (MRI), to determine the proper diagnosis. In unclear cases, laboratory findings, morphological follow-up, and response to anticoagulant therapy can help to clarify the diagnosis.\nA 47-year-old previously healthy man with worsening effort dyspnoea underwent chest computed tomography (CT) for suspicion of PE, which showed a pedunculated eccentric mass at the origin of the pulmonary artery causing severe stenosis. The patient was started on anticoagulation therapy, but, after TEE and cardiac MRI, a neoplastic fibroelastic mass was suspected. Unexpectedly, 18fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT revealed a unique area of glucose uptake in the superior lobe of the left lung and not in the pulmonary artery. The biopsy was consistent with pleomorphic high-grade lung sarcoma. After 3 months of chemotherapy, a CT scan showed progression of the lung disease with no change in the arterial mass, which was therefore confirmed as pulmonary fibroelastoma.\nDue to the rarity of pulmonary artery tumours, they can be initially misdiagnosed as PE or a metastasis of a lung sarcoma. Three-dimensional TEE and cardiac MRI are particularly useful in differentiating tumours from PE.",
"affiliations": "Cardiology Unit, Department of Emergency and Organ Transplant, University Hospital Policlinico of Bari, Piazza Giulio Cesare, 11 70124 (BARI), Italy.;Cardiology Unit, Miulli Hospital, Strada provinciale 127 Acquaviva-Santeramo, 70021 Acquaviva delle Fonti (BARI), Italy.;Department of Biomedical Sciences and Human Oncology, University Hospital Policlinico of Bari, Piazza Giulio Cesare, 11 70124 (BARI), Italy.;Department of Cardiology, University Hospital Policlinico of Bari, Piazza Giulio Cesare, 11 70124 (BARI), Italy.",
"authors": "Piscitelli|Laura|L|0000-0003-3918-8680;Dentamaro|Ilaria|I|;Pezzicoli|Gaetano|G|0000-0002-5491-0590;D'Agostino|Carlo|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytaa551",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytaa551\nytaa551\nCase Report\nAcademicSubjects/MED00200\nMultimodality imaging of a rare pulmonary artery sessile mass: a case report\nhttp://orcid.org/0000-0003-3918-8680\nPiscitelli Laura 1\nDentamaro Ilaria 2\nhttp://orcid.org/0000-0002-5491-0590\nPezzicoli Gaetano 3\nD’Agostino Carlo 4\nVoges Inga Handling Editor\nDuplyakov Dmitry Editor\nSantoro Ciro Editor\nKurdi Hibba Editor\nGuella Elhosseyn Editor\n1 Cardiology Unit, Department of Emergency and Organ Transplant, University Hospital Policlinico of Bari, Piazza Giulio Cesare, 11 70124 (BARI), Italy\n2 Cardiology Unit, Miulli Hospital, Strada provinciale 127 Acquaviva-Santeramo, 70021 Acquaviva delle Fonti (BARI), Italy\n3 Department of Biomedical Sciences and Human Oncology, University Hospital Policlinico of Bari, Piazza Giulio Cesare, 11 70124 (BARI), Italy\n4 Department of Cardiology, University Hospital Policlinico of Bari, Piazza Giulio Cesare, 11 70124 (BARI), Italy\nCorresponding author. Tel: +393495438622, Email: piscitellilaura92@gmail.com\n2 2021\n04 1 2021\n04 1 2021\n5 2 ytaa55115 6 2020\n29 7 2020\n08 12 2020\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground \n\nPrimary pulmonary artery masses are unusual entities that mimic pulmonary embolism (PE) in clinical presentation and on imaging studies. It is necessary to perform advanced diagnostic exams, such as transesophageal echocardiography (TEE) and cardiac magnetic resonance imaging (MRI), to determine the proper diagnosis. In unclear cases, laboratory findings, morphological follow-up, and response to anticoagulant therapy can help to clarify the diagnosis.\n\nCase summary \n\nA 47-year-old previously healthy man with worsening effort dyspnoea underwent chest computed tomography (CT) for suspicion of PE, which showed a pedunculated eccentric mass at the origin of the pulmonary artery causing severe stenosis. The patient was started on anticoagulation therapy, but, after TEE and cardiac MRI, a neoplastic fibroelastic mass was suspected. Unexpectedly, 18fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT revealed a unique area of glucose uptake in the superior lobe of the left lung and not in the pulmonary artery. The biopsy was consistent with pleomorphic high-grade lung sarcoma. After 3 months of chemotherapy, a CT scan showed progression of the lung disease with no change in the arterial mass, which was therefore confirmed as pulmonary fibroelastoma.\n\nDiscussion \n\nDue to the rarity of pulmonary artery tumours, they can be initially misdiagnosed as PE or a metastasis of a lung sarcoma. Three-dimensional TEE and cardiac MRI are particularly useful in differentiating tumours from PE.\n\nPulmonary artery\nThromboembolism\nMass\nCase report\nMultimodality imaging\n==== Body\nLearning points\n\nThe diagnosis of neoplastic masses should be considered in patients with suspicion of pulmonary embolism, especially those with poor response to anticoagulant therapy.1,2\n\nThrombus and mass are difficult to differentiate. Three-dimensional transesophageal echocardiography and cardiac magnetic resonance imaging are helpful for the complete morphological and functional evaluation of cardiac masses.3\n\nIntroduction\n\nPrimary cardiac masses are rare entities that can be easily mistaken for thromboembolic events, with serious prognostic implications. We report a case in which a pulmonary artery mass and its clinical presentation played a pivotal role in diagnosing a high-grade pulmonary sarcoma that was clinically silent.\n\nTimeline\n\nDay 0\tThe patient presented with sudden dyspnoea.\n\nComputed tomography (CT): pulmonary artery obstruction, probably due to embolism. An oral anticoagulant therapy was started.\n\nElectrocardiogram (ECG): right axial deviation. High T waves.\n\n\t\nWeek 2\tTransesophageal echocardiography: 17 × 13 mm sessile mass at the right ventricle outflow tract.\n\nMagnetic resonance imaging (MRI): 13 × 53 mm fibrous vegetation, extended to pulmonary bifurcation.\n\n\t\nWeek 3\t18FDG PET-CT: area of glucose uptake at the superior lobe of the left lung, no uptake in the heart.\t\nMonth 2\tNew admission for:\n\ncontrol CT and US-guided biopsy of the pulmonary mass that revealed a pleomorphic high-grade sarcoma.\n\n\t\nMonth 3\tAdmission in oncology with new cardiac MRI.\n\nStarting of 1st line chemotherapy: doxorubicin-ifosfamide.\n\n\t\nMonth 7 (after 3 cycles)\tFollow-up CT: increase in the size of the lung sarcoma, with no change of the pulmonary artery mass.\t\nMonth 7\tStarting of the 2nd line chemotherapy: gemcitabine-paclitaxel.\t\nMonth 12\tPatient’s death\t\n\nCase presentation\n\nWe report the case of a 47-year-old white male smoker with a family history of lung cancer. No major comorbidities were reported. Initially, he presented with sudden dyspnoea on exertion, without any other symptoms such as fever, weight loss, or night sweats (B symptoms in lymphoma clinical presentation). The haemodynamic parameters were stable (BP 140/90 mmHg, HR 70 b.p.m.) and the physical examination was normal. Electrocardiogram (ECG) showed right axial deviation and high T waves in precordial leads. He underwent chest computed tomography (CT) for suspicion of pulmonary embolism (PE). Computed tomography imaging showed a filling defect ∼22 mm in diameter at the origin of the pulmonary artery causing severe stenosis. Although the patient was started on anticoagulant therapy, transthoracic echocardiogram (TTE) and transesophageal echocardiography (TEE) confirmed a fixed 17 × 13 mm sessile mass at the right ventricular outflow tract (RVOT), just before the pulmonary valve, and severe stenosis of the pulmonary artery main trunk, with a maximum gradient of 100 mmHg and a mean gradient of 68 mmHg (n.v. maximum gradient <36 mmHg).