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"abstract": "The treatment of patients with refractory/relapsed B cell non-Hodgkin lymphoma (NHL) is evolving because of the availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and mortality remain a matter of concern. We conducted a multicenter prospective phase II trial to evaluate the benefit of including only 1 dose of rituximab in the conditioning regimen before alloSCT. The primary endpoint was progression-free survival. The study enrolled 121 patients with relapsed/refractory B cell lymphomas. The conditioning regimen consisted of thiotepa, cyclophosphamide, fludarabine, and rituximab (500 mg/m2). Rabbit antithymocyte globulin was administered only in case of unrelated donors. Sixty-seven (55%) and 54 (45%) patients received grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of nonrelapse mortality (NRM) was 21% at 3 years. The CCIs of chronic graft-verus-host disease (GVHD) at 3 years were 54% and 31% in recipients of matched sibling and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-year progression-free and overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite endpoint of GVHD-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a prospective trial of lymphoma patients: the 1-year and 3-year GRFS were 40% and 34%, respectively. AlloSCT can cure a fraction of patients with rather low NRM and an encouraging PFS and GRFS.",
"affiliations": "Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. Electronic address: anna.dodero@istitutotumori.mi.it.;Department of Hematology, University of Udine, Udine, Italy.;Department of Hematology, Azienda Ospedaliera Universitaria, Presidio Ospedaliero Ferrarotto, Catania, Italy.;Department of Hematology, Humanitas Cancer Center, Rozzano, Italy.;Department of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.;Department of Hematology, Umberto I, Roma, Italy.;Department of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.;Department of Hematology, Ospedale San Gerardo Monza, Monza, Italy.;Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.;Department of Hematology, Ospedale di Alessandria, Alessandria, Italy.;Department of Transplantation, Azienda Ospedaliero-Univerisitaria Carreggi, Firenze, Italy.;Department of Stem Transplantation, Ospedale San Martino, Genova, Italy.;Department of Hematology, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Department of Hematology, Universita' di Modena, Milan, Italy.;Department of Hematology, Ospedale Policlinico di Modena, Modena, Italy.;Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.;University of Milan, Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.;Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; Dept of Oncology, University of Milan, Milan, Italy.",
"authors": "Dodero|Anna|A|;Patriarca|Francesca|F|;Milone|Giuseppe|G|;Sarina|Barbara|B|;Miceli|Rosalba|R|;Iori|Anna|A|;Barretta|Francesco|F|;Terruzzi|Elisabetta|E|;Mussetti|Alberto|A|;Pini|Massimo|M|;Bosi|Alberto|A|;Dominietto|Alida|A|;Cascavilla|Nicola|N|;Onida|Francesco|F|;Narni|Franco|F|;Farina|Lucia|L|;Rambaldi|Alessandro|A|;Corradini|Paolo|P|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2017.03.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "23(7)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Graft-versus-host disease–free/relapse-free survival; Lymphoma; Rituximab",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D000069283:Rituximab; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1102-1109",
"pmc": null,
"pmid": "28390983",
"pubdate": "2017-07",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen.",
"title_normalized": "allogeneic stem cell transplantation for relapsed refractory b cell lymphomas results of a multicenter phase ii prospective trial including rituximab in the reduced intensity conditioning regimen"
} | [
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"companynumb": "IT-BAXTER-2017BAX020277",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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"actiondrug": "5",
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"activesubstancename": "RITUXIMAB"
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{
"abstract": "Sinonasal anaplastic lymphoma kinase(ALK)-negative anaplastic large cell lymphoma(ALCL) without nodal involvement is exceedingly rare and the rarity of this tumor often engenders diagnostic dilemma. It has been mostly reported in pediatric, adolescent and young adult patients, mostly of Asian origin. A 70-year-old female patient presented with a mass in the left nasal cavity causing nasal obstruction for 5 months. On clinical and radiological examination, there was a 5.7 cm mass in the left nasal cavity, completely obliterating the left ethmoid sinus. Biopsy from the nasal mass showed a poorly differentiated malignant tumour with large cells arranged in sheets. On immunohistochemistry, the tumour cells were positive for leukocyte common antigen(LCA), CD30, CD43, BCL6 and focally for CD5, TIA1, granzyme B and epithelial membrane antigen(EMA), and were negative for CD56, EBV-LMP1, CD79a, PAX5, myeloperoxidase, CD34, CD7, CD4, CD8, CD138, ALK and p63, suggestive of ALK-negative ALCL. Rest of the lymphoma work-up was essentially normal and she had stage IE disease. She was treated with prephase chemotherapy (Vincristine and Prednisolone) followed by 4 cycles of CEOP[Cyclophosphamide, Etoposide (from 2nd cycle onwards), Vincristine and Prednisolone] regimen and local radiotherapy (36 Gy/20 fractions/4 weeks) by intensity modulated radiotherapy(IMRT) technique resulting in complete clinical and radiological response. At last follow-up visit, 15 months from the initial diagnosis, she was alive and disease free. Sinonasal ALK-negative ALCL is a rare tumor which can be effectively treated with a combination of multi-agent CHOP/CHOP-like regimen and local conformal radiotherapy in geriatric patients.",
"affiliations": "Departments of Radiotherapy & Oncology, All India Institute of Medical Sciences, New Delhi, India. dr_ahitagni@yahoo.co.in.;Departments of Radiotherapy & Oncology, All India Institute of Medical Sciences, New Delhi, India.;Departments of Radiotherapy & Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Biswas|Ahitagni|A|http://orcid.org/0000-0002-3453-5340;Shishak|Sorun|S|;Roy|Swarnaditya|S|;Kakkar|Aanchal|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12105-020-01276-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1936-055X",
"issue": "15(4)",
"journal": "Head and neck pathology",
"keywords": "Anaplastic large cell lymphoma; Anaplastic lymphoma kinase; Intensity modulated radiotherapy; Lymphoma; Sinonasal",
"medline_ta": "Head Neck Pathol",
"mesh_terms": null,
"nlm_unique_id": "101304010",
"other_id": null,
"pages": "1335-1344",
"pmc": null,
"pmid": "33398683",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "26770602;9680346",
"title": "Combined Modality Management of Sinonasal Anaplastic Lymphoma Kinase Negative Anaplastic Large Cell Lymphoma in a Geriatric Patient-Report of a Rare Case.",
"title_normalized": "combined modality management of sinonasal anaplastic lymphoma kinase negative anaplastic large cell lymphoma in a geriatric patient report of a rare case"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "4",
"drugadministratio... |
{
"abstract": "BACKGROUND\nLong-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.\n\n\nMETHODS\nStandard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).\n\n\nRESULTS\n2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.\n\n\nCONCLUSIONS\nZoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.\n\n\nBACKGROUND\nCancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.",
"affiliations": "Warwick Medical School, University of Warwick, Coventry, UK; University Hospitals Birmingham NHS Foundation Trust, The Medical School, University of Birmingham, Birmingham, UK.;MRC Clinical Trials Unit at UCL, London, UK. Electronic address: m.sydes@ucl.ac.uk.;Department of Urology, The Christie and Salford Royal NHS Foundation Trusts, Manchester, UK.;Cardiff University School of Medicine, Velindre Hospital, Cardiff, UK.;The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.;MRC Clinical Trials Unit at UCL, London, UK.;MRC Clinical Trials Unit at UCL, London, UK.;The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.;Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.;The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.;Department of Urology, Leeds Teaching Hospitals NHS Trust, Leeds.;Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.;Department of Urology, University Hospital, Bern, Switzerland.;MRC Clinical Trials Unit at UCL, London, UK.;Patient rep, MRC Clinical Trials Unit at UCL, London, UK.;Patient rep, MRC Clinical Trials Unit at UCL, London, UK.;Department of Oncology, Weston Park Hospital, Sheffield & Doncaster, UK.;Kent Oncology Centre, Maidstone Hospital, Maidstone, UK.;Department of Oncology, Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK.;Department of Oncology, Poole Hospital NHS Foundation Trust and Royal Bournemouth Hospital NHS Foundation Trust, Chur, Switzerland.;Kantonsspital Graubünden, Chur, Switzerland.;Department of Oncology, Derby Hospitals NHS Foundation Trust, Royal Derby Hospital, Derby, UK.;Department of Medical Oncology, Guy's Hospital, London, UK.;Department of Oncology, Cheltenham General Hospital & Hereford County Hospital, UK.;Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK.;Oncology and Haematology Clinical Trials Unit, Queen Alexandra Hospital, Portsmouth, UK.;Department of Oncology, Queen's Hospital, Romford, UK.;Beacon Centre, Musgrove Park Hospital, Taunton, UK.;Department of Urology, Hull & East Yorkshire Hospitals NHS Trust, Hull, UK.;Mount Vernon Group, Mount Vernon Hospital, Middlesex, UK.;Department of Oncology, Royal Surrey County Hospital, Guildford, UK.;Department of Oncology, East Sussex Hospitals Trust, East Sussex, UK.;Department of Oncology, Western General Hospital, Edinburgh, UK.;Centre for Cancer Research and Cell Biology, Queens University Belfast/Belfast City Hospital, Belfast, UK.;Department of Oncology, East Lancashire Hospitals NHS Trust, East Lancashire, UK.;Department of Oncology & Radiotherapy, South Tees NHS Trust, Middlesbrough, UK.;Department of Oncology, Churchill Hospital, Oxford, UK.;Department of Oncology, Sussex Cancer Centre, Brighton, UK.;Department of Oncology, Shrewsbury & Telford Hospitals NHS Trust, Shrewsbury, UK.;Department of Oncology, Royal Devon & Exeter Hospital, Exeter, UK/Torbay Hospital, Torquay, UK.;Cardiff University School of Medicine, Velindre Hospital, Cardiff, UK.;Department of Oncology, Nottingham University Hospitals NHS trust, Nottingham, UK.;Department of Oncology & Radiotherapy, Clatterbridge Cancer Centre, Wirral, UK.;Department of Oncology, Southend & Basildon Hospitals, Essex, UK.;The South West Wales Cancer Institute and Swansea University College of Medicine, Swansea, UK.;MRC Clinical Trials Unit at UCL, London, UK.",
"authors": "James|Nicholas D|ND|;Sydes|Matthew R|MR|;Clarke|Noel W|NW|;Mason|Malcolm D|MD|;Dearnaley|David P|DP|;Spears|Melissa R|MR|;Ritchie|Alastair W S|AW|;Parker|Christopher C|CC|;Russell|J Martin|JM|;Attard|Gerhardt|G|;de Bono|Johann|J|;Cross|William|W|;Jones|Rob J|RJ|;Thalmann|George|G|;Amos|Claire|C|;Matheson|David|D|;Millman|Robin|R|;Alzouebi|Mymoona|M|;Beesley|Sharon|S|;Birtle|Alison J|AJ|;Brock|Susannah|S|;Cathomas|Richard|R|;Chakraborti|Prabir|P|;Chowdhury|Simon|S|;Cook|Audrey|A|;Elliott|Tony|T|;Gale|Joanna|J|;Gibbs|Stephanie|S|;Graham|John D|JD|;Hetherington|John|J|;Hughes|Robert|R|;Laing|Robert|R|;McKinna|Fiona|F|;McLaren|Duncan B|DB|;O'Sullivan|Joe M|JM|;Parikh|Omi|O|;Peedell|Clive|C|;Protheroe|Andrew|A|;Robinson|Angus J|AJ|;Srihari|Narayanan|N|;Srinivasan|Rajaguru|R|;Staffurth|John|J|;Sundar|Santhanam|S|;Tolan|Shaun|S|;Tsang|David|D|;Wagstaff|John|J|;Parmar|Mahesh K B|MK|;|||",
"chemical_list": "D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D004164:Diphosphonates; D007093:Imidazoles; D043823:Taxoids; D000077143:Docetaxel; D000077211:Zoledronic Acid",
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nLancetLancetLancet (London, England)0140-67361474-547XElsevier S0140-6736(15)01037-510.1016/S0140-6736(15)01037-5ArticlesAddition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial James Nicholas D ProfPhDabSydes Matthew R MScm.sydes@ucl.ac.ukc*Clarke Noel W ProfChMdMason Malcolm D ProfMDeDearnaley David P ProfMDfSpears Melissa R MSccRitchie Alastair W S MDcParker Christopher C MDfRussell J Martin FRCRgAttard Gerhardt MD PhDfde Bono Johann ProfPhDfCross William PhDhJones Rob J ProfPhDgThalmann George ProfMDiAmos Claire PhDcMatheson David PhDjMillman Robin jAlzouebi Mymoona FRCRkBeesley Sharon FRCRlBirtle Alison J MDmBrock Susannah FRCRnCathomas Richard MDoChakraborti Prabir FRCRpChowdhury Simon MDqCook Audrey FRCRrElliott Tony PhDsGale Joanna DMtGibbs Stephanie FRCRuGraham John D FRCPvHetherington John FRCS[Eng]wHughes Robert FRCRxLaing Robert FRCRyMcKinna Fiona FRCRzMcLaren Duncan B FRCR, FRCP[Ed]aaO'Sullivan Joe M ProfMDabParikh Omi FRCRacPeedell Clive FRCRadProtheroe Andrew PhDaeRobinson Angus J FRCRafSrihari Narayanan MDagSrinivasan Rajaguru FRCRahStaffurth John MDeSundar Santhanam FRCRaiTolan Shaun MDajTsang David MCRPakWagstaff John ProfMDalParmar Mahesh K B ProfDPhilcfor the STAMPEDE investigators†a Warwick Medical School, University of Warwick, Coventry, UKb University Hospitals Birmingham NHS Foundation Trust, The Medical School, University of Birmingham, Birmingham, UKc MRC Clinical Trials Unit at UCL, London, UKd Department of Urology, The Christie and Salford Royal NHS Foundation Trusts, Manchester, UKe Cardiff University School of Medicine, Velindre Hospital, Cardiff, UKf The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UKg Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UKh Department of Urology, Leeds Teaching Hospitals NHS Trust, Leedsi Department of Urology, University Hospital, Bern, Switzerlandj Patient rep, MRC Clinical Trials Unit at UCL, London, UKk Department of Oncology, Weston Park Hospital, Sheffield & Doncaster, UKl Kent Oncology Centre, Maidstone Hospital, Maidstone, UKm Department of Oncology, Rosemere Cancer Centre, Royal Preston Hospital, Preston, UKn Department of Oncology, Poole Hospital NHS Foundation Trust and Royal Bournemouth Hospital NHS Foundation Trust, Chur, Switzerlando Kantonsspital Graubünden, Chur, Switzerlandp Department of Oncology, Derby Hospitals NHS Foundation Trust, Royal Derby Hospital, Derby, UKq Department of Medical Oncology, Guy's Hospital, London, UKr Department of Oncology, Cheltenham General Hospital & Hereford County Hospital, UKs Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UKt Oncology and Haematology Clinical Trials Unit, Queen Alexandra Hospital, Portsmouth, UKu Department of Oncology, Queen's Hospital, Romford, UKv Beacon Centre, Musgrove Park Hospital, Taunton, UKw Department of Urology, Hull & East Yorkshire Hospitals NHS Trust, Hull, UKx Mount Vernon Group, Mount Vernon Hospital, Middlesex, UKy Department of Oncology, Royal Surrey County Hospital, Guildford, UKz Department of Oncology, East Sussex Hospitals Trust, East Sussex, UKaa Department of Oncology, Western General Hospital, Edinburgh, UKab Centre for Cancer Research and Cell Biology, Queens University Belfast/Belfast City Hospital, Belfast, UKac Department of Oncology, East Lancashire Hospitals NHS Trust, East Lancashire, UKad Department of Oncology & Radiotherapy, South Tees NHS Trust, Middlesbrough, UKae Department of Oncology, Churchill Hospital, Oxford, UKaf Department of Oncology, Sussex Cancer Centre, Brighton, UKag Department of Oncology, Shrewsbury & Telford Hospitals NHS Trust, Shrewsbury, UKah Department of Oncology, Royal Devon & Exeter Hospital, Exeter, UK/Torbay Hospital, Torquay, UKai Department of Oncology, Nottingham University Hospitals NHS trust, Nottingham, UKaj Department of Oncology & Radiotherapy, Clatterbridge Cancer Centre, Wirral, UKak Department of Oncology, Southend & Basildon Hospitals, Essex, UKal The South West Wales Cancer Institute and Swansea University College of Medicine, Swansea, UK* Correspondence to: Mr Matthew R Sydes, MRC Clinical Trials Unit at UCL, London WC2B 6NH, UKCorrespondence to: Mr Matthew R SydesMRC Clinical Trials Unit at UCLLondonWC2B 6NHUK m.sydes@ucl.ac.uk† Members listed at end of paper\n\n19 3 2016 19 3 2016 387 10024 1163 1177 © 2016 James et al. Open Access article distributed under the terms of CC BY2016This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Summary\nBackground\nLong-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.\n\nMethods\nStandard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).\n\nFindings\n2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.\n\nInterpretation\nZoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.\n\nFunding\nCancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.\n==== Body\nResearch in Context\nEvidence before this study\n\nSystemic treatment has changed little for newly diagnosed men with high-risk locally advanced or metastatic prostate cancer since the development of gonadotropin-releasing hormone analogues a generation ago. The only major change has been the use of radical radiotherapy for men whose disease had not spread. This century, new agents began to show valuable activity in relapsed, metastatic, castrate-refractory prostate cancer—including zoledronic acid, which was approved in 2002 on the basis of reduced morbidity in men with bone metastases (a site of spread in up to 90% of castrate-refractory prostate cancer), and docetaxel, with improved survival demonstrated in 2004. Several other trials in addition to STAMPEDE have assessed both drugs in the newly diagnosed setting, most notably GETUG-15 and CHAARTED, which assessed docetaxel in the metastatic setting (about 60% of the population used in our trial). A systematic review and meta-analysis was done in parallel to preparation of this report and contains details of the review strategy.\n\nAdded value of this study\n\nOur results for zoledronic acid show no convincing evidence of worthwhile benefit either on failure-free or overall survival. These results are congruent with emerging results from other trials in men starting long-term hormone therapy. The docetaxel results showed an improvement in overall survival (HR 0·78; 95% CI 0·66–0·93; p=0·006). There was a notable improvement in survival for the metastatic subset, which is consistent with findings from GETUG-15 and CHAARTED which both also showed gains in failure-free survival with docetaxel. GETUG-15 showed a non-significant improvement in overall survival, and CHAARTED reported a statistically significant improvement in overall survival.\n\nImplications of all the available evidence\n\nTogether, these trials provide evidence that six cycles of docetaxel should be added to standard androgen deprivation therapy for men with metastatic disease commencing treatment. Men with non-metastatic disease had better prognoses, and failure-free survival was clearly improved by docetaxel; however, there were relatively few deaths in those with non-metastatic disease, so statements about overall survival in this population remain underpowered.\n\n\n\nIntroduction\nSince October, 2005, the STAMPEDE randomised controlled trial has recruited men with metastatic (M1), high-risk localised (N0), or node-positive (N+) prostate cancer who were newly diagnosed or had high-risk recurrent disease following previous local therapy. All were commencing first-line long-term hormone therapy. Prognosis for these patient groups had altered little since the first description of the effects of hormone therapy in the 1940s. This began to change in the early 21st century with licensing of agents that improved survival (ie, docetaxel, abiraterone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T),1, 2, 3, 4, 5, 6, 7, 8 and disease-modifying agents that reduced morbidity (zoledronic acid and denosumab).9, 10 However, these agents have all shown their benefits in the setting of castrate-refractory prostate cancer (ie, after first-line hormone therapy has ceased working).\n\nSTAMPEDE uses a multiarm, multistage (MAMS) platform design to test whether the addition of treatments at the time of long-term hormone therapy initiation improves overall survival. Here, we evaluate and report findings for zoledronic acid and docetaxel; data for celecoxib, abiraterone, enzalutamide in combination with abiraterone, and (in patients with newly diagnosed metastatic disease only) prostate radiotherapy will be reported elsewhere. We have previously reported the celecoxib-containing groups which closed to recruitment early after a pre-planned second intermediate analysis failed to show sufficient effect on failure-free survival.11 We have also previously reported control group outcome data for patients with metastatic12 and non-metastatic13 disease. We report here the first survival data for the following original groups in this platform trial: zoledronic acid, docetaxel, and their combination. Other trials have also examined similar strategies, both in patients with non-metastatic disease and in those with metastatic disease, usually with single drugs. A meta-analysis with other docetaxel and zoledronic acid-containing trials has been conducted and is reported separately.14\n\nZoledronic acid was licensed in 2002 on the basis of an improvement in a composite outcome measure of time to first skeletal-related event, with a risk ratio of 0·64 (95% CI 0·49 to 0·85) in castrate-refractory prostate cancer, and subsequent reduction in further skeletal-related events using the 4 mg schedule.9 There was limited evidence of a benefit in survival, although the study was underpowered. Two previous UK trials, PR04 and PR05, used sodium clodronate in patients with non-metastatic and metastatic disease, respectively. The PR05 trial showed improved survival with concurrent hormone therapy plus clodronate but no evidence of benefit was seen in PR04.15\n\nDocetaxel (75 mg/m2) 3-weekly (ie, given every 3 weeks) was licensed for metastatic castrate-refractory prostate cancer in 2004, on the basis of two trials comparing mitoxantrone and prednisone with docetaxel and either prednisone2 or estramustine.1 The median survival benefit observed was about 3 months, with a hazard ratio (HR) of 0·76 (0·62–0·94)2 for docetaxel compared with mitoxantrone.\n\nThe STAMPEDE trial16, 17 used interim activity analyses, based on failure-free survival, to select groups to continue accrual for fully powered survival analysis. We report here overall, failure-free, and prostate-cancer-specific survival data from the zoledronic acid and docetaxel groups and their combination, together with adverse event data and treatment after relapse.\n\nMethods\nStudy design and participants\nWe used a MAMS platform trial approach, incorporating a seamless phase 2/3 design.18 The rationale and design have been described previously.16, 17, 19 Full details are in the protocol. In summary, eligible patients had prostate cancer that was newly diagnosed as metastatic, node positive, or high-risk locally advanced (with at least two of T3/4, Gleason score of 8–10, and prostate-specific antigen ≥40 ng/mL); or previously treated with radical surgery, radiotherapy, or both and relapsing with high-risk features. All patients were intended for long-term hormone therapy, started no longer than 12 weeks before randomisation. There were no age restrictions; patients were required to be fit for chemotherapy with no clinically significant cardiovascular history.\n\nRandomisation and masking\nPatients were randomised centrally using a computerised algorithm, developed and maintained by the trials unit. Minimisation with a random element of 80% was used, stratifying for hospital, age at randomisation, presence of metastases, planned radiotherapy use, nodal involvement, WHO performance status, planned hormone therapy, and regular use of aspirin or another non-steroidal anti-inflammatory drug. Allocation was in a 2:1:1:1 ratio to standard of care only (SOC-only), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care plus zoledronic acid and docetaxel (SOC + ZA + Doc). Masking to treatment allocation was considered impracticable and of limited value given the primary outcome measure.\n\nProcedures\nStandard of care was hormone therapy for at least 2 years with gonadotropin-releasing hormone agonists or antagonists or, only between 2006 and 2011 for patients with non-metastatic disease, oral anti-androgens alone. Orchidectomy was an allowable alternative to drug therapy. No recommendations around the use of granulocyte colony stimulating factor with docetaxel were given. Radiotherapy, at 6–9 months after randomisation, was encouraged for patients with N0M0 disease, until November, 2011, then mandated; radiotherapy was optional for patients with N+M0 disease; staging was with the Union for International Cancer Control (UICC) TNM staging criteria. Guidance on radiotherapy techniques are described elsewhere.13 Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years. Docetaxel (75 mg/m2) was given for six 3-weekly cycles with prednisolone (10 mg) daily, and standard premedication before each injection. Dose modifications were described in the protocol. Trial therapy was discontinued after disease progression or intolerable adverse events.\n\nPatients were followed up 6-weekly to 6 months, 12-weekly to 2 years, 6-monthly to 5 years, then annually. Prostate-specific antigen was measured at every follow-up; further tests were at the clinician's discretion. Nadir prostate-specific antigen was the lowest value reported within 24 weeks after enrolment. Adverse events were graded with Common Toxicity Criteria (CTCAE) version 3.0; toxic effects and symptoms were reported at regular follow-up visits. Serious adverse events, including serious adverse reactions, were reported accordingly. The trial was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki, and had the relevant regulatory and ethics approvals (eg, in the UK we obtained national ethics approval, national regulatory approval, and local implementation). All patients gave written, informed consent.\n\nOutcomes\nThe definitive and intermediate primary outcome measures were overall survival and failure-free survival, respectively. Overall survival was defined as time from randomisation to death from any cause. Failure-free survival, which is commonly used to drive decisions in the clinic, was selected because it is on the causal pathway to death from prostate cancer and was not required to be a surrogate for overall survival. It was defined as time from randomisation to first evidence of at least one of: biochemical failure; progression either locally, in lymph nodes, or in distant metastases; or death from prostate cancer. Biochemical failure was defined as a rise of 50% above the within-24-week nadir and above 4 ng/mL and confirmed by retest or treatment.12 We expected prostate-specific antigen failure to be the most common manifestation of failure-free survival events. Cause of death was determined by masked central review. Death from prostate cancer was recorded when classified by the reviewer as “definitely” or “probably” prostate cancer. The site investigator's determination was used for deaths not yet reviewed.\n\nStatistical analysis\nThe sample size was calculated using nstage and its predecessor programmes in Stata, which enables design of MAMS trials.20 Assuming, for the control group, 2 years' median failure-free survival, and median overall survival between 4 and 5 years, we targeted a 25% relative improvement (HR 0·75) in both failure-free survival and overall survival for each comparison of research group with control. Accumulating data were reviewed by an Independent Data Monitoring Committee, guided by lack-of-benefit stopping guidelines.16, 17, 18 The efficacy stage analysis of each pairwise comparison of research against control for overall survival required around 400 deaths in the control arm for 90% power and 2·5% one-sided α (corresponding to a two-sided α of 5%), accounting for three intermediate analyses on failure-free survival (analysed March, 2010, April, 2011, and May, 2012). The research groups within STAMPEDE were seen to test distinct hypotheses, and the trial was purposely not designed as a factorial trial.17 In this situation, many methodologists would not be concerned about the family-wise error rate.3, 21, 22, 23 However, for completeness we calculated the maximum family-wise error rate as 6·75% for these three research groups.\n\nPatients without the event of interest were censored at the time last known to be event free. Standard survival analysis methods were used to analyse time-to-event data. Cox proportional hazards regression models were used to estimate most relative treatment effects. This model was adjusted for stratification factors (except hospital and planned hormone therapy), and stratified by time periods defined by addition of a new research group or end in recruitment to an ongoing research group. An HR below 1·00 favoured the research group. Flexible parametric models were constructed with 4 degrees of freedom for each of the baseline hazard function and time-dependent effect, and adjusted for stratification factors and time periods.24 Medians and 5-year estimates come from the flexible parametric model fitted to the data; these are more reliable than reading the Kaplan-Meier curves. The proportional hazards assumption was tested; restricted mean survival time was emphasised in the presence of non-proportionality. Fine and Gray regression models were used for competing risk analysis of prostate-cancer-specific survival (non-metastatic prostate-cancer-specific survival analyses did not adjust for time period due to lack of convergence). Prespecified analyses looked at consistency of treatment effect within stratification factors, over time period, and also by categorised Gleason score (≤7, 8+, unknown), recurrent disease, and prostate-specific antigen values before hormone therapy. The statistical analysis plan was modified to include an analysis of the subset of patients with metastatic disease at randomisation after the presentation of CHAARTED25 and GETUG-1526 and before this primary analysis was performed. All tests were two-sided, with confidence intervals given at the 95% level.\n\nMedian follow-up was determined through the standard approach of reverse-censoring on death, in which survival is treated as the event and death as censoring. All patients are included in the efficacy analyses according to allocated treatment on an intention-to-treat basis. Adverse event data are shown for the safety population, comprising patients who received any study drug and underwent adverse event assessment, and analysed according to treatment initiated irrespective of study group assignment; a sensitivity analysis of safety was done on an intention-to-treat basis. Safety data were assessed continuously; we also present a safety analysis at 1 year, chosen to assess whether chemotherapy side-effects had ameliorated by this timepoint. A formal comparison of those research groups showing a survival advantage, compared with SOC-only, was done, and a pre-planned factorial analysis (without an interaction term) is included for completeness. Data on first skeletal-related event and osteonecrosis of the jaw are also presented. All other analyses are exploratory. Statistical analyses were done with Stata version 14 and nstage. The trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).\n\nRole of the funding source\nThe trial was sponsored by the MRC and conducted by the MRC Clinical Trials Unit at UCL with the Swiss Group for Clinical Cancer Research. MRC employees were central to the conduct of the trial and the development of this manuscript. Only authors MRSp and MRSy had access to raw data; processed data released by the Independent Data Monitoring Committee and Trial Steering Committee were available to all coauthors. Cancer Research UK (MRC PR08, CRUK/06/019) approved, but had no further input into, the trial design. Pfizer, Novartis, and Sanofi-Aventis approved the initial and amended trial design and participated in discussions on the progress of the trial. Representatives from these industry partners were invited to comment on the report. The analyses were driven by prespecified criteria and the decision to submit for publication was made by the Trial Management Group.\n\nResults\nBetween Oct 5, 2005, and March 31, 2013, 2962 patients were randomised from more than 100 UK and Swiss sites: 1184 to SOC-only, 593 SOC + ZA, 592 SOC + Doc, and 593 SOC + ZA + Doc. Data were frozen on May 13, 2015, with a cutoff of March 4, 2015. The appendix shows an overview of the broader trial design and groups recruiting over time, whereas figure 1 shows the CONSORT flow diagram for analyses presented here. Table 1 gives baseline characteristics of these patients. Median follow-up was 43 months (IQR 30–60). Most patients (94%) were newly diagnosed. 1738 (62%) of 2797 newly diagnosed patients had metastatic disease at entry, compared with 79 (48%) of 165 patients with recurrent disease. Median age was 65 years (IQR 60–71), median prostate-specific antigen 65 ng/mL (IQR 23–184), and 2092 (71%) patients were Gleason score 8–10.\n\nMedian time to starting zoledronic acid was about 2 weeks after randomisation, and about 8 weeks from starting hormone therapy (most patients started hormone therapy before randomisation). Median duration of zoledronic acid was 16·6 months (IQR 7·8–23·2) for SOC + ZA and 19·5 months (IQR 9·1–23·4) for SOC + ZA + Doc, with the difference in duration being driven by differences in time to progression (table 2). Of patients allocated to receive zoledronic acid as part of trial treatment, overall about 40% of patients completed 2 years of zoledronic acid therapy (table 2). When less than 2 years of treatment was received, progression was the most common reason for stopping. Zoledronic acid was not started in eight (1%) patients assigned to SOC + ZA and 49 (8%) patients assigned to SOC + ZA + Doc, mostly due to treatment refusal.\n\nMedian time to starting docetaxel was about 2 weeks after randomisation and 9 weeks after starting hormone therapy. Of patients allocated to receive docetaxel as part of trial treatment, 456 (77%) patients assigned to SOC + Doc and 422 (71%) to SOC + ZA + Doc received the full six cycles, whereas 477 (81%) assigned to SOC + Doc and 446 (75%) to SOC + ZA + Doc received at least five cycles (table 3). When five or fewer cycles were reported, toxic effects were the most common reason for stopping (table 3), with few patients reporting stopping for disease progression. Docetaxel was not started in 46 (8%) patients assigned to SOC + Doc and 70 (12%) to SOC + ZA + Doc, again mostly due to treatment refusal, patient choice, or withdrawal from the trial.\n\nPlanned use of standard of care radiotherapy was similar across groups (28–29%), with reported use being 323 (27%) patients for SOC-only; 155 (26%) for SOC + ZA; 154 (26%) for SOC + Doc; and 148 (25%) for SOC + ZA + Doc. In patients with non-metastatic disease, 62% were planned for radiotherapy, with the corresponding figures for reported use being 289 (63%) for SOC-only, 136 (60%) for SOC + ZA, 131 (57%) for SOC + Doc, and 130 (57%) for SOC + ZA + Doc; higher proportions of N0 than N+ patients received radiotherapy (appendix page 9).\n\nThere were 415 deaths (347 prostate cancer deaths; 84%) in patients receiving SOC-only; median survival was 71 months (IQR 32 to not reached) and 5-year survival was 55%. These data form the reference for each comparison of research group with control.\n\n201 patients in the SOC + ZA group died (169 prostate cancer; 84%), with no evidence of a survival advantage compared with SOC-only (HR 0·94, 95% CI 0·79–1·11; p=0·450); median survival was not reached (IQR 32 to not reached), and 5-year survival was 57%. However, there was evidence of a survival advantage for SOC + Doc (HR 0·78, 95% CI 0·66–0·93; p=0·006) with 175 deaths (143 prostate cancer; 82%), median survival 81 months (IQR 41 to not reached), and 5-year survival of 63%. There was also evidence of survival advantage for SOC + ZA + Doc (HR 0·82, 95% CI 0·69–0·97; p=0·022) with 187 deaths (150 prostate cancer; 80%), median survival 76 months (IQR 39 to not reached), and 5-year survival of 60%. There was no evidence of non-proportional hazards. Plots for survival are shown in figure 2.\n\nWe found no evidence of heterogeneity of treatment effect across predefined subsets (figure 3). Pre-planned subset analyses in all 1817 patients with metastatic disease at randomisation included around 500 deaths per comparison. This included 350 deaths in patients on SOC-only (median survival 45 months [IQR 23–91], 5-year survival 39%). There were 170 deaths on SOC + ZA (HR 0·93, 95% CI 0·77–1·11; p=0·416), with median survival 46 months (IQR 24 to not reached) and 5-year survival of 43%. There were 144 deaths on SOC + Doc (HR 0·76, 95% CI 0·62–0·92; p=0·005), with median survival 60 months (IQR 27–103) and 5-year survival of 50% (appendix page 5). Finally, there were 158 deaths on SOC + ZA + Doc (HR 0·79, 95% CI 0·66–0·96; p=0·015), with median survival 55 months (IQR 29–88) and 5-year survival of 46%. Similar comparisons in patients without metastatic disease at randomisation are immature at this time, with fewer than 100 deaths per comparison.\n\nComparing the two research groups that demonstrated a survival advantage over the control group (SOC + Doc and SOC + ZA + Doc), we noted no evidence of an advantage when adding zoledronic acid to docetaxel (HR 1·06, 95% CI 0·86–1·30; p=0·592). In an exploratory analysis of the effect of docetaxel on survival in the context of zoledronic acid (ie, comparing SOC + ZA with SOC + ZA + Doc), the hazard ratio was 0·87 (95% CI 0·71–1·06). Analysis of the main effects of zoledronic acid and docetaxel in a single factorial model, without a treatment-interaction term, showed docetaxel to be associated with a survival advantage (HR 0·82, 95% CI 0·72–0·93; p=0·003), but not zoledronic acid (HR 0·98, 95% CI 0·86–1·11; p=0·726). An exploratory factorial model, including an interaction term, found no evidence of treatment interaction (p=0·401); the individual treatment effects were the same as in the pairwise comparisons.\n\nFigure 2 shows the failure-free survival plot for each research comparison, and the appendix page 10 shows the form of that failure-free survival event. There were 761 events in patients on SOC-only; median failure-free survival 20 months; 5-year failure-free survival 28%. With 374 events there was no evidence of improvement in failure-free survival with SOC + ZA (HR 0·92, 95% CI 0·81–1·04; p=0·198); median failure-free survival was 22 months and 5-year failure-free survival was 31%. There was, however, evidence of an improvement in failure-free survival both for SOC + Doc, with 315 events (HR 0·61, 95% CI 0·53–0·70; p=0·413 × 10−13), median failure-free survival 37 months, and 5-year failure-free survival 38%; and for SOC + ZA + Doc, with 318 events (HR 0·62, 95% CI 0·54–0·70; p=0·134 × 10−12), median failure-free survival 36 months, 5-year failure-free survival 34%. There was strong evidence of non-proportional hazards for both comparisons showing an improvement in failure-free survival (SOC + Doc and SOC + ZA + Doc). In these cases, restricted mean survival time is preferred to the hazard ratio for summarising the treatment effect. Mean failure-free survival, restricted to the first 84 months on trial, was 34·8 months on SOC-only, compared to 44·2 months on SOC + Doc (difference 9·4 months, 95% CI 6·6–12·3; p=0·556 × 10−10) and compared to 43·1 months on SOC + ZA + Doc (difference 8·3 months, 95% CI 5·5–11·1; p=0·480 × 10−8).\n\nAs with survival, there was no evidence of heterogeneity in failure-free survival across the same predefined subsets (appendix page 3). Considering metastatic status subsets, treatment effect was broadly consistent within both non-metastatic and metastatic populations, for all research comparisons, and indicated that docetaxel improved failure-free survival for non-metastatic disease (HR 0·60, 95% CI 0·45–0·80; p=0·283 × 10−3) as for metastatic disease (HR 0·61, 95% CI 0·53–0·71; p=0·283 × 10−10).\n\nAt the time of this analysis, a total of 978 men had died, 809 (83%) from prostate cancer. The proportion of deaths attributed to prostate cancer was increased in men presenting with metastases: 703 (86%) of 822 deaths in the 1817 men presenting with metastases, compared with 106 (68%) of 156 deaths in 1145 men presenting without metastases. Adjusted competing risks regression for prostate-cancer-specific survival showed an advantage over SOC-only for SOC + Doc (subHR 0·79, 95% CI 0·65–0·96; p=0·019) and SOC + ZA + Doc (0·78, 0·65–0·95; p=0·013), but not SOC + ZA (0·95, 0·79–1·15; p=0·613). For patients with metastatic disease, the subHR for SOC + Doc was 0·80 (95% CI 0·65–0·99; p=0·033), for SOC + ZA was 0·92 (0·75–1·12), and for SOC + ZA + Doc was 0·78 (0·64–0·96); for patients with non-metastatic disease, the subHR for SOC + Doc was 0·82 (95% CI 0·48–1·40; p=0·475), for SOC + ZA was 1·08 (0·66–1·76), and for SOC + ZA + Doc was 0·81 (CI 0·46–1·43). We noted particularly limited power for subset analyses at this time for both settings.\n\nAmongst patients randomly assigned to SOC-only, 328 of 1184 reported at least one skeletal-related event. Time to first skeletal-related event was improved with SOC + Doc (112 patients reported skeletal-related event; HR 0·60, 95% CI 0·48–0·74; p=0·127 × 10−5) and SOC + ZA + Doc (108 patients; HR 0·55, 95% CI 0·44–0·69; p=0·277 × 10−7), but not SOC + ZA (153 patients; HR 0·89, 95% CI 0·73–1·07; p=0·221). There was strong evidence of non-proportional hazards for both comparisons showing improvement in time to first skeletal-related event (SOC + Doc and SOC + ZA + Doc). In these cases, restricted mean survival time is preferred for summarising treatment effect. Mean time to skeletal-related event, restricted to within the first 84 months on trial, was 61·4 months (95% CI 59·5–63·2) on SOC-only, compared with 68·0 months on SOC + Doc (difference 6·6 months, 95% CI 3·6–9·6; p=0·177 × 10−4) and 68·3 (65·6–70·3) on SOC + ZA + Doc (difference 6·9 months, 95% CI 4·1–9·8; p=0·249 × 10−5). In the patient group with bone metastases at presentation, SOC + ZA similarly had no evidence of an effect (HR 0·94, 95% CI 0·76–1·16; p=0·564).\n\nFigure 4 shows time to first of any treatment after a failure-free survival event and time to first life-extending therapy (defined as available agents with proven survival gain in castrate-refractory prostate cancer: docetaxel, abiraterone, cabazitaxel, enzalutamide, and radium-223). There were no obvious differences either in time to any therapy or life-extending therapies between groups. There were however, differences in the pattern of therapy depending on whether patients were docetaxel-exposed upfront (figure 4). Analysis of zoledronic acid use after relapse is provided in the appendix page 7. Overall exposure to treatment for progression is summarised in table 4, showing slightly higher rates of exposure to subsequent therapy in the control group. Use of cabazitaxel, enzalutamide, and radium-223 were low across all groups (appendix page 6).\n\nThe proportion of patients reporting worst adverse event ever as grade 3 or higher was highest with SOC + Doc (288 patients [52%]) and SOC + ZA + Doc (269 [52%]; table 5). This was mostly due to events during the first 6 months on trial, when the proportions were 17% (n=203) for SOC-only, 15% (n=91) for SOC + ZA, 36% (n=198) for SOC + Doc, and 39% (n=202) for SOC + ZA + Doc, with docetaxel seeming to contribute the most toxicity. For 1998 patients with adverse event data around 1 year after randomisation (ie, worst adverse event grade reported at 48 or 60 weeks of follow-up), the proportions of grade 3 or higher toxic effects were balanced, with 10% (n=76) patients reporting a worst adverse event as grade 3 or higher with SOC-only, 10% (n=41) with SOC + ZA, 10% with (n=43) SOC + Doc, and 12% (n=49) with SOC + ZA + Doc. The pattern and levels of adverse events were similar in the safety and intention-to-treat populations. There were ten (2%) reported cases of osteonecrosis of the jaw on SOC + ZA and 20 (4%) on SOC + ZA + Doc. There were eight deaths probably or possibly related to the research treatment: one on SOC + Doc (neutropenic sepsis), and seven on SOC + ZA + Doc (four neutropenic sepsis, one pneumocystic pneumonia, one interstitial pneumonitis, and one pneumonia).\n\nDiscussion\nThe STAMPEDE randomised controlled trial is investigating the effectiveness of the front-line use of various treatments in men commencing long-term hormone therapy for newly diagnosed locally advanced or metastatic prostate cancer, or who have relapsed after local therapy with poor prognosis features. The MAMS design used in STAMPEDE has allowed us to address multiple treatment questions simultaneously within a single trial platform.18 We will report further randomised comparisons from STAMPEDE in the coming years (appendix page 2), meaning that, through this single protocol, we will have answered at least eight different primary questions in 15 years. To have addressed as many questions in separate, sequential trials would have taken many decades and far more patients, notably allocated to control groups. We recommend that academic and industry researchers consider this design in the future, to make faster progress and good use of limited trial resources.\n\nThese are the first mature, comparative, randomised data to emerge from the trial. We found that the addition of docetaxel to standard of care was associated with improved survival, with an HR of 0·78 and a difference in median survival of 10 months, as well as improvements in prostate-cancer-specific survival, failure-free survival, and skeletal-related events. The combination of zoledronic acid and docetaxel was associated with similar improvements, although the benefit observed was smaller. We will report cost-effectiveness and patient-reported outcomes separately.\n\nDocetaxel is a widely used drug with a familiar toxicity profile. Docetaxel was well tolerated in this population, with most patients completing all six cycles in a timely fashion and good dose intensity. Predictable chemotherapy toxic effects, including neutropenia and febrile neutropenia, were observed but few patients stopped treatment because of side-effects. Toxic effects in both docetaxel-containing groups seemed higher than in previous studies of this drug in patients with castrate-refractory prostate cancer (eg, TAX327), but the studies have used different populations.27, 28 The protocol made no recommendations about growth factor support, and we have not collected information about its use.29, 30\n\nDocetaxel significantly prolonged failure-free and overall survival across the trial population with no evidence that the effect varied across different groups in the population; in particular, there is no evidence of a difference of the effect of docetaxel by metastatic status, for either of these outcome measures. The beneficial effect on survival is clear in the larger metastatic subpopulation, which accounted for 61% of patients in the trial and 84% of deaths. There were fewer patients with non-metastatic disease and, with their generally more favourable prognosis, there were relatively few deaths in this group; all survival analyses for this subset are currently underpowered. In this non-metastatic subset of men, death from causes other than prostate cancer was more common than in men with metastatic disease, and therefore any effect of docetaxel on overall survival will be diluted. We will report longer-term follow-up in due course, but note that estimates of the treatment effect in failure-free survival and prostate-cancer-specific survival are extremely similar for patients with and without metastases at presentation.\n\nFor zoledronic acid, the results show no evidence of efficacy on failure-free survival, skeletal-related events, or overall survival, despite good compliance with therapy and good levels of exposure, with target duration of 2 years. Few patients stopped treatment for side-effects; the most frequent reason for stopping trial therapy within 2 years was disease progression. This differed between the SOC + ZA and SOC + ZA + Doc groups because failure-free survival was increased in the latter group by docetaxel, indirectly leading to increased exposure to zoledronic acid as well. Despite this increased exposure, zoledronic acid showed no evidence of an advantage when added to docetaxel (HR 1·06).\n\nThe effect of docetaxel on survival was positive, but clinically significant toxicity did occur; in clinical practice, consideration could be given to early use of growth factor support to enable treatment delivery. There was one treatment-related death in the SOC + Doc group and seven in the combination group. This difference, combined with a more modest survival benefit for the combination treatment, raises the possibility of some interaction (or antagonism) between docetaxel and zoledronic acid in the treatment of this group of men.\n\nA number of trials have now examined docetaxel in the hormone-naive context in both the non-metastatic and metastatic settings, of which STAMPEDE is the largest.25, 26, 31, 32, 33, 34 These findings are discussed elsewhere but consistently show an improvement in failure-free survival.14 The CHAARTED trial25 recently reported improved survival in metastatic disease whereas GETUG-15,26 a similar trial, did not report a differential effect. Taken with our results, there is compelling evidence that front-line docetaxel substantially improves survival in patients with metastatic disease. In the non-metastatic setting, there are insufficient mature survival results in the literature, so further follow-up and engagement in planned meta-analyses are needed to further delineate the effect of docetaxel on survival in this setting. The impact on failure-free survival is both clear and large in favour of docetaxel in STAMPEDE.\n\nThe case mix of patients joining the trial included men with newly diagnosed disease and a small proportion of patients with recurrent disease. The recurrent disease subset is small and thus it is unrealistic to look for statistically reliable results in such men; however, we note that estimates of the effect of docetaxel are consistent with that seen in the population as a whole.\n\nFor zoledronic acid, there are now several trials showing no evidence of a survival gain with upfront use,14, 35, 36, 37 as discussed in the accompanying meta-analysis. This contrasts with the results from MRC PR0515 with sodium clodronate (another bisphosphonate), in which a survival benefit was reported in a metastatic population. The companion non-metastatic trial showed no evidence of an effect on survival with the same agent.15\n\nMen in the STAMPEDE trial did better than we had expected in terms of survival. We believe this resulted from second-line and third-line treatments which were unavailable when the trial was designed. The timing of second-line therapy after relapse was similar across groups, but choice of which treatment to use was at the investigator's discretion, and, consequently, was varied. This choice would have been affected by local practice and availability of newer treatments over time, such as abiraterone, enzalutamide, radium-223, and cabazitaxel, as well as allocated treatment in the trial.\n\nThere are several strengths to note in the STAMPEDE trial and specifically for the analyses reported here. First, the data were prospectively collected and randomised, from nearly 3000 men with patient characteristics that were well balanced by group, and we achieved good median follow-up (43 months). Second, the data were very recently frozen (May, 2015) at a pre-planned analysis point of roughly 400 control group deaths, meaning the primary outcome results are both well powered and have been reported promptly. Third, the patients contributing to these analyses came from more than 100 sites across the UK and Switzerland, suggesting the results to be generalisable. Fourth, the design allows easy understanding of effect across multiple randomisations. Finally, treatment compliance among patients starting treatment was good.\n\nWe are aware that there are also limitations within the data. First, the proportion of patients not starting treatment, especially docetaxel, will have a small diluting effect. Linkage to hospital records is required to report more detailed information on skeletal-related events. The impact of therapies that do not target androgen receptors on recurrence (as assessed by prostate-specific antigen) is likely to be complex. Finally, power for assessing the consistency of effects across subsets is inevitably low; we will report long-term follow-up in due course when the maturity will be much greater both across the trial and particularly in the non-metastatic subset.\n\nIn conclusion, we have shown improved survival across a population of men commencing first-line long-term hormone therapy through the addition of docetaxel chemotherapy but not by adding zoledronic acid. Therefore, zoledronic acid should not become part of standard of care. Standard of care should be updated to include docetaxel chemotherapy in suitable patients with metastatic disease, and docetaxel may be considered for men with high-risk non-metastatic prostate cancer with or without radiotherapy.\n\nSupplementary Material\nSupplementary appendix\n \n\nAcknowledgments\nDPD, CCP, GA, and JdB acknowledge support from the National Institute for Health Research to the Royal Marsden NHS Trust and The Institute of Cancer Research Biomedical Research Centre. Support for the STAMPEDE trial has been provided by Novartis Pharmaceuticals UK Limited (educational grant, free drug, distribution costs) and Sanofi-Aventis (education grant, free and discounted drug). Affiliations and full details of contributions made by STAMPEDE investigators are provided in the appendix page 11.\n\nContributors\nNDJ designed these trial comparisons, was a grant holder, collected or collated data, interpreted data, wrote critical sections of the report, and reviewed and agreed the manuscript. MRSy designed these trial comparisons, was a grant holder, collected or collated data, performed or oversaw statistical analyses, interpreted data, wrote critical sections of the report, and reviewed and agreed the report. NWC, MDM, and DPD designed these trial comparisons, were grant holders, collected or collated data, interpreted data, and reviewed and agreed the report. MRSp collected or collated data, performed or oversaw statistical analyses, interpreted data, wrote critical sections of the report, and reviewed and agreed the report. AWSR collected or collated data, interpreted data, wrote critical sections of the report, and reviewed and agreed the report. CCP, JMR, GA, JdB, WC, RJJ, GT, CA, DM, RM, MA, SBe, AJB, SBr, RC, PC, SC, AC, TE, JG, SG, JDG, JH, RH, RL, FM, DBM, JMOS, OP, CCP, AP, AJR, NS, RS, JS, SS, ST, DT, and JW collected or collated data, interpreted data, and reviewed and agreed the report. MKBP conceived the original MAMS idea, designed these trial comparisons, was a grant holder, collected or collated data, performed or oversaw statistical analyses, interpreted data, wrote critical sections of the report, and reviewed and agreed the report.\n\nSTAMPEDE investigators and trial committees\nSTAMPEDE investigators (UK): Fawzi Adab, Adebanji Adeyoju, Imtiaz Ahmed, Christopher Alcock, Abdulla Al-hasso, Roberto Alonzi, Mymoona Alzouebi, Gerard Andrade, Stephen Andrews, Jawaher Ansari, Nicola Anyamene, Ashraf Azzabi, Amit Bahl, David Ballesteros-Quintail, Gautam Banerjee, Jim Barber, Karin Baria, Ronald Beaney, Sharon Beesley, Mark Beresford, Gianfilippo Bertelli, Neeraj Bhalla, Rajanee Bhana, Alison Birtle, David Bloomfield, Jo Bowen, Joanne Brady, Robert Brierly, Sue Brock, B Brown Richard, Simon Brown, Michael Button, Philip Camilleri, Lisa Capaldi, Fiona Castell, Eliot Chadwick, Prabir Chakraborti, Andrew Chan, Olivia Chan, Natalie Charnley, Shan Chetiyawardana, Ananya Choudhurey, Ananya Choudhury, Simon Chowdhury, Mark Churn, Amanda Clarke, Noel Clarke, J Cole David, Audrey Cook, Richard Cowan, Simon Crabb, Michael Crawford, Perric Crellin, William Cross, Tathagata Das, Joe Davies, Joseph Davies, David Dearnaley, Jeanette Dickson, Sajid Durrani, Albert Edwards, Andrew Eichholz, Tony Elliott, Chinnamani Eswar, Alison Falconer, Catherine Ferguson, Daniel Ford, Victoria Ford, John Frew, Olivera Frim, Joanna Gale, Stephanie Gibbs, Hilary Glen, John D Graham, Warren Grant, Emma Gray, Teresa Guerrero-Urbano, Nishi Gupta, Abdel Hamid, Joanna Hamilton, John Hardman, Stephen Harland, Peter Harper, Catherine Heath, Ann Henry, Chris Herbert, John Hetherington, Esme Hill, Serena Hilman, Mohan Hingorani, Uschi Hofmann, Peter Hoskin, Robert Huddart, Robert Hughes, Simon Hughes, Azman Ibrahim, Suneil Jain, Sunjay Jain, Nicholas James, Peter Jenkins, Rob Jones, Mohammed Kagzi, Stephen Karp, Penny Kehagioglou, Kay Kelly, Pek Keng Koh, Manjusha Keni, Sara Khaksar, Omar Khan, Vincent Khoo, Peter Kirkbride, Anil Kumar, Muthar Kumar, Satish Kumar, Robert Laing, Carolynn Lamb, Maurice Lau, Kathryn Lees, Priscilla Leone, Jason Lester, John Littler, Jacqueline Livsey, John Logue, Carmel Loughrey, Anna Lydon, Carol Macgregor, Satish Maddineni, Rana Mahmood, Zafar Malik, Stephen Mangar, Malcolm Mason, Danish Mazhar, Ursula McGovern, Fiona McKinna, Duncan McLaren, Rhona McMenemin, Neil McPhail, Lucinda Melcher, Jamie Mills, Darren Mitchell, Natasha Mithal, Julian Money-Kyrle, Amir Montazeri, Stephen Morris, Diana Mort, Tanmay Mukhopadhyay, Dakshinamoorthy Muthukumar, Farhad Neave, Jackie Newby, Hugh Newman, Jonathon Nicoll, Ashok Nikapota, Helen O'Donnell, Peter Ostler, Joe O'Sullivan, Nachiappan Palaniappan, Miguel Panades, Michael Pantelides, Udaiveer Panwar, Omi Parikh, Christopher C Parker, Pugazhenthi Pattu, Alan Paul, Heather Payne, Ian Pedley, Clive Peedell, Don Phan Mau, Lisa Pickering, Katherine Pigott, George Plataniotis, Rick Popert, Emilio Porfiri, Ravi Prashant, Stephen Prescott, Andrew Protheroe, Delia Pudney, Thinn Pwint, Prakash Ramachandra, Rakesh Raman, Yvonne Rimmer, Angus J Robinson, Peter Robson, Paul Rogers, Martin Russell, Ami Sabharwal, Azmat Sadozye, Vijay Sangar, Naveed Sarwar, Daniel Saunders, Ian Sayers, Christopher Scrase, Clara Sentamans, Richard Shaffer, Devadasan Shakespeare, Denise Sheehan, Lin Shum Poh, Norma Sidek, Norma Sidek, Matthew Simms, Asha Sivapalasuntharam, Bruce Sizer, Mike Smith-Howell, Geoffrey Sparrow, Thiagarajan Sreenivasan, Narayanan Srihari, Rajaguru Srinivasan, John Staffurth, David Stewart, Simon Stewart, Andrew Stockdale, Ramachandran Subramaniam, Santhanam Sundar, Isabel Syndikus, Jacob Tanguay, Henry Taylor, Carys Thomas, Anna Thompson, Karen Tipples, Shaun Tolan, Anna Tran, David Tsang, Hans Van der Voet, Vilarino Varela Maria, Mohini Varughese, Ramachandran Venkitaraman, Balaji Venugopal, John Wagstaff, Georgina Walker, Jan Wallace, Paula Wells, Charlotte Westbury, Matthew Wheater, Peter Whelan, Marie Wilkins, Paula Wilson, Marcus Wise, Katie Wood, Cathryn Woodward, Jane Worlding, James Wylie, Anjali Zarkar.\n\nSTAMPEDE investigators (Switzerland): Dominik Berthold, Richard Cathomas, Donat Durr, Daniel Engeler, Fernanda Herrera, Patrice Jichlinski, Razvan Popescu, Stefan Prensser, Cyrill Rentsch, Beat Roth, Bettina Seifest, Daniele Siciliano, Raeto Strebel, George Thalmann.\n\nIndependent Data Monitoring Committee: John Yarnold (from 2014, chair), Chris Williams (to 2014, chair), Doug Altman, Reg Hall, Bertrand Tombal.\n\nTrial Steering Committee: Jonathan Ledermann, Jim Paul, David Kirk (to 2015), John Fitzpatrick (2014).\n\nMRC Clinical Trials Unit at UCL: Matthew Sydes, Max Parmar, Melissa Spears, Gordana Jovic, Rachel Jinks, Patrick Royston, Sophie Barthel, Babak Choodari-Oskooei, Daniel Bratton, Claire Amos, Sharon Naylor, Neil Kelk, James Latham, Jacqui Nuttall, Karen Sanders, Tom Fairfield, Charlene Griffiths, Francesca Schiavone, Alanna Brown, Orla Prendiville, Neil Kelk, Karen Sanders, Tom Fairfield, Charlene Green, Emma Donoghue, Tim Smith, Jacque Millett, Shama Hassan, Philip Pollock, Richard Gracie, Laura Van Dyck, Charlene Green, Elizabeth Clark, Sara Peres, Hannah Gardner, Dominic Hague, Katie Ward, Peter Vaughan, Andrew Whitney, Eva Ades, Hannah Babiker, Carly Au, Zhorah Khan, Nadine Van Looy, Zaheer Islam, Sajad Khan, Sarah Meredith, Ruth Langley.\n\nSanofi-Aventis: Christine Geffriaud-Ricouard, Paul Cadle.\n\nCancer Research UK: Kate Law (to 2015).\n\nDeclaration of interests\nGA reports personal fees from Sanofi-Aventis; personal fees and non-financial support from Astellas; personal fees from Novartis; grants, personal fees, and non-financial support from Janssen, personal fees and non-financial support from Roche/Ventana, personal fees and non-financial support from Medivation, personal fees from Millennium Pharmaceuticals, personal fees and non-financial support from Abbott Laboratories, personal fees from Essa Pharmaceuticals, personal fees and non-financial support from Bayer Healthcare Pharmaceuticals, personal fees from Takeda, and grants from AstraZeneca. AJB reports other support from Janssen, Sanofi, and Astellas, outside the submitted work. RC reports personal fees as a Consultant for Sanofi-Aventis, outside the submitted work. SC reports grants and personal fees from Sanofi-Aventis, outside the submitted work. JdB reports advisory boards and paid participation for Sanofi-Aventis. DPD reports grants from Cancer Research UK, during the conduct of the study; personal fees from Takeda Pharmaceuticals, outside the submitted work. TE reports that patients entering this study received docetaxel free of charge (Sanofi) and has previously received per-patient payment for entering patients in other commercial trials investigating docetaxel. JDG reports other support as a local principal investigator for a study of radium-223 in prostate cancer funded by Bayer, and other support as a local principal investigator for a study of LHRH antagonist in prostate cancer funded by Millennium Pharmaceuticals, outside the submitted work. NDJ reports grants and personal fees from Sanofi, and grants and personal fees from Novartis, during the conduct of the study; grants and personal fees from Janssen, grants and personal fees from Astellas, and grants and personal fees from Bayer, outside the submitted work. RJJ reports grants from Sanofi, and grants and non-financial support from Novartis, during the conduct of the study; grants, personal fees, and non-financial support from Sanofi, grants, personal fees, and non-financial support from Novartis, outside the submitted work. MDM reports personal fees from Sanofi, personal fees from Bayer, personal fees from Dendreon, personal fees from Bristol-Myers, and personal fees from Janssen, outside the submitted work. CCP reports personal fees from Sanofi-Aventis, research funding and speaker's honoraria from Bayer, and Bavarian Nordic and Janssen, outside the submitted work. MKBP reports funding from Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network (formerly National Cancer Research Network), and SAKK—Swiss Group for Clinical Cancer Research, during the conduct of the study. JMR reports personal fees from Janssen (lecture fee), outside the submitted work. MRSp reports grants and non-financial support from Sanofi-Aventis, grants and non-financial support from Novartis, grants and non-financial support from Pfizer, grants and non-financial support from Janssen, and grants and non-financial support from Astellas, during the conduct of the study. JS reports support for travel and speakers fees for the following companies in the field of prostate cancer, not related to this paper: Janssen Bayer and Astellas. SS reports personal fees and non-financial support from Sanofi-Aventis, outside the submitted work. MRSy reports grants and non-financial support from Sanofi-Aventis, grants and non-financial support from Novartis, grants and non-financial support from Pfizer, grants and non-financial support from Janssen, grants and non-financial support from Astellas, during the conduct of the study; and personal fees from Eli-Lilly, outside the submitted work. ST reports other from Sanofi, other support from Astellas, personal fees from Astellas, and other support from Janssen, outside the submitted work. JW reports a paid consultancy for Janssen. Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent. All other authors declare no competing interests.\n\nFigure 1 Trial profile\n\nSOC-only=standard of care only. SOC + ZA=standard of care plus zoledronic acid. SOC + Doc=standard of care plus docetaxel. SOC + ZA + Doc=standard of care plus zoledronic acid and docetaxel.\n\nFigure 2 Failure-free and overall survival\n\nFigure shows Kaplan-Meier curves and flexible parametric models fitted to the data. Number at risk (events) shows the number of individuals at risk (ie, the number who were event free) at each timepoint, with parentheses showing the number of individuals who developed events in the period between each timepoint. SOC-only=standard of care only. SOC + ZA=standard of care plus zoledronic acid. SOC + Doc=standard of care plus docetaxel. SOC + ZA + Doc=standard of care plus zoledronic acid and docetaxel.\n\nFigure 3 Forest plots of treatment effect on survival within subsets\n\nData are deaths/N or HR (95% CI). All p values were statistically non-significant. For SOC-only vs SOC + ZA, all p>0·09, PSA p=0·116, time-period p=1·000. For SOC-only vs SOC + Doc, all p>0·06, PSA p=0·589, time-period p=1·000. For SOC-only vs SOC + ZA + Doc, all p>0·23 except previously treated p=0·023, PSA p=0·254, time-period p=1·000. X axis provided with natural log scaling. SOC-only=standard of care only. SOC + ZA=standard of care plus zoledronic acid. SOC + Doc=standard of care plus docetaxel. SOC + ZA + Doc=standard of care plus zoledronic acid and docetaxel. PSA=prostate-specific antigen. NSAID=non-steroidal anti-inflammatory drug.\n\nFigure 4 Time to treatment after progression\n\nFigure shows treatments ever used at relapse, at the discretion of the treating clinician, by group, cumulative incidence curves. (A) Time to any treatment after progression. (B) Time to any life-prolonging treatment after progression. (C) Time to docetaxel after progression. (D) Time to abiraterone after progression. SOC-only=standard of care only. SOC + ZA=standard of care plus zoledronic acid. SOC + Doc=standard of care plus docetaxel. SOC + ZA + Doc=standard of care plus zoledronic acid and docetaxel. FFS=failure-free survival.\n\nTable 1 Baseline characteristics\n\n\t\tStandard of care (n=1184)\tStandard of care plus zoledronic acid (n=593)\tStandard of care plus docetaxel (n=592)\tStandard of care plus zoledronic acid and docetaxel (n=593)\t\nAge, years\t\nMedian (IQR)\t65 (60–70)\t66 (61–71)\t65 (61–71)\t66 (60–70)\t\nRange\t41–82\t42–82\t40–81\t42–84\t\nProstate-specific antigen (ng/mL)\t\nMedian (IQR)\t67 (23–200)\t59 (22–172)\t70 (27–181)\t63 (21–183)\t\nRange\t0–15747\t0–13300\t1–9999\t1–8503\t\nDays from diagnosis\t\nMedian (IQR)\t75 (55–99)\t76 (56–101)\t76 (56–99)\t76 (56–100)\t\nRange\t0–4070\t1–4174\t3–5033\t6–4485\t\nMissing\t5\t8\t7\t6\t\nPain from prostate cancer\t\nAbsent\t984 (85%)\t496 (84%)\t490 (84%)\t483 (84%)\t\nPresent\t179 (15%)\t93 (16%)\t96 (16%)\t94 (16%)\t\nMissing\t21\t4\t6\t16\t\nT category at randomisation\t\nT0\t7 (1%)\t3 (1%)\t2 (0%)\t2 (0%)\t\nT1\t21 (2%)\t7 (1%)\t0 (0%)\t5 (1%)\t\nT2\t113 (10%)\t53 (9%)\t60 (10%)\t67 (11%)\t\nT3\t756 (64%)\t395 (67%)\t390 (66%)\t371 (63%)\t\nT4\t211 (18%)\t92 (16%)\t105 (18%)\t100 (17%)\t\nTX\t76 (6%)\t43 (7%)\t35 (6%)\t48 (8%)\t\nN category at randomisation\t\nN0\t522 (44%)\t258 (44%)\t260 (44%)\t265 (45%)\t\nN+\t594 (50%)\t303 (51%)\t298 (50%)\t293 (49%)\t\nNX\t68 (6%)\t32 (5%)\t34 (6%)\t35 (6%)\t\nMetastases\t\nNone\t460 (39%)\t227 (38%)\t230 (39%)\t228 (38%)\t\nAny metastases\t724 (61%)\t366 (62%)\t362 (61%)\t365 (62%)\t\n\tBone metastases\t634 (54%)\t302 (51%)\t307 (52%)\t310 (52%)\t\n\tLiver metastases\t15 (1%)\t12 (2%)\t6 (1%)\t9 (2%)\t\n\tLung metastases\t33 (3%)\t17 (3%)\t13 (2%)\t14 (2%)\t\n\tNodal metastases\t220 (19%)\t120 (20%)\t102 (17%)\t116 (20%)\t\n\tOther metastases\t46 (4%)\t33 (6%)\t25 (4%)\t21 (4%)\t\nBroad disease grouping\t\nNewly diagnosed N0M0\t256 (22%)\t120 (20%)\t131 (22%)\t131 (22%)\t\nNewly diagnosed N+M0\t171 (14%)\t88 (15%)\t86 (15%)\t76 (13%)\t\nNewly diagnosed M1\t690 (58%)\t351 (59%)\t347 (59%)\t350 (59%)\t\nPreviously treated M0\t33 (3%)\t19 (3%)\t13 (2%)\t21 (4%)\t\nPreviously treated M1\t34 (3%)\t15 (3%)\t15 (3%)\t15 (3%)\t\nGleason sum score\t\n≤7\t282 (24%)\t122 (21%)\t110 (19%)\t117 (20%)\t\n8–10\t810 (68%)\t421 (71%)\t436 (74%)\t425 (72%)\t\nUnknown\t92 (8%)\t50 (8%)\t46 (8%)\t51 (9%)\t\nAspirin or NSAID use\t\nNo\t891 (75%)\t448 (76%)\t444 (75%)\t445 (75%)\t\nYes\t293 (25%)\t145 (24%)\t148 (25%)\t148 (25%)\t\nPlanned or current hormone therapy*\t\nOrchidectomy\t5 (0%)\t4 (1%)\t2 (0%)\t3 (1%)\t\nLHRH-based\t1166 (98%)\t581 (98%)\t581 (98%)\t582 (98%)\t\nBicalutamide\t11 (1%)\t7 (1%)\t9 (2%)\t8 (2%)\t\nMaximum androgen blockade\t2 (0%)\t1 (0%)\t0 (0%)\t0 (0%)\t\nTime to starting hormone therapy (days)\t\nMedian (IQR)\t−41 (−63 to −20)\t−40 (−62 to −20)\t−43 (−66 to −21)\t−43 (−63 to −22)\t\nRange\t−105 to 77\t−193 to 32\t−108 to 45\t−142 to 28\t\nMissing\t1\t0\t2\t0\t\nPlanned anti-androgen use\t\nNo\t102 (9%)\t67 (12%)\t52 (9%)\t57 (10%)\t\nShort-term anti-androgen\t876 (76%)\t420 (72%)\t437 (75%)\t434 (75%)\t\nLong-term anti-androgen\t178 (15%)\t95 (16%)\t92 (16%)\t91 (16%)\t\nMissing\t28\t11\t11\t11\t\nRadiotherapy planned\t\nNo\t844 (71%)\t421 (71%)\t424 (72%)\t423 (71%)\t\nYes\t340 (29%)\t172 (29%)\t168 (28%)\t170 (29%)\t\nDoes patient smoke?\t\nNo\t1006 (87%)\t492 (84%)\t506 (86%)\t496 (84%)\t\nYes\t157 (13%)\t93 (16%)\t81 (14%)\t92 (16%)\t\nMissing on assessment\t16\t6\t4\t4\t\nAssessment not received\t5\t2\t1\t1\t\nDoes patient have diabetes\t\nNo\t1058 (90%)\t544 (92%)\t535 (91%)\t516 (88%)\t\nYes, type 1\t29 (2%)\t11 (2%)\t26 (4%)\t16 (3%)\t\nYes, type 2\t89 (8%)\t36 (6%)\t30 (5%)\t57 (10%)\t\nMissing on assessment\t3\t0\t0\t3\t\nAssessment not received\t5\t2\t1\t1\t\nMyocardial infarction\t\nNo\t1146 (97%)\t578 (98%)\t575 (98%)\t571 (97%)\t\nYes, but still fit for trial\t31 (3%)\t13 (2%)\t14 (2%)\t18 (3%)\t\nMissing on assessment\t2\t0\t2\t3\t\nAssessment not received\t5\t2\t1\t1\t\nCerebrovascular disease\t\nNo\t1164 (99%)\t579 (98%)\t583 (99%)\t580 (98%)\t\nYes, but still fit for trial\t13 (1%)\t12 (2%)\t6 (1%)\t9 (2%)\t\nMissing on assessment\t2\t0\t2\t3\t\nAssessment not received\t5\t2\t1\t1\t\nCongestive heart failure\t\nNo\t1172 (100%)\t588 (99%)\t588 (100%)\t589 (100%)\t\nYes, but still fit for trial\t5 (0%)\t3 (1%)\t2 (0%)\t0 (0%)\t\nMissing on assessment\t2\t0\t1\t3\t\nAssessment not received\t5\t2\t1\t1\t\nAngina\t\nNo\t1138 (97%)\t567 (96%)\t574 (97%)\t569 (97%)\t\nYes, but still fit for trial\t39 (3%)\t24 (4%)\t17 (3%)\t20 (3%)\t\nMissing on assessment\t2\t0\t0\t3\t\nAssessment not received\t5\t2\t1\t1\t\nHypertension\t\nNo\t741 (63%)\t384 (65%)\t383 (65%)\t385 (65%)\t\nYes, but still fit for trial\t437 (37%)\t206 (35%)\t208 (35%)\t204 (35%)\t\nMissing on assessment\t1\t1\t0\t3\t\nAssessment not received\t5\t2\t1\t1\t\nData are median (IQR), range, or n (%). NSAID=non-steroidal anti-inflammatory drug. LHRH=luteinising hormone-releasing hormone.\n\n* Further information provided in the appendix.\n\nTable 2 Treatment with zoledronic acid\n\n\t\tStandard of care plus zoledronic acid (n=593)\tStandard of care plus zoledronic acid and docetaxel (n=593)\t\nNumbers reporting starting\t585 (99%)\t544 (92%)\t\nNumbers not reporting starting\t8 (1%)\t49 (8%)\t\nTime to starting from randomisation, weeks\t1·9 (1·0–2·9)\t2·4 (1·6–3·7)\t\nTime from starting hormone therapy to starting zoledronic acid, weeks\t8·0 (5·0–11·3)\t8·6 (5·9–11·9)\t\nTime from starting to last administration, months\t16·6 (7·8–23·2)\t19·5 (9·1–23·4)\t\nReported reasons for stopping (if started):\t\t\t\n\tTreatment complete\t206 (35%)\t218 (40%)\t\n\tProgressive disease\t231 (39%)\t119 (22%)\t\n\tToxicity\t43 (7%)\t66 (12%)\t\n\tUnknown\t38 (6%)\t41 (8%)\t\n\tTreatment refusal*\t26 (4%)\t46 (8%)\t\n\tDental treatment\t11 (2%)\t23 (4%)\t\n\tDeath\t15 (3%)\t13 (2%)\t\n\tIntercurrent illness\t5 (1%)\t12 (2%)\t\n\tOther\t10 (2%)\t6 (1%)\t\n* Including treatment refusal, patient decision, clinician decision, administrative reasons, and withdrawal from trial.\n\nTable 3 Treatment with docetaxel\n\n\t\tStandard of care plus docetaxel (n=592)\tStandard of care plus zoledronic acid and docetaxel (n=593)\t\nNumbers reporting starting\t546 (92%)\t523 (88%)\t\nNumbers not reporting starting\t46 (8%)\t70 (12%)\t\nTime to starting from randomisation, weeks\t2·1 (1·6–3·1)\t2·4 (1·6–3·7)\t\nTime from starting hormone therapy to starting docetaxel, weeks\t8·6 (5·6–11·9)\t8·7 (5·9–11·7)\t\nNumber of cycles reported:\t\t\t\n\t0\t46 (8%)\t70 (12%)\t\n\t1\t27 (5%)\t22 (4%)\t\n\t2\t17 (3%)\t19 (3%)\t\n\t3\t12 (2%)\t18 (3%)\t\n\t4\t13 (2%)\t18 (3%)\t\n\t5\t21 (4%)\t24 (4%)\t\n\t6\t456 (77%)\t422 (71%)\t\nReported reasons for stopping (if started):\t\t\t\n\tTreatment complete\t454 (83%)\t423 (81%)\t\n\tToxicity\t72 (13%)\t66 (13%)\t\n\tTreatment refusal*\t6 (1%)\t8 (2%)\t\n\tProgressive disease\t5 (1%)\t8 (2%)\t\n\tIntercurrent illness\t5 (1%)\t7 (1%)\t\n\tDeath\t2 (0%)\t5 (1%)\t\n\tUnknown\t2 (0%)\t5 (1%)\t\n\tDental treatment\t0 (0%)\t1 (0%)\t\n* Including treatment refusal, patient decision, clinician decision, and withdrawal from trial. Not all patients who reported stopping reason as “treatment complete” reported six cycles; similarly, not all patients reporting six cycles reported stopping reason as “treatment complete”.\n\nTable 4 Treatments ever used at relapse, at the discretion of the treating clinician\n\n\t\tStandard of care\tStandard of care plus zoledronic acid\tStandard of care plus docetaxel\tStandard of care plus zoledronic acid and docetaxel\t\nPatients with progression\t761\t374\t315\t318\t\nReported new treatment\t671 (88%)\t303 (81%)\t260 (83%)\t257 (81%)\t\nReported (new) life-extending treatment\t383 (50%)\t172 (46%)\t139 (44%)\t136 (43%)\t\nLife-extending treatment\t\t\t\t\t\n\tDocetaxel\t313 (41%)\t136 (36%)\t44 (14%)\t49 (15%)\t\n\tAbiraterone\t177 (23%)\t72 (19%)\t89 (28%)\t88 (28%)\t\n\tEnzalutamide\t66 (9%)\t18 (5%)\t25 (8%)\t26 (8%)\t\n\tCabazitaxel\t26 (3%)\t14 (4%)\t22 (7%)\t30 (9%)\t\n\tRadium-223\t6 (1%)\t1 (0%)\t6 (2%)\t3 (1%)\t\nOther treatments\t\t\t\t\t\n\tAnti-androgens\t512 (67%)\t234 (63%)\t181 (57%)\t174 (55%)\t\n\tZoledronic acid\t128 (17%)\t50 (13%)\t35 (11%)\t36 (11%)\t\n\tDexamethasone\t104 (14%)\t42 (11%)\t39 (12%)\t29 (9%)\t\n\tDiethylstilbestrol (also known as stilboestrol)\t84 (11%)\t43 (11%)\t38 (12%)\t41 (13%)\t\n\tPrednisolone\t72 (9%)\t22 (6%)\t28 (9%)\t23 (7%)\t\n\tOther chemotherapy*\t26 (3%)\t17 (5%)\t21 (7%)\t15 (5%)\t\n\tOther bisphosphonate†\t22 (3%)\t3 (1%)\t8 (3%)\t5 (2%)\t\n\tStrontium\t12 (2%)\t3 (1%)\t2 (1%)\t4 (1%)\t\n\tCox-2 inhibition\t0 (0%)\t1 (0%)\t0 (0%)\t0 (0%)\t\n* Not docetaxel or cabazitaxel.\n\n† Not zoledronic acid\n\nTable 5 Worst adverse event (grade) reported over entire time on trial\n\n\t\tStandard of care (n=1184)\tStandard of care plus zoledronic acid (n=593)\tStandard of care plus docetaxel (n=592)\tStandard of care plus zoledronic acid and docetaxel (n=593)\t\nSafety population\t\nNumber of patients included in analysis*\t1228\t608\t550\t516\t\nGrade 1–5 adverse event\t1213 (99%)\t604 (99%)\t550 (100%)\t515 (100%)\t\nGrade 3–5 adverse event\t399 (32%)\t197 (32%)\t288 (52%)\t269 (52%)\t\nGrade 5 adverse event\t5\t1\t4\t6\t\nMost frequent adverse events reported as grade 3–5\t\t\t\t\t\n\tEndocrine disorder (including impotence, hot flushes)\t145 (12%)\t74 (12%)\t57 (10%)\t64 (12%)\t\n\tFebrile neutropenia\t15 (1%)\t5 (<1%)\t84 (15%)\t74 (14%)\t\n\tNeutropenia (neutrophils)\t6 (0%)\t3 (<1%)\t66 (12%)\t62 (12%)\t\n\tGeneral disorder (including lethargy, fever, asthenia)\t46 (4%)\t28 (5%)\t34 (7%)\t56 (11%)\t\n\tMusculoskeletal (including bone pain, generalised pain)\t69 (6%)\t35 (6%)\t32 (6%)\t44 (9%)\t\n\tGastrointestinal disorder (including diarrhoea, abdominal pain, constipation, vomiting)\t36 (3%)\t19 (3%)\t45 (8%)\t37 (7%)\t\n\tRenal (including renal impairment, urinary-tract infection)\t71 (6%)\t30 (5%)\t23 (4%)\t25 (5%)\t\n\tNotable adverse events\t\t\t\t\t\n\tRespiratory disorder (including dyspnoea, upper respiratory-tract infection)\t27 (2%)\t13 (2%)\t29 (5%)\t23 (4%)\t\n\tCardiac disorder (including hypertension, myocardial infarction)\t35 (3%)\t19 (3%)\t16 (3%)\t19 (4%)\t\n\tOsteonecrosis of the jaw\t0 (0%)\t10 (2%)\t0 (0%)\t21 (4%)\t\n\tNervous system other (including peripheral neuropathy)\t20 (2%)\t8 (1%)\t19 (3%)\t19 (4%)\t\n\tNail changes\t0 (0%)\t0 (0%)\t5 (1%)\t4 (1%)\t\nITT population\t\nNumber of patients included in analysis†\t1173\t587\t579\t563\t\nGrade 1–5 adverse event\t1160 (99%)\t583 (99%)\t577 (100%)\t562 (100%)\t\nGrade 3–5 adverse event\t375 (32%)\t184 (31%)\t298 (51%)\t296 (53%)\t\nGrade 5 adverse event\t4\t1\t4\t7\t\nGrade 5 adverse events were not necessarily treatment-related; similarly treatment-related deaths were not always grade 5 adverse events. ITT=intention-to-treat.\n\n* Analysis by actual treatment initiated (irrespective of assigned study arm) in patients who underwent adverse event assessment.\n\n† Analysis by assigned study arm in patients who underwent adverse event assessment.\n==== Refs\nReferences\n1 Petrylak DP Tangen CM Hussain MH Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer N Engl J Med 351 2004 1513 1520 15470214 \n2 Tannock IF de Wit R Berry WR Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer N Engl J Med 351 2004 1502 1512 15470213 \n3 de Bono JS Logothetis CJ Molina A Abiraterone and increased survival in metastatic prostate cancer N Engl J Med 364 2011 1995 2005 21612468 \n4 Scher HI Fizazi K Saad F Increased survival with enzalutamide in prostate cancer after chemotherapy N Engl J Med 367 2012 1187 1197 22894553 \n5 Beer TM Armstrong AJ Rathkopf DE Enzalutamide in metastatic prostate cancer before chemotherapy N Engl J Med 371 2014 424 433 24881730 \n6 de Bono JS Oudard S Ozguroglu M Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial Lancet 376 2010 1147 1154 20888992 \n7 Parker C Nilsson S Heinrich D Alpha emitter radium-223 and survival in metastatic prostate cancer N Engl J Med 369 2013 213 223 23863050 \n8 Kantoff PW Higano CS Shore ND Sipuleucel-T immunotherapy for castration-resistant prostate cancer N Engl J Med 363 2010 411 422 20818862 \n9 Saad F Gleason DM Murray R for the Zoledronic Acid Prostate Cancer Study Group Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer J Natl Cancer Inst 96 2004 879 882 15173273 \n10 Smith MR Egerdie B Hernandez Toriz N Denosumab in men receiving androgen-deprivation therapy for prostate cancer N Engl J Med 361 2009 745 755 19671656 \n11 James ND Sydes MR Mason MD Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial Lancet Oncol 13 2012 549 558 22452894 \n12 James ND Spears MR Clarke NW Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019) Eur Urol 67 2015 1028 1038 25301760 \n13 James ND Spears MR Clarke NW Failure-free survival and radiotherapy in patients with newly diagnosed nonmetastatic prostate cancer: data from patients in the control arm of the STAMPEDE trial JAMA Oncol 25 2015 1 10 \n14 Vale CL Burdett S Rydzewska LHM Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data Lancet Oncol 2015 published online Dec 21. http://dx.doi.org/10.1016/S1470-2045(15)00489-1 \n15 Dearnaley DP Mason MD Parmar MK Sanders K Sydes MR Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials Lancet Oncol 10 2009 872 876 19674936 \n16 Sydes MR Parmar MK Mason MD Flexible trial design in practice-stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial Trials 13 2012 168 22978443 \n17 Sydes MR Parmar MK James ND Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial Trials 10 2009 39 19519885 \n18 Parmar MK Barthel FM Sydes M Speeding up the evaluation of new agents in cancer J Natl Cancer Inst 100 2008 1204 1214 18728279 \n19 James ND Sydes MR Clarke NW STAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer—a multi-arm multi-stage randomised controlled trial Clin Oncol 20 2008 577 581 \n20 Barthel FM-S Royston P Parmar MKB A menu-driven facility for sample-size calculation in novel multiarm, multistage randomized controlled trials with a time-to-event outcome Stata J 9 2009 505 \n21 Wason JM Stecher L Mander AP Correcting for multiple-testing in multi-arm trials: is it necessary and is it done? Trials 15 2014 364 25230772 \n22 Follmann DA Proschan MA Geller NL Monitoring pairwise comparisons in multi-armed clinical trials Biometrics 50 1994 325 336 8068834 \n23 Cook R Farewell VT Multiplicity considerations in the design and analysis of clinical trials J R Stat Soc Series A 159 1996 93 110 \n24 Royston P Parmar MK Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modelling and estimation of treatment effects Stat Med 21 2002 2175 2197 12210632 \n25 Sweeney CJ Chen YH Carducci M Chemohormonal therapy in metastatic hormone-sensitive prostate cancer N Engl J Med 373 2015 737 746 26244877 \n26 Gravis G Fizazi K Joly F Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial Lancet Oncol 14 2013 149 158 23306100 \n27 Franke RM Carducci MA Rudek MA Baker SD Sparreboom A Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer J Clin Oncol 28 2010 4562 4567 20855838 \n28 Omlin A Sartor O Rothermundt C Analysis of side effect profile of alopecia, nail changes, peripheral neuropathy, and dysgeusia in prostate cancer patients treated with docetaxel and cabazitaxel Clin Genitourin Cancer 13 2015 e205 e208 25733056 \n29 Smith TJ Khatcheressian J Lyman GH 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline J Clin Oncol 24 2006 3187 3205 16682719 \n30 Aapro MS Bohlius J Cameron DA 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours Eur J Cancer 47 2011 8 32 21095116 \n31 Schweizer MT Huang P Kattan MW Adjuvant leuprolide with or without docetaxel in patients with high-risk prostate cancer after radical prostatectomy (TAX-3501): important lessons for future trials Cancer 119 2013 3610 3618 23943299 \n32 Gravis G Boher JM Joly F Androgen deprivation therapy (ADT) plus docetaxel (D) versus ADT alone for hormone-naïve metastatic prostate cancer (Pca): long-term analysis of the GETUG-AFU-15 phase III trial Proc Am Soc Clin Oncol GU suppl 2015 140 (abstr). \n33 Fizazi K Laplanche A Lesaunier F Docetaxel–estramustine in localized high-risk prostate cancer: results of the French Genitourinary Tumor Group GETUG 12 phase III trial Proc Am Soc Clin Oncol 32 suppl 2014 A5005 \n34 Sandler HM Hu C Rosenthal SA A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with doxetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521) Proc Am Soc Clin Oncol 33 suppl 2015 LBA52022 \n35 Denham JW Joseph D Lamb DS Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial Lancet Oncol 15 2014 1076 1089 25130995 \n36 Wirth M Tammela T Cicalese V Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS) Eur Urol 67 2015 482 491 24630685 \n37 Smith MR Halabi S Ryan CJ Efficacy and safety of zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (Alliance) J Clin Oncol 13 2014 27\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0140-6736",