\n\nThe right ventricle was mildly dilated, hypertrophic, and showed a mild decrease in contractile function (Figures 1 and 2, Videos 1–3). To investigate the nature of the lesion, the patient underwent cardiac magnetic resonance imaging (MRI), which characterized the sessile mass as a 13 × 53 mm fibrous vegetation next to the anterior leaflet of the pulmonary valve that extended to the pulmonary bifurcation (Figure 3). For the high suspicion of a neoplastic origin, the patient underwent 18fluorodeoxyglucose (18FDG) positron emission tomography (PET)-CT. Unexpectedly, PET showed an area of intense glucose uptake at the superior lobe of the left lung, in the subpleural region. The patient was re-admitted with a second CT that showed persistence of the pulmonary artery mass despite anticoagulant therapy with warfarin (2 months) and no peripheral filling defects of the pulmonary arteries. The CT also revealed a 7 cm-wide solid neoformation at the superior lobe of the left lung. An ultrasonography (US)-guided biopsy of the lung parenchymal area was therefore performed. The pathology report was consistent with a pleomorphic high-grade sarcoma. A team including an US specialist, a cardiovascular surgeon, an oncologist, and a pathologist was assembled to decide the best therapeutic management. No surgical approach was possible, so the patient was started on first-line chemotherapy including doxorubicin (25 mg/m2 per day, Days 1–3) plus ifosfamide (10 g/m2 over 4 days), with mesna (0.5 g/m2 by intravenous bolus before ifosfamide, 1.5 g/m2 concurrent with ifosfamide, and 1 g/m2 orally 2 and 6 h after completion of ifosfamide infusion) and pegfilgrastim (6 mg subcutaneously, Day 5) as support, in 3-week cycles, up to a maximum of six cycles.4 After 3 months, the clinical condition of the patient worsened, with chest pain and rest dyspnoea occurrence. The restaging CT and MRI showed no change in the size of the pulmonary artery mass (Figures 4 and 5), but an increase in the size of the pulmonary mass, which now reached a diameter of 18 cm (Figure 5). Moreover, a new lesion was observed in the inferior lobe of the right lung. According to response evaluation criteria in solid tumours (RECIST), the patient was considered to have progressive disease, and therefore, a second line of chemotherapy was started, consisting of gemcitabine (900 mg/m2 on Days 1 and 8) and docetaxel (70 mg/m2 on Day 8) in 3-week cycles.5 After 5 months, the patient died.\n\nFigure 1 (A) Two-dimensional transthoracic echocardiogram, pulmonary off-axis view. It shows right ventricular outflow tract, pulmonary valve, and pulmonary artery in longitudinal axis. Right ventricular outflow tract is mildly dilated with a fixed 15 × 14 rounded isoechogenic mass inside. (B) Three-dimensional transthoracic echocardiogram, PSAX focused on large vessels (aorta and pulmonary artery). Three-dimensional technique gives a volumetric characterization of the sessile mass located in the right ventricular outflow tract eccentrically, just before the pulmonary valve.\n\nFigure 2 Two-dimensional transesophageal echocardiography 30 degrees short axis at great vessels level. It shows the aortic valve in cross-section and, just below, a 17 × 13 mm sessile mass at the right ventricular outflow tract (RVOT).\n\nFigure 3 Cardiac magnetic resonance imaging, March 2019: Segmented steady-state free precession cine imaging sequences in short-axis view. We can see a small and round mass, with a homogenous hypointense signal intensity, attached to the right ventricular outflow tract by a short stalk.\n\nFigure 4 Cardiac magnetic resonance imaging, October 2019: Cine imaging sequences in short-axis and oblique coronal views showing the mass with the same signal intensity and no change in its size. However, a large pericardial effusion appears.\n\nFigure 5 Computed tomography and magnetic resonance imaging showing an increase of the lung disease with no change in the size of the cardiac mass.\n\nDiscussion\n\nThis case is interesting, first, because of the diagnostic path: the differential diagnosis of PE and cardiac masses remains a challenge. And second, because multimodality advanced imaging techniques such as 3D TEE and cardiac MRI play an important role in characterizing the precise location of the pulmonary artery tumour (Supplementary material online, Table).3 A multidisciplinary team including cardiologists, oncologists, radiologists, and pathologists is essential to determine the most probable diagnosis and choose the optimal therapy. The unchanged persistence of the pulmonary artery mass together with the absence of glucose uptake, in contrast to the lung sarcoma, allow us to diagnose its benign nature with unlikely relationship between this and the primary lung masses identified (Supplementary material online, Table). Given its location, shape, and structure, the most likely differential diagnosis is a sessile fibroelastoma, a benign cardiac neoplasia that arises from the endocardium and that can be dangerous due to the risk of peripheric embolization.6 Other plausible hypotheses include a fibroelastic reaction to the lung neoplasia (paraneoplastic syndrome) or, less likely, a fibrotic organized thromboembolic lesion caused by the lung neoplasia. This latter possibility was excluded because of the low mass mobility and the absence of modification despite intensive anticoagulant therapy (Supplementary material online, Table). Determining the true nature of the mass is complex: a biopsy with a histological diagnosis would be required to definitively diagnose the mass. However, in this case, that would have been too dangerous for the patient and would likely not have changed the therapeutic strategy, which was largely determined by the lung tumour.\n\nConclusion\n\nBecause of the low incidence of pulmonary artery tumours, together with their clinical presentation with dyspnoea, they can be easily mistaken for a thromboembolic process. Thanks to multimodality cardiac imaging (TEE and MRI), it was possible to make a difficult diagnosis.4 Additionally, having an interdisciplinary team was fundamental for us to obtain a more complete overview of this rare condition and determine the best management.\n\nLead author biography\n\nDr Laura Piscitelli is actually a Cardiology resident in the Cardiology Department of University Hospital Policlinico of Bari, in Italy. She graduated in the University of Bari in 2017. She has a knee interest in Cardiac Imaging, in particular advanced echocardiography applied in valvular heart disease.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSupplementary Material\n\nytaa551_Supplementary_Data Click here for additional data file.\n\nAcknowledgements\n\nWe would like to acknowledge the significant contribution of Prof. Paolo Colonna as imaging expert and reviewer of the manuscript.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: none declared.\n\nFunding: none declared.\n==== Refs\nReferences\n\n1 KahlbauH , AntunesHT , RodriguesI , CarvalhoR , FragataJ. Pulmonary artery sarcoma masquerading as subchronic pulmonary thromboembolism. J Card Surg 2016;31 :529–530.27334035\n2 ChenP-W , LiuP-Y. Pulmonary artery sarcoma mimicking pulmonary embolism. BMJ Case Rep 2018;2018 :bcr2018226999.\n3 GulatiG , SharmaS , KothariSS , JunejaR , SaxenaA , TalwarKK. Comparison of echo and MRI in the imaging evaluation of intracardiac masses. Cardiovasc Intervent Radiol 2004;27 :459–469.15383848\n4 JudsonI , VerweijJ , GelderblomH , HartmannJT , SchöffskiP , BlayJY et al ; European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014;15 :415–423.24618336\n5 HaraH , KawamotoT , FukaseN , KawakamiY , TakemoriT , FujiwaraS et al Gemcitabine and docetaxel combination chemotherapy for advanced bone and soft tissue sarcomas: protocol for an open-label, non-randomised, Phase 2 study. BMC Cancer 2019;19 :725.31337342\n6 GeorgeJC , TangA , MarkowitzA , GilkesonR , HoitBD. Papillary fibroelastoma of the pulmonic valve: evaluation by echocardiography and magnetic resonance imaging. Echocardiography 2008;25 :433–435.18177386\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(2)",
"journal": "European heart journal. Case reports",
"keywords": "Case report; Mass; Multimodality imaging; Pulmonary artery; Thromboembolism",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytaa551",
"pmc": null,
"pmid": "33738410",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "15383848;27334035;18177386;31337342;30185456;24618336",
"title": "Multimodality imaging of a rare pulmonary artery sessile mass: a case report.",
"title_normalized": "multimodality imaging of a rare pulmonary artery sessile mass a case report"
} | [
{
"companynumb": "IT-AMGEN-ITASP2021169641",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "4",
... |
{
"abstract": "Acute myeloid leukemia (AML) is a rare malignancy with increased incidence in the kidney transplantation (KT) population for which immunosuppression has been implicated as a putative cause. The average time interval from KT to AML development is 5 years. We present the case of a 61-year-old man who was found to have peripheral blood blasts on a postoperative day 20 routine blood draw after an uneventful unrelated living donor kidney transplant. He subsequently had a bone marrow biopsy and next-generation sequencing (NGS)-based molecular testing, which demonstrated AML characterized by SMC1A and TET2 mutations. He received induction chemotherapy followed by hematopoietic cell transplantation (HCT) from the kidney donor, who happened to be matched at one haplotype. At 12 months after his HCT and 15 months after his KT, his AML remained in remission, normal renal function was preserved, no active graft-versus-host disease was present, and immunosuppression was tapering. With full donor-derived hematopoietic chimerism, we expect to be able to discontinue immunosuppression shortly, thereby achieving tolerance. The short time interval between KT and development of AML suggests the malignancy was likely present before KT. Modern NGS-based analysis offers a promising method of identifying transplant candidates with unexplained hematologic abnormalities on pre-KT testing who may benefit from formal hematologic evaluation.",
"affiliations": "Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut.;Transfusion Medicine, Clinical Laboratory, Hartford Hospital, Hartford, Connecticut; Hartford Hospital Transplant and Comprehensive Liver Center, Hartford, Connecticut.;Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.;Hartford Hospital Transplant and Comprehensive Liver Center, Hartford, Connecticut.;Hartford Hospital Transplant and Comprehensive Liver Center, Hartford, Connecticut.;Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut; Hartford Hospital Transplant and Comprehensive Liver Center, Hartford, Connecticut.;Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut; Hartford Hospital Transplant and Comprehensive Liver Center, Hartford, Connecticut.;Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut; Hartford Hospital Transplant and Comprehensive Liver Center, Hartford, Connecticut. Electronic address: Oscar.Serrano@hhchealth.org.",
"authors": "Yu|Jielin|J|;Sherburne|Bradford|B|;Chen|Yi-Bin|YB|;Kutzler|Heather L|HL|;Tremaglio|Joseph|J|;Rochon|Caroline|C|;Sheiner|Patricia|P|;Serrano|Oscar K|OK|",
"chemical_list": "D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C085098:structural maintenance of chromosome protein 1; D049308:Dioxygenases; C541081:TET2 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D001853:Bone Marrow; D018797:Cell Cycle Proteins; D046528:Chimerism; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D049308:Dioxygenases; D006086:Graft vs Host Disease; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016030:Kidney Transplantation; D015470:Leukemia, Myeloid, Acute; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins; D012074:Remission Induction",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1360-1364",
"pmc": null,
"pmid": "33888344",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Myeloid Leukemia Presenting Less Than 3 Weeks After Living Donor Kidney Transplant: A Case Report.",
"title_normalized": "acute myeloid leukemia presenting less than 3 weeks after living donor kidney transplant a case report"
} | [
{
"companynumb": "US-MYLANLABS-2022M1002617",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHepatocellular carcinoma (HCC) is a highly vascularized tumor in which abnormal blood vessels contribute to poor treatment efficacy and prognosis. In this study, we assessed the efficacy, safety, and potential ability of bevacizumab to normalize tumor vascularity in patients with advanced HCC.\n\n\nMETHODS\nPatients with histologically or clinically confirmed advanced HCC that were refractory to conventional transarterial chemoembolization (c-TACE) received a transarterial infusion of bevacizumab (5 mg/kg), followed by c-TACE (named as BEVA-TACE). The primary endpoint was overall survival (OS), which was defined as the time from a patient identified as TACE refractory to the occurrence of death. The secondary endpoints included progression-free survival (PFS) and the disease control rate (DCR).\n\n\nRESULTS\nFrom January 2014 to December 2017, 20 patients with Barcelona Clinic Liver Cancer (BCLC) staging scores C (80.0%) or D (20.0%) received BEVA-TACE. The median OS time was 9.2 months [95% confidence interval (CI): 2.1-22.6 months]. The median PFS time was 6.3 months (95% CI: 1.0-10.5 months). Despite the late stage, 1 patient (5.0%) had a complete response (CR), 6 patients (30.0%) had a partial response (PR), and 10 patients (50.0%) had stable disease (SD) [overall response rate (ORR) 30.0%; DCR 85.0%]. The most common adverse events (AEs) were postembolic syndrome (25%), hyperbilirubinemia (10.0%), and melena (10.0%). Severe III-IV oral mucositis and hypertension were observed in only 1 patient (5.0%) during the follow-up period.\n\n\nCONCLUSIONS\nBEVA-TACE showed clinical efficacy, and patients with TACE-refractory HCC had acceptable AE rates. A low dose of targeted localized vessel bevacizumab infusion may normalize the condition of tumor blood vessels in patients with advanced HCC.",
"affiliations": "Interventional Radiology Department, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.;Interventional Radiology Department, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.;Interventional Radiology Department, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.;Interventional Radiology Department, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.;Interventional Radiology Department, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.;Interventional Radiology Department, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.;Interventional Radiology Department, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.;Interventional Radiology Department, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.",