"issue": "387(10024)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D004164:Diphosphonates; D018450:Disease Progression; D000077143:Docetaxel; D004334:Drug Administration Schedule; D006801:Humans; D007093:Imidazoles; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms; D043823:Taxoids; D016896:Treatment Outcome; D000077211:Zoledronic Acid",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1163-77",
"pmc": null,
"pmid": "26719232",
"pubdate": "2016-03-19",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "15470214;23863050;23306100;22978443;23943299;24590644;24881730;25130995;25230772;24630685;25301760;25733056;26244877;26718929;26606329;12210632;15173273;15470213;8068834;16682719;18728279;18760574;19519885;19671656;19674936;20818862;20888992;20855838;21095116;21612468;22452894;22894553",
"title": "Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.",
"title_normalized": "addition of docetaxel zoledronic acid or both to first line long term hormone therapy in prostate cancer stampede survival results from an adaptive multiarm multistage platform randomised controlled trial"
} | [
{
"companynumb": "GB-PFIZER INC-2017121585",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "The purine analogue 2-chloro-deoxyadenosine (2-CDA, cladribine) +/- rituximab has been successfully tested in mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) patients. However, studies using cladribine in other indications have reported the potential for prolonged hematological side effects and secondary hematologic and non-hematologic malignancies. To date, there have been no data on long-term effects of cladribine in MALT lymphoma patients. We have analyzed a large number of 49 patients treated with cladribine at our institution 1997-2011. All patients were treated within clinical trials and had undergone a standardized follow-up protocol minimizing a potential bias in the detection of late sequels and relapses. After a median follow-up time of 61 months (interquartile range: 43-72) for 49 analyzed patients, 35 (71%) are alive, while 14 (29%) have died. In the entire collective, three cases (6%) of prolonged pancytopenia including manifest myelodysplastic syndrome in one patient (2%), three cases (6%) of secondary lymphoid malignancies, and five cases (10%) of non-hematologic cancers were documented. In terms of outcome, 42/49 (86%) patients responded to cladribine-containing treatment, and only 10/42 (24%) responding patients needed further treatment after a median time to progression of 14 months (interquartile range, 8-34). Currently, 25/35 (71%) patients being alive are in ongoing complete remission and 2/35 (6%) in ongoing stable disease, respectively. Eight patients (23%) are free of lymphoma after second-line therapy, with the median overall survival not having been reached. Our data suggest that cladribine might be safely applied in patients with MALT lymphoma, also in terms of long-term toxicities. These data also confirm the potential of cladribine to induce durable remissions. Copyright © 2015 John Wiley & Sons, Ltd.",
"affiliations": "Department of Internal Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.;Department of Internal Medicine III, Clinical Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.;Department of Pathology, Medical University of Vienna, Vienna, Austria.;Department of Radiology, Medical University of Vienna, Vienna, Austria.;Department of Internal Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.",
"authors": "Kiesewetter|Barbara|B|;Dolak|Werner|W|;Simonitsch-Klupp|Ingrid|I|;Mayerhoefer|Marius E|ME|;Raderer|Markus|M|",
"chemical_list": "D000970:Antineoplastic Agents; D017338:Cladribine",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-0232",
"issue": "35(2)",
"journal": "Hematological oncology",
"keywords": "2-chloro-deoxyadenosine (2-CDA); MALT lymphoma; cladribine; extranodal marginal zone lymphoma; indolent lymphoma",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D017338:Cladribine; D005260:Female; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone; D008297:Male; D008875:Middle Aged; D010198:Pancytopenia; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "177-186",
"pmc": null,
"pmid": "26580149",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term safety and activity of cladribine in patients with extranodal B-cell marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) lymphoma.",
"title_normalized": "long term safety and activity of cladribine in patients with extranodal b cell marginal zone lymphoma of the mucosa associated lymphoid tissue malt lymphoma"
} | [
{
"companynumb": "AT-MYLANLABS-2017M1048646",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Restless legs syndrome is a chronic disorder that is characterized by an urge to move the legs and unpleasant sensations in the lower extremities. Its symptoms develop slowly and a sudden onset is very unusual, which may be confusing for the emergency physician. We describe a case of an abrupt presentation of restless legs syndrome symptoms induced by infusion of metoclopramide during treatment of a migraine attack in settings of an emergency department. The patient shortly after infusion of metoclopramide started to experience rapid movements of the legs, claiming that it was the only way to relieve extremely unpleasant sensations in her legs. The symptoms subsided after saline infusion and did not appear again.",
"affiliations": "Department of Emergency Medicine, Medical University of Gdansk, Gdansk, Poland.;Department of Emergency Medicine, Medical University of Gdansk, Gdansk, Poland.",
"authors": "Sieminski|Mariusz|M|;Zemojtel|Lukasz|L|",
"chemical_list": "D065127:Dopamine D2 Receptor Antagonists; D000077330:Saline Solution; D008787:Metoclopramide",
"country": "United States",
"delete": false,
"doi": "10.5664/jcsm.7774",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "15(5)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "antiemetic; ferritin; migraine; metoclopramide; restless legs syndrome",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D065127:Dopamine D2 Receptor Antagonists; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D008787:Metoclopramide; D012148:Restless Legs Syndrome; D000077330:Saline Solution",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "779-780",
"pmc": null,
"pmid": "31053217",
"pubdate": "2019-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11152983;19886950;20191944;21709418;23456369;25201131;26944272",
"title": "Acute Drug-Induced Symptoms of Restless Legs Syndrome in an Emergency Department.",
"title_normalized": "acute drug induced symptoms of restless legs syndrome in an emergency department"
} | [
{
"companynumb": "PL-IPCA LABORATORIES LIMITED-IPC-2019-PL-000698",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"dr... |
{
"abstract": "To describe clinical consequences of risperidone medication errors in children of less than 13 years and to estimate a clinically relevant toxic dose.\n\n\n\nAll cases of risperidone medication errors managed by French Poison Centres from 2001 to 2012 were analyzed. Inclusion criteria were a delay of at least 2 hours between ingestion and request to the FPC in asymptomatic children, an ingested dose above two-fold the maximal daily dose for children above 5 years or any symptomatic patient at the time of first contact.\n\n\n\nOne hundred and sixty cases met our criteria. Median age was 8 years (range 0.9-12) and 28.1% were aged 5 years or less. Causes of the error were an incorrect dose in treated children (84.2%) or a dose given to a wrong child (15.8%). The median ingested dose was 0.1 mg/kg or 3.3-fold the maximum recommended dose. Overall, 59 children had no symptoms, 95 experienced minor symptoms and six moderate symptoms. Somnolence/sedation was the most common (73.3%). Of the 17 children who developed extrapyramidal disorders, all had minor or moderate symptoms and only five required a symptomatic treatment.\n\n\n\nRisperidone medication errors in children cause minimal effects. Somnolence and mild to moderate extrapyramidal reactions were the main features of toxicity, and significant cardiac or other neurological features were not observed. No case with severe toxicity was noted. At home surveillance can be proposed for children exposed to a dose ≤0.15 mg/kg.",
"affiliations": "a Department of Pharmacotoxicology , Lyon University Hospital, Hospices Civils de Lyon , France.;a Department of Pharmacotoxicology , Lyon University Hospital, Hospices Civils de Lyon , France.;a Department of Pharmacotoxicology , Lyon University Hospital, Hospices Civils de Lyon , France.;b Poison Control Center , Angers University Hospital , France.;c Poison Control Center, Marseille University Hospital, Assistance Publique Hôpitaux de Marseille , France.;d Poison Control Center, Lille University Hospital , France.;e Poison Control Center, Paris University Hospital, Assitance Publique Hôpitaux de Paris , France.;f Department of Pharmacotoxicology and UMR 5588-CNRS, Lyon University Hospital , France.",
"authors": "Vial|Thierry|T|;Patat|Anne-Marie|AM|;Paret|Nathalie|N|;Boels|David|D|;Torrents|Romain|R|;Nisse|Patrick|P|;Villa|Antoine|A|;Kassai|Behrouz|B|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2018.1523424",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "57(5)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Risperidone; atypical antipsychotics; children; medication errors; toxic dose",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000367:Age Factors; D014150:Antipsychotic Agents; D001480:Basal Ganglia Diseases; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005602:France; D006801:Humans; D007223:Infant; D008297:Male; D008508:Medication Errors; D011039:Poison Control Centers; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D018967:Risperidone; D000077260:Sleepiness",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "362-367",
"pmc": null,
"pmid": "30449187",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risperidone medication errors in children: an analysis of French poison centres data.",
"title_normalized": "risperidone medication errors in children an analysis of french poison centres data"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-210098",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
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{
"abstract": "The feasibility of nonmyeloablative stem cell transplantation (NST) was evaluated in 22 adults with high-risk ALL. 16/22 patients had advanced disease and 11/22 had Ph+ ALL. Eleven patients received NST as first stem cell transplantation (SCT). Eleven patients had relapses after allogeneic or autologous SCT and underwent a salvage NST. 18/22 patients (82%) engrafted after NST. 13/16 patients (81%) with active disease reached complete remission (CR). 11 of 13 patients developed GVHD. After first NST 10/11 patients (91%) engrafted. Six of seven patients with active disease reached CR. Three of five relapsing patients reached subsequent CR after donor lymphocyte infusions, termination of immunosuppression or imatinib. Three of 11 patients (27%) are alive in CR 5 to 30 months after NST. Eight of 11 patients have died, 3/8 from leukemia and 5/8 from transplant-related causes. After salvage NST, 8/11 patients (73%) engrafted. Seven of nine patients with active disease reached CR. Only one of 11 patients transplanted, who was in CR before undergoing salvage NST is alive 19 months after NST. Five of 11 have died from leukemia, one of 11 after graft failure and four of 11 from transplant-related causes. Four of 22 patients (18%) are alive in CR 5, 14, 19 and 30 months after NST. NST is feasible in adults with high risk ALL. However, transplant-related mortality remains high and only patients transplanted in CR seem to have long-term disease-free survival.",
"affiliations": "Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Universitätsklinikum Charité, Berlin, Germany.",
"authors": "Arnold|R|R|;Massenkeil|G|G|;Bornhäuser|M|M|;Ehninger|G|G|;Beelen|D W|DW|;Fauser|A A|AA|;Hegenbart|U|U|;Hertenstein|B|B|;Ho|A D|AD|;Knauf|W|W|;Kolb|H J|HJ|;Kolbe|K|K|;Sayer|H G|HG|;Schwerdtfeger|R|R|;Wandt|H|H|;Hoelzer|D|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2402712",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "16(12)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000328:Adult; D003131:Combined Modality Therapy; D018450:Disease Progression; D005240:Feasibility Studies; D005260:Female; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D010865:Pilot Projects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction; D012306:Risk; D016879:Salvage Therapy; D016019:Survival Analysis; D015996:Survival Rate; D019172:Transplantation Conditioning",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "2423-8",
"pmc": null,
"pmid": "12454748",
"pubdate": "2002-12",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease.",
"title_normalized": "nonmyeloablative stem cell transplantation in adults with high risk all may be effective in early but not in advanced disease"
} | [
{
"companynumb": "PHHY2018DE065007",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
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{
"abstract": "We evaluated the efficacy and tolerability of continuous ixazomib-thalidomide-dexamethasone (ITd: 4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly). A total of 39 patients with relapsed/refractory multiple myeloma (RRMM) aged ≥18 years with one to three prior lines of therapy were enrolled from two tertiary centres in Victoria and South Australia, Australia. The overall response rate (ORR) was 56·4% with a clinical benefit rate of 71·8%. The median progression-free survival was 13·8 months [95% confidence interval (CI) 8·2-22·2] and median overall survival was not reached. The median time to best response and duration of response was 3·7 months (95% CI 2·8-10·5) and 18·4 months (95% CI 10·2-31·0) respectively. Prior immunomodulatory drug (IMID) exposure was associated with a lower ORR (40% vs. 73·7%, P = 0·03). Survival outcomes in patients with prior proteasome inhibitor (PI) and/or IMID exposure were similar. Patients received a median (range) of 11 (1-31) cycles of therapy and six patients (15%) remained on therapy at the time of final analysis. Grade 3/4 haematological and non-haematological adverse events were reported in 7·7% and 20·6% of patients respectively. ITd dose reductions were required in 15·4%, 48·7% and 35·9% of patients respectively. The present study demonstrates promising effectiveness and tolerability of ITd as an affordable all-oral PI-IMID approach for RRMM.",
"affiliations": "Alfred Health-Monash University, Melbourne, Victoria, Australia.;Alfred Health, Melbourne, Victoria, Australia.;Flinders Medical Centre, Bedford Park, South Australia, Australia.;Alfred Health-Monash University, Melbourne, Victoria, Australia.;Alfred Health, Melbourne, Victoria, Australia.;Alfred Health-Monash University, Melbourne, Victoria, Australia.;Alfred Health-Monash University, Melbourne, Victoria, Australia.",
"authors": "Bergin|Krystal|K|0000-0001-8694-2813;Yuen|Flora|F|;Wallington-Beddoe|Craig|C|0000-0002-7457-5937;Kalff|Anna|A|0000-0003-2468-450X;Sirdesai|Shreerang|S|;Reynolds|John|J|;Spencer|Andrew|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17504",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "194(3)",
"journal": "British journal of haematology",
"keywords": "clinical trial; dexamethasone; ixazomib; myeloma; thalidomide",
"medline_ta": "Br J Haematol",
"mesh_terms": null,
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "580-586",
"pmc": null,
"pmid": "33991421",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase II trial of continuous ixazomib, thalidomide and dexamethasone for relapsed and/or refractory multiple myeloma: the Australasian Myeloma Research Consortium (AMaRC) 16-02 trial.",
"title_normalized": "a phase ii trial of continuous ixazomib thalidomide and dexamethasone for relapsed and or refractory multiple myeloma the australasian myeloma research consortium amarc 16 02 trial"
} | [
{
"companynumb": "AU-CELGENEUS-AUS-20210505627",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Mycosis fungoides with penile involvement is extremely rare. Previous reports have shown successful treatment with imiquimod or a combination of beam radiation and chemotherapy. We present a patient with mycosis fungoides and penile involvement. The penile lesions were initially treated with topical imiquimod; however, he developed worsening glandular lesions and discharge. Therefore the treatment was discontinued. Subsequent treatment with brentuximab (anti-CD30) targeted therapy resulted in complete resolution of the penile lesions. To our knowledge, this represents the first case of a complete penile mycosis fungoides response to brentuximab therapy. Brentuximab may be considered for refractory penile mycoses fungoides.",
"affiliations": "University of Connecticut Health Center, Division of Urology, 263 Farmington Avenue, Farmington, CT, 06030, United States.;University of Connecticut Health Center, Division of Dermatology, 263 Farmington Avenue, Farmington, CT, 06030, United States.;University of Connecticut Health Center, Division of Medicine, 263 Farmington Avenue, Farmington, CT, 06030, United States.;University of Connecticut Health Center, Division of Urology, 263 Farmington Avenue, Farmington, CT, 06030, United States.",
"authors": "Schaufler|Christian|C|;Ferenczi|Katalin|K|;Hegde|Upendra|U|;Ristau|Benjamin T|BT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2020.101460",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30349-1\n10.1016/j.eucr.2020.101460\n101460\nOncology\nComplete response of penile mycosis fungoides with systemic brentuximab therapy\nSchaufler Christian Schaufler@uchc.edua Ferenczi Katalin Ferenczi@uchc.edub Hegde Upendra uhedge@uchc.educ Ristau Benjamin T. benristaumd@gmail.coma∗ a University of Connecticut Health Center, Division of Urology, 263 Farmington Avenue, Farmington, CT, 06030, United States\nb University of Connecticut Health Center, Division of Dermatology, 263 Farmington Avenue, Farmington, CT, 06030, United States\nc University of Connecticut Health Center, Division of Medicine, 263 Farmington Avenue, Farmington, CT, 06030, United States\n∗ Corresponding author. UConn Health – Urology Outpatient Pavilion, 7th floor 263 Farmington Avenue Farmington, CT, 06030, United States. benristaumd@gmail.com\n21 10 2020 \n1 2021 \n21 10 2020 \n34 1014609 10 2020 20 10 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Mycosis fungoides with penile involvement is extremely rare. Previous reports have shown successful treatment with imiquimod or a combination of beam radiation and chemotherapy. We present a patient with mycosis fungoides and penile involvement. The penile lesions were initially treated with topical imiquimod; however, he developed worsening glandular lesions and discharge. Therefore the treatment was discontinued. Subsequent treatment with brentuximab (anti-CD30) targeted therapy resulted in complete resolution of the penile lesions. To our knowledge, this represents the first case of a complete penile mycosis fungoides response to brentuximab therapy. Brentuximab may be considered for refractory penile mycoses fungoides.\n\nKeywords\nMycosis fungoidesBrentuximabAnti-CD30ImiquimodRemission\n==== Body\nAbbreviations\n1. MFMycosis Fungoides\n\n2. CTCLCutaneous T-cell lymphoma\n\n3. CHOPCyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone\n\nIntroduction\nMycosis fungoides (MF) is the predominant form of cutaneous T-cell lymphoma (CTCL) and accounts for 50–65% of cases.1 MF is rare, with an incidence in the United States of only 0.3–1 cases per 100,000. MF can be identified as erythematous patches or plaques, most often in a non-sun-exposed (so-called bathing trunk) distribution. Most patients present with patches or plaques, representing early stage disease; rarely, MF can progress to more advance stages with tumors or erythroderma.\n\nTreatment of early stage MF commonly includes topical therapies such as corticosteroids, nitrogen mustard, phototherapy, imiquimod, retinoids and local radiation.2,3 Advanced disease requires systemic treatment, such as bexarotene, methotrexate, histone deacetylase inhibitors, pralatrexate, brentuximab vedotin (anti-CD30), and/or allogeneic stem cell transplantation.2,4 Early diagnosis and treatment is generally associated with a good prognosis, and 5-year survival rates approach 90%.1 Penile involvement with MF is rare with only 2 cases reported in the literature.3,5 We present the first report of complete response of penile MF with systemic brentuximab therapy.\n\nCase presentation\nA 71 year old uncircumcised Caucasian male with history of diabetes mellitus and MF, presented with new onset lesions on his glans and penile shaft. He had been originally diagnosed with MF, stage IB, in 2014. At the time of the diagnosis, he had plaques involving the lower abdomen, left flank and proximal left thigh. His lesions were initially under control with narrow-band ultraviolet therapy and methotrexate; however, 3 years later, he developed new erythematous plaques on his glans and shaft associated with a decreased urinary stream. Oral antibiotic and topical antifungal treatment provided only temporary improvement of his symptoms. He denied dysuria, penile discharge, fevers or weight loss. Physical examination demonstrated an uncircumcised penis with phimotic foreskin, a 1.5cm erythematous, non-tender, mobile lesion on the right inner preputial surface, and inflammation on the glans penis surrounding the urethral meatus. There were no lesions or stricture involving the urethral mucosa. Biopsies were obtained from the abnormal areas.\n\nHistology showed a dense mononuclear inflammatory infiltrate involving the epidermis and dermis. Numerous atypical, enlarged lymphocytes with hyperchromatic nuclei were noted in the epidermis, superficial and mid-dermis with evidence of fibroplasia (Fig. 1). The cells were predominantly CD3 positive T-cells, with rare CD30 cells. These findings were consistent with his previous biopsies and a diagnosis of MF. Following the biopsy a urethral dilation was performed, which resulted in improvement of the patient's stream.Fig. 1 Histologic features showed a dense mononuclear inflammatory infiltrate in the epidermis and mid-dermis (A), H&E 4x; Note the presence of enlarged atypical lymphocytes with hyperchromatic nuclei in the epidermis (B), H&E, 40x.\n\nFig. 1\n\nIn order to improve hygiene he underwent a circumcision, after which he developed purulent exudates on the glans penis. Topical imiquimod 5% was started; however, the patient discontinued treatment after 3 weeks due to increased purulent secretions (Fig. 2A) and further weakening of urinary stream secondary to involvement of the urethral meatus. Shortly thereafter, he presented with swelling over the left eyelid consistent with progression of MF and underwent local radiation therapy as treatment. Unfortunately, he progressed further with lesions to the right orbit, lateral mouth, and chest. At this point systemic brentuximab therapy was initiated at 1.8mg/kg every three weeks. After two infusions, the patient noted a marked improvement in his urinary stream, and physical exam demonstrated normal epidermal skin on the glans (Fig. 2B). Initial side effects of brentuximab included mild GI upset and fatigue. After 3 infusions peripheral neuropathy was noted. Treatment was discontinued after 7 infusions due to refractory neuropathy. Eight months following cessation of brentuximab infusions, no further lesions were noted on the penis. However, his diseased recurred with large cell transformation, sparing the penis, while he was off treatment. The patient underwent further treatment with pralatrexate and gemcitabine, but unfortunately passed away from refractory disease 4 months after restarting chemotherapy.Fig. 2 Gross images of penile mycosis fungoides before (A) and after (B) 2 brentuximab infusions.\n\nFig. 2\n\nDiscussion\nPenile involvement in MF is rare, with only 2 case reports in the literature to date. Reports of MF of the penis have shown tissue preserving remission with immune system modifiers and combinations of electron beam radiation and chemotherapy.3,5 Chiam and Chan reported a case of a 32 year old healthy man from Bangladesh with a pink plaque on the glans that had been present for 15 years.3 After 6 weeks of treatment with topical clobetasol propionate, which failed to provide improvement, he was switched to 5% imiquimod. After 4–5 months of therapy the patient was in complete remission. During treatment he developed pain at the application site and a skin erosion requiring cessation of therapy. A second case reported by O'Brien et al. involved a 64 year old with an ulcer on the penile meatus.5 The patient initially underwent surgical excision of the lesion, and was later treated with 15 fractions of 27 Gy radiotherapy and mini-CHOP. This combination treatment provided a complete response.\n\nOur case is unique, as complete response of penile MF to brentuximab systemic therapy has not yet been reported. Brentuximab vedotin is an anti-CD30 monoclonal antibody that has been shown to provide effective targeted therapy for cutaneous T-cell lymphomas.2 Brentuximab was initially approved for the treatment of Hodgkin's lymphoma to target CD30 on Reed-Sternberg cells.4 The Food Drug Administration approved its use for the treatment of patients with CTCL in 2017. Initially, it was used to treat patients with CD30 expressing CTCL, such as primary cutaneous anaplastic large cell lymphoma and CD30 expressing MF. However, Brentuximab has shown efficacy in CTCL patients with low CD30 expression, as it was the case in our patient.2 Potential side effects of brentuximab therapy include neuropathy, leukopenia and fatigue.4 Additionally there are multiple reports indicating that progressive multifocal leukoencephalopathy is associated with treatment. Our patient developed neuropathy leading to gait instability after 7 cycles, at which point therapy was stopped. In patients with refractory Hodgkin lymphoma, brentuximab chemotherapy is commonly followed by hematopoietic stem cell transplant.4 Our patient was not a suitable candidate for stem cell transplantation due to underlying comorbidities. As brentuximab was the likely cause of the patient's neuropathy, hematopoietic stem cell transplant may have provided a more tolerable treatment.\n\nConclusion\nIn summary, brentuximab systemic targeted therapy may be considered as a treatment option for patients with penile MF refractory to more traditional topical therapies.\n\nConsent\nThe patient provided consent for this case report including the use of images.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\nThe authors have no conflicts of interest to disclose.\n\nAcknowledgements\nThank you to the patient and to the supporting clinical staff.\n==== Refs\nReferences\n1 Amorim G.M. Niemeyer-Corbellini J.P. Quintella D.C. Cuzzi T. Ramos-e-Silva M. Clinical and epidemiological profile of patients with early stage mycosis fungoides An Bras Dermatol 93 4 2018 546 552 10.1590/abd1806-4841.20187106 30066762 \n2 Prince H.M. Kim Y.H. Horwitz S. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial Lancet 390 10094 2017 555 566 10.1016/S0140-6736(17)31266-7 28600132 \n3 Chiam L.Y. Chan Y.C. Solitary plaque mycosis fungoides on the penis responding to topical imiquimod therapy Br J Dermatol 156 3 2007 560 562 10.1111/j.1365-2133.2006.07599.x 17300249 \n4 Ishizawa K. Yanai T. Hematopoietic stem cell transplantation and brentuximab vedotin for patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large-cell lymphoma Adv Ther 36 10 2019 2679 2696 10.1007/s12325-019-01046-w 31392578 \n5 O'Brien J.S. Manning T. Perera M. Prince H.M. Lawrentschuk N. Blueprint unknown: a case for multidisciplinary management of advanced penile mycosis fungoides Can J Urol 24 6 2017 9139 9144 http://www.ncbi.nlm.nih.gov/pubmed/29260643 29260643\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "34()",
"journal": "Urology case reports",
"keywords": "Anti-CD30; Brentuximab; Imiquimod; Mycosis fungoides; Remission",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101460",
"pmc": null,
"pmid": "33194554",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": "30066762;31392578;28600132;29260643;17300249",
"title": "Complete response of penile mycosis fungoides with systemic brentuximab therapy.",
"title_normalized": "complete response of penile mycosis fungoides with systemic brentuximab therapy"
} | [
{
"companynumb": "US-TEVA-2021-US-1935781",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": null,
... |
{
"abstract": "A 71-year-old woman diagnosed with left breast cancer underwent mastectomy and axillary dissection in 1987. Pathological findings showed invasive ductal carcinoma that was ER and PgR positive and HER2 negative.5 -FU and tamoxifen were administered for 2 years as adjuvant therapy.Bone metastasis was found in 2002, and endocrine therapy was started, using anastrozole, exemestane, letrozole, medroxyprogesterone acetate, and fulvestrant.However, liver, lung, pleural, penetiral, and lymph-node metastases were observed, and the following chemotherapy regimen was administered: CAF, capecitabine, paclitaxel, vinorelbine, gemcitabine, methotrexate plus mitomycin C, and eribulin.Then, estrogen therapy with ethinylestradiol( EE2)was started in December 2013.T he pleural effusion disappeared and the liver metastases were reduced.After 11 months of progression-free survival(PFS), regrowth of the liver metastases was seen.Thus, everolimus plus exemestane was administered, and approximately 8 months of PFS was obtained.Therefore, both EE2 and everolimus are effective therapy even for heavily pretreated metastatic breast cancer.",
"affiliations": "Dept. of Breast Surgery, Tokyo Women's Medical University, Medical Center East.",
"authors": "Matsuoka|Aya|A|;Hirano|Akira|A|;Hattori|Akinori|A|;Ogura|Kaoru|K|;Inoue|Hiroaki|H|;Yukawa|Hiroko|H|;Sakaguchi|Shiho|S|;Tanaka|Natsuko|N|;Kodera|Asaka|A|;Kamimura|Mari|M|;Naritaka|Yoshihiko|Y|;Shimizu|Tadao|T|",
"chemical_list": "D004997:Ethinyl Estradiol; D000068338:Everolimus",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D015914:Estrogen Replacement Therapy; D004997:Ethinyl Estradiol; D000068338:Everolimus; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008197:Lymph Node Excision; D008408:Mastectomy; D017698:Postmenopause",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1219-1222",
"pmc": null,
"pmid": "27760942",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ethinylestradiol Following Everolimus plus Exemestane Was Effective in Postmenopausal Endocrine-Responsive Metastatic Breast Cancer - A Case Report.",
"title_normalized": "ethinylestradiol following everolimus plus exemestane was effective in postmenopausal endocrine responsive metastatic breast cancer a case report"
} | [
{
"companynumb": "JP-CIPLA LTD.-2017JP13280",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "Acute Intermittent Porphyria (AIP) usually presents with abdominal pain, peripheral neuropathy and psychiatric manifestations. Incidence of AIP being 5 in 1,00,000. We present a case of an 11-year-old male child with multiple cranial nerve involvement, quadriparesis, focal convulsions, hypertension, hyponatremia with history of recurrent abdominal pain. His complete haemogram, ultrasonography (USG) abdomen, renal function tests were normal, he was also evaluated for tuberculosis which was negative. On further evaluation Electroencephalography (EEG) was suggestive of a generalised seizure disorder, MRI Brain suggestive of Posterior Reversible Encephalopathy Syndrome (PRES), Electromyography revealed a sensory motor axonal polyneuropathy and urine UV fluoresence test was positive for porphobilinogen which clinched the diagnosis of AIP.",
"affiliations": "Senior Resident, Department of Pediatrics, Topiwala National Medical College and BYL Nair CH. Hospital , Mumbai, Maharashtra, India .;Professor, Department of Pediatrics, Topiwala National Medical College and BYL Nair CH. Hospital , Mumbai, Maharashtra, India .;Associate Professor, Department of Pediatrics, Topiwala National Medical College and BYL Nair CH. Hospital , Mumbai, Maharashtra, India .;Associate Professor, Department of Pediatrics, Topiwala National Medical College and BYL Nair CH. Hospital , Mumbai, Maharashtra, India .;Resident, Department of Pediatrics, Topiwala National Medical College and BYL Nair CH. Hospital , Mumbai, Maharashtra, India .",
"authors": "Mohanlal|Smilu|S|;Ghildiyal|Radha Gulati|RG|;Kondekar|Alpana|A|;Wade|Poonam|P|;Sinha|Richa|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/20464.8609",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "10(10)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Abdominal pain; Posterior reversible encephalopathy syndrome; Seizures",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "SD01-SD02",
"pmc": null,
"pmid": "27891417",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": "26366103;18403560;7677301;10602858;9350165;12389134;19268004;21724399;15767622;16469935;25372274",
"title": "A Commonly Missed Well Known Entity- Acute Intermittent Porphyria: A Case Report.",
"title_normalized": "a commonly missed well known entity acute intermittent porphyria a case report"
} | [
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"companynumb": "IN-UCBSA-2016049809",
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"activesubstancename": "VALPROATE SODIUM"
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"drugadditional": "3",
... |
{
"abstract": "Enteric hyperoxaluria (EH) occurs with a rate of 5-24% in patients with inflammatory bowel disease, ileal resection and modern bariatric surgery. The excessive absorption of calcium oxalate causes chronic kidney disease (CKD) in patients with EH. In the literature, a single experience was reported in combined intestine-kidney transplantation (CIKTx) in patients with CKD due to EH.\n\n\n\nAfter a report of 2 successful cases of CIKTx in patients with EH and CKD, one was performed at our center in a 59-year-old Caucasian female who developed intestinal failure with total parenteral nutrition (TPN) dependence after a complication post-bariatric surgery. Before CIKTx, she underwent kidney transplantation alone (KTA) twice, which failed due to oxalate nephropathy.\n\n\n\nIn July 2014, the patient underwent CIKTx and bilateral allograft nephrectomy to avoid EH and oxalate stone burden. The postoperative course was complicated with acute tubular necrosis due to the use of high pressors related to perioperative bleeding. The patient was discharged 79 days after CIKTx with a serum creatinine (sCr) of 1.2 mg/dl and free of TPN. Her sCr increased at 7 months and a renal biopsy showed oxalate nephropathy. SLC26A6 (oxalate transporter) staining was significantly diminished in native duodenum/rectum as well as in intestinal allograft compared to control.\n\n\n\nKTA in patients with CKD secondary to EH should not be recommended due to high risk of recurrence. Although other centers showed good long-term outcomes in CIKTx, our patient experienced recurrence of EH due to oxalate transporter defect, early kidney allograft dysfunction and prolonged antibiotic use.",
"affiliations": "Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, Ind., USA.",
"authors": "Ekser|Burcin|B|;Mangus|Richard S|RS|;Kubal|Chandrashekhar A|CA|;Fridell|Jonathan A|JA|;Powelson|John A|JA|;Nagaraju|Santosh|S|;Mihaylov|Plamen|P|;Phillips|Carrie L|CL|;Saxena|Romil|R|;Goggins|William C|WC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D026901:Membrane Transport Proteins; C439529:SLC26A6 protein, human; D000076988:Sulfate Transporters; D014662:Vasoconstrictor Agents; D002129:Calcium Oxalate; D003404:Creatinine",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000447785",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-8095",
"issue": "44(2)",
"journal": "American journal of nephrology",
"keywords": null,
"medline_ta": "Am J Nephrol",
"mesh_terms": "D064591:Allografts; D000900:Anti-Bacterial Agents; D001706:Biopsy; D016913:Blood Component Transfusion; D016063:Blood Loss, Surgical; D002129:Calcium Oxalate; D002432:Cecum; D003404:Creatinine; D051799:Delayed Graft Function; D005260:Female; D015390:Gastric Bypass; D005919:Glomerular Filtration Rate; D006801:Humans; D006959:Hyperoxaluria; D045822:Intestinal Volvulus; D007422:Intestines; D007668:Kidney; D016030:Kidney Transplantation; D007683:Kidney Tubular Necrosis, Acute; D026901:Membrane Transport Proteins; D008875:Middle Aged; D010288:Parenteral Nutrition; D011183:Postoperative Complications; D012008:Recurrence; D051436:Renal Insufficiency, Chronic; D000076988:Sulfate Transporters; D014184:Transplantation, Homologous; D014552:Urinary Tract Infections; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "8109361",
"other_id": null,
"pages": "85-91",
"pmc": null,
"pmid": "27410399",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrence of Hyperoxaluria and Kidney Disease after Combined Intestine-Kidney Transplantation for Enteric Hyperoxaluria.",
"title_normalized": "recurrence of hyperoxaluria and kidney disease after combined intestine kidney transplantation for enteric hyperoxaluria"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP016840",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"abstract": "We report a case of hepatosplenic T-cell lymphoma (HSTL) transplanted from an HLA-haploidentical daughter. A 51-year-old man was referred due to liver function test abnormalities and fever. He was confirmed to have γδ-type HSTL by bone marrow and liver biopsies. He was treated with five cycles of a CHOP regimen. Although metabolic complete response (CR), as defined by positron emission tomography, was achieved, his bone marrow still contained tumor cells on polymerase chain reaction (PCR). He underwent transplantation using unmanipulated peripheral blood stem cells from his HLA-haploidentical daughter. The preconditioning regimen consisted of fludarabine, melphalan, busulfan and antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and short-term methotrexate. Neutrophil engraftment was achieved on day 14. His bone marrow exhibited a completely female phenotype by fluorescence in situ hybridization, and no lymphoma cells were detected by PCR on day 30. Although he developed grade II acute GVHD on day 47, it was successfully treated by prednisolone. He has a limited type of skin chronic GVHD and still receives oral immunosuppressive therapy. He remains in CR four years after transplantation.",
"affiliations": "Department of Hematology, Toyama Red Cross Hospital, Toyama, Japan.;Department of Hematology, Toyama Red Cross Hospital, Toyama, Japan.;Department of Hematology, Toyama Red Cross Hospital, Toyama, Japan.;Division of Diagnostic Pathology, Toyama Red Cross Hospital, Toyama, Japan.;Department of Hematology, Toyama Red Cross Hospital, Toyama, Japan.",
"authors": "Iwaki|Noriko|N|;Mochizuki|Kanako|K|;Ozaki|Jun|J|;Maeda|Yoshinobu|Y|;Kurokawa|Toshiro|T|",
"chemical_list": "D006680:HLA Antigens; D007166:Immunosuppressive Agents; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D016559:Tacrolimus; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.3960/jslrt.20003",
"fulltext": "\n==== Front\nJ Clin Exp Hematop\nJ Clin Exp Hematop\njslrt\nJournal of Clinical and Experimental Hematopathology : JCEH\n1346-4280 1880-9952 JSLRT \n\n32404572\n20003\n10.3960/jslrt.20003\nCase Report\nA case of hepatosplenic T-cell lymphoma successfully treated by HLA\nhaploidentical stem cell transplantation\nIwaki Noriko \n1\n Mochizuki Kanako \n1\n Ozaki Jun \n1\n Maeda Yoshinobu \n2\n Kurokawa Toshiro \n1\n 1)Department of Hematology,\nToyama Red Cross Hospital, Toyama,\nJapan, 2)Division of Diagnostic Pathology, Toyama Red Cross\nHospital, Toyama, Japan\nCorresponding author: Toshiro Kurokawa, MD, Department of Hematology,\nToyama Red Cross Hospital, Ushijima-honmachi 2-1-58, Toyama 930-0859, Japan. E-mail:\nkurokawa@toyama-med.jrc.or.jp\n13 5 2020 \n6 2020 \n60 2 55 59\n24 1 2020 16 2 2020 28 2 2020 © 2020 by The Japanese Society for Lymphoreticular Tissue\nResearch2020The Japanese Society for Lymphoreticular Tissue\nResearchThis is an open-access article distributed under the terms of the Creative\nCommons Attribution ShareAlike (CC BY-NC-SA) 4.0 License.We report a case of hepatosplenic T-cell lymphoma (HSTL) transplanted from an\nHLA-haploidentical daughter. A 51-year-old man was referred due to liver function test\nabnormalities and fever. He was confirmed to have γδ-type HSTL by bone marrow and liver\nbiopsies. He was treated with five cycles of a CHOP regimen. Although metabolic complete\nresponse (CR), as defined by positron emission tomography, was achieved, his bone marrow\nstill contained tumor cells on polymerase chain reaction (PCR). He underwent\ntransplantation using unmanipulated peripheral blood stem cells from his\nHLA-haploidentical daughter. The preconditioning regimen consisted of fludarabine,\nmelphalan, busulfan and antithymocyte globulin. Graft-versus-host disease (GVHD)\nprophylaxis consisted of tacrolimus and short-term methotrexate. Neutrophil engraftment\nwas achieved on day 14. His bone marrow exhibited a completely female phenotype by\nfluorescence in situ hybridization, and no lymphoma cells were detected by\nPCR on day 30. Although he developed grade II acute GVHD on day 47, it was successfully\ntreated by prednisolone. He has a limited type of skin chronic GVHD and still receives\noral immunosuppressive therapy. He remains in CR four years after transplantation.\n\nKeywords: \nhepatosplenic T-cell lymphoma (HSTL)haploidentical stem cell transplantationgraft-versus-host disease (GVHD)\n==== Body\nINTRODUCTION\nHepatosplenic T-cell lymphoma (HSTL) is a rare subtype of lymphoma that accounts for 1.4%\nof mature T- and NK-cell neoplasms.1 This\ndisease typically presents in young men and is known to be highly aggressive, being\ncharacterized by hepatosplenomegaly, thrombocytopenia and systemic symptoms without\nlymphadenopathy.2,3 Tumor cells are usually positive for CD3,\nCD2, CD7 and CD56, but negative for CD4, CD8 and CD5.4 Although most cases express γδ T-cell receptor (TCR), some express\nαβ TCR. Both TCR αβ and γδ types present with a similar onset and clinical course, and the\nαβ subtype of HSTL is considered an immuno-phenotypic variant.5 HSTL is associated with a recurrent chromosome abnormality of\nisochromosome 7q, and less often with that of trisomy 8.6 Recently genomic abnormalities, including SETD2,\nSTAT5B and PIK3CD, were reported to be mutated and\nrelated to the pathogenesis of HSTL.7\n\nHSTL has a poor prognosis with a 5-year survival of only 7%.1 CHOP or CHOP-like first-line regimens have been reported to be\ninsufficient against HSTL,4 and only\nallogeneic transplantation has been reported as a useful treatment associated with a\ncure.8\n\nWe report a case of γδ HSTL that was successfully treated by HLA haploidentical stem cell\ntransplantation.\n\nCASE REPORT\nA previously healthy 51-year-old man was referred to our hospital because of abnormalities\non liver function tests and thrombocytopenia found during a health examination and a 2-day\nhistory of fever. He had not received immunosuppressive medications or biological agents.\nHis Eastern Cooperative Oncology Group (ECOG) performance status was 1. Physical examination\nrevealed a temperature of 38.4 °C, hepatomegaly (extending 7.5 cm below the right costal\nmargin) and splenomegaly (extending 6 cm below the left costal margin), but no superficial\nlymphadenopathy. Laboratory findings included a white blood cell count of 4,900/μL\n(including 3% abnormal lymphocytes), hemoglobin of 11.5 g/dL, platelet count of\n4.9×104/μL, AST of 200 IU/L, ALT of 135 IU/L, ALP of 727 IU/L, LDH of 997 IU/L\n(normal range 110-210 IU/mL), γ-GTP of 107 IU/L, T.Bil of 1.8 mg/dL and sIL-2R of 1,858\nU/mL, with no evidence of viral etiology (Table 1).\n18F-Fluorodeoxyglucose positron emission tomography/computed tomography\n(18F-FDG PET/CT) demonstrated marked hepatosplenomegaly with uniform uptake of\nFDG (standardized uptake value (SUV) max was 4.9) and no significant uptake in bone marrow\n(BM) (Figure 1A). BM aspiration revealed the presence\nof 55.2% abnormal lymphocytes (Figure 2A), which were\npositive for CD3, CD2, CD7, CD16 and TCR-γδ (detected by IMMU510 antibody, Beckman Coulter),\nbut were negative for CD4, CD8, CD5, CD25, CD56 and TCR-αβ (detected by WT31 antibody,\nBecton Dickinson) on flow cytometry. TCR gene rearrangement was analyzed by polymerase chain\nreaction (PCR) using a marrow sample, which revealed clonal rearrangement of the γ chain. A\nnormal karyotype was found by G-banding. Based on fluorescence in situ\nhybridization (FISH) analyses, 15% of cells harbored 6 to 8 copies of 7q31 (D7S486 probe\nwith Spectrum Orange), in contrast to 2 copies of chromosome 7 centromere (D7Z1 probe with\nSpectrum Green), suggesting the presence of isochromosome 7q or amplification of 7q31. BM\nbiopsy revealed the diffuse proliferation of medium-sized lymphoma cells (Figure 2B, 2C). Immunohistochemical staining of BM biopsy\nspecimens demonstrated positivity for T-cell intracellular antigen-1, and negativity for\nGranzyme B and perforin. EBV-encoded RNA by in situ hybridization was\nnegative. Liver biopsy revealed sinusoidal infiltration by medium-sized lymphoid cells\n(Figure 2D, 2E). He was diagnosed with the γδ subtype\nof HSTL. Staging according to the Ann Arbor system was IVB, with the involvement of the BM,\nliver and spleen.9 The International\nPrognostic Index placed him in the high intermediate risk group,10 and the prognostic index for peripheral T-cell lymphoma was\ngroup 3.11 He was treated using CHOP,\nwhich consisted of cyclophosphamide, doxorubicin, vincristine and prednisolone, every three\nweeks. After five cycles of CHOP, he achieved metabolic complete response (CR), as defined\nby PET (Figure 1B). Although there were no lymphoma\ncells observed on microscopic examination, TCR-γ rearrangement was still detected in BM by\nPCR.\n\nTable 1 WBC\t4900\t/μL\tTP\t7.5\tg/dL\t\nmeta\t1\t%\tAST\t200\tIU/L\t\nstab\t9\t%\tALT\t135\tIU/L\t\nseg\t42\t%\tALP\t727\tIU/L\t\neos\t0\t%\tLD\t997\tIU/L\t\nbaso\t0\t%\tγ-GTP\t107\tIU/L\t\nmo\t11\t%\tT.Bil\t1.8\tmg/dL\t\nlym\t34\t%\tBUN\t10\tmg/dL\t\natyp. cell\t3\t%\tCr\t0.53\tmg/dL\t\nEbl\t3\t/100 WBC\tUA\t6.9\tmg/dL\t\nRBC\t369\tx104/μL\tNa\t136\tmEq/L\t\nHb\t11.5\tg/dL\tK\t3.8\tmEq/L\t\nHt\t34.1\t%\tCl\t101\tmEq/L\t\nPlt\t4.9\tx104/μL\tCa\t8.5\tmg/dL\t\n\t\t\tGlu\t146\tmg/dL\t\nPT-INR\t1.11\t\tHbA1c\t5.3\t%\t\nAPTT\t41.4\tsec\t\t\t\t\nFbg\t149\tmg/dL\tCRP\t0.98\tmg/dL\t\nFDP\t11.8\tμg/mL\tIgG\t2439\tmg/dL\t\nDD\t3.3\tμg/mL\tIgA\t296\tmg/dL\t\n\t\t\tIgM\t107\tmg/dL\t\n\t\t\tFerritin\t525.2\tng/mL\t\n\t\t\tβ2MG\t6.1\tmg/L\t\n\t\t\tsIL-2R\t1858\tU/mL\t\n\t\t\tHTLV-1\t(-)\t\t\n\t\t\tHIV\t(-)\t\t\n\t\t\tEBV\t\t\t\n\t\t\tVCA-IgG\tx320\t\t\n\t\t\tEBNA\tx320\t\t\nFig. 1 (A) 18F-FDG PET/CT showed marked hepatosplenomegaly at the diagnosis,\nand (B) the liver and spleen normalized in size after five cycles of\nCHOP treatment.\n\nFig. 2 (A) A bone marrow smear revealed 55.2% abnormal lymphocytes at the\ndiagnosis. (B) Bone marrow biopsy showed diffuse proliferation of\nmedium-sized lymphoma cells with pale cytoplasm and (C) CD3 staining.\n(D) On liver biopsy, the liver sinus was filled with lymphoma cells\nwith the same morphological features and (E) CD2 staining.\n\nWe planned to treat him by allogeneic hematopoietic stem cell transplantation (HSCT).\nHowever, no HLA-identical related or unrelated donors in the Japan Marrow Donor Program were\nfound. We therefore chose his daughter, who had a haploidentical HLA, as a donor. He had no\nHLA antibodies. She was primed with granulocyte-colony stimulating factor (Lenograstim, 500\nµg/day) injected subcutaneously for 5 days. On the fifth day, peripheral blood stem cells\n(PBSCs) were collected with a COBE Spectra (COBE BCT Inc., Lakewood, CO, USA). T cell\ndepletion was not performed. The interval from diagnosis to transplantation was five months.\nThe hematopoietic cell transplantation (HCT)-specific comorbidity index (HCT-CI) score was\n0.12 He received a non-myeloablative\n(reduced intensity) preconditioning regimen that consisted of 30 mg/m2 of\nfludarabine for 6 days (day -7 to day -2), 3.2 mg/kg/day of intravenous busulfan for 2 days\n(day -5 to day -4), 50 mg/m2 of melphalan for 2 days (day -3 to day -2) and 2.5\nmg/kg of rabbit antithymocyte globulin (ATG) (Thymoglobuline) for 1 day (day -2), as\npreviously described.13 He was infused\nwith donor PBSCs containing 2.96×106 CD34+ cells/kg and\n1.41×108 CD3+ cells/kg. Tacrolimus (TAC) was initiated on the day\nbefore transplantation at 0.02 mg/kg/day in a continuous infusion. The target blood\nconcentration of TAC was set at 10-15 ng/mL up to day 30 and thereafter tapered in the\nabsence of acute graft-versus-host disease (GVHD).\n\nNeutrophil and platelet engraftment were noted on days 14 and 22, respectively. The patient\ndid not receive cytomegalovirus (CMV) prophylaxis. CMV antigenemia was diagnosed on day 22\n(3 CMV-positive leukocytes per 50,000 white blood cells using the peroxidase-labeled\nmonoclonal antibody, HRP-C7), and he was successfully treated with ganciclovir on days\n24-30. On day 30, his BM demonstrated a normal female karyotype by G-banding and a 98.6%\nfemale type by XY FISH with no TCR-γ rearrangement on PCR. He was classified as being in\nmolecular CR because his minimal residual disease (MRD) became negative. On day 47, small\neruptions spread over his trunk and extremities. He was diagnosed with acute GVHD by skin\nbiopsy. The grade of acute GVHD was II (skin stage 3, liver stage 0 and gut stage 0), and he\nwas administered 0.5 mg/kg of prednisolone (PSL). He was discharged from the hospital on day\n52. He continued to have limited skin lesions and was diagnosed clinically with a\nprogressive onset type of chronic GVHD on day 118. He started to work again six months after\ntransplantation. His skin still has a limited type of chronic GVHD, requiring 5 mg of TAC\nand 5 mg of PSL. He has continued to be in CR and his ECOG performance status has been 0,\nwith his peripheral blood exhibiting a female type by FISH at four years after\nhaploidentical transplantation.\n\nDISCUSSION\nHSTL is a rare type of T-cell lymphoma with a poor prognosis and a median survival time of\n< 2 years.4 Yabe et al.\nanalyzed 28 patients with HSTL, and the risk factors associated with a poor outcome included\na high serum bilirubin level, trisomy 8 and the expression of αβ TCR,14 none of which our patient had. Intensive induction\nchemotherapy beyond CHOP and HSCT at the first CR may improve the survival of patients with\nHSTL.15 Allogeneic transplantation was\nreported to be potentially curative in cases of aggressive T-cell lymphoma, including HSTL,\ndue to the graft-versus-lymphoma (GVL) effect.16 Tanase et al. reported allogeneic and autologous\nstem cell transplantation for HSTL. Although 5 of 7 patients relapsed after autologous\ntransplantation, only 2 of 18 allotransplanted patients relapsed. GVL activity can result in\nlong-term survival for a substantial proportion of patients with HSTL.8 Although most cases of HSTL express γδ-type TCR, a small\nsubset expresses αβ TCR, which is considered an immunophenotypic variant of the same disease\nentity. One case with the aggressive αβ variant of HSTL was reported to have been\nsuccessfully rescued by haploidentical transplantation.5 To our knowledge, this is the first report of a case of γδ-type\nHSTL successfully treated by haploidentical transplantation.\n\nThe present patient had an excellent clinical course. Several reasons for this were\npresumed. First, he underwent allogeneic transplantation at a relatively young age and his\nHCT-CI score was 0. Second, his tumor burden was low at transplantation. When he achieved\nmetabolic CR, as defined by PET, after induction therapy, his BM had a small amount of\nlymphoma cells only detected by PCR. Lastly, he underwent transplantation from a\nhaploidentical donor and had a chronic limited type of skin GVHD, which may have induced the\nGVL effect. Our haploidentical transplantation procedure did not include\npost-transplantation cyclophosphamide for GVHD prophylaxis,17 but alternatively employed a method previously reported by Hyogo\nCollege of Medicine in Japan.18 In this\napproach, patients are infused with unmanipulated source stem cells from a haploidentical\ndonor using fludarabine, busulfan, low-dose ATG and steroids. This transplantation protocol\nwas reported to be safe and feasible if a suitable donor cannot be found in a timely\nmanner.\n\nIn conclusion, we treated a patient with rare and aggressive γδ HSTL who achieved long-term\nremission, probably due to the GVL effect after haploidentical transplantation.\nHaploidentical transplantation may be a viable alternative technique for patients with HSTL\nwhen HLA-compatible siblings or unrelated donors are unavailable.\n\nCONFLICT OF INTEREST: The authors declare that they have no conflict of interest.\n==== Refs\nREFERENCES\n1 Vose J Armitage J Weisenburger D International\nT-Cell Lymphoma Project \nInternational\nperipheral T-cell and natural killer/T-cell lymphoma study: pathology findings and\nclinical outcomes.\n\nJ Clin Oncol . 2008 ; 26 :\n4124 -4130\n. 18626005 \n2 Farcet JP Gaulard P Marolleau JP \nHepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant\ncells expressing the T-cell receptor gamma delta.\n\nBlood . 1990 ; 75 :\n2213 -2219\n. 2140703 \n3 Cooke CB Krenacs L Stetler-Stevenson M \nHepatosplenic T-cell lymphoma: a distinct clinicopathologic entity of\ncytotoxic gamma delta T-cell origin.\n\nBlood . 1996 ; 88 :\n4265 -4274\n. 8943863 \n4 Belhadj K Reyes F Farcet JP \nHepatosplenic T-cell lymphoma is a rare clinicopathologic entity with poor\noutcome: report on a series of 21 patients.\n\nBlood . 2003 ; 102 :\n4261 -4269\n. 12907441 \n5 Catania G Zallio F Monaco F \nSuccessful HLA haploidentical myeloablative stem cell transplantation for\naggressive hepatosplenic alpha/beta (αβ) T-cell lymphoma.\n\nLeuk Res Rep . 2014 ; 3 :\n90 -93\n. 25429355 \n6 Travert M Huang Y de\nLeval L \nMolecular features of hepatosplenic T-cell lymphoma unravels potential\nnovel therapeutic targets.\n\nBlood . 2012 ; 119 :\n5795 -5806\n. 22510872 \n7 McKinney M Moffitt AB Gaulard P \nThe genetic basis of hepatosplenic T-cell lymphoma.\n\nCancer Discov . 2017 ; 7 :\n369 -379\n. 28122867 \n8 Tanase A Schmitz N Stein H Lymphoma\nWorking Party of the EBMT \nAllogeneic and\nautologous stem cell transplantation for hepatosplenic T-cell lymphoma: a retrospective\nstudy of the EBMT Lymphoma Working Party.\n\nLeukemia . 2015 ; 29 :\n686 -688\n. 25234166 \n9 Carbone PP Kaplan HS Musshoff K Smithers DW Tubiana M \nReport of the committee on Hodgkin’s disease staging\nclassification.\n\nCancer Res . 1971 ; 31 :\n1860 -1861\n.5121694 \n10 Ansell SM Habermann TM Kurtin PJ \nPredictive capacity of the International Prognostic Factor Index in\npatients with peripheral T-cell lymphoma.\n\nJ Clin Oncol . 1997 ; 15 :\n2296 -2301\n. 9196143 \n11 Gallamini A Stelitano C Calvi R Intergruppo\nItaliano Linfomi \nPeripheral T-cell lymphoma\nunspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical\nstudy.\n\nBlood . 2004 ; 103 :\n2474 -2479\n. 14645001 \n12 Sorror ML Maris MB Storb R \nHematopoietic cell transplantation (HCT)-specific comorbidity index: a new\ntool for risk assessment before allogeneic HCT.\n\nBlood . 2005 ; 106 :\n2912 -2919\n. 15994282 \n13 Kurokawa T Ishiyama K Ozaki J \nHaploidentical hematopoietic stem cell transplantation to adults with\nhematologic malignancies: analysis of 66 cases at a single Japanese\ncenter.\n\nInt J Hematol . 2010 ; 91 :\n661 -669\n. 20390388 \n14 Yabe M Medeiros LJ Tang G \nPrognostic factors of hepatosplenic T-cell lymphoma: clinicopathologic\nstudy of 28 cases.\n\nAm J Surg Pathol . 2016 ; 40 :\n676 -688\n. 26872013 \n15 Voss MH Lunning MA Maragulia JC \nIntensive induction chemotherapy followed by early high-dose therapy and\nhematopoietic stem cell transplantation results in improved outcome for patients with\nhepatosplenic T-cell lymphoma: a single institution experience.\n\nClin Lymphoma Myeloma Leuk . 2013 ; 13 :\n8 -14\n. 23107915 \n16 Le\nGouill S Milpied N Buzyn A Société\nFrançaise de Greffe de Moëlle et de Thérapie Cellulaire \nGraft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a\nstudy by the Société Francaise de Greffe de Moëlle et de Thérapie\nCellulaire.\n\nJ Clin Oncol . 2008 ; 26 :\n2264 -2271\n. 18390969 \n17 Martínez C Gayoso J Canals C Lymphoma\nWorking Party of the European Group for Blood and Marrow\nTransplantation \nPost-transplantation\ncyclophosphamide-based haploidentical transplantation as alternative to matched sibling\nor unrelated donor transplantation for Hodgkin lymphoma: A registry study of the\nlymphoma working party of the European Society for Blood and Marrow\nTransplantation.\n\nJ Clin Oncol . 2017 ; 35 :\n3425 -3432\n. 28846465 \n18 Ikegame K Yoshida T Yoshihara S \nUnmanipulated haploidentical reduced-intensity stem cell transplantation\nusing fludarabine, busulfan, low-dose antithymocyte globulin, and steroids for patients\nin non-complete remission or at high risk of relapse: A prospective multicenter phase\nI/II study in Japan.\n\nBiol Blood Marrow Transplant . 2015 ; 21 :\n1495 -1505\n. 25921715\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1346-4280",
"issue": "60(2)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": "graft-versus-host disease (GVHD); haploidentical stem cell transplantation; hepatosplenic T-cell lymphoma (HSTL)",
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D006086:Graft vs Host Disease; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008113:Liver Neoplasms; D016399:Lymphoma, T-Cell; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011239:Prednisolone; D013160:Splenic Neoplasms; D016559:Tacrolimus; D000075442:Transplantation, Haploidentical; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "55-59",
"pmc": null,
"pmid": "32404572",
"pubdate": "2020-06-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25921715;26872013;18390969;28846465;23107915;15994282;20390388;28122867;14645001;5121694;18626005;8943863;25234166;22510872;12907441;2140703;25429355;9196143",
"title": "A case of hepatosplenic T-cell lymphoma successfully treated by HLA haploidentical stem cell transplantation.",
"title_normalized": "a case of hepatosplenic t cell lymphoma successfully treated by hla haploidentical stem cell transplantation"
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"drugad... |
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"abstract": "BACKGROUND\nThis study was conducted to determine the efficacy and safety of low-dose chemotherapy with methotrexate (MTX) and vinblastine (VBL) for patients with desmoid tumors refractory to meloxicam treatment, focusing in particular on the relationship between the efficacy of this chemotherapy and catenin β-1 (CTNNB1) mutation status.\n\n\nMETHODS\nSince March 2003, patients pathologically diagnosed with extraperitoneal desmoid tumors have been prospectively treated with meloxicam, a COX-2 inhibitor, at our institution. Patients with inoperable tumors who were resistant to meloxicam treatment underwent MTX and VBL therapy every other week. The responses of all patients were evaluated, and factors that were correlated with efficacy were analyzed, including CTNNB1 mutation status.\n\n\nRESULTS\nSixty-eight patients were prospectively treated with meloxicam. MTX + VBL therapy was administered in 15 patients. Six patients showed a partial response. Only one patient presented disease progression. A few patients showed grade 3-4 treatment-related toxicity with the administration of MTX and VBL every other week. Intriguingly, CTNNB1 status did not affect the efficacy of this treatment.\n\n\nCONCLUSIONS\nMTX and VBL treatment every other week is well tolerated and achieved a favorable response in patients resistant to meloxicam treatment, regardless of CTNNB1 mutation status.",
"affiliations": "Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan. ynishida@med.nagoya-u.ac.jp.;Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan.;Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan.;Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan.;Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan.;Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Graduate School and School of Medicine, 65-Tsurumai, Showa, Nagoya, 466-8550, Japan.;Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan.",
"authors": "Nishida|Yoshihiro|Y|;Tsukushi|Satoshi|S|;Urakawa|Hiroshi|H|;Hamada|Shunsuke|S|;Kozawa|Eiji|E|;Ikuta|Kunihiro|K|;Ando|Yuichi|Y|;Ishiguro|Naoki|N|",
"chemical_list": "C495270:CTNNB1 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D013843:Thiazines; D013844:Thiazoles; D051176:beta Catenin; D014747:Vinblastine; D000077239:Meloxicam; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-015-0829-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "20(6)",
"journal": "International journal of clinical oncology",
"keywords": "CTNNB1; Desmoid tumor; Methotrexate; Vinblastine",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D052246:Cyclooxygenase 2 Inhibitors; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D018221:Fibromatosis, Abdominal; D006801:Humans; D008297:Male; D000077239:Meloxicam; D008727:Methotrexate; D008875:Middle Aged; D009154:Mutation; D019233:Retreatment; D013843:Thiazines; D013844:Thiazoles; D014747:Vinblastine; D055815:Young Adult; D051176:beta Catenin",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "1211-7",
"pmc": null,
"pmid": "25899770",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16382119;24740659;12663732;21447727;11313976;21844500;10570430;11571741;2916941;24425345;23913621;20724445;20622000;10738207;10458229;25341748;23281268;19722232;17709227;20187095;20026797;19097774;17290057;16505440;24390670;24325833;17470870;21444357;18832571;19950127;18810472;24788118;9217047;20197769",
"title": "Low-dose chemotherapy with methotrexate and vinblastine for patients with desmoid tumors: relationship to CTNNB1 mutation status.",
"title_normalized": "low dose chemotherapy with methotrexate and vinblastine for patients with desmoid tumors relationship to ctnnb1 mutation status"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP09290",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MELOXICAM"
},
"drugadditional": null,
... |
{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) is an infrequent, but severe, adverse drug-induced reaction which occurs due to massive T-cell stimulation resulting in cytotoxicity and eosinophil activation and recruitment. The incidence is 0.4 cases per 100, 0000 in the general population; the mortality rate is up to 10%. Therefore, we believe that recognizing this syndrome is of particular importance. The problem we notice is that DRESS is often seen and described in patients receiving rheumatologic or anticonvulsant drugs, but very rarely in psychiatric hospitals, where Clozapine is frequently used, and that is the importance of this paper. DRESS Syndrome must be recognized promptly, and causative drugs withdrawn. Indeed, it has been reported that the earlier the drug withdrawal, the better the prognosis. In this paper, we present three cases of Clozapine-induced DRESS. All cases were recorded in the Multicenter Drug Safety Surveillance Project (AMSP).",
"affiliations": "Department of Psychiatry, Ludwig Maximilian University, Munich, Germany.;Department of Psychiatry, Ludwig Maximilian University, Munich, Germany.;Department of Psychiatry, University Clinic Basel, Basel, Switzerland.;Psychiater Luzern Dr. Sabine Abele AG, Luzern/Lucerne, Switzerland.;Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover, Germany.;Department of Psychiatry, Ludwig Maximilian University, Munich, Germany.;Deparment of Psychiatry, Kbo-IAK, Academic Teaching Hospital of the Ludwig Maximilian University, Haar/Munich, Germany.",
"authors": "Sanader|Bruna|B|;Grohmann|Renate|R|;Grötsch|Philipp|P|;Schumann|Thomas|T|;Toto|Sermin|S|;Fernando|Piyumi|P|;Stübner|Susanne|S|",
"chemical_list": "D000927:Anticonvulsants; D003024:Clozapine",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-0586-8983",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0176-3679",
"issue": "52(3)",
"journal": "Pharmacopsychiatry",
"keywords": null,
"medline_ta": "Pharmacopsychiatry",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D003024:Clozapine; D003863:Depression; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8402938",
"other_id": null,
"pages": "156-159",
"pmc": null,
"pmid": "29554696",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Clozapine-Induced DRESS Syndrome: A Case Series From the AMSP Multicenter Drug Safety Surveillance Project.",
"title_normalized": "clozapine induced dress syndrome a case series from the amsp multicenter drug safety surveillance project"
} | [
{
"companynumb": "DE-ACCORD-065165",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FINASTERIDE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nAbout one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination.\n\n\nMETHODS\nWe conducted a multicenter retrospective study among centers from the French Groupe d'Etudes des Tumeurs Uro Genitales (GETUG). Patients with bone metastases who received concurrently or sequentially AA therapy and Dmab were included in this study.\n\n\nRESULTS\nA total of 41 patients with mRCC were enrolled. Although no patient presented with severe hypocalcemia, ONJ occurred in 7 (17%) of 41 patients. Interestingly, all patients with ONJ received the Dmab and AA combination in the first line of treatment; among these patients, 3 patients had no risk factor other than the Dmab and AA combination.\n\n\nCONCLUSIONS\nThe incidence of ONJ was high in this real-life population of patients with mRCC treated with AA therapies combined with Dmab. This toxicity signal should warn physicians about this combination in the mRCC population.",
"affiliations": "Department of Medical Oncology, Institut de cancérologie Lucien Neuwirth, Saint-Priest-en-Jarez, France.;Hôpital Henri Mondor, APHP, Créteil, France.;Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Centre François Baclesse, Caen, France.;Centre Léon Bérard, Lyon, France.;Hôpital Saint-Louis, AP-HP, Paris, France.;IUCT Oncopole, Toulouse France Centre Jean Perrin, France.;Centre Jean-Perrin, Medical Oncology, Clermont-Ferrand, France.;Institut de Cancérologie du Gard, Nîmes, France.;Institut Bergonié, Bordeaux, France.;Institut Paoli Calmette, Marseille, France.;Hôpitaux Universitaires de Lyon, Lyon, France.;Institut Gustave Roussy, Villejuif, France.;Department of Medical Oncology, Institut de cancérologie Lucien Neuwirth, Saint-Priest-en-Jarez, France.;Department of Medical Oncology, Institut de cancérologie Lucien Neuwirth, Saint-Priest-en-Jarez, France.;Department of Biostatistics, Institut de Cancérologie Lucien Neuwirth, Saint-Priest-en-Jarez, France.;Department of Radiotherapy, Institut de Cancérologie Lucien Neuwirth, Saint-Priest-en-Jarez, France.;Department of Medical Oncology, Institut de cancérologie Lucien Neuwirth, Saint-Priest-en-Jarez, France. Electronic address: wafa.bouleftour@icloire.fr.;Hôpital Saint-Louis, AP-HP, Paris, France.;Institut Gustave Roussy, Villejuif, France.",