"authors": "Zhang|Haixiao|H|;Cao|Gengfei|G|;Ren|Weixin|W|;Gu|Junpeng|J|;Ji|Weizheng|W|;Zhu|Diwen|D|;Bao|Yingjun|Y|;Hasimu|Asihaer|A|",
"chemical_list": "D000068258:Bevacizumab",
"country": "China",
"delete": false,
"doi": "10.21037/apm-21-2123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": "10(8)",
"journal": "Annals of palliative medicine",
"keywords": "Hepatocellular carcinoma (HCC); bevacizumab; vascular normalization therapy",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D000068258:Bevacizumab; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D003131:Combined Modality Therapy; D006801:Humans; D008113:Liver Neoplasms",
"nlm_unique_id": "101585484",
"other_id": null,
"pages": "9149-9156",
"pmc": null,
"pmid": "34488400",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Vascular normalization therapy with targeted localized vessel bevacizumab infusion in hepatocellular carcinoma after transarterial chemoembolization failure.",
"title_normalized": "vascular normalization therapy with targeted localized vessel bevacizumab infusion in hepatocellular carcinoma after transarterial chemoembolization failure"
} | [
{
"companynumb": "CN-ROCHE-2911887",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The tumor necrosis factor-α (TNF-α) antagonists infliximab, adalimumab, and etanercept have been approved for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, and psoriatic arthritis. Manifestations of demyelinating disease have been reported for patients receiving TNF-α antagonists. We describe a rare manifestation of a chronic inflammatory process affecting both the central and peripheral nervous system in a patient who received infliximab for the treatment of psoriasis and psoriatic arthritis. Infliximab therapy was discontinued and symptoms improved under high-dose intravenous glucocorticoid pulse therapy.",
"affiliations": "aDepartment of Neurology, University Hospital Göttingen, Göttingen, Germany.;bDepartment of Dermatology, University Hospital Rostock, Rostock, Germany.;cRadiology Practice, Am Bethanien Krankenhaus, Frankfurt am Main, Germany.;dDepartment of Neurorehabilitation, Krankenhaus St. Elisabeth, Damme, Germany.;aDepartment of Neurology, University Hospital Göttingen, Göttingen, Germany.;eDepartment of Dermatology, University Hospital Göttingen, Göttingen, Germany.;fDepartment of Neurology, Nordwest-Krankenhaus Sanderbusch, Sande, Germany.",
"authors": "Signore|Sandra C|SC|;Brauns|Birka|B|;Schütze|Gunther|G|;Dohm|Christoph P|CP|;Bähr|Mathias|M|;Mössner|Rotraut|R|;Kermer|Pawel|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000485499",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000485499crn-0010-0012Case ReportInfliximab-Associated Chronic Inflammatory Central Nervous System Disease and Peroneal Nerve Injury in a Psoriatic Patient Refractory to Treatment: Case Report with 10-Year Follow-Up Signore Sandra C. a*Brauns Birka bSchütze Gunther cDohm Christoph P. dBähr Mathias aMössner Rotraut eKermer Pawel faDepartment of Neurology, University Hospital Göttingen, Göttingen, GermanybDepartment of Dermatology, University Hospital Rostock, Rostock, GermanycRadiology Practice, Am Bethanien Krankenhaus, Frankfurt am Main, GermanydDepartment of Neurorehabilitation, Krankenhaus St. Elisabeth, Damme, GermanyeDepartment of Dermatology, University Hospital Göttingen, Göttingen, GermanyfDepartment of Neurology, Nordwest-Krankenhaus Sanderbusch, Sande, Germany*Sandra C. Signore, Department of Neurology, University Hospital Göttingen, Robert-Koch-Strasse 40, DE–37075 Göttingen (Germany), E-Mail ssignore@web.deJan-Apr 2018 19 1 2018 19 1 2018 10 1 12 17 15 5 2017 21 11 2017 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.The tumor necrosis factor-α (TNF-α) antagonists infliximab, adalimumab, and etanercept have been approved for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, and psoriatic arthritis. Manifestations of demyelinating disease have been reported for patients receiving TNF-α antagonists. We describe a rare manifestation of a chronic inflammatory process affecting both the central and peripheral nervous system in a patient who received infliximab for the treatment of psoriasis and psoriatic arthritis. Infliximab therapy was discontinued and symptoms improved under high-dose intravenous glucocorticoid pulse therapy.\n\nKeywords\nInfliximabChronic inflammatory central nervous system diseasePeroneal nerve injuryTreatment-refractory psoriasis\n==== Body\nCase Report\nA 45-year-old male patient with chronic plaque psoriasis since the age of 26 developed joint symptoms with pain and swelling 10 years ago. Arterial hypertension, which was well controlled by the antihypertensive drug amlodipine, was the only known comorbidity. Serological investigations including serology for Lyme borreliosis, antinuclear antibodies, antibodies for anti-dsDNA, rheumatoid factor, and uric acid were negative or within normal limits, and the diagnosis of psoriatic arthritis was established. After therapies with oral methotrexate and cyclosporine had proved ineffective in controlling joint and skin symptoms, a therapy with tumor necrosis factor-α (TNF-α) antagonists was initiated. Both subcutaneous etanercept at a dose of 2 × 25 mg/week over 6 months and subcutaneous adalimumab at a dose of 40 mg every other week over 4 months were discontinued because of insufficient improvement of skin and joint symptoms. In June 2008, intravenous therapy with infliximab (5 mg/kg every 8 weeks) was initiated. Two months into therapy joint and skin symptoms were greatly improved, with a reduction of the Psoriasis Area and Severity Index from 23.4 prior to infliximab therapy (Fig. 1a) to 3.9, and the therapeutic effect could be maintained throughout the following months of therapy (Fig. 1b).\n\nIn January 2009, 1 month after the fourth infusion, the patient noticed weakness of the left arm and right leg with hypesthesia in the absence of other accompanying symptoms such as fever or bladder or bowel incontinence. The patient's family history was negative for multiple sclerosis (MS) and other acute or chronic inflammatory central nervous system (CNS) or peripheral nervous system (PNS) diseases.\n\nNeurological examination revealed a paresis of 4/5 strength at the proximal right leg and 3/5 at the distal right leg. A central paresis of 4/5 at the left arm was also documented. The left arm and right leg showed hypesthesia which could not be described by dermatomes or peripheral nerve territories. Tendon reflexes were decreased on the upper and lower extremities.\n\nElectrophysiological examination revealed a proximal and distal axonal neuropathy of the peroneal nerves (right > left) without proximal conduction block at the neck of the fibula. F-waves were not detectable. Additional electromyography showed chronic nerve damage in the right anterior tibial muscle without acute denervation revealing additional peripheral nerve damage.\n\nA complete blood cell count, liver enzymes, electrolytes, thyroidal gland hormones, and urine values were all within normal limits. MRI scans in February 2009 revealed a lesion in the left peritrigonal region (Fig. 2a, b, arrows) which showed no contrast enhancement, but due to its localization and shape, an inflammatory process was most likely. Lumbar puncture showed a slightly elevated cell count of 5 cells/mm3 (normal range: 0–4 cells/mm3) and a mildly increased total protein level of 531 mg/L (normal range: 150–450 mg/L). An elevation of immunoglobulin G with presence of oligoclonal bands supported the findings of an inflammatory component, which was not explainable due to other causes since there was no acute infection and due to the negative patient history. Clinical examination and neurological workup suggested the diagnosis of an inflammatory process affecting both the CNS and the PNS, whereas the chronic inflammatory CNS disease did not fulfil the diagnostic criteria for MS. Infliximab therapy was discontinued and the patient treated with high-dose intravenous methylprednisolone (1 g/day i.v. over 3 days), resulting in a marked improvement of pareses and hypesthesia of the upper and lower extremities.\n\nAt discharge, the patient denied any hypesthesia and pareses were barely detectable. In line with lacking exacerbation of neurological symptoms upon control examination 4 weeks later, MRI scans showed a regression of the left peritrigonal lesion, underlining the primary suspicion of an inflammatory lesion. Nine months later, hypesthesia of the left arm was still absent, while paresis of the right foot and hypesthesia of the right anterior lower leg had recurred. The patient received a second cycle of high-dose intravenous methylprednisolone pulse therapy (1 g/day i.v. for 3 days) which resulted in a rapid improvement of hypesthesia and paresis, but not in a complete disappearance of symptoms. At further follow-up examinations, a paresis of the distal right leg of 4/5 strength and hypesthesia in an area around the ankle of the right foot remained.\n\nCurrently, after 10 years, the patient is in stable neurological condition. Electrophysiological results such as neuropathy of the peroneal nerves deteriorated, and the patient also showed pathological visual evoked potentials on both sides, further confirming the chronic inflammatory CNS disease, but not fulfilling the criteria for MS yet. At the moment he is getting ustekinumab regularly as dermatologic treatment without suffering severe side effects.\n\nDiscussion\nManifestations of demyelinating disorders have been reported in association with TNF-α antagonists [1, 2], especially for adalimumab [3], etanercept [4], and infliximab [5]. Patients typically suffer from a variety of symptoms such as paresis, paresthesia, optic neuritis, and gait disturbances, with usually a relatively good outcome after discontinuation of anti-TNF drugs, sometimes in combination with usual treatments for demyelinating neuropathies [1, 2, 3, 4, 5, 6]. According to the literature, TNF antagonist therapies can be associated with Guillain-Barré and Miller Fischer syndrome [7]. Furthermore, there are cases described in whom TNF-α antagonists induced MS and transverse myelitis [1, 2] and vasculitis [2, 8]. With respect to several publications describing demyelinating diseases during anti-TNF-α treatment, there are also cases with peripheral mononeuropathy [9], multifocal motor neuropathy [10], and polyradiculoneuropathy [11] described.\n\nTNF-α is a proinflammatory and immunoregulatory cytokine which is believed to be involved in the pathogenesis of several CNS disorders such as MS, myasthenia gravis, and amyotrophic lateral sclerosis [2, 11, 12]. As TNF is able to induce the production of other cytokines and adhesion molecules for leukocyte migration [13], it can also have neurotoxic effects by the production of reactive oxygen species. On the other hand, neuroprotective effects of TNF-α have been described [14, 15].\n\nAfter discontinuing the reported patient's infliximab therapy and initiating high-dose methylprednisolone pulse therapy, the pareses improved. Based on clinical examination, lumbar puncture, and MRI studies, the patient suffers from chronic inflammatory CNS disease, but does not fulfil the diagnostic criteria for MS. The differential diagnosis of a vascular CNS lesion caused by hypertonia was unlikely due to localization, shape, and reduction after high-dose infusion with methylprednisolone. Due to the chronological association of the manifestation of the neurological symptoms with infliximab therapy, it is likely that this drug triggered or caused their manifestation, particularly as the patient's family history was negative for MS and other acute or chronic inflammatory CNS diseases. Still, it cannot be excluded that the patient already had a latent chronic inflammatory CNS disease as neither MRI nor lumbar puncture were performed prior to initiation of infliximab therapy. This view is supported by the fact that electrophysiological measurements proved some progression over the follow-up time of almost 10 years. In addition, it could be possible that not only infliximab, but also the other two TNF antagonists that the patient had taken previously contributed to the manifestation of neurological symptoms or that their side effects were enhanced.\n\nIn summary, this case shows a rare manifestation of a combined chronic inflammatory CNS and PNS disease during infliximab therapy which, to our knowledge, has not been reported yet. It shows the importance of follow-up examinations, including neurological status, for patients with an anti-TNF-α therapy for early detection of inflammatory diseases in the nervous system. In these cases, discontinuation of the anti-TNF-α therapy and the initiation of a therapy for chronic inflammatory disease is recommended.\n\nStatement of Ethics\nAll authors hereby state that the patient gave his informed consent for publication of this case report and that all applicable subject protection guidelines and regulations were followed in the conduct of this research.\n\nDisclosure Statement\nThere are no conflicts of interest.\n\nFig. 1. a Sharply delineated erythematosquamous psoriatic plaques of the right leg before infliximab therapy in May 2008. b After the fourth infusion of infliximab at a dose of 5 mg/kg in February 2009, the psoriatic lesions on the right leg had almost disappeared.\n\nFig. 2. a, b Magnetic resonance images of the brain in February 2009. T2-weighted images show a lesion in the left peritrigonal region without contrast agent enhancement (arrows) indicative of an inflammatory lesion.