"authors": "Guillot|Aline|A|;Joly|Charlotte|C|;Barthélémy|Philippe|P|;Meriaux|Emeline|E|;Negrier|Sylvie|S|;Pouessel|Damien|D|;Chevreau|Christine|C|;Mahammedi|Hakim|H|;Houede|Nadine|N|;Roubaud|Guilhem|G|;Gravis|Gwenaelle|G|;Tartas|Sophie|S|;Albiges|Laurence|L|;Vassal|Cécile|C|;Oriol|Mathieu|M|;Tinquaut|Fabien|F|;Espenel|Sophie|S|;Bouleftour|Wafa|W|;Culine|Stéphane|S|;Fizazi|Karim|K|",
"chemical_list": "D050071:Bone Density Conservation Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D000069448:Denosumab; C516667:pazopanib; D000068338:Everolimus; D000077784:Axitinib; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clgc.2018.08.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "17(1)",
"journal": "Clinical genitourinary cancer",
"keywords": "Anti-angiogenic therapies; Bone metastasis; Desosumab; Metastatic renal cell carcinoma; Osteonecrosis of the jaw",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077784:Axitinib; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D002292:Carcinoma, Renal Cell; D000069448:Denosumab; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006996:Hypocalcemia; D007191:Indazoles; D007680:Kidney Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011743:Pyrimidines; D012189:Retrospective Studies; D013449:Sulfonamides; D000077210:Sunitinib",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "e38-e43",
"pmc": null,
"pmid": "30279115",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Denosumab Toxicity When Combined With Anti-angiogenic Therapies on Patients With Metastatic Renal Cell Carcinoma: A GETUG Study.",
"title_normalized": "denosumab toxicity when combined with anti angiogenic therapies on patients with metastatic renal cell carcinoma a getug study"
} | [
{
"companynumb": "FR-AMGEN-FRASP2017005181",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nDrug-induced liver injury (DILI) is a frequent cause of pediatric liver disease; however, the data on DILI are remarkably limited.\n\n\nMETHODS\nAll 69 children hospitalized with DILI between January 2009 and December 2011 were retrospectively studied.\n\n\nRESULTS\nA total of 37.7% of the children had medical histories of respiratory infection. The clinical injury patterns were as follows hepatocellular 89.9%, cholestatic 2.9%, and mixed 7.2%. Liver biopsies from 55 children most frequently demonstrated chronic (47.3%) and acute (27.3%) hepatitis. Hypersensitivity features, namely, fever (31.9%), rash (21.7%), and eosinophilia (1.4%), were found. Twenty-four children (34.8%) developed chronic DILI. Antibiotics (26.1%) were the most common Western medicines (WMs) causing DILI, and the major implicated herbs were Ephedra sinica and Polygonum multiflorum. Compared with WM, the children whose injuries were caused by Chinese herbal medicine (CHM) showed a higher level of total bilirubin (1.4 mg/dL vs. 16.6 mg/dL, p=0.004) and a longer prothrombin time (11.8 seconds vs. 17.3 seconds, p=0.012), but they exhibited less chronic DILI (2/15 vs. 18/39, p=0.031).\n\n\nCONCLUSIONS\nMost cases of DILI in children are caused by antibiotics or CHM used to treat respiratory infection and present with hepatocellular injury. Compared with WM, CHM is more likely to cause severe liver injury, but liver injury caused by CHM is curable.",
"affiliations": "Integrative Medicine Center, 302 Military Hospital, China.;Integrative Medicine Center, 302 Military Hospital, China.;China Military Institute of Chinese Medicine, Beijing, China.;Department of Pathology, 302 Military Hospital, Beijing, China.;Integrative Medicine Center, 302 Military Hospital, China.;China Military Institute of Chinese Medicine, Beijing, China.;Integrative Medicine Center, 302 Military Hospital, China.;Integrative Medicine Center, 302 Military Hospital, China.;Integrative Medicine Center, 302 Military Hospital, China.;China Military Institute of Chinese Medicine, Beijing, China.",
"authors": "Zhu|Yun|Y|;Li|Yong-Gang|YG|;Wang|Jia-Bo|JB|;Liu|Shu-Hong|SH|;Wang|Li-Fu|LF|;Zhao|Yan-Ling|YL|;Bai|Yun-Feng|YF|;Wang|Zhong-Xia|ZX|;Li|Jian-Yu|JY|;Xiao|Xiao-He|XH|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004365:Drugs, Chinese Herbal; D001663:Bilirubin",
"country": "Korea (South)",
"delete": false,
"doi": "10.5009/gnl14184",
"fulltext": "\n==== Front\nGut LiverGut LiverGut and Liver1976-22832005-1212Gut and Liver 2571705010.5009/gnl14184gnl-09-525Original ArticleCauses, Features, and Outcomes of Drug-Induced Liver Injury in 69 Children from China Zhu Yun *†Li Yong-gang *Wang Jia-bo ‡Liu Shu-hong §Wang Li-fu *Zhao Yan-ling ‡Bai Yun-feng *Wang Zhong-xia *Li Jian-yu *Xiao Xiao-he ‡* Integrative Medicine Center, 302 Military Hospital, Beijing, \nChina† Medical School of Chinese PLA, Beijing, \nChina‡ China Military Institute of Chinese Medicine, Beijing, \nChina§ Department of Pathology, 302 Military Hospital, Beijing, \nChinaCorrespondence to: Xiao-he Xiao, China Military Institute of Chinese Medicine, 302 Military Hospital, No. 100, the 4th West Ring Road, Beijing 10039, China, Tel: +86-10-6693-3322, Fax: +86-10-6693-3322, E-mail: pharmacy302@126.com7 2015 26 2 2015 9 4 525 533 11 5 2014 21 7 2014 21 8 2014 Copyright © 2015 by The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association for the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer.2015This 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.Background/Aims\nDrug-induced liver injury (DILI) is a frequent cause of pediatric liver disease; however, the data on DILI are remarkably limited.\n\nMethods\nAll 69 children hospitalized with DILI between January 2009 and December 2011 were retrospectively studied.\n\nResults\nA total of 37.7% of the children had medical histories of respiratory infection. The clinical injury patterns were as follows: hepatocellular 89.9%, cholestatic 2.9%, and mixed 7.2%. Liver biopsies from 55 children most frequently demonstrated chronic (47.3%) and acute (27.3%) hepatitis. Hypersensitivity features, namely, fever (31.9%), rash (21.7%), and eosinophilia (1.4%), were found. Twenty-four children (34.8%) developed chronic DILI. Antibiotics (26.1%) were the most common Western medicines (WMs) causing DILI, and the major implicated herbs were Ephedra sinica and Polygonum multiflorum. Compared with WM, the children whose injuries were caused by Chinese herbal medicine (CHM) showed a higher level of total bilirubin (1.4 mg/dL vs 16.6 mg/dL, p=0.004) and a longer prothrombin time (11.8 seconds vs 17.3 seconds, p=0.012), but they exhibited less chronic DILI (2/15 vs 18/39, p=0.031).\n\nConclusions\nMost cases of DILI in children are caused by antibiotics or CHM used to treat respiratory infection and present with hepatocellular injury. Compared with WM, CHM is more likely to cause severe liver injury, but liver injury caused by CHM is curable.\n\nPediatricHepatotoxicityDiagnosisChinese herbal medicineLiver biopsy\n==== Body\nINTRODUCTION\nDrug-induced liver injury (DILI) is one of the most common reasons for pediatric liver disease and has become an important area of concern for clinicians, regulatory agencies, and pharmaceutical companies. In a retrospective research from China, 64 pediatric cases of DILI accounted for 10% of 641 cases of children hospitalized with liver injury over a period of 5 years.1 Drug-induced acute liver failure (ALF) has been reported to be the main cause of ALF in children in the United States, Canada, and the United Kingdom.2,3\n\nSystematic studies on children with DILI are scarce compared to the increasing number of reports on DILI in adults across all regions of the world. In the last decade, DILI in children has been described in case reports or small series.4–7 A recent prospective study over more than 5 years from Drug-Induced Liver Injury Network (DILIN) has reported the clinical and pathological characteristics of 30 children with DILI.8 Compared with adults, drug metabolism in children differs in terms of absorption, distribution, metabolism, and excretion.9,10 For example, the level of cytochromes P450, a class of enzymes responsible for metabolizing drugs, increases with age.11 Because of the scarcity of studies on DILI in children and age-related differences in drug metabolism, a National Institutes of Health clinical research workshop in 2008 concluded that additional studies of pediatric DILI were needed.12\n\nRecently herbal therapy is increasingly being used in pediatric populations. In the United States, an estimated 2.9 million children and adolescents used herbs or dietary supplements according to the 2007 National Health Interview Survey.13 With the historical background of the use of Chinese herbal medicine (CHM), CHM is an important cause of DILI in China in both children and adults.6,14 Despite the worldwide application of herbal products, data regarding herbal hepatotoxicity in children and adolescents are remarkably limited. Thus, it is imperative to recognize and investigate herbal hepatotoxicity in children.15\n\nTherefore, we undertook this study to analyze the causes, clinical, laboratory, and pathological features, and outcomes of DILI in children up to 14 years of age and compare the differences between CHM and Western medicine (WM) as implicated agents of pediatric liver injury.\n\nMATERIALS AND METHODS\nWe retrospectively collected and analyzed all children up to 14 years of age hospitalized with DILI between January 2009 and December 2011 in the 302 Hospital of PLA, Beijing, China. Children were considered to have DILI if they met the following criteria:16–18 a clinical suspicion of drug-induced hepatotoxicity, as defined as recent onset abnormalities in liver tests, such as rise in serum total bilirubin (TB) of at least 2 mg/dL, and/or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN), or rise in alkaline phosphatase (ALP) >2 times the ULN with any rise in TB or ALT or AST; exclusion of viral hepatitis A to E, hepatitis caused by nonhepatotropic virus, autoimmune liver disease, hepatolenticular degeneration, and other causes of liver diseases; and based on the Roussel Uclaf Causality Assessment Method (RUCAM), highly probable (>8), probable (6 to 8), or possible (3 to 5) are considered drug-induced liver injury. The diagnosis of drug-induced liver injury in children is shown in Fig. 1. Demographic, clinical, laboratory, and pathological data of children with DILI were extracted from hospital records.\n\nAccording to the Council for International Organizations of Medical Sciences (CIOMS) scale, DILI is classified into either hepatocellular, cholestatic, or mixed patterns on the ratio of ALT (as a multiple of its ULN) to ALP (as a multiple of its ULN), designated as the R (for ratio) value.19 Hepatocellular DILI is defined as R ≥5, cholestatic as R ≤2, and mixed as R >2 to R <5. A diagnosis of drug-induced ALF was made from established criteria:2 children with no known evidence of chronic liver disease, biochemical evidence of acute liver injury, and hepatic-based coagulopathy defined as a prothrombin time (PT) ≥15 seconds not corrected by Vitamin K in the presence of clinical hepatic encephalopathy or a PT ≥20 seconds regardless of the presence or absence of clinical hepatic encephalopathy. Based on established guidelines, Chronic DILI is considered as persistent biochemical abnormalities 3 months after drug discontinuation for cases of hepatocellular DILI, and persistent abnormalities for 6 months for cases of cholestatic/mixed DILI.19\n\nLiver biopsies were reviewed by two hepatopathologists who were blinded to clinical and demographic information. According to standard criteria, the pathological pattern of injury was categorized into acute hepatitis (predominantly lobular inflammation, with or without confluent or bridging necrosis; absence of cholestasis), chronic hepatitis (portal inflammation with interface hepatitis, with or without portal-based fibrosis; no cholestasis), acute cholestasis (hepatocellular and/or canalicular cholestasis; minimal inflammation), chronic cholestasis (duct sclerosis and loss; periportal cholate stasis; portal-based fibrosis; copper accumulation), cholestatic hepatitis (acute or chronic hepatitis pattern plus cholestasis) and other patterns.20,21 Individual histologic features were also recorded.\n\nSimple descriptive statistics including medians, 25th to 75th percentiles, frequencies, and percentages were used to summarize the data. Continuous variables were compared using the Mann-Whitney U test. Chi-square and Fisher exact tests were used to compare nominal variables. A p-value <0.05 (two-tailed) was considered statistically significant. All of the calculations were performed using SPSS version 16.0 software (SPSS Inc., Chicago, IL, USA).\n\nRESULTS\n1. Clinical presentations\nOf 1,544 children hospitalized due to liver injury between January 2009 and December 2011, there were 69 children (4.5%) with DILI. Demographic, clinical, and laboratory characteristics were shown in Table 1. The median age of these cases was 8 years (range, 0.2 to 14.0 years). No child had pregnancy or alcohol or tobacco consumption. Among 65 children without hematological disorders, the white blood cell count at baseline was abnormally decreased in 83.1%, and the platelet count was more than 300×109/L in 58.5% of the cases. Only one case had peripheral eosinophilia. Autoantibodies were detected in 32 children with DILI: antinuclear antibody was positive in four children and anti-liver-kidney microsome antibody was positive in one child.\n\n2. Implicated agents\nA list of agents implicated was provided in Table 2. Fifteen children (21.7%) had been exposed to more than one type of drug before the liver injury occurred, with antibiotics commonly being combined with antipyretic analgesics and/or CHM for respiratory infection (n=9) or fever of unknown origin (FUO) (n=3). Four cases were caused by VitC-yin-qiao tablet consisting of acetaminophen, chlorpheniramine maleate, vitamin C, Lonicera japonica, Forsythia suspensa, Schizonepeta tenuifolia, Glycine max, Lophatherum gracile, Arctium lappa, Platycodon grandiflorum, Phragmites communis, Glycyrrhiza uralensis, and menthol. Among children in whom one type of drug was implicated, the major classes of WM causing DILI were as follows: antibiotics in 26.1%, antituberculosis agents in 8.7%, antipyretic analgesics in 5.8%, antineoplastic agents in 5.8%, and glucocorticoids in 4.3%. Cephalosporin (n=8) and macrolides (n=6) were the most commonly implicated antibiotic agents. In 15 cases (21.7%), CHM was implicated, and the details were shown in Table 3. The major implicated herbs were Ephedra sinica (n=3) and Polygonum multiflorum (n=3). The characteristics of cases caused by CHM compared with WM were listed in Table 4. Of the six children with ALF, four were treated with CHM for tinea corporis (n=1), vitiligo (n=2), and poor appetite (n=1), one was caused by azithromycin for FUO, and another was induced by cephalosporins, antipyretic analgesics, and antiviral agents for pneumonia. Twenty-four chronic DILI cases were caused by antituberculosis agents (20.8%), antineoplastic agents (16.7%), antibiotics (16.7%), combination of implicated drugs (16.7%), glucocorticoids (12.5%), CHM (8.3%), and antipyretic analgesics (8.3%), respectively.\n\n3. Pathological features\nLiver biopsies were performed in 59 children (85.5%) and the pathological patterns of injury in 55 children were listed in Table 1, whereas four of the cases could not be classified into any pattern because of mild histological changes. Liver cell degeneration, necrosis, and lobular inflammation were common findings, with typical confluent necrosis in 11 cases (18.6%), bridging necrosis in five cases (8.5%), and submassive necrosis in one case who did not present with clinical features of liver failure. Twenty-nine biopsies (49.2%) showed various degrees of interface hepatitis. Hepatocellular and/or canalicular cholestasis were observed in 16 cases (27.1%). Twenty-nine biopsies (49.2%) demonstrated eosinophil infiltration and none had duct sclerosis or loss. Typical examples of pathological patterns were described in Fig. 2. In 15 cases (25.4%), the liver biopsy after the normalization of liver biochemistry still showed the histologic features of chronic hepatitis, such as moderate portal inflammation, interface hepatitis, fibroplastic proliferation, and fibrous septa formation. All three cases with ALF showed the pathological characteristics of cholestatic hepatitis involving confluent and bridging necrosis, cholestasis, interface hepatitis, and fibrous septa formation, but none demonstrated submassive necrosis.\n\n4. Outcomes\nThere were two deaths caused by herbal decoctions for tinea corporis and poor appetite, respectively. Six cases presented with acute liver failure and 24 cases developed into chronic DILI. Fourteen children with a median TB level of 14.5 (6.9, 19.9) mg/dL were treated with corticosteroids, of which seven developed chronic DILI, two presented with bacterial respiratory infection, two with oral cavity fungal infection, one with pulmonary fungal infection, and one with pyemia. In six children with ALF, two died, and the others recovered. The prognosis of the children with DILI caused by CHM and WM was shown in Table 4.\n\nDISCUSSION\nThe diagnosis of DILI is challenging, especially in children, because there are no specific markers of DILI and the diagnosis largely depends on a high index of suspicion and the exclusion of other causes of liver diseases.10\n\nDILI must always be considered, when there is a temporal association between observed liver injury and the exposure to drugs. The warning signal of liver injury has been either non-specific symptoms (e.g., fatigue, nausea, vomiting, or jaundice) or, more commonly, biochemical dysfunction, which includes raised levels of ALT, ALP, or TB. Then viral (hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, cytomegalovirus, and Epstein-Barr virus), autoimmune (antinuclear antibody and antismooth muscle antibody), and metabolic (Wilson’s disease and α1-antitrypsin deficiency) disorders must be excluded. In some cases, liver biopsy may be indicated to exclude other diseases and to help make a diagnosis of DILI.10,22\n\nThe RUCAM is the most widely used for aiding in the causality assessment of DILI, but there have been several pitfalls in applying this method in children.23 No child has pregnancy or alcohol consumption, and therefore, no points are given in the risk factor components of age, alcohol, and pregnancy. In cases with multiple possible implicated agents, the combination of implicated drugs had been considered to be one pathogenic factor because it was technically difficult to identify which drug was the most likely cause of liver injury.22 CHM is less likely to be well characterized with regard to hepatotoxicity information, and this may compromise the RUCAM score for CHM because no points are given for herbs without existing information on hepatotoxicity.15 Therefore, the diagnostic test for DILI in children needs further investigation and validation.\n\nThe characteristics of DILI in children are different from those in adults due to age-related changes in drug metabolism and the special requirements of medication given to children. Although the data were from a single center, the results of this study might provide an opportunity to analyze the characteristics of DILI in children.\n\nSimilar to adult studies, a combination of implicated drugs is a major cause of DILI in children and antibiotics are the most commonly implicated drug class.16,24 In this study, antibiotics were commonly combined with antipyretic analgesics and/or CHM for FUO and respiratory infection, and the major implicated antibiotics were cephalosporin and macrolides. Compared with the DILIN prospective study, CHM is the main etiological agent of DILI in children in China because of the historical background of the use of CHM.8 In this study, the major implicated herbs were Ephedra sinica for respiratory infection and Polygonum multiflorum for skin diseases. The medical history of respiratory infection in 41.4% of cases is notable and may help the clinician identify children at risk.\n\nSimilar to adult, the most common pattern of DILI in children is hepatocellular injury, both in clinical (87.9%) and pathological (76%) categorization.16,21 The common presenting symptoms were fatigue, jaundice, and gastrointestinal reaction. However, this group of 58 cases in this study exhibited fewer hypersensitivity features (defined as fever, rash, and eosinophilia) than reported in pediatric DILI studies from Western countries and Indian.8,17,25 17.2% of the 58 cases had allergic history and 13.3% of 30 cases had positive autoantibody, significantly lower than the 43% and 64% reported in the DILIN study, respectively.8 But our results were similar to other studies from China. In a similar study from China, 25.8% of 31 children with DILI showed hypersensitivity features: itching in 3.2%, fever in 6.5%, rash in 3.2%, and eosinophilia in 12.9%.6 Rash (16%) and fever (14%) were observed in 64 children with DILI in a single-center retrospective study from China.26 The difference in hypersensitivity features between China and Western countries needs further study and might be related to different classes of implicated agents and race-related genetic background.\n\nAlthough most DILI resolves following drug discontinuation, up to 20% of patients progress to chronic DILI further challenging the clinicians diagnostic and management skills.27 This study revealed more frequent chronic DILI cases (25.9%), defined as persistent biochemical abnormalities according to CIOMS, than reported in adult studies, which might be related to few cases with hypersensitivity features and the application of corticosteroids in this study.16,19,24 Compared to cases without hypersensitivity, children with hypersensitivity DILI present earlier, have less severe liver disease, and experience complete recovery.17 In this study, corticosteroids were used in 14 cases (24.1%) with hyperbilirubinemia, 50% of which developed chronic DILI and 43% presented with side effects of bacterial or fungal infection. However, it is likely that more severe and chronic cases of DILI were included in this study than are encountered in the general population, because all of the cases were hospitalized children in this study.\n\nSeveral histologic features of DILI in children were illustrated in the present report. Nearly half of the cases were classified into chronic hepatitis in the pathological injury pattern, and 26.4% of liver biopsies after the normalization of liver tests still showed the pathological features of chronic hepatitis. Moreover, no case of ALF demonstrated submassive necrosis, and only one biopsy with submassive necrosis did not present the clinical features of liver failure. Thus, the correlation between the clinical pattern and the pathological categorization of injury is limited.21\n\nHerbal medicine is widely used for treating diseases, improving symptoms, and overall health care, especially in China. Herbs have long been thought to be natural and safe. However, an increasing number of herbs and herbal products have been reported to cause liver injury.28,29 In this study, several characteristics of DILI in children caused by CHM were observed. Liver injury caused by CHM was hepatocellular, the severity ranged from mild injury to ALF, and the major implicated herbs were Ephedra sinica for respiratory infection and Polygonum multiflorum for skin diseases. Numerous herbs have been described to cause hepatotoxicity, including Ephedra sinica, Polygonum multiflorum, Mentha haplocalyx, Scutellaria baicalensis, Xanthium sibiricum, Andrographis paniculata (dehydroandrographolide succinate), Agkistrodon halys pallas, Smilax glabra, Tripterygium wilfordii, and Psoralea corylifolia.15,30–33\n\nHowever, it is extremely difficult to identify the exact causative hepatotoxic compounds and the mechanisms of their hepatotoxicity, because CHM consists of multiple herbs or constituents and there are herb-drug or herb-herb interactions leading to potentiation of risk for hepatotoxicity.15,28 Many herbals, such as Glycyrrhiza uralensis, Arctium lappa, Glycine max, Pueraria lobota, and Atractylodes macrocephala, have been identified as substrates, inhibitors, or inducers of cytochromes P450.15,34,35\nGlycyrrhiza uralensis, Arctium lappa, and Glycine max are constituents of VitC-yin-qiao tablet, and whether these herbs might potentiate the intrinsic hepatotoxicity of acetaminophen requires further study.\n\nIn this study, the cases caused by CHM showed more severe liver injury. Three cases with ALF and only one death were caused by CHM. Compared with WM, the cases with DILI caused by CHM have higher median levels of TB and total biliary acid, longer PT, lower prothrombin activity and lower cholinesterase (all p<0.05). According to Hy’s law, jaundice is a good predictor of mortality in DILI.36 In general, the higher the serum bilirubin, the more severe the liver injury.37 According to a research from multicenters in China, CHM was also reported be the main etiological agent of acute severe DILI and the cure rate of acute severe DILI was low (6.6%).14 However, 13.3% of the cases caused by CHM were associated with chronic DILI, less than that caused by WM (46.2%) (p=0.031). CHM is likely to cause severe liver injury and even death, but the liver injury caused by CHM could be curable after stopping causative CHM and being treated. In the chronic DILI cases caused by WM, some needed continue treatment of primary diseases, such as tuberculosis, malignant tumor, and hematological disorders. Prolonged medication administration and drug rechallenge might be risk factors for developing chronic DILI.38 Antituberculosis agents, antineoplastic agents, antibiotics, glucocorticoids, and antipyretic analgesics have been reported to cause chronic DILI.39,40 In the multicenter prospective study, malignancy receiving antineoplastic agents might be a risk factor for developing chronic DILI.40 However, there was selection bias because all of the cases were hospitalized and it could result in more chronic DILI cases. In additional, the children with DILI caused by CHM had a greater median number of days from drug start to symptoms than WM, but this trend was of borderline statistical significance (p=0.048).\n\nNotably, the preparation of some CHM has not been provided and even some Chinese patent medicines have not been approved by China Food and Drug Administration. The dosage and course of treatment for children have not been provided in the instructions for most Chinese patent medicines. Thus, studies are strongly needed to improve CHM safety in children.\n\nAlthough this study, which reported the largest number of children with DILI, was one of the few efforts to investigate DILI in children, it was a single-center and retrospective survey and was limited by potential selection bias because all of the cases were hospitalized children, leading to a poor outcome and low presentation in the general population.\n\nIn summary, the clinical characteristics of pediatric DILI are diverse, ranging from asymptomatic hepatitis to acute liver failure, and both chronicity and mortality are observed. Most of children with DILI typically present with hepatocellular injury pattern. It is important for pediatricians to evaluate the potential hepatotoxicity of commonly used CHM or antibiotics, especially the combination of these drugs, for respiratory infection, and monitor children with DILI during the recovery phase because of the slow pathological repair of liver injury after the normalization of liver biochemistry. Pediatricians should pay great attention to herbal hepatotoxicity and take measures to prevent development of severe liver injury induced by CHM. DILI is an important and problematic cause of liver injury in children, and further efforts are needed to study the mechanisms, risk factors, and outcomes of pediatric DILI and to develop methods for its diagnosis, prevention, and treatment.\n\nACKNOWLEDGEMENTS\nThis work was funded by the National Natural Science Foundation of China (number: 81303120) and the National Key Technology R&D Program (number: 2012BAI29B02).\n\nCONFLICTS OF INTEREST\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Flowchart depicting the diagnosis of drug-induced liver injury (DILI) in children.\n\nRUCAM, Roussel Uclaf Causality Assessment Method.\n\nFig. 2 Examples of the most common pathological injury patterns. (A) Acute hepatitis due to herbal decoction with Ephedra sinica for respiratory infection. Biopsy shows confluent and bridging necrosis around the central vein and significant lobular inflammation. (B) Chronic hepatitis due to the combination of cephalosporin antibiotics and antipyretic analgesics for fever of unknown origin. Liver biopsy shows fibrous septa formation and moderate interface hepatitis. (C) Acute cholestasis due to azithromycin. Biopsy showed hepatocellular and canalicular cholestasis with bile plugs. (D, E) Cholestatic hepatitis due to herbal decoction with Polygonum multiflorum for vitiligo. Biopsy showed prominent canalicular cholestasis, confluent necrosis, and neutrophilic infiltration (H&E stain, ×200; for orientation, V indicates the central vein, P indicates the portal area, and arrows indicate cholestasis).\n\nTable 1 Demographic, Clinical, Laboratory, and Pathological Characteristics of Children with Drug-Induced Liver Injury\n\nCharacteristic\tValue\t\nGender: boy\t66.7\t\nAge, yr\t8 (3, 12)\t\nMedical history\t\n Respiratory infection\t37.7\t\n Fever of unknown origin\t15.9\t\n Tuberculosis*\t10.1\t\n Skin diseases\t7.2\t\n Hematological disorders\t5.8\t\n Urinary diseases\t2.9\t\n Malignant tumor\t2.9\t\n Ear, nose, and throat diseases\t2.9\t\n Other†\t14.6\t\nAllergic history\t20.3\t\nClinical signs and symptom\t\n Jaundice\t59.4\t\n Splenomegaly‡\t47.8\t\n Gastrointestinal reaction\t44.9\t\n Hepatomegaly‡\t36.2\t\n Fatigue\t34.8\t\n Fever\t31.9\t\n Rash\t21.7\t\n Itching\t14.5\t\n Arthralgia\t2.9\t\n No symptoms\t20.3\t\nClinical pattern of liver injury\t\n Hepatocellular\t89.9\t\n Cholestatic\t2.9\t\n Mixed\t7.2\t\nLaboratory variable\t\t\n Peak ALT, U/L\t649 (215, 1,125)\t\n Peak AST, U/L\t434 (145, 968)\t\n Peak ALP, U/L\t287 (224, 419)\t\n Peak GGT, U/L\t100 (39, 176)\t\n Peak TB, mg/dL\t4.1 (0.5, 14.8)\t\n Peak TBA, μmol/L\t93 (12, 342)\t\n Lowest ALB, g/L\t37 (34, 40)\t\n Lowest CHE, U/L\t5,205 (3,900, 7,921)\t\n Peak PT, sec\t12.1 (11.2, 16.5)\t\n Lowest PA, %\t85.0 (51.8, 97.5)\t\n WBC count at baseline, 109/L§\t5.5 (4.1, 8.2)\t\n PLT count at baseline, 109/L§\t321 (260, 431)\t\nPathological pattern of liver injury (n=55)||\t\n Acute hepatitis\t27.3\t\n Chronic hepatitis\t47.3\t\n Acute cholestasis\t3.6\t\n Cholestatic hepatitis\t21.8\t\nData are presented as median (25th, 75th) or percent.\n\nALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase; GGT, γ-glutamyltransferase; TB, total bilirubin; TBA, total biliary acid; ALB, albumin; CHE, cholinesterase; PT, prothrombin time; PA, prothrombin activity; WBC, white blood cell; PLT, platelet.\n\n* One child exhibited the complication of epilepsy, and one developed nephrotic syndrome;\n\n† Six children received Chinese herbal medicine to improve symptoms. Two cases were caused by antibiotics, administered as prophylaxis against surgical infection; one was induced by montelukast for asthma; and one was caused by sotalol, administered for paroxysmal supraventricular tachycardia;\n\n‡ Found by physical examination or abdominal ultrasound;\n\n§ Except for four children with hematological disorders;\n\n|| Liver biopsies were performed in 59 children; however, four cases could not be classified into any pattern because of mild histological changes.\n\nTable 2 Implicated Agents in 69 Children with Drug-Induced Liver Injury\n\nImplicated agent\tValue\t\nCombination of implicated drug\t15 (21.7)\t\n VitC-yin-qiao tablet*\t4\t\n Antibiotics+CHM+antipyretic analgesics\t3\t\n Antibiotics+CHM\t3\t\n Antibiotics+antipyretic analgesics\t2\t\n Antibiotics+antipyretic analgesics+antiviral agents\t1\t\n Antibiotics+CHM+antiparasitic agents\t1\t\n Antituberculosis agents+antiepileptic agents\t1\t\nWestern medicine\t39 (56.6)\t\n Antibiotics\t18 (26.1)\t\n Cephalosporins (cephalexin, cefmetazole, cefoperazone, ceftriaxone)\t8\t\n Macrolides (azithromycin, roxithromycin)\t6\t\n Penicillins (amoxicillin)\t3\t\n Quinolones (norfloxacin)\t1\t\n Antituberculosis agents\t6 (8.7)\t\n Antineoplastic agents\t4 (5.8)\t\n Antipyretic analgesics\t4 (5.8)\t\n Glucocorticoids\t3 (4.3)\t\n Antiviral agents\t2 (2.9)\t\n Drug for asthma (montelukast)\t1 (1.5)\t\n Drug for paroxysmal supraventricular tachycardia (sotalol)\t1 (1.5)\t\nCHM\t15 (21.7)\t\n Chinese patent medicine\t9\t\n Herbal decoction\t6\t\nData are presented as number (%).\n\nCHM, Chinese herbal medicine.\n\n* VitC-yin-qiao tablet consists of acetaminophen, chlorpheniramine maleate, vitamin C, Lonicera japonica, Forsythia suspensa, Schizonepeta tenuifolia, Glycine max, Lophatherum gracile, Arctium lappa, Platycodon grandiflorum, Phragmites communis, Glycyrrhiza uralensis, and menthol.\n\nTable 3 Chinese Herbal Medicine Used to Treat Drug-Induced Liver Injury in 15 Children\n\nName\tAims of application\tClassification\tPotential herbals with hepatotoxicity\t\nChinese patent medicine (n=9)\t\n Gan-mao soft capsule\tURI\tOTC\tEphedra sinica Scutellaria baicalensis; Mentha haplocalyx\t\n Xiao-er-ke-chuan-ling granule\tURI\tOTC\tEphedra sinica\t\n Dan-xiang-bi-yan tablet\tSinusitis\tPx\tXanthium sibiricum Mentha haplocalyx\t\n Yan-hu-ning injection\tPneumonia\tPx\tAndrographis paniculata (dehydroandrographolide succinate)\t\n Xiao-er-kang granule\tPoor appetite\tPx\tUnknown\t\n Shou-wu-yan-shou tablet\tVitiligo\tOTC\tPolygonum multiflorum\t\n Zang-qi-xue-yu capsule\tIncreasing energy levels\tNot approved by CFDA\tAgkistrodon halys pallas\t\n Xiao-er-pai-qian oral liquid\tHyperactivity\tNot approved by CFDA\tSmilax glabra\t\n Main-yi-wang capsule\tIncreasing energy levels\tNot approved by CFDA\tUnknown\t\nHerbal decoction (n=6)\t\n\tURI\t\tEphedra sinica\t\n\tVitiligo\t\tPolygonum multiflorum\t\n\tVitiligo\t\tPsoralea corylifolia\t\n\tTinea corporis\t\tPolygonum multiflorum\t\n\tJRA\t\tTripterygium wilfordii\t\n\tPoor appetite\t\tUnknown\t\nURI, upper respiratory infection; OTC, over-the-counter drug; Px, prescribed drug; CFDA, China Food and Drug Administration; JRA, juvenile rheumatoid arthritis.\n\nTable 4 Characteristics of Children with Drug-Induced Liver Injury Caused by Chinese Herbal Medicine Compared with Western Medicine\n\nCharacteristic\tChinese herbal medicine (n=15)\tWestern medicine (n=39)\tp-value\t\nAge, yr\t10 (4, 12)\t7 (3, 12)\t0.438\t\nGender: boy\t60.0\t71.8\t0.403\t\nAllergic history\t20.0\t23.1\t1.000\t\nDays from drug start to symptoms\t30 (7, 90)\t10 (3, 30)\t0.048\t\nLiver tests\t\n Peak ALT, U/L\t649 (349, 1,010)\t529 (186, 1,038)\t0.569\t\n Peak AST, U/L\t597 (253, 942)\t425 (135, 826)\t0.354\t\n Peak ALP, U/L\t298 (243, 438)\t274 (191, 439)\t0.329\t\n Peak GGT, U/L\t87 (31, 140)\t117 (31, 186)\t0.599\t\n Peak TB, mg/dL\t16.6 (3.7, 22.2)\t1.4 (0.4, 10.1)\t0.004\t\n Peak TBA, μmol/L\t342 (38, 446)\t32 (8, 283)\t0.032\t\n Lowest ALB, g/L\t37 (31, 40)\t38 (35, 39)\t0.394\t\n Lowest CHE, U/L\t3,833 (2,471, 4,632)\t6,493 (4,312, 8,022)\t0.011\t\n Peak PT, sec\t17.3 (11.6, 26.6)\t11.8 (10.9, 12.9)\t0.012\t\n Lowest PA, %\t45 (31, 89)\t90 (74, 102)\t0.006\t\nClinical pattern of liver injury\t\n Hepatocellular\t100.0\t87.2\t0.347\t\n Cholestatic\t0\t2.6\t\t\n Mixed\t0\t10.3\t\t\nPrognosis\t\n Chronic\t13.3\t46.2\t0.031\t\n ALF\t26.7\t2.6\t0.018\t\n Death\t13.3\t0\t0.073\t\nData are presented as median (25th, 75th) or percent.\n\nALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase; GGT, γ-glutamyltransferase; TB, total bilirubin; TBA, total biliary acid; ALB, albumin; CHE, cholinesterase; PT, prothrombin time; PA, prothrombin activity; ALF, acute liver failure.\n==== Refs\nREFERENCES\n1 Zhu XX Zhu Y Wan CM Clinical features of drug-induced liver injury in children Zhongguo Dang Dai Er Ke Za Zhi 2012 14 131 133 22357473 \n2 Squires RH Jr Shneider BL Bucuvalas J 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diagnosis, and natural history of drug-induced liver injury Semin Liver Dis 2014 34 134 144 10.1055/s-0034-1375955 24879979 \n28 Schoepfer AM Engel A Fattinger K Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products J Hepatol 2007 47 521 526 10.1016/j.jhep.2007.06.014 17692989 \n29 Li FY Li J Xiao XH Research status of herbal drug-induced liver injury Chin J Tradit Chin Med Pharmacol 2009 24 265 269 \n30 Skoulidis F Alexander GJ Davies SE Ma huang associated acute liver failure requiring liver transplantation Eur J Gastroenterol Hepatol 2005 17 581 584 10.1097/00042737-200505000-00017 15827451 \n31 Liu HC Liu HY The liver damage of herbs and the other botanical herbs Chin Hepatol 2001 6 52 53 \n32 Liu SM Herbal drug-induced liver injury Beijing China Press of Traditional Chinese Medicine 2007 68 70 248 250 278 280 \n33 Nam SW Baek JT Lee DS Kang SB Ahn BM Chung KW A case of acute cholestatic hepatitis associated with the seeds of Psoralea corylifolia (Boh-Gol-Zhee) Clin Toxicol (Phila) 2005 43 589 591 10.1081/CLT-200068863 16255343 \n34 Dong Y Wang J Yang Q Wang YW Zhu XX Current status on the interaction of cytochrome P450 and metabolism of Chinese materia medica Chin J Inf Tradit Chin Med 2011 18 100 103 \n35 Guerra MC Speroni E Broccoli M Comparison between chinese medical herb Pueraria lobata crude extract and its main isoflavone puerarin antioxidant properties and effects on rat liver CYP-catalysed drug metabolism Life Sci 2000 67 2997 3006 10.1016/S0024-3205(00)00885-7 11133012 \n36 Björnsson E Drug-induced liver injury: Hy’s rule revisited Clin Pharmacol Ther 2006 79 521 528 10.1016/j.clpt.2006.02.012 16765139 \n37 Verma S Kaplowitz N Diagnosis, management and prevention of drug-induced liver injury Gut 2009 58 1555 1564 10.1136/gut.2008.163675 19834119 \n38 Aithal PG Day CP The natural history of histologically proved drug induced liver disease Gut 1999 44 731 735 10.1136/gut.44.5.731 10205214 \n39 Rangnekar AS Fontana RJ An update on drug induced liver injury Minerva Gastroenterol Dietol 2011 57 213 229 21587150 \n40 Fontana RJ Hayashi PH Gu J Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset Gastroenterology 2014 147 96 108.e4 10.1053/j.gastro.2014.03.045 24681128\n\n",
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"keywords": "Chinese herbal medicine; Diagnosis; Hepatotoxicity; Liver biopsy; Pediatric",
"medline_ta": "Gut Liver",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001663:Bilirubin; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D002681:China; D004365:Drugs, Chinese Herbal; D005260:Female; D006801:Humans; D008099:Liver; D008297:Male; D011517:Prothrombin Time; D012141:Respiratory Tract Infections; D012189:Retrospective Studies",
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"title": "Causes, Features, and Outcomes of Drug-Induced Liver Injury in 69 Children from China.",
"title_normalized": "causes features and outcomes of drug induced liver injury in 69 children from china"
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"abstract": "Brenner tumor accounts for 1.5 to 2.5% of ovarian tumors. Nearly all are benign and 1% malignant. Less than twenty-five cases of borderline Brenner tumor have been reported worldwide. Our case is the first one related to a bilateral ovarian serous cystadenofibroma and endometrioid adenocarcinoma. This unusual case increases the limited data for borderline Brenner tumors.",
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"title": "An unusual case of a borderline Brenner tumor associated with bilateral serous cystadenoma and endometrial carcinoma.",
"title_normalized": "an unusual case of a borderline brenner tumor associated with bilateral serous cystadenoma and endometrial carcinoma"
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"abstract": "BACKGROUND\nTypically, fibrin sealants (FSs) and fibrin glues (FGs) are used to strengthen dural repairs during spinal surgery. In 2014, Epstein demonstrated that one FS/FG, Tisseel (Baxter International Inc., Westlake Village, CA, USA) equalized the average times to drain removal and length of stay (LOS) for patients with versus without excess bleeding (e.g. who did not receive Tisseel) undergoing multilevel laminectomies with 1-2 level noninstrumented fusions (LamF).[6].\n\n\nMETHODS\nHere Tisseel was utilized to promote hemostasis for two populations; 39 patients undergoing average 4.4 level lumbar laminectomies with average 1.3 level noninstrumented fusions (LamF), and 48 patients undergoing average 4.0 level laminectomies alone (Lam). We compared the average operative time, estimated blood loss (EBL), postoperative drainage, LOS, and transfusion requirements for the LamF versus Lam groups.\n\n\nRESULTS\nThe average operative times, EBL, postoperative drainage, LOS, and transfusion requirements were all greater for LamF versus Lam patients; operative times (4.1 vs. 3.0 h), average EBL (192.3 vs. 147.9 cc), drainage (e.g. day 1; 199.6 vs. 167.4 cc; day 2; 172.9 vs. 63.9 cc), average LOS (4.6 vs. 2.5 days), and transfusion requirements (11 LamF patients; 18 Units [U] RBC versus 2 Lam patients; 3 U RBC).\n\n\nCONCLUSIONS\nUtilizing Tisseel to facilitate hemostasis in LamF versus Lam still resulted in greater operative times, EBL, postoperative average drainage, LOS, and transfusion requirements for patients undergoing the noninstrumented fusions. Although Tisseel decreases back bleeding within the spinal canal, it does not reduce blood loss from LamF decorticated transverse processes.",
"affiliations": "Chief of Neurosurgical Spine and Education, Department of Neuro Science, Winthrop University Hospital, Mineola, NY 11501, USA.",
"authors": "Epstein|Nancy E|NE|",
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"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-6-17210.4103/2152-7806.156561Surgical Neurology International: SpineTisseel does not reduce postoperative drainage, length of stay, and transfusion requirements for lumbar laminectomy with noninstrumented fusion versus laminectomy alone Epstein Nancy E. nancy.epsteinmd@gmail.com*Chief of Neurosurgical Spine and Education, Department of Neuro Science, Winthrop University Hospital, Mineola, NY 11501, USA* Corresponding author\n2015 07 5 2015 6 Suppl 4 SNI: Spine, a supplement to Surgical Neurology InternationalS172 S176 17 2 2015 19 2 2015 Copyright: © 2015 Epstein NE.2015This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background:\nTypically, fibrin sealants (FSs) and fibrin glues (FGs) are used to strengthen dural repairs during spinal surgery. In 2014, Epstein demonstrated that one FS/FG, Tisseel (Baxter International Inc., Westlake Village, CA, USA) equalized the average times to drain removal and length of stay (LOS) for patients with versus without excess bleeding (e.g. who did not receive Tisseel) undergoing multilevel laminectomies with 1-2 level noninstrumented fusions (LamF).[6]\n\nMethods:\nHere Tisseel was utilized to promote hemostasis for two populations; 39 patients undergoing average 4.4 level lumbar laminectomies with average 1.3 level noninstrumented fusions (LamF), and 48 patients undergoing average 4.0 level laminectomies alone (Lam). We compared the average operative time, estimated blood loss (EBL), postoperative drainage, LOS, and transfusion requirements for the LamF versus Lam groups.\n\nResults:\nThe average operative times, EBL, postoperative drainage, LOS, and transfusion requirements were all greater for LamF versus Lam patients; operative times (4.1 vs. 3.0 h), average EBL (192.3 vs. 147.9 cc), drainage (e.g. day 1; 199.6 vs. 167.4 cc; day 2; 172.9 vs. 63.9 cc), average LOS (4.6 vs. 2.5 days), and transfusion requirements (11 LamF patients; 18 Units [U] RBC versus 2 Lam patients; 3 U RBC).\n\nConclusions:\nUtilizing Tisseel to facilitate hemostasis in LamF versus Lam still resulted in greater operative times, EBL, postoperative average drainage, LOS, and transfusion requirements for patients undergoing the noninstrumented fusions. Although Tisseel decreases back bleeding within the spinal canal, it does not reduce blood loss from LamF decorticated transverse processes.\n\nFibrin sealanthemostasislaminectomy alonelength of staylumbar surgerymultilevel laminectomynoninstrumented fusionstenosistisseel\n==== Body\nINTRODUCTION\nTypically, fibrin sealants (FSs) and fibrin glues (FGs) have been utilized to strengthen repairs of deliberate (e.g. intradural tumors) or traumatic cerebrospinal fluid (CSF) fistulas occurring during spinal surgery. In 2014, Epstein documented that one FS, Tiseeel (Baxter International Inc., Westlake Village, CA, USA), equalized the average times to drain removal and length of stay (LOS) for patients undergoing multilevel laminectomies and 1-2 level noninstrumented fusions (LamF) with versus without increased bleeding (the latter did not receive Tisseel).[6] Here we compared the average operative time, estimated blood loss (EBL), postoperative average drainage, LOS, and transfusion requirements for 39 patients undergoing LamF versus 48 patients undergoing multilevel laminectomies (Lam) alone.\n\nMATERIALS AND METHODS\nThirty-nine patients undergoing multilevel laminectomies/noninstrumented fusions\nThe 39 patients undergoing LamF averaged 66.5 years of age, and included more females than males (28 females, 11 males) [Table 1]. Patients underwent average 4.4 level laminectomies with average 1.3 level noninstrumented fusions. Only 5 patients had accompanying disc herniations, while 15 had synovial cysts. The average operative time, EBL, and average postoperative drainage, LOS, and transfusion requirements were evaluated for these patients.\n\nTable 1 Clinical data for patients undergoing multilevel laminectomy with versus without noninstrumented fusions using tisseel for hemostasis\n\nForty-eight patients undergoing multilevel laminectomies alone without fusions\nThe 48 patients undergoing Lam averaged 58 years of age, and included more males than females (30 males 18 females) [Table 1]. Patients underwent average 4.0 level Lam alone without fusions. A greater number of patients had accompanying disc herniations (22 patients), while fewer had synovial cysts (11 patients) when compared with the LamF group. For Lam patients, the average operative time, EBL, and postoperative average drainage, LOS, and transfusion requirements were also evaluated and compared with these data for LamF.\n\nUse of tisseel to facilitate hemostasis\nAll patients in both series undergoing multilevel laminectomies with noninstrumented fusions (LamF) or with Lam alone received Tisseel intraoperatively to facilitate hemostasis in the spinal canal (e.g. from the epidural venous plexus or laminectomy bone back-bleeding). Additionally, Tisseel was utilized to facilitate treatment of CSF fistulas for LamF versus Lam patients; six LamF and one Lam patient exhibited CSF fistulas attributed to preoperative epidural steroid injections (ESI), while one patient in each group exhibited a traumatic intraoperative CSF fistula [Table 1].\n\nRESULTS\nGreater EBL, postoperative drainage, time to drain removal, and longer length of stay for lamF versus Lam alone patients\nLamF patients exhibited greater EBL, postoperative drainage, longer times to drain removal, and LOS versus Lam alone patients. The intraoperative EBL was greater for LamF versus Lam patients (192.3 vs. 147.9 cc). The average amount of daily postoperative drainage was greater for LamF versus Lam patients particularly on postoperative days 1 and 2 when drains had not yet been removed in any patients; day 1: 199.6 versus 167.4 cc, and day 2; 172.9 versus 63.9 cc [Table 2]. For LamF patients, drains were mostly removed on postoperative days 3–4 (day 3; 21 drains, day 4; 17 drains), while for Lam patients, drains were mostly out by the second and third postoperative days (day 2; 29 drains, day 3; 18 drains). These data also correlated with the longer average LOS of 4.6 days for the LamF patients versus the average LOS of 2.5 days for the Lam alone patients.\n\nTable 2 Estimated blood loss, postoperative drainage, length of stay, and transfusion requirements following multilevel laminectomy with/without noninstrumented fusions using tisseel for hemostasis\n\nGreater transfusion requirements for LamF versus Lam alone patients\nLamF patients additionally exhibited greater transfusion requirements due to back-bleeding from decorticated transverse processes (TP) occurring during noninstrumented fusions versus Lam alone [Table 2]. Eleven of 39 LamF patients required 18 units (U) of packed red blood cells (RBC), 5 U of fresh frozen plasma (FFP), and 4 U of platelets (Plts) versus only 2 of 48 patients undergoing Lam alone requiring 3 U RBC and 2 U Plts (note: one patient with a coagulopathy required 2 U RBC/2 U Plts).\n\nDISCUSSION\nFrequency of dural tears\nTraumatic dural tears (DT) occur during 1–17% of lumbar spinal surgical procedures, 1% for anterior cervical discectomy/fusion (ACDF), 1.7% for single-level anterior cervical corpectomy/fusion (ACF), and up to 12.5% for multilevel ACF involving resection of ossification of the posterior longitudinal ligament (OPLL).[24910] Additionally, Epstein reported that for 33 patients undergoing LamF who received an average of 4.1 (range 2–12) preoperative lumbar ESI, 6 (18.2%) patients had DT documented intraoperatively that warranted surgical repair.[7]\n\nSafety/efficacy of “fibrin sealants” and “fibrin glues” to repair DT\nEpstein reviewed the relative safety/efficacy of supplementing/strengthening repairs of spinal DT utilizing two “FSs” or two “FG” [Table 1].[5] The FS included DuraSeal (Confluent Surgical Inc., Waltham, MA, USA) and BioGlue (Cryolife, Kennesaw, GA, USA), while the two FGs included Evicel (Johnson and Johnson Wound Management, Ethicon Inc., Somerville, NJ, USA) and Tisseel (Baxter International Inc., Westlake Village, CA, USA).\n\nParalytic complications with duraseal (FS)\nAlthough the Food and Drug Administration (FDA) approved Duraseal (FS) for use in the brain and spine in 2009, Duraseal contributed to two cases of reported paralysis due to spinal injections. In 2009, Mulder et al. noted that DuraSeal, applied in the lumbar spine to facilitate DT repair following a laminotomy/diskectomy, migrated superiorly, became “swollen,” and contributed to a cauda equina syndrome 6 days postoperatively.[12] In 2010, Thavarajah et al. used DuraSeal to repair a traumatic anterior C5-C6 cervical diskectomy/fusion CSF fistula; postoperatively, the patient's quadriplegia was similarly due to “swollen” Duraseal, which was then surgically removed.[14]\n\nUse of tisseel for hemostasis in cranial and anterior cervical surgery\nInjecting Tisseel facilitated hemostasis both intracranially and in the anterior cervical spine. In 2007, Sekhar et al. safely achieved hemostasis by injecting Tisseel into the cranial epidural space (n = 200 patients), anterior cavernous sinus (n = 46 patients), and vertebral venous plexus (n = 20 patients); however, it resulted in venous occlusion/brain stem infarction when injected into the superior petrosal sinus.[13] In 2008, Yeom et al. showed that Tisseel (2.0 mL of aerosolized spray) reduced postoperative drainage and LOS following 30 multilevel ACDF (3 or more levels) versus 30 comparable controls.[19] Tisseel successfully reduced the total postoperative drainage (47 vs. 98 ml), time to drain removal (17 vs. 24 h), and average LOS (1.2 vs. 2.1 days).[19]\n\nSandwich versus conventional dural repair techniques utilizing fibrin sealant\nWang et al. compared the efficacy of utilizing the “sandwich” (interlocking suture/FS/FG glue/gelatin sponge/FS/FG glue) versus conventional (interlocking sutures/gelatin sponge) techniques for dural repair following removal of 54 spinal subdural tumors to prevent recurrent postoperative CSF leaks.[17] Sandwich repairs were more effective as they significantly reduced postoperative drainage while avoiding recurrent CSF fistulas.\n\nTisseel's safety/efficacy in reducing spinal surgical site infections\nIn 2012 and 2013, two authors noted that Tisseel impregnated with antibiotics reduced the risk of spinal infection.[316] In 2012, utilizing both an in-vitro model and a clinical series, Tofuku et al. demonstrated that antibiotic-impregnated FS (AFS) helped prevent instrumented surgical site infections (SSI).[16] When 5 of 10 infected nuts were exposed to vancomycin-impregnated FS, antimicrobial efficacy was documented using agar diffusion testing. Additionally, deep-instrumented SSI were reduced to 0% for 196 clinical procedures utilizing AFS versus a much higher 11 (5.8 %) of 188 patients undergoing instrumented spinal fusions without AFS. In 2013, Cashman et al. utilized in-vitro and in-vivo rat animal models to assess whether FS could effectively administer antibiotics to infected instrumented spinal fusions.[3] Both required mixing cefazolin, fusidic acid, or 5-fluorouracil with Vitagel (Orthovita, Malvern, Pennsylvania, USA) tissue sealant. When exposed to Staphylococcus aureus\nin vitro (e.g. zone of inhibition), and in vivo (e.g. a rat instrumented spinal fusion model), over a 2- to 4-day period, Vitagel/FS effectively delivered antibacterial activity.\n\nFS and evicel; successful hemostatic agents in total joint surgery\nIn total joint surgery in 2009, Thoms and Marwin found that FS reduced the time to achieve intraoperative hemostasis, EBL, and the incidence of infections, while facilitating wound healing, and increasing postoperative range of motion.[15] Later, in 2014, Bou Monsef et al. found that the addition of Evicel (Johnson and Johnson Wound Management, Ethicon, Somerville, NJ) reduced blood loss, and therefore, the need for autologous preoperative blood donation (PABD) for anemic patients undergoing total knee replacement (TKR).[1]\n\nDifferent FS/FG promote intraoperative lumbar spinal hemostasis\nDifferent FS/FG have been utilized to promote intraoperative lumbar spinal hemostasis.[68] In 2014, Epstein applied Tisseel in 22 of 39 patients undergoing LamF who exhibited increased intraoperative bleeding; notably, the 17 LamF patients who did not demonstrate increased bleeding did not receive Tisseel. The addition of Tisseel in the LamF versus no Tisseel in the Lam patients equalized the time to drain removal for both groups (e.g. 3.41 days with vs. 3.38 days without Tisseel) along with the LOS (e.g. 5.86 days with vs. 5.82 days without), without increasing the infection rates or the average times to fusion (e.g. 5.9 vs. 5.5 months).[6] Also in 2014, Misusci et al. compared the short/long-term (e.g. 3 months, and 1 year) safety/efficacy of BioGlue versus Tisseel for DT repairs during noninstrumented lumbar fusions in 23 patients.[11] They found that all fistulas in both groups resolved without new neurological deficits or infections, and that patients demonstrated comparable outcomes (Visual Analog Scales, VAS). Additionally in 2014 Wu et al. evaluated 82 consecutive patients undergoing posterior lumbar fusion (PLF) or posterior lumbar interbody fusion (PLIF) who were randomized to receive absorbable gelatin sponge versus no sponge.[18] They found that those receiving the gelatin sponge versus no sponge showed reduced average drainage (173 ml vs. 392 ml), reduced perioperative blood transfusion requirements (34.15% vs. 58.5%), and reduced LOS (12.58 vs. 14.46 days) without adverse sequelae.\n\nTisseel in LamF patients undergoing noninstrumented postero-lateral fusions does not limit back bleeding from decorticated transverse processes\nDespite the use of Tisseel to facilitate hemostasis in the LamF versus Lam groups, noninstrumented fusions with decorticated TP for uniquely contributed to greater operative times, intraoperative EBL, postoperative drainage, LOS, and transfusion requirements. Although LamF versus Lam patients underwent nearly comparable multilevel laminectomies (4.4 vs. 4.0 levels), the average 1.3 level noninstrumented fusions were responsible for these differences. LamF patients exhibited longer operative times (e.g. 1.1 h more), higher average EBL (44.4 cc), greater average daily drainage (day 1: 32.3 cc, day 2: 109 cc), longer times until drain removal (e.g. LamF days 3–4 [38 of 39 patients] vs. Lam days 2–3 [47 of 48 patients]), greater transfusion requirements (11 LamF patients requiring 18 U RBC vs. 2 Lam patients requiring 3U RBC), and longer LOS (average 4.6 vs. 2.5 days).\n\nCONCLUSION\nTisseel, applied in the lumbar spinal canal locally limits drainage from epidural veins and largely stops back bleeding from the exposed edges of laminectomy defects. It cannot, however, limit back bleeding from TP decorticated during the performance of noninstrumented postero-lateral fusions. The intent of this study was to document for LamF versus Lam patients that the noninstrumented fusions contributed to the longer operative times, greater average EBL, higher volume of postoperative drainage, longer LOS, and higher transfusion requirements. These data may prove useful when deciding whether to perform LamF versus Lam alone especially in older patients with greater comorbidities who may not tolerate the greater risks enumerated above associated with the noninstrumented fusions.\n\nAvailable FREE in open access from: http://www.surgicalneurologyint.com/text.asp?2015/6/5/172/156561\n==== Refs\nREFERENCES\n1 Bou Monsef J Buckup J Waldstein W Cornell C Boettner F Fibrin sealants or cell saver eliminate the need for autologous blood donation in anemic patients undergoing primary total knee arthroplasty Arch Orthop Trauma Surg 2014 134 53 8 24190654 \n2 Cammisa FP Jr Girardi FP Sangani PK Parvataneni HK Cadag S Sandhu HS Incidental durotomy in spine surgery Spine (Phila Pa 1976) 2000 25 2663 7 11034653 \n3 Cashman JD Jackson JK Mugabe C Gilchrist S Ball K Tredwell S The use of tissue sealants to deliver antibiotics to an orthopaedic surgical site with a titanium implant J Orthop Sci 2013 18 165 74 23096950 \n4 Dafford EE Anderson PA Comparison of dural repair techniques Spine J 2013 pii 13 S1529 9430 00719-5 23973097 \n5 Epstein NE Dural repair with four spinal sealants: Focused review of the manufacturers’ inserts and the current literature Spine J 2010 10 1065 8 21094467 \n6 Epstein NE Tisseel utilized as a hemostatic in spine surgery impacts time to drain removal and length of stay Surg Neurol Int 2014 5 Suppl 7 S354 61 25289160 \n7 Epstein NE Commentary: Unnecessary preoperative epidural steroid injections lead to cerebrospinal fluid leaks confirmed during spinal stenosis surgery Surg Neurol Int 2014 5 Suppl 7 S325 8 25289153 \n8 Epstein NE Hemostasis and other benefits of fibrin sealants/glues in spine surgery beyond cerebrospinal fluid leak repairs Surg Neurol Int 2014 5 Suppl 7 S304 14 25289150 \n9 Hannalah D Lee J Khan M Donaldson WF Kang JD Cerebrospinal fluid leaks following cervical spine surgery J Bone Joint Surg Am 2008 90 1101 5 18451403 \n10 Jankowitz BT Atteberry DS Gerszten PC Karausky P Cheng BC Faught R Effect of fibrin glue on the prevention of persistent cerebral spinal fluid leakage after incidental durotomy during lumbar spinal surgery Eur Spine J 2009 18 1169 74 19283413 \n11 Miscusi M Polli FM Forcato S Coman MA Ricciardi L Ramieri A The use of surgical sealants in the repair of dural tears during non-instrumented spinal surgery Eur Spine J 2014 23 1761 6 24384831 \n12 Mulder M Crosier J Dunn R Cauda equina compression by hydrogel dural sealant after a laminotomy and discectomy: Case report Spine (Phila Pa 1976) 2009 34 E144 8 19214084 \n13 Sekhar LN Natarajan SK Manning T Bhagawati D The use of fibrin glue to stop venous bleeding in the epidural space, vertebral venous plexus, and anterior cavernous sinus: Technical note Neurosurgery 2007 61 3 Suppl E51 17876220 \n14 Thavarajah D De Lacy P Hussain R Redfern RM Postoperative cervical cord compression induced by hydrogel (DuraSeal): A possible complication Spine (Phila Pa 1976) 2010 35 E25 6 20042944 \n15 Thoms RJ Marwin SE The role of fibrin sealants in orthopaedic surgery J Am Acad Orthop Surg 2009 17 727 36 19948697 \n16 Tofuku K Koga H Yanase M Komiya S The use of antibiotic-impregnated fibrin sealant for the prevention of surgical site infection associated with spinal instrumentation Eur Spine J 2012 21 2027 33 22820952 \n17 Wang HR Cao SS Jiang YQ Li JN Li XL Fu YG A comparison between “sandwich” and conventional methods of repairing spinal dura rupture Orthop Surg 2012 4 233 40 23109308 \n18 Wu J Jin Y Zhang J Shao H Yang D Chen J Hemostatic Techniques Following Multilevel PosteriorLumbar Spine Surgery: A Randomized Control Trial J Spinal Disord Tech 2014 27 442 6 24335723 \n19 Yeom JS Buchowski JM Shen HX Liu G Bunmaprasert T Riew KD Effect of fibrin sealant on drain output and duration of hospitalization after multilevel anterior cervical fusion: A retrospective matched pair analysis Spine (Phila Pa 1976) 2008 33 E543 7 18628695\n\n",
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"issue": "6(Suppl 4)",
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"keywords": "Fibrin sealant; hemostasis; laminectomy alone; length of stay; lumbar surgery; multilevel laminectomy; noninstrumented fusion; stenosis; tisseel",
"medline_ta": "Surg Neurol Int",
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"title": "Tisseel does not reduce postoperative drainage, length of stay, and transfusion requirements for lumbar laminectomy with noninstrumented fusion versus laminectomy alone.",
"title_normalized": "tisseel does not reduce postoperative drainage length of stay and transfusion requirements for lumbar laminectomy with noninstrumented fusion versus laminectomy alone"
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"abstract": "BACKGROUND\nImmunoglobulin G4-related disease is increasingly recognized as a systemic autoimmune disorder characterized by immunoglobulin G4-positive lymphocyte infiltration. Organ biopsy and histopathology are the most important diagnostic methods; however, the significance of a cytological examination in immunoglobulin G4-related disease cases is still unclear.\n\n\nMETHODS\nA 73-year-old Asian man who was a former tobacco smoker presented with progressive exertional dyspnea, systemic edema, and pericardial effusion. A cytological examination of his pericardial effusion detected three or four plasma cells per high-power field by Giemsa staining. Moreover, immunoglobulin G4-positive plasma cells were detected by immunostaining. Cardiac catheterization after pericardiocentesis revealed that both ventricular pressure traces showed an early diastolic dip and plateau. Positron-emission tomography with 18F-fluorodeoxyglucose imaging revealed inflammatory foci in his pericardium. A surgical pericardiectomy was performed and the resultant specimen showed significant immunoglobulin G4-positive plasma cell infiltration and marked fibrous thickening of his pericardium; therefore, a diagnosis of constrictive pericarditis due to immunoglobulin G4-related disease was made. Oral administration of 0.6-mg/kg/day prednisolone resolved his heart failure and he was discharged on foot 1 week later.\n\n\nCONCLUSIONS\nOur experience with this case indicates that cytological examination of pericardial effusion was useful in the diagnosis of immunoglobulin G4-related disease.",
"affiliations": "Department of Cardiovascular Medicine, Sendai Kousei Hospital, Sendai, Miyagi, Japan. horihori1015@gmail.com.;Department of Cardiovascular Medicine, Sendai Kousei Hospital, Sendai, Miyagi, Japan.;Department of Radiology, Sendai Kousei Hospital, Sendai, Miyagi, Japan.;Department of Respiratory Surgery, Sendai Kousei Hospital, Sendai, Miyagi, Japan.;Department of Pathology, Sendai Kousei Hospital, Sendai, Miyagi, Japan.;Department of Cardiovascular Medicine, Sendai Kousei Hospital, Sendai, Miyagi, Japan.",
"authors": "Horie|Kazunori|K|;Tada|Norio|N|;Yamaguchi|Keiichirou|K|;Inazawa|Keitarou|K|;Endo|Mareyuki|M|;Inoue|Naoto|N|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 115910.1186/s13256-016-1159-1Case ReportImmunoglobulin G4-related constrictive pericarditis identified by cytological examination of pericardial effusion: a case report Horie Kazunori +81-22-222-6181horihori1015@gmail.com 15Tada Norio noriotada@hotmail.com 1Yamaguchi Keiichirou yamakei@sendai-kousei-hospital.jp 2Inazawa Keitarou inazawa-ind@umin.ac.jp 3Endo Mareyuki mare-path@sendai-kousei-hospital.jp 4Inoue Naoto inouena@est.hi-ho.ne.jp 11 Department of Cardiovascular Medicine, Sendai Kousei Hospital, Sendai, Miyagi Japan 2 Department of Radiology, Sendai Kousei Hospital, Sendai, Miyagi Japan 3 Department of Respiratory Surgery, Sendai Kousei Hospital, Sendai, Miyagi Japan 4 Department of Pathology, Sendai Kousei Hospital, Sendai, Miyagi Japan 5 Division of Cardiovascular Medicine, Sendai Kousei Hospital, 4-15 Hirose-cho, Aoba-ku, Sendai, Miyagi 980-0873 Japan 20 12 2016 20 12 2016 2016 10 35912 5 2016 24 11 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nImmunoglobulin G4-related disease is increasingly recognized as a systemic autoimmune disorder characterized by immunoglobulin G4-positive lymphocyte infiltration. Organ biopsy and histopathology are the most important diagnostic methods; however, the significance of a cytological examination in immunoglobulin G4-related disease cases is still unclear.\n\nCase presentation\nA 73-year-old Asian man who was a former tobacco smoker presented with progressive exertional dyspnea, systemic edema, and pericardial effusion. A cytological examination of his pericardial effusion detected three or four plasma cells per high-power field by Giemsa staining. Moreover, immunoglobulin G4-positive plasma cells were detected by immunostaining. Cardiac catheterization after pericardiocentesis revealed that both ventricular pressure traces showed an early diastolic dip and plateau. Positron-emission tomography with 18F-fluorodeoxyglucose imaging revealed inflammatory foci in his pericardium. A surgical pericardiectomy was performed and the resultant specimen showed significant immunoglobulin G4-positive plasma cell infiltration and marked fibrous thickening of his pericardium; therefore, a diagnosis of constrictive pericarditis due to immunoglobulin G4-related disease was made. Oral administration of 0.6-mg/kg/day prednisolone resolved his heart failure and he was discharged on foot 1 week later.\n\nConclusion\nOur experience with this case indicates that cytological examination of pericardial effusion was useful in the diagnosis of immunoglobulin G4-related disease.\n\nKeywords\nIgG4-related diseaseCytological examinationConstrictive pericarditisPositron-emission tomographyCase reportissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nImmunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic inflammatory disease characterized by IgG4-positive lymphocyte infiltration that causes fibrosclerotic change in various tissues and organs [1, 2]. Although the diagnostic criteria for IgG4-RD include histopathological findings in a biopsy specimen [2], the significance of a cytological examination is still unknown. Here, we describe the case of a patient with IgG4-RD who presented with constrictive pericarditis (CP) that was identified by IgG4-positive plasma cells in pericardial effusion and was confirmed by a surgical pericardiectomy.\n\nCase presentation\nA 73-year-old Asian man, a former tobacco smoker with hypertension and diabetes, presented to the emergency department in our hospital with a 2-month history of progressive exertional dyspnea. He was diagnosed with congestive heart failure due to arterial fibrillation and tricuspid regurgitation; he had been hospitalized five times over the previous 5 years and had been treated with bisoprolol and furosemide. Pericardial friction rub or knock, or pericardial effusion was not detected in any previous hospitalizations. He had a family history of congestive heart failure, lung cancer, and gallbladder cancer. He was prescribed 2.5 mg bisoprolol, 40 mg furosemide, 60 mg azosemide, and 80 mg valsartan before the current illness. An initial physical examination on the first day of hospitalization revealed the following: blood pressure, 101/56 mmHg; pulse rate, 108 beats/minute; respiratory rate, 20 breaths/minute; body temperature, 37.0 °C; and oxygen saturation 95% while he was breathing room air. Jugular venous distension, Kussmaul’s sign, and leg edema were observed. A neurological examination did not reveal any abnormal objective findings. Chest radiography revealed bilateral pleural effusion with an increased cardiothoracic ratio of 84.4% (Fig. 1a). Laboratory tests indicated that his serum levels of immunoglobulin G (IgG) (1729 mg/dL) and its subclass IgG4 (122.0 mg/dL) were elevated. His serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone were all within normal limits. He was negative for an antinuclear antibody, an anti-deoxyribonucleic acid enzyme-linked immunosorbent assay, p-antineutrophil or c-antineutrophil cytoplasmic antibodies, and a lupus anticoagulant. Sputum acid-fast bacillus cultures and the tuberculin test were also negative.Fig. 1 The findings of chest X-ray and transthoracic echocardiography during hospitalization. a The chest X-ray on the first day of hospitalization showed an increased cardiothoracic ratio of 84.4% and bilateral pleural effusion. b The end-diastolic ventricular septal shift was still present after removal of the pericardial effusion, as evaluated by transthoracic echocardiography. c A chest X-ray after the administration of oral corticosteroid therapy detected a reduced cardiothoracic ratio of 73.4%. d Transthoracic echocardiography after the administration of oral corticosteroid therapy detected that the diastolic ventricular septal shift was improved at discharge\n\n\n\n\nTransthoracic echocardiography (TTE) demonstrated pericardial effusion with a pericardial cavity that was 24-mm thick. Pericardiocentesis revealed 900 mL of exudative effusion, Giemsa staining revealed three or four plasma cells per high-power field in the pericardial effusion (Fig. 2a), and IgG4-positive plasma cells were detected by immunostaining (Fig. 2b). Even after pericardial drainage, his symptoms persisted and TTE showed an end-diastolic ventricular septal shift (Fig. 1b). Cardiac catheterization revealed that both ventricular pressure traces showed an early diastolic dip and plateau. Moreover, significant reductions in both ventricular peak systolic pressures during inspiration were observed. Although intravenous furosemide and dobutamine infusion in addition to 15.0 mg of oral tolvaptan were prescribed, his symptoms were not resolved. Positron-emission tomography (PET) imaging detected an abnormal uptake of 18F-fluorodeoxyglucose (18F-FDG) in his pericardium as well as in his gastric wall and in his hilar lymph nodes (Fig. 3a). Serial horizontal cross-sectional images demonstrated 18F-FDG uptake in both sides of his pericardium (Fig. 3b–e).Fig. 2 The findings from cytological examination of the pericardial effusion. a Giemsa staining revealed three or four plasma cells per high-power field in the pericardial effusion (white arrows). b Immunoglobulin G4-positive plasma cells were detected in the pericardial effusion by immunostaining (black arrows)\n\n\nFig. 3 The inflammatory foci in the pericardium as detected by positron emission tomography with 18F-fluorodeoxyglucose. a Positron emission tomography imaging detected localized uptake of 18F-fluorodeoxyglucose in the pericardium (black arrows). b to e Serial horizontal cross-sectional images demonstrating the accumulation of 18F- fluorodeoxyglucose in both sides of the pericardium (white arrows)\n\n\n\n\nA thoracoscopic pericardiectomy was performed and a histopathological analysis demonstrated lymphoplasmacytic inflammation with scattered plasma cells among a fibrous stroma in specimens of the pericardium in hematoxylin and eosin-stained sections (Fig. 4a). Elastica Masson–Goldner-stained sections revealed fibrous thickening of the pericardium (Fig. 4b). Immunostaining showed an IgG4/IgG-positive plasma cell ratio of 42% (Fig. 4c and d). Although our patient’s serum IgG4 level did not reach the diagnostic criterion of >135.0 mg/dL, he was diagnosed as having IgG4-RD because of typical histopathological features and the clinical symptoms of CP [2]. He was administered 30 mg of oral prednisolone (0.6 mg/kg/day) for 2 weeks and the dose was gradually decreased over the following 2 months to a maintenance dose of 2.5 to 5.0 mg daily [2]. Soon after starting on prednisolone, his dyspnea and leg edema dramatically improved over a 1-week period. An X-ray showed the resolution of bilateral pleural effusion and a decreased cardiothoracic ratio to 73.4% (Fig. 1c). Moreover, TTE revealed that the end-diastolic ventricular septal shift had disappeared (Fig. 1d). He was discharged on foot 1 week after he had been introduced to corticosteroid therapy.Fig. 4 The histopathological appearance of the pericardium. a A hematoxylin and eosin-stained section of the pericardium showed lymphoplasmacytic inflammation with scattered plasma cells among a fibrous stroma (original magnification, ×200). b The elastica Masson–Goldner-stained section showed marked fibrous thickening of the pericardium extending into the fatty tissue (original magnification, ×40). c and d Formalin-fixed, paraffin-embedded tissue with immunostaining directed against immunoglobulin G (c) and immunoglobulin G4 (d); immunoglobulin G and immunoglobulin G4 staining, original magnifications, ×200. The ratio of immunoglobulin G4-positive plasma cells/immunoglobulin G-positive plasma cells was 42%\n\n\n\n\nDiscussion\nIgG4-RD may affect multiple organs in 60 to 90% of patients with IgG4-RD, including cardiovascular organs [3–5]; it responds positively to corticosteroid therapy [1]. Previous studies have suggested that CP could often develop after mediastinal or idiopathic retroperitoneal fibrosis due to IgG4-RD [5] and pleural and/or cardiac effusion was sometimes observed continuously [6]. However, few reports have assessed the effusion by cytological examination with immunostaining. Diagnostic criteria for IgG4-RD have been proposed as follows [2]: (1) typical tissue fibrosclerosis; (2) elevated serum IgG4 (>135 mg/dL); and (3) histopathological features, including lymphocyte infiltration and a high ratio of IgG4-positive plasma cells/IgG-positive plasma cells (>40%). In our case, our patient’s serum IgG4 level did not exceed the reference value; however, IgG4-positive lymphocytes in his cardiac effusion led us to perform further examinations of IgG4-RD. Because the findings of the cytological examination did not meet diagnostic criterion (3) properly, we performed an 18F-FDG-PET scanning to judge the extent of inflammatory foci [7–10]. The 18F-FDG-PET scanning showed abnormal uptake in atypical organs such as his pericardium, his gastric wall, and in his hilar lymph nodes, but not in his pancreas, his lacrimal and salivary glands, or kidneys that were reported as common sites of IgG4-RD [3]. Finally, we performed a thoracoscopic pericardiectomy because of 18F-FDG-PET findings.\n\nOnly a few studies have reported cytological examinations in patients with IgG4-RD. Kabara et al. [11] demonstrated a case of IgG4-RD in which IgG4-positive plasma cells were detected in the pericardial effusion by fine-needle aspiration cytology [11]. They diagnosed the case as having IgG4-RD and prescribed prednisolone; however, gallium scintigraphy showed no abnormal uptake and a histopathological evaluation was not performed. Therefore, they did not indicate the association between inflammatory foci and IgG4-related plasma cells in the pericardium. The possible reason for insufficient proof of inflammation was that gallium scintigraphy might have a low signal-to-noise ratio in diagnostic imaging of IgG4-RD [12]. On the other hand, a previous report demonstrated that 18F-FDG-PET revealed hypermetabolic lesions in 97.1% patients with IgG4-RD [13] and was a superior imaging modality for demonstrating the extent, compared to 67gallium scintigraphy [12]. Our case report suggested that 18F-FDG-PET scanning should be chosen to make a definitive histopathological diagnosis after identifying the presence of IgG4-RD by a cytological evaluation.\n\nConclusion\nWe report the rare case of a patient with IgG4-RD who presented with CP that was identified by a cytological examination in pericardial effusion and diagnosed by a histopathological analysis of the pericardium.\n\nAbbreviations\n18F-FDG\n18F-fluorodeoxyglucose\n\nCPConstrictive pericarditis\n\nIgGImmunoglobulin G\n\nIgG4Immunoglobulin G4\n\nIgG4-RDImmunoglobulin G4-related disease\n\nPETPositron-emission tomography\n\nTTETransthoracic echocardiography\n\nAcknowledgements\nNone.\n\nFunding\nThis work was not supported by any sponsor.\n\nAvailability of data and materials\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nKH and NT made the clinical diagnosis and interpreted the patient data. NI supervised the manuscript drafting. KH drafted the first manuscript, reviewed the literature, and was involved in the direct management of the patient. KY reported on the PET scans. KI performed a thoracoscopic pericardiectomy. ME made the histopathological diagnosis. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nEthical approval to report this paper was obtained from the institutional review board of the Sendai Kousei Hospital on 20 January 2016. The reference number is 27–33.\n==== Refs\nReferences\n1. Stone JH Zen Y Deshpande V IgG4-related disease N Engl J Med 2012 366 539 51 10.1056/NEJMra1104650 22316447 \n2. Umehara H Okazaki K Masaki Y Kawano M Yamamoto M Saeki T Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011 Mod Rheumatol 2012 22 21 30 10.3109/s10165-011-0571-z 22218969 \n3. Mori K Yamada K Konno T Inoue D Uno Y Watanabe M Pericardial Involvement in IgG4-related Disease Intern Med 2015 54 1231 5 10.2169/internalmedicine.54.3856 25986262 \n4. Okazaki K Tomiyama T Mitsuyama T Sumito K Uchida K Diagnosis and classification of autoimmune pancreatitis Autoimmun Rev 2014 13 451 8 10.1016/j.autrev.2014.01.010 24424184 \n5. Bahler C Hammoud Z Sundaram C Mediastinal fibrosis in a patient with idiopathic retroperitoneal fibrosis Interact Cardiovasc Thorac Surg 2008 7 336 8 10.1510/icvts.2007.166033 18218652 \n6. Ishida M Hodohara K Furuya A Fujishiro A Okuno H Yoshii M Horinouchi A Shirakawa A Harada A Iwai M Yoshida K Kagotani A Yoshida T Okabe H Concomitant occurrence of IgG4-related pleuritis and periaortitis: a case report with review of the literature Int J Clin Exp Pathol 2014 7 808 14 24551308 \n7. Nguyen VX De Petris G Nguyen BD Usefulness of PET/CT imaging in systemic IgG4-related sclerosing disease. A report of three cases JOP 2011 12 297 305 21546713 \n8. Ebbo M Grados A Guedj E Gobert D Colavolpe C Zaidan M 18 F-FDG PET/CT for staging and evaluation of treatment response in IgG4-related disease: a retrospective multicenter study Arthritis Care Res (Hoboken) 2014 66 86 96 10.1002/acr.22058 23836437 \n9. Taniguchi Y Ogata K Inoue K Terada Y Clinical implication of FDG-PET/CT in monitoring disease activity in IgG4-related disease Rheumatology (Oxford) 2013 52 1508 10.1093/rheumatology/ket182 23674816 \n10. Kamisawa T Okamoto A Funata N Clinicopathological features of autoimmune pancreatitis in relation to elevation of serum IgG4 Pancreas 2005 31 28 31 10.1097/01.mpa.0000167000.11889.3a 15968244 \n11. Kabara M Nakagawa N Chinda J Hirai T Nimura A Ota H Tanabe Y Fujino T Sato N Hasebe N Diagnosis of IgG4-related systemic disease by cytology of large pericardial effusion with fine needle aspiration Int J Cardiol 2011 148 392 3 10.1016/j.ijcard.2010.12.057 21194763 \n12. Nakatani K Nakamoto Y Togashi K Utility of FDG PET/CT in IgG4-related systemic disease Clin Radiol 2012 67 297 305 10.1016/j.crad.2011.10.011 22119099 \n13. Zhang J Chen H Ma Y Xiao Y Niu N Lin W Characterizing IgG4-related disease with 18 F-FDG PET/CT: a prospective cohort study Eur J Nucl Med Mol Imaging 2014 41 1624 34 10.1007/s00259-014-2729-3 24764034\n\n",