\n==== Refs\nReferences\n1 Zhu TH Nakamura M Abrouk M Farahnik B Koo J Bhutani T Demyelinating disorders secondary to TNF-inhibitor therapy for the treatment of psoriasis: a review J Dermatolog Treat 2016 27 406 413 26837667 \n2 Theibich A Dreyer L Magyari M Locht H Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic: description of six cases Clin Rheumatol 2014 33 719 723 24202614 \n3 Berthelot CM George SJ Hsu S Distal lower paresthesia and foot drop developing during adalimumab therapy J Am Acad Dermatol 2005 53 260 262 \n4 Sukal SA Nadiminti L Granstein RD Etanercept and demyelinating disease in a patient with psoriasis J Am Acad Dermatol 2006 54 160 164 16384777 \n5 Lozeron P Denier C Lacroix C Adams D Long-term course of demyelinating neuropathies occurring during tumor necrosis factor-alpha-blocker therapy Arch Neurol 2009 66 490 497 19364934 \n6 Felekis T Katsanos K Christodoulou D Asproudis I Tsianos EV Reversible bilateral optic neuritis after infliximab discontinuation in a patient with Crohn's disease J Crohns Colitis 2009 3 212 214 21172274 \n7 Shin IS Baer AN Kwon HJ Papadopoulos EJ Siegel JN Guillain-Barré and Miller Fisher syndromes occurring with tumor necrosis factor alpha antagonist therapy Arthritis Rheum 2006 54 1429 1434 16645971 \n8 Jarrett SJ Cunnane G Conaghan PG Bingham SJ Buch MH Quinn MA Emery P Anti-tumor necrosis factor-alpha therapy-induced vasculitis: case series J Rheumatol 2003 30 2287 2291 14528531 \n9 Hanaoka BY Libecco J Rensel M Hajj-Ali RA Peripheral mononeuropathy with etanercept use: case report J Rheumatol 2008 35 182 18176996 \n10 Kelly S Connolly S McCarthy A Hutchinson M Murphy S Turbridy N PONM12. Multifocal motor neuropathy due to infliximab J Neurol Neurosurg Psychiatry 2010 81 63 \n11 Solomon AJ Spain RI Kruer MC Bourdette D Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors Mult Scler 2011 17 1472 1487 21816758 \n12 Ghezzi P Mennini T Tumor necrosis factor and motoneuronal degeneration: an open problem Neuroimmunomodulation 2001 9 178 182 11847479 \n13 Weisman MH Moreland LW Furst DE Weinblatt ME Keystone EC Paulus HE Teoh LS Velagapudi RB Noertersheuser PA Granneman GR Fischkoff SA Chartash EK Efficacy, pharmacokinetic and safety assessment of adalimumab, a fully tumor-necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study Clin Ther 2003 25 1700 1721 12860493 \n14 Segal BM Cross AH Fas(t) track to apoptosis: TNF receptors may suppress or potentiate CNS demyelination Neurology 2000 55 906 907 11061241 \n15 Robinson WH Genovese MC Moreland LW Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 2001 44 1977 1983 11592357\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "10(1)",
"journal": "Case reports in neurology",
"keywords": "Chronic inflammatory central nervous system disease; Infliximab; Peroneal nerve injury; Treatment-refractory psoriasis",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "12-17",
"pmc": null,
"pmid": "29515419",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "11592357;16227104;21816758;16384777;14528531;12860493;18176996;19364934;16645971;26837667;21172274;11847479;11061241;24202614",
"title": "Infliximab-Associated Chronic Inflammatory Central Nervous System Disease and Peroneal Nerve Injury in a Psoriatic Patient Refractory to Treatment: Case Report with 10-Year Follow-Up.",
"title_normalized": "infliximab associated chronic inflammatory central nervous system disease and peroneal nerve injury in a psoriatic patient refractory to treatment case report with 10 year follow up"
} | [
{
"companynumb": "DE-JNJFOC-20180634557",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "A 33-year-old woman with T(4c)N(3) breast cancer with metastases in the skeleton (M(1)) received five cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC regimen) before conception and during the first trimester. Salvage radiotherapy (28 Gy) was delivered during the 17th week. Tamoxifen and zolendronic acid were also administered throughout the second and third trimesters. The patient was not aware of her pregnancy until the 28th week. A female phenotypically normal infant was delivered in the 35th week of gestation by cesarean section. The child is functioning normally 12 months after delivery. The literature of anthracycline treatment during conception and the first trimester is reviewed. The effects of tamoxifen and biphosphonate therapy on the fetus during pregnancy are also discussed.",
"affiliations": "3rd Department of Clinical Oncology, Theagenion Cancer Hospital of Thessaloniki, 540 07 Thessaloniki, Greece. elkageba@otenet.gr",
"authors": "Andreadis|Charalampos|C|;Charalampidou|Martha|M|;Diamantopoulos|Nikolaos|N|;Chouchos|Nikolaos|N|;Mouratidou|Despina|D|",
"chemical_list": "D004164:Diphosphonates; D007093:Imidazoles; D013629:Tamoxifen; D015251:Epirubicin; D000077211:Zoledronic Acid; D003520:Cyclophosphamide; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2004.06.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "95(1)",
"journal": "Gynecologic oncology",
"keywords": null,
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D004164:Diphosphonates; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007093:Imidazoles; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D016879:Salvage Therapy; D013629:Tamoxifen; D000077211:Zoledronic Acid",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "252-5",
"pmc": null,
"pmid": "15385141",
"pubdate": "2004-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combined chemotherapy and radiotherapy during conception and first two trimesters of gestation in a woman with metastatic breast cancer.",
"title_normalized": "combined chemotherapy and radiotherapy during conception and first two trimesters of gestation in a woman with metastatic breast cancer"
} | [
{
"companynumb": "PHHY2019GR150161",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "The coexistence of carotid artery stenosis and cerebral aneurysm in a patient presents challenges for treatment decision-making. The purpose of this study was to evaluate the technical feasibility and clinical outcome after single-stage extracranial carotid artery stenting (CAS) and ipsilateral intracranial aneurysm coiling in a single institution. From March 2005 to February 2011, 17 patients with 21 aneurysms underwent single-stage CAS and coiling for ipsilateral aneurysms. There were symptomatic atherosclerotic carotid stenoses with unruptured aneurysms in eight, ruptured or symptomatic aneurysms with simultaneous asymptomatic carotid stenoses in two and asymptomatic lesions in seven. CAS was followed by aneurysm coiling in all 17 patients. Clinical and radiological data were reviewed. There were two procedure-related complications: acute in-stent thrombosis in one and premature aneurysmal rupture in the other. After aneurysm coiling, complete occlusion was demonstrated in 17 aneurysms and near-total occlusion in four. No neurological deficit was found at discharge and follow-up outcomes were excellent in all the patients (mean, 32.9 months). Follow-up imaging studies were performed in all the patients, including neck CT angiography in 14 (mean, 26.1 months), brain MR angiography in 14 (mean, 31.2 months), and conventional angiography in three (mean, 14.7 months). They revealed two asymptomatic, mild carotid re-stenoses and one major aneurysmal recanalization requiring re-coiling. A single-stage CAS and coiling procedure appears to be feasible and the complication rate seems to be reasonable. We suggest that there is no need for separate therapeutic procedures when a patient has carotid artery stenosis and accompanying ipsilateral intracranial aneurysm.",
"affiliations": "Department of Neurosurgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.",
"authors": "Park|J C|JC|;Kwon|B J|BJ|;Kang|H-S|HS|;Kim|J E|JE|;Kim|K M|KM|;Cho|Y D|YD|;Han|M H|MH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/159101991301900213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "19(2)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": null,
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001807:Blood Vessel Prosthesis; D016893:Carotid Stenosis; D003131:Combined Modality Therapy; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D011859:Radiography; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "228-34",
"pmc": null,
"pmid": "23693048",
"pubdate": "2013-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "889489;12867109;21206764;16866060;6732329;9030344;18617588;7723155;10908914;22193563;20465929;15026733;20634431",