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"title": "Immunoglobulin G4-related constrictive pericarditis identified by cytological examination of pericardial effusion: a case report.",
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"affiliations": "*Division of Infection and Immunity, University College London, London United Kingdom; †Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; ‡Children's Infectious Diseases Clinical Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; §Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom; ||HJF-DAIDS, a Division of the Henry M Jackson Foundation for the Advancement of Military Medicine Inc, Contractor, NIAID, NIH, Department of Health and Human Services, Bethesda, MD; ¶Anova Health Institute, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa; and #Africa Centre for Health and Population Studies, University of KwaZulu Natal.",
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"mesh_terms": "D002675:Child, Preschool; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005260:Female; D016679:Genome, Viral; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D019562:Viral Load",
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"title": "Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.",
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"abstract": "Clozapine is the preferred antipsychotic used for the treatment of resistant schizophrenia with suicidal ideation. The drug is started at a low dose and gradually increased to a target dose of 300-450 mg/day. It is well known to cause agranulocytosis and neutropenia. Several cases of fatal sepsis have been reported in neutropenic patients and emphasis is placed on monitoring for agranulocytosis; however, clozapine also causes intestinal hypomotility and constipation, which if unrecognized can lead to intestinal obstruction, bowel necrosis, and intra-abdominal sepsis. Reduced behavioral pain reactivity in schizophrenics may alter the ability to express pain, potentially leading to a delay in the presentation for medical attention. We report a case of fatal intra-abdominal sepsis secondary to an unrecognized case of clozapine-related constipation.",
"affiliations": "Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.;Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA.",
"authors": "Oke|Vikram|V|;Schmidt|Frances|F|;Bhattarai|Bikash|B|;Basunia|Md|M|;Agu|Chidozie|C|;Kaur|Amrit|A|;Enriquez|Danilo|D|;Quist|Joseph|J|;Salhan|Divya|D|;Gayam|Vijay|V|;Mungikar|Prajakta|P|",
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"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S86716imcrj-8-189Case ReportUnrecognized clozapine-related constipation leading to fatal intra-abdominal sepsis – a case report Oke Vikram Schmidt Frances Bhattarai Bikash Basunia Md Agu Chidozie Kaur Amrit Enriquez Danilo Quist Joseph Salhan Divya Gayam Vijay Mungikar Prajakta Department of Pulmonary Medicine, Interfaith Medical Center, NY, USACorrespondence: Vikram Oke, Interfaith Medical Center, 1545 Atlantic Avenue, Brooklyn, NY 11213, USA, Email vikramoke@gmail.com2015 11 9 2015 8 189 192 © 2015 Oke et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Clozapine is the preferred antipsychotic used for the treatment of resistant schizophrenia with suicidal ideation. The drug is started at a low dose and gradually increased to a target dose of 300–450 mg/day. It is well known to cause agranulocytosis and neutropenia. Several cases of fatal sepsis have been reported in neutropenic patients and emphasis is placed on monitoring for agranulocytosis; however, clozapine also causes intestinal hypomotility and constipation, which if unrecognized can lead to intestinal obstruction, bowel necrosis, and intra-abdominal sepsis. Reduced behavioral pain reactivity in schizophrenics may alter the ability to express pain, potentially leading to a delay in the presentation for medical attention. We report a case of fatal intra-abdominal sepsis secondary to an unrecognized case of clozapine-related constipation.\n\nKeywords\nantipsychoticsclozapineschizophreniasyncopeconstipationsepsis\n==== Body\nIntroduction\nClozapine is an antipsychotic that is used to treat schizophrenia. It has minimal extrapyramidal side effects compared to first-generation antipsychotics.1 Several cases of fatal sepsis have been reported in neutropenic patients and emphasis is placed on monitoring for agranulocytosis.2 Clozapine-related constipation is a recognized side effect, but unfortunately not well known. If not recognized early, the consequences can be deleterious. We discuss just such a fatal case of intra-abdominal sepsis secondary to unrecognized clozapine constipation.\n\nCase report\nA 61-year-old Hispanic male with a history of undifferentiated schizophrenia was admitted to the intensive care unit after a rapid response team evaluated him in the psychiatric unit for a syncopal episode.\n\nThe patient was being managed in the psychiatry floor for agitation and aggressive behavior and had been there for 5 weeks before this presentation. Patient had multiple psychiatry admissions for similar reasons. At baseline, the patient was unable to speak in meaningful sentences but responded by answering “yes” or “no” to goal-directed questions.\n\nThe patient was on levothyroxine for hypothyroidism, which was well controlled with free thyroid-stimulating hormone of 1.20 for 2 weeks before the current presentation. He also had seizure disorder, which was being treated with divalproex sodium extended release 1,000 mg daily, and levetiracetam 750 mg twice daily.\n\nThe patient was being treated with clozapine for his schizophrenia. The treatment of the patient was started with clozapine 5 weeks back during the current psychiatric admission, and dose gradually increased to 150 mg everyday in the morning and 150 mg everyday in the evening. His evening dose was increased to 175 mg everyday in the evening 5 days before this presentation. He had glaucoma for which he was receiving dorzolamide/timolol eye drops. He was not on any other medications. He was given a regular diet and was encouraged to take plenty of fluids and fibers. He did not have any surgical history.\n\nThe patient was apparently well until the day of this presentation when the patient was noted to walk around the nursing station and appeared as if about to fall and developed a syncopal episode. The vitals were temperature 98°F (36.6°C), blood pressure 86/54 mmHg, pulse 127 beats/min, regular, respiratory rate 16 breaths/min, and oxygen saturation 100% while breathing ambient air. Intravenous access was obtained and normal saline of 500 mL bolus was administered. The patient became responsive within few minutes and tried to get up. He was moving all his limbs and did not appear to have any focal motor deficits. No seizure activity was noted. He was confused, agitated, and unable to provide any history. The patient was transferred to the intensive care unit.\n\nPhysical examination was significant for abdominal distension with hypoactive bowel sounds. Rectal examination revealed hard impacted stool in the rectal vault. Stool qualitative guaiac test was performed, which was negative.\n\nThe complete blood count revealed leukocyte count of 17,300/mm3 with neutrophil differential of 52% with absolute neutrophil count (ANC) of 9,000/mm3 with band neutrophils of 12%. Prior to the syncopal episode, the weekly leukocyte counts after the initiation of clozapine were as follows:\nWeek 1 – Leukocyte count 7,100/mm3 with neutrophil differential of 45% (ANC, 3,195/mm3).\n\nWeek 2 – Leukocyte count 6,600/mm3 with neutrophil differential of 61% (ANC, 4,026/mm3).\n\nWeek 3 – Leukocyte count 5,400/mm3 with neutrophil differential of 65% (ANC, 3,510/mm3).\n\nWeek 4 – Leukocyte count 5,200/mm3 with neutrophil differential of 60% (ANC, 3120/mm3).\n\nWeek 5 – Leukocyte count 6,500/mm3 with neutrophil differential of 67% (ANC, 4,355/mm3).\n\n\n\nHemoglobin was 18.6 g/dL, the baseline range was 13–14 g/dL. Comprehensive metabolic panel was significant for elevated blood urea nitrogen (BUN)/creatinine of 34/1.4; however, baseline BUN/creatinine range was 13.0–17.0/0.8–1.0. Liver function tests were within normal limits. Sodium, potassium, magnesium, and phosphorous were normal. Serum bicarbonate was low at 18 mmol/L with low serum chloride of 100 mmol/L and elevated anion gap of 17. Serum lactic acid was elevated at 115.4 mg/dL. Serum total protein, albumin, globulin, and creatine kinase were normal. Serum valproic level was 60 µg/mL, serum clozapine level was not available.\n\nElectrocardiogram revealed sinus tachycardia without any acute ST-T segment changes. Serum troponin I was normal.\n\nUrinalysis revealed high specific gravity, with no bacteria or elevated nitrate. Urine toxicology was negative.\n\nChest X-ray (Figure 1) was significant for elevated hemidiaphragm with low lung volumes and clear lung fields. Abdominal X-ray (Figure 2) revealed large amount of fecal content in the colon and dilated small bowel suggestive of bowel obstruction from fecal impaction. The patient was started on broad spectrum antibiotics after pan cultures were obtained and intravenous fluids were administered; however, he had a rapid decline in clinical status with worsening hypotension. Surgical evaluation was requested for possible surgical intervention of bowel obstruction; however, he was deemed to be too unstable for any surgical intervention. He was being managed as per surviving sepsis guidelines for septic shock.3 He developed cardiac arrest and unfortunately expired within 12 hours of presentation. The blood culture revealed Escherichia coli within 24 hours. Urine culture revealed no growth.\n\nThe patient did not have a prior history of constipation or fecal impaction, or any other risk factors for constipation. He was described as being minimally communicative, often mumbling incoherent words, and disorganized and aggressive at times.\n\nDiscussion\nClozapine is a second-generation antipsychotic with antagonistic actions at dopamine (D1, D2, D3, D4, D5), serotonin (5-HT1A, 5-HT2A, 5-HT2C), muscarinic (M1, M2, M3, M5), α1- and α2-adrenergic, and histamine (H1) receptors. Clozapine is an agonist at muscarinic (M4) receptors.1\n\nClozapine leads to minimal extrapyramidal symptoms compared to first-generation antipsychotics. It is a preferred medication in patients with treatment-resistant schizophrenia and also in schizophrenia with suicidal ideation.1\n\nTreatment is usually started at low doses of 12.5–25 mg once or twice daily and gradually increased by 25–50 mg/day until a target dose of approximately 200–400 mg/day is achieved.1,4\n\nClozapine is metabolized by CYP1A2 enzyme. If CYP 450 inducers and inhibitors have to be used in patients treated with clozapine, they should be used judiciously.1,4\n\nPatients should have baseline leukocyte, including ANCs, before treatment with clozapine is initiated and these should be monitored weekly for first 6 months and then every 2 weeks.4\n\nAgranulocytosis (ANC <1,000), severe orthostatic hypotension, bradycardia, syncope may occur with the use of clozapine. Fatal cases of myocarditis/cardiomyopathy have also occurred. Clozapine is not approved for dementia-related psychosis.2,5,6\n\nConstipation can occur in up to 60% of patients treated with clozapine.7 Ileus is seen in close to 1.3% of patients treated with clozapine.8 Gastric outlet obstruction can occur in up to 33% of patients treated with clozapine. There have been case reports on fatal bowel ischemia on patients treated with clozapine.9–11 Mortality from complications secondary to constipation is higher with clozapine than other antipsychotic medications.12–14 These side effects can be explained by the antimuscarinic action of clozapine. Concomitant use of other antidepressants, antipsychotics, poor dietary habits with low fiber diets, and sedentary lifestyle seem to compound this problem.15 The prevalence and severity of constipation may be dose dependent.16 Doses that cause serum levels to increase above 500 mg/dL are not advised and should be lowered to target the serum level between 200 and 400 mg/dL.1,17 However, recent data indicate that there is minimal correlation between clozapine levels and side effects except for sedation, hypotension, and seizure activity, and that monitoring clozapine levels might be indicated when >600 mg/day doses are prescribed, there is a change in concomitant medications or cigarette use or suboptimal therapeutic response.18 CYP inhibitors should be avoided as they could worsen these side effects potentially by increasing serum levels of clozapine. Whether schizophrenic patients are relatively insensitive to pain is debatable. It has been reported that up to 37% of schizophrenic patients with acute appendicitis and up to 21% of patients with perforated peptic ulcer did not report pain, which led to surgical intervention late in the course of the disease.19–21 Recent studies have shown that there is little evidence to support the relative pain insensitivity in these patients. However, behavioral reactivity to pain and self-reported response to pain may be reduced. Negative symptoms of schizophrenia may alter the ability of patients from expressing pain.22 These factors may potentially lead to the delay in presentation for medical attention. Physicians should maintain a high level of suspicion of serious medical illnesses during evaluation of schizophrenic patients.23–27 Our patient was minimally communicative and likely could not report constipation by himself. Upon questioning, he denied having any pain or discomfort; however, there was no emphasis laid on asking specifically about constipation.\n\nThese symptoms of constipation may be trivialized and may not be appreciated as precursors of a possible fatal condition in the background of a psychotic condition.28 Constipation could lead to intestinal obstruction with resulting bowel necrosis.10 In the absence of an autopsy, it is very difficult to establish an exact diagnosis, but we hypothesize that fatal sepsis resulted from bacterial translocation secondary to clozapine induced constipation or its sequelae-like bowel obstruction, infarction.\n\nConclusion\nConstipation is a recognized side effect of clozapine, which unfortunately is not as well known as it should be. Reduced behavioral reactivity to pain may alter the ability of patients to express pain. With the increasing use of clozapine for treatment of resistant schizophrenia, patients should be monitored for the development of constipation as it may herald a life-threatening complication. Physicians involved in the care of patients treated with clozapine should have a high index of suspicion for constipation and intestinal obstruction, and a bowel chart may be used for the daily assessment of admitted patients treated with clozapine. Increased fluid and fiber intake could be protective.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Chest X-ray showing clear lung fields with low lung volumes (yellow arrows), elevated hemi diaphragm (black arrow).\n\nFigure 2 Abdominal X-ray with dilated small bowel (yellow arrows) and fecal impaction (black arrows).\n==== Refs\nReferences\n1 American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia 2nd ed Arlington, VA American Psychiatric Association 2004 73 77 \n2 Alvir JM Lieberman JA Safferman AZ Schwimmer JL Schaaf JA Clozapine-induced agranulocytosis – incidence and risk factors in the United States N Engl J Med 1993 329 3 162 167 8515788 \n3 Dellinger RP Levy MM Rhodes A Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 Crit Care Med 2013 41 2 580 637 23353941 \n4 Novartis Pharmaceuticals Corporation Clairol Prescribing Information East Hanover, NJ Novartis Pharmaceuticals Corporation 2003 Available from: http://www.clozaril.com \n5 Marinkovic D Timotijevic I Babinski T Totic S Paunovic VR The side-effects of clozapine: a four year follow-up study Prog Neuropsychopharmacol Biol Psychiatry 1994 18 3 537 544 8078987 \n6 Safferman A Lieberman JA Kane JM Szymanski S Kinon B Update on the clinical efficacy and side effects of clozapine Schizophr Bull 1991 17 2 247 261 1882209 \n7 Young CR Bowers MB Mazure CM Management of the adverse effects of clozapine Schizophr Bull 1998 24 3 381 390 9718630 \n8 Lu MK Clinical analysis in the main side effects of clozapine: enclosed 600 cases report Zhonghua Shen Jing Jing Shen Ke Za Zhi 1991 24 2 71 74 Chinese 1860384 \n9 Bourgeois OD James A Clozapine, fluoxetine, and benztropine-associated ileus: case report Jefferson J Psychiatry 2007 21 1 1 \n10 Tang WK Ungvari GS Clozapine-induced intestinal obstruction Aust N Z J Med 1999 29 4 560 560 10868537 \n11 Townsend G Curtis D Case report: rapidly fatal bowel ischaemia on clozapine treatment BMC Psychiatry 2006 6 1 43 17052340 \n12 Cohen D Bogers JP van Dijk D Bakker B Schulte PF Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy J Clin Psychiatry 2012 73 10 1307 1312 23140648 \n13 De Hert M Hudyana H Dockx L Second-generation antipsychotics and constipation: a review of the literature Eur Psychiatry 2011 26 1 34 44 20542667 \n14 Baptista T A fatal case of ischemic colitis during clozapine administration Rev Bras Psiquiatr 2014 36 4 358 358 25517419 \n15 Nielsen J Meyer JM Risk factors for ileus in patients with schizophrenia Schizophr Bull 2012 38 3 592 598 21112965 \n16 Pare J Riffand P Baurdeix I The clozapine in France Inf Psychiatr 1993 4 389 397 \n17 Perry PJ Miller DD Arndt SV Cadoret RJ Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients Am J Psychiatry 1991 148 2 231 235 1670979 \n18 Stark A Scott J A review of the use of clozapine levels to guide treatment and determine cause of death Aust N Z J Psychiatry 2012 46 9 816 825 22327098 \n19 Dworkin RH Pain insensitivity in schizophrenia: a neglected phenomenon and some implications Schizophr Bull 1994 20 235 248 8085127 \n20 Marchand WE Sarota B Marble HC Leary TM Burbank CB Bellinger MJ Occurrence of painless acute surgical disorders in psychotic patients N Engl J Med 1959 260 12 580 585 13632932 \n21 West BM Hecker AO Peptic ulcer: incidence and diagnosis in psychotic patients Am J Psychiatry 1952 109 1 35 37 14923922 \n22 Pelizza L De Luca P La Pesa M Borella D Clozapine-induced intestinal occlusion: a serious side effect Acta Biomed 2007 78 2 144 148 17933283 \n23 Singh MK Giles LL Nasrallah HA Pain insensitivity in schizophrenia: trait or state marker? J Psychiatr Pract 2006 12 2 90 102 16728905 \n24 Bonnot O Tordjman S Schizophrenia and pain reactivity Presse Med 2008 37 11 1561 1568 French 18774679 \n25 Autié A Montreuil M Moulier V Braha S Wojakiewicz A Januel D Pain and schizophrenia: myth and reality Encephale 2009 35 4 297 303 French 19748365 \n26 Bonnot O Anderson GM Cohen D Willer JC Tordjman S Are patients with schizophrenia insensitive to pain? A reconsideration of the question Clin J Pain 2009 25 3 244 252 19333176 \n27 Rosenthal SH Porter KA Coffey B Pain insensitivity in schizophrenia: case report and review of the literature Gen Hosp Psychiatry 1990 12 5 319 322 2210350 \n28 Levin TT Barrett J Mendelowitz A Death from clozapine-induced constipation: case report and literature review Psychosomatics 2002 43 1 71 73 11927763\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-142X",
"issue": "8()",
"journal": "International medical case reports journal",
"keywords": "antipsychotics; clozapine; constipation; schizophrenia; sepsis; syncope",
"medline_ta": "Int Med Case Rep J",
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"nlm_unique_id": "101566269",
"other_id": null,
"pages": "189-92",
"pmc": null,
"pmid": "26392790",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "1882209;22327098;13632932;18774679;19333176;19748365;25517419;1860384;8078987;21112965;10868537;17052340;8515788;9718630;11927763;17933283;1670979;8085127;14923922;2210350;20542667;16728905;23140648;23353941",
"title": "Unrecognized clozapine-related constipation leading to fatal intra-abdominal sepsis - a case report.",
"title_normalized": "unrecognized clozapine related constipation leading to fatal intra abdominal sepsis a case report"
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"abstract": "This paper presents autopsy findings of 3 COVID-19 patients randomly selected for post-mortem from two tertiary referral Polish hospitals. Analysis of macroscopic, histopathological findings with clinical features was performed. All 3 deceased patients were Caucasian males (average age 61 years, range from 56 to 68 years). Using real-time polymerase chain reaction assay, the patients were confirmed (antemortem) to have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Two patients were obese, and 1 patient had type 2 diabetes mellitus. The medical history of 1 patient included hemorrhagic pancreatitis, gangrenous cholecystitis, Acinetobacter baumanii sepsis, and cholecystectomy. Pulmonary embolism was diagnosed in 2 patients. At autopsy, in 1 case, the lungs showed bilateral interstitial pneumonia with diffuse alveolar damage (DAD), while in another case, interstitial pulmonary lymphoid infiltrates and enlarged atypical pneumocytes were present but without DAD. Microthrombi in lung vessels and capillaries were observed in 2 cases. This study revealed thrombotic complications of COVID-19 and interstitial pneumonia with DAD presence as the main autopsy findings in patients with SARS-CoV-2 infection that was confirmed antemortem with molecular tests. Autopsy studies using tissue sections handled in accordance with SARS-CoV-2 biosafety guidelines are urgently needed, especially in the case of subjects who were below the age of 60.",
"affiliations": "Tumor Pathology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland, ewachmielik@gmail.com.;Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland.;Chair of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland.;Pathomorphology Department, Central Clinical Hospital of the MSWiA in Warsaw, Warsaw, Poland.;Pathomorphology Department, Central Clinical Hospital of the MSWiA in Warsaw, Warsaw, Poland.;Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland.;Chair of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland.",
"authors": "Chmielik|Ewa|E|;Jazowiecka-Rakus|Joanna|J|;Dyduch|Grzegorz|G|;Nasierowska-Guttmejer|Anna|A|;Michalowski|Lukasz|L|;Sochanik|Aleksander|A|;Ulatowska-Bialas|Magdalena|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000512768",
"fulltext": null,
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"issn_linking": "1015-2008",
"issue": "88(1)",
"journal": "Pathobiology : journal of immunopathology, molecular and cellular biology",
"keywords": "Autopsy; COVID-19; Diffuse alveolar damage; Pulmonary embolism",
"medline_ta": "Pathobiology",
"mesh_terms": "D000328:Adult; D000368:Aged; D001344:Autopsy; D000086382:COVID-19; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D000086402:SARS-CoV-2",
"nlm_unique_id": "9007504",
"other_id": null,
"pages": "78-87",
"pmc": null,
"pmid": "33254171",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "COVID-19 Autopsies: A Case Series from Poland.",
"title_normalized": "covid 19 autopsies a case series from poland"
} | [
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"abstract": "BACKGROUND\nSARS-CoV-2 infection has been associated with various neurological manifestations. Since patients affected by SARS-CoV-2 infection present coagulation and immune system dysregulation, ischemic or haemorragic stroke is not uncommon, irrespective of respiratory distress. However, the occurrence of focal neurological deficits together with other symptoms like headache, cortical blindness, seizure and altered mental status should prompt the diagnosis of Posterior Reversible Encephalopathy Syndrome (PRES). Antithrombotic treatment, the alteration of endothelial function, and coagulopathy due to COVID-19 and PRES leading to the breakdown of blood-brain barrier may then contribute to the occurrence of a brain haemorrhage.\n\n\nMETHODS\nWe describe the case of a COVID-19 patient who developed bilateral occipital lobe haemorrhages suggestive of haemorrhagic PRES. We then reviewed the available literature about haemorrhagic evolution of PRES in COVID-19.\n\n\nRESULTS\nWe describe the clinical and radiological features of five COVID-19 patients who developed haemorrhagic PRES.\n\n\nCONCLUSIONS\nCoagulopathy and endothelial dysfunction resulting from the massive release of cytokines during the host immune response may be key factors in the pathogenesis of COVID-19-related PRES. Antithrombotic therapy and the leakage of the blood-brain barrier can subsequently increase the risk of haemorrhagic transformation of the lesioned brain tissue. A prompt diagnosis of PRES is mandatory, since the timely interruption/reversal of antithrombotic therapy may be a key determinant for a good prognosis.",
"affiliations": "Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy. f.motolese@unicampus.it.;Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy.;Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy.;Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy.;Departmental Faculty of Medicine and Surgery, Unit of Diagnostic Imaging and Interventional Radiology, Università Campus Bio-Medico di Roma, Rome, Italy.;Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy.;Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy.;Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy.;Emergency Department, Università Campus Bio-Medico di Roma, Rome, Italy.;Division of Geriatric Medicine, Università Campus Bio-Medico di Roma, Rome, Italy.;Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy.;Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, Viale Alvaro del Portillo, 21, 00128, Rome, Italy.",
"authors": "Motolese|Francesco|F|http://orcid.org/0000-0003-1542-3738;Ferrante|Mario|M|;Rossi|Mariagrazia|M|;Magliozzi|Alessandro|A|;Sbarra|Martina|M|;Ursini|Francesca|F|;Marano|Massimo|M|;Capone|Fioravante|F|;Travaglino|Francesco|F|;Antonelli Incalzi|Raffaele|R|;Di Lazzaro|Vincenzo|V|;Pilato|Fabio|F|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-021-10709-0",
"fulltext": null,
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"issn_linking": "0340-5354",
"issue": "268(12)",
"journal": "Journal of neurology",
"keywords": "COVID-19; Haemorrhage; PRES; Posterior Reversible Encephalopathy Syndrome; SARS-CoV-2",
"medline_ta": "J Neurol",
"mesh_terms": "D000086382:COVID-19; D006801:Humans; D020300:Intracranial Hemorrhages; D054038:Posterior Leukoencephalopathy Syndrome; D000086402:SARS-CoV-2; D012640:Seizures",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "4407-4414",
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"pmid": "34291313",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "32622375;33743344;33378608;32822622;33484980;31445327;26184985;17698535;5533845;29849301;32117007;6374982;21703874;33630183;7051550;28289809;32302442;32882182;32432996;32819899;33264547;32381264;32306492;32415579;32681845;7172722;32852642;33161843;32558075;33331467;32439646",
"title": "Posterior Reversible Encephalopathy Syndrome and brain haemorrhage as COVID-19 complication: a review of the available literature.",
"title_normalized": "posterior reversible encephalopathy syndrome and brain haemorrhage as covid 19 complication a review of the available literature"
} | [
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"abstract": "Imiquimod is an immunomodifier recently approved for the treatment of superficial basal cell carcinomas (sBCC). Although local adverse events (AEs) are the most commonly reported, systemic AEs have also been described. We present the case of a 60-year-old woman who, after the application of two sachets of imiquimod cream per day for 5 days/week to two large sBCCs, developed pemphigus-like lesions both at and distant from the application site. Histological examination of a skin biopsy found intraepidermal acantholytic blistering but results of direct immunofluorescence examination were negative. The lesions resolved after cessation of imiquimod. Two previous cases of imiquimod-induced pemphigus have been reported, but this is the first case with lesions distant from the site of application. We suggest that systemic absorption of the drug or greatly increased synthesis of cytokines could explain this reaction and recommend the use of low doses of imiquimod in the treatment of large or multiple sBCCs.",
"affiliations": "Department of Dermatology, Son Dureta University Hospital, Palma de Mallorca, Mallorca, Spain. abauza@aedv.es",
"authors": "Bauza|A|A|;Del Pozo|L J|LJ|;Saus|C|C|;Martin|A|A|",
"chemical_list": "D000634:Aminoquinolines; D000970:Antineoplastic Agents; D000077271:Imiquimod",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2230.2008.03181.x",
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"issn_linking": "0307-6938",
"issue": "34(5)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002280:Carcinoma, Basal Cell; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D000077271:Imiquimod; D008875:Middle Aged; D010392:Pemphigus; D012878:Skin Neoplasms",
"nlm_unique_id": "7606847",
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"pages": "e60-2",
"pmc": null,
"pmid": "19438577",
"pubdate": "2009-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pemphigus-like lesions induced by imiquimod.",
"title_normalized": "pemphigus like lesions induced by imiquimod"
} | [
{
"companynumb": "ES-BAUSCH-BL-2019-022940",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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"activesubstance": {
"activesubstancename": "IMIQUIMOD"
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{
"abstract": "Simultaneous bilateral acute angle closure crisis (AACC) is a sight-threatening ocular emergency. Many \"cold and flu\" preparations contain compounds with sympathomimetic or anticholinergic qualities that confer a risk of inducing AACC. We present a review of cold and flu preparation-induced AACC, and present a case of simultaneous bilateral AACC triggered by a single oral dose of pseudoephedrine. The challenges facing the clinician in recognizing simultaneous bilateral AACC in the context of an upper respiratory tract infection are addressed. An awareness of this uncommon clinical entity, its pertinent clinical features, risk factors, and the drug classes that may precipitate an attack is critical for the timely diagnosis and management of this ocular emergency. Notably, clinicians must be aware that even a single dose of an implicated medication may trigger an attack of AACC.",
"affiliations": "Training Medical Officer Unit, Flinders Medical Centre, Adelaide, South Australia, Australia.;Neurology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.;Neurology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.;Ophthalmology Department, Flinders Medical Centre, Adelaide, South Australia, Australia.",
"authors": "Spencer|Benjamin G|BG|;Baskin|Jonathan|J|;Giarola|Blake F|BF|;Craig|Jamie E|JE|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000503854",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com 10.1159/000503854cop-0010-0365Case ReportSingle Dose of Pseudoephedrine Induces Simultaneous Bilateral Acute Angle Closure Crisis Spencer Benjamin G. a*Baskin Jonathan bGiarola Blake F. bCraig Jamie E. caTraining Medical Officer Unit, Flinders Medical Centre, Adelaide, South Australia, AustraliabNeurology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, AustraliacOphthalmology Department, Flinders Medical Centre, Adelaide, South Australia, Australia*Dr. Benjamin G. Spencer, Training Medical Officer Unit, Flinders Medical Centre, Flinders Drive, Bedford Park, Adelaide, SA 5042 (Australia), E-Mail benjamin.spencer@sa.gov.auSep-Dec 2019 24 10 2019 24 10 2019 10 3 365 368 10 8 2019 2 10 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This 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.Simultaneous bilateral acute angle closure crisis (AACC) is a sight-threatening ocular emergency. Many “cold and flu” preparations contain compounds with sympathomimetic or anticholinergic qualities that confer a risk of inducing AACC. We present a review of cold and flu preparation-induced AACC, and present a case of simultaneous bilateral AACC triggered by a single oral dose of pseudoephedrine. The challenges facing the clinician in recognizing simultaneous bilateral AACC in the context of an upper respiratory tract infection are addressed. An awareness of this uncommon clinical entity, its pertinent clinical features, risk factors, and the drug classes that may precipitate an attack is critical for the timely diagnosis and management of this ocular emergency. Notably, clinicians must be aware that even a single dose of an implicated medication may trigger an attack of AACC.\n\nKeywords\nAngle closureGlaucomaPseudoephedrineDecongestants\n==== Body\nIntroduction\nAcute angle closure crisis (AACC) is a sight-threatening ocular emergency. It typically presents as acute unilateral ocular/periocular pain and headache with rapidly progressive visual loss, sometimes associated with nausea and vomiting [1]. Examination of the affected eye typically reveals a mid-dilated unreactive or sluggish pupil, ciliary injection, a shallow anterior chamber, markedly reduced visual acuity (6/60 to hand motion), markedly raised intraocular pressure (above 50 mm Hg), and corneal haze due to corneal oedema [1]. AACC occurs due to occlusion of the trabecular meshwork by the peripheral iris, thus preventing outflow of aqueous humour from the anterior chamber of the eye [1]. This occlusion may be precipitated by a medication (typically a mydriatic) in an individual with ocular anatomy that predisposes them to AACC. Anatomical risk factors include having a small anterior segment (commonly seen in hypermetropes) and a crowded anterior segment which is usually due to an enlarged crystalline lens through normal ageing or cataract [2]. AACC is more prevalent in women and in East Asian and Inuit populations relative to Caucasian populations [1, 2, 3].\n\nAACC can be triggered by numerous drug classes. Mydriasis is the mechanism of closure for adrenergic agonists, anticholinergics, and drugs with anticholinergic side effects [4]. Cholinergic agents may also induce AACC through anterior movement of the lens-iris diaphragm [4]. Sulfa-based drugs can induce AACC by causing ciliary body oedema and anterior displacement of the lens-iris diaphragm [4]. Cabergoline, a potent dopamine receptor agonist, has been implicated in one case of bilateral AACC with ciliary body effusion and anterior rotation postulated as possible mechanisms [5]. Oral, inhaled, intranasal, and topical preparations of the aforementioned classes may all induce AACC [6].\n\nOur literature review revealed that numerous remedies for “cold and flu” symptoms have been implicated in triggering AACC. Cold and flu remedies often contain sympathomimetics aimed at causing vasoconstriction of blood vessels in the nasal mucosa to reduce secretions and congestion [7], and antihistamines (with anticholinergic side effects) aimed at blocking histamine release and subsequent coryzal symptoms [8]. In a case series of 72 patients presenting with AACC to a hospital in Hong Kong, 6 of these patients had taken “antitussive” agents which may have contained anticholinergic components [3]. A case of unilateral AACC was reported in a middle-aged man triggered by a cold preparation containing dextromethorphan (an opiate), promethazine (an antihistamine with anticholinergic side effects), and phenylpropanolamine (a sympathomimetic) [9]. Four cases of simultaneous bilateral AACC precipitated by cold and flu medications are reported in the medical literature. One case involved a middle-aged man who took over-the-counter nasal drops containing the adrenergic sympathomimetics, phenylephrine and naphazoline [10]. Another case involved a middle-aged woman who took a preparation containing Atropa belladonna, a herb with anticholinergic properties [2]. The third case involved a middle-aged man who took tablets containing the α-1 adrenergic receptor agonist, phenylephrine, and an antihistamine with anticholinergic properties, pheniramine maleate [11]. The fourth case was precipitated by a 5-day course of oral pseudoephedrine, a selective α-1 adrenergic receptor agonist [12].\n\nWe present a case of simultaneous bilateral AACC in a middle-aged woman triggered by the use of over-the-counter cold and flu preparation, Mucinex D®, containing pseudoephedrine hydrochloride 60 mg and an expectorant, guaifenesin 600 mg. To our knowledge, this is the second published case of bilateral AACC induced by oral pseudoephedrine, and the first reported case of AACC precipitated by a single dose of a cold and flu remedy.\n\nCase Report\nA 59-year-old lady presented to a tertiary hospital emergency department with a 2-day history of blurred vision and headache in the context of an upper respiratory tract infection. She had taken a single tablet of “Mucinex D” prior to the onset of her visual disturbance. She denied any ocular trauma and had no significant ophthalmic history. Her medical history was only significant for hypothyroidism for which she took thyroxine as her only regular medication. On examination, her visual acuity (pinhole) was 6/60 + 2 on the right and hand motion on the left. The conjunctivae were injected bilaterally, and both pupils were mid-dilated and unreactive to light. The patient was referred to the neurology service for further assessment. The neurology service promptly referred the patient to the ophthalmology service given concerns of possible AACC.\n\nFurther ophthalmic assessment revealed bilaterally oedematous corneas, shallow anterior chambers, and intraocular pressures of 53 and 51 mm Hg on the right and left, respectively. A diagnosis of simultaneous bilateral AACC was made. She received acetazolamide 500 mg i.v. in addition to brinzolamide, brimonidine, latanoprost, timolol, and pilocarpine drops. She then underwent bilateral YAG peripheral iridotomy with argon-pre-treatment. Post-procedure pressures were 9 and 32 mm Hg on the right and left, respectively. She was commenced on dexamethasone 0.1% topically bilaterally q.i.d., travoprost topically in the left eye only, and continued on the timolol and brinzolamide topically in the left eye only. The following day her visual acuity (pinhole) was 6/9 + 1 and 6/15 in the right and left eyes, respectively. Her pressures were 7 and 8 mm Hg, respectively.\n\nDiscussion/Conclusion\nSimultaneous bilateral AACC is an uncommon but sight-threatening condition for which clinicians must be highly vigilant. This is particularly the case in patients presenting with symptoms in the context of an upper respiratory tract infection for which a decongestant preparation has been used by the patient. The symptomology of simultaneous bilateral AACC, including headache, ocular pain, and red eye, may overlap with the flu-like symptoms for which the medications that might trigger AACC are taken. Furthermore, blurred vision is a well-recognised side effect of anticholinergic and sympathomimetic decongestants, and thus this symptom may not alert the patient or clinician to the seriousness of the situation. The simultaneous bilateral onset of visual disturbance may erroneously lead a clinician away from suspecting an ophthalmic process in favour of a central neurological pathology, as initially occurred in this case. As was also illustrated by this case, obtaining a complete drug history is imperative, as even a single dose of an over-the-counter preparation can precipitate AACC. The progressive nature of symptoms after taking an implicated medication should prompt the clinician to consider simultaneous bilateral AACC as a possible diagnosis. Urgent ophthalmological assessment is indicated in suspected cases.\n\nStatement of Ethics\nThis case complies with the tenets of the Declaration of Helsinki. The patient gave written informed consent for the publication of this case report.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNo funding was received or utilised in relation to the preparation of this case report.\n\nAuthor Contributions\nBenjamin J. Spencer: drafting of the manuscript, patient consenting, and literature review. Jonathan Baskin: patient assessment and manuscript review. Blake F. Giarola: patient assessment, data collection, and manuscript review. Jamie E. Craig: review of the manuscript, provision of specialist knowledge in analysis of the case, and interpretation of significance in the context of the literature review.\n==== Refs\nReferences\n1 Ah-Kee EY Egong E Shafi A Lim LT Yim JL A review of drug-induced acute angle closure glaucoma for non-ophthalmologists Qatar Med J 2015 5 2015 (1) 6 26535174 \n2 Rudkin AK Gray TL Awadalla M Craig JE Bilateral simultaneous acute angle closure glaucoma precipitated by non-prescription cold and flu medication Emerg Med Australas 2010 10 22 (5) 477 9 21040488 \n3 Lai JS Liu DT Tham CC Li RT Lam DS Epidemiology of acute primary angle-closure glaucoma in the Hong Kong Chinese population: prospective study Hong Kong Med J 2001 6 7 (2) 118 23 11514744 \n4 Tripathi RC Tripathi BJ Haggerty C Drug-induced glaucomas: mechanism and management Drug Saf 2003 26 (11) 749 67 12908846 \n5 Razmjoo H Rezaei L Dehghani A Peyman A Akhlaghi M Bilateral angle-closure glaucoma in a young female receiving cabergoline: a case report Case Rep Ophthalmol 2011 1 2 (1) 30 3 21347189 \n6 Lai JS Gangwani RA Medication-induced acute angle closure attack Hong Kong Med J 2012 4 18 (2) 139 45 22477738 \n7 Johnson DA Hricik JG The pharmacology of alpha-adrenergic decongestants Pharmacotherapy 1993 Nov-Dec 13 (6 Pt 2) 110S 5S 7507588 \n8 De Sutter AI Lemiengre M Antihistamines for the common cold. Cochrane Database Syst Rev [Internet] 2003 Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001267/abstract \n9 Barrett V Jordan T Angle closure risk from proprietary medicines Eye (Lond) 2001 4 15 (Pt 2) 248 9 11339612 \n10 Khan MA Watt LL Hugkulstone CE Bilateral acute angle-closure glaucoma after use of Fenox nasal drops Eye (Lond) 2002 9 16 (5) 662 3 12194094 \n11 Nicoară SD Damian I Bilateral simultaneous acute angle closure attack triggered by an over-the-counter flu medication Int Ophthalmol 2018 8 38 (4) 1775 8 28669099 \n12 Ah-Kee EY Li Yim JF Bilateral acute angle closure glaucoma precipitated by over the counter oral decongestant Int J Ophthalmol 2014 4 7 (2) 387 8 24790890\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "10(3)",
"journal": "Case reports in ophthalmology",
"keywords": "Angle closure; Decongestants; Glaucoma; Pseudoephedrine",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "365-368",
"pmc": null,
"pmid": "31762769",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11339612;12194094;22477738;24790890;7507588;12917904;26535174;11514744;28669099;21040488;12908846;21347189",
"title": "Single Dose of Pseudoephedrine Induces Simultaneous Bilateral Acute Angle Closure Crisis.",
"title_normalized": "single dose of pseudoephedrine induces simultaneous bilateral acute angle closure crisis"
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"activesubstancename": "GUAIFENESIN"
},
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"abstract": "Ceftaroline is a broad-spectrum, methicillin-resistant Staphylococcus aureus (MRSA)-active β-lactam approved for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired pneumonia. Because of its favorable spectrum and pharmacokinetics, ceftaroline is frequently utilized for infections such as osteomyelitis and endocarditis. Ceftaroline has been associated with neutropenia, but evaluation of other adverse events remains limited.\n\n\n\nTo describe the rates and types of ceftaroline-associated adverse events and determine if patients' baseline allergies affect the rates of an adverse event.\n\n\n\nA single-center, retrospective, observational analysis was conducted of all patients who received ceftaroline between November 4, 2011, and March 28, 2017, at the VA Saint Louis Health Care System. The Naranjo algorithm was utilized as a standardized method to evaluate likelihood that the adverse events were caused by ceftaroline therapy. Ceftaroline dose, duration, indication, and baseline allergy information were collected for all patients.\n\n\n\nThere were 75 patients who received 78 courses of ceftaroline identified for inclusion. The most common indications were osteomyelitis (51.3%) and ABSSSI (16.7%). Overall, 13/75 (17.3%) patients developed an adverse event, and 10/75 (13.3%) required discontinuation of ceftaroline. Rash was the most common adverse reaction and occurred in 7/75 (9.3%) patients, followed by neutropenia in 3/75 (4.0%) patients. There were no differences in baseline allergy characteristics between patients who experienced an adverse reaction to ceftaroline and those who did not.\n\n\n\nWhen compared with clinical trials, ceftaroline use appears to be associated with an increased rate of overall adverse events, which is driven by cutaneous reactions.",
"affiliations": "1 SCL Saint Vincent Healthcare, Billings, MT, USA.;2 VA Saint Louis Health Care System, Saint Louis, MO, USA.",
"authors": "Jansen|Jeffrey W|JW|;Moenster|Ryan P|RP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C490727:T 91825",
"country": "United States",
"delete": false,
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"issue": "52(3)",
"journal": "The Annals of pharmacotherapy",
"keywords": "adverse events; ceftaroline; neutropenia; rash; toxicity",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D005076:Exanthema; D005260:Female; D006801:Humans; D006967:Hypersensitivity; D015994:Incidence; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D009503:Neutropenia; D013203:Staphylococcal Infections",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "235-239",
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"pmid": "28980484",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Rate and Incidence of Adverse Reactions Associated With Ceftaroline Exposure: Importance of Cutaneous Manifestations.",
"title_normalized": "rate and incidence of adverse reactions associated with ceftaroline exposure importance of cutaneous manifestations"
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"abstract": "Iatrogenic Cushing syndrome induced by oral and parenteral corticosteroid administration is a well-known complication, and necessary precautions have to be taken. Cushing syndrome, however, following treatment with glucocorticoid-containing eye drops is a very rare complication. To the best of our knowledge, there have been only four reported cases in the literature. Herein, we present an infant boy who developed Cushing syndrome after receiving dexamethasone-containing eye drops after bilateral cataract extraction to prevent postoperative inflammatory complications. At the age of 5 months, after approx. 3 months of dexamethasone therapy, the patient presented with cushingoid facies, nephrocalcinosis and failure to grow. Iatrogenic Cushing syndrome was diagnosed and dexamethasone-containing eye drops were reduced and eventually stopped. Follow-up examinations revealed catch-up growth.\n\n\nCONCLUSIONS\nOcularly administered corticosteroids may have substantial systemic side effects in infants.",
"affiliations": "General Paediatrics, University Children's Hospital, 8032, Zurich, Switzerland, karin.scherrer@kispi.uzh.ch.",
"authors": "Scherrer|Karin Sofia|KS|;Weitz|Marcus|M|;Eisenack|Johannes|J|;Truffer|Béatrice|B|;Konrad|Daniel|D|",
"chemical_list": "D005938:Glucocorticoids; D009883:Ophthalmic Solutions; D003907:Dexamethasone",
"country": "Germany",
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"issue": "174(3)",
"journal": "European journal of pediatrics",
"keywords": null,
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D002386:Cataract; D002387:Cataract Extraction; D003480:Cushing Syndrome; D003907:Dexamethasone; D005938:Glucocorticoids; D006801:Humans; D007223:Infant; D008297:Male; D009883:Ophthalmic Solutions; D011183:Postoperative Complications",
"nlm_unique_id": "7603873",
"other_id": null,
"pages": "399-401",
"pmc": null,
"pmid": "25535172",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9732346;11820911;8501158;15121994;329678;21686405;4575724;17396439;20972726;11004305;16294208",
"title": "Cushing syndrome after bilateral lensectomy.",
"title_normalized": "cushing syndrome after bilateral lensectomy"
} | [
{
"companynumb": "CH-BAUSCH-BL-2015-000697",
"fulfillexpeditecriteria": "1",
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... |
{
"abstract": "BACKGROUND\nFulminant type 1 diabetes (FT1D) is a subtype of type 1 diabetes characterized by an extremely abrupt onset. FT1D cases associated with the drug-induced hypersensitivity syndrome (DIHS) have recently been reported.\n\n\nOBJECTIVE\nThe clinical characteristics of FT1D associated with DIHS were investigated in this study.\n\n\nMETHODS\nCase reports of FT1D associated with DIHS in Japanese subjects were collected and analyzed by means of a questionnaire to the authors. A nationwide questionnaire survey was administered to dermatology specialists, concerning the frequency of FT1D associated with DIHS.\n\n\nRESULTS\nIn 15 case reports, the mean age at onset of FT1D was 53.4 yr and the mean time for its development from the onset of DIHS was 39.9 d. A higher frequency of human leukocyte antigen (HLA) B62, but not of HLA DR was found in FT1D with DIHS than that for cases without DIHS (P < 0.001). The reactivation of herpes virus 6 and cytomegalovirus was detected in 11 and four cases, respectively. Among 746 patients with DIHS in the nationwide survey, four developed FT1D during a 3-yr period. The frequency of FT1D in DIHS (0.54%) was much higher than that in the general Japanese population (0.010%).\n\n\nCONCLUSIONS\nThe clinical characteristics of FT1D with DIHS were similar to those without DIHS except for the high frequency of HLA B62, which may be involved in the pathogenesis of FT1D with DIHS. Because the frequency was much higher than that in the general Japanese population, FT1D should be kept in mind when DIHS develops.",
"affiliations": "Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, To-on, Ehime, 791-0295 Japan. onuma@m.ehime-u.ac.jp",
"authors": "Onuma|Hiroshi|H|;Tohyama|Mikiko|M|;Imagawa|Akihisa|A|;Hanafusa|Toshiaki|T|;Kobayashi|Tetsuro|T|;Kano|Yoko|Y|;Ohashi|Jun|J|;Hashimoto|Koji|K|;Osawa|Haruhiko|H|;Makino|Hideichi|H|;|||;|||",
"chemical_list": "D015235:HLA-B Antigens",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2012-2054",
"fulltext": null,
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"issn_linking": "0021-972X",
"issue": "97(12)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000328:Adult; D000368:Aged; D044466:Asians; D003625:Data Collection; D003922:Diabetes Mellitus, Type 1; D018450:Disease Progression; D004342:Drug Hypersensitivity; D005260:Female; D005787:Gene Frequency; D015235:HLA-B Antigens; D006801:Humans; D008297:Male; D008875:Middle Aged; D013577:Syndrome; D055815:Young Adult",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "E2277-81",
"pmc": null,
"pmid": "23071161",
"pubdate": "2012-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "High frequency of HLA B62 in fulminant type 1 diabetes with the drug-induced hypersensitivity syndrome.",
"title_normalized": "high frequency of hla b62 in fulminant type 1 diabetes with the drug induced hypersensitivity syndrome"
} | [
{
"companynumb": "JP-PFIZER INC-2019345391",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
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"drugadditional": "3",
... |
{
"abstract": "Warfarin is an anticoagulant suppressing the synthesis of the specific vitamin K-dependent coagulation factors II, VII, IX and X as well as two vitamin K-dependent plasma proteins C and S. Warfarin therapy may bring about severe consequences including warfarin embryopathy associated with maternal warfarin ingestion, warfarin resistance, excessive anticoagulation and warfarin reversal. A 51-year-old female patient experienced warfarin resistance as well as subsequent excessive coagulation and warfarin reversal. With regulation of warfarin dosage and close monitoring of the international normalized ratio, she eventually obtained a proper target international normalized ratio with stable warfarin dose. The patient was more likely to have an acquired warfarin resistance. To regulate dietary habit might be a good solution for the resistance to this drug. In addition, individualized regimen for warfarin use should be established based on the conditions of individual patient including patient's age, gender, body surface area, dietary habit and target international normalized ratio, etc.",
"affiliations": "Department of Cardiothoracic Surgery, The First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, Fujian Province, People's Republic of China.",
"authors": "Yuan|Shi-Min|SM|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "Pakistan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1011-601X",
"issue": "28(4)",
"journal": "Pakistan journal of pharmaceutical sciences",
"keywords": null,
"medline_ta": "Pak J Pharm Sci",
"mesh_terms": "D000925:Anticoagulants; D004351:Drug Resistance; D005260:Female; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008875:Middle Aged; D008943:Mitral Valve; D014859:Warfarin",
"nlm_unique_id": "9426356",
"other_id": null,
"pages": "1351-5",
"pmc": null,
"pmid": "26142525",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Warfarin use and dose adjustment in a patient with mitral valve replacement.",
"title_normalized": "warfarin use and dose adjustment in a patient with mitral valve replacement"
} | [
{
"companynumb": "CN-IPCA LABORATORIES LIMITED-IPC201509-000589",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditio... |
{
"abstract": "OBJECTIVE\nWe report a novel case of \"grand mal on awakening\" from sleep presenting with intractable insomnia associated with interictal epileptiform activity (IEA) during sleep.\n\n\nMETHODS\nA 36-year-old woman with a seizure history of grand mal on awakening since age 13 years suffered from severe, persistent insomnia despite seizure control with daytime valproic acid therapy. Bedtime hypnotic therapy with zolpidem and clonazepam was ineffective. An overnight polysomnographic (PSG) study with expanded EEG seizure montage found IEA with microarousals or full arousals from sleep, with a mean rate of IEA events of 19.0 per hour. The sleep macrostructure (the cycling and distribution of sleep stages) was disturbed by the IEA events, and the sleep efficiency was 67.2%. Bedtime valproic acid therapy, 500 mg, was rapidly effective. A follow-up PSG study documented a reduced mean rate of IED events of 5.8 per hour, and an improved sleep efficiency of 87.7%.\n\n\nCONCLUSIONS\nSevere persistent insomnia with sleep-related IEA can occur as a major comorbidity of grand mal on awakening despite full seizure control. Although standard hypnotic therapy (benzodiazepine receptor agonist; benzodiazepine) was ineffective, bedtime monotherapy with valproic acid was promptly effective, with objectively-documented improvement. Therefore, when remitted epilepsy patients complain of persistent insomnia, clinicians should consider sleep-related IEA activity, with sleep disruption and poor sleep efficiency, in the differential diagnosis. A diagnostic PSG study with expanded EEG seizure montage should be considered.",
"affiliations": "Department of Neurology (and Sleep Center), Changhua Christian Hospital Yun Lin Branch and Department of Neurology (and Sleep Center), St Martin de Porres Hospital.;Minnesota Regional Sleep Disorders Center and Department of Psychiatry, Hennepin County Medical Center and the University of Minnesota Medical School, Minneapolis, MN, USA.",
"authors": "Yeh|Shih-Bin|SB|;Schenck|Carlos|C|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-768X",
"issue": "24(3)()",
"journal": "Acta neurologica Taiwanica",
"keywords": null,
"medline_ta": "Acta Neurol Taiwan",
"mesh_terms": "D000328:Adult; D015897:Comorbidity; D004569:Electroencephalography; D004830:Epilepsy, Tonic-Clonic; D005260:Female; D006801:Humans; D017286:Polysomnography; D007319:Sleep Initiation and Maintenance Disorders",
"nlm_unique_id": "9815355",
"other_id": null,
"pages": "82-6",
"pmc": null,
"pmid": "27333831",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intractable Insomnia as a Major Comorbidity of Grand Mal on Awakening: Case Report with Diagnostic Polysomnographic Findings and Successful Treatment Outcome.",
"title_normalized": "intractable insomnia as a major comorbidity of grand mal on awakening case report with diagnostic polysomnographic findings and successful treatment outcome"
} | [
{
"companynumb": "PHHY2016TW021571",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nIonic contrast, if accidentally injected into the intrathecal space during routine imaging studies or interventional procedures, may significantly interfere with neuronal activity, potentially causing ascending tonic-clonic seizure syndrome and even death. As a result, ionic contrast is strictly contraindicated for intrathecal use. Rapid recognition of the condition followed by prompt management, typically involving aggressive cerebrospinal fluid (CSF) drainage, is critical to improving patient outcome. Lumbar drain has previously been well described as a management strategy.\n\n\nMETHODS\nWe present a case of accidental intrathecal injection of an ionic contrast agent, iothalamate meglumine, in a patient undergoing cervical epidural steroid injection. This patient was managed successfully with drainage of CSF using an external ventricular drain alone.\n\n\nCONCLUSIONS\nOur literature review and analysis of the previously published cases demonstrate that aggressive CSF drainage is essential to improve outcomes, and in some cases an external ventricular drain alone may be effectively used.",
"affiliations": "Department of Neurological Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. Electronic address: joseph-hudson@uiowa.edu.;Department of Neurological Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.;Department of Neurological Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.;Department of Neurological Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.",
"authors": "Hudson|Joseph S|JS|;Abode-Iyamah|Kingsley|K|;Nagahama|Yasunori|Y|;Reddy|Chandan G|CG|",
"chemical_list": "D011220:Pralidoxime Compounds; C028797:pralidoxime; D007482:Iothalamate Meglumine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2016.10.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "97()",
"journal": "World neurosurgery",
"keywords": "Accidental intrathecal injection; Ascending tonic-clonic seizure syndrome; Ionic contrast; Myelography",
"medline_ta": "World Neurosurg",
"mesh_terms": "D001927:Brain Diseases; D004322:Drainage; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D007482:Iothalamate Meglumine; D008508:Medication Errors; D008875:Middle Aged; D011220:Pralidoxime Compounds; D013122:Spinal Diseases; D016896:Treatment Outcome; D017287:Ventriculoperitoneal Shunt",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "757.e1-757.e9",
"pmc": null,
"pmid": "27765719",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Accidental Intrathecal Injection of Ionic Contrast: Case Report and Review of the Literature.",
"title_normalized": "accidental intrathecal injection of ionic contrast case report and review of the literature"
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"abstract": "METHODS\nThe case involves a 35-year-old man, with a history of retinitis pigmentosa, who presented with a bilateral cystoid macular oedema associated with bilateral epiretinal membrane, which was resistant to treatment with oral acetazolamide and intravitreal bevacizumab. The treatment with oral eplerenone was able to improve the visual acuity and macular thickness of this patient.\n\n\nCONCLUSIONS\nA variety of treatments have been proposed for the management of cystoid macular oedema, associated with retinitis pigmentosa, with variable results. The treatment with oral eplerenone might be a good option for the control of this condition.",
"affiliations": "Servicio de Oftalmología, Hospital Virgen del Puerto, Plasencia (Cáceres), España. Electronic address: rafacampospolo@hotmail.com.;Servicio de Oftalmología, Hospital Virgen del Puerto, Plasencia (Cáceres), España.;Servicio de Oftalmología, Hospital Virgen del Puerto, Plasencia (Cáceres), España.;Servicio de Oftalmología, Hospital Virgen del Puerto, Plasencia (Cáceres), España.",
"authors": "Campos Polo|R|R|;Rubio Sánchez|C|C|;García Guisado|D M|DM|;Díaz Luque|M J|MJ|",
"chemical_list": "D000077545:Eplerenone",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.oftal.2017.05.002",
"fulltext": null,
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"issn_linking": "2173-5794",
"issue": "93(1)",
"journal": "Archivos de la Sociedad Espanola de Oftalmologia",
"keywords": "Cystoid macular oedema; Edema macular quístico; Epiretinal membrane; Eplerenona; Eplerenone; Grosor macular; Macular thickness; Membrana epirretiniana; Retinitis pigmentosa; Retinosis pigmetaria",
"medline_ta": "Arch Soc Esp Oftalmol (Engl Ed)",
"mesh_terms": "D000328:Adult; D000077545:Eplerenone; D006801:Humans; D008269:Macular Edema; D008297:Male; D012174:Retinitis Pigmentosa",
"nlm_unique_id": "101715860",
"other_id": null,
"pages": "38-41",
"pmc": null,
"pmid": "28624313",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Eplerenone, a new treatment for an old problem: Retinitis pigmentosa with recalcitrant macular edema.",
"title_normalized": "eplerenone a new treatment for an old problem retinitis pigmentosa with recalcitrant macular edema"
} | [
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"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-144545",
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"abstract": "Granulomatosis with polyangiitis (GPA) is a primary, systemic small vessel vasculitis. The respiratory tract is typically involved in the course of the disease. Abnormalities on the chest radiograph are noted in more than 70% patients at some point during their disease history. In some clinical situations it is difficult to distinguish whether symptoms result from the underlying disease or are a symptom of infection. In these clinical situations, chest computed tomography (CT) can be very useful. We present a patient with GPA localized mainly in the respiratory tract with sudden deterioration of the general state and new abnormalities revealed in the CT of the chest.",
"affiliations": "Chair and Department of Internal Diseases, Connective Tissue Disease and Geriatrics, Medical University of Gdansk, Poland.;Chair and Department of Endocrinology and Internal Diseases, Medical University of Gdansk, Poland.;Chair and Department of Internal Diseases, Connective Tissue Disease and Geriatrics, Medical University of Gdansk, Poland.",
"authors": "Masiak|Anna|A|;Struk-Panfill|Małgorzata|M|;Zdrojewski|Zbigniew|Z|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/reum.2015.55833",