"title": "Single-stage extracranial carotid artery stenting and intracranial aneurysm coiling: technical feasibility and clinical outcome.",
"title_normalized": "single stage extracranial carotid artery stenting and intracranial aneurysm coiling technical feasibility and clinical outcome"
} | [
{
"companynumb": "KR-SA-2022SA134706",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "Cytomegalovirus (CMV) central nervous system disease after hematopoietic stem cell transplantation (HSCT) is a rare but life-threatening complication. Here, we report a patient who developed CMV meningitis after HSCT and was treated with the combination therapy of intrathecal high-titer CMV immunoglobulin and antiviral drugs. A 38-year-old man with myelodysplastic syndrome received a cord blood transplant after graft failure. On day 147, he was diagnosed with CMV meningitis based on pleocytosis and CMV DNA in the cerebrospinal fluid (CSF). Intravenous ganciclovir, foscarnet, and immunoglobulin were administered; however, CMV DNA in the CSF was continuously detected. The addition of intrathecal high-titer CMV immunoglobulin resulted in CMV DNA in the CSF becoming undetectable. On day 241, CMV DNA in the CSF was detected again, but both intrathecal immunoglobulin and intravenous ganciclovir led to its disappearance. No adverse effects related to intrathecal administration were observed. The intrathecal administration of immunoglobulin may be safe and effective for CMV meningitis.",
"affiliations": "Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.;Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.;Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.;Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.;Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.;Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.;Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.;Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.",
"authors": "Fujiwara|Shin-Ichiro|S|;Muroi|Kazuo|K|;Tatara|Raine|R|;Ohmine|Ken|K|;Matsuyama|Tomohiro|T|;Mori|Masaki|M|;Nagai|Tadashi|T|;Ozawa|Keiya|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/272458",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2014/272458Case ReportIntrathecal Administration of High-Titer Cytomegalovirus Immunoglobulin for Cytomegalovirus Meningitis Fujiwara Shin-ichiro *Muroi Kazuo Tatara Raine Ohmine Ken Matsuyama Tomohiro Mori Masaki Nagai Tadashi Ozawa Keiya Division of Cell Therapy and Hematology, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan*Shin-ichiro Fujiwara: sfujiwar@jichi.ac.jpAcademic Editor: Akimichi Ohsaka\n\n2014 8 5 2014 2014 27245812 3 2014 27 4 2014 Copyright © 2014 Shin-ichiro Fujiwara et al.2014This 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.Cytomegalovirus (CMV) central nervous system disease after hematopoietic stem cell transplantation (HSCT) is a rare but life-threatening complication. Here, we report a patient who developed CMV meningitis after HSCT and was treated with the combination therapy of intrathecal high-titer CMV immunoglobulin and antiviral drugs. A 38-year-old man with myelodysplastic syndrome received a cord blood transplant after graft failure. On day 147, he was diagnosed with CMV meningitis based on pleocytosis and CMV DNA in the cerebrospinal fluid (CSF). Intravenous ganciclovir, foscarnet, and immunoglobulin were administered; however, CMV DNA in the CSF was continuously detected. The addition of intrathecal high-titer CMV immunoglobulin resulted in CMV DNA in the CSF becoming undetectable. On day 241, CMV DNA in the CSF was detected again, but both intrathecal immunoglobulin and intravenous ganciclovir led to its disappearance. No adverse effects related to intrathecal administration were observed. The intrathecal administration of immunoglobulin may be safe and effective for CMV meningitis.\n==== Body\n1. Introduction\n\nCMV disease is still one of the most serious complications after HSCT. By preemptive therapy against CMV reactivation, CMV disease has been successfully reduced during the first several months after HSCT. In contrast, late-onset CMV disease after the completion of monitoring the viral load is now frequently observed in high-risk patients [1]. CMV central nervous system (CNS) disease developing at such a stage has rarely been reported [2, 3]. The occurrence of CMV CNS disease is associated with high mortality due to impaired CMV-specific immunity, antiviral drug resistance, or both [2]. Therefore, new therapeutic strategies for CMV CNS disease are needed.\n\n2. Case Presentation\nA 38-year-old man with myelodysplastic syndrome (refractory anemia with excess blasts-2) received a cord blood transplant. Conditioning was a myeloablative conditioning regimen consisting of cyclophosphamide and total body irradiation. The treatment for the prevention of the graft-versus-host disease (GVHD) was tacrolimus and short-term methotrexate. Cord blood (0.67 × 105 CD34+ cells/kg) was infused and granulocyte colony-stimulating factor (G-CSF) was given from day 1. On day 29, the patient suffered from primary graft failure caused by hemophagocytic syndrome. Following nonmyeloablative conditioning including fludarabine (30 mg/m2/day, 2 days), etoposide (30 mg/m2, 1 day), and antithymocyte globulin (2.5 mg/kg/day, 2 days), cord blood (0.76 × 105 CD34+ cells/kg) was infused again [4]. GVHD prophylaxis was tacrolimus alone (0.03 mg/kg/day, continuous infusion from day 1), and G-CSF was given from day 1. On day 16, from the second cord blood transplantation, meningitis due to Enterococcus faecalis developed. The administration of intravenous linezolid and intrathecal vancomycin resulted in the negativity of the bacteria in the cerebrospinal fluid (CSF). Neutrophilic engraftment was achieved on day 46. After engraftment, CMV antigenemia was repeatedly positive, and preemptive ganciclovir and foscarnet were effective for CMV viremia. CMV retinitis developed on day 96 and ganciclovir led to an improvement of fundus lesions due to CMV. There were no signs of GVHD, and tacrolimus was discontinued on day 137. From day 138, he complained of headache, high fever, and ocular pain. Magnetic resonance imaging of the brain did not show encephalitis. On day 147, a lumbar puncture revealed meningitis based on an increased number of CSF cells (404 cells/mm3), increased level of CSF protein (148 mg/dL), and decreased level of CSF glucose (39 mg/dL). The CMV DNA level in the CSF was 1.8 × 105 copies/mL measured with a qualitative polymerase-chain-reaction method, and the patient was diagnosed with CMV meningitis. Ganciclovir, foscarnet, and immunoglobulin were intravenously administered, but it should be noted that ganciclovir must be stopped in the presence of a bleeding tendency and thrombocytopenia. CMV DNA in the CSF was continuously detected and headache developed again on day 201 (Figure 1). The dose of ganciclovir must have been reduced by myelosuppression. Neurological symptoms caused by CMV meningitis worsened progressively. Therefore, after obtaining permission from the division director and consent from the patient, high-titer CMV immunoglobulin (hCMV-IG: complete-type immunoglobulin, Kenketsu Venilon-I, Kaketsuken, Kumamoto, Japan) was intrathecally administered from day 208. Firstly, 0.25 g taken from a 5 g of hCMV-IG was administered intrathecally and the remaining 4.75 g was administered intravenously. Subsequently, 0.5 g of hCMV-IG was administered intrathecally and 4.5 g of the agent was administered intravenously [5, 6]. Intrathecal hCMV-IG administration was performed weekly until day 223 (a total of 3 doses). No adverse effects related to the intrathecal administration of hCMV-IG, such as neurological symptoms and allergic reactions, were observed. The intrathecal IgG level (mean 27, range 25–28 mg/dL) was lower than serum IgG (mean 923, range 900–960 mg/dL). Following the intrathecal administration of hCMV-IG, CMV DNA became undetectable and ganciclovir and foscarnet were discontinued. Although headache and CMV DNA in the CSF reappeared on day 241, the administration of intrathecal hCMV-IG (a total of 2 doses) and intravenous ganciclovir resulted in its disappearance. No adverse effects associated with hCMV-IG administration were observed. Although the number of neutrophils and immunoglobulin levels recovered to normal range, cellular immune deficiency continued after the second transplantation. The number of lymphocytes, CD4 cells, and CD8 cells remained at less than 500, 100, and 100/mm3, respectively. CMV-specific cytotoxic T lymphocytes were not detected on a tetramer assay after hCMV-IG intrathecal administration (data not shown). CMV meningitis worsened from around day 300, and it was difficult to continue treatment due to deterioration of the patient's general condition. The patient died of sepsis on day 338, and an autopsy was not performed.\n\n3. Discussion\nImmunoglobulin available in Japan can be categorized into two types: incomplete and complete. The former is a disconnected Fc region, while the latter has an intact Fc region. Intrathecal administration of the incomplete type has been approved in Japan. Regarding the complete type, there have been several reports on intrathecal administration for refractory bacterial meningitis and other conditions [5–8]. To our knowledge, ours is the first reported case where CMV meningitis was treated with the combination therapy of intrathecal hCMV-IG and antiviral drugs. In our case, one or two doses of intrathecal hCMV-IG administration led to the clearance of CMV DNA in the CSF. The initial response may have simply reflected the effects of ganciclovir and foscarnet. However, the long-term administration of either ganciclovir or foscarnet or both is impossible due to their toxic effects such as causing myelosuppression and renal dysfunction. Intrathecal immunoglobulin administration may be worth trying, along with an anti-CMV agent, for an immediate response in CMV meningitis patients.\n\nhCMV-IG administered intrathecally may neutralize cell-free CMV, inhibit cell-to-cell virus spread, and reduce CMV mRNA levels in infected cells [8]. In addition to such direct effects, intrathecally administered immunoglobulin may neutralize inflammatory cytokines aggravating meningitis, such as interleukin-1 and tumor necrosis factor, as shown by dexamethasone for bacterial meningitis [9]. In our case, as reported previously [5, 6], 0.5 g of complete-type immunoglobulin was safe and effective when administered intrathecally. Further studies are needed to determine the optimal dose of intrathecal immunoglobulin.\n\nThe effect of intrathecal hCMV-IG did not persist for a long time. Surviving patients with CMV CNS disease showed cellular immune recovery against CMV [2, 3]. Therefore, CMV-specific T cells are essential in the control of CMV disease. In our case, CMV-specific T cells were absent throughout the course after second cord blood transplantation. The absence of cellular immunity may have resulted in a short-term effect of hCMV-IG against CMV meningitis. Recently, the clinical use of CMV-specific cytotoxic T cells against CMV disease has progressed [10]. The combination of intrathecal hCMV-IG administration and such adoptive immune cell therapy may be meaningful for CMV CNS disease in immunocompromised patients after HSCT.\n\nIn conclusion, we are the first to demonstrate that the combination of intrathecal hCMV-IG and antiviral drugs is safe and effective for CMV meningitis. Because CMV CNS disease is still fatal, intrathecal hCMV-IG administration may be a treatment option in addition to antiviral therapy and adoptive immune cell therapy.\n\nConflict of Interests\nThe authors state that they have no conflict of interests.\n\nFigure 1 Clinical course of patient. Day means day from second cord blood transplantation. CMV: cytomegalovirus, CSF: cerebrospinal fluid.\n==== Refs\n1 Asano-Mori Y Kanda Y Oshima K Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation International Journal of Hematology 2008 87 3 310 318 2-s2.0-46149109475 18320138 \n2 Reddy SM Winston DJ Territo MC Schiller GJ CMV central nervous system disease in stem-cell transplant recipients: An increasing complication of drug-resistant CMV infection and protracted immunodeficiency Bone Marrow Transplantation 2010 45 6 979 984 2-s2.0-77954860536 20190836 \n3 Tam DY Cheng FW Chan PK Intact survival of refractory CMV limbic encephalitis in a patient with severe aplastic anemia after unrelated bone marrow transplantation Journal of Pediatric Hematology/Oncology 2012 34 472 474 22430584 \n4 Sumi M Shimizu I Sato K Graft failure in cord blood transplantation successfully treated with short-term reduced-intensity conditioning regimen and second allogeneic transplantation International Journal of Hematology 2010 92 5 744 750 2-s2.0-78751566374 21052879 \n5 Nishizawa E Yamamoto H Kawano T Kamata K The clinical study of intrathecal administration of immune globulin against meningitis The Journal of Therapy 1988 70 996 1002 \n6 Tokito S Ohyama M Motoghishita T Yamashita H Experience of intrathecal administration of Venilon in neurosurgery area Medical Consultation & New Remedies 1981 18 1143 1148 \n7 Watanabe H Hasegawa T Saito T Intrathecal and intravenous combined administration of Venoglobulin—I for meningitis Journal of New Remedies & Clinics 1984 33 579 582 \n8 Kudoh C Ikegami Y Sugiura K Combined treatment of pH4 treated acidic human normal immunoglobulin and antibiotics for severe infections in a neurosurgical patients Japanese Journal of Neurosurgery 1995 4 6 533 537 Abstract in English 2-s2.0-0028884711 \n9 Lutsar I Friedland IR Jafri HS Factors influencing the anti-inflammatory effect of dexamethasone therapy in experimental pneumococcal meningitis Journal of Antimicrobial Chemotherapy 2003 52 4 651 655 2-s2.0-0141997707 12951330 \n10 Sellar RS Peggs KS Therapeutic strategies for the prevention and treatment of cytomegalovirus infection Expert Opinion on Biological Therapy, Informa Healthcare 2012 12 1161 1172\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2014()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
"mesh_terms": null,
"nlm_unique_id": "101576456",
"other_id": null,
"pages": "272458",
"pmc": null,
"pmid": "24900929",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "22650422;21052879;18320138;20190836;22430584;12951330",
"title": "Intrathecal administration of high-titer cytomegalovirus immunoglobulin for cytomegalovirus meningitis.",
"title_normalized": "intrathecal administration of high titer cytomegalovirus immunoglobulin for cytomegalovirus meningitis"
} | [
{
"companynumb": "JP-CLINIGEN GROUP PLC/ CLINIGEN HEALTHCARE LTD-JP-CLGN-18-00210",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FOSCARNET SODIUM"
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.