"fulltext": "\n==== Front\nReumatologiaReumatologiaRUReumatologia0034-62332084-9834Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 5583310.5114/reum.2015.55833Case ReportInfectious complication or exacerbation of granulomatosis with polyangiitis? Masiak Anna 1Struk-Panfill Małgorzata 2Zdrojewski Zbigniew 11 Chair and Department of Internal Diseases, Connective Tissue Disease and Geriatrics, Medical University of Gdansk, Poland2 Chair and Department of Endocrinology and Internal Diseases, Medical University of Gdansk, PolandAddress for correspondence: Anna Masiak, Chair and Department of Internal Diseases, Connective Tissue Disease and Geriatrics, Medical University of Gdansk, Dębinki 7, 80-001 Gdansk, Poland. e-mail: anna.masiak@wp.pl08 12 2015 2015 53 5 286 291 14 7 2015 19 10 2015 Copyright © Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 20152015This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Granulomatosis with polyangiitis (GPA) is a primary, systemic small vessel vasculitis. The respiratory tract is typically involved in the course of the disease. Abnormalities on the chest radiograph are noted in more than 70% patients at some point during their disease history. In some clinical situations it is difficult to distinguish whether symptoms result from the underlying disease or are a symptom of infection. In these clinical situations, chest computed tomography (CT) can be very useful. We present a patient with GPA localized mainly in the respiratory tract with sudden deterioration of the general state and new abnormalities revealed in the CT of the chest.\n\ngranulomatosis with polyangiitiscomputed tomographyinfectious complicationsrespiratory tract stenosis\n==== Body\nIntroduction\nGranulomatosis with polyangiitis (GPA) is a systemic vasculitis of the medium and small arteries, as well as the venules and arterioles, usually associated with ANCA (anti-neutrophil cytoplasmic antibodies). It typically produces granulomatous inflammation of the upper and lower respiratory tracts and necrotizing, pauci-immune glomerulonephritis in the kidneys. Pulmonary involvement is observed in the majority of patients. Abnormalities on the chest radiograph are noted in more than 70% of patients at the some point of the disease history. The clinical pulmonary manifestations in course of GPA include cough, hemoptysis (due to alveolar hemorrhage and/or tracheobronchial disease), dyspnea, and less commonly pleuritic pain [1]. Infections are frequent in vasculitis patients andstudies have shown that in patients with GPA more often Staphylococcus aureus colonization is found than in the healthy population. Also the carriers of Staphylococcus aureus are an independent factor contributing to recurrence of the GPA.\n\nIt was shown that infectious agents (specially Staphylococcus aureus) may trigger vasculitis and may stimulate the progression of the disease [2]. It is believed that the microorganisms may in different ways be responsible for the development of vasculitis – both the damage to the walls of the endothelial cells, effect of immune complexes and the effect of superantigens (SAgs) highly stimulating lymphocytes. As sources of superantigens beyond Staphylococcus aureus may be for e.g. Mycoplasma, Pseudomonas aeruginosa, Yersinia or Mycobacterium tuberculosis [3].\n\nInfections are also well known complications of immunosuppressive treatment. In some clinical situations, it is difficult to distinguish whether symptoms are due to exacerbation of the disease whether they are a symptom of infection. Clinical presentation, laboratory findings as well as chest radiographs, especially high resolution computed tomography (HRCT), are necessary for differential diagnosis.\n\nCase report\nA 57-year-old woman with a history of hypertension, chronic obstructive pulmonary disease, hypothyroidism, diabetes mellitus type 2, was admitted to the hospital with cough, progressive shortness of breath, low-grade fever, joint pain, leakage of both ears with left ear hearing loss, bloody discharge and obstruction of the nose with severe crusting and peripheral left facial nerve paralysis. Physical examination revealed bloody discharge from the nose, nasal crusting, hearing loss, left facial nerve paralysis, dyspnea, cough and wheezing at auscultation, pulse oxygen saturation 89%. Laboratory test have shown leukocytosis (14.4 G/l), thrombocytosis (PLT 606 G/l), marked elevation of inflammatory markers (C-reactive protein – CRP: 100 mg/l, erythrocyte sedimentation rate – ESR: 90 mm/h), proteinuria, and an active urine sediment with red cells and white cells. The plasma creatinine was normal. Immunological tests shown presence of cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA 1 : 40, n < 1 : 10 U/ml), and anti-proteinase 3 antibodies (anti-PR3 27 U/ml, n < 20 U/ml). Antinuclear antibodies (ANA) were negative. Nasal swab culture showed growth of Staphylococcus aureus. Bronchofiberoscopy was performed in which no pathological lesions were found in the trachea or large bronchi. CT scan of the chest revealed a focal lesion with a diameter of 9 mm in the right lung (Fig. 1).\n\nFig. 1 Computed tomography scan of the chest in the diagnosis of GPA. The trachea of normal size just above the bifurcation (A). Right lung nodule with a diameter of 9 mm (B).\n\nAlso during the diagnosis the nasal mucosa biopsy was performed. Histopathological examination revealed purulent exudate, fibrinoid necrosis, polynuclear giant cells, infiltration of T and B lymphocytes as well as neutrophils and eosinophils. Considering the clinical course, CT imaging, laboratory results and histopathological findings confirmed the diagnosis of GPA. The activity of the disease was measured using Birmingham Vasculitis Activity Score (BVAS/GPA = 20 points). The patient received steroid therapy (oral prednisone 1 mg per kilogram of body weight per day) and cyclophosphamide (CF, 15 mg per kilogram of body weight i.v. every 3 weeks). Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole (160 mg/800 mg three times per week) was administrated. After 3 months of therapy the patient's complaints included persistent inspiratory dyspnea, very tiring cough with sputum difficult to expectorate and persisting left ear hearing loss. Auscultation revealed symmetrical rales at the base of both lungs and between the shoulder blades, inspiratory stridor audible over the trachea, small ulcers on the neck and legs like pyodermia gangrenosum (biopsy wasn't performed). Laboratory tests revealed only slightly elevated ESR (24 mm/h) and CRP (7.65 mg/l), leukocytosis (13.8 G/l) and thrombocytosis (420 G/l), but no abnormalities in urine analysis. Also creatinine level was normal. The patient got the fourth pulse of CF (1 g i.v., the total dose administered 4 g). Since then, she reported malaise, severe weakness and nausea. Significant increase of CRP (112 mg/l), pulse oxygen saturation 92% was found in laboratory results. Chest CT revealed conglomerates of small nodules in both lungs, reticulo-nodular lesions in stromal throughout the lungs (Fig. 2A) and a segmental, significant narrowing of the trachea up to 7 mm in diameter at a distance of approximately 1.5 cm with a concentric thickening of its walls (Fig. 2B).\n\nFig. 2 Computed tomography scan of the chest performed after 3 months of immunosuppressive therapy while worsening of clinical symptoms. CT scans show a conglomerate of small nodules in both lungs, reticulo- nodular lesions in stromal throughout the lungs (A) and narrowing of the trachea up to 7 mm in diameter at a distance of approximately 1.5 cm with a concentric thickening of its walls (B).\n\nThe differential diagnosis of clinical deterioration included: the progression of the underlying disease, infectious complication of immunosuppressive therapy, tuberculosis, sarcoidosis or spread of the cancer of unknown origin. During bronchofiberoscopy, the narrowing of the trachea was found with the retention of purulent contents in the bronchi. Microbiologic analysis of sputum and bronchial aspirate excluded active tuberculosis (direct smear), but revealed growth of mixed hospital's bacteria: Acinetobacter baumannii, Streptococcus pneumoniae, methicyllin-resistant Staphylococcus aureus (MRSA) and Candida albicans. Targeted antibiotic therapy was applied – vancomycin, imipenem, fluconazole. Gradually, the patient's clinical condition was improving and normalization of CRP (1.1 mg/l) was noted.\n\nThe control chest CT found almost complete regression of reticulo-nodular lesions and interstitial changes (Fig. 3A). Initially described nodule in the right lung was reduced to the size of 7.5 mm (Fig. 3B).\n\nFig. 3 Computed tomography scan of the chest after anti-bacterial treatment. Small nodules disappeared (A). Primary right lung nodule is smaller compared to pre-treatment CT scans (B).\n\nTherefore it was decided to continue the treatment of CF and prednisone. After 6 months of immunosuppressive treatment (total dose of cyclophosphamide 6 g, prednisone 10 mg/d) disease activity was assessed using Birmingham Vasculitis Activity Score (BVAS/GPA = 12 points).\n\nThe patient reported dyspnea of constant intensity, limited exercise tolerance, periodic dry cough. She denied fever. Clinical examination revealed hearing impairment, perforation of the nasal septum, mild left eye stare, small skin ulcers on the neck, back and limbs, pulse oxygen saturation 93%. Mild normocytic anemia (Hgb 11.7 g/dl), leukocytosis (WBC 12.6 G/l), thrombocytosis (PLT 469 G/l), increased ESR (43 mm/h) and CRP (14 mg/l) were found in laboratory tests. Immunological tests revealed also the presence of cANCA antibodies (cANCA 1 : 80, normal < 1 : 40), but ANCA-PR3 antibodies were negative. Nasal swab culture was negative. CT of the chest revealed the progression of the main disease (Fig. 4).\n\nFig. 4 Computed tomography scan of the chest reveals a progression of the main disease – numerous cavitating lung nodules typical for GPA on both sides.\n\nThe patient was repeatedly referred to thoracic surgeons, but further bronchoscopy showed no significant stenosis of trachea so it was not decided on surgery. Pulmonary function tests (spirometry, body plethysmography, single-breath diffusing capacity for carbon monoxide – DLCO) revealed a very severe airway obstruction with significant air trapping (RV – residual volume – 197%) and a slight decrease in gas diffusion capacity in the lung (DLCO – 67.2%). The patient initially refused on biological treatment, so CF therapy was continued to a total dose 13.0 g. Steroids were also given in tapering doses. Finally because of lack of remission, after obtaining the consent of the patient, intravenous infusion of rituximab in total dose of 2 g was applied (2 × 1 g every two weeks). Three months later the patient reported a partial improvement in general state. Dyspnea, cough and permanent deterioration in exercise tolerance as well as skin changes were still present but less intense. Unfortunately, four months after the initiation of rituximab therapy the patient choked on food and died.\n\nDiscussion\nGranulomatosis with polyangiitis is a systemic vasculitis of the medium and small arteries, as well as the venules and arterioles, usually associated with ANCA. It typically produces granulomatous inflammation of the upper and lower respiratory tracts and necrotizing, pauci-immune glomerulonephritis in the kidneys. The most common lower respiratory tract symptoms in GPA are cough, hemoptysis (due to alveolar hemorrhage and/or tracheobronchial disease), dyspnea, and pleuritic pain [1]. The severity of symptoms and signs varies considerably from asymptomatic (one-third of patients) to acute and fulminant alveolar hemorrhage with respiratory failure. The specific clinical manifestations vary depending on whether the patient has tracheobronchial disease, lung parenchymal nodules, or alveolar hemorrhage. Initial lung presentation in described patient was single nodule, but in the course of disease the radiological image has changed and significant narrowing of trachea appeared. Also deterioration of general condition was associated with the emergence of numerous new conglomerates of small nodules in the lungs.\n\nThe differential diagnosis of multiple pulmonary nodules includes metastatic solid organ malignancy, non-Hodgkin lymphoma, septic embolism, granulomatous infections (e.g., Mycobacteria, histoplasmosis, coccidioidomycosis, cryptococcosis, aspergillosis), sarcoidosis, rheumatoid arthritis, lymphomatoid granulomatosis, inflammatory myofibroblastic tumor, silicosis, and coal-worker's pneumoconiosis. Differentiation is based on history of exposures, presence of other features (e.g., erosive arthritis, cutaneous lesions), serology, special stains and culture, and histopathology. Sudden deterioration of the patients state strongly suggested infectious complication of immunosuppressive treatment. Infections are frequent in vasculitis patients and can be severe. They are sometimes life threatening and are one of the major causes of deaths [4–6]. They require rapid diagnosis and targeted therapy. Patients with clinical deterioration raise a differential diagnosis of infection, drug toxicity, disease relapse or a new, unrelated disease. A study by Bradley et al. [7] found that 10% of vasculitis patients who had been treated with cyclophosphamide developed clinically important infections (sepsis and pneumonia) even when patients with drug-induced leucopenia were excluded. Fungal infections, suchas aspergillosis or candidiasis, although not very frequent, remain a concern for clinicians. Bronchial aspirate culture revealed mixed hospital's bacterial and fungal flora in our patient, which were considered the etiological agents of her clinical deterioration.\n\nHigh-resolution computed tomography (HRCT) is an optimal diagnostic tool to assess pulmonary changes in many connective tissue diseases (e.g. systemic lupus erythematosus) [8]. It makes it possible to detect lesions significantly earlier and much more precisely than can be done with other imaging tests. Imaging studies in small-vessel vasculitides are important for determining disease extent and activity. Ground-glass opacities, cavitating nodules and masses measuring > 3 cm represent active disease. One should remember, that patchy ground glass attenuation can be due to cyclophosphamide-induced acute alveolar damage as well as Pneumocystis jiroveci pneumonia. Because the Pneumocystis jiroveci infection can be very severe in patients during immunosuppressive treatment, prophylaxis with trimethoprim-sulfamethoxazole is recommended. For GPA patients with a persistent lung nodule, the risk of developing aspergillosis must be always considered. Candidiasis should be systematically sought in patients with chronic fever particularly with chronic neutropenia. But these complications are not observed in most patients, so systematic prophylaxis is not recommended [6].\n\nGranulomatosis with polyangiitis may also involve the tracheobronchial tree in 12–23% of cases [9]. Tracheobronchial involvement has several manifestations, including subglottic stenosis, tracheal and bronchial stenosis, mass lesions (inflammatory pseudotumors) and tracheoesophageal fistulae [10, 11].\n\nIt is often asymptomatic initially, but becomes apparent as hoarseness, pain, cough, wheezing or stridor. As the airway caliber narrows, mucous plugging becomes a greater concern, as it can cause acute stridulous exacerbations and airway obstruction. CT scans are often useful, but the most accurate means of assessing tracheal stenosis is by direct laryngoscopy. Patients should be carefully assessed for critical airway obstruction and treated with medical treatment especially since the course of bronchial stenosis, as well as subglottic stenosis, seems to be independent of systemic disease activity. Our patient had regular endoscopic examinations performed, but the narrowing seemed stable, so it was decided not to perform surgery.\n\nUp to 80% of patients may require surgical management of subglottic stenosis, and the remaining 20% will respond to systemic medical therapy (conventional immunosuppressive therapy, endoscopic dilation, endoscopic or laser excision, and surgical resection of the stenotic segment followed by reconstruction). The use of local steroid injections is restricted to subglottic stenosis whereas stenting represent a therapeutic option in patients with bronchial stenosis. The optimal endoscopic interventions providing the best efficacy and the best timing for such interventions remain unclear.\n\nTerrier et al. [9] observed that a shorter time from GPA diagnosis to endoscopic procedure was associated with a higher cumulative incidence of treatment failure. Authors suggested that endoscopic procedures should be performed long after maximal inflammatory activity of tracheobronchial stenosis [9]. There are two main parameters that should be taken into consideration in the assessment of indications for treatment: patients complaints and physical signs [12].\n\nOur patients complaints were still on the same level and there was no progression in narrowing of the trachea. Also the location of stenosis in our patient significantly limited the possibility of endoscopic treatment (only stenting was taken into account). The question whether earlier surgical intervention would prevent the fatal outcome in our patient, remains open. It was planned for a period of remission which she has not reached.\n\nThe current standards in the treatment of anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) have been optimized on the basis of a number of randomized studies conducted over the past 20 years and adjusted to the duration and severity of the disease [13]. Two randomized clinical trials, RITUXVAS (Randomised Trial of Rituximab versus Cyclophosphamide for ANCA Associated Renal Vasculitis) and RAVE (Rituximab for ANCA-associated Vasculitis), categorically confirmed the equivalent efficacyof rituximab (RTX) and cyclophosphamide in the induction treatment of AAV. RTX should be taken into account particularly in refractory and relapsing forms of the disease as in the present case. It can be administered in two schemes: 4 × 375 mg/m2 BS (RITUXVAS trial, RAVE trial) or 2 × 1 g every two weeks [14]. Our patient received RTX according to the second scheme.\n\nSummary\nIn conclusion it's worth to mention that careful monitoring for complications is absolutely necessary to minimize the morbidity and mortality of the disease and its therapies. In the assessment of pulmonary changes CT in connection with clinical presentation and laboratory tests allows the diagnosis of organ damage in an early stage and the introduction of appropriate treatment.\n\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Madej M Matuszewska A Białowąs K Wiland P Clinical forms of granulomatosis with polyangiitis Reumatologia 2014 52 332 338 \n2 Tadema H Heeringa P Kallenberg CG Bacterial infections in Wegener's granulomatosis: mechanisms potentially involved in autoimmune pathogenesis Curr Opin Rheumatol 2011 23 366 371 21494184 \n3 Wiatr E Gawryluk D Nowe aspekty patogenezy ziarniniakowatości Wegenera Pneumonol Alergol Pol 2002 70 326 333 12518633 \n4 Goupil R Brachemi S Nadeau-Fredette AC Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis Clin J Am Soc Nephrol 2013 8 416 423 23220426 \n5 Hoffman GS Kerr GS Leavitt RY Wegener granulomatosis: An analysis of 158 patients Ann Intern Med 1992 116 488 498 1739240 \n6 Guillevin L Infections in vasculitis Best Prac Res Clin Rheumatol 2013 27 19 31 \n7 Bradley JD Brandt KD Katz BP Infectious complications of cyclophosphamide treatment for vasculitis Arthritis Rheum 1989 32 45 53 2563226 \n8 Jeka S Żuchowski P Dura M Assessment of pulmonary changes in the course of systemic lupus erythematosus – application of high resolution computed tomography Reumatologia 2014 52 339 343 \n9 Terrier B Dechartres A Girard C Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicenter experience Rheumatology (Oxford) 2015 54 1852 1857 26001634 \n10 Langford C Sneller M Hallahan C Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis Arthritis Rheum 1996 39 1754 1760 8843868 \n11 Lebovics R Hoffman G Leavitt R The management of subglottic stenosis in patients with Wegener's granulomatosis Laryngoscope 1992 102 1341 1345 1453838 \n12 Schokkenbroek A Franssen C Dikkers F Dilatation tracheoscopy for laryngeal and tracheal stenosis in patients with Wegener's granulomatosis Eur Arch Otorhinolaryngol 2008 265 549 555 18000676 \n13 Zdrojewski Z Individualization of the ANCA-associated vasculitis treatment Reumatologia 2014 52 221 223 \n14 Jones RB Ferraro AJ Chaudhry AN A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis Arthritis Rheum 2009 60 2156 2168 19565480\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0034-6233",
"issue": "53(5)",
"journal": "Reumatologia",
"keywords": "computed tomography; granulomatosis with polyangiitis; infectious complications; respiratory tract stenosis",
"medline_ta": "Reumatologia",
"mesh_terms": null,
"nlm_unique_id": "20130190R",
"other_id": null,
"pages": "286-91",
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"pubdate": "2015",
"publication_types": "D016428:Journal Article",
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"title": "Infectious complication or exacerbation of granulomatosis with polyangiitis?",
"title_normalized": "infectious complication or exacerbation of granulomatosis with polyangiitis"
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"abstract": "Oligodendroglioma is defined by IDH mutation and 1p/19q codeletion. Normal TP53 status is also its molecular feature. We report a case of oligodendroglioma that acquired imbalanced 1p/19q codeletion and TP53 mutation at recurrence after temozolomide therapy. The primary and recurrent tumors shared IDH1 and TERT promoter mutations. Although 1p/19q was codeleted in the primary tumor, it was imbalanced in the recurrent tumor harboring TP53 mutation. The copy-neutral loss of heterozygosity might have imbalanced the 1p/19q codeletion, while temozolomide therapy possibly caused the TP53 mutation. Such phenomena, although rare, should be noted during the clinical treatment of oligodendrogliomas.",
"affiliations": "Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, Akita, 010-8543, Japan. t.ono@med.akita-u.ac.jp.;Department for Neuropathology and CCU Neuropathology, University of Heidelberg and DKFZ, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.;Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, Akita, 010-8543, Japan.;Department of Clinical Pathology, Akita University Hospital, 1-1-1, Hondo, Akita, Akita, 010-8543, Japan.;Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.;Department for Neuropathology and CCU Neuropathology, University of Heidelberg and DKFZ, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.;Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, Akita, 010-8543, Japan.",
"authors": "Ono|Takahiro|T|;Reinhardt|Annekathrin|A|;Takahashi|Masataka|M|;Nanjo|Hiroshi|H|;Kamataki|Akihisa|A|;von Deimling|Andreas|A|;Shimizu|Hiroaki|H|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007521:Isocitrate Dehydrogenase; D000077204:Temozolomide",
"country": "Austria",
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"doi": "10.1007/s00701-020-04514-3",
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"issue": "162(12)",
"journal": "Acta neurochirurgica",
"keywords": "1p/19q codeletion; Case report; Copy-neutral loss of heterozygosity; Methylation profile; Oligodendroglioma; TP53 mutation",
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"title": "Comparative molecular analysis of primary and recurrent oligodendroglioma that acquired imbalanced 1p/19q codeletion and TP53 mutation: a case report.",
"title_normalized": "comparative molecular analysis of primary and recurrent oligodendroglioma that acquired imbalanced 1p 19q codeletion and tp53 mutation a case report"
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"abstract": "A 78 year-old man, who received levofloxacin eye drops as a perioperative prophylactic antibacterial agent for cataract surgery, developed pyrexia and dyspnea, followed by respiratory failure. He was diagnosed as drug-induced lung injury due to levofloxacin, and the symptoms improved after the administration of corticosteroids and discontinuation of levofloxacin eye drops. The incidence of levofloxacin-induced lung injury is rare for its frequent prescription. Moreover, eye drops of it has never been reported to cause lung injury. We should be aware of eye drops as a causative dosage forms of drug-induced lung injury.",
"affiliations": "Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Chuo, Yamanashi, Japan.;Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Chuo, Yamanashi, Japan.;Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Chuo, Yamanashi, Japan.;Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Chuo, Yamanashi, Japan.",
"authors": "Hosogaya|Naoki|N|;Toida|Kazuhiro|K|;Ishihara|Hiroshi|H|;Kugiyama|Kiyotaka|K|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30050-910.1016/j.rmcr.2018.03.010Case ReportA case of drug induced lung injury caused by levofloxacin eye drops Hosogaya Naoki naokih@yamanashi.ac.jp∗Toida Kazuhiro Ishihara Hiroshi Kugiyama Kiyotaka Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Chuo, Yamanashi, Japan∗ Corresponding author. Department of Internal Medicine II, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. naokih@yamanashi.ac.jp16 3 2018 2018 16 3 2018 24 12 15 6 3 2018 15 3 2018 15 3 2018 © 2018 The Authors. Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 78 year-old man, who received levofloxacin eye drops as a perioperative prophylactic antibacterial agent for cataract surgery, developed pyrexia and dyspnea, followed by respiratory failure. He was diagnosed as drug-induced lung injury due to levofloxacin, and the symptoms improved after the administration of corticosteroids and discontinuation of levofloxacin eye drops. The incidence of levofloxacin-induced lung injury is rare for its frequent prescription. Moreover, eye drops of it has never been reported to cause lung injury. We should be aware of eye drops as a causative dosage forms of drug-induced lung injury.\n\nKeywords\nLevofloxacinEye dropOphthalmic solutionDrug-induced lung injuryEosinophilic pneumoniaAbbreviations\nCT, computed tomographyBNP, brain natriuretic peptideTAZ/PIPC, tazobactam/piperacillinMEPM, meropenemBALF, bronchoalveolar lavage fluidDLST, drug lymphocyte stimulation testPMDA, Pharmaceuticals and Medical Devices AgencyEP, eosinophilic pneumonia\n==== Body\n1 Introduction\nProphylactic antibiotic administration for cataract and vitreous surgery has been reported to significantly contribute to sterilization of the surgical fields [1], and antibiotic ophthalmic solutions such as cephems and quinolones are used routinely [2]. Drug-induced lung injury due to quinolones is rare, and only six cases associated with tablets or injections have been reported previously [[3], [4], [5], [6], [7], [8]]. Furthermore, most of the adverse effects caused by levofloxacin ophthalmic solutions are local reactions. Here we present the first case of drug-induced lung injury considered to be due to levofloxacin eye drops.\n\n2 Case report\nA 78-year-old man was admitted to the Department of Ophthalmology for binocular cataract surgery. He was a current smoker, and had a past history of hypertension and hyperlipidemia. He had been treated with nifedipine, candesartan, atorvastatin, doxazosin and sarpogrelate for three years. However, he had never had an allergic reaction. The history of pre-exposure of levofloxacin was not clear. He had no abnormality in preoperative examination. On the day of admission, levofloxacin eye drops were started as a perioperative prophylactic antibacterial drug, and the operation was performed on the next day without complications. On day 3, he presented with fever and dyspnea but with no change in the surgical sites; he was treated with cefcapene pivoxil. However, the hypoxia and oliguria rapidly worsened, and laboratory examination revealed neutrophilia, elevation of the C-reactive protein, and impairment of liver and kidney function (Table 1). Chest X-ray and computed tomography (CT) showed bilateral non-segmental consolidation with thickening of the bronchovascular bundles and pleural effusion, mainly in the left upper lobe (Fig. 1). No abnormal findings were noted in electrocardiogram and ultrasound cardiography. As we considered the differential diagnosis (bacterial pneumonia followed by sepsis, acute renal failure, or diastolic heart failure since brain natriuretic peptide [BNP] was 511 pg/mL), continuous hemodiafiltration and treatment with tazobactam/piperacillin (TAZ/PIPC) were started along with ventilatory support in the intensive care unit. After that, the renal function improved, but respiratory failure and fever were prolonged in spite of changing TAZ/PIPC to meropenem (MEPM). Furthermore, an increase in airway pressure with accompanying wheezes developed, but these symptoms were temporarily improved with corticosteroid treatment. Various microbial examinations and tests for autoantibodies were negative (Table 1). On day 10, bronchoalveolar lavage fluid (BALF) was obtained revealing an increase in lymphocytes and eosinophils (Table 1). Based on these results, we considered a diagnosis of drug-induced lung injury, so we stopped nicardipine hydrochloride and sivelestat sodium and changed MEPM to levofloxacin injection. However, the patient's respiratory condition worsened, and liver dysfunction also re-emerged. Therefore, levofloxacin injections were stopped, and we administered steroid therapy. Afterwards, the respiratory failure and liver dysfunction gradually improved. However, since the fever continued, we reconfirmed the patient's list of drugs in detail and found that levofloxacin eye drops had been continued. The drops were immediately discontinued. After that, the fever and respiratory failure resolved, and the patient was extubated on day 22. We made the diagnosis of lung injury induced by levofloxacin eye drops based on the positive results of a drug lymphocyte stimulation test (DLST) of levofloxacin (Table 2) and the episode of deterioration after levofloxacin injection. The patient was discharged on day 57, and he was weaned from steroids gradually without recurrence (Fig. 2).Fig. 1 Chest X-ray and chest plain computed tomography (CT) on postoperative day 2. (A) Chest radiograph showed ground glass attenuations (GGAs) and consolidation in the right upper lung fields and left upper and middle lung fields. (B) and (C) CT showed bilateral non-segmental consolidation and GGAs with thickening of bronchovascular bundles and pleural effusion mainly in the left upper lobes.\n\nFig. 1Fig. 2 Clinical course. Steroid therapy and levofloxacin withdrawal resulted in improvement of respiratory failure and liver function. FOM, fosfomycyn; LVFX, levofloxacin; DKB, Dibekacin; TAZ/PIPC, tazobactam/piperacillin; MEPM, meropenem; CHDF, continuous hemodiafiltration; CS, corticosteroids; mPSL, methylprednisolone; PSL, prednisolone.\n\nFig. 2Table 1 Laboratory findings on postoperative day 2.\n\nTable 1CBC\tBlood chemistry\t(1 → 3)-β-D-glucan\t<5.0\tpg/mL\t\nWBC\t12780\t/μL\tTP\t5.3\tg/dL\tAspergillus antigen\tnegative\t\nNeu\t90\t%\tAlb\t2.4\tg/dL\tCryptococcus antigen\tnegative\t\nLym\t7\t%\tT-bil\t1.6\tmg/dL\tC. pneumoniae IgG\tpositive\t\nEos\t0\t%\tAST\t92\tU/L\tC. pneumoniae IgA\tnegative\t\nRBC\t3.67 × 106\t/μL\tALT\t130\tU/L\tC. pneumoniae IgM\tnegative\t\nHb\t11.6\tg/dL\tLDH\t234\tU/L\tM. pneumoniae antibody\tnegative\t\nHt\t34.0\t%\tBUN\t60.1\tmg/dL\tRapid-Antigen Tests\t\nPlt\t17.5 × 104\t/μL\tCRE\t2.77\tmg/dL\tInfluenza\tnegative\t\nCoagulation test\tNa\t138\tmEq/L\tLegionella pneumophila\tnegative\t\nPT-INR\t1.27\t\tK\t4.8\tmEq/L\tStreptococcus pneumonia\tnegative\t\nAPTT\t29.8\ts\tSerology\tCulture\t\nFib\t795\tmg/dL\tCRP\t26.45\tmg/dL\tBlood, Sputum, Urine, BALF\tnegative\t\nFDP\t3.0\tng/mL\tKL-6\t188\tU/mL\tBALF (day10)\t\nArterial blood gases\tSP-D\t534\tng/mL\tTotal cell counts\t3.2 × 105\t%\t\nmask with reservoir 10L/min\tIgE\t892.8\tIU/mL\tMac\t14.4\t%\t\npH\t7.318\t\tAnti-nuclear antibody\t<40\ttiter\tNeu\t34.6\t%\t\npO2\t62.0\tTorr\tRF\t<10\tIU/mL\tLym\t36.2\t%\t\npCO2\t40.7\tTorr\tMPO-ANCA\t<1.0\t\tEos\t14.8\t%\t\nHCO3-\t20.3\tmEq/L\tPR3-ANCA\t<1.0\t\tCD4/8\t2.55\t\t\nAbbreviation: BALF, bronchoalveolar lavage.\n\nTable 2 Drug-induced Lymphocyte Stimulation Test.\n\nTable 2Drugs\tMeasured value (cpm)\tStimulation Index (%)\t\nlevofloxacin intravenous drip infusion\t1237\t327\t\nlevofloxacin ophthalmic solution\t917\t242\t\nfosfomycin (intravenous)\t328\t86\t\ncefcapene pivoxil\t341\t90\t\ntazobactam piperacillin\t331\t87\t\nmeropenem\t331\t87\t\ndiclofenac ophthalmic solution\t243\t64\t\ncontrol\t378\t\t\nBold font: positive for DLST.\n\n\n\n3 Discussion\nWe experienced a suspected case of levofloxacin eye drops induced lung injury. Drug-induced lung injury caused by levofloxacin is rare compared with the frequency of its use, but it is a serious adverse event. Table 3 shows a summary of reported cases of drug-induced lung injury due to quinolones. To the best of our knowledge, there are only four cases of drug-induced lung injury due to levofloxacin, which were induced by tablets or injections [[3], [4], [5], [6]]. As for other quinolones, there was only one case associated with ciprofloxacin and tosufloxacin, respectively [7,8]. Levofloxacin ophthalmic solution is one of the most widely used antimicrobial eye drops in the world, and adverse effects are mostly local reactions. Systemic adverse effects are very few and include only anaphylaxis and contact dermatitis [9,10]. As far as we could investigate in the published literature and in information about cases of suspected adverse drug reactions reported to the Pharmaceuticals and Medical Devices Agency (PMDA), drug-induced lung injury due to ophthalmic antibacterial agents has never been reported; thus, this is the first reported case of drug-induced lung injury due to levofloxacin eye drops [11].Table 3 Clinical features of fluoroqinolone-induced pneumonia.\n\nTable 3Authors\tSuspected Drugs\tForm\tAge\tSex\tPeripheral Eosinophil\tIgE (IU/L)\tBAL (%) Eos/Lym\tPathological Diagnosis (Collection Method)\tLST\tChallenge Test\tTherapy\t\nFujimori et al. [3]\tlevofloxacin\ttablet\t76\tF\t24% (2784/μl)\t112\t55/24\teosinophilic pneumonia (TBLB)\tpositive (LMIF)\tNR\tdrug\nwithdrawal\t\nTohyama et al. [4]\tLevofloxacin shin-i-seihai-to\ttablet\t55\tF\t6.2% (390/μl)\t197\t12/34\torganizing pneumonia (TBLB)\tpositive (DLST)\tNR\tdrug\nwithdrawal\t\nSibusa et al. [5]\tlevofloxacin\nroxoprophen\ttablet\t39\tM\t0%\tNR\t43/0\tNR\tpositive (DLST)\tNR\tsteroid\t\nNicola et al. [6]\tlevofloxacin\tinjection\t44\tM\tNR\tNR\t28/15\teosinophilic pneumonia (TBLB)\tNR\tpositive\tsteroid\t\nSteiger et al. [7]\tciprofloxacin\ttablet\t68\tF\tNR\tNR\t87/0\thypersensitivity pneumonitis (SLB)\tnegative (DLST)\tNR\tsteroid\t\nKimura et al. [8]\ttosufloxacin\ttablet\t74\tM\t7% (931/μl)\t16196\t21/38\teosinophilic pneumonia (TBLB)\tnegative (DLST)\tpositive\tsteroid\t\nThis case\tlevofloxacin\teye drop; injection\t78\tM\t0%\t892.8\t14.8/36.2\tnot done\tpositive (DLST)\tpositive\tsteroid\t\nAbbreviation: NR, not recorded; Eos/Lym, eosinophil/lymphocyte; TBLB, transbronchial lung biopsy; SLB, surgical lung biopsy; LST, lymphocyte stimulation test; LMIT, lymphocyte migration inhibitory test; DLST, drug lymphocyte stimulation test.\n\n\n\nThe pathophysiologic mechanism of drug-induced lung injury is mostly unknown except for a small number of drugs; basically, it is considered that drugs have direct toxicity, act like a hapten, or mimic an antigen that activates immune cells [12]. Levofloxacin ophthalmic solution is absorbed into the systemic circulation from the nasal mucosa via the conjunctival blood vessels and the nasolacrimal ducts after ocular administration, but its plasma concentration is extremely low as compared with oral administration. One possibility is that this case was sensitized by an extremely small amount of levofloxacin in the systemic circulation. Although the patient did not show any local symptoms after ocular instillation, another possibility is sensitization by the antigen presented to the Langerhans cells in the conjunctiva, followed by pulmonary injury expressed as a delayed type of allergy [13,14]. DLST indicates the presence of sensitized lymphocytes, and the patient had a positive DLST for levofloxacin [15]. Based on all of these findings, we concluded that delayed allergy due to cellular immunity caused this adverse effect.\n\nWe diagnosed lung injury induced by levofloxacin eye drops because of the following points: an episode of deterioration after levofloxacin injection, negative results of the examination for infections and autoimmune diseases, and improvement after administration of steroids and discontinuation of levofloxacin administration by both injection and eye drops. In addition, positive DLST results with only levofloxacin eye drops and injection (Stimulation Index 242, 327), even during steroid administration, helped to confirm the diagnosis (Table 2). In the past reports of quinolone-induced lung injury (Table 3), three of five cases had a positive DLST, resulting in the same positive rate of 60.0% that Kondo et al. reported [16]. We consider that DLST is a meaningful test when a drug challenge test is difficult, as in the current case.\n\nIn this case, the radiographic findings showed non-segmental consolidation, ground glass attenuations with thickening of the bronchovascular bundles, pleural effusion and mild lymphadenopathy. BALF analysis revealed higher lymphocyte number compared to eosinophil number. These results indicated the possibility of eosinophilic pneumonia (EP) pattern or organizing pneumonia pattern. Although we could not make a pathological diagnosis due to the patient's severe respiratory failure, we finally assessed pulmonary condition of this case as EP pattern based on the BALF analysis showing increased eosinophil number and increased total serum IgE level. EP case showing higher lymphocyte number compared to eosinophil number in BALF was reported [8]. In addition, previously reported cases diagnosed as fluoroqinolone-induced pneumonia tended to show EP pattern than other patterns (Table 3). And we also considered the possibility that eosinophil in BALF may have been affected by the corticosteroid, as BALF was performed after its administration. Moreover, levofloxacin has low cardiotoxicity, and there are only four reports of pulmonary edema or cardiac failure in the information about reported cases of suspected adverse drug reaction by PMDA [11,17]. However, based on the elevation of the BNP and radiographic changes, it is also possible that diastolic heart failure may have occurred concomitantly.\n\nThere were some limitations in this case. We could not completely confirm the diagnosis as having lung injury induced by levofloxacin eye drops because we could not exclude the possibility that lung injury was induced by other drugs such as meropenem or dicrofenac [18,19], or infection was complicated with lung injury. In addition, we could not do rechallenge test of levofloxacin eye drops because drug induced lung injury was life-threatening.\n\nThe basis of the treatment of drug-induced lung injury is to discontinue the causative drug immediately. In this case, fever and respiratory failure were prolonged even after initiation of steroid administration and finally improved after discontinuation of levofloxacin eye drops. Levofloxacin, which has high efficacy and tolerability, is widely used in various dosage forms. As cataracts are still the most common cause of blindness, cataract surgery is expected to continue to increase in the future [20]. Drug-induced lung injury may occur with any drug and by any route of administration; eye drops are especially easy to overlook as causative drugs, and special attention is required.\n\nConflict of interest\nThe authors have no potential conflicts of interest to disclose.\n\nFunding sources\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Inoue Y. Usui M. Shiota H. Yamazaki T. Preoperative Disinfection Study Group. Perioperative disinfection of the conjunctival sac with antibiotics and iodine compounds: a prospective randomized multicenter study Jpn. J. Ophthalmol. 52 2008 151 161 18661264 \n2 Matsuura K. Mori T. Miyamoto T. Suto C. Saeki Y. Survey of Japanese ophthalmic surgeons regarding perioperative disinfection and antibiotic prophylaxis in cataract surgery Clin. Ophthalmol. 8 2014 2013 2018 25302013 \n3 Fujimori K. Shimatsu Y. Suzuki E. Arakawa M. Gejyo F. Levofloxacin-induced eosinophilic pneumonia complicated by bronchial asthma Nihon Kokyuki Gakkai Zasshi 38 2000 385 390 (in Japanese, Abstract in English) 10921286 \n4 Tohyama M. Arakaki N. Tamaki K. Shimoji T. A case of drug-induced pneumonitis due to levofloxacin and kanpo medicine Nihon Kokyuki Gakkai Zasshi 44 2006 951 956 (in Japanese, Abstract in English) 17233393 \n5 Shibusa T. Onuma K. A case of possible drug-induced lung injury caused by levofloxacin Nihon Kyoubu Rinsho 74 2015 691 696 (in Japanese, Abstract in English) \n6 Facciolongo N. Menzella F. Castagnetti C. Cavazza A. Piro R. Eosinophilic infiltrate in a patient with severe legionella pneumonia as a levofloxacin-related complication: a case report J. Med. Case Rep. 4 2010 360 21070648 \n7 Steiger D. Bubendorf L. Oberholzer M. Tamm M. Leuppi J.D. Ciprofloxacin-induced acute intestinal pneumonitis Eur. Respir. J. 23 2004 172 174 14738249 \n8 Kimura N. Miyazaki E. Matsuno O. Abe Y. Tsuda T. Drug-induced pneumonitis with eosinophilic infiltration due to tosufloxacin tosilete Nihon Kokyuki Gakkai Zassi 36 1998 618 622 (in Japanese, Abstract in English) \n9 Saito M. Nakada T. Contact urticaria syndrome from eye drops: levofloxacin hydrate ophthalmic solution J. Dermatol. 40 2013 130 131 23110602 \n10 Santen Pharmaceutical Co., Ltd. Cravit ophthalmic solution 0.5%, Iyakuhin interview form Internet. Tokyo: Pharmaceuticals and Medical Devices Agency. www.info.pmda.go.jp/go/interview/1/300237_1319742Q1039_1_1F [3 May 2018] (in Japanese).\n11 Information about reported cases suspected adverse drug reaction. Pharmaceuticals and Medical Devices Agency. http://www.info.pmda.go.jp/fsearchnew/jsp/menu_fukusayou_base.jsp [Accessed 3 May 2018] (in Japanese).\n12 Kubo K. Azuma A. Kanazawa M. Kameda H. Kusumoto M. Consensus statement for the diagnosis and treatment of drug-induced-lung injuries Respir. Investig. 51 2013 260 277 \n13 Gillette T.E. Chandler J.W. Greiner J.V. Langerhans cells of the ocular surface Ophthalmology 89 1982 700 711 7122047 \n14 Metz D.P. Bacon A.S. Holgate S. Lightman S.L. Phenotypic characterization of T cells infiltrating the conjunctiva in chronic allergic eye disease J. Allergy Clin. Immunol. 98 1996 686 696 8828547 \n15 Pichler W.J. Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity Allergy 59 2004 809 820 15230812 \n16 Kondo A. Drug-induced pneumonitis Kekkaku 74 1999 33 41 (in Japanese) 10067054 \n17 Carbon C. Levofloxacin adverse effects, data from clinical trials and pharmacovigilance Therapie 56 2001 35 40 11322015 \n18 Celik Al Deniz A. Tangalay M. Karaaslan M.B. Kılıç Bağır Eosinophilic myocarditis associated with eosinophilic pneumonia and eosinophilia following antibiotic and narcotic analgesic treatment Turk Kardiyol Dern Ars 44 2016 511 513 27665334 \n19 Khalil H. Molinar E. Stoller J.K. Diclofenac (Voltaren)-induced eosinophilic pneumonitis. Case report and review of the literature Arch. Intern. Med. 26 1993 1649 1652 \n20 Boume R.R. Stevens G.A. White R.A. Smith J.L. Flaxman S.R. Causes of vision loss worldwide, 1990-2010: a systemic analysis Lancet Glob. Health 1 2013 e339 349 25104599\n\n",
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"journal": "Respiratory medicine case reports",
"keywords": "BALF, bronchoalveolar lavage fluid; BNP, brain natriuretic peptide; CT, computed tomography; DLST, drug lymphocyte stimulation test; Drug-induced lung injury; EP, eosinophilic pneumonia; Eosinophilic pneumonia; Eye drop; Levofloxacin; MEPM, meropenem; Ophthalmic solution; PMDA, Pharmaceuticals and Medical Devices Agency; TAZ/PIPC, tazobactam/piperacillin",
"medline_ta": "Respir Med Case Rep",
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"title": "A case of drug induced lung injury caused by levofloxacin eye drops.",
"title_normalized": "a case of drug induced lung injury caused by levofloxacin eye drops"
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"abstract": "Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, and the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome are two distinct clinical conditions caused by heterozygous mutations of the PSTPIP1 gene. While skin and joint involvements are shared by both conditions, PAMI is characterized by hepatosplenomegaly, pancytopenia, and growth failure. Kidney involvement is exceptional in PSTPIP1-mediated disorders. The two missense PSTPIP1 variants associated with PAMI syndrome are p.E250K and p.E257K. Long-term treatment with interleukin (IL)-1 inhibitors is effective to control inflammatory manifestations and is usually well-tolerated. We report a case of a patient carrying the PSTPIP1 p.E250K mutation who developed a late-onset kidney involvement despite a long treatment with canakinumab and anakinra. Kidney biopsy showed focal segmental glomerulosclerosis that was treated with tacrolimus (0.1 mg/kg/day in two doses). A literature revision with the aim to assess the proportion and type of kidney involvement in PAMI syndrome revealed that heterogeneous nephropathies may be part of the clinical spectrum. Our study supports the importance of a periodic diagnostic work-up, including kidney laboratory tests and kidney biopsy, in individuals affected with PAMI syndrome. Kidney and liver functions may be impaired regardless of anti-cytokines treatments and additional therapy approaches (i.e., multi-drugs, hematopoietic stem cell transplantation) should be carefully considered.",
"affiliations": "Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Science (DINOGMI), Università degli Studi di Genova, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Science (DINOGMI), Università degli Studi di Genova, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Science (DINOGMI), Università degli Studi di Genova, Genoa, Italy.;Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Laboratorio di Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto Giannina Gaslini, Genoa, Italy.",
"authors": "Borgia|Paola|P|;Papa|Riccardo|R|;D'Alessandro|Matteo|M|;Caorsi|Roberta|R|;Piaggio|Giorgio|G|;Angeletti|Andrea|A|;Ceccherini|Isabella|I|;Ghiggeri|Gian Marco|GM|;Gattorno|Marco|M|",
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"doi": "10.3389/fmed.2021.759092",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.759092\nMedicine\nCase Report\nKidney Involvement in PSTPIP1 Associated Inflammatory Diseases (PAID): A Case Report and Review of the Literature\nBorgia Paola 1 †\n\nPapa Riccardo 1 2 †\n\nD'Alessandro Matteo 1 3\nCaorsi Roberta 2\n\nPiaggio Giorgio 3\nAngeletti Andrea 3 4\n\nCeccherini Isabella 5\n\nGhiggeri Gian Marco 3 4\n\nGattorno Marco 2 *\n\n1Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Science (DINOGMI), Università degli Studi di Genova, Genoa, Italy\n2Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto Giannina Gaslini, Genoa, Italy\n3Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy\n4Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy\n5Laboratorio di Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Genoa, Italy\nEdited by: Xu-jie Zhou, Peking University First Hospital, China\n\nReviewed by: Angelo Valerio Marzano, University of Milan, Italy; David Andrew Fulcher, Australian National University, Australia\n\n*Correspondence: Marco Gattorno marcogattorno@gaslini.org\nThis article was submitted to Nephrology, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work and share first authorship\n\n29 10 2021\n2021\n8 75909215 8 2021\n27 9 2021\nCopyright © 2021 Borgia, Papa, D'Alessandro, Caorsi, Piaggio, Angeletti, Ceccherini, Ghiggeri and Gattorno.\n2021\nBorgia, Papa, D'Alessandro, Caorsi, Piaggio, Angeletti, Ceccherini, Ghiggeri and Gattorno\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nPyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, and the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome are two distinct clinical conditions caused by heterozygous mutations of the PSTPIP1 gene. While skin and joint involvements are shared by both conditions, PAMI is characterized by hepatosplenomegaly, pancytopenia, and growth failure. Kidney involvement is exceptional in PSTPIP1-mediated disorders. The two missense PSTPIP1 variants associated with PAMI syndrome are p.E250K and p.E257K. Long-term treatment with interleukin (IL)-1 inhibitors is effective to control inflammatory manifestations and is usually well-tolerated. We report a case of a patient carrying the PSTPIP1 p.E250K mutation who developed a late-onset kidney involvement despite a long treatment with canakinumab and anakinra. Kidney biopsy showed focal segmental glomerulosclerosis that was treated with tacrolimus (0.1 mg/kg/day in two doses). A literature revision with the aim to assess the proportion and type of kidney involvement in PAMI syndrome revealed that heterogeneous nephropathies may be part of the clinical spectrum. Our study supports the importance of a periodic diagnostic work-up, including kidney laboratory tests and kidney biopsy, in individuals affected with PAMI syndrome. Kidney and liver functions may be impaired regardless of anti-cytokines treatments and additional therapy approaches (i.e., multi-drugs, hematopoietic stem cell transplantation) should be carefully considered.\n\nPSTPIP1\nPAPA syndrome\nPAMI syndrome\nkidney\nIL-1 inhibitors\n==== Body\npmcIntroduction\n\nProline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) is a cytoskeleton adaptor protein mainly expressed in hematopoietic cells. Mutations of the PSTPIP1 gene were associated with a large group of inflammatory disorders collected under the term PSTPIP1-associated inflammatory diseases (PAID) (1, 2). The clinical spectrum of PAID ranges from a prevalent skin and joint involvement in case of pyogenic arthritis, pyoderma gangrenosum, and acne (pyoderma gangrenosum, acne, pyogenic arthritis, PAPA) syndrome, to more complex phenotypes involving several organs in case of the PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome (3, 4).\n\nThe PAMI syndrome is due to the p.E250K and p.E257K missense mutations of the PSTPIP1 gene. Clinical manifestations may include cytopenia, recurrent infections, vasculitis-associated skin ulcers, hepatomegaly, splenomegaly, lymphadenopathy, and growth failure. High serum calprotectin and zinc concentration is the laboratory hallmark of the disease.\n\nSteroid administration represents the cornerstone of treatment, resulting in effectiveness in about 55% of cases (5). In remaining cases, also the steroid-sparing drugs, such as the anti-cytokines biologics, may result not be completely effective in preventing the long-term complications. Hematopoietic stem cell transplantation has been recently proposed for the management of severe hematological manifestations (i.e., cytopenia) in complicated forms not responsive to conventional anti-cytokine treatments (6).\n\nHere, we report a 22-year-old male previously included in a PAMI cohort (1), receiving chronic treatment with interleukin (IL)-1 inhibitor and presenting kidney involvement resulting in chronic kidney disease. We also present a literature review of this rare complication.\n\nCase Presentation\n\nA 4-year-old Caucasian boy was referred to our unit for recurrent episodes of asymmetrical polyarthritis at the large joints of the lower limbs (Table 1). Family history was negative. Since he was 6 months, physical examination revealed mild hepatomegaly and splenomegaly. Laboratory tests showed microcytic anemia (hemoglobin 11 g/dL, mean corpuscular volume 70 fL), neutropenia (780 neutrophils/mm3), and the bone marrow analysis revealed dyserythropoiesis. Joint aspirations showed sterile but purulent fluid. Partial control of the symptoms was achieved with multiple intra-articular steroid injections.\n\nTable 1 Characteristics of the patient.\n\nAge (years)\t4\t8\t12\t15\t19\t20\t21\t22\t\nClinical manifestations\t\t\t\t\t\t\t\t\t\nSterile pyogenic arthritis\t+\t–\t–\t–\t–\t–\t–\t–\t\nPyoderma gangrenosum\t–\t+\t+\t–\t–\t–\t–\t–\t\nCystic acne\t–\t–\t+\t–\t–\t+\t–\t–\t\nHepato\nsplenomegaly\t+\t+\t+\t+\t+\t+\t+\t+\t\nGrowth failure\t–\t–\t–\t+\t+\t+\t+\t+\t\nLaboratory tests\t\t\t\t\t\t\t\t\t\nHemoglobin (g/dL)\t11\t10\t11\t11\t11\t11\t11\t11\t\nWhile blood cells (number/mmc)\t3,000\t3,760\t3,000\t3,260\t7,270\t10,630\t4,900\t4,000\t\nC-reactive protein (mg/dL)\tND\tND\t5.32\t1.64\t1.3\t11.8\t0.86\t0.6\t\nSerum amyloid A (mg/L)\tND\tND\t73\t14.8\t42.6\t213\t3.7\t4\t\nCreatininemia (mg/dL)\tND\tND\t0.54\t0.81\t0.79\t1.55\t1.57\t1.7\t\nProteinuria (g/24 h)\tAbsent\tAbsent\tAbsent\tAbsent\t4.49\t4.28\t3.18\t3.2\t\nTreatments\t\t\t\t\t\t\t\t\t\nIntra-articular steroid injections\t+\t–\t–\t–\t–\t–\t–\t–\t\nTopical steroids and antibiotics\t–\t+\t+\t–\t–\t–\t–\t–\t\nOral prednisone\t–\t–\t–\t–\t–\t+\t+\t–\t\nCanakinumab\t–\t–\t–\t+\t+\t–\t+\t+\t\nTacrolimus\t–\t–\t–\t–\t–\t+\t–\t–\t\nAllopurinol\t–\t–\t–\t–\t–\t+\t+\t+\t\nACE inhibitor\t–\t–\t–\t–\t–\t–\t+\t+\t\nACE, angiotensin-converting enzyme; ND, not determined.\n\nSince 8 years of age, severe pyoderma gangrenosum started at the periorbital and periungual area [refer to Figure 1B of reference (1)]. Local treatments with antibiotics and steroids were ineffective, and surgical exportation was needed. Due to the very early onset of atypical inflammatory skin and joint involvement and the evidence of high serum levels of zinc and calprotectin (113 μmol/L, normal <50, and 14 μg/mL, normal <0.5, respectively), the Sanger sequencing analysis of the PSTPIP1 gene was performed, revealing the heterozygous c.748G>A, p.E250K mutation. Therefore, the diagnosis of PAMI syndrome was confirmed.\n\nSince 10 years of age, only the inflammatory skin manifestations persisted: biweekly infusion of human monoclonal anti-tumor necrosis factor (TNF)α antibody adalimumab resulted ineffectively. Since 13 years of age, severe nodulocystic acne has also developed in the face. Oral colchicine was administered but early stopped after 2 weeks due to abdominal pain. IL-1 receptor 1 (IL1R1) antagonist (anakinra) was then attempted, resulting in a prompt clinical improvement of skin lesions. Due to poor patient's compliance, after 2 years, anakinra was replaced with a monthly infusion of the fully human monoclonal anti-IL-1beta antibody canakinumab (7).\n\nAt 15 years of age, the weight and height were 48 kg and 147 cm, respectively, revealing a growth failure (10th and <3rd percentile based on Tanner's growth charts). The low serum IGF-1 levels and the abnormal provocative test with arginine confirmed a growth hormone deficiency: the recombinant growth hormone therapy was proposed but refused by the family. After that, the patient performed a blood and urine test every 6 months. At the age of 18, the patient was transferred to a local adult rheumatology unit. Due to administrative issues, the supply of IL-1 monoclonal antibody by the local health system was not regular, leading to transient flares of the skin manifestations, treated with an oral steroid.\n\nAt the age of 19 years, the patient was seen for a long-term follow-up visit in our center. Laboratory tests showed new onset of proteinuria in the nephrotic range (4.5 g/daily), microhematuria, and hyperuricemia (9 mg/dL), with normal kidney function (creatininemia 0.8 mg/dl, estimated glomerular filtration rate 129 ml/min/1.73 m2). Mild hypoalbuminemia (3,340 mg/dl) and slightly elevated acute phase reactants (C-reactive protein 1.30 mg/dl, serum amyloid A 42.6 mg/L) were also reported. The patient was referred to a local adult nephrologist for competence. Needle kidney biopsy revealed focal segmental glomerulosclerosis (FSGS) without evidence of amyloid deposition. Canakinumab was discontinued, and prednisone (30 mg daily) was started. After 5 months, proteinuria was still in the nephrotic range (4.3 g/daily) with worsening of renal function (creatininemia 1.5 mg/dL, eGFR 63 ml/min/1.73 m2). Tacrolimus (maintaining serum range of 4–6 ng/dl) was started, and canakinumab restarted due to worsening of the skin inflammatory manifestations (Figure 1A), resulting in a prompt clinical improvement of skin lesions (Figure 1B). One year later, due to the persistence of proteinuria in the nephrotic range (3.2 g/daily) with stable renal function (creatininemia 1.7 mg/dL, eGFR 56 ml/min/1.73 m2), a second kidney biopsy was performed in our center, showing interstitial fibrosis (Figures 1C–F). Thus, tacrolimus was discontinued, prednisone gradually tapered, and he is still receiving canakinumab at the dose of 150 mg monthly.\n\nFigure 1 Skin manifestations and kidney histology of the patient. Photos show cystic acne before (A) and after (B) rechallenge of canakinumab. Histology analysis shows interstitial fibrosis with interstitial infiltration by mononuclear cells and tubular atrophy, classical and with aspects of thyroidization; tubular lumens are dilated and with flaking material; epithelium of some tubules appears vacuolated; segmental hyalinosis of arteriole is also present (C,D; periodic acid–Schiff staining; original magnification × 50 and × 200, respectively). Diffuse interstitial fibrosis (E,F; trichrome staining; original magnification at × 50 and × 200, respectively).\n\nThe acute phase reactants were almost completely normalized (Table 1). Of note, mild anemia and neutropenia persist together with hepatosplenomegaly.\n\nDiscussion\n\nIn the context of the clinical spectrum of PSTPIP1-related disorders, renal involvement is reported only in PAMI syndrome. All the English articles found in the PubMed database by querying MEDLINE with the keywords “PSTPIP1” or “PAPA” or “PAMI” were revised. We found 179 articles, among them, only seven articles reported patients with p.E250K or p.E257K mutation, of which four did not report a kidney involvement. In total, only five subjects with the PAMI-associated PSTPIP1 mutations displayed a renal involvement with at least three different phenotypes: glomerular vasculitis in three subjects, tubule-interstitial infiltration, probably related to a systemic inflammatory state, in one subject, and glomerular calprotectin deposition in the remaining one. No evidence of amyloid or immune complex deposition has been reported. Thus, kidney involvement in PAMI seems to present with heterogeneous manifestations and is linked with specific variants of the PSTPIP1 gene. Of note, 2/6 (33%) patients in Table 2 developed end-stage liver cirrhosis, leading them to liver transplant.\n\nTable 2 Reported cases of kidney involvement in PSTPIP1-associated inflammatory diseases.\n\nPatient number\t1\t2\t3\t4\t5\t6\t\nStudy\tHolzinger et al. (1)\tHolzinger et al. (1)\tHolzinger et al. (1)\tLindwall et al. (8)\tDai et al. (9)\tPresent case\t\nGender\tMale\tFemale\tMale\tMale\tFemale\tMale\t\nAge (years)\t35*\t9\t16\t25\t56\t22\t\nAge at onset (years)\t6\t0\t1\t4\t18\t4\t\nDisease duration (years)\t29\t9\t15\t19\t38\t18\t\nPSTPIP1 p.E250K\tY\tY\tY\tY\tY\tY\t\nClinical manifestations\t\nArthritis\tY\tN\tY\tY\tY\tY\t\nPyoderma gangrenosum\tY\tN\tY\tY\tN\tY\t\nCystic acne\tN\tY\tY\tY\tN\tY\t\nSkin ulcers\tY\tN\tN\tY\tN\tN\t\nPoor wound healing\tY\tN\tN\tN\tY\tY\t\nHepatomegaly\tY\tY\tY\tY\tY\tY\t\nSplenomegaly\tY\tY\tY\tN\tY\tY\t\nGrowth failure\tN\tY\tY\tN\tN\tY\t\nKidney involvement\tMinimal-change glomerulonephritis\tIgA nephropathy\tGlomerulonephritis\tAcute kidney failure\tPodocyte effacement and glomerular calprotectin dense deposits\tFocal segmental glomerulosclerosis\t\nOthers\tLiver cirrhosis, post liver transplant complications\tMild lymphadenopathy, arthralgia, gastrostomy tube feeding, familiarity for early gout\tAseptic necrosis of femoral head\tOsteomyelitis, acute cholecystitis, sepsis, colitis, cellulitis, acute respiratory failure, epistaxis, joint and skin laxity, familiarity for psoriatic arthritis\tRecurrent pneumonia, lymphadenopathy, macronodular cirrhosis with mild portal hypertension\tGrowth hormone deficiency\t\nLaboratory tests\t\nAnemia\tY\tY\tY\tY\tY\tY\t\nNeutropenia\tY\tY\tY\tY\tY\tY\t\nOthers\tN\tThrombocytopenia, MEFV p.E148Q carrier\tN\tN\tVon Willebrand's factor deficiency, high agammaglobulinemia\tDyserythropoiesis at the bone marrow biopsy\t\nTreatments\t\nSteroid-sparing drugs (duration; clinical response)\tAnakinra (2 months; partial), infliximab (3 months; partial)\tCyclosporin (ND; partial), colchicine (NT) anakinra (ND; complete)\tCyclosporin (ND; partial), mycophenolate mofetil (ND; none), rituximab (NT), tocilizumab (ND; partial)\tInfliximab (ND; none)\tSulfasalazine (ND; none), methotrexate (ND; none), colchicine (ND; complete)\tColchicine (NT), adalimumab (3 months; none), anakinra (ND; complete), canakinumab (ND; complete), tacrolimus (ND; partial)\t\n* Age of death; ND, not determined; NT, not tolerated; PSTPIP1, proline-serine-threonine phosphatase-interacting protein 1.\n\nThe triad of vasculitis, cytopenia, and lymphoproliferation described in PAMI can be related to specific ligands of the PSTPIP1 protein. In fact, PSTPIP1 is not expressed primitively in the kidney, whereas it is highly expressed in hematopoietic cells. The protein is able to bind with immune-related proteins, like the cytosolic protein tyrosine phosphatase (PTP-PEST), the Wiskott–Aldrich syndrome protein (WASP), the c-Abl kinase (ABL), the CD2, and the Fas ligand, probably with the aim to counteract the cytotoxic cell functioning (10) (Figure 2).\n\nFigure 2 Simplified structure of PSTPIP1 protein. Fes/CIP4 homology domain (FCH), CDC15-like adaptor protein (CDC15-like), SRC Homology 3 Domain (SH3) are shown. Note the position of the PAMI-associated mutations (E250K and E257K). PSTPIP1 interacting proteins include the protein-tyrosine phosphatase (PTP-PEST), pyrin, the Wiskott–Aldrich syndrome protein (WASP), the c-Abl kinase, CD2, and the Fas ligand (FASL). PSTPIP1, proline-serine-threonine phosphatase-interacting protein 1.\n\nMutations associated with PAID decrease the binding activity of the protein to PTP-PEST (11), suggesting that gain and loss of function should be considered. Furthermore, despite T cells do not show a prevalent involvement in PAID lesions, the mild lymphoproliferation described in some patients with PAMI may be related to a T-cell activation defect caused by abnormal CD2 binding activity or absence of the Fas ligand, may be due to its sequestration into lysosomes. Moreover, WASP and ABL are actin-related proteins and the cytopenia and vasculitis of PAMI patients may be secondary to their dysfunction, as reported in patients with actin remodeling defects (12, 13). Thus, PAMI syndrome represents the most severe form of the PAID spectrum, and its clinical manifestations may be secondary also to actin remodeling defect and lymphocytes hyperactivation, other than the high IL-1 production as for others PAID.\n\nAs reported, kidney biopsy was negative for amyloid deposition (14), in line with previous reports (Table 2), and the histological findings do not support calprotectin deposition as recently described (9). Therefore, other pathogenic mechanisms causing kidney lesions should be investigated. In the first kidney biopsy, a diagnosis of FSGS was reported. The pathogenic mechanism of FSGS remains still poorly understood (15). Recent findings demonstrated the role of the IL-1 pathway as a possible pathogenic mechanism in proteinuric disease, supporting therefore the administration of treatments blocking the IL-1β/IL-1R1 signaling to delay the development of sclerotic lesions (16). In the second kidney biopsy, performed despite stable renal function and proteinuria, a diffused tubule-interstitial fibrosis was revealed, probably due to tacrolimus administration, thus discontinued. Notably, our patient developed proteinuria after irregular administration of IL-1 inhibitors: scarce adherence to IL-1 receptor antagonist (anakinra) was admitted, as above reported and, due to local administrative issues, the supplying of canakinumab was rather inconstant. At this stage, it is difficult to determine the real IL-1 dependence of the renal manifestation.\n\nAs reported in Table 2, in patient 4, colchicine was effective in reversing proteinuria. A multi-drug approach may control various manifestations of PAMI by silencing the concomitant defects of different components of the immune system. Furthermore, it remains a matter of speculation that the kidney involvement of other pyrin-related autoinflammatory disorders may not be due only to amyloid deposition. More studies are required to investigate the mechanisms of renal involvement and the possible role of anti-IL drugs against these manifestations.\n\nIn conclusion, PAMI syndrome is a rare inflammatory disorder and the most severe phenotype among PAID, characterized by alterations of various immune system agents. The severe kidney involvement of our patient is, according to our best knowledge, the first subjected to a documented histological modification after anti-IL-1 treatment.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Ethics Committee Genoa, Italy. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nPB, RP, AA, GG, and MG conceptualized the manuscript. PB and RP conducted the literature review and drafted the manuscript. MD'A, RC, and GP were involved in the clinical care of the patient. IC performed the genetic analysis. All authors read and approved the final version of the submitted manuscript.\n\nFunding\n\nThe study was supported with public funds granted by the Italian Ministry of Health.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThe authors would like to thank the patient and his family. Several authors of the present paper are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases—Project ID No 739543.\n==== Refs\nReferences\n\n1. Holzinger D Fassl SK de Jager W Lohse P Röhrig UF Gattorno M . Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)–associated inflammatory diseases. J Allergy Clin Immunol. (2015) 136 :1337–45. 10.1016/j.jaci.2015.04.016 26025129\n2. Huang X Xu M Dai S Wang M Zheng H Zeng K . Rare cases of PAMI syndrome in both father and son with the same missense mutation in PSTPIP1 gene and literature review. J Dermatol. (2021) 48 :519–28. 10.1111/1346-8138.15706 33458872\n3. Boursier G Piram M Rittore C Sarrabay G Touitou I . Phenotypic associations of PSTPIP1 sequence variants in PSTPIP1-associated autoinflammatory diseases. J Invest Dermatol. (2021) 141 :1141–7. 10.1016/j.jid.2020.08.028 33218716\n4. Genovese G Moltrasio C Garcovich S Marzano AV . PAPA spectrum disorders. G Ital Dermatol Venereol. (2020) 155 :542–50. 10.23736/S0392-0488.20.06629-8 32618443\n5. Holzinger D Roth J . Alarming consequences-autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1. Curr Opin Rheumatol. (2016) 28 :550–9. 10.1097/BOR.0000000000000314 27464597\n6. Laberko A Burlakov V Maier S Abinun M Skinner R Kozlova A . HSCT is effective in patients with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome. J Allergy Clin Immunol. (2021) 148 :250–5.e1. 10.1016/j.jaci.2020.11.043 33338535\n7. Omenetti A Carta S Caorsi R Finetti M Marotto D Lattanzi B . Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome. Rheumatology. (2016) 55 :1325–35. 10.1093/rheumatology/kew031 26989109\n8. Lindwall E Singla S Davis WE Quinet RJ . Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. Semin Arthritis Rheum. (2015) 45 :91–3. 10.1016/j.semarthrit.2015.02.012 25845478\n9. Dai P Furlong T Gracie G Huang ML Yang T Wu KHC . Autoinflammation masquerading as autoimmunity in an adult with heterozygous p.E250K PSTPIP1 mutation. J Clin Immunol. (2019) 39 :519–22. 10.1007/s10875-019-00646-z 31119601\n10. Smith JE Allantaz F Bennett L Zhang D Gao X Wood G . Clinical, molecular, and genetic characteristics of PAPA syndrome: a review. Curr Genomics. (2010) 11 :519–27. 10.2174/138920210793175921 21532836\n11. Wise CA Gillum JD Seidman CE Lindor NM Veile R Bashiardes S . Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. (2002) 11 :961–9. 10.1093/hmg/11.8.961 11971877\n12. Papa R Penco F Volpi S Gattorno M . Actin remodeling defects leading to autoinflammation and immune dysregulation. Front Immunol. (2021) 11 :604206. 10.3389/fimmu.2020.604206 33488606\n13. Starnes TW Bennin DA Bing X Eickhoff JC Grahf DC Bellak JM . The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages. Blood. (2014) 123 :2703–14. 10.1182/blood-2013-07-516948 24421327\n14. Papa R Lachmann HJ . Secondary, AA, amyloidosis. Rheum Dis Clin North Am. (2018) 44 :585–603. 10.1016/j.rdc.2018.06.004 30274625\n15. Fogo AB . Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol. (2015) 11 :76–87. 10.1038/nrneph.2014.216 25447132\n16. Angeletti A Cantarelli C Petrosyan A Andrighetto S Budge K D'Agati VD . Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis. J Exp Med. (2020) 217 :e20191699. 10.1084/jem.20191699 32717081\n\n",
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"title": "Kidney Involvement in PSTPIP1 Associated Inflammatory Diseases (PAID): A Case Report and Review of the Literature.",
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"affiliations": "Department of Internal Medicine, Baystate Medical Center, Springfield, MA.;Department of Cardiology, Baystate Medical Center, Springfield, MA.;Department of Cardiology, Baystate Medical Center, Springfield, MA.",
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"title": "Capecitabine-Induced Takotsubo Cardiomyopathy: A Case Report.",
"title_normalized": "capecitabine induced takotsubo cardiomyopathy a case report"
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"activesubstancename": "CLONAZEPAM"
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"abstract": "We report a novel association between the commonly used antimalarial medication atovaquone/proguanil and drug-induced autoimmune-like hepatitis. The patient developed severe liver disease fulfilling biochemical, immunologic, and histologic criteria for the diagnosis of autoimmune hepatitis after the inadvertent rechallenge with the offending drug, which had caused self-limited hepatitic symptoms a year previously. Over a period of 18 months, the patient underwent two follow-up liver biopsies showing progressive resolution of the liver inflammation and achieved complete biochemical and immunologic remission on steroids. This remission persisted for 20 months following treatment withdrawal. Conclusion: This well documented case raises awareness of the potential hepatotoxicity of atovaquone/proguanil. (Hepatology Communications 2017;1:293-298).",
"affiliations": "Epatocentro Ticino Lugano Switzerland.;Paediatric Liver, GI and Nutrition Centre King's College Hospital London United Kingdom.;Regional Pharmacovigilance Center, Division of Clinical Pharmacology and Toxicology Ente Ospedaliero Cantonale Lugano Switzerland.;Istituto Cantonale di Patologia Locarno Switzerland.;Institute of Pharmacology and Toxicology Paracelsus Medical University Salzburg Austria.;Center for Health and Bioresources Austrian Institute of Technology Vienna Austria.;Institute of Liver Studies King's College Hospital London United Kingdom.",
"authors": "Terziroli Beretta-Piccoli|Benedetta|B|;Mieli-Vergani|Giorgina|G|;Bertoli|Raffaela|R|;Mazzucchelli|Luca|L|;Nofziger|Charity|C|;Paulmichl|Markus|M|;Vergani|Diego|D|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1002/hep4.1039",
"fulltext": "\n==== Front\nHepatol CommunHepatol Commun10.1002/(ISSN)2471-254XHEP4Hepatology Communications2471-254XJohn Wiley and Sons Inc. Hoboken 10.1002/hep4.1039HEP41039Original ArticleOriginal ArticlesAtovaquone/proguanil‐induced autoimmune‐like hepatitis Terziroli Beretta‐Piccoli et al.Terziroli Beretta‐Piccoli et al.Terziroli Beretta‐Piccoli Benedetta benedetta.terziroli@hin.ch \n1\nMieli‐Vergani Giorgina \n2\nBertoli Raffaela \n3\nMazzucchelli Luca \n4\nNofziger Charity \n5\nPaulmichl Markus \n6\nVergani Diego \n7\n\n1 \nEpatocentro Ticino\nLugano\nSwitzerland\n\n2 \nPaediatric Liver, GI and Nutrition Centre\nKing's College Hospital\nLondon\nUnited Kingdom\n\n3 \nRegional Pharmacovigilance Center, Division of Clinical Pharmacology and Toxicology\nEnte Ospedaliero Cantonale\nLugano\nSwitzerland\n\n4 \nIstituto Cantonale di Patologia\nLocarno\nSwitzerland\n\n5 \nInstitute of Pharmacology and Toxicology\nParacelsus Medical University\nSalzburg\nAustria\n\n6 \nCenter for Health and Bioresources\nAustrian Institute of Technology\nVienna\nAustria\n\n7 \nInstitute of Liver Studies\nKing's College Hospital\nLondon\nUnited Kingdom\n* ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:\nBenedetta Terziroli Beretta‐Piccoli, M.D.\nEpatocentro Ticino\nVia Soldino 5\n6900 Lugano, Switzerland\nE‐mail: benedetta.terziroli@hin.ch\nTel.: +41‐91‐960‐85‐03\n08 5 2017 6 2017 1 4 10.1002/hep4.v1.4293 298 22 11 2016 04 4 2017 08 4 2017 © 2017 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.We report a novel association between the commonly used antimalarial medication atovaquone/proguanil and drug‐induced autoimmune‐like hepatitis. The patient developed severe liver disease fulfilling biochemical, immunologic, and histologic criteria for the diagnosis of autoimmune hepatitis after the inadvertent rechallenge with the offending drug, which had caused self‐limited hepatitic symptoms a year previously. Over a period of 18 months, the patient underwent two follow‐up liver biopsies showing progressive resolution of the liver inflammation and achieved complete biochemical and immunologic remission on steroids. This remission persisted for 20 months following treatment withdrawal. Conclusion: This well documented case raises awareness of the potential hepatotoxicity of atovaquone/proguanil. (Hepatology Communications 2017;1:293–298)\n\n source-schema-version-number2.0component-idhep41039cover-dateJune 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:08.12.2017Potential conflict of interest: Nothing to report.\n==== Body\nAbbreviations\nAIHautoimmune hepatitis\n\nANAanti‐nuclear antibodies\n\nDIAILHdrug‐induced autoimmune‐like hepatitis\n\nDILIdrug‐induced liver injury\n\ngDNAgenomic DNA\n\nHLAhuman leukocyte antigen\n\nIAIHGInternational Autoimmune Hepatitis Group\n\nIgGimmunoglobulinG\n\nPCRpolymerase chain reaction\n\nULNupper limit of normal\n\nIntroduction\nAutoimmune hepatitis (AIH) is a rare immune‐mediated liver disorder of unknown etiology. It is characterized by elevated transaminase and immunoglobulin G (IgG) levels, positive auto‐antibodies, histologic evidence of interface hepatitis, and good response to steroid treatment.1, 2 Drug‐induced liver injury (DILI) can mimic AIH.3 On the one hand, a drug can unmask or induce classical AIH in a predisposed individual who will often have fibrotic changes on liver biopsy at presentation4 and who will need chronic treatment with immunosuppressants1; on the other hand, a drug can cause a clinical picture indistinguishable from AIH but without fibrosis and without long‐term steroid dependence.3 The International Autoimmune Hepatitis Group (IAIHG) criteria for the diagnosis of definite or probable AIH1, 2 are fulfilled both in classical AIH and in drug‐induced autoimmune‐like hepatitis (DIAILH). The best documented drugs linked to DIAILH are minocycline and nitrofurantoin.1, 2 DIAILH has a more benign course than classical AIH3 as steroid therapy can be withdrawn without recurrence. Although rechallenge with the offending drug is not advisable unless it is a life‐saving drug, the recurrence of DIAILH after inadvertent rechallenge strongly weighs in favor of a causative link.4 We report for the first time a well‐documented case of atovaquone/proguanil‐induced DIAILH that recurred with a more severe liver injury after inadvertent rechallenge with the antimalarial compound.\n\nCase Report\nA 65‐year‐old woman presented with a 10‐day history of fatigue, jaundice, and dark urine after returning from Tanzania. She is a retired operating‐room nurse and was previously in good health. She was on no other drugs, did not drink alcohol or smoke, and had no family or personal history of liver or autoimmune diseases. She had visited Tanzania yearly for 5 years, taking malaria prophylaxis with atovaquone/proguanil from 2 days before until 7 days after returning. After returning the previous year, she developed jaundice and fatigue, which were attributed to azithromycin, which was prescribed for acute bronchitis and was taken for 5 days, beginning 3 days following cessation of the malaria prophylaxis. She presented with malaise and fatigue 21 days after withdrawal of malaria prophylaxis and 14 days after withdrawal of azithromycin. At that time, her bilirubin level reached 240 μmol/L (upper limit of normal [ULN] 17 μmol/L), alanine transaminase was 1,382 IU/L (ULN 37 IU/L), international normalized ratio was 1.2, and blood eosinophil count was normal (205 × 109/L). Acute viral hepatitis A, B, C, and E were ruled out as were acute Epstein‐Barr virus and cytomegalovirus infection. Anti‐nuclear antibodies (ANAs) were positive at a titer of 1:320, with a homogeneous immunofluorescence pattern on HEp2 cells. A liver biopsy was not performed. She recovered spontaneously within 2 weeks.\n\nAt current presentation, she was in poor general condition, deeply jaundiced, with moderate ascites and no fever or rash. Atovaquone/proguanil was stopped 4 days before presentation because of the appearance of jaundice. Laboratory values over time are shown in Table 1. Acute viral hepatitis A, B, C, and E were excluded again. A liver ultrasound showed mild ascites, normal spleen size (9 cm), normal portal vein blood flow (21 cm/second), and absence of focal liver lesions. A liver biopsy, performed with a transjugular approach due to ascites and coagulopathy, showed portal inflammation with plasma cell‐rich interface activity, severe zone 3 necrosis, but no significant fibrosis (Fig. 1A‐D). Genetic testing for AIH susceptibility showed a heterozygous presence of the human leukocyte antigen (HLA) DRB1*0401 genotype. Based on these clinical, biochemical, serologic, genetic, and histologic findings as well as an IAIHG scoring of 8, indicating definite AIH, a tentative diagnosis of type 1 AIH was made. Intravenous steroid therapy was started (prednisone 60 mg/day), and a rapid biochemical response followed. The prednisone dose was gradually tapered over 3 months to 5 mg/day. During a 6‐month follow‐up on prednisone 5 mg/day, transaminase levels reached and remained within the normal range, IgG normalized, and ANAs and anti‐smooth muscle antibodies became negative (Table 1). Nevertheless, a liver biopsy continued to show mild lymphocytic portal infiltrates with a few plasma cells but no interface hepatitis (Fig. 1E). Because of the severity of the original presentation, the genetic background, and the persistence of portal hepatitis, prednisone 5 mg/day was continued for a further year despite persistently normal transaminase and IgG levels and negative auto‐antibodies. At the end of the year, a further liver biopsy showed normal histology (Fig. 1F). Prednisone was then slowly withdrawn (1 mg/month) with no biochemical alterations. The patient is well with normal transaminase and IgG levels and negative auto‐antibodies 20 months after stopping steroid treatment (Table 1).\n\nTable 1 LABORATORY TESTS AT PRESENTATION AND DURING LONG‐TERM FOLLOW‐UP\n\n\t\nAST\n\nIU/L\t\nALT\n\nIU/L\t\nALP\n\nIU/L\t\nTotal Bilirubin\n\nμmol/L\tINR\t\nIgG\n\ng/L\tANA\tSMA\tAnti‐LKM\tAMA\tANCA\t\nNormal range\t<36\t<37\t35‐104\t<19.0\t\t7.37‐16.04\t<1:80\t<1:40\t<1:20\t<1:40\t<1:20\t\nAt presentation\t3,707\t2,371\t140\t404\t2.0\t20.1\t1:320a\n\t1:40\tneg\tneg\tneg\t\n1 week on PDN\t191\t648\t\t104.7\t1.2\t\t\t\t\t\t\t\n2 weeks on PDN\t63\t251\t107\t77.6\t1.0\t\t\t\t\t\t\t\n4 weeks on PDN\t27\t33\t52\t27.9\t1.0\t\t\t\t\t\t\t\n3 months on PDN\t17\t10\t39\t12.7\t1.0\t\t1:80\tneg\t\t\t\t\n6 months on PDN\t18\t10\t40\t7.2\t0.9\t12.4\tneg\tneg\t\t\t\t\n18 months on PDN\t9\t10\t54\t13.9\t1.0\t11.4\tneg\tneg\t\t\t\t\n1 month off PDN\t14\t13\t59\t13.2\t0.9\t\tneg\tneg\t\t\t\t\n6 month off PDN\t9\t10\t59\t11.8\t0.9\t11.7\tneg\tneg\t\t\t\t\n18 month off PDN\t10\t<10\t51\t10.7\t1.0\t10.9\tneg\tneg\t\t\t\t\na Homogeneous immunofluorescence pattern on HEp2 cells\n\nAbbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, anti‐mitochondrial antibody; ANA, anti‐nuclear antibody; ANCA, anti‐neutrophil cytoplasmic antibody; anti‐LKM, anti‐liver/kidney microsomal antibody; AST, aspartate aminotransferase; IgG, immunoglobulin G; INR, international normalized ratio; neg, negative; PDN, prednisone; SMA, smooth muscle antibody.\n\nFigure 1 Liver biopsy at presentation. (A) Marked portal inflammation with interface activity (HE stain, ×200 original magnification). (B) Severe zone 3 necrosis, loss of hepatocytes around the central vein (HE stain, ×200). (C) Syncytial giant cell transformation of hepatocytes (HE stain, ×400) and (D) numerous plasma cells at the interface highlighted by immunohistochemical staining for CD38 (×200). (E) Liver biopsy after 6 months of prednisone treatment (HE stain, ×200 original magnification) with mild interface hepatitis; (F) liver biopsy after 18 months of prednisone treatment (HE stain, ×100) showing absence of inflammatory infiltrates and a normal portal tract. Abbeviation: HE, hematoxylin and eosin.\n\nThe patient was investigated for genetic variations known to alter the function of CYP2C19 (*1A, *2, *3, *4, *5, *6, *7, *8, *9, *12, and *17), the enzyme involved in proguanil metabolism. Briefly, whole blood was collected in ethylene diamine tetraacetic acid K Monovettes by venipuncture. Genomic DNA (gDNA) was isolated from ∼350 μL blood with the EZ1 DNA Blood 350 μL Kit (Qiagen) on the EZ1 Advanced XL platform (Qiagen) according to the manufacturer's instructions. gDNA was quantified with the QIAxpert (Qiagen) spectrophotometer and had an absorbance (A)260/A280 between 1.7 and 1.9. Equal volumes of gDNA (∼50 ng/μL) and 2X TaqMan OpenArray real‐time polymerase chain reaction (PCR) master mix were loaded onto the TaqMan OpenArray PGx panel with the OpenArray AccuFill system and run on the QuantStudio 12K Flex real‐time PCR system according to the manufacturer's instructions. Results were analyzed by TaqMan Genotyper Software version 1.3 and verified by visual inspection of the real‐time PCR amplification traces. All reagents, analysis software, and specialized equipment were from Thermo Fisher Scientific. The principle of this methodology is based on genotyping of single nucleotide polymorphisms by allele‐specific hydrolysis probes, using endpoint fluorescence values generated by real‐time PCR.5\n\n\nDiscussion\nWe describe for the first time a case of DIAILH related to the intake of the combined antimalaria drugs atovaquone and proguanil, followed up biochemically and histologically for 3.5 years until complete resolution of the liver pathology and absence of recurrence after treatment withdrawal.\n\nDIAILH has been mostly reported in association with nitrofurantoin and minocycline treatment,1, 2, 3 and more recently with statins,6 antitumour necrosis factor α agents,7 and black cohosh (Cimicifuga racemosa, Actaea racemosa), an herbal remedy widely used to treat menopause symptoms.8, 9, 10\n\n\nAtovaquone/proguanil is a double‐compound medication widely used for both prevention and treatment of malaria, with no DILI‐resembling AIH having been reported. Mild transaminase elevation occurs in a small proportion of treated patients. A single case of acute hepatitis has been reported11 with spontaneous recovery within 8 weeks after the last intake of the drug. A liver biopsy was not performed, and serum auto‐antibodies (ANA, anti‐mitochondrial antibody, anti‐liver/kidney microsome antibody, anti‐double‐stranded DNA) were absent. Because atovaquone/proguanil is a double‐compound medication, it is unclear which of the two drugs is responsible for DIAILH. In this context, the report of a patient who developed hepatotoxicity in association with the repeated use of a combination of chloroquine and proguanil is of interest12 as it suggests a mechanism of sensitization similar to that observed in our case and a possible causative role for proguanil. This latter patient, however, was auto‐antibody negative, did not undergo a liver biopsy, and recovered spontaneously within 1 month of stopping the drug.\n\nThat atovaquone/proguanil is the likely cause of the liver pathology in our case is corroborated by the severe relapse of liver disease after an inadvertent rechallenge with the drug due to the fact that the original hepatopathy had been attributed to azithromycin, a macrolide antibiotic reported to induce a hepatitic picture in 1% to 2% of patients treated for short periods.13 Using the Council of International Organizations of Medical Sciences classification system, called the Roussel Uclaf Causality Assessment Method,14 our case has a score of 10 for atovaquone/proguanil, which suggests a highly probable adverse drug reaction, and has a score of 7 for azithromycin, which suggests a probable adverse drug reaction. The relative high value of the score for azithromycin is due to its well‐recognized hepatotoxicity, which is not the case for atovaquone/proguanil. Although the first hepatitis episode was reasonably attributed to azithromycin, the subsequent clinical course indicates that atovaquone/proguanil was probably responsible for the liver injury because acute hepatitis recurred after rechallenge with the latter drug combination and without exposure to azithromycin. Positive rechallenge is considered as the most reliable evidence of DILI.4 Nevertheless, because this is the first report of DIAILH related to atovaquone/proguanil, we cannot exclude that the hepatitic episode and the exposure to the double‐compound medication was just coincidental until at least a second similar convincing case is reported.\n\nWe note that the first symptomatic episode of liver toxicity was mild and resolved spontaneously after withdrawal of the offending drug in our patient; asymptomatic episodes during the previous exposures cannot be excluded. This could suggest that an immune‐mediated sensitization occurred, as suggested for proguanil in the above‐mentioned case report,12 and for other drugs, such as halothane.15 Halothane is metabolized by the CYP2E1 enzyme; its metabolite trifluoroacetyl can covalently bind to CYP2E1 to form protein adducts, which act as neo‐antigens and are targeted by auto‐antibodies, triggering immune‐mediated hepatotoxicity.16 Proguanil is metabolized by the CYP2C19 enzyme. The analysis of genetic variations known to alter CYP2C19 function (*1A, *2, *3, *4, *5, *6, *7, *8, *9, *12, and *17) showed that the patient is heterozygous for both *2 and *17 and is classified as an intermediate metabolizer with reduced capacity for metabolizing drugs by means of CYP2C19. It is therefore possible that the patient was exposed to an excessive proguanil concentration that could have led to the formation of protein adducts, giving rise to neo‐antigens that subsequently were recognized by the immune system, leading to the observed DILI. Possible mechanisms could include but are not limited to formation of hapten–carrier complexes or the pharmacological interaction with immune receptors, also known as the p‐i‐concept, both increasing the risk of immune‐mediated hepatotoxicity.17\n\n\nDifferentiation between DIAILH and classical AIH is difficult and not facilitated by the application of the IAIHG scoring system, as confirmed in our case with a definite AIH score. Clinical presentation, biochemical and immunologic profiles, as well as liver histology in our patient were indistinguishable from those found in classical AIH. In addition, as in AIH, there was a swift response to corticosteroids. The fact that the first follow‐up liver biopsy, performed 6 months after starting treatment, still showed some evidence of portal tract inflammation despite normalization of biochemical and immunologic indices was compatible with either diagnosis. The third biopsy, however, showing normal liver histology and the long‐term follow‐up without relapse after discontinuing steroids supports the diagnosis of DIAILH. Current guidelines1 suggest treating cases of AIH‐like disease after drug ingestion with steroids alone to be gradually tapered and stopped after normalization of liver function; if the disease does not relapse, a diagnosis of DIAILH is made. In our case, liver inflammation took a long time to resolve even in the presence of normal liver function tests, allowing a firm diagnosis of DIAILH only 3 years after presentation and underscoring the difficulty in clinical practice to assign a case to one or the other category.\n\nTo add complexity to the diagnostic workup, our patient is positive for HLA‐DRB1*0401, an allele predisposing to adult‐onset AIH type I without concomitant autoimmune disorders,18 the association being strong enough to be considered of diagnostic relevance by the IAIHG.19 Although it could be argued that this genetic background has played a predisposing role in the development of DIAILH, a recent paper on a large number of DILI with features of AIH could not demonstrate an association with possession of specific genes in the HLA region.20\n\n\nIn conclusion, we report a well‐documented association between exposure to atovaquone/proguanil and DIAILH. As this is the first case description, the reporting of at least a second convincing case is needed to confirm the rare but potentially severe hepatotoxicity of this commonly used antimalarial prophylaxis/treatment. In our patient, the hepatotoxicity was possibly related to a CYP2C19 polymorphism.\n\nAuthor names in bold designate shared co‐first authorship.\n\nAcknowledgment\nWe thank Michael Morris (Synlab Lausanne) for support with the pharmacogenetic testing and for critical reading of the manuscript. We also thank Fondazione Epatocentro Ticino for assistance in manuscript editing.\n==== Refs\nREFERENCES\n1 \nEuropean Association for the Study of the Liver \n. EASL Clinical Practice Guidelines: autoimmune hepatitis . J Hepatol \n2015 ;63 :971 ‐1004 .\n26341719 \n2 \n\nManns \nMP \n, \n\nCzaja \nAJ \n, \n\nGorham \nJD \n, \n\nKrawitt \nEL \n, \n\nMieli‐Vergani \nG \n, \n\nVergani \nD \n, et al. Diagnosis and management of autoimmune hepatitis . Hepatology \n2010 ;51 :2193 ‐2213 .\n20513004 \n3 \n\nCzaja \nAJ \n. Drug‐induced autoimmune‐like hepatitis . Dig Dis Sci \n2011 ;56 :958 ‐976 .\n21327704 \n4 \n\nAndrade \nRJ \n, \n\nRobles \nM \n, \n\nLucena \nMI \n. Rechallenge in drug‐induced liver injury: the attractive hazard . Expert Opin Drug Saf \n2009 ;8 :709 ‐714 .\n19968572 \n5 \n\nMalkki \nM \n, \n\nPetersdorf \nEW \n. Genotyping of single nucleotide polymorphisms by 5′ nuclease allelic discrimination . Methods Mol Biol \n2012 ;882 :173 ‐182 .\n22665234 \n6 \n\nPerdices \nEV \n, \n\nMedina‐Cáliz \nI \n, \n\nHernando \nS \n, \n\nOrtega \nA \n, \n\nMartín‐Ocaña \nF \n, \n\nNavarro \nJM \n, et al. Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry . Rev Esp Enferm Dig \n2014 ;106 :246 ‐254 .\n25075655 \n7 \n\nEfe \nC \n, \n\nPurnak \nT \n, \n\nOzaslan \nE \n, \n\nWahlin \nS \n. Drug‐induced autoimmune hepatitis caused by anti‐tumor necrosis factor α agents . Hepatology \n2010 ;52 :2246 ‐2247 .\n20715094 \n8 \n\nGuzman \nG \n, \n\nKallwitz \nER \n, \n\nWojewoda \nC \n, \n\nChennuri \nR \n, \n\nBerkes \nJ \n, \n\nLayden \nTJ \n, et al. Liver injury with features mimicking autoimmune hepatitis following the use of black cohosh . Case Rep Med \n2009 ;2009 :918156 .\n20130783 \n9 \n\nCohen \nSM \n, \n\nO'Connor \nAM \n, \n\nHart \nJ \n, \n\nMerel \nNH \n, \n\nTe \nHS \n. Autoimmune hepatitis associated with the use of black cohosh: a case study . Menopause \n2004 ;11 :575 ‐577 .\n15356412 \n10 \n\nEnbom \nET \n, \n\nLe \nMD \n, \n\nOesterich \nL \n, \n\nRutgers \nJ \n, \n\nFrench \nSW \n. Mechanism of hepatotoxicity due to black cohosh (Cimicifuga racemosa): histological, immunohistochemical and electron microscopy analysis of two liver biopsies with clinical correlation . Exp Mol Pathol \n2014 ;96 :279 ‐283 .\n24657312 \n11 \n\nGrieshaber \nM \n, \n\nLämmli \nJ \n, \n\nMarcus \nL \n. Acute hepatitis and atovaquone/proguanil . 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Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane . J Pharmacol Exp Ther \n1988 ;245 :1103 ‐1109 .\n3385639 \n17 \n\nPichler \nWJ \n, \n\nAdam \nJ \n, \n\nWatkins \nS \n, \n\nWuillemin \nN \n, \n\nYun \nJ \n, \n\nYerly \nD \n. Drug hypersensitivity: how drugs stimulate T cells via pharmacological interaction with immune receptors . Int Arch Allergy Immunol \n2015 ;168 :13 ‐24 .\n26524432 \n18 \n\nde Boer \nYS \n, \n\nvan Gerven \nNM \n, \n\nZwiers \nA \n, \n\nVerwer \nBJ \n, \n\nvan Hoek \nB \n, \n\nvan Erpecum \nKJ \n, et al. Genome‐wide association study identifies variants associated with autoimmune hepatitis type 1 . Gastroenterology \n2014 ;147 :443 ‐452 .e5.\n24768677 \n19 \n\nAlvarez \nF \n, \n\nBerg \nPA \n, \n\nBianchi \nFB \n, \n\nBianchi \nL \n, \n\nBurroughs \nAK \n, \n\nCancado \nEL \n, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis . J Hepatol \n1999 ;31 :929 ‐938 .\n10580593 \n20 \n\nde Boer \nYS \n, \n\nKosinski \nAS \n, \n\nUrban \nTJ \n, \n\nZhao \nZ \n, \n\nLong \nN \n, \n\nChalasani \nN \n, et al. Features of autoimmune hepatitis in patients with drug‐induced liver injury . Clin Gastroenterol Hepatol \n2017 ;15 :103 ‐112 .e2\n27311619\n\n",
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"title": "Atovaquone/proguanil-induced autoimmune-like hepatitis.",
"title_normalized": "atovaquone proguanil induced autoimmune like hepatitis"
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"abstract": "Pediatric cranial radiotherapy (CrRT) markedly increases risk of meningiomas. We studied meningioma risk factors with emphasis on independent and joint effects of CrRT dose, exposed cranial volume, exposure age, and chemotherapy.\n\n\n\nThe Dutch Cancer Oncology Group-Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort includes 5-year childhood cancer survivors (CCSs) whose cancers were diagnosed in 1963-2001. Histologically confirmed benign meningiomas were identified from the population-based Dutch Pathology Registry (PALGA; 1990-2015). We calculated cumulative meningioma incidence and used multivariable Cox regression and linear excess relative risk (ERR) modeling.\n\n\n\nAmong 5843 CCSs (median follow-up: 23.3 y, range: 5.0-52.2 y), 97 developed a benign meningioma, including 80 after full- and 14 after partial-volume CrRT. Compared with CrRT doses of 1-19 Gy, no CrRT was associated with a low meningioma risk (hazard ratio [HR] = 0.04, 95% CI: 0.01-0.15), while increased risks were observed for CrRT doses of 20-39 Gy (HR = 1.66, 95% CI: 0.83-3.33) and 40+ Gy (HR = 2.81, 95% CI: 1.30-6.08). CCSs whose cancers were diagnosed before age 5 versus 10-17 years showed significantly increased risks (HR = 2.38, 95% CI: 1.39-4.07). In this dose-adjusted model, volume was not significantly associated with increased risk (HR full vs partial = 1.66, 95% CI: 0.86-3.22). Overall, the ERR/Gy was 0.30 (95% CI: 0.03-unknown). Dose effects did not vary significantly according to exposure age or CrRT volume. Cumulative incidence after any CrRT was 12.4% (95% CI: 9.8%-15.2%) 40 years after primary cancer diagnosis. Among chemotherapy agents (including methotrexate and cisplatin), only carboplatin (HR = 3.55, 95% CI: 1.62-7.78) appeared associated with meningioma risk. However, we saw no carboplatin dose-response and all 9 exposed cases had high-dose CrRT.\n\n\n\nAfter CrRT 1 in 8 survivors developed late meningioma by age 40 years, associated with radiation dose and exposure age, relevant for future treatment protocols and awareness among survivors and physicians.",
"affiliations": "Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.;Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.;Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Department of Pediatric Oncology and Hematology, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, the Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Department of Pediatric Oncology/Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.;Dutch Childhood Oncology Group, Utrecht, the Netherlands.;Department of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands.;Department of Radiation Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.;Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Department of Radiation Oncology, University of Groningen/University Medical Center Groningen, Groningen, the Netherlands.;Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.;Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, the Netherlands.;Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.;Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.",
"authors": "Kok|Judith L|JL|;Teepen|Jop C|JC|;van Leeuwen|Flora E|FE|;Tissing|Wim J E|WJE|;Neggers|Sebastian J C M M|SJCMM|;van der Pal|Helena J|HJ|;Loonen|Jacqueline J|JJ|;Bresters|Dorine|D|;Versluys|Birgitta|B|;van den Heuvel-Eibrink|Marry M|MM|;van Dulmen-den Broeder|Eline|E|;van der Heiden-van der Loo|Margriet|M|;Aleman|Berthe M P|BMP|;Daniels|Laurien A|LA|;Haasbeek|Cornelis J A|CJA|;Hoeben|Bianca|B|;Janssens|Geert O|GO|;Maduro|John H|JH|;Oldenburger|Foppe|F|;van Rij|Caroline|C|;Tersteeg|Robbert J H A|RJHA|;Hauptmann|Michael|M|;|||;Kremer|Leontien C M|LCM|;Ronckers|Cécile M|CM|",
"chemical_list": null,
"country": "England",
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"doi": "10.1093/neuonc/noy124",
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"issn_linking": "1522-8517",
"issue": "21(3)",
"journal": "Neuro-oncology",
"keywords": "childhood cancer survivors; cranial radiotherapy; meningioma; radiation dose; radiation volume",
"medline_ta": "Neuro Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000073116:Cancer Survivors; D002648:Child; D002675:Child, Preschool; D016371:Cranial Irradiation; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008577:Meningeal Neoplasms; D008579:Meningioma; D009369:Neoplasms; D009381:Neoplasms, Radiation-Induced; D009426:Netherlands; D058958:Organs at Risk; D016016:Proportional Hazards Models; D011829:Radiation Dosage; D012306:Risk; D055815:Young Adult",
"nlm_unique_id": "100887420",
"other_id": null,
"pages": "392-403",
"pmc": null,
"pmid": "30099534",
"pubdate": "2019-02-19",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21079138;28530852;25057388;10204198;17429138;23281199;10438710;17007558;28339329;17077355;23816298;12381708;19747876;8622039;15799699;20634481;28245323;24606096",
"title": "Risk of benign meningioma after childhood cancer in the DCOG-LATER cohort: contributions of radiation dose, exposed cranial volume, and age.",
"title_normalized": "risk of benign meningioma after childhood cancer in the dcog later cohort contributions of radiation dose exposed cranial volume and age"
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"abstract": "Acute erythroid leukemia, also known as acute myeloid leukemia-M6, may be associated with previous chemotherapy or immunosuppressive therapy. For 10 years, a 69-year-old Japanese female patient with pure erythroid leukemia (or acute myeloid leukemia-M6b) was treated for polymyositis with 50-100 mg/day azathioprine. She complained of dyspnea with low-grade fever and was diagnosed as having pure erythroid leukemia. Chromosomal analysis revealed a complex karyotype abnormality, with the deletion of 5q, -6, -7 and addition of 11q13. No morphological myelodysplastic changes were observed in her bone marrow cells. In this study, azathioprine accumulation was considered to be associated with the patient's leukemogenesis.",
"affiliations": "Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Miki, Japan.;Department of Laboratory Medicine, Kagawa University Hospital, Miki, Japan.;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Miki, Japan.;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Miki, Japan.;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Miki, Japan.;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Miki, Japan.",
"authors": "Imataki|Osamu|O|;Takeuchi|Akihiro|A|;Uchida|Shumpei|S|;Yokokura|Shigeyuki|S|;Uemura|Makiko|M|;Kadowaki|Norimitsu|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2036361318773847",
"fulltext": "\n==== Front\nRare TumorsRare TumorsRTUsprtuRare Tumors2036-36052036-3613SAGE Publications Sage UK: London, England 10.1177/203636131877384710.1177_2036361318773847Case ReportPure erythroid leukemia in a polymyositis patient treated with azathioprine Imataki Osamu 1Takeuchi Akihiro 2Uchida Shumpei 1Yokokura Shigeyuki 1Uemura Makiko 1Kadowaki Norimitsu 11 Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Miki, Japan2 Department of Laboratory Medicine, Kagawa University Hospital, Miki, JapanOsamu Imataki, Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, Kita, Kagawa, Japan. Email: oima@med.kagawa-u.ac.jp14 5 2018 2018 10 20363613187738476 6 2017 21 3 2018 © The Author(s) 20182018SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Acute erythroid leukemia, also known as acute myeloid leukemia-M6, may be associated with previous chemotherapy or immunosuppressive therapy. For 10 years, a 69-year-old Japanese female patient with pure erythroid leukemia (or acute myeloid leukemia-M6b) was treated for polymyositis with 50–100 mg/day azathioprine. She complained of dyspnea with low-grade fever and was diagnosed as having pure erythroid leukemia. Chromosomal analysis revealed a complex karyotype abnormality, with the deletion of 5q, -6, -7 and addition of 11q13. No morphological myelodysplastic changes were observed in her bone marrow cells. In this study, azathioprine accumulation was considered to be associated with the patient’s leukemogenesis.\n\nAcute myeloid leukemiapure erythroid leukemiaerythroleukemiapolymyositisazathioprinemyelodysplastic syndromecover-dateJanuary-December 2018\n==== Body\nIntroduction\nPure erythroid leukemia (PEL), a rare hematological malignancy, is defined as the presence of >80% of proliferating erythroblasts among all nucleated bone marrow cells. According to the classification by the World Health Organization in 2008, PEL is classified as acute myeloid leukemia (AML) not otherwise specified.1 In addition, according to the French–American–British classification, PEL is categorized as AML-M6b. The M6a subtype is simply known as acute erythroleukemia. AML-M6a accounts for 2%–3% of all AML cases, whereas AML-M6b accounts for only 1%.2 Thus, PEL is considered to be rare, with a prevalence of less than 1% of all AML cases. The two erythroleukemia subtypes have similar features but different pathogenesis.3 AML-M6b is considered to have a worse prognosis than AML-6a, with a median survival of approximately 4 months,3 because of its severe resistance to chemotherapy and complex karyotypes that are frequently observed after the progression of myelodysplastic syndrome (MDS) to AML. AML-M6 cases may be associated with chemotherapy or immunosuppressive therapy.4–7 Regardless of whether an antecedent diagnosis of MDS has been established, complex karyotypes are prominent characteristics of AML-M6, particularly of the AML-M6b subtype.3,8 In this study, a patient who developed AML-M6b during long-term azathioprine treatment for polymyositis was treated.\n\nCase presentation\nA 69-year-old Japanese female was treated for polymyositis at our hospital. She received 50–100 mg/day azathioprine for 10 years. The total estimated lifetime dose of azathioprine was 297 g. During one of her outpatient clinic visits, which occurred at 3 month intervals, she complained of dyspnea with low-grade fever. Laboratory test results indicated severe anemia (hemoglobin, 7.1 g/dL), leukocytopenia (white blood cell count, 1300/µL), and thrombocytopenia (platelet count, 10.0 × 104/µL). Bone marrow aspiration results revealed prominent proliferation of erythrocytes with 83% proerythroblasts. She was diagnosed with PEL, also known as AML-M6b (Figure 1). Chromosomal analysis revealed a complex karyotype abnormality, with deletion of 5q, -6, -7 and addition of 11q13. The karyotype of the patient’s leukemic cells was as follows:45, XX, del(5) (q?), -6 add(6) (q21), -7, add(8) (p11.2), add(9) (q13), add(11) (q13), add(11) (q13), -12, add(16) (q12.1), add(16) (q24), der(19) add(19) (p13) add(19) (q13.1), +2 mar\n\n\n\nFigure 1. Bone-marrow finding in the patient. A number of nuclear cells were 1.97 × 104/µL. Megakaryocyte were scanty. Blast count was 0.2%. Proerythrocytes increased to 70.0% of all nuclear cells, which were partially positive for PAS and negative for peroxidase, α-naphthyl butyrate esterase, and naphthol AS-D chloroacetate esterase.\n\nNo morphological myelodysplastic changes were observed in the patient’s bone marrow cells. Induction chemotherapy comprising idarubicin and cytosine arabinoside was initiated soon after leukemia was diagnosed. However, initial chemotherapy did not eliminate the leukemic cells but only attenuated the proliferation of proerythroblasts in the bone marrow to 67.0% of all nucleated cells. Following chemotherapy induction, complications such as acute heart failure, multiple intestinal ulcerations, and progressive polymyositis symptoms developed. These complications led to the discontinuation of chemotherapy, and 96 days after diagnosis, the patient died owing to PEL.\n\nThe Institutional Review Board (IRB) of Kagawa Medical University approved the case report and submission of medical literature. We obtained the approval from the IRB (IRB approval No. H23-23).\n\nWritten informed consent was obtained from the patient for publication of this case series and any accompanying images.\n\nDiscussion\nWe assumed that the patient developed azathioprine-associated leukemogenesis. To date, only one case report of azathioprine-associated acute erythroleukemia has been published,6 in which der(1;7) (q10;p10) was reported to be the sole acquired cytogenetic abnormality. Furthermore, only a single case report has been published regarding azathioprine treatment for Crohn’s disease in a patient who developed AML with multilineage dysplasia (World Health Organization (WHO) classification).5 This case, which was complicated by Crohn’s disease, showed a complex karyotype that included -7 and -13. The authors analyzed the activity of thiopurine S-methyltransferase, which metabolizes azathioprine, and found that the patient was a poor metabolizer. Furthermore, the authors discussed the association between PEL pathogenesis and concurrent immunosuppressive therapy with azathioprine, myelodysplastic changes, and monosomy seven karyotypes. They also demonstrated that poor azathioprine metabolism is associated with a subset of PEL with dysplasia.\n\nIn addition to azathioprine metabolism, the leukemogenic mechanism of azathioprine is an important issue. A cytogenetic study of 75 patients with erythroleukemia revealed no specific karyotype abnormality.9 In this study, an association between the subcategory AML-M6a and MDS refractory anemia with excess blasts in transformation was observed. Moreover, the M6b subtype (PEL) harbored t(9;22) (q34;q11), that is, Philadelphia chromosome translocation, in four of seven cases. Other PEL cases revealed that the preexisting risks for PEL were chemoradiotherapy exposure and antecedent MDS.8 An investigation of secondary MDS cases after azathioprine treatment revealed an association of MDS onset with the abnormal karyotype of chromosome 7.10 Kwong et al.11 analyzed three patients with AML who underwent azathioprine treatment for autoimmune diseases; in addition, a comprehensive review discussed the association between azathioprine and AML.12 The carcinogenic potential of azathioprine was introduced and a strong association between therapy-related MDS and chromosomal 7 abnormalities was suggested. Thus, the leukemogenic mechanism of azathioprine, which involved karyotyped events, was hypothesized. In addition, autoimmune diseases increase the risk for hematological malignancies.13 An association between azathioprine and MDS/AML was etiologically determined in a recent observational study,14 which demonstrated that azathioprine increased the risk for myeloid neoplasms (MDS/AML) by 7.05-fold in patients with autoimmune diseases. The study also suggested that the effect of azathioprine on MDS/AML was much stronger than that on autoimmune diseases. In this study, the cytogenetic abnormalities detected were characterized as karyotypes for MDS, including 5q and -7. Although bone marrow cells showed no apparent dysplastic changes, our case could be linked to preexisting MDS. Knipp et al. reported a high frequency of chromosomal aberrancies associated with MDS/AML-M6b. MDS-based leukemogenesis is more closely associated with AML-M6b (PEL) than with AML-M6a.\n\nHow the use of azathioprine promotes the onset of leukemia is a major concern. Among azathioprine-associated MDS cases, the median treatment duration was 83 months (range, 24–168 months), and the median cumulative azathioprine dose was 253 g (range, 27–765 g).10 In this study, azathioprine (accumulated dose of 297 g over 10 years) was sufficient to contribute to the onset of PEL.10 However, another study reported no significant association between the duration of exposure to azathioprine and the onset of MDS/AML;14 the accumulated drug exposure was similar between MDS/AML cases and controls. Therefore, the risk threshold for the onset of leukemia was unknown. As a result, azathioprine metabolism vulnerability in each patient should be considered as a contributor to the onset of MDS/AML.5\n\nIn conclusion, because case reports of PEL after azathioprine treatment remain scarce, we hope that our case report will contribute to the discussion of azathioprine as a potential etiology of PEL.\n\nConflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 \nVardiman JW Thiele J Arber DA et al \nThe 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes . Blood . 2009 ;114 (5 ): 937 –951 .19357394 \n2 \nLiu W Hasserjian RP Hu Y et al \nPure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification . Mod Pathol \n2011 ; 24 (3 ): 375 –383 .21102413 \n3 \nSantos FP Faderl S Garcia-Manero G et al \nAdult acute erythroleukemia: an analysis of 91 patients treated at a single institution . Leukemia \n2009 ; 23 (12 ): 2275 –2280 .19741728 \n4 \nSadrzadeh H Hasserjian R Fathi AT. \nPure erythroid leukemia evolving from a therapy-related myelodysplastic syndrome secondary to treatment for chronic lymphocytic leukemia . Am J Hematol \n2013 ; 88 (3 ): 240 –241 .22565525 \n5 \nYenson PR Forrest D Schmiegelow K et al \nAzathioprine-associated acute myeloid leukemia in a patient with Crohn’s disease and thiopurine S-methyltransferase deficiency . Am J Hematol \n2008 ; 83 (1 ): 80 –83 .17696202 \n6 \nPark TS Cheong JW Song J et al \nAcute erythroleukemia with der(1;7)(q10; p10) as a sole acquired abnormality after treatment with azathioprine . Cancer Genet Cytogenet \n2008 ; 186 (1 ): 58 –60 .18786444 \n7 \nGupta SK Kumar R Chharchhodawala T et al \nSecondary pure erythroid leukaemia in relapsed acute lymphoblastic leukaemia: lineage switch or chemotherapy effect? \nBMJ Case Rep . Epub ahead of print 19 May 2014. DOI: 10.1136/bcr-2013-201724 .\n8 \nWong E Ling V Westerman D et al \nHow unique is pure erythroid leukaemia? A retrospective analysis of seven cases and review of the literature . J Clin Pathol \n2015 ; 68 (4 ): 301 –305 .25609576 \n9 \nLessard M Struski S Leymarie V et al ; Groupe Francophone de Cytogénétique Hématologique (GFCH) . Cytogenetic study of 75 erythroleukemias . Cancer Genet Cytogenet \n2005 ; 163 (2 ): 113 –122 .16337853 \n10 \nKnipp S Hildebrandt B Richter J et al \nSecondary myelodysplastic syndromes following treatment with azathioprine are associated with aberrations of chromosome 7 . Haematologica \n2005 ; 90 (5 ): 691 –693 .\n11 \nKwong YL Au WY Liang RH. \nAcute myeloid leukemia after azathioprine treatment for autoimmune diseases: association with -7/7q- . Cancer Genet Cytogenet \n1998 ; 104 (2 ): 94 –97 .9666800 \n12 \nKwong YL. \nAzathioprine: association with therapy-related myelodysplastic syndrome and acute myeloid leukemia . J Rheumatol \n2010 ; 37 (3 ): 485 –490 .20080917 \n13 \nAnderson LA Pfeiffer RM Landgren O et al \nRisks of myeloid malignancies in patients with autoimmune conditions . Br J Cancer \n2009 ; 100 (5 ): 822 –828 .19259097 \n14 \nErtz-Archambault N Kosiorek H Taylor GE et al \nAssociation of therapy for autoimmune disease with myelodysplastic syndromes and acute myeloid leukemia . JAMA Oncol \n2017 ; 3 (7 ): 936 –943 .28152123\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-3605",
"issue": "10()",
"journal": "Rare tumors",
"keywords": "Acute myeloid leukemia; azathioprine; erythroleukemia; myelodysplastic syndrome; polymyositis; pure erythroid leukemia",
"medline_ta": "Rare Tumors",
"mesh_terms": null,
"nlm_unique_id": "101526926",
"other_id": null,
"pages": "2036361318773847",
"pmc": null,
"pmid": "29785257",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
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"title": "Pure erythroid leukemia in a polymyositis patient treated with azathioprine.",
"title_normalized": "pure erythroid leukemia in a polymyositis patient treated with azathioprine"
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"abstract": "Soft tissue myoepithelial carcinomas are a rare, malignant subgroup of myoepithelial tumours mostly arising in the extremities with equal predilection for women and men. The mainstay of management of localised disease is complete surgical resection. Despite optimal treatment, 40-45% of tumours recur. Data regarding the efficacy of systemic therapy for advanced and metastatic disease are lacking. The primary aim of this study was to evaluate the outcome of all patients with soft tissue myoepithelial carcinoma treated at a single referral centre. The secondary aim was to establish the efficacy of systemic therapies in patients with advanced disease. A retrospective review of the prospectively maintained Royal Marsden Sarcoma Unit database was performed to identify soft tissue myoepithelial carcinoma patients treated between 1996 and 2019. Patient baseline characteristics and treatment history were recorded. Response to systemic therapy was evaluated using RECIST 1.1. We identified 24 patients treated at our institution between 1996 and 2019,12 males and 12 females. Median age at presentation was 49.6 years [interquartile range (IQR) 40.5-63.3 years]. Twenty-two out of 24 patients (91.7%) underwent primary surgical resection. Nine patients (37.5%) received systemic treatment. A partial response was documented in one patient treated with doxorubicin. The median progression-free survival for first-line chemotherapy was 9.3 months. Myoepithelial carcinoma frequently recurs after complete surgical resection. Conventional chemotherapy demonstrated some activity in myoepithelial carcinoma, however, more effective systemic therapies are required and enrolment in clinical trial should be encouraged.",
"affiliations": "The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;Institute of Cancer Research, 15 Cotswold Road, Sutton, London, SM2 5NG, UK.;Maisonneuve-Rosemont Hospital, 5415 Assumption Blvd, Montreal, QC, H1T 2M4, Canada.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;Institute of Cancer Research, 15 Cotswold Road, Sutton, London, SM2 5NG, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.;The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK. robin.jones4@nhs.net.",
"authors": "Chamberlain|Florence|F|;Cojocaru|Elena|E|;Scaranti|Mariana|M|;Noujaim|Jonathan|J|;Constantinou|Anastasia|A|;Thway|Khin|K|;Fisher|Cyril|C|;Messiou|Christina|C|;Strauss|Dirk C|DC|;Miah|Aisha|A|;Zaidi|Shane|S|;Benson|Charlotte|C|;Gennatas|Spyridon|S|;Jones|Robin L|RL|",
"chemical_list": "D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin",
"country": "United States",
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"doi": "10.1007/s12032-019-1335-4",
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"issue": "37(2)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": "Chemotherapy; Malignant myoepithelioma; Sarcomas; Soft tissue myoepithelial carcinoma/tumour; Soft tissue tumour; Treatment",
"medline_ta": "Med Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009208:Myoepithelioma; D009367:Neoplasm Staging; D011446:Prospective Studies; D012189:Retrospective Studies; D012983:Soft Tissue Neoplasms; D015996:Survival Rate; D059005:Topoisomerase II Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "13",
"pmc": null,
"pmid": "31879796",
"pubdate": "2019-12-27",
"publication_types": "D016428:Journal Article",
"references": "19097774;28390395;27134707;21177214;25253093;30886937;18306544;16796029;25299310;29023697;23616091;25693574;24585572;25804378;12960802;24993038;21251814;20815032;19033866;18503832;29117335;25588630;28458787;27746887",
"title": "Adult soft tissue myoepithelial carcinoma: treatment outcomes and efficacy of chemotherapy.",
"title_normalized": "adult soft tissue myoepithelial carcinoma treatment outcomes and efficacy of chemotherapy"
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"abstract": "BACKGROUND\nAs suggested by the 2012 KDIGO guidelines, persistent elevation of serum creatinine > 3.5 mg/dl (> 309 μmol/l) (or an estimated glomerular filtration rate < 30 ml/min per 1.73 m is one of contradictions for the use of immunosuppressive therapy in membranous nephropathy.\nA 45-year-old man with membranous nephropathy negative for serum anti-phospholipase-A2-receptor antibody, showed no response to corticosteroids and cyclophosphamide. He progressed to chronic kidney disease stage 4 (CKD4) under tacrolimus and relapsed after withdrawal.\nThe patient received repeated renal biopsy, comfirming the diagnosis of membranous nephropathy with progressive glomerular and tubulointerstitial scarring.\n\n\nMETHODS\nHe was treated with successfully four times with lose-dose (180 mg/m every 2-3 months) rituximab (RTX) depending on his B cell counts, aiming to remain at 0-5 cells/μl.\n\n\nRESULTS\nThe patient was followed-up for almost 6 years. He achieved a partial remission at 11 months and a complete remission of the nephritic range of proteinuria at 34 months following infusion of RTX. RTX was well tolerated and the patient's renal function improved. He had no edema and his dosage of corticosteroids could be discontinued.\n\n\nCONCLUSIONS\nThis case strongly suggested that rituximab has promising therapeutic significance, even in patients progressing to CKD4.",
"affiliations": "Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, and Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China.",
"authors": "Zhou|Xu-Jie|XJ|;Zhou|Fu-De|FD|;Wang|Su-Xia|SX|;Zhao|Ming-Hui|MH|",
"chemical_list": "D007155:Immunologic Factors; D054507:Receptors, Phospholipase A2; D000069283:Rituximab",
"country": "United States",
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"doi": "10.1097/MD.0000000000011184",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29924035MD-D-18-0148310.1097/MD.0000000000011184111845200Research ArticleClinical Case ReportA case report of remission of refractory membranous nephropathy progressing to stage 4 chronic kidney disease using low-dose rituximab A long-term follow-upZhou Xu-Jie MD, PhDZhou Fu-De MD∗Wang Su-Xia MDZhao Ming-Hui MD, PhDNA. Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, and Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China.∗ Correspondence: Fu-De Zhou, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, No 8 Xi Shi Ku Street, Xi Cheng District, Beijing 100034, China (e-mail: zhoufude1801@vip.sina.com).6 2018 22 6 2018 97 25 e111841 3 2018 29 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 License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nAs suggested by the 2012 KDIGO guidelines, persistent elevation of serum creatinine > 3.5 mg/dl (> 309 μmol/l) (or an estimated glomerular filtration rate < 30 ml/min per 1.73 m2 is one of contradictions for the use of immunosuppressive therapy in membranous nephropathy.\n\nPatient concerns:\nA 45-year-old man with membranous nephropathy negative for serum anti-phospholipase-A2-receptor antibody, showed no response to corticosteroids and cyclophosphamide. He progressed to chronic kidney disease stage 4 (CKD4) under tacrolimus and relapsed after withdrawal.\n\nDiagnoses:\nThe patient received repeated renal biopsy, comfirming the diagnosis of membranous nephropathy with progressive glomerular and tubulointerstitial scarring.\n\nInterventions:\nHe was treated with successfully four times with lose-dose (180 mg/m2 every 2-3 months) rituximab (RTX) depending on his B cell counts, aiming to remain at 0-5 cells/μl.\n\nOutcomes:\nThe patient was followed-up for almost 6 years. He achieved a partial remission at 11 months and a complete remission of the nephritic range of proteinuria at 34 months following infusion of RTX. RTX was well tolerated and the patient's renal function improved. He had no edema and his dosage of corticosteroids could be discontinued.\n\nLessons:\nThis case strongly suggested that rituximab has promising therapeutic significance, even in patients progressing to CKD4.\n\nKeywords\nCKD4membranous nephropathyrefractoryrituximabOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nMembranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults. Although several diseases such as viral infections, autoimmune diseases, certain drugs, and malignancies may cause secondary MN, most cases of MN are idiopathic MN (IMN).[1] M-type phospholipase A2 receptor (PLA2R) was identified as the major autoantigen for primary MN in adults.[2,3] The treatment of IMN is heavily debated.[4] Although one-third of the patients can develop a spontaneous remission during the first year of follow-up, about one-third will progress to end-stage renal disease.\n\nConventional therapies, consisting of corticosteroids and immunosuppressive agents, might induce significant adverse side-effects and are not effective in all patients. The current Kidney Disease Improving Global Outcomes (KDIGO) guideline favors treatment to be restricted to high-risk patients with use of alkylating agents or calcineurin inhibitors as an alternative therapy.[4] It did not suggest using immunosuppressive therapy in patients with a serum creatinine (SCr) persistently >3.5 mg/dL (>309 μmol/L) (or an estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m2) or those with concomitant severe or potentially life threatening infections.[4] It was reported that rituximab (RTX) administered at a dose of two 1 g infusions 2 weeks apart, or 4 once-weekly infusions of 375 mg/m2, could achieve complete remission (CR) or partial remission (PR) of proteinuria in 50% and 80% of patients at 1 year and at 2 years, respectively.[5–12] Indeed, it has been suggested that RTX might replace steroids plus cyclical cyclophosphamide (CTX) as the first-line immunosuppressive therapy or as a rescue therapy. However, there is still a lack of data on the efficacy of RTX in patients with chronic kidney disease stage 4 (CKD4) (or an eGFR <30 mL/min per 1.73 m2).\n\nWe present a case of MN negative for serum anti-PLA2R, who previously showed no response to corticosteroids and CTX, and who progressed to CKD4 under tacrolimus (Tac) and relapsed after withdrawal. However, the patient was treated successfully with 4 low doses of RTX therapy. RTX induced prolonged remission and enabled discontinuation of other immunosuppressive agents without substantially increasing the risk of infections and other serious adverse events (SAEs). Importantly, we observed that infusions of low-dose RTX with “the B-cell-driven protocol” were effective in inducing remission without increasing the risk of SAEs. This case and data from literature support the idea that RTX could be used as a first-line therapy for patients at risk of progression because of persistent NS caused by IMN.\n\nWritten informed consent was obtained from the patient for the administration of RTX and for the publication of this report.\n\n2 Case report\nA 45-year-old man was admitted to another hospital because of newly developed peripheral edema 5 years ago. A urinalysis showed proteinuria with the excretion of 7.86 g/d, and laboratory tests revealed hypoalbuminemia with albumin levels of 22 g/L (day 0). The patient was diagnosed with NS. The patient's renal function was normal (serum creatinine 79.3 μmol/L, eGFR 103 mL/min per 1.73 m2). Immediately after hospitalization a percutaneous renal biopsy was performed, which disclosed features of stage II MN under light and immunofluorescence microscopy. Initially, the patient was treated with an angiotensin II receptor blocker (valsartan), anticoagulant, prednisone (Pre; 60 mg/day), and intravenous CTX (0.6 g biweekly with a cumulative dose 1.2 g). CTX was stopped because of severe gastrointestinal discomfort and Tac (4 mg/d, 0.05 mg/kg∗d) was subsequently started. Four weeks later (2nd month), his clinical condition had not improved. In 2012, he was admitted to our hospital for further investigation.\n\nOn admission to our hospital, the patient had a blood pressure of 130/90 mm Hg and a body weight of 95 kg. A physical examination was nonspecific, except for edema of the lower extremities. A urinalysis showed proteinuria with the excretion of 8.25 g/d and 2 to 5 urinary red blood cells per high power field. The laboratory tests revealed a normal serum creatinine concentration of 102 μmol/L (eGFR 76 mL/min per 1.73 m2), and a serum albumin concentration of 18.1 g/L. Anti-PLA2R antibodies were not detected. The plasma trough concentration of Tac was 4.1 ng/mL. The routine blood tests were normal and immune indices were negative. Markers and imaging tests for tumors were negative. Serum and urine immunoelectrophoresis showed no monoclonal bands. The serum complement titers were within the normal limits. Hepatitis B surface antigen was negative. Antihepatitis B surface, antihepatitis B core, and antihepatitis B antibodies were positive and hepatitis B virus DNA was detected at <100 copies/mL. The dosage of Tac was adjusted to obtain a trough concentration in the range of 3.7 to 7.7 ng/mL. After 4 months of treatment with Tac and prednisone, the clinical condition of the patient had not improved. He received a second percutaneous renal biopsy (5th month) (Fig. 1A–C). Light microscopy showed 25 nonsclerotic glomeruli, and Jones silver staining showed that the glomerular basement membrane (GBM) was thickened with spikes. Tubular atrophy and interstitial fibrosis were moderate, with patchy infiltration of mononuclear cells. Immunofluorescence staining revealed fine granular staining of IgG, and C3 in the capillary walls. Staining for IgG subclasses showed intense IgG1 and IgG4 staining, and trace amounts of IgG2 and IgG3. By electron microscopy, subepithelial electron dense deposits with diffusely effaced foot processes of podocytes were observed. Therefore, continuation of Tac was prescribed, with a trough concentration in the range of 2.1 to 8 ng/mL. PR was achieved at 6 months, with a serum albumin concentration that increased to 36.9 g/L (9th month). Urinary protein excretion was significantly decreased to 0.66 g/d (15th month). However, the serum creatinine levels began to increase (132 μmol/L, 15th month) without infection or novel medications. Despite tapering the Tac dose to achieve a trough concentration of 2.1 to 2.5 ng/mL, his serum creatinine increased to 202 μmol/L and proteinuria increased to 5.71 g/d. Repeated markers and imaging tests including 18F-fluorodeoxyglucose positron emission tomography-computed tomography for tumors were negative. Thus, Tac was stopped and the patient was switched to oral CTX (50 mg/d, 0.5 mg/kg∗d). Although no further increase in serum creatinine was observed (stable for 6 months), NS relapsed with proteinuria increasing to 15.1 g/d and serum albumin decreasing to 29.4 g/L (25th month). In addition, he had an episode of herpes zoster (26th month), and CTX was stopped with cumulative dose of about 9 g. The treatment was then complemented by intermittent intravenous immunoglobulin (IVIG) with 3 pulses of 0.4 g/kg for 3 consecutive, repeated every month for a 3-month period. However, his serum creatinine then increased to 413 μmol/L (30th month), with 30 to 40 urinary red blood cells per high power field. Repeated serological workup for the hepatitis B surface antigen, hepatitis C antibody, antinuclear antibody, antineutrophil cytoplasmic antibody, anti-GBM antibody, and rheumatoid factor were all negative. To exclude crescentic nephritis or IVIG induced “sucrose nephropathy”, a third percutaneous renal biopsy was performed (30th month) (Fig. 1D–F). In contrast to the second biopsy, the third biopsy indicated that glomerular, as well as tubulointerstitial scarring had progressed, with increased filtrates of eosinophils. Under light microscopy, 20 glomeruli were observed, including 4 fibrous crescents with sclerosis, 2 cellular crescents, 1 fibrocellular crescent, and 1 segmental sclerosis. Thus prednisone was increase from 5 to 30 mg/d (30th month), but without improvement. His serum creatinine increased to 504 μmol/L, and proteinuria increased to 20.9 g/d. Anti-PLA2R antibodies was still negative. Therefore, he was administered RTX at 180 mg/m2, half of the suggested dose of 375 mg/m2 in the standard protocol, considering his previous long-term use of immunosuppressive regimens and deteriorated renal function. The infusion was well tolerated. Circulating B cells decreased from 95 to 1 cell/μL. One month later, his serum creatinine decreased to 360 μmol/L and stabilized. Prednisone was gradually tapered and stopped. He received 3 subsequent administrations (every 2–3 months) of RTX with the same dose depending on his B-cell counts, aiming to remain 0 to 5 cells/μL. At 11 months after the RTX treatment, the patient achieved PR with a 24-h urinary protein output of 2.48 g/d and serum albumin in normal range. The patient then approached CR of nephritic syndrome with an albumin-to-creatinine ratio of 214 mg/g at the last visit (67th month), which was 35 months after the therapy. His serum creatinine was 297 μmol/L, with an eGFR of 20 mL/min per 1.73 m2. In the recent 3-year follow-up after RTX, NS was not observed; anti-PLA2R antibodies were negative; the serum creatinine levels (range 300–340 μmol/L), blood pressure (108–138/72–88 mm Hg), hemoglobin (117–132 g/L), and body weight (75–80 kg) remained stable. The RTX treatment brought a remarkable improvement in the refractory MN of our patient (Fig. 2).\n\nFigure 1 Renal biopsy samples showing membranous nephropathy in the patient. (A–C) In the second biopsy, using light microscopy, 25 glomeruli were observed. Thickening of the glomerular basement membrane was observed. Endocapillary hypercellularity, and extracapillary proliferation were not observed except for mild mesangial proliferation. Tubular atrophy and interstitial fibrosis were moderate with patchy infiltration of mononuclear cells. (D–F) The third biopsy, in contrast to the second biopsy, indicated that glomerular as well as tubulointerstitial scarring had progressed, with increased filtrates of eosinophils. Under light microscopy, 20 glomeruli were observed, including 4 fibrous crescents with sclerosis, 2 cellular crescents, 1 fibrocellular crescent, and 1 segmental sclerosis.\n\nFigure 2 The clinical course of the current case. CTX = cyclophosphamide, Pre = prednisone, RB = renal biopsy, RTX = rituximab, SCr = serum creatinine, Tac = tacrolimus, UP = urine protein. The Y-axes show serum creatinine on the left and urine protein on the right. The X-axis shows the follow-up month.\n\n3 Discussion\nWe reported a case of refractory IMN progressing to CKD4 that was successfully treated with RTX. In the course of IMN, when the risks of immunosuppressive drugs become unacceptable and futile, there is still no agreed definition of the “no return point.”[2,4] However, as suggested by the 2012 KDIGO guidelines, those likely indicators included the presence of severe tubular interstitial fibrosis, tubular atrophy, and glomerular obsolescence on biopsy, persistent elevation of SCr >3.5 mg/dL (>309 μmol/L) (or eGFR <30 mL/min per 1.73 m2), and reduction in kidney size on ultrasound. RTX-induced remission of proteinuria and stabilization of renal function in this refractory IMN patient with high risk of renal progression.[13] This case strongly suggested that RTX would have promising therapeutic effects, even in patients progressing to CKD4.\n\nThe optimal dosage of RTX may vary when it is used to treat different diseases. The appropriate dose, the number of doses, and the appropriate treatment period for MN remain unclear.[2,4,6–12,14–20] In the current case, previous long-term immunosuppression and deteriorated renal function prompted us to be cautious when administering of RTX, using only half of the standard four 375 mg/m2 doses, and adjusting the treatment period according to the patient's B-cell count (in the B-cell-driven protocol, patients receive a second infusion of RTX only if they had more than 5 B cells per mm3 of peripheral blood). Several observational studies support the view that low-dose RTX can be effective to treat NS, at a lower cost and with fewer SEAs. However, there are also data suggesting that low-dose RTX obtains remission in <50% of IMN patients. It was suggested that patients with normal renal function, lower proteinuria, lower anti-PLA2R antibodies, and those who responded to previous treatments were the most likely to achieve a response with low-dose RTX (375 mg/m2 once or twice).[20] However, the follow-up time was limited and the duration of B-cell suppression was not checked. The remarkable reduction in treatment costs, means that the B-cell-driven protocol should facilitate access to RTX even in resource-limited settings.[10–12]\n\nThe patient was followed-up regularly for a long period (almost 6 years). The remission of NS was unlikely to have been spontaneous and RTX showed a favorable therapeutic effect. The patient achieved PR at 11 months and CR at 34 months following the infusion of RTX. Although the patient achieved a transient CR when he was treated with combination of Tac and low-dose steroid, it was observed a very short time. In addition, his renal function deteriorated even at a comparatively low plasma trough concentration of Tac after 1 year. The likely reason may be because of glomerular as well as tubulointerstitial scarring. The progression of tubulointerstitial damage may produce poor outcomes. However, the third renal biopsy showed evidence of crescents formation. Renal function was maintained by the administration of CTX; however, a more favorable prognosis of NS was not associated with CTX after a 1-year follow-up interval. In addition, considering the side-effects of infection (herpes zoster), continuation of CTX was another concern; however, the patient's the renal function progressively deteriorated. The condition was unchanged until RTX was adopted as the second-line therapy. RTX was well tolerated and the patient's renal function and NS improved. He had no edema and his dosage of corticosteroids could be discontinued. After a 5-year follow-up, his renal function is stable, and even slightly increased.\n\nIn summary, we presented patient with IMN that progressed to CKD4, which was refractory to alkylating agents and calcineurin inhibitors. The patient achieved CR with low-dose RTX, which suggested RTX as an economical and effective treatment for IMN.\n\nAcknowledgment\nThe authors thank the patient for devotion.\n\nAuthor contributions\nXJZ and FDZ were involved in the acquisition and analysis of data; wrote the manuscript; XJZ, SXW, MHZ, and FDZ revised the manuscript critically for important intellectual content; FDZ supervised the whole research group and has given the final approval of the version to be published.\n\nConceptualization: Xu-Jie Zhou, Fu-De Zhou.\n\nData curation: Xu-Jie Zhou, Su-Xia Wang, Fu-De Zhou.\n\nFormal analysis: Xu-Jie Zhou.\n\nInvestigation: Xu-Jie Zhou, Su-Xia Wang, Fu-De Zhou.\n\nMethodology: Xu-Jie Zhou, Su-Xia Wang.\n\nResources: Fu-De Zhou.\n\nSupervision: Fu-De Zhou, Su-Xia Wang, Ming-Hui Zhao.\n\nWriting – original draft: Xu-Jie Zhou, Fu-De Zhou.\n\nWriting – review & editing: Xu-Jie Zhou, Fu-De Zhou.\n\nAbbreviations: CKD4 = chronic kidney disease stage 4, CNI = calcineurin inhibitor, CR = complete remission, CTX = cyclophosphamide, eGFR = estimated glomerular filtration rate, GBM = glomerular basement membrane, IMN = idiopathic membranous nephropathy, IVIG = intravenous immunoglobulin, KDIGO = Kidney Disease Improving Global Outcomes, NS = nephrotic syndrome, PLA2R = M-type phospholipase A2 receptor, PR = partial remission, RTX = rituximab, SAEs = serious adverse events, Tac = tacrolimus.\n\nThe study was approved by the medical ethics committee of Peking University. The patient provided informed consent. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nThe data that support the findings of this study are available from the corresponding author (FDZ) upon reasonable request.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Ponticelli C Glassock RJ \nGlomerular diseases: membranous nephropathy - a modern view . Clin J Am Soc Nephrol \n2014 ;9 :609 –16 .23813556 \n[2] Beck LJ Salant DJ \nMembranous nephropathy: recent travels and new roads ahead . Kidney Int \n2010 ;77 :765 –70 .20182413 \n[3] Beck LJ Bonegio RG Lambeau G \nM-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy . N Engl J Med \n2009 ;361 :11 –21 .19571279 \n[4] Chapter 7: Idiopathic membranous nephropathy. Kidney Int Suppl (2011). 2012; 2(2):186–197 .\n[5] Ruggenenti P Cravedi P Chianca A \nRituximab in idiopathic membranous nephropathy . J Am Soc Nephrol \n2012 ;23 :1416 –25 .22822077 \n[6] Ruggenenti P Chiurchiu C Brusegan V \nRituximab in idiopathic membranous nephropathy: a one-year prospective study . J Am Soc Nephrol \n2003 ;14 :1851 –7 .12819245 \n[7] Waldman M Austin HR \nTreatment of idiopathic membranous nephropathy . J Am Soc Nephrol \n2012 ;23 :1617 –30 .22859855 \n[8] Remuzzi G Chiurchiu C Abbate M \nRituximab for idiopathic membranous nephropathy . Lancet \n2002 ;360 :923 –4 .12354476 \n[9] Angioi A Lepori N López AC \nTreatment of primary membranous nephropathy: where are we now? \nJ Nephrol \n2017 ;doi: 10.1007/s40620-017-0427-5 .\n[10] Sinha A Bagga A \nRituximab therapy in nephrotic syndrome: implications for patients’ management . Nat Rev Nephrol \n2013 ;9 :154 –69 .23338210 \n[11] Hofstra JM Fervenza FC Wetzels JF \nTreatment of idiopathic membranous nephropathy . Nat Rev Nephrol \n2013 ;9 :443 –58 .23820815 \n[12] Ruggenenti P Fervenza FC Remuzzi G \nTreatment of membranous nephropathy: time for a paradigm shift . Nat Rev Nephrol \n2017 ;13 :563 –79 .28669992 \n[13] Wang X Cui Z Zhang YM \nRituximab for non-responsive idiopathic membranous nephropathy in a Chinese cohort . Nephrol Dial Transplant \n2017 ;doi: 10.1093/ndt/gfx295 .\n[14] Cravedi P Sghirlanzoni MC Marasa M \nEfficacy and safety of rituximab second-line therapy for membranous nephropathy: a prospective, matched-cohort study . Am J Nephrol \n2011 ;33 :461 –8 .21508634 \n[15] Ruggenenti P Chiurchiu C Abbate M \nRituximab for idiopathic membranous nephropathy: who can benefit? \nClin J Am Soc Nephrol \n2006 ;1 :738 –48 .17699281 \n[16] Busch M Ruster C Schinkothe C \nRituximab for the second- and third-line therapy of idiopathic membranous nephropathy: a prospective single center study using a new treatment strategy . Clin Nephrol \n2013 ;80 :105 –13 .23587125 \n[17] Ponticelli C \nWhat is the role of rituximab in idiopathic membranous nephropathy? \nExpert Rev Clin Immunol \n2013 ;9 :13 –6 .23256760 \n[18] Katsuno T Ozaki T Kim H \nSingle-dose rituximab therapy for refractory idiopathic membranous nephropathy: a single-center experience . Intern Med \n2017 ;56 :1679 –86 .28674357 \n[19] van den Brand J Ruggenenti P Chianca A \nSafety of rituximab compared with steroids and cyclophosphamide for idiopathic membranous nephropathy . J Am Soc Nephrol \n2017 ;28 :2729 –37 .28487395 \n[20] Moroni G Depetri F Del VL \nLow-dose rituximab is poorly effective in patients with primary membranous nephropathy . Nephrol Dial Transplant \n2017 ;32 :1691 –6 .27387472\n\n",
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"mesh_terms": "D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D015433:Glomerulonephritis, Membranous; D006801:Humans; D007155:Immunologic Factors; D007668:Kidney; D008297:Male; D008875:Middle Aged; D011507:Proteinuria; D054507:Receptors, Phospholipase A2; D012074:Remission Induction; D051436:Renal Insufficiency, Chronic; D000069283:Rituximab; D016896:Treatment Outcome",
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"title": "A case report of remission of refractory membranous nephropathy progressing to stage 4 chronic kidney disease using low-dose rituximab: A long-term follow-up.",
"title_normalized": "a case report of remission of refractory membranous nephropathy progressing to stage 4 chronic kidney disease using low dose rituximab a long term follow up"
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"abstract": "Histoplasmosis has been observed in patients with immunosuppression in the form of isolated pulmonary involvement and disseminated disease. However, very few cases of this type that involved pleural effusion have been reported, and none have been reported in a case individual with mixed-phenotype acute leukemia (MPAL). Herein, we report a case involving a 23 year old Punjabi man having fever and breathlessness in the postinduction therapy period for mixed-phenotype acute leukemia (MPAL) with diagnosis of histoplasmosis based on the results of pleural fluid cytologic testing. The diagnosis of histoplasmosis may be missed in routine pleural fluid cytology testing; however, a high degree of suspicion for opportunistic infections in patients with immunocompromised state can aid diagnosis.",
"affiliations": "Departments of Cytology and Gynaecologic Pathology.;Departments of Cytology and Gynaecologic Pathology.;Internal Medicine and Clinical Hematology.;Departments of Cytology and Gynaecologic Pathology.;Internal Medicine and Clinical Hematology.;Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Sharma|Sudha|S|;Singh|Priya|P|;Sahu|Kamal Kant|KK|;Rajwanshi|Arvind|A|;Malhotra|Pankaj|P|;Naseem|Shano|S|",
"chemical_list": "D007166:Immunosuppressive Agents",
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"issue": "48(3)",
"journal": "Laboratory medicine",
"keywords": "fluid cytology; histoplasma; immunocompromised host; mixed phenotype acute leukemia; opportunistic infection; pleural fluid",
"medline_ta": "Lab Med",
"mesh_terms": "D000328:Adult; D006660:Histoplasmosis; D006801:Humans; D007166:Immunosuppressive Agents; D007938:Leukemia; D008297:Male; D009894:Opportunistic Infections; D010996:Pleural Effusion; D055815:Young Adult",
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"references": null,
"title": "Histoplasmosis in Pleural Effusion in a 23-Year-Old Man With Mixed-Phenotype Acute Leukemia.",
"title_normalized": "histoplasmosis in pleural effusion in a 23 year old man with mixed phenotype acute leukemia"
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"abstract": "OBJECTIVE\nTo investigate the safety and efficacy of rituximab (RTX) in patients with refractory Wegener's granulomatosis (WG).\n\n\nMETHODS\nEight consecutive patients with active refractory WG were included. In all patients disease activity had persisted despite standard treatment with cyclophosphamide and prednisolone, as well as tumour necrosis factor alpha blockade 3 months before inclusion in the study. Patients had particular granulomatous manifestations like retro-orbital granulomata (n=5), nodules of the lungs (n=1), and subglottic stenosis (n=2). RTX was given intravenously every 4th week in combination with the standard treatment in five patients and with methotrexate in two others. Disease extent and activity were monitored clinically by interdisciplinary care, immunodiagnostics (ANCA serology, B cells by flow cytometry), and magnetic resonance imaging.\n\n\nRESULTS\nBeneficial response and a reduction in disease activity were seen in three patients, two of whom went into complete remission. In three other patients, disease activity remained unchanged while the disease progressed in the remaining two patients. In all patients peripheral blood B cells fell to zero during treatment with RTX. cANCA titres remained unchanged in all except one patient.\n\n\nCONCLUSIONS\nIn this pilot study, B lymphocyte depletion was not associated with a change of the ANCA titres or obvious clinical improvement of refractory granulomatous disease in patients with WG. Further studies are needed to evaluate the role of RTX in WG.",
"affiliations": "University Hospital Schleswig-Holstein, Campus Luebeck, Department of Rheumatology and Rheumaklinik Bad Bramstedt, Germany. aries@rheuma-zentrum.de",
"authors": "Aries|P M|PM|;Hellmich|B|B|;Voswinkel|J|J|;Both|M|M|;Nölle|B|B|;Holl-Ulrich|K|K|;Lamprecht|P|P|;Gross|W L|WL|",
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"issue": "65(7)",
"journal": "Annals of the rheumatic diseases",
"keywords": null,
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D001402:B-Lymphocytes; D001799:Blood Sedimentation; D002675:Child, Preschool; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D018655:Lymphocyte Count; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009915:Orbit; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "853-8",
"pmc": null,
"pmid": "16269425",
"pubdate": "2006-07",
"publication_types": "D016428:Journal Article",
"references": "10211889;10817555;11200865;11562512;11762944;11920557;12000723;12422004;12422006;12538745;12607731;12794814;12846808;12905467;15150076;15173206;15448215;15641069;15641078;15774931;7554518;7621588;7820541;9217150;9529153",
"title": "Lack of efficacy of rituximab in Wegener's granulomatosis with refractory granulomatous manifestations.",
"title_normalized": "lack of efficacy of rituximab in wegener s granulomatosis with refractory granulomatous manifestations"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2020069414",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
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... |
{
"abstract": "OBJECTIVE\nEvaluate post-tonsillectomy outcomes in children discharged with ibuprofen versus those without.\n\n\nMETHODS\nThis was a retrospective review of children who underwent tonsillectomy ± adenoidectomy from 2012 to 2016 at a tertiary care children's hospital. Main outcome measures included bleed rates, ER visits, and nurse phone calls.\n\n\nRESULTS\nSeven hundred and seventy-three patients were included; 504 had ibuprofen at discharge (ID) and 269 did not (NID). There were significant differences in mean age, 6.7 years in the ID group years versus 8.6 for the NID group (P < 0.001). Indication for surgery was sleep apnea in 70.5% of ID patients and 44.0% of NID patients (P < 0.001). Post-tonsillectomy bleeds occurred in 8.7% in the ID group and 5.9% of the NID group (P = 0.168). Other outcome measures revealed no significant differences between the two groups. There was no significant difference in the outcome measures between patients with sleep apnea or recurrent tonsillitis. Age was important; 12.1% of children 9-18 years versus 4.8% in children 3.1-6 years (P = 0.006) had post-tonsillectomy bleeding. For children 9-18 years old, 16.7% in the ID group bled versus 7.5% in the NID group (P = 0.039). Logistical regression revealed that age contributed to post-op bleeding, and ibuprofen contributed to number of ER visits.\n\n\nCONCLUSIONS\nIbuprofen is associated with significantly elevated post-tonsillectomy bleeding in older children, further research is needed and other analgesics should be considered.",
"affiliations": "College of Medicine, The Pennsylvania State University, College of Medicine, Hershey, PA, United States.;Department of Public Health Sciences, Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, United States.;Department of Otolaryngology-Head and Neck Surgery, West Virginia University, Morgantown, WV, United States. Electronic address: mmc0040@hsc.wvu.edu.",
"authors": "Swanson|Robert T|RT|;Schubart|Jane R|JR|;Carr|Michele M|MM|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjoto.2018.05.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0709",
"issue": "39(5)",
"journal": "American journal of otolaryngology",
"keywords": "Hemorrhage; Ibuprofen; Pediatric; Surgery; Tonsillectomy",
"medline_ta": "Am J Otolaryngol",
"mesh_terms": "D000233:Adenoidectomy; D000293:Adolescent; D018712:Analgesics, Non-Narcotic; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007223:Infant; D008297:Male; D010149:Pain, Postoperative; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D014068:Tonsillectomy; D014069:Tonsillitis",
"nlm_unique_id": "8000029",
"other_id": null,
"pages": "618-622",
"pmc": null,
"pmid": "29843898",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association of ibuprofen use with post-tonsillectomy bleeding in older children.",
"title_normalized": "association of ibuprofen use with post tonsillectomy bleeding in older children"
} | [
{
"companynumb": "US-JNJFOC-20170923161",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "Transbronchial lung biopsy using cryoadhesion is a diagnostic technique gaining in popularity. Several studies have been performed on its diagnostic yield and safety profile. However, definitive conclusions are limited due to the heterogeneity of results. The most common complications described in the current literature are pneumothorax and hemorrhage. This case describes a 60-year-old female who developed a cavitary lung lesion shortly after undergoing transbronchial lung cryobiopsy, highlighting the need for further research on the rarer complications that may be associated with this promising procedure.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Wakemed Health and Hospitals, Raleigh, North Carolina, USA.;Department of Medicine, Campbell University School of Osteopathic Medicine, Lillington, North Carolina, USA.;Division of Pulmonary and Critical Care Medicine, Wakemed Health and Hospitals, Raleigh, North Carolina, USA.",
"authors": "Pathak|Vikas|V|;Zhou|Christine|C|;George|Ezmin|E|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/lungindia.lungindia_21_18",
"fulltext": "\n==== Front\nLung IndiaLung IndiaLILung India : Official Organ of Indian Chest Society0970-21130974-598XMedknow Publications & Media Pvt Ltd India 30604706LI-36-6010.4103/lungindia.lungindia_21_18Case ReportCavitary lung disease following transbronchial biopsy using cryoadhesion in a patient with diffuse parenchymal lung disease Pathak Vikas Zhou Christine 1George Ezmin Division of Pulmonary and Critical Care Medicine, Wakemed Health and Hospitals, Raleigh, North Carolina, USA1 Department of Medicine, Campbell University School of Osteopathic Medicine, Lillington, North Carolina, USAAddress for correspondence: Dr. Vikas Pathak, 3000 New Bern Avenue, Raleigh, North Carolina 27610, USA. E-mail: drvikaspathak@gmail.comJan-Feb 2019 36 1 60 62 Copyright: © 2018 Indian Chest Society2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Transbronchial lung biopsy using cryoadhesion is a diagnostic technique gaining in popularity. Several studies have been performed on its diagnostic yield and safety profile. However, definitive conclusions are limited due to the heterogeneity of results. The most common complications described in the current literature are pneumothorax and hemorrhage. This case describes a 60-year-old female who developed a cavitary lung lesion shortly after undergoing transbronchial lung cryobiopsy, highlighting the need for further research on the rarer complications that may be associated with this promising procedure.\n\nKEY WORDS:\nCryoadhesioncryobiopsydiffuse parenchymal lung diseaseinterstitial lung diseasetransbronchial biopsy\n==== Body\nINTRODUCTION\nTraditionally, transbronchial lung biopsies (TBLBs) have been performed using forceps to obtain a tissue sample. If the tissue provided from TBLB is nondiagnostic, a surgical lung biopsy (SLB) may be performed to obtain a larger sample.[1] Transbronchial lung cryobiopsy (TBLC) is a relatively new diagnostic technique that has been increasingly used as an alternative to SLB in the diagnosis of diffuse parenchymal lung disease.[12] TBLC provides a larger specimen than conventional transbronchial biopsy through use of a cryoprobe tip to flash-freeze sections of tissue.[3] The most common complications of this procedure are pneumothorax and hemorrhage although more severe complications have also been reported, such as acute respiratory failure.[2] Here, we present a unique complication of a new cavitary lung lesion after TBLC.\n\nCASE REPORT\nA 60-year-old female on prednisone 60 mg daily for a medical history of unspecified rheumatologic disorder was suspected to have interstitial lung disease seen on computed tomography scan of the chest [Figure 1]. She underwent bronchoscopy with bronchoalveolar lavage and TBLC. Her steroids were not held before the procedure. Bronchoalveolar lavage was done in the right upper lobe posterior segment, with 150 mL instilled and 120 mL recovered. A biopsy was obtained with the cryoprobe from the superior segment of the right lower lobe. One sample was obtained with one pass, complicated only by mild bleed that resolved after administration of cold saline and 3 mL epinephrine. She was discharged home several hours later without further complication.\n\nFigure 1 Computed tomography chest before bronchoscopy demonstrating widespread airspace disease in the lower lobes bilaterally without volume loss, air bronchograms, or cavitation\n\nNine days later, the patient was admitted to the hospital with right upper quadrant abdominal pain, fever, and leukocytosis with a white blood cell count of 31,000. Computed tomography scan of the chest revealed right lower lobe cavitary lesion measuring 2.6 cm × 3.5 cm × 4 cm in the superior segment where the cryobiopsy was taken [Figure 2]. This lesion was new compared to imaging from 2 weeks prior. The patient was empirically placed on vancomycin and piperacillin-tazobactam with continuation of steroids. The fungal culture from prior bronchoscopy grew Fusarium species, and cryobiopsy tissue revealed only sparse chronic inflammation.\n\nFigure 2 Computed tomography chest showing cavitation in the right lower lobe with an air-fluid level that measures 2.6 cm × 3.2 cm, highly suggestive of lung abscess\n\nAfter consultation with infectious disease, antimicrobial therapy was narrowed to voriconazole to cover fungal species. A steroid taper was started to allow for healing and clearance of suspected abscess. Repeat bronchoscopy performed during hospitalization revealed only mild erythema of airways and small old blood in the anterior distal trachea.\n\nDISCUSSION\nIn recent years, TBLC has become an increasingly popular method of obtaining an adequate lung sample for diagnosis of parenchymal lung disease. Traditional TBLB with forceps has limited diagnostic yield, primarily due to an inability to obtain an appropriate amount of tissue required for pathologic diagnosis.[3] On the other hand, SLB has a significantly higher complication risk compared to bronchoscopy.[14] Definite conclusions are difficult to draw as few studies directly compare TBLC to the gold standard SLB. Theoretically, TBLC combines the best of both worlds: samples obtained through TBLC are generally larger than TBLB with decreased crush artifact and provide an estimated diagnostic yield similar to SLB at 83%,[25] while avoiding the risks of the more invasive SLB.[4]\n\nMost published data thus far suggest that TBLC has a safety profile similar to TBLB. The most commonly reported complications are pneumothorax and hemorrhage.[246] Unfortunately, there is a significant heterogeneity of reported complication rates. The reported frequency rate of pneumothorax ranges from 0% to 26% and the frequency of bleeding ranges even further from 0% to 78%.[4] The variability of results may be due to the lack of standardization in procedure methodology. For example, the use of fluoroscopy or occlusion balloon may decrease incidence of pneumothorax and moderate/severe bleeding, respectively, but neither is routinely included in methodology of studies assessing TBLC.[5] This suggests that the lack of clarity about the safety of TBLC may be further elucidated with investigation into the superiority of different procedural techniques.\n\nInterestingly, pulmonary abscess is not a complication mentioned in recently published meta-analyses on the safety of TBLC[32456] although they have been reported as an uncommon complication after TBLB.[78] In 2016, Skalski et al. were the first to our knowledge to document a case of TBLC complicated by pulmonary abscess.[9] Our patient here is now the second. This raises a new concern of the possibility of other rare yet important complications of TBLC that have yet to be studied and highlights the need for continued research evaluating the risks of this promising procedure.\n\nIt should be noted that both the case reported by Skalski et al.[9] and the case reported here involved the use of corticosteroids in the time around the procedure. The causative organism for this patient's infection, Fusarium species, is also known to cause opportunistic infections, especially in patients with an immunocompromised state.[10] As steroids are a well-known cause of immunosuppression, it is possible that this complication is primarily contained to the subset of patients on corticosteroids at the time of procedure or those patients who are already colonized with an opportunistic pathogen of some kind. Without further studies, no definitive correlation can be declared. Currently, there are no guidelines on the use of corticosteroids during or after bronchoscopy. However, considering this theoretical increased infection risk, the continued use of corticosteroids around the time of procedure should be monitored carefully until proven otherwise.\n\nThe most recent guidelines from the British Thoracic Society published in 2011 do not recommend the use of prophylactic antibiotics in patients undergoing bronchoscopy.[11] A large survey performed in Japan by Asano et al. published in 2012 documented a rate of <0.3% for pulmonary infection as a complication of bronchoscopy,[12] supporting this recommendation. However, Ishida et al. suggest that the incidence rate of lung abscess after bronchoscopy may be as high as 10% in patients with certain risk factors.[8] Considering these two cases of abscess following TBLC in the setting of immunosuppressive factors, there may be merit in considering prophylactic antibiotics in those patients with risk factors for infection. Determination of these risk factors requires continued research.\n\nRegardless of whether the focus is on common complications such as pneumothorax and bleeding or rare complications such as pulmonary abscess, further research is needed to clarify the safety of TBLC. Direct comparison studies between different procedural techniques may contribute to understanding of various risk factors for complications. Larger studies comparing diagnostic yield and safety of TBLC to SLB would assist in determining whether tissue samples obtained with TBLC can be considered an adequate replacement for surgically obtained tissue. Until then, increasing the usage of TBLC in diagnosing lung disease should be done cautiously, with a careful eye for possible risk factors.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Poletti V Casoni GL Gurioli C Ryu JH Tomassetti S Lung cryobiopsies: A paradigm shift in diagnostic bronchoscopy? Respirology 2014 19 645 54 24862226 \n2 Johannson KA Marcoux VS Ronksley PE Ryerson CJ Diagnostic yield and complications of transbronchial lung cryobiopsy for interstitial lung disease. A Systematic review and metaanalysis Ann Am Thorac Soc 2016 13 1828 38 27466899 \n3 Casoni GL Tomassetti S Cavazza A Colby TV Dubini A Ryu JH Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung diseases PLoS One 2014 9 e86716 24586252 \n4 Ravaglia C Bonifazi M Wells AU Tomassetti S Gurioli C Piciucchi S Safety and diagnostic yield of transbronchial lung cryobiopsy in diffuse parenchymal lung diseases: A Comparative study versus video-assisted thoracoscopic lung biopsy and a systematic review of the literature Respiration 2016 91 215 27 26926876 \n5 Dhooria S Mehta RM Srinivasan A Madan K Sehgal IS Pattabhiraman V The safety and efficacy of different methods for obtaining transbronchial lung cryobiopsy in diffuse lung diseases Clin Respir J 2018 12 1711 20 29105361 \n6 DiBardino DM Haas AR Lanfranco AR Litzky LA Sterman D Bessich JL High complication rate after introduction of transbronchial cryobiopsy into clinical practice at an academic medical center Ann Am Thorac Soc 2017 14 851 7 28231021 \n7 Hsu JT Barrett CR Jr Lung abscess complicating transbronchial biopsy of a mass lesion Chest 1981 80 230 2 7249773 \n8 Ishida M Shimazaki T Suzuki M Ariyoshi K Morimoto K Case series of lung abscesses following flexible bronchoscopy Respir Investig 2015 53 129 32 \n9 Skalski JH Kern RM Midthun DE Edell ES Maldonado F Pulmonary abscess as a complication of transbronchial lung cryobiopsy J Bronchology Interv Pulmonol 2016 23 63 6 26705015 \n10 Muhammed M Anagnostou T Desalermos A Kourkoumpetis TK Carneiro HA Glavis-Bloom J Fusarium infection: Report of 26 cases and review of 97 cases from the literature Medicine (Baltimore) 2013 92 305 16 24145697 \n11 Du Rand IA Barber PV Goldring J Lewis RA Mandal S Munavvar M Summary of the british thoracic society guidelines for advanced diagnostic and therapeutic flexible bronchoscopy in adults Thorax 2011 66 1014 5 22003155 \n12 Asano F Aoe M Ohsaki Y Okada Y Sasada S Sato S Deaths and complications associated with respiratory endoscopy: A survey by the Japan society for respiratory endoscopy in 2010 Respirology 2012 17 478 85 22222022\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0970-2113",
"issue": "36(1)",
"journal": "Lung India : official organ of Indian Chest Society",
"keywords": "Cryoadhesion; cryobiopsy; diffuse parenchymal lung disease; interstitial lung disease; transbronchial biopsy",
"medline_ta": "Lung India",
"mesh_terms": null,
"nlm_unique_id": "8405380",
"other_id": null,
"pages": "60-62",
"pmc": null,
"pmid": "30604706",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "22003155;22222022;24145697;24586252;24862226;25951100;26705015;26926876;27466899;28231021;29105361;7249773",
"title": "Cavitary lung disease following transbronchial biopsy using cryoadhesion in a patient with diffuse parenchymal lung disease.",
"title_normalized": "cavitary lung disease following transbronchial biopsy using cryoadhesion in a patient with diffuse parenchymal lung disease"
} | [
{
"companynumb": "PHHY2017US127640",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
"druga... |
{
"abstract": "The Common Terminology Criteria for Adverse Events (CTCAE) were developed to document the adverse effects of chemotherapy but are now also used to document immune-related adverse events (irAE). Characterization of irAE by the CTCAE has implications for determining dose-limiting toxicity (DLT) and, consequently, the recommended phase II dose (RP2D) of investigational agents. In the phase I trial of nivolumab + ipilimumab, an asymptomatic increase in lipase was the primary DLT that informed the RP2D. We performed a retrospective study of 119 patients with melanoma who were treated at Memorial Sloan Kettering Cancer Center with the combination of nivolumab + ipilimumab to investigate the relationship between asymptomatic grade 3 or higher increases in amylase and/or lipase and pancreatitis, a known irAE. Of the 119 patients, there were only two cases of pancreatitis, representing 20% of patients with grade 3 or higher amylase, 6.3% of patients with grade 3 or higher lipase, and 20% of patients with grade 3 or higher elevations of both enzymes. The application of the CTCAE, especially in grading independent lab values, should be considered carefully in clinical trials of novel immunotherapeutic agents.",
"affiliations": "Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).;Affiliations of authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (CFF, VC, TB, ANS, PM, MKC, JDW, PBC, MDH, MAP); Weill Cornell Medical College, New York, NY (CFF, AVR, ANS, PM, MKC, JDW, PBC, MDH, MAP).",
"authors": "Friedman|Claire F|CF|;Clark|Varina|V|;Raikhel|Andrew V|AV|;Barz|Tim|T|;Shoushtari|Alexander N|AN|;Momtaz|Parisa|P|;Callahan|Margaret K|MK|;Wolchok|Jedd D|JD|;Chapman|Paul B|PB|;Hellmann|Matthew D|MD|;Postow|Michael A|MA|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D000077594:Nivolumab; D008049:Lipase; D000681:Amylases",
"country": "United States",
"delete": false,
"doi": "10.1093/jnci/djw260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0027-8874",
"issue": "109(4)",
"journal": "Journal of the National Cancer Institute",
"keywords": null,
"medline_ta": "J Natl Cancer Inst",
"mesh_terms": "D000681:Amylases; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008049:Lipase; D008297:Male; D008545:Melanoma; D000077594:Nivolumab; D010195:Pancreatitis; D012189:Retrospective Studies",
"nlm_unique_id": "7503089",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28040701",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": "23724867;19223884;27085692;25891304;17142107;11095328;23100216;10235202;26027431",
"title": "Thinking Critically About Classifying Adverse Events: Incidence of Pancreatitis in Patients Treated With Nivolumab + Ipilimumab.",
"title_normalized": "thinking critically about classifying adverse events incidence of pancreatitis in patients treated with nivolumab ipilimumab"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-16507444",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
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{
"abstract": "Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are an immunocompromised group who are likely to develop severe complications and mortality because of coronavirus disease 2019 (COVID-19). We report here a 61-year-old male patient of primary myelofibrosis who underwent an allo-HSCT 6 years earlier, had chronic graft-versus-host disease (cGVHD) involving the liver, lung, eyes, and skin, (with recurrent episodes of pulmonary infections) who developed severe COVID-19. The patient was treated with tocilizumab, and a combination of lopinavir/ritonavir, ribavirin, interferon-β1b. He was discharged after 31 days with full recovery. Tocilizumab, a humanized monoclonal antibody against IL6, has been shown to benefit respiratory manifestations in severe COVID19. However, this is first report, to our knowledge, of its use and benefit in a post HSCT recipient.",
"affiliations": "Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Homi Bhabha National Institute, Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Homi Bhabha National Institute, Mumbai, Maharashtra, India.;Homi Bhabha National Institute, Mumbai, Maharashtra, India.;Homi Bhabha National Institute, Mumbai, Maharashtra, India.;Homi Bhabha National Institute, Mumbai, Maharashtra, India.;Homi Bhabha National Institute, Mumbai, Maharashtra, India.;Homi Bhabha National Institute, Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.;Department of Medical Oncology, ACTREC - Tata Memorial Centre, Navi Mumbai, Maharashtra, India.",
"authors": "Mirgh|Sumeet|S|https://orcid.org/0000-0003-0642-2207;Gokarn|Anant|A|;Punatar|Sachin|S|;Chichra|Akanksha|A|;Singh|Anuj|A|;Rajendra|Akhil|A|;Babu Goli|Vasu|V|;Trivedi|Bhakti|B|;Joshi|Amit|A|;Patkar|Nikhil|N|;Tembhare|Prashant|P|;Subramanian|P G|PG|;Shetty|Nitin|N|;Chavan|Preeti|P|;Bhat|Vivek|V|;Gupta|Sudeep|S|;Khattry|Navin|N|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; C502936:tocilizumab",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "GVHD; allogeneic; coronavirus disease (COVID19); stem cell transplant; tocilizumab",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D000086382:COVID-19; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D000086402:SARS-CoV-2; D033581:Stem Cell Transplantation",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13576",
"pmc": null,
"pmid": "33523551",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Clinical course of severe COVID19 treated with tocilizumab and antivirals post-allogeneic stem cell transplant with extensive chronic GVHD.",
"title_normalized": "clinical course of severe covid19 treated with tocilizumab and antivirals post allogeneic stem cell transplant with extensive chronic gvhd"
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"companynumb": "IN-MYLANLABS-2021M1088162",
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"abstract": "A 67-year-old woman presented with left-sided headache and blurred vision, worse during hypertensive episodes. CT angiography showed a 4 mm left internal carotid artery (ICA) aneurysm incorporating the ophthalmic artery. She passed a test balloon occlusion, so the aneurysm was coil occluded, without immediate complication. Four days postprocedure she experienced sudden loss of vision in the left eye and funduscopy showed central retinal artery occlusion secondary to emboli from the coiled aneurysm. She was treated promptly with intravenous acetazolamide and ocular massage and regained full visual acuity. Thromboembolism to the eye during or after neurointerventional treatment is a relatively rare but devastating complication. This report demonstrates the effectiveness of combined intravenous acetazolamide and ocular massage in dealing with this complication when delivered promptly.",
"affiliations": "St George's Hospital, London, UK.;Department of Radiology, Royal Free Hospital, London, UK.;London, UK.;London, UK.",
"authors": "Duxbury|Oliver|O|;Bhogal|Pervinder|P|;Cloud|Geoffrey|G|;Madigan|Jeremy|J|",
"chemical_list": "D000086:Acetazolamide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000086:Acetazolamide; D000368:Aged; D000783:Aneurysm; D000792:Angiography; D021721:Balloon Occlusion; D003131:Combined Modality Therapy; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008405:Massage; D009880:Ophthalmic Artery; D015356:Retinal Artery Occlusion; D042262:Retinoscopy; D018570:Risk Assessment; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014786:Vision Disorders; D014792:Visual Acuity",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25480141",
"pubdate": "2014-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "4619853;19160204;20609991;9098313;11005400;18420951;1907333;677642;23070637;18984082;9081535",
"title": "Successful treatment of central retinal artery thromboembolism with ocular massage and intravenous acetazolamide.",
"title_normalized": "successful treatment of central retinal artery thromboembolism with ocular massage and intravenous acetazolamide"
} | [
{
"companynumb": "GB-BAYER-2017-148535",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"activesubstance": {
"activesubstancename": "ASPIRIN"
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"abstract": "Background: FOLFIRI regimen, which is composed of 5-FU, Leucovorin, and Irinotecan, is used in the first-line\nchemotherapy of metastatic colorectal cancer. Irinotecan life threatening toxicity is partly related to cytotoxic drug\nmetabolite which is primarily inactivated by the UGT1A1 enzyme. The primary aim of the present research was to\nfind the correlation between UGT1A1-genotype and clinical toxicity of irinotecan. Methods: In a prospective study\nfrom March 2011 to December 2013, all patients with metastatic colorectal cancer who had been referred to Medical\nOncology Department of Iran Cancer Institute were genotyped for UGT1A1*28 before the first cycle of chemotherapy.\nAll of the patients signed informed consent and trial approved by Ethics Committee of the Tehran University of\nMedical Sciences. Reduction of the standard dose of Irinotecan (180 mg/m2 body surface area) was measured based\non NCI toxicity criteria after the first cycle of chemotherapy. Patients with previous treatment with Oxaliplatin and\nfluorouracil (5-FU) in the adjuvant setting and adequate liver, kidney, and heart function were included in the trial. Both\nsynchronous and metachronous metastatic disease were noticeable. Results: A total of 50 patients with median age of\n52 years were included. Most (70%) of the patients had more than one site of metastases in peritoneum, liver, and/or\nlung. Thirty-one patients had UGT1A1*1 normal genotype, 13 were in heterozygote and 6 were in homozygote state\nofUGT1A1*28/*28. A clinically relevant increase in early toxicity was found in patients carrying the UGT1A1*28/*28\ngenotype with odds Ratio (OR) of 2.6 (95%CI 2.5-27.28). Similarly, there was a trend of lower overall survival in\nhomozygote group with an HR (Hazardous Ratio) of 2.76 (95%CI .88-.61). No statistically significant relationship was\nfound between UGT1A1genotypes and response to therapy. Conclusions: UGT1A1 28*/28* is strongly associated\nwith drug’s life-threatening toxicity even in a moderate dose of Irinotecan. On the other hand, UGT1A1 genotype data\nwas not helpful to differentiate response to treatment.",
"affiliations": "Hematology-Medical Oncology Department Cancer Research Center, Cancer Institute of Iran, Tehran University Medical Sciences, Tehran, Iran. Email: s.sadighi@hotmail.com",
"authors": "Emami|A H|AH|;Sadighi|S|S|;Shirkoohi|R|R|;Mohagheghi|M A|MA|",
"chemical_list": null,
"country": "Thailand",
"delete": false,
"doi": "10.22034/APJCP.2017.18.10.2803",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1513-7368",
"issue": "18(10)",
"journal": "Asian Pacific journal of cancer prevention : APJCP",
"keywords": "Irinotecan; pharmacogenomic; toxicity; colon; cancer",
"medline_ta": "Asian Pac J Cancer Prev",
"mesh_terms": null,
"nlm_unique_id": "101130625",
"other_id": null,
"pages": "2803-2807",
"pmc": null,
"pmid": "29072417",
"pubdate": "2017-10-26",
"publication_types": "D016428:Journal Article",
"references": "23208557;15355920;26681736;10778957;10541982;25175642;28280378;19795123;17990354;20177420;23089672;21412232;20602618;11990381;15007088;17728214;19530960;12571262",
"title": "Prediction of Response to Irinotecan and Drug Toxicity Based on Pharmacogenomics Test: A Prospective Case Study in Advanced Colorectal Cancer",
"title_normalized": "prediction of response to irinotecan and drug toxicity based on pharmacogenomics test a prospective case study in advanced colorectal cancer"
} | [
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"companynumb": "IR-CIPLA (EU) LIMITED-2018IR05983",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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"drugadditional": "3... |
{
"abstract": "Aquagenic wrinkling of the palms (AWP) is a rare, acquired condition of the skin, defined by transient rapidly developing white to translucent papules on palms and/or soles after brief exposure to water. Aquagenic wrinkling of the palms is associated with cystic fibrosis (CF). Therefore, the diagnosis of AWP can be important. Etiopathogenesis of AWP is still unclear. Treatment is often unsatisfactory and can be very challenging. This article contributes to the knowledge of AWP as we describe two new cases of aquagenic wrinkling of the palms: one patient with familial history of CF and one patient with AWP that was presumed to be induced by use of non-steroidal anti-inflammatory drugs. In addition, we present a review of the literature on drug-induced AWP.",
"affiliations": "Department of Dermatology, Martini Hospital, Groningen. bouwman.silke.klasiena@gmail.com.",
"authors": "Bouwman|K|K|;Menichino|S|S|;Kruithof|I|I|;Aalfs|A S|AS|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; D014867:Water; C116926:rofecoxib; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "26(11)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D005260:Female; D006225:Hand; D006801:Humans; D007052:Ibuprofen; D007101:Immersion; D007783:Lactones; D008297:Male; D012867:Skin; D013450:Sulfones; D014867:Water",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33342182",
"pubdate": "2020-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Two new cases of aquagenic wrinkling of the palms and literature review on drug interactions.",
"title_normalized": "two new cases of aquagenic wrinkling of the palms and literature review on drug interactions"
} | [
{
"companynumb": "NL-ALKEM LABORATORIES LIMITED-NL-ALKEM-2021-03591",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOBRAMYCIN"
},
"druga... |
{
"abstract": "Among implantable cardioverter-defibrillator (ICD) recipients, there are patients with recurrent episodes of electrical storm (ES), retractable to the optimal antiarrhythmic drug therapy or invasive ablation procedures. A relatively novel anti-ischemic drug with also antiarrhythmic properties, ranolazine, may effectively suppress ventricular arrhythmias in such patients for a long period of time.",
"affiliations": "st1st Cardiology Department General Hospital of Nikea-Piraeus \"Agios Panteleimon\" Nikea-Piraeus Greece.;st1st Cardiology Department General Hospital of Nikea-Piraeus \"Agios Panteleimon\" Nikea-Piraeus Greece.;st1st Cardiology Department General Hospital of Nikea-Piraeus \"Agios Panteleimon\" Nikea-Piraeus Greece.;st1st Cardiology Department General Hospital of Nikea-Piraeus \"Agios Panteleimon\" Nikea-Piraeus Greece.;st1st Cardiology Department General Hospital of Nikea-Piraeus \"Agios Panteleimon\" Nikea-Piraeus Greece.",
"authors": "Margos|Panagiotis|P|0000-0001-6327-5130;Margos|Nikolaos|N|;Mokadem|Nadiya|N|;Patsiotis|Ilias|I|;Kranidis|Athanasios|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1019",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1019CCR31019Case ReportCase ReportsRanolazine: safe and effective in a patient with hypertensive cardiomyopathy and multiple episodes of electrical storm P. Margos et al.Margos Panagiotis http://orcid.org/0000-0001-6327-5130pmargos@yahoo.gr \n1\nMargos Nikolaos \n1\nMokadem Nadiya \n1\nPatsiotis Ilias \n1\nKranidis Athanasios \n1\n1 st1st Cardiology DepartmentGeneral Hospital of Nikea‐Piraeus “Agios Panteleimon”Nikea‐PiraeusGreece* Correspondence\n\nPanagiotis Margos, 1st Cardiology department, General Hospital of Nikea‐Piraeus “Agios Panteleimon”, Dimitriou Mantouvalou 3, Nikea‐Piraeus, PC: 18454, Greece. Tel: 00306932102248, 00302102824290; Fax: 00302132077352; E‐mail: pmargos@yahoo.gr\n02 6 2017 7 2017 5 7 10.1002/ccr3.2017.5.issue-71170 1175 16 1 2017 11 3 2017 09 4 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nAmong implantable cardioverter‐defibrillator (ICD) recipients, there are patients with recurrent episodes of electrical storm (ES), retractable to the optimal antiarrhythmic drug therapy or invasive ablation procedures. A relatively novel anti‐ischemic drug with also antiarrhythmic properties, ranolazine, may effectively suppress ventricular arrhythmias in such patients for a long period of time.\n\nAntiarrhythmicdefibrillatorelectrical stormranolazine source-schema-version-number2.0component-idccr31019cover-dateJuly 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.2 mode:remove_FC converted:03.07.2017\n==== Body\nIntroduction\nElectrical storm (ES) is an unstable and potentially lethal medical condition of heart rhythm, characterized by at least three episodes of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) in a period of 24 h, requiring acute medical intervention. Typically, ES may occur during the acute phase of ST elevation myocardial infarction. In the modern era of implantable cardioverter defibrillators (ICDs), ES is even more common (5–20% of ICD recipients 1, 2), especially among patients treated with ICDs for secondary prevention after a first episode of sustained ventricular arrhythmia (VA).\n\nRegarding drug therapy for secondary prevention of VA, b‐blockers in combination with amiodarone is the cornerstone in patients with at least moderate structural heart disease 3, 4. Although short‐term effectiveness of drug therapy is generally high, especially with the addition of mexiletine 5 in resistant cases, toxicity with multiple side effects of both amiodarone and mexiletine attenuates the favorable outcomes in the long term. Radiofrequency (RF) ablation is routinely applied in patients with ICD and drug‐refractory VA, but its long‐term efficacy is also not too high 6, 7. Thus, a small subgroup of ICD recipients develops drug‐ and ablation‐refractory VA. These patients with inevitably high burden of ICD shocks present with impaired quality of life and increased mortality, due to the deleterious effect of multiple shocks in psychic sphere and myocardium, respectively. Further therapeutic approach in such patients is challenging. Literature presents limited data and suggestions, including off‐label drug administration.\n\nCase Report\nA 75‐year‐old man with NYHA‐II class systolic heart failure due to hypertensive cardiomyopathy (history of long‐lasting arterial hypertension, concentric left ventricular hypertrophy with diffuse hypokinesia – LVEF = 40% in echocardiographic study and extreme coronary artery tortuosity without significant atheromatic disease in coronary angiography) underwent an ICD implantation in March 2013, after an episode of sustained VT with hemodynamic collapse, which required urgent cardioversion.\n\nSoon after the implantation, ES occurred with multiple episodes of sustained VT, requiring either antitachycardia pacing (ATP) or shock therapy for sinus rhythm restoration (Fig. 1). Intravenous amiodarone was administered acutely, followed by chronic per os intake. New episodes of ES occurred during the following period, with no detectable triggering condition. Two transvenous ablation procedures were performed within 6 months, both without success. In both electrophysiological studies, ventricular stimulation was characterized by the induction of at least five different morphologies of sustained VT. During follow‐up, three different high‐dose b‐blocker agents were administered consecutively (carvedilol, metoprolol, or bisoprolol in combination with amiodarone), as well as sotalol, with no clinical response. Mexiletine was added for a period of only 2 months. It was prematurely discontinued due to severe central nervous system toxicity.\n\nFigure 1 (A) Episode of sustained ventricular tachycardia (cycle length 380 ms) which terminates after application of atnitachycardia pacing. (B) Episode of sustained ventricular tachycardia (cycle length 350 ms), resistant to atnitachycardia pacing. (C) Episode of ventricular fibrillation which terminates after application of high‐energy DC shock.\n\nIn summary, during the period of 16 months after implantation, 211 appropriate ATP and 91 appropriate shocks occurred (Fig. 2), despite our attempts to reduce shock burden, through adequate adjustment of therapy‐zone parameters. More specifically, the lower limit of VT zone was gradually elevated from 136 beats per minute (bpm) tο 162 bpm (detection: 20 beats, redetection: 12 beats), as even long‐lasting slow VT episodes were well tolerated, with no obvious hemodynamic deterioration. Additionally, the application of burst sequences (three sequences, 88%, 10 pulses) of VT zone was proven to be (more or less) ineffective. Thus, burst sequences were replaced by a more aggressive (and more effective) protocol of 3 plus 3 Ramp+ sequences (84%/78%/75%, eight pulses and 75%/69%/66%, eight pulses, respectively). In general, ATP and shocks were distributed normally in time, without long periods of recession. As a consequence, energy depletion of the device occurred prematurely (September 2014, device replacement). The heart rate spectrum of VTs was wide (120–230 bpm) and many episodes of sustained VT were only monitored without any intervention, displaying R‐R interval above the therapy zones (heart rate 120–162 bpm, monitor‐only zone). During this period, the patient underwent multiple hospitalizations, mainly receiving I.V. amiodarone. His quality of life clearly deteriorated, with new‐onset symptoms of anxiety and depression (psychiatric consultation was also performed). Despite multiple shock therapies, four consecutive echocardiographic studies were fortunately comparable to the initial one, with no clear deterioration of left ventricular systolic function.\n\nFigure 2 First device lifetime episodes (211 ATP, 91 shocks in total), in a period of 18 months.\n\nAfter device replacement, new ES episodes occurred, as expected. The pattern of VTs and subsequent device interventions was somewhat different, with lower mean heart rate of VT episodes, many hundreds of ATP and only few shocks, always appropriate (Fig. 3). Fifteen months after device replacement, subclinical hyperthyroidism was detected (December 2015, no previous history). Amiodarone was replaced by flecainide, with no clear clinical response (new episodes of VT occurred, with even lower mean heart rate, new therapeutic interventions – mainly ATP – were detected).\n\nFigure 3 Second device episodes for a total period of 26 months. Extremely high burden of ATP (2660) and only 18 shocks, during the initial period of 19 months (Sep 2014 to Mar 2016). No ATP or shock occurred during the following period of 7 months (Apr‐Oct 2016, patient under ranolazine).\n\nThree months after amiodarone discontinuation, in March 2016, ranolazine was added to the antiarrhythmic therapy (patient under carvedilol 12.5 mg × 3 and flecainide 100 mg × 2), with up‐titration to the dose of 750 mg × 2. Surprisingly, during the following 7 months (March to October 2016), no VT or VF episode occurred, in complete contrast to the displayed history of the previous 3 years, since first ICD implantation, with a total burden of 2871 ATP and 109 shocks, all appropriate (Fig. 3). It should be mentioned that no reversible underlying arrhythmogenic conditions (other than cardiomyopathy) were ever detected in our patient. Additionally, the patient's adherence to medical advisory was reliable and constant during the long period of 3.5 years of follow‐up. Currently, the patient is under a good psychologic and a stable functional status (NYHA‐II).\n\nDiscussion\nElectrical storm is an increasingly common, life‐threatening clinical situation, mainly presented in ICD recipients. Attending physicians should always be concentrated to the aim of primary or secondary prevention of ES during close follow‐up. This goal is served not only through drug suppression of arrhythmias, but also with the parallel attempt for detection and restoration of any potentially reversible underlying condition that contributes to arrhythmogenesis (i.e., reversible ischemia, electrolytic disorders, inadequate or inconsistent drug intake in total, dietary incompliance).\n\nUnfortunately, few antiarrhythmic drugs are currently available for the prevention or suppression of potentially lethal VA in patients with cardiomyopathy. Beyond b‐blockers and amiodarone, only sotalol can be used in patient with mildly reduced LVEF, like our patient 8. For the rest of the patients with at least moderate left ventricular systolic dysfunction, administration of other antiarrhythmic agents not only lacks favorable clinical outcome, but even displays deleterious (proarrhythmic) effect 9. Nevertheless, flecainide (like our case) and quinidine may contribute to the reduction in VA burden in selected patients with structural heart disease, under the protection of ICD 8, 9, 10.\n\nRanolazine is a relatively novel drug that intervenes in transmembrane cardiac action potential by ion current inhibition. The resultant reduction in intracellular Na+ concentration inhibits partially the Na+/Ca++ exchange current, preventing the deleterious effect of intracellular Ca++ overload under the trigger of ischemia. This indirect decrease in intracellular Ca++ concentration is responsible for the well‐documented antianginal effect of ranolazine 11, 12. In the field of clinical studies, ranolazine is presented as an effective, well‐tolerated, and safe drug, in patients with coronary artery disease and residual reversible ischemia 13, 14.\n\nBeyond anti‐ischemic properties, ranolazine displays remarkable similarity with class I and class III antiarrhythmic drugs, as a pure ion current inhibitor 15, 16. Experimental evidence emphasizes the increase in VF threshold and the suppression of ischemia‐induced arrhythmias by ranolazine 17, 18. According to MERLIN‐TIMI 36 trial, ranolazine suppresses VA during the first week after admission for non‐ST elevation acute coronary syndrome 14. In such patients, even short VT episodes of only few beats are associated with the risk of sudden cardiac death 19.\n\nImplantable cardioverter defibrillator recipients who present with antiarrhythmic drug‐refractory VA and recurrent ICD shocks provide an urgent therapeutic challenge. Limited therapeutic options are available, as mentioned before. In such intractable cases, previous reports support the adjunct role of ranolazine to the usual medical care. Bunch et al. 20 reported the effectiveness of ranolazine in 11 of 12 patients with refractory VT. Notably, 10 of them had ischemic heart disease. Ranolazine‐induced VA suppression has also been reported in patients with nonischemic cardiomyopathy 10, 20. Additionally, in patient with quite frequent premature ventricular complexes (PVC > 10%), ranolazine decreased PVC burden, approximately 60%, especially among individuals with impaired left ventricular function 21.\n\nAtrial fibrillation (AF) is another potential therapeutic target for ranolazine. A trend for reduced episodes of new‐onset AF was already mentioned in MERLIN‐TIMI 36 trial 14. Several subsequent reports highlight the positive effect of ranolazine against atrial fibrillation in specific populations: post‐CABG, for the conversion of recent‐onset atrial fibrillation or in cardioversion‐resistant patients 15, 22, 23, 24, 25, 26, 27, 28. Moreover, RAFFAELLO trial 29 demonstrated that ranolazine in doses of 500 and 750 mg reduced AF recurrences compared to placebo (borderline significance).\n\nIn patients with long QT syndrome, ranolazine shortens the prolonged QTc and suppresses early afterdepolarizations and TdP episodes 30, 31, 32. Currently, ranolazine displays a IIb indication (as add‐on therapy to b‐blocker) in LQTS3 patients with a QTc > 500 msec, in order to shorten the QT interval 33.\n\nA recent review article summarizes the antiarrhythmic role of ranolazine in general, emphasizing on its relatively few side effects, in comparison with other pure antiarrhythmic drugs 34. Currently, a randomized trial (Ranolazine Implantable Cardioverter Defibrillator – RAID trial), investigates the efficacy of routine ranolazine administration, beyond standard antiarrhythmic therapy, in patients with ICDs 35.\n\nRegarding our patient, the total burden of VA and ES was extremely high during three‐year follow‐up after the initial ICD implantation, with no long periods of recession. Amiodarone toxicity (subclinical hyperthyroidism), in combination with ablation failure, set a deadlock in our therapeutic approach. Although flecainide is contraindicated in patients with structural heart disease (increased mortality), it is well known that it decreases the burden of VA 36. ICD presence allowed flecainide administration, which offered an initial benefit in VA suppression. Subsequently, ranolazine was added, despite the absence of significant coronary artery disease and ischemia‐triggered VA, as recent reports highlight ranolazine‐induced VA suppression, even in nonischemic cardiomyopathy 10. This is attributed to its pure antiarrhythmic effect, in the absence of active ischemia. The effectiveness of ranolazine was impressive (VA elimination for an ongoing period of 7 months), better than expected, with no notable side effects. Notably, left ventricular systolic function and functional class (NYHA‐II) were not affected during the three‐year unstable period, while psychiatric consultation contributed to the restriction of anxiety and depression symptoms.\n\nIn conclusion, this is a quite rare case of an ICD recipient with an extremely high burden of VA and multiple episodes of ES, despite the appropriate antiarrhythmic therapy. After amiodarone and mexiletine discontinuation, due to toxicity, ranolazine administration, in combination with carvedilol and flecainide, offered total suppression of VA, for an ongoing period of 7 months. Ranolazine may be a quite valuable therapeutic option in such patients with multiple, retractable ventricular arrhythmias and episodes of electrical storm.\n\nAuthorship\nPM, NM, NM, IP, and AK: were all contributors to the study design/conception and data acquisition, analysis, and interpretation.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nSesselberg , H. W. \n, \nA. J. \nMoss \n, \nS. \nMcNitt \n, \nW. \nZareba \n, \nJ. P. \nDaubert \n, \nM. L. \nAndrews \n, et al. 2007 \nVentricular arrhythmia storms in postinfarction patients with implantable defibrillators for primary prevention indications: AMADIT‐II substudy . Heart Rhythm \n4 :1395 –1402 .17954398 \n2 \n\nExner , D. V. \n, \nS. L. \nPinski \n, \nD. G. \nWyse \n, \nE. G. \nRenfroe \n, \nD. \nFollmann \n, \nM. \nGold \n, et al. 2001 \nAntiarrhythmics versus implantable defibrillators. Electrical storm presages nonsudden death: the antiarrhythmics versus implantable defibrillators (AVID) trial . Circulation \n103 :2066 –2071 .11319196 \n3 \n\nPacifico , A. \n, \nS. H. \nHohnloser \n, \nJ. H. \nWilliams \n, et al. 1999 \nPrevention of implantable‐defibrillator shocks by treatment with sotalol. d, l‐Sotalol Implantable Cardioverter‐Defibrillator Study Group . N. Engl. J. Med. \n340 :1855 –1862 .10369848 \n4 \n\nPacifico , A. \n, \nS. H. \nHohnloser \n, \nJ. H. \nWilliams \n, \nB. \nTao \n, \nS. \nSaksena \n, \nP. D. \nHenry \n, et al. 2006 \nComparison of beta‐blockers, amiodarone plus beta‐blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial . JAMA \n295 :165 –171 .16403928 \n5 \n\nGao , D. \n, \nH. \nVan Herendael \n, \nL. \nAlshengeiti \n, \nP. \nDorian \n, \nI. \nMangat \n, \nV. \nKorley \n, et al. 2013 \nMexiletine as an adjunctive therapy to amiodarone reduces the frequency of ventricular tachyarrhythmia events in patients with an implantable defibrillator . J. Cardiovasc. Pharmacol. \n62 :199 –204 .23609328 \n6 \n\nWissner , E. \n, \nW. G. \nStevenson \n, and \nK. H. \nKuck \n. 2012 \nCatheter ablation of ventricular tachycardia in ischaemic and non‐ischaemic cardiomyopathy: where are we today? A clinical review \nEur. Heart J. \n33 :1440 –1450 .22411192 \n7 \n\nStevenson , W. G. \n, \nD. J. \nWilber \n, \nA. \nNatale \n, \nW. M. \nJackman \n, \nF. E. \nMarchlinski \n, \nT. \nTalbert \n, et al. 2008 \nIrrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: the multicenter thermocool ventricular tachycardia ablation trial . Circulation \n118 :2773 –2782 .19064682 \n8 \n\nSorajja , D. \n, \nT. M. \nMunger \n, and \nW.‐K. \nShen \n. 2015 \nOptimal antiarrhythmic drug therapy for electrical storm . J. Biomed. Res. \n29 :20 –34 .25745472 \n9 \n\nDhein , S. \n, \nA. \nMüller \n, \nR. \nGerwin \n, and \nW. \nKlaus \n. 1993 \nComparative study on the proarrhythmic effects of some antiarrhythmic agents . Circulation \n87 :617 –630 .8425305 \n10 \n\nVizzardi , E. \n, \nA. \nD'Aloia \n, \nF. \nSalghetti \n, \nO. \nAljassim \n, \nA. \nRaweh \n, \nI. \nBonadei \n, et al. 2013 \nEfficacy of ranolazine in a patient with idiopathic dilated cardiomyopathy and electrical storm . Drug Discov. Ther. \n7 :43 –45 .23524943 \n11 \n\nBoden , W. E. \n, \nR. A. \nO'Rourke \n, \nK. K. \nTeo \n, \nP. M. \nHartigan \n, \nD. J. \nMaron \n, \nW. J. \nKostuk \n, et al. 2007 \nOptimal medical therapy with or without PCI for stable coronary disease . N. Engl. J. Med. \n356 :1503 –1516 .17387127 \n12 \n\nSendón , J. L. \n, \nS. \nLee \n, \nM. L. \nCheng \n, and \nO. \nBen‐Yehuda \n. 2012 \nEffects of ranolazine on exercise tolerance and angina frequency in patients with severe chronic angina receiving maximally‐tolerated background therapy: analysis from the Combination Assessment of Ranolazine In Stable Angina (CARISA) randomized trial . Eur. J. Prev. Cardiol. \n19 :952 –959 .22689417 \n13 \n\nPatel , P. \n, and \nR. \nArora \n. 2008 \nUtility of ranolazine in chronic stable angina patients . Vasc. Health Risk Manag. \n4 :819 –824 .19065998 \n14 \n\nScirica , B. M. \n, \nD. A. \nMorrow \n, \nH. \nHod \n, \nS. A. \nMurphy \n, \nL. \nBelardinelli \n, \nC. M. \nHedgepeth \n, et al. 2007 \nEffect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST‐segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST‐Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN‐TIMI 36) randomized controlled trial . Circulation \n116 :1647 –1652 .17804441 \n15 \n\nAntzelevitch , C. \n, and \nA. \nBurashnikov \n. 2011 \nSerge Sicouri, and Luiz Belardinelli Electrophysiologic basis for the antiarrhythmic actions of ranolazine . Heart Rhythm \n8 :1281 –1290 .21421082 \n16 \n\nVizzardi , E. \n, \nA. \nD'Aloia \n, \nF. \nQuinzani \n, \nI. \nBonadei \n, \nR. \nRovetta \n, \nL. \nBontempi \n, et al. 2012 \nA focus on antiarrhythmic properties of ranolazine . J. Cardiovasc. Pharmacol. Ther. \n17 :353 –356 .22492919 \n17 \n\nVerrier , R. \n, \nK. \nKumar \n, \nT. \nNieminen \n, and \nL. \nBelardinelli \n. 2013 \nMechanisms of ranolazine's dual protection against atrial and ventricular fibrillation . Europace \n15 :317 –324 .23220484 \n18 \n\nDhalla , A. K. \n, \nW. Q. \nWang \n, \nJ. \nDow \n, \nJ. C. \nShryock \n, \nL. \nBelardinelli \n, \nA. \nBhandari \n, et al. 2009 \nRanolazine, an antianginal agent, markedly reduces ventricular arrhythmias induced by ischemia and ischemia‐reperfusion . Am. J. Physiol. Heart Circ. Physiol. \n297 :H1923 –H1929 .19767532 \n19 \n\nScirica , B. M. \n, \nE. \nBraunwald \n, \nL. \nBelardinelli \n, \nC. M. \nHedgepeth \n, \nJ. \nSpinar \n, \nW. \nWang \n, et al. 2010 \nRelationship between nonsustained ventricular tachycardia after non‐ST‐elevation acute coronary syndrome and sudden cardiac death: observations from the metabolic efficiency with ranolazine for less ischemia in non‐ST‐elevation acute coronary syndrome‐thrombolysis in myocardial infarction 36 (MERLIN‐TIMI 36) randomized controlled trial . Circulation \n122 :455 –462 .20644019 \n20 \n\nBunch , T. J. \n, \nS. \nMahapatra \n, and \nD. \nMurdock \n. 2011 \nRanolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug‐refractory ICD shocks . Pacing Clin. Electrophysiol. \n34 :1600 –1606 .21895727 \n21 \n\nYeung , E. \n, \nM. J. \nKrantz \n, \nJ. L. \nSchuller \n, \nR. A. \nDale \n, and \nM. C. \nHaigney \n. 2014 \nRanolazine for the suppression of ventricular arrhythmia: a case series . Ann. Noninvasive Electrocardiol. \n19 :345 –350 .24533675 \n22 \n\nTagarakis , G. I. \n, \nI. \nAidonidis \n, \nS. S. \nDaskalopoulou \n, \nV. \nSimopoulos \n, \nV. \nLiouras \n, \nM. E. \nDaskalopoulos \n, et al. 2013 \nEffect of ranolazine in preventing postoperative atrial fibrillation in patients undergoing coronary revascularization surgery . Curr. Vasc. Pharmacol. \n11 :988 –991 .23140547 \n23 \n\nMiles , R. H. \n, \nR. \nPassman \n, and \nD. K. \nMurdock \n. 2011 \nComparison of effectiveness and safety of ranolazine versus amiodarone for preventing atrial fibrillation after coronary artery bypass grafting . Am. J. Cardiol. \n108 :673 –676 .21726841 \n24 \n\nHammond , D. A. \n, \nC. \nSmotherman \n, \nC. A. \nJankowski \n, \nS. \nTan \n, \nO. \nOsian \n, \nD. \nKraemer \n, et al. 2015 \nShort‐course of ranolazine prevents postoperative atrial fibrillation following coronary artery bypass grafting and valve surgeries . Clin. Res. Cardiol. \n104 :410 –417 .25416563 \n25 \n\nFragakis , N. \n, \nK. C. \nKoskinas \n, \nD. G. \nKatritsis \n, \nE. D. \nPagourelias \n, \nT. \nZografos \n, and \nP. \nGeleris \n. 2012 \nAm. J. Cardiol. \n110 :673 –677 .22621799 \n26 \n\nSimopoulos , V. \n, \nG. I. \nTagarakis \n, \nS. S. \nDaskalopoulou \n, \nM. E. \nDaskalopoulos \n, \nA. \nLenos \n, \nK. \nChryssagis \n, et al. 2014 \nRanolazine enhances the antiarrhythmic activity of amiodarone by accelerating conversion of new‐onset atrial fibrillation after cardiac surgery . Angiology \n65 :294 –297 .23427280 \n27 \n\nMurdock , D. K. \n, \nM. \nKersten \n, \nJ. \nKaliebe \n, and \nGerman \nLarrain \n. 2009 \nThe use of oral ranolazine to convert new or paroxysmal atrial fibrillation: a review of experience with implications for possible “pill in the pocket” approach to atrial fibrillation . Indian Pacing Electrophysiol. J. \n9 :260 –267 .19763194 \n28 \n\nMurdock , D. K. \n, \nJ. \nKaliebe \n, and \nG. \nLarrain \n. 2012 \nThe use of ranolazine to facilitate electrical cardioversion in cardioversion‐resistant patients: a case series . Pacing Clin. Electrophysiol. \n35 :302 –307 .22229482 \n29 \n\nDe Ferrari , G. M. \n, \nL. S. \nMaier \n, \nL. \nMont \n, \nP. J. \nSchwartz \n, \nG. \nSimonis \n, \nM. \nLeschke \n, et al. 2015 \nRanolazine in the treatment of atrial fibrillation: results of the dose‐ranging RAFFAELLO (Ranolazine in Atrial Fibrillation Following an Electrical Cardioversion) study . Heart Rhythm \n12 :872 –878 .25602175 \n30 \n\nMoss , A. J. \n, \nW. \nZareba \n, \nK. Q. \nSchwarz \n, \nS. \nRosero \n, \nS. \nMcNitt \n, and \nJ. L. \nRobinson \n. 2008 \nRanolazine shortens repolarization in patients with sustained inward sodium current due to type‐3 long‐QT syndrome . J. Cardiovasc. Electrophysiol. \n19 :1289 –1293 .18662191 \n31 \n\nParikh , A. \n, \nR. \nMantravadi \n, \nD. \nKozhevnikov \n, \nM. A. \nRoche \n, \nY. \nYe \n, \nL. J. \nOwen \n, et al. 2012 \nRanolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2 . Heart Rhythm \n9 :953 –960 .22245792 \n32 \n\nvan den Berg , M. P. \n, \nF. \nvan den Heuvel \n, \nJ. P. \nvan Tintelen \n, \nP. G. \nVolders \n, and \nI. C. \nvan Gelder \n. 2014 \nSuccessful treatment of a patient with symptomatic long QT syndrome type 3 using ranolazine combined with a beta‐blocker . Int. J. Cardiol. \n171 :90 –92 .24342415 \n33 \n\nPriori , S. G. \n, \nC. \nBlomström‐Lundqvist \n, \nA. \nMazzanti \n, \nN. \nBlom \n, \nM. \nBorggrefe \n, \nJ. \nCamm \n et. al 2015 \n2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death . Eur. Heart J. \n36 :2739 –867 . https://doi.org/10.1093/eurheartj/ehv316.\n34 \n\nSaad , M. \n, \nA. \nMahmoud \n, \nI. Y. \nElgendy \n, and \nC. \nRichard \n. 2016 \nRanolazine in cardiac arrhythmia . Clin. Cardiol. \n3 :170 –178 .\n35 \nUS National Institutes of Health, ClinicalTrials.gov \n. Ranolazine Implantable Cardioverter‐Defibrillator Trial (RAID) . Available at http://clinicaltrials.gov/show/NCT01215253. (accessed 30 May 2015).\n36 \nThe Cardiac Arrhythmia Suppression Trial (CAST) Investigators \n. 1989 \nEffect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction . N. Engl. J. Med. \n321 :406 –412 .2473403\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "5(7)",
"journal": "Clinical case reports",
"keywords": "Antiarrhythmic; defibrillator; electrical storm; ranolazine",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1170-1175",
"pmc": null,
"pmid": "28680620",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports",
"references": "19767532;21895727;2473403;10369848;16403928;22245792;22689417;23609328;18662191;22492919;19763194;8425305;22621799;21421082;22229482;17804441;19064682;24342415;25416563;23220484;23140547;23524943;23427280;19065998;24533675;26320108;26459200;22411192;25745472;21726841;20644019;25602175;17954398;11319196;17387127",
"title": "Ranolazine: safe and effective in a patient with hypertensive cardiomyopathy and multiple episodes of electrical storm.",
"title_normalized": "ranolazine safe and effective in a patient with hypertensive cardiomyopathy and multiple episodes of electrical storm"
} | [
{
"companynumb": "GR-GLAXOSMITHKLINE-GR2017112587",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugadditional": "3",
... |
{
"abstract": "Osteosarcoma (OS) is the most common primary bone sarcoma in childhood. High-dose methotrexate, doxorubicine, cisplatin, and/or ifosfamide combinations are used as standard treatment in chemotherapy and could cause serious toxicity. Another alternative chemotherapy protocol is consisting of epirubicin, ifosfamide, and cisplatin (ECI), which we use in our center. The aim of this study was to evaluate the patients with OS who were treated with ECI protocol, retrospectively. Forty-three patients with OS diagnosed at our center between December 1995 and September 2017 were evaluated retrospectively. The mean follow-up period was 31 months (5-145 months). Recurrence was detected in 15 of 43 patients. When the factors affecting relapse are examined, recurrence was higher in patients who were older than 10 years at the time of diagnosis, upper extremity involvement, osteoblastic, and chondroblastic subgroups, but there was no statistically significant difference. Five-year and 10-year overall survival rates were 67.4% and 58.9%, and event-free survival rates were 54% and 47.3%, respectively. While 5-year overall survival rate was 86.7% in nonrecurrent cases, this rate was 40.9% in recurrent cases and this difference was statistically significant (p = 0.023). Just two patients died because of the toxicity. The prognosis of OS is still poor in relapse cases, so the choice of chemotherapy for neoadjuvant and adjuvant therapy is vital. When the risk of toxicity is also considered, the first step of ECI protocol is seen as a preferable treatment option because the survival rates are similar to the literature.",
"affiliations": "Department of Pediatric Hematology Oncology, Marmara University, Marmara Faculty of Medicine, Istanbul, Turkey.;Department of Pediatric Hematology Oncology, Marmara University, Marmara Faculty of Medicine, Istanbul, Turkey.;Department of Pediatric Hematology Oncology, Marmara University, Pendik Education and Research Hospital, Istanbul, Turkey.;Department of Public Health, Marmara University, Marmara Faculty of Medicine, Istanbul, Turkey.;Department of Radiology, and Marmara University, Marmara Faculty of Medicine, Istanbul, Turkey.;Department of Orthopedic Surgery, Marmara University, Marmara Faculty of Medicine, Istanbul, Turkey.;Department of Pediatric Hematology Oncology, Marmara University, Pendik Education and Research Hospital, Istanbul, Turkey.;Department of Pediatric Hematology Oncology, Marmara University, Marmara Faculty of Medicine, Istanbul, Turkey.",
"authors": "Eker|Nurşah|N|https://orcid.org/0000-0002-7707-3035;Tokuc|Ayşe G|AG|;Yılmaz|Barış|B|;Aktaş|Zeynep|Z|;Buğdaycı|Onur|O|;Erol|Bülent|B|;Senay|Emel|E|;Aras|Seda|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/jayao.2021.0075",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2156-5333",
"issue": null,
"journal": "Journal of adolescent and young adult oncology",
"keywords": "chemotherapy; children; osteosarcoma",
"medline_ta": "J Adolesc Young Adult Oncol",
"mesh_terms": null,
"nlm_unique_id": "101543508",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34342492",
"pubdate": "2021-08-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of Osteosarcoma in Children Without High-Dose Methotrexate: Could It Be Less Toxic Without Effecting Survival Rates?",
"title_normalized": "outcomes of osteosarcoma in children without high dose methotrexate could it be less toxic without effecting survival rates"
} | [
{
"companynumb": "TR-PFIZER INC-202101140567",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "The cost-effectiveness of letermovir as cytomegalovirus (CMV) prophylaxis in adult seropositive patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), compared with the conventional strategy of preemptive treatment, has not been evaluated in Asia.\nA decision analytical model, simulating the clinical progression of CMV infection on a lifetime horizon, was developed to compare prophylactic strategy with letermovir with preemptive therapy alone as anti-CMV strategies. Prophylaxis comprised administering letermovir for 14 weeks, with clinical outcomes measured at 24 weeks, followed by preemptive therapy if CMV infection occurred. This approach was modeled on outcomes of the letermovir phase 3 clinical study. The model enumerated the cost of letermovir prophylaxis, quality-adjusted life years (QALYs), and incremental cost per QALYs gained with prophylaxis. The opposite arm involved regular monitoring and preemptive therapy for CMV reactivation. Real-world costs from the adult HSCT center at Queen Mary Hospital, Hong Kong, were adopted for analysis. Costs and clinical benefits, expressed as QALYs, were discounted at 3% per year.\nLetermovir prophylaxis compared with preemptive therapy only would lead to an increase of life-year and QALYs at increased costs. Incremental cost-effectiveness analysis showed that letermovir prophylaxis had an associated cost of HKD 193,580 for each life-year gained, and HKD 234,675 for each QALY gained. Probabilistic sensitivity analysis showed that the majority of incremental cost-effectiveness ratio fell below the cost-effectiveness threshold of HKD 382,046 (one gross domestic product per capita) per QALY gained.\nLetermovir prophylaxis would be cost-effective for preventing CMV infection in adult seropositive allogeneic HSCT recipients in Hong Kong.",
"affiliations": "Department of Medicine, Queen Mary Hospital, Hong Kong, China.;Global Medical & Scientific Affairs, MSD, Hong Kong, Hong Kong.;Global Medical & Scientific Affairs, MSD, Taipei, Taiwan.;Global Medical & Scientific Affairs, MSD, Hong Kong, Hong Kong.;Global Medical & Scientific Affairs, MSD, Hong Kong, Hong Kong.;Centre for Observational and Real-world Evidence, MSD, Seoul, Korea.;Merck & Co., Inc., Kenilworth, NJ, USA.;Department of Medicine, Queen Mary Hospital, Hong Kong, China.",
"authors": "Chan|Thomas Sau-Yan|TS|;Cheng|Sally Shuk-Yee|SS|;Chen|Wei-Ting|WT|;Hsu|Danny Chung|DC|;Chau|Rene Wing-Yan|RW|;Kang|Suk Hyun|SH|;Alsumali|Adnan|A|;Kwong|Yok-Lam|YL|",
"chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C000588473:letermovir",
"country": "England",
"delete": false,
"doi": "10.1080/13696998.2020.1843321",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1369-6998",
"issue": "23(12)",
"journal": "Journal of medical economics",
"keywords": "Allogenic hematopoietic stem cell transplantation; Hong Kong; I10; I18; cost effectiveness analysis; cytomegalovirus; letermovir",
"medline_ta": "J Med Econ",
"mesh_terms": "D000085:Acetates; D000328:Adult; D000998:Antiviral Agents; D003362:Cost-Benefit Analysis; D003587:Cytomegalovirus; D018380:Hematopoietic Stem Cell Transplantation; D006723:Hong Kong; D006801:Humans; D011799:Quinazolines",
"nlm_unique_id": "9892255",
"other_id": null,
"pages": "1485-1492",
"pmc": null,
"pmid": "33155494",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cost-effectiveness of letermovir as cytomegalovirus prophylaxis in adult recipients of allogeneic hematopoietic stem cell transplantation in Hong Kong.",
"title_normalized": "cost effectiveness of letermovir as cytomegalovirus prophylaxis in adult recipients of allogeneic hematopoietic stem cell transplantation in hong kong"
} | [
{
"companynumb": "HK-ROCHE-2879660",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "The current status of and prospects for acute stroke care in Asia in the situation where both intravenous thrombolysis and endovascular therapies have been recognized as established strategies for acute stroke are reviewed. Of 15 million people annually having stroke worldwide, ≈9 million are Asians. The burdens of both ischemic and hemorrhagic strokes are severe in Asia. The unique features of stroke in Asia include susceptibility to intracranial atherosclerosis, high prevalence of intracerebral hemorrhage, effects of dietary and lifestyle habits, and several disorders with genetic causes. These features affect acute stroke care, such as the dosage of alteplase for thrombolysis and consideration of bleeding complications during antithrombotic therapy. Acute endovascular thrombectomy, as well as intravenous thrombolysis, is relatively prevalent in East Asia, but most of the other Asian countries need to develop their human resources and fundamental medical infrastructure for stroke care. A limitation of endovascular therapy in East Asia is the high prevalence of intracranial atherosclerosis that can cause recanalization failure and require additional angioplasty or permanent stent insertion although intracranial stenting is not an established strategy. Multinational collaboration on stroke research among Asian countries is infrequent. Asians should collaborate to perform their own thrombolytic and endovascular trials and seek the optimal strategy for stroke care specific to Asia.",
"affiliations": "From the Department of Cerebrovascular Medicine (K.T., M.H.), Division of Stroke Care Unit (M.K.), and Department of Neurology (H.Y.), National Cerebral and Cardiovascular Center, Suita, Japan. toyoda@ncvc.go.jp.;From the Department of Cerebrovascular Medicine (K.T., M.H.), Division of Stroke Care Unit (M.K.), and Department of Neurology (H.Y.), National Cerebral and Cardiovascular Center, Suita, Japan.;From the Department of Cerebrovascular Medicine (K.T., M.H.), Division of Stroke Care Unit (M.K.), and Department of Neurology (H.Y.), National Cerebral and Cardiovascular Center, Suita, Japan.;From the Department of Cerebrovascular Medicine (K.T., M.H.), Division of Stroke Care Unit (M.K.), and Department of Neurology (H.Y.), National Cerebral and Cardiovascular Center, Suita, Japan.",
"authors": "Toyoda|Kazunori|K|;Koga|Masatoshi|M|;Hayakawa|Mikito|M|;Yamagami|Hiroshi|H|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1161/STROKEAHA.115.008781",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0039-2499",
"issue": "46(6)",
"journal": "Stroke",
"keywords": "Asia; anticoagulants; cerebral hemorrhage; intracranial atherosclerosis; stroke; thrombectomy; thrombolysis, therapeutic",
"medline_ta": "Stroke",
"mesh_terms": "D002986:Clinical Trials as Topic; D003695:Delivery of Health Care; D057510:Endovascular Procedures; D005202:Far East; D005247:Feeding Behavior; D005343:Fibrinolytic Agents; D006801:Humans; D002537:Intracranial Arteriosclerosis; D020300:Intracranial Hemorrhages; D008019:Life Style; D015424:Reperfusion; D020521:Stroke; D017131:Thrombectomy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "0235266",
"other_id": null,
"pages": "1474-81",
"pmc": null,
"pmid": "25944322",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Acute reperfusion therapy and stroke care in Asia after successful endovascular trials.",
"title_normalized": "acute reperfusion therapy and stroke care in asia after successful endovascular trials"
} | [
{
"companynumb": "JP-ROCHE-1635064",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Many mfERG displays show normal responses that are larger at the center than peripherally, and the typical linear display of signals is inaccurate with respect to the retinal location of the signals. Printouts do not always indicate retinal or field view, they sometimes emphasize 3-D topographic plots which are not always representative of physiologic signals, and they show ring response densities which are different in every ring and hard to interpret without norms. These problems limit the clinical usefulness of the mfERG and limit communication in the literature. We share our Stanford Display to illustrate possible solutions to these problems.\n\n\n\nWe have changed the scaling factor for our mfERG unit to produce a trace array with near equal signals everywhere. We display responses is a spatially scaled array, in a retinal view, so that signals appear in their correct anatomic locations relative to a fundus image. The 3-D display is minimized on the page of signal analysis, and we emphasize ring response averages rather than ring response densities.\n\n\n\nThe new scaling and trace array display greatly facilitate the analysis of retinal disease. Regions of loss are easily recognized in their fundus location. Ring ratios based upon response amplitudes all have a normal value of 1.0 which simplifies analysis. A case of early hydroxychloroquine retinopathy demonstrates the use of this Stanford display.\n\n\n\nRecognition of these recording and display options may help mfERG users to maximize the value of the test. Proper scaling of the mfERG stimulus array facilitates localization of retinal disease and simplifies ring response analysis. Different laboratories will have different priorities for signal analysis, but mfERG displays should always indicate the eccentricity of responses, and the use of a retina or field view.",
"affiliations": "Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA, 94303, USA. marmor@stanford.edu.;Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA, 94303, USA.",
"authors": "Marmor|Michael F|MF|http://orcid.org/0000-0001-6057-440X;Cabael|Lorella|L|",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10633-018-9650-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-4486",
"issue": "137(1)",
"journal": "Documenta ophthalmologica. Advances in ophthalmology",
"keywords": "Hydroxychloroquine retinopathy; Retinal view; Ring ratios; Ring response averages; Stimulus scaling factor; Stretch factor; mfERG",
"medline_ta": "Doc Ophthalmol",
"mesh_terms": "D018501:Antirheumatic Agents; D003626:Data Display; D004596:Electroretinography; D005260:Female; D005654:Fundus Oculi; D006801:Humans; D006886:Hydroxychloroquine; D008875:Middle Aged; D012016:Reference Values; D012160:Retina; D012164:Retinal Diseases",
"nlm_unique_id": "0370667",
"other_id": null,
"pages": "63-70",
"pmc": null,
"pmid": "30030672",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17336914;19229576;22038576",
"title": "Clinical display of mfERG data.",
"title_normalized": "clinical display of mferg data"
} | [
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"companynumb": "US-TEVA-2018-US-950325",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "HYDROXYCHLOROQUINE"
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{
"abstract": "Cytomegalovirus (CMV) is a double-stranded DNA virus, which infects a large portion of the adult population. In immunocompetent patients, it typically is asymptomatic or manifests as mild and self-limiting flu-like illness symptoms, whereas in immunocompromised patients, CMV can cause significant disease. Herein we report an unusual case of CMV pancreatitis in an immunocompetent 75-year-old female. Patient developed severe significant pancreatic necrosis that failed non-operative management, and ultimately underwent pancreatic necrosectomy. Later on, she developed three spontaneous gastric perforations. The first two perforations were managed operatively, but after the third perforation family decided not to undergo another operation. The CMV pancreatitis diagnosis was based on pancreatic histopathology and confirms by a prompt response to ganciclovir. Patient was promptly started on intravenous (IV) ganciclovir which resulted in clinical recovery and she remained asymptomatic more than one-year post op. This is a rare case of CMV pancreatitis with gastric perforations in an immunocompetent patient. High degree of suspicion and appropriate treatment are important for such clinical scenarios.",
"affiliations": "Division of Transplant Surgery, Department of Surgery, Augusta University Medical Center, Augusta, GA, United States.;Department of Pharmacy, Augusta University Medical Center, Augusta, GA, United States.;Department of Pathology, Augusta University Medical Center, Augusta, GA, United States.;Division of Nephrology, Hypertension and Transplant Medicine Department of Medicine, Augusta University Medical Center, Augusta, GA, United States.;Division of Nephrology, Hypertension and Transplant Medicine Department of Medicine, Augusta University Medical Center, Augusta, GA, United States.;Division of Transplant Surgery, Department of Surgery, Augusta University Medical Center, Augusta, GA, United States.",
"authors": "Saeed|Muhammad I|MI|;Stephens|Rachel|R|;Nwogbo|Okechukwu|O|;Gani|Imran Y|IY|;Kapoor|Rajan|R|;Doroodchi|Atbin|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e00932",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30240-7\n10.1016/j.idcr.2020.e00932\ne00932\nCase Report\nCytomegalovirus pancreatitis in an immunocompetent patient\nSaeed Muhammad I. a Stephens Rachel b Nwogbo Okechukwu c Gani Imran Y. d Kapoor Rajan d Doroodchi Atbin adoroodchi@augusta.edua⁎ a Division of Transplant Surgery, Department of Surgery, Augusta University Medical Center, Augusta, GA, United States\nb Department of Pharmacy, Augusta University Medical Center, Augusta, GA, United States\nc Department of Pathology, Augusta University Medical Center, Augusta, GA, United States\nd Division of Nephrology, Hypertension and Transplant Medicine Department of Medicine, Augusta University Medical Center, Augusta, GA, United States\n⁎ Corresponding author at: 1120 15th Street, AD-3401, Augusta, GA, 30912, United States. adoroodchi@augusta.edu\n18 8 2020 \n2020 \n18 8 2020 \n22 e009321 6 2020 11 8 2020 12 8 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cytomegalovirus (CMV) is a double-stranded DNA virus, which infects a large portion of the adult population. In immunocompetent patients, it typically is asymptomatic or manifests as mild and self-limiting flu-like illness symptoms, whereas in immunocompromised patients, CMV can cause significant disease. Herein we report an unusual case of CMV pancreatitis in an immunocompetent 75-year-old female. Patient developed severe significant pancreatic necrosis that failed non-operative management, and ultimately underwent pancreatic necrosectomy. Later on, she developed three spontaneous gastric perforations. The first two perforations were managed operatively, but after the third perforation family decided not to undergo another operation. The CMV pancreatitis diagnosis was based on pancreatic histopathology and confirms by a prompt response to ganciclovir. Patient was promptly started on intravenous (IV) ganciclovir which resulted in clinical recovery and she remained asymptomatic more than one-year post op. This is a rare case of CMV pancreatitis with gastric perforations in an immunocompetent patient. High degree of suspicion and appropriate treatment are important for such clinical scenarios.\n\nAbbreviations\nCMV, cytomegalovirusCKD, chronic kidney diseaseBMI, body mass IndexCT, computed tomographyOR, operating roomICU, intensive care unitPOD, post-operative dayPCR, polymerase chain reactionEGD, esophagogastroduodenoscopyAST, aspartate transferaseALT, alanine transferaseEBV, Epstein Barr virusDIC, disseminated intravascular coagulationGI, gastrointestinalKeywords\nPancreatitisCytomegalovirusPancreatic necrosisGastric perforationGanciclovir\n==== Body\nIntroduction\nCytomegalovirus or human herpes virus (HHV-5) belongs to Herpesviridae family and forms characteristic intra-nuclear inclusion bodies. Initially, German scientists noticed these inclusion bodies in 1881 and later, Weller, Smith and Rowe independently isolated and grew CMV from man and mice in 1956−57 [1]. CMV infection in immunocompetent subjects is usually asymptomatic and viral shedding can happen in saliva, breast milk, uterine, cervical secretions and semen [1]. According to The National Health and Nutrition Examination Surveys (NHANES) in the period of 1988–2004, CMV seroprevalence in United States ranged from 32 %–90 %. CMV seropositivity was independently associated with older age, female sex, foreign birthplace, low socioeconomic status, high household crowding and low education level [2]. CMV infection in immunocompetent hosts is usually a benign, self-limiting, viral-like syndrome that may manifest as a mononucleosis like illness [3]. On the contrary, CMV can cause significant morbidity and mortality in immunocompromised patients, especially HIV patients, organ transplant recipients, and newborns [2,3].\n\nCase presentation\nThe patient was a 75-year-old female with past medical history significant for hypertension, diabetes mellitus type II, chronic kidney disease (CKD stage II), obesity (BMI 38.4 kg/m2) and hyperlipidemia who was transferred from an outside facility with a diagnosis of gallstone pancreatitis. She had experienced right upper quadrant abdominal pain for almost two weeks associated with nausea, and vomiting. On admission, she was afebrile with stable vital signs; however, her abdominal exam was notable for epigastric tenderness. The patient’s laboratory work was significant for white blood cell count of 22,200/μL, serum lipase of 804 U/L and amylase level of 484 U/L. Computed tomography (CT) of the abdomen at the time of admission showed a small gallstone in gallbladder without any signs of cholecystitis, or intra or extrahepatic biliary ductal dilatation, as well as greater than 75 % necrosis of pancreas with surrounding inflammatory changes as well as non-occlusive splenic vein thrombosis (Fig. 1).Fig. 1 CT scan with IV contrast demonstrating pancreatic necrosis with surrounding inflammation.\n\nFig. 1\n\nPatient’s lipid profile was within normal limits while on lipid lowering therapy and her calcium level was in normal range. She drank alcohol occasionally and was not taking any medications with side effect of pancreatitis. The CT scan did not show any anatomic anomaly and patient also denied any recent gastrointestinal procedure.\n\nPatient was treated with intravenous fluid, IV antibacterials, analgesics and bowel rest. Her serum lipase and amylase level started improving; however, she continued to experience persistent leukocytosis with inability to tolerate oral intake and progressed to hypoxemic respiratory failure requiring intubation and mechanical ventilation. Due to lack of clinical improvement and persistent leukocytosis, a repeat CT scan abdomen/pelvis with contrast was performed and showed a large collection (13 × 19 × 23 cm) with no active bleeding or signs of infection. Patient was taken to the operating room (OR) for pancreatic necrosectomy, abdominal washout and wide drainage. Postoperatively, she was transferred to the surgical intensive care unit for vasopressor requirements and ventilator support. On post-operative day (POD) 10, a repeat CT scan of abdomen/pelvis was performed due to persistent leukocytosis despite patient being on antimicrobial and anti-fungal therapy and it showed a posterior wall gastric perforation (Fig. 2A). Patient was taken back to the OR and the gastric perforation was repaired primarily in two layers. Patient’s vasopressor requirements decreased, but she required continuous close monitoring in the surgical ICU. One week after gastric perforation repair, patient had another febrile episode with elevated WBC count, and another posterior wall gastric perforation was discovered on CT imaging (Fig. 2B). Patient was taken back to the OR for primary repair of the second gastric perforation and abdominal washout. We also performed more pancreatic necrosectomy on both subsequent surgeries.Fig. 2 A: Initial CT scan demonstrating gastric perforation in the lesser sac. B: CT scan demonstrating second perforation in greater curvature of stomach.\n\nFig. 2\n\nTwenty-eight days later from index operation, patient developed a third posterior wall gastric perforation. After detailed discussion with family, they elected not to pursue an additional surgery at that time. Her pancreatic histopathology report from last operation showed pancreatic necrosis with clusters of cells with CMV inclusion bodies on Hematoxylin and Eosin (H&E) and CMV antibody stains (Fig. 3).Fig. 3 Histology slides demonstrating A: necrotic pancreas (black arrow) and cluster of CMV cells (yellow arrow) slides and B: positive immune stain for CMV (black arrow).\n\nFig. 3\n\nAt this point we checked patient’s HIV status and it was negative. We immediately initiated intravenous ganciclovir 200 mg IV every 12 h. Lab work at this point, revealed negative CMV IgM titer, positive CMV IgG titer and a CMV PCR of 3,860,104 IU/mL. After initiation of ganciclovir, she started to clinically improve, and her leukocytosis started trending down. Patient was able to be weaned off vasopressors. Her CMV PCR titer decreased to 259 IU/mL after 14 days of ganciclovir treatment. Other supportive care consisted of total parenteral nutrition (TPN) tracheostomy and a jejunostomy feeding tube placement. Ganciclovir was discontinued after 16 days of therapy. Her hospital course was later complicated with abdominal wound dehiscence for which she underwent debridement, negative pressure wound therapy and skin grafting later. Of note, her urine and bronchoalveolar lavage cultures were positive for Candida albicans and Pseudomonas aeruginosa, which were treated appropriately. Patient was discharged to a rehabilitation center initially then home in a stable condition. Her tracheostomy was decannulated, and she was gradually started on regular diet with no evidence of leak on follow up CT scans. Five months later, an outpatient esophagogastroduodenoscopy (EGD) was performed, which were negative for any malignancy, Helicobacter pylori and CMV infection.\n\nDiscussion\nAlthough clinically significant CMV infection is considered rare in immunocompetent individuals, there are multiple reports in literature highlighting that it should be considered in differential diagnoses [[3], [4], [5], [6], [7], [8], [9]]. Multiple organ systems can be affected by CMV, the most common being gastrointestinal tract with manifestations such as colitis, gastritis, gastric ulcer [10,11], hepatitis [12], pancreatitis [[12], [13], [14], [15]], duodenitis, or enteritis. Other organ systems affected by CMV include central nervous system (meningitis, encephalitis, and transverse myelitis), hematological disorders (hemolytic anemia, thrombocytopenia), vascular thrombosis (venous thromboembolism, portal vein thrombosis), and ocular involvement (uveitis) and lung disease (pneumonitis).\n\nAfter primary exposure, there are three different CMV manifestations in a human host: latent CMV, CMV infection and CMV disease. Latent CMV refers to presence of CMV viral DNA within the human host cells without detectable active replication. CMV infection refers to evidence of active viral replication without symptoms and CMV disease refers to CMV infection with overt symptoms [8]. Primary CMV infection in an immunocompetent patient manifests as flu-like symptoms or mononucleosis-like syndrome, consisting of prolonged fever, myalgia, malaise with less than 5% patients presenting with jaundice. Liver function tests (AST, ALT, total bilirubin and alkaline phosphatase) are usually three times of the upper normal limit and in rare cases they can be elevated to five times the upper limit. Diagnosis of CMV mononucleosis-like syndrome is made after exclusion of Epstein-Barr virus (EBV) mononucleosis. Other supportive lab results for diagnosis are lymphocytosis (>4000/μL), CMV IgM titer (positive) and a 4-fold increase in IgG titers within 2 weeks. Additional evidence of active CMV replication includes positive pp65 antigenemia (>10/250,000 leukocytes) or a serum CMV PCR > 104 copies/mL of whole blood [5,8]. In immunocompetent patients, CMV disease generally is self-limited, but severe disease is associated with critical illness. A Swedish case series showed 3.4 % of ICU patients with severe CMV disease had multi-organ involvement (>2 organ systems) [5,8].\n\nOn a literature search, and to the best of our knowledge, we were able to find only four case reports with documented pancreatitis and CMV infection in immunocompetent patients [13,[15], [16], [17]]. Chan, et al., diagnosed CMV pancreatitis based on a tissue sample after pancreatoduodenectomy done for biliary stricture. The CMV serology was IgM (negative), IgG (positive) and CMV PCR (negative) and the patient was treated with ganciclovir [12]. Oku, et al., reported a case of CMV pancreatitis in a patient with pancreatic divisum and distal bile duct stricture, leading to pancreatoduodenectomy to rule out malignancy due to inconclusive work up. Diagnosis was confirmed by observing inclusion bodies in the ductular or acinar cells and patient was not treated with antiviral medications [14]. Yasumoto, et al. described a case of systemic CMV disease triggering pancreatitis followed by diabetic ketoacidosis, rhabdomyolysis and acute kidney failure. CMV infection was confirmed serologically as well as by infiltration of T cell lymphocytes predominantly in her muscles and thrombocytopenia without any disseminated intravascular coagulation (DIC). There were no inclusion bodies found either in muscle or renal biopsy specimens [13]. Sakakibara, et al., reported a case of acute pancreatitis caused by CMV associated duodenal papillitis [15]. In last two case reports there was no pancreatic tissue biopsy specimen.\n\nCMV pancreatitis diagnosis is more difficult to establish than other CMV infection in gastrointestinal (GI) tract. Biopsy of pancreas is generally not recommended. In our case, diagnosis was made based on the pathology report, and our patient also had CMV IgG and PCR positive results.\n\nGastric perforations in general can be secondary to peptic ulcer disease, malignancy, trauma, radiation, infection vascular and iatrogenic causes. We presume recurrent gastric perforations in our patient was due to pancreatic enzymatic digestion of the posterior stomach wall. Although conclusive diagnosis of gastric CMV involvement could not be made without a gastric wall biopsy in our case but retrospectively, our patient clinically improved after antiviral treatment and did not develop any further perforations. Stomach and esophagus biopsy done at a later date were negative for CMV and malignancy, but those samples were obtained after ganciclovir treatment.\n\nAn underestimated complication of CMV infection is venous/portal thrombosis which was seen in our patient. A review article from Abgueguen, et al. found 19 reported cases of venous thrombosis and pulmonary embolism in immunocompetent patient with active CMV injection. There are several proposed mechanisms for CMV induced-vascular thrombosis described by Abgueguen, et al. [16].\n\nThe diagnosing and predicting complications of CMV disease can be challenging, but there are several reviews and case reports discussing CMV diagnosis. Al-Omari, et al. provided a summary of studies published regarding CMV disease in ICU patients from 1990 to 2015 and discussed challenges in diagnosis and developing a predictive model for CMV disease in critical care setting [17]. Kanno, et al. also published a series of seven patients with histopathologically proven CMV disease, but none of them had pancreatitis [18]. Von Müller, et al. shared their prospective study results of 25 immunocompetent CMV-seropositive patients with septic shock with > 7 days of ICU stay. Many factors can stimulate CMV reactivation in patients with septic shock, e.g. pro-inflammatory cytokines, transient immune paralysis and medications [19]. Despite the difficulty in diagnosing and predicting CMV complications, when treated, patients have good outcomes. Guidelines in immunocompromised patients, recommend either IV ganciclovir or oral valganciclovir for the treatment of CMV infections. Ganciclovir, which was used in this case, is to be dosed as 5 mg/kg every 12 h with normal renal function [20]. Evidence supporting the use of ganciclovir for the treatment of CMV infections in immunocompetent patient was presented by Eddleston, et al. in 1997 [21]. In the absence of multicenter trial, initiation of antiviral treatment is the treating physician’s judgement and our literature search supported better outcomes in immunocompetent patients who received treatment as in our case too [[17], [18], [19],21].\n\nConclusion\nCMV is reported to cause self-limited disease in immunocompetent patients. Pancreatitis and pancreatic necrosis secondary to CMV is rare; however, it should be considered in the differential diagnosis if a patient is experiencing symptoms of systemic inflammation unresponsive to standard of care. Non-invasive test such as serum PCR can aid in establishing diagnosis but in some cases tissue biopsy may be needed. Based on extensive literature search, this is the first reported case of CMV pancreatitis in an immunocompetent patient resulting in pancreatic necrosis and possible recurrent gastric perforations. Treatment with ganciclovir and necrosectomy played a significant role in patient recovery.\n\nDeclaration of Competing Interest\nThe authors report no declarations of interest.\n\nConsent\nWritten informed consent for publication of clinical details, and images was obtained from the patient.\n\nAuthor contributions\nMS: Patient management, data collection, extensive literature review, drafting and editing.\n\nAD: Patient management, data collection, initial draft, literature review.\n\nON: Provided histopathological data and figures.\n\nRS: Critical review of manuscript, editing and feedback.\n\nIG: Critical review of manuscript, editing and feedback.\n\nRK: Critical review of manuscript, editing and feedback.\n\nAuthor statement\nIn preparation of this case report, Muhammad I. Saeed, Atbin Doroodchi were involved in patient management, data collection, literature review, as well as drafting and editing the manuscript. Okechukwu Nwogbo was involved in providing and analyzing histopathological data. Imran Gani, Rajan Kapoor, and Rachel Stephens participated in critical review of manuscript, and its editing. The manuscript was reviewed by all authors listed.\n\nAcknowledgement\nSpecial Thanks to Melissa Laub Pharm D for proofreading this manuscript.\n==== Refs\nReferences\n1 Ho M. The history of cytomegalovirus and its diseases Med Microbiol Immunol 197 2 2008 65 73 18087722 \n2 Bate S.L. Dollard S.C. Cannon M.J. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004 Clin Infect Dis 50 11 2010 1439 1447 20426575 \n3 Rafailidis P.I. Mourtzoukou E.G. Varbobitis I.C. Falagas M.E. Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review Virol J 5 2008 47 18371229 \n4 Horwitz C.A. Henle W. Henle G. Snover D. Rudnick H. Balfour H.H. Jr. Clinical and laboratory evaluation of cytomegalovirus-induced mononucleosis in previously healthy individuals. Report of 82 cases Medicine (Baltimore) 65 2 1986 124 134 3005799 \n5 Orasch C. Conen A. Severe primary cytomegalovirus infection in the immunocompetent adult patient: a case series Scand J Infect Dis 44 12 2012 987 991 22831702 \n6 Nolan N. Halai U.A. Regunath H. Smith L. Rojas-Moreno C. Salzer W. Primary cytomegalovirus infection in immunocompetent adults in the United States – a case series IDCases 10 2017 123 126 29159070 \n7 Nangle S. Mitra S. Roskos S. Havlichek D. Cytomegalovirus infection in immunocompetent adults: Is observation still the best strategy? IDCases 14 2018 e00442 \n8 Fakhreddine A.Y. Frenette C.T. Konijeti G.G. A practical review of cytomegalovirus in gastroenterology and hepatology Gastroenterol Res Pract 2019 2019 6156581 \n9 Chaemsupaphan T. Limsrivilai J. Thongdee C. Sudcharoen A. Pongpaibul A. Pausawasdi N. Patient characteristics, clinical manifestations, prognosis, and factors associated with gastrointestinal cytomegalovirus infection in immunocompetent patients BMC Gastroenterol 20 1 2020 22 32000707 \n10 Ebisutani C. Kawamura A. Shibata N. Nasu M. Ueno R. Mimura K. Gastric ulcer associated with cytomegalovirus in an immunocompetent patient: method for diagnosis Case Rep Gastroenterol 6 2 2012 365 368 22740812 \n11 Krajicek E. Shivashankar R. Hansel S. Cytomegalovirus and the seemingly immunocompetent host: a case of a perforating gastric ulcer ACG Case Rep J 4 2017 e27 28286792 \n12 Chan A. Bazerbachi F. Hanson B. Alraies M.C. Duran-Nelson A. Cytomegalovirus hepatitis and pancreatitis in the immunocompetent Ochsner J 14 2 2014 295 299 24940147 \n13 Yasumoto N. Hara M. Kitamoto Y. Nakayama M. Sato T. Cytomegalovirus infection associated with acute pancreatitis, rhabdomyolysis and renal failure Intern Med 31 3 1992 426 430 1319248 \n14 Oku T. Maeda M. Waga E. Wada Y. Nagamachi Y. Fujita M. Cytomegalovirus cholangitis and pancreatitis in an immunocompetent patient J Gastroenterol 40 10 2005 987 992 16261436 \n15 Sakakibara Y. Nakazuru S. Kodama Y. Mita E. Acute pancreatitis caused by cytomegalovirus-associated duodenal papillitis Ann Gastroenterol 31 1 2018 122 29333078 \n16 Abgueguen P. Delbos V. Ducancelle A. Jomaa S. Fanello S. Pichard E. Venous thrombosis in immunocompetent patients with acute cytomegalovirus infection: a complication that may be underestimated Clin Microbiol Infect 16 7 2010 851 854 19686279 \n17 Al-Omari A. Aljamaan F. Alhazzani W. Salih S. Arabi Y. Cytomegalovirus infection in immunocompetent critically ill adults: literature review Ann Intensive Care 6 1 2016 110 27813024 \n18 Kanno M. Chandrasekar P.H. Bentley G. Vander Heide R.S. Alangaden G.J. Disseminated cytomegalovirus disease in hosts without acquired immunodeficiency syndrome and without an organ transplant Clin Infect Dis 32 2 2001 313 316 11170926 \n19 von Muller L. Klemm A. Weiss M. Schneider M. Suger-Wiedeck H. Durmus N. Active cytomegalovirus infection in patients with septic shock Emerg Infect Dis 12 10 2006 1517 1522 17176565 \n20 Razonable R.R. Humar A. Cytomegalovirus in solid organ transplant recipients-guidelines of the American society of transplantation infectious diseases community of practice Clin Transplant 33 9 2019 e13512 \n21 Eddleston M. Peacock S. Juniper M. Warrell D.A. Severe cytomegalovirus infection in immunocompetent patients Clin Infect Dis 24 1 1997 52 56 8994755\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "22()",
"journal": "IDCases",
"keywords": "ALT, alanine transferase; AST, aspartate transferase; BMI, body mass Index; CKD, chronic kidney disease; CMV, cytomegalovirus; CT, computed tomography; Cytomegalovirus; DIC, disseminated intravascular coagulation; EBV, Epstein Barr virus; EGD, esophagogastroduodenoscopy; GI, gastrointestinal; Ganciclovir; Gastric perforation; ICU, intensive care unit; OR, operating room; PCR, polymerase chain reaction; POD, post-operative day; Pancreatic necrosis; Pancreatitis",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00932",
"pmc": null,
"pmid": "33299793",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "Cytomegalovirus pancreatitis in an immunocompetent patient.",
"title_normalized": "cytomegalovirus pancreatitis in an immunocompetent patient"
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"abstract": "Complex regional pain syndrome (CRPS) is a severely disabling condition that typically develops after an inciting traumatic event. Ketamine infusion in subanesthetic dose provides sustained analgesia in selected cases of CRPS. In general, ketamine treatment does not significantly affect electrolyte or water balance. Here, we report a case of a CRPS patient on intrathecal baclofen pump developing syndrome of inappropriate antidiuretic hormone release (SIADH) during ketamine infusion. Prophylactic treatment with intravenous loop diuretics was successful in preventing the development of SIADH during ketamine infusion during subsequent infusions in this case.",
"affiliations": "From the Department of Medicine.;Division of Nephrology.;Division of Pulmonology and Critical Care, Drexel University College of Medicine, Philadelphia, Pennsylvania.",
"authors": "Shenoda|Botros B|BB|;Krevolin|Larry E|LE|;Sherman|Michael|M|",
"chemical_list": "D049994:Sodium Potassium Chloride Symporter Inhibitors; D007649:Ketamine; D001418:Baclofen",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001091",
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"issn_linking": "2575-3126",
"issue": "13(10)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D001418:Baclofen; D020918:Complex Regional Pain Syndromes; D005260:Female; D006801:Humans; D007177:Inappropriate ADH Syndrome; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D007649:Ketamine; D008875:Middle Aged; D049994:Sodium Potassium Chloride Symporter Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "386-388",
"pmc": null,
"pmid": "31609723",
"pubdate": "2019-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Syndrome of Inappropriate Antidiuretic Hormone Release During Ketamine Infusion in Complex Regional Syndrome Patient Receiving Intrathecal Baclofen: A Case Report.",
"title_normalized": "syndrome of inappropriate antidiuretic hormone release during ketamine infusion in complex regional syndrome patient receiving intrathecal baclofen a case report"
} | [
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"companynumb": "US-PFIZER INC-2020125612",
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{
"abstract": "The COVID-19 pandemic has changed everyday life tremendously in a short period of time. After a brief timeline of the Dutch situation and our management strategy to adapt geriatric mental health care, we present a case-series to illustrate the specific challenges for geriatric psychiatrists.",
"affiliations": "Department of Old-age Psychiatry, GGNet Mental Health, Apeldoorn, The Netherlands. Electronic address: p.naarding@ggnet.nl.;Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands.;Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands.",
"authors": "Naarding|P|P|;Oude Voshaar|R C|RC|;Marijnissen|R M|RM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jagp.2020.05.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-7481",
"issue": "28(8)",
"journal": "The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry",
"keywords": "Covid-19; Netherlands; Old-age psychiatry; mental health; pandemic; telehealth",
"medline_ta": "Am J Geriatr Psychiatry",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D005852:Geriatric Psychiatry; D006801:Humans; D008297:Male; D001523:Mental Disorders; D009426:Netherlands; D058873:Pandemics; D005791:Patient Care; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D017216:Telemedicine",
"nlm_unique_id": "9309609",
"other_id": null,
"pages": "839-843",
"pmc": null,
"pmid": "32565007",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32235486;32085843;31910981;32242888;32246787;25790413;32245346;32240670;32199471",
"title": "COVID-19: Clinical Challenges in Dutch Geriatric Psychiatry.",
"title_normalized": "covid 19 clinical challenges in dutch geriatric psychiatry"
} | [
{
"companynumb": "NL-MYLANLABS-2020M1074629",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadditional": "3",
... |
{
"abstract": "We present the case of a 39-year-old woman with postpartum cerebellar infarction (CI) following spinal anesthesia for cesarean delivery. The patient experienced mild headache after postoperative day 1 and returned on postoperative day 6 with a severe headache. For the subsequent 3 days, she underwent conservative treatment for presumed postdural puncture headache (PDPH) before neurologic decline and diagnosis of CI on postoperative day 9. She subsequently underwent craniotomy and debridement of necrotic tissues. Prolonged or position-independent postpartum headache should prompt broadening of the differential diagnosis beyond PDPH to include other more rare but serious causes of postpartum headache.",
"affiliations": "From the Department of Neurosurgery, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Oregon Anesthesiology Group, Department of Anesthesiology, Legacy Emanuel Medical Center, Portland, Oregon.;Department of Obstetrics and Gynecology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Department of Anesthesiology, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Anesthesiology, Jacobi Medical Center, Albert Einstein College of Medicine, PGY1 Preliminary Resident, New York, New York.;Department of Anesthesiology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.",
"authors": "Zandi|Shokrollah|S|;Atcheson|Carrie Leigh Hamby|CLH|;Yousefi|Seyedeh Reyhaneh|SR|;Zahedi|Farhad|F|;Mirkarimi|Sadafsadat|S|;Nasseri|Karim|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001190",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "14(6)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000328:Adult; D000775:Anesthesia, Spinal; D020520:Brain Infarction; D002585:Cesarean Section; D003399:Craniotomy; D003646:Debridement; D003951:Diagnostic Errors; D005260:Female; D006261:Headache; D006801:Humans; D051299:Post-Dural Puncture Headache; D049590:Postpartum Period; D011247:Pregnancy; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01190",
"pmc": null,
"pmid": "32224699",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Postpartum Headache due to Cerebellar Infarct Initially Misdiagnosed as Postdural Puncture Headache: A Case Report.",
"title_normalized": "postpartum headache due to cerebellar infarct initially misdiagnosed as postdural puncture headache a case report"
} | [
{
"companynumb": "IR-FRESENIUS KABI-FK202013187",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
"drugadditional": null,
... |
{
"abstract": "Cardiac angiosarcoma (AS) is an extremely rare, malignant vascular tumor with <10 cases reported in the pediatric literature. Prognosis is dismal with overall survival often <1 year from initial diagnosis. In this report, we present the case of a 10-year-old boy with metastatic cardiac AS who is currently alive and is the longest pediatric survivor of metastatic cardiac AS reported in the literature. This is the only published pediatric case to successfully use a combination of surgical resection, conventional chemotherapy, radiation and targeted therapies including bevacizumab and pazopanib for metastatic cardiac AS.",
"affiliations": "Department of Pediatric Hematology/Oncology/Bone Marrow Transplant, University of Colorado School of Medicine.;Department of Pediatric Hematology/Oncology/Bone Marrow Transplant, University of Colorado School of Medicine.;Departments of Pathology and Laboratory Medicine.;Radiology, Children's Hospital Colorado, Aurora, CO.;Department of Pediatric Hematology/Oncology/Bone Marrow Transplant, University of Colorado School of Medicine.",
"authors": "Koo|Jane|J|;Knight-Perry|Jessica|J|;Galambos|Csaba|C|;Browne|Lorna P|LP|;Cost|Carrye R|CR|",
"chemical_list": "D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D000068258:Bevacizumab; C516667:pazopanib",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001674",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(2)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D059248:Chemoradiotherapy; D002648:Child; D003131:Combined Modality Therapy; D006338:Heart Neoplasms; D006394:Hemangiosarcoma; D006801:Humans; D007191:Indazoles; D008297:Male; D016609:Neoplasms, Second Primary; D011379:Prognosis; D011743:Pyrimidines; D013449:Sulfonamides; D013514:Surgical Procedures, Operative",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e203-e206",
"pmc": null,
"pmid": "31725539",
"pubdate": "2021-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pediatric Metastatic Cardiac Angiosarcoma Successfully Treated With Multimodal Therapy: Case Report and Review of Literature.",
"title_normalized": "pediatric metastatic cardiac angiosarcoma successfully treated with multimodal therapy case report and review of literature"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/21/0133798",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHepatitis B virus (HBV) infection remains a global public health threat, with approximately 257 million people suffering from chronic HBV infection worldwide in 2015. HBV reactivation is a known complication of immunosuppressive therapy in people suffering with chronic HBV. Medications commonly associated with HBV reactivation include B-cell depleting agents and anthracycline derivatives. There have been very few documented cases of chemoradiation inducing HBV reactivation among scientific literature.\n\n\nMETHODS\nA 44-year-old woman with chronic HBV infection and [FIGO] stage IIIB cervical cancer developed marked transaminitis and increased HBV viral load after receiving treatment with three doses of cisplatin and one dose of carboplatin with concurrent radiation for cervical cancer.Management and outcome: The patient was admitted for acute liver failure and quickly developed encephalopathy, with treatment complicated by coagulopathy, hypoglycemia, and metabolic acidosis. The patient remained unresponsive to maximal therapeutic efforts and was mechanically ventilated for airway protection. She subsequently died after experiencing ventricular tachycardia followed by asystole.\n\n\nCONCLUSIONS\nThere are currently no standardized guidelines for the screening of HBV infection or prophylaxis treatment algorithm for patients undergoing chemoradiation. When initiating treatment with immunosuppressive therapy, it is important to screen all patients for chronic HBV infection and to work with an interdisciplinary team of oncologists, hepatologists, and pharmacists to initiate prophylactic antiviral therapy and closely monitor to minimize the risk of HBV reactivation.",
"affiliations": "Department of Pharmacy, Boston Medical Center, Boston, MA, USA.;Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA.;Department of Pharmacy, Boston Medical Center, Boston, MA, USA.;Department of Pharmacy, Boston Medical Center, Boston, MA, USA.",
"authors": "Dimond|Colin|C|https://orcid.org/0000-0002-5312-8011;Negroiu|Andreea|A|;M Hughes|David|D|https://orcid.org/0000-0002-0971-7265;Patel|Jasmine|J|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220964256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Chemoradiation; cervical cancer; cisplatin; hepatitis b; hepatitis b reactivation",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D017809:Fatal Outcome; D005260:Female; D019694:Hepatitis B, Chronic; D006801:Humans; D002583:Uterine Cervical Neoplasms; D014775:Virus Activation",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1296-1301",
"pmc": null,
"pmid": "33054690",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal hepatitis B reactivation in a patient receiving chemoradiation for cervical cancer.",
"title_normalized": "fatal hepatitis b reactivation in a patient receiving chemoradiation for cervical cancer"
} | [
{
"companynumb": "US-ACCORD-207616",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Sublingual buprenorphine is used in opioid maintenance treatment but buprenorphine is also widely abused and causes fatal poisonings. The aim of this study was to investigate buprenorphine-positive fatalities in order to gain novel information on the magnitude and nature of buprenorphine abuse. All post-mortem toxicology cases positive for urinary buprenorphine, including fatal poisonings caused by buprenorphine and fatalities in which the cause of death was unrelated to buprenorphine, in the five year period of 2010-2014 in Finland were characterized according to urine buprenorphine and naloxone concentrations (n=775). Urine concentrations were used to assess which buprenorphine preparation had been used; mono-buprenorphine or a buprenorphine-naloxone combination, and whether they had been administered parenterally. In at least 28.8% of the buprenorphine-positive cases the drug had been administered parenterally. The majority of the parenteral users (68.6%) had taken mono-buprenorphine. Fatal poisoning was significantly more common among the identified parenteral users (65.5%) than among other users of buprenorphine products (45.3%). The proportion of buprenorphine-related poisoning was similar in identified parenteral users of mono-buprenorphine (68.6%) and buprenorphine-naloxone (64.1%). In nearly all of the fatal poisoningss the deceased had used other drugs and/or alcohol along with buprenorphine (98.7%). The median age of the deceased increased significantly over the study period, from 32 to 38 years. Our results show that there is ongoing parenteral abuse of both mono-buprenorphine and buprenorphine-naloxone combination. Parenteral users of buprenorphine put themselves into a great risk of fatal poisoning or other accidental injury death which is further exacerbated by the frequent poly-drug use.",
"affiliations": "Forensic Toxicology Unit, National Institute for Health and Welfare, P.O.Box 30, 00271 Helsinki, Finland; Department of Forensic Medicine, University of Helsinki, Finland. Electronic address: pirkko.kriikku@thl.fi.;A-Clinic Foundation, Addiction Hospital, Finland.;Forensic Toxicology Unit, National Institute for Health and Welfare, P.O.Box 30, 00271 Helsinki, Finland; Department of Forensic Medicine, University of Helsinki, Finland.",
"authors": "Kriikku|Pirkko|P|;Häkkinen|Margareeta|M|;Ojanperä|Ilkka|I|",
"chemical_list": "D000067401:Blood Alcohol Content; D009270:Naloxone; D002047:Buprenorphine; C043585:norbuprenorphine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2018.08.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "291()",
"journal": "Forensic science international",
"keywords": "Buprenorphine; Drug abuse; Fatal poisoning; Opioid maintenance treatment; Overdose",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000067401:Blood Alcohol Content; D002047:Buprenorphine; D002853:Chromatography, Liquid; D062787:Drug Overdose; D005260:Female; D005387:Finland; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009270:Naloxone; D009293:Opioid-Related Disorders; D017678:Sex Distribution; D015819:Substance Abuse, Intravenous; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "76-82",
"pmc": null,
"pmid": "30170272",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High buprenorphine-related mortality is persistent in Finland.",
"title_normalized": "high buprenorphine related mortality is persistent in finland"
} | [
{
"companynumb": "FI-MYLANLABS-2019M1025499",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCritically ill COVID-19 patients are at high risk for nosocomial bacterial and fungal infections due to several predisposing factors such as intensive care unit stay, mechanical ventilation, and broad-spectrum antibiotics. Data regarding multidrug resistant (MDR) Candida species in COVID-19 patients is scarce, and nonexistent regarding Candida duobushaemulonii superinfections.\n\n\nMETHODS\nA 34-year-old male presented to our institution with acute respiratory distress syndrome (ARDS) due to COVID-19 infection and developed Candida duobushaemulonii fungemia after multiple courses of antibiotics and prolonged mechanical ventilation. He died after recurrent pneumothorax led to respiratory failure and cardiac arrest.\n\n\nCONCLUSIONS\nBacterial and fungal infections are common complications of viral pneumonia in critically ill patients. Data regarding these infections in COVID-19 patients has been poorly studied with only a few cases reporting secondary infection, mostly without identifying specific pathogens. Prolonged hospital stays, invasive interventions (central venous catheter, mechanical ventilation), and the use of broad-spectrum antibiotics in COVID-19 infections could carry a high risk of bacterial and/or fungal superinfections.\n\n\nCONCLUSIONS\nStrategies to improve outcome in COVID-19 ICU patients should include early recognition of candidemia and appropriate antifungal therapy.",
"affiliations": "Department of Internal Medicine, Division of Infectious Diseases, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon. Electronic address: wa79@aub.edu.lb.;Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Internal Medicine, Division of Infectious Diseases, American University of Beirut Medical Center, Beirut, Lebanon.",
"authors": "Awada|Bassem|B|;Alam|Walid|W|;Chalfoun|Maria|M|;Araj|George|G|;Bizri|Abdul Rahman|AR|",
"chemical_list": "D000935:Antifungal Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2021.101168",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "31(3)",
"journal": "Journal de mycologie medicale",
"keywords": "Broad-spectrum antibiotics; COVID-19; Candida duobushaemulonii; ICU; Mechanical ventilation; Multidrug resistance",
"medline_ta": "J Mycol Med",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D000086382:COVID-19; D002175:Candida; D058387:Candidemia; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome; D004718:Saccharomycetales; D015163:Superinfection",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "101168",
"pmc": null,
"pmid": "34186378",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "COVID-19 and Candida duobushaemulonii superinfection: A case report.",
"title_normalized": "covid 19 and candida duobushaemulonii superinfection a case report"
} | [
{
"companynumb": "LB-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-325146",
"fulfillexpeditecriteria": "1",
"occurcountry": "LB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"dr... |
{
"abstract": "Natalizumab is a potent immunosuppressive monoclonal antibody used for the treatment of multiple sclerosis (MS). While definite guidelines for the safety of natalizumab prescriptions are available in all countries, there are no specific recommendations on how to withdraw the drug if the need arises. There are reports describing MS complications after natalizumab infusions were stopped. Most neurologists seem to stop natalizumab treatment according to their idea on how to best carry out the withdrawal. The present study shows the very different manners in which expert neurologists from 14 MS units in Brazil stopped natalizumab in their patients. The authors concluded that pharmacovigilance on natalizumab must persist after the drug is withdrawn in order to have enough data for adequate recommendations.",
"affiliations": "MS Reference Center, Medical School, Universidade Metropolitana de Santos, Santos, SP, Brazil.",
"authors": "Fragoso|Yara D|YD|;Arruda|Niedja M|NM|;Arruda|Walter O|WO|;Brooks|Joseph B B|JB|;Correa|Eber C|EC|;Damasceno|Alfredo|A|;Damasceno|Carlos A|CA|;Ferreira|Maria L B|ML|;Giacomo|Maria C B|MC|;Gomes|Sidney|S|;Gonçalves|Marcus V M|MV|;Grzesiuk|Anderson K|AK|;Kaimen-Maciel|Damacio R|DR|;Lopes|Josiane|J|;Machado|Suzana C N|SC|;Oliveira|Celso L S|CL|;Stella|Carla R A V|CR|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D000069442:Natalizumab",
"country": "England",
"delete": false,
"doi": "10.1586/14737175.2014.874947",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-7175",
"issue": "14(2)",
"journal": "Expert review of neurotherapeutics",
"keywords": null,
"medline_ta": "Expert Rev Neurother",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D007166:Immunosuppressive Agents; D009103:Multiple Sclerosis; D000069442:Natalizumab; D010818:Practice Patterns, Physicians'",
"nlm_unique_id": "101129944",
"other_id": null,
"pages": "127-30",
"pmc": null,
"pmid": "24417188",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "We know how to prescribe natalizumab for multiple sclerosis, but do we know how to withdraw it?",
"title_normalized": "we know how to prescribe natalizumab for multiple sclerosis but do we know how to withdraw it"
} | [
{
"companynumb": "BR-BIOGENIDEC-2014BI009622",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": ": The last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the \"right drug\" for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues. In this article, we review the key considerations involved in clinical decision making while reviewing a molecular genotyping report. We present the case of a 67-year-old postmenopausal female with metastatic estrogen receptor-positive (ER+) breast cancer, whose tumor progressed on multiple endocrine therapies. Molecular genotyping of the metastatic lesion revealed the presence of an ESR1 mutation (encoding p.Tyr537Asn), which was absent in the primary tumor. The same ESR1 mutation was also detected in circulating tumor DNA (ctDNA) extracted from her blood. The general approach for interpretation of genotyping results, the clinical significance of the specific mutation in the particular cancer, potential strategies to target the pathway, and implications for clinical practice are reviewed in this article.\n\n\n\nER+ breast tumors are known to undergo genomic evolution during treatment with the acquisition of new mutations that confer resistance to treatment.ESR1 mutations in the ligand-binding domain of ER can lead to a ligand-independent, constitutively active form of ER and mediate resistance to aromatase inhibitors.ESR1 mutations may be detected by genomic sequencing of tissue biopsies of the metastatic tumor or by sequencing the circulating tumor cells or tumor DNA (ctDNA).Sequencing results may lead to a therapeutic \"match\" with an existing FDA-approved drug or match with an experimental agent that fits the clinical setting.",
"affiliations": "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA bardia.aditya@mgh.harvard.edu.;Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.;Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.;Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.;Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"authors": "Bardia|Aditya|A|;Iafrate|John A|JA|;Sundaresan|Tilak|T|;Younger|Jerry|J|;Nardi|Valentina|V|",
"chemical_list": "D047072:Aromatase Inhibitors; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2016-0240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "21(9)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000368:Aged; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha; D005260:Female; D005838:Genotype; D006769:Hospitals, General; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating; D057285:Precision Medicine",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1035-40",
"pmc": null,
"pmid": "27551012",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22149876;27174596;24185512;17391073;26261103;25635347;23814157;25458054;25264305;26762157;23983159;23000897;24217577;25384085;25013076;24185510;24074785",
"title": "Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital.",
"title_normalized": "metastatic breast cancer with esr1 mutation clinical management considerations from the molecular and precision medicine map tumor board at massachusetts general hospital"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201608641",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
... |
{
"abstract": "This report highlights zonisamide as a potential cause of serious cutaneous reactions as well as its cross-reactivity with other sulfonamides. Here, we present a case of SJS-TEN due to zonisamide, which was effectively treated with IVIg. Subsequently, the patient was transitioned to levetiracetam for seizure control.",
"affiliations": "Department of Dermatology and Cutaneous Surgery University of South Florida Tampa Florida.;Department of Dermatology and Cutaneous Surgery University of South Florida Tampa Florida.;Department of Dermatology and Cutaneous Surgery University of South Florida Tampa Florida.",
"authors": "Vivar|Karina L|KL|0000-0003-1434-6638;Mancl|Kimberly|K|;Seminario-Vidal|Lucia|L|0000-0002-6004-2451",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1288",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 2944545810.1002/ccr3.1288CCR31288Case ReportCase ReportsStevens–Johnson syndrome/toxic epidermal necrolysis associated with zonisamide K. L. Vivar et al.Vivar Karina L. http://orcid.org/0000-0003-1434-6638\n1\nMancl Kimberly \n1\nSeminario‐Vidal Lucia http://orcid.org/0000-0002-6004-2451luciasem@health.usf.edu \n1\n\n1 \nDepartment of Dermatology and Cutaneous Surgery\nUniversity of South Florida\nTampa\nFlorida\n* Correspondence\n\nLucia Seminario‐Vidal, Morsani Center for Advanced Healthcare, 13330 USF Laurel Drive, 6th Floor, Tampa, 33612 FL. Tel: 813‐974‐3712; Fax: 813‐332‐0942; E‐mail: luciasem@health.usf.edu\n20 12 2017 2 2018 6 2 10.1002/ccr3.2018.6.issue-2258 261 31 7 2017 29 9 2017 28 10 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nThis report highlights zonisamide as a potential cause of serious cutaneous reactions as well as its cross‐reactivity with other sulfonamides. Here, we present a case of SJS‐TEN due to zonisamide, which was effectively treated with IVIg. Subsequently, the patient was transitioned to levetiracetam for seizure control.\n\nDrug rashpediatricStevens–Johnson syndrometoxic epidermal necrolysiszonisamide source-schema-version-number2.0component-idccr31288cover-dateFebruary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:19.02.2018\n\nClinical Case Reports \n2018 ; 6 (2 ): 258 –261 \n29445458\n==== Body\nIntroduction\nZonisamide is a second‐generation antiepileptic drug (AED) that was approved by the U.S. Food and Drug Administration in 2000 as an adjunctive therapy for partial seizures in adults with epilepsy 1. It was first used in Japan starting in the 1970s as a psychiatric medication and later in Japan and Korea in the 1990s for treatment of seizures. As a synthetic 1,2‐benzisoxazole‐3‐methanesulfonamide, zonisamide is chemically related to atypical, second‐generation antipsychotic agents like risperidone as opposed to the first‐generation AEDs such as carbamazepine 2.\n\nThe use of zonisamide as an antiepileptic agent in both children and adults has been increasing after it was demonstrated to be as effective as first‐generation AEDs for the treatment of partial epilepsy 3. Zonisamide is also being used as off‐label monotherapy and adjunctive therapy for psychiatric disorders such as alcohol abuse, bipolar disorder, and binge‐eating disorder 4. Advantages of zonisamide, particularly in the pediatric population, include its once‐daily dosing (divided dosing can be used if needed), being relatively well tolerated, being unlikely to react with other medications, and not requiring serum level measurements 3, 5.\n\nHere, we present the youngest patient with SJS‐TEN overlap syndrome secondary to zonisamide.\n\nCase Report\nA 2‐year‐old African American girl with a past medical history of extreme prematurity born at 25 weeks of gestational age and seizure disorder was transferred to our hospital with a rash for 1 day, with associated conjunctival injection and crusting around the eye. The mother reported that the girl did not want her skin to be touched, possibly secondary to pain. The mother also reported fever, decreased appetite, and decreased energy. There was no prior history of a similar rash. The patient had no rhinorrhea, cough, or congestion. Her medication history was significant for a change from levetiracetam to zonisamide for seizure control about two and a half weeks prior to presentation. Neurology had recommended the change for improved seizure control and for improved adherence since zonisamide was once‐daily dosing. The patient did not have any other new medications including antibiotics within the past month prior to presentation.\n\nOn physical examination, the patient was afebrile and difficult to console. She had erythematous targetoid macules, papules, and plaques with dusky centers on her face, neck, chest, abdomen, back, bilateral upper extremities, and bilateral lower extremities involving 75% body surface area (BSA). Nikolsky sign was positive in 9% BSA upon presentation, and the rash progressed within 24 h to approximately 20% BSA Nikolsky positive. Tense bullae were noted on her face, arms, and legs with sloughing on the left upper arm at site of prior bandage. Mucosal lesions included erosions and crusting of her lips, conjunctival injection, and erythema and erosions of her labia minora (Figs 1 and 2).\n\nFigure 1 Clinical photograph of patient demonstrating dusky, erythematous macules, and papules as well as crusting and erosions of the lips.\n\nFigure 2 Clinical photograph of patient's bullae and full‐thickness epidermal desquamation.\n\nBiopsies for frozen section and permanent pathology revealed full‐thickness epidermal necrosis with a pauci‐inflammatory infiltrate (Fig. 3). Herpes simplex virus and varicella zoster virus polymerase chain reaction tests from a bulla were negative. Laboratory studies revealed significant transaminitis with alanine aminotransferase (ALT) of 891 U/L and aspartate aminotransferase (AST) of 595 U/L. Alkaline phosphatase was also elevated at 304 IU/L. Complete blood count, electrolytes, and kidney function were within normal limits. Respiratory viral panel, hepatitis A immunoglobulin M (IgM) antibody, hepatitis B core IgM antibody, hepatitis B surface antigen, and hepatitis C antibody were negative. Serum urea, bicarbonate, and glucose levels were within normal limits. The patient was admitted to the pediatric intensive care unit with the diagnosis of Stevens–Johnson syndrome/toxic epidermal necrolysis overlap. Her severity of illness scale for toxic epidermal necrolysis (SCORTEN) was one 6.\n\nFigure 3 Biopsy specimen demonstrating full‐thickness epidermal necrosis, 100X.\n\nZonisamide was discontinued immediately, and intravenous immunoglobulin (IVIg, 1 g/kg/day) for 3 days was administered without complications. Neurology restarted the patient on levetiracetam for her seizure disorder. Her skin improved significantly over the next 2 weeks, and at the time of discharge, only mild crusting of her lips remained with all other cutaneous lesions healed. Her transaminitis resolved during admission as well.\n\nDiscussion\nTo our knowledge, this is the second case of SJS‐TEN overlap syndrome associated with zonisamide reported in the United States 7.\n\nThough usually well tolerated, common side effects of zonisamide include dizziness, sedation, headache, weight loss, decreased appetite, and decreased bicarbonate levels 3, 8. Rashes occur in up to 2% of patients treated with zonisamide and may be more common in patients receiving zonisamide in combination with first‐generation AEDs 9, 10. Serious cutaneous reactions include drug‐induced hypersensitivity syndrome, SJS, and TEN 9.\n\nThe incidence of SJS/TEN in the setting of zonisamide is not known. In the United States, the only reported case was a 16‐year‐old female adolescent with bipolar disorder who was switched from valproic acid to zonisamide secondary to weight gain. After 2 weeks of zonisamide, she developed a painful, bullous eruption and was diagnosed with TEN. This patient's mother reported being allergic to sulfa medications 7. In addition, one case of SJS was reported in a postmarketing surveillance study of 1938 patients treated with zonisamide who were followed for at least twelve weeks 8. Other details of the case were not published. Teraki et al. reported a 71‐year‐old man who was initially on valproate sodium for epilepsy and then started on zonisamide for seizure recurrence. Twenty‐three days after initiation of the zonisamide, the patient developed a targetoid, blistering eruption consistent with TEN. Interestingly, IgG titers and human herpesvirus 6 (HHV6) DNA levels in the patient's blood increased over the progression of his eruption, suggesting HHV6 reactivation 11. The other reported cases come from case series in Japan, where 13 patients with epilepsy were taking zonisamide and developed SJS/TEN. Three of the patients were taking zonisamide in combination with one aromatic antiepileptic such as phenytoin or carbamazepine. There were five females and eight males in this group. The median age of these patients was 52 years old, ranging from 6 to 71 years old. The average time to development of SJS/TEN was about 23 days 12.\n\nIn the two cases reported in detail in the literature and our case reported here, all three patients developed TEN within 2–4 weeks of starting zonisamide. Additionally, all cases were on zonisamide as monotherapy after prior exposure to another agent, either valproic acid or levetiracetam. Notably, our patient was the youngest to develop SJS/TEN in the setting of zonisamide. IVIg was used effectively in the case reported by Teraki et al. as well as in the present case. The third case by Majeres and Suppes did not report management.\n\nGiven the increasing use of zonisamide for neurological and psychiatric disorders, it has become important to determine the risk of potentially fatal cutaneous reactions such as SJS/TEN. Prior use of levetiracetam or valproic acid may play a role in predisposing to TEN. Family history of sulfa allergy may also be clinically significant 7. In Japan, where zonisamide has been prescribed for a longer period than in the United States, studies have shown that HLA‐A*02:07 may be a biomarker for susceptibility to zonisamide‐induced SJS/TEN 12.\n\nAdditionally, a study of in vitro cross‐reactivity between zonisamide and either sulfonamides or first‐generation AEDs underscores the chemical relatedness of zonisamide to sulfa medications. Lymphocyte toxicity assays (LTAs) from 20 patients with known DIHS to sulfamethoxazole demonstrated cross‐reactivity between sulfonamides and zonisamide. In contrast, LTAs from 20 patients with known DIHS to first‐generation AEDs did not cross‐react with zonisamide 9. Especially in light of recent case reports of HHV6 reactivation in SJS/TEN patients, classically thought of in DIHS, future studies may evaluate whether LTAs can also be used to predict SJS/TEN secondary to zonisamide 11, 13.\n\nIn sum, the risk of SJS/TEN associated with zonisamide appears to be low but real. The incidence of these serious and life‐threatening cutaneous eruptions due to zonisamide needs to be further investigated. The development of screening tests such as HLA typing and LTAs may also identify at‐risk patients. Clinicians should maintain high clinical suspicion in order to promptly discontinue the culprit drug and initiate appropriate intensive inpatient SJS/TEN management including diligent wound care, fluid and electrolyte management, and systemic therapies like steroids, intravenous immunoglobulin, or other immunomodulators. Importantly, clinicians should also be aware of the cross‐reactivity of zonisamide with other sulfa medications in order to counsel patients to avoid all sulfa medications in the future.\n\nConflict of Interest\nThe authors have no financial or other conflict of interests to disclose.\n\nAuthorship\nKLV, KAM, and LS‐V: had full access to all of the data in the study, take responsibility for the integrity of the data and the accuracy of the data analysis, and involved in acquisition, analysis, and interpretation of data. KLV and LS‐V: involved in study concept and design. KLV and KAM: drafted the manuscript and provided administrative, technical, or material support. LS‐V: critically revised the manuscript for important intellectual content and supervised the study. None: performed statistical analysis and obtained funding.\n==== Refs\nReferences\n1 \nU.S. Food and Drug Administration, Center for Drug Evaluation and Research \n. Zonegran NDA 20‐789 approval letter , March 27, 2000. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/020789_Zonegran_Approv.pdf (accessed 9 May 2017).\n2 \n\nBiton , V. \n\n2007 \nClinical pharmacology and mechanism of action of zonisamide . Clin. Neuropharmacol. \n30 :230 –240 .17762320 \n3 \n\nBaulac , M. \n, \nM. J. \nBrodie \n, \nA. \nPatten \n, \nJ. \nSegieth \n, and \nL. \nGiorgi \n. 2012 \nEfficacy and tolerability of zonisamide versus controlled‐release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomized, double‐blind, non‐inferiority trial . Lancet Neurol. \n11 :579 –588 .22683226 \n4 \n\nBuoli , M. \n, \nS. \nGrassi \n, \nV. \nCiappolino \n, \nM. \nSerati \n, and \nA. C. \nAltamura \n. 2017 \nThe use of zonisamide for the treatment of psychiatric disorders: a systematic review . Clin. Neuropharmacol. \n40 :85 –92 .28195838 \n5 \n\nBaulac , M. \n, \nA. \nPatten \n, and \nL. \nGiorgi \n. 2014 \nLong‐term safety and efficacy of zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy: results of a phase III, randomized, double‐blind study . Epilepsia \n55 :1534 –1543 .25109239 \n6 \n\nSorrell , J. \n, \nL. \nAnthony \n, \nA. \nRademaker \n, \nS. M. \nBelknap \n, \nS. \nCallahan \n, \nD. P. \nWest \n, et al. 2017 \nScore of toxic epidermal necrosis predicts outcomes of pediatric epidermal necrolysis . Pediatr. Dermatol. \n34 :433 –437 .28508417 \n7 \n\nMajeres , K. D. \n, and \nT. \nSuppes \n. 2004 \nA cautionary note when using zonisamide in youths: a case report of associated toxic epidermal necrolysis . J. Clin. Psychiatry \n65 :1720 .\n8 \n\nLee , H. J. \n, \nJ. M. \nSon \n, \nJ. \nMun \n, and \nD. W. \nKim \n. 2015 \nSafety and efficacy of zonisamide in patients with epilepsy: a post‐marketing surveillance study . J. Epilepsy Res. \n5 :89 –95 .26819941 \n9 \n\nNeuman , M. G. \n, \nN. H. \nShear \n, \nI. M. \nMalkiewicz \n, \nM. \nKessas \n, \nA. W. \nLee \n, and \nL. \nCohen \n. 2008 \nPredicting possible zonisamide hypersensitivity syndrome . Exp. Dermatol. \n17 :1045 –1051 .18637135 \n10 \n\nLeppik , I. E. \n, \nL. J. \nWillmore \n, \nR. W. \nHoman \n, \nG. \nFromm \n, \nK. J. \nOommen \n, \nJ. K. \nPenry \n, et al. 1993 \nEfficacy and safety of zonisamide: results of a multicenter study . Epilepsy Res. \n14 :165 –173 .8453952 \n11 \n\nTeraki , Y. \n, \nH. \nMurota \n, and \nS. \nIzaki \n. 2008 \nToxic epidermal necrolysis due to zonisamide associated with reactivation of Human Herpesvirus 6 . Arch. Dermatol. \n144 :232 –235 .18283181 \n12 \n\nKaniwa , N. \n, \nE. \nSugiyama \n, \nY. \nSaito \n, \nK. \nKurose \n, \nK. \nMaekawa \n, \nR. \nHasegawa \n, et al. 2013 \nSpecific HLA types are associated with antiepileptic drug‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis in Japanese subjects . Pharmacogenomics \n14 :1821 –1831 .24236482 \n13 \n\nPeppercorn , A. F. \n, \nM. B. \nMiller \n, \nD. \nFitzgerald \n, \nD. J. \nWeber \n, \nP. A. \nGroben \n, and \nB. A. \nCairns \n. 2010 \nHigh‐level human herpesvirus‐6 viremia associated with onset of Stevens‐Johnson syndrome: report of two cases . J. Burn Care Res. \n31 :365 –368 .20182379\n\n",
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"title": "Stevens-Johnson syndrome/toxic epidermal necrolysis associated with zonisamide.",
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"title": "First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer.",
"title_normalized": "first in human study of inhaled azacitidine in patients with advanced non small cell lung cancer"
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"abstract": "We report a HIV uninfected neonate born to HIV positive mother, who had tachypnoea at birth. On investigations, he was found to have hyperlactataemia. All the secondary causes for elevated lactate were ruled out. Hyperlactataemia was attributed to the perinatal exposure, to maternal antiretroviral (ARV) drugs, mainly nucleoside analogues. Asymptomatic and symptomatic hyperlactataemia is not uncommon in HIV-exposed infants. Neonates with tachypnoea, who are HIV- and ARV-exposed with no obvious cause, should be screened for raised arterial lactate.",
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"abstract": "Metastatic gastric cancer (GC) and oesophagogastric junctional (OGJ) adenocarcinoma have a poor clinical outcome with a high worldwide burden of disease. A 65-year old male patient with microcytic anemia was diagnosed with stage IV OGJ adenocarcinoma with multiple liver metastases. Immunohistochemical analysis revealed a high expression of HER2 (3+). Palliative chemotherapy with FLOT (oxaliplatin, 5-fluorouracil, leucovorin and docetaxel) in combination with trastuzumab was initiated. Due to severe adverse events, the therapy was de-escalated to trastuzumab monotherapy after six months of treatment. Initial restaging revealed partial response after the combination therapy of FLOT with trastuzumab. After reduction to trastuzumab monotherapy, the disease remained stable for two years until radiological complete response was observed. Trastuzumab monotherapy was continued for another two years to maintain complete response. Eleven months after the discontinuation of the therapy, no recurrence of the disease was detected. In conclusion, complete response can be achieved under trastuzumab monotherapy in exceptional responders.",
"affiliations": "Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. tobias.gutting@umm.de.;Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. nadine.schulte@medma.uni-heidleberg.de.;Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. sebastian.belle@umm.de.;Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. johannes.betge@medma.uni-heidelberg.de.;Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. nicolai.haertel@umm.de.;Institute of Pathology, Ludwigshafen, Germany. j.wilke@pathologie-ludwigshafen.de.;Gastroenterologische Schwerpunktpraxis, Mannheim, Germany. j.weers@gmx.de.;Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. matthias.ebert@medma.uni-heidelberg.de.;Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. tianzuo.zhan@umm.de.",
"authors": "Gutting|Tobias|T|;Schulte|Nadine|N|;Belle|Sebastian|S|;Betge|Johannes|J|;Härtel|Nicolai|N|;Wilke|Jürgen|J|;Weers|Jürgen|J|;Ebert|Matthias P|MP|;Zhan|Tianzuo|T|",
"chemical_list": "C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "Romania",
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004334:Drug Administration Schedule; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D018719:Receptor, ErbB-2; D012074:Remission Induction; D000068878:Trastuzumab",
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"title": "Complete Remission of Metastatic HER2+ Oesophagogastric Junctional Adenocarcinoma under long-term Trastuzumab Treatment.",
"title_normalized": "complete remission of metastatic her2 oesophagogastric junctional adenocarcinoma under long term trastuzumab treatment"
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},
"drugadditional": "1",
"d... |
{
"abstract": "BACKGROUND\nReiki therapy is documented for relief of pain and stress. Energetic healing has been documented to alter biologic markers of illness such as hematocrit. True random number generators are reported to be affected by energy healers and spiritually oriented conscious awareness.\n\n\nMETHODS\nThe patient was a then 54-year-old severely ill man who had hepatitis C types 1 and 2 and who did not improve with conventional therapy. He also suffered from obesity, the metabolic syndrome, asthma, and hypertension. He was treated with experimental high-dose interferon/riboviron therapy with resultant profound anemia and neutropenia. Energetic healing and Reiki therapy was administered initially to enhance the patient's sense of well-being and to relieve anxiety. Possible effects on the patient's absolute neutrophil count and hematocrit were incidentally noted. Reiki therapy was then initiated at times of profound neutropenia to assess its possible effect on the patient's absolute neutrophil count (ANC). Reiki and other energetic healing sessions were monitored with a true random number generator (RNG).\n\n\nRESULTS\nStatistically significant relationships were documented between Reiki therapy, a quieting of the electronically created white noise of the RNG during healing sessions, and improvement in the patient's ANC. The immediate clinical result was that the patient could tolerate the high-dose interferon regimen without missing doses because of absolute neutropenia. The patient was initially a late responder to interferon and had been given a 5% chance of clearing the virus. He remains clear of the virus 1 year after treatment.\n\n\nCONCLUSIONS\nThe association between changes in the RNG, Reiki therapy, and a patient's ANC is the first to the authors' knowledge in the medical literature. Future studies assessing the effects of energetic healing on specific biologic markers of disease are anticipated. Concurrent use of a true RNG may prove to correlate with the effectiveness of energetic therapy.",
"affiliations": "Institute for Scientific Study of Consciousness, Georgetown, DE 19947, USA. melvinmorse@hotmail.com",
"authors": "Morse|Melvin L|ML|;Beem|Lance W|LW|",
"chemical_list": "D012254:Ribavirin; D007372:Interferons",
"country": "United States",
"delete": false,
"doi": "10.1089/acm.2010.0238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-5535",
"issue": "17(12)",
"journal": "Journal of alternative and complementary medicine (New York, N.Y.)",
"keywords": null,
"medline_ta": "J Altern Complement Med",
"mesh_terms": "D001007:Anxiety; D003243:Consciousness; D006400:Hematocrit; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D007372:Interferons; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D019222:Mind-Body Relations, Metaphysical; D009503:Neutropenia; D009504:Neutrophils; D012254:Ribavirin; D012720:Severity of Illness Index; D029181:Spirituality; D019124:Therapeutic Touch",
"nlm_unique_id": "9508124",
"other_id": null,
"pages": "1181-90",
"pmc": null,
"pmid": "22132706",
"pubdate": "2011-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17550344;17477690;15992246;17371590;17627194;11372012;7663213;10836918;17560356;18194788;19305476;17544681;17560365",
"title": "Benefits of Reiki therapy for a severely neutropenic patient with associated influences on a true random number generator.",
"title_normalized": "benefits of reiki therapy for a severely neutropenic patient with associated influences on a true random number generator"
} | [
{
"companynumb": "US-ROCHE-1072521",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2A"
},
"drugadditional": null,
... |
{
"abstract": "Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis.\n\n\n\nWe performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed.\n\n\n\nA total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03).\n\n\n\nAmong patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).",
"affiliations": "From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.;From the Montreal Heart Institute (J.-C.T., R.I., J.C.G., M.-A.L., M.-P.D., D.R., P.L.L.) and the Montreal Health Innovations Coordinating Center (M.P., L.B., A.O., M.-C.G.), Montreal, Centre Hospitalier Régional de Lanaudière, Joliette (S.K.), and Institut de Cardiologie et Pneumologie de Québec, Quebec City (O.F.B.) - all in Canada; San Francisco General Hospital, San Francisco (D.D.W.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.P.M.); Santa Maria University Hospital (Centro Hospitalar Universitário Lisboa Norte), Centro Académico de Medicina de Lisboa, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.); Fattouma Bourguiba University Hospital, Monastir, Tunisia (H.G.); Bellevue Medical Center, Beirut, Lebanon (G.S.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, and NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (C.B.); Hospital Universitario La Paz, Universidad Autónoma de Madrid, Instituto de Investigación La Paz, Centro de Investigación Biomédica en Red-Enfermedades Cardiovasculares, Madrid (J.L.-S.); Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic (P.O.); Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours (D.A.), and PhyMedExp (Physiologie et Médecine Expérimentale du Cœur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, Montpellier (F.R.) - all in France.",
"authors": "Tardif|Jean-Claude|JC|;Kouz|Simon|S|;Waters|David D|DD|;Bertrand|Olivier F|OF|;Diaz|Rafael|R|;Maggioni|Aldo P|AP|;Pinto|Fausto J|FJ|;Ibrahim|Reda|R|;Gamra|Habib|H|;Kiwan|Ghassan S|GS|;Berry|Colin|C|;López-Sendón|José|J|;Ostadal|Petr|P|;Koenig|Wolfgang|W|;Angoulvant|Denis|D|;Grégoire|Jean C|JC|;Lavoie|Marc-André|MA|;Dubé|Marie-Pierre|MP|;Rhainds|David|D|;Provencher|Mylène|M|;Blondeau|Lucie|L|;Orfanos|Andreas|A|;L'Allier|Philippe L|PL|;Guertin|Marie-Claude|MC|;Roubille|François|F|",
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"journal": "The New England journal of medicine",
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"mesh_terms": "D000368:Aged; D000787:Angina Pectoris; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D002097:C-Reactive Protein; D002318:Cardiovascular Diseases; D003078:Colchicine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015994:Incidence; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D016016:Proportional Hazards Models; D012008:Recurrence; D020521:Stroke",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "2497-2505",
"pmc": null,
"pmid": "31733140",
"pubdate": "2019-12-26",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction.",
"title_normalized": "efficacy and safety of low dose colchicine after myocardial infarction"
} | [
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"companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2019-10495",
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"abstract": "Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL.\n\n\n\nIn the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose-limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR).\n\n\n\nTwenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively.\n\n\n\nAlthough the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL.",
"affiliations": "The Ohio State University, James Cancer Center, Columbus, OH. Electronic address: joseph.maly@osumc.edu.;The Ohio State University, James Cancer Center, Columbus, OH.;The Ohio State University, James Cancer Center, Columbus, OH.;The Ohio State University, James Cancer Center, Columbus, OH.;The Ohio State University, James Cancer Center, Columbus, OH.;The Ohio State University, James Cancer Center, Columbus, OH.;The Ohio State University, James Cancer Center, Columbus, OH.;Washington University School of Medicine, St Louis, MO.;Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.;The Ohio State University, James Cancer Center, Columbus, OH.;Washington University School of Medicine, St Louis, MO.;The Ohio State University, James Cancer Center, Columbus, OH.",
"authors": "Maly|Joseph J|JJ|;Christian|Beth A|BA|;Zhu|Xiaohua|X|;Wei|Lai|L|;Sexton|Jennifer L|JL|;Jaglowski|Samantha M|SM|;Devine|Steven M|SM|;Fehniger|Todd A|TA|;Wagner-Johnston|Nina D|ND|;Phelps|Mitch A|MA|;Bartlett|Nancy L|NL|;Blum|Kristie A|KA|",
"chemical_list": "D006877:Hydroxamic Acids; D007211:Indoles; D013792:Thalidomide; D000077767:Panobinostat; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2017.05.008",
"fulltext": null,
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"issn_linking": "2152-2669",
"issue": "17(6)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Clinical trial; Hodgkin’s lymphoma; Lenalidomide; Panobinostat; Relapsed/refractory",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D006877:Hydroxamic Acids; D007211:Indoles; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077767:Panobinostat; D012074:Remission Induction; D013792:Thalidomide; D055815:Young Adult",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "347-353",
"pmc": null,
"pmid": "28622959",
"pubdate": "2017-06",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "22547596;23950178;17242396;20956622;19951978;19863533;25796459;25482239;22955172;15797261;24097867;22408261;19663825;12089788;20229590;26504410;18708993;16569772;25533035;17234786;21825263;21937701",
"title": "A Phase I/II Trial of Panobinostat in Combination With Lenalidomide in Patients With Relapsed or Refractory Hodgkin Lymphoma.",
"title_normalized": "a phase i ii trial of panobinostat in combination with lenalidomide in patients with relapsed or refractory hodgkin lymphoma"
} | [
{
"companynumb": "US-CELGENEUS-USA-20170607335",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
"abstract": "BACKGROUND Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm (MPN) characterized by sustained thrombocytosis in peripheral blood. Patients typically have gene mutations like JAK2V617F, CALR, and MPLW515L/K. This report describes a young man with ET without any of the above mutations who had paradoxical bleeding due to acquired Von-Willebrand disease. CASE REPORT A young man with a medical history of thrombocytosis on aspirin presented with acute chest pain and was found to have had a myocardial infarction. Emergency cardiac catheterization revealed a thrombotic occlusion of the left anterior descending (LAD) artery and the right posteriolateral system, with an ejection fraction of 25%. He underwent thrombectomy and balloon angioplasty with LAD stenting, and an Impella 2.5 was inserted due to severe left ventricular dysfunction with akinesia. Aspirin and ticagrelor were administered, but the patient later experienced postoperative bleeding from the site of the Impella device. The bleeding was attributed to acquired Von-Willebrand disease secondary to ET. Emergency plateletpheresis was recommended. Further workup demonstrated that he was triple-negative for JAK2, MPL, and CALR gene mutations. CONCLUSIONS The paradoxical bleeding resulting from acquired Von-Willebrand disease was likely an entirely separate entity from the hyper-thrombotic state expected from ET. Careful assessment of clinical symptoms and laboratory markers, in addition to a high degree of suspicion, are needed to diagnose acquired Von-Willebrand disease as a complication of ET.",
"affiliations": "Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, PA, USA.;Department of Internal Medicine, Drexel University College of Medicine, Philadelphia, PA, USA.;Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, PA, USA.;Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, PA, USA.;Department of Hematology/Oncology, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Camp Hill, PA, USA.",
"authors": "Kanderi|Tejaswi|T|;Puthenpura|Max|M|;Shrimanker|Isha|I|;Sapna|Fnu|F|;Felter|Scott C|SC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.924560",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32829377\n10.12659/AJCR.924560\n924560\nArticles\nTriple-Negative Essential Thrombocythemia Complicated by Thrombosis and Acquired von Willebrand Disease in a Young Man\nKanderi Tejaswi ABEF1 Puthenpura Max DEF2 Shrimanker Isha F1 Sapna Fnu E1 Felter Scott C. BD3 \n1 Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, PA, U.S.A.\n\n2 Department of Internal Medicine, Drexel University College of Medicine, Philadelphia, PA, U.S.A.\n\n3 Department of Hematology/Oncology, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Camp Hill, PA, U.S.A.\nCorresponding Author: Tejaswi Kanderi, e-mail: kanderit2@upmc.eduAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n23 8 2020 \n21 e924560-1 e924560-5\n24 3 2020 24 6 2020 07 7 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 25-year-old\n\nFinal Diagnosis: Acquired von Willebrand deficiency\n\nSymptoms: Bleeding • chest discomfort\n\nMedication: —\n\nClinical Procedure: Bleeding • chest discomfort\n\nSpecialty: Laboratory Diagnostics • Hematology • General and Internal Medicine • Physiology\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nEssential thrombocythemia (ET) is a type of myeloproliferative neoplasm (MPN) characterized by sustained thrombocytosis in peripheral blood. Patients typically have gene mutations like JAK2V617F, CALR, and MPLW515L/K. This report describes a young man with ET without any of the above mutations who had paradoxical bleeding due to acquired Von-Willebrand disease.\n\nCase Report:\nA young man with a medical history of thrombocytosis on aspirin presented with acute chest pain and was found to have had a myocardial infarction. Emergency cardiac catheterization revealed a thrombotic occlusion of the left anterior descending (LAD) artery and the right posteriolateral system, with an ejection fraction of 25%. He underwent thrombectomy and balloon angioplasty with LAD stenting, and an Impella 2.5 was inserted due to severe left ventricular dysfunction with akinesia. Aspirin and ticagrelor were administered, but the patient later experienced postoperative bleeding from the site of the Impella device. The bleeding was attributed to acquired Von-Willebrand disease secondary to ET. Emergency plateletpheresis was recommended. Further workup demonstrated that he was triple-negative for JAK2, MPL, and CALR gene mutations.\n\nConclusions:\nThe paradoxical bleeding resulting from acquired Von-Willebrand disease was likely an entirely separate entity from the hyper-thrombotic state expected from ET. Careful assessment of clinical symptoms and laboratory markers, in addition to a high degree of suspicion, are needed to diagnose acquired Von-Willebrand disease as a complication of ET.\n\nMeSH Keywords:\nJanus Kinase 2Thrombocythemia, Essentialvon Willebrand Diseasesvon Willebrand Factor\n==== Body\nBackground\nEssential thrombocythemia (ET) is a type of myeloproliferative neoplasm (MPN) characterized by sustained thrombocytosis, defined as ≥450,000 platelets/µl blood, as well as an increased number of mature megakaryocytes in bone marrow [1–3]. This chronic clonal stem cell disorder has a prevalence of 0.6 to 2.4 per 100,000 people [1,2,4]. Bone marrow biopsy is usually recommended for diagnosis, after excluding secondary causes of thrombocytosis [5]. The etiology of ET is primarily genetic, with most patients having mutations in the JAK2, CALR or MPL gene, including 50–60% with JAK2 V617F, 15–30% with CALR, and (1–5%) with MPL mutations, with studies showing differences in the prevalence of JAK2 mutations [3,5–13]. Some patients with ET, however, lack mutations in all three genes [14], although symptoms in these “triple-negative” patients are similar to those in patients with mutations.\n\nET results in high susceptibility to vascular thromboses [2,3]. Paradoxically, an acquired version of von Willebrand’s disease may manifest in patients with elevated platelet count [14], as excess platelet activation depletes clotting factors and high molecular weight multimers of von Willebrand factor (VWF) [15]. This rare phenomenon has been reported associated with myelo and lymphoproliferative disorders, causing unusual bleeding after major and minor surgical procedures [15–18]. ET should be strongly suspected in patients with a hypercoagulable state who are also susceptible to bleeding.\n\nET is manageable provided it is diagnosed and treated before the development of severe symptoms of a hypercoagulable state or bleeding. Depending on risk stratification, patients are usually managed on an outpatient basis, with the objective of therapy being the prevention of vascular complications [19,20]. Low-dose aspirin, cytoreductive therapy with hydroxyurea, inter-feron-alpha, and anagrelide have been effective in preventing thrombotic episodes on an outpatient basis, whereas platelet-pheresis and VWF-containing concentrates are generally reserved for life-threatening bleeding [1,21–24].\n\nThis report describes a young man with triple-negative ET who presented with thrombosis. He later developed severe bleeding due to acquired Von-Willebrand disease and required emergency plateletpheresis [22,24].\n\nCase Report\nA 25-year-old Caucasian man with a medical history of anxiety presented to the emergency department with acute chest discomfort. Initial examination showed a body temperature of 97.4ºF, a pulse of 98 beats/min, a respiratory rate of 20 breaths/min, a blood pressure of 192/139 mm Hg, and 100% oxygen saturation on room air. A physical examination showed significant diaphoresis and distress. A cardiovascular examination yielded normal results, with regular S1 and S2 and no additional sounds, murmurs, rubs, or gallops. Laboratory tests showed a white blood cell count of 19.8×103/µl (reference 4–9×103/µl), a hemoglobin concentration of of 15.5 g/dl (reference 12–16 g/dl), a platelet count of 1472×103/µl (reference 140–350×103/µl), a PTT of 32.8 sec (reference 25–37 sec), and an INR of 1.1 (reference 0.8–1.1), with other laboratory tests, including blood chemistry and a coagulation panel, yielding results within normal limits. Chest X-rays were negative for any acute pathology. Troponin tended to increase, from 0.41 μg/l to 72 μg/l. An electrocardiogram (EKG) showed significant ST elevation in the anterior precordial leads, consistent with anterior ST-elevated myocardial infarction (STEMI) (Figure 1).\n\nEmergency cardiac catheterization revealed thrombotic occlusion of the proximal and apical left anterior descending (LAD) artery, requiring thrombectomy, balloon angioplasty, and drug-eluting stent placement. Moderate disease was observed in his mid-right coronary artery and diagonal branch (Figures 2, 3).\n\nAn Impella 2.5 was inserted because his ejection fraction was severely decreased, at 25%, accompanied by akinesis of the inferior apex and the mid to distal anterior wall. After the procedure, the patient was continued on the antiplatelet agent Tirofiban (Aggrastat), in addition to a loading dose of dual antiplatelet therapy (DAPT) with aspirin and ticagrelor. He started bleeding from the Impella insertion site, and the bleeding could not be controlled with FemoStop or manual pressure application. Despite placement of a 50-pound bag, blood constantly oozed from the site, but there was no active bleeding at any other site. He was suspected of having acquired Von-Willebrand’s syndrome (AVWS) secondary to his thrombocytosis, in addition to acute platelet dysfunction secondary to treatment with aspirin and ticagrelor. We elected not to treat his AVWS with 1-desamino-8-d-arginine-vasopressin (DDAVP) or the antihemophilic factor/Von Willebrand factor complex Humate P due to the risk that they would increase thrombogenicity. Rather, emergency plateletpheresis was deemed necessary.\n\nIn addition to undergoing a workup for ET, this patient had been diagnosed with thrombocythemia 1 month before presentation and had been prescribed oral aspirin 81 mg/day. A peripheral blood smear showed prominent thrombocytosis with occasional giant forms. A bone marrow aspirate and biopsy showed significant numbers of atypical megakaryocytes (data not shown). Genetic testing showed that he was negative for JAK2, MPL, and CALR gene mutations. Further testing during hospitalization revealed low VWF ristocetin cofactor activity, consistent with AVWS. His platelet count was 1393×103/µl two weeks after discharge, decreasing significantly to 652×103/µl three months after discharge. The patient continued treatment with aspirin and ticagrelor.\n\nDiscussion\nIdentifying patients with ET who are at high risk of developing AVWS can facilitate appropriate treatment and improve outcomes [15]. AVWS presents similar to the hereditary form of VWS, except that the acquired form is diagnosed at an older age as these patients tend not to have a family history or prior bleeding episodes.\n\nOur patient had triple-negative ET, which usually presents at a younger age and is associated with fewer thrombotic events and favorable overall survival than patients with the genetic form of ET [2]. The incidence of vascular complications has been reported higher among patients positive than negative for JAK2 mutations, for reasons that remain unclear, indicating the need for routine genetic testing to anticipate the risk of complications and treat high-risk individuals aggressively. Vascular complications, both thrombosis and bleeding, are major causes of death among patients with ET [20]. Major risk factors for thrombosis include prior thrombotic episodes and age >60 years. Cardiovascular risk factors, including diabetes, hypertension, and hyperlipidemia, should also be evaluated in ET patients, although the effect of cardiovascular risk factors on the risk of thrombosis in low to intermediate-risk groups remains uncertain. Leukocytosis and mutational status may be additional risk factors [22,25], although further validation is needed.\n\nYounger age, elevated hemoglobin concentration and/or platelet counts, and the presence of a JAK2 mutation have been associated with a higher risk for AVWS, although the evidence remains uncertain [16,26–28]. Current guidelines recommend routine testing of VWF ristocetin cofactor activity in patients with platelet counts over 1000×109/L, although a significant proportion of patients who developed AVWS had lower platelet counts [15,16]. These findings indicate a need for retrospective analysis to modify guidelines and affect management with antiplatelet agents. Low platelet count may protect against the development of AVWS [16]. We recommend adequate control of ET with stable low platelet count and testing for AVWS when there is evidence of bleeding, irrespective of platelet count [15]. Guidelines indicate that the functional activity of VWF be tested with the VWF ristocetin cofactor assay and that factor VIII and VWF levels be measured [16,15,29]. Interestingly antiplatelet agents do not interfere with VWF ristocetin cofactor assays or Factor VIII levels.\n\nPatients with JAK2 mutations are at greater risk of developing AVWS than patients with CALR mutations despite the former having lower platelet counts [16]. Retrospective studies have found concomitant Von Willebrand disease in as many as 20% of patients with ET, indicating the need to consider AVWS when managing patients with ET [15,30].\n\nAspirin is recommended for all patients with ET if there is no contraindication, although a platelet count >1000×109/L is considered a relative contraindication [21]. A randomized study of high-risk patients showed that treatment with hydroxyurea significantly reduced the rate of thrombotic events when compared with a control group [21].\n\nMultiple variants have been observed in patients with triple-negative disease, but the clinical correlations of these variants with symptoms and the development of vascular complications are unclear, indicating the need for further exploration of the genetic component of this disease [31]. Next generation sequencing has shown mutations in several genes, including the TET2, SH2B3, and ASXL1 genes, in patients with triple-negative disease, although these results require validation in large cohorts [32].\n\nConclusions\nAdequate management of ET can help prevent the development of AVWS. Patients with ET and high platelet counts who experience bleeding complications should be suspected of having AVWS, as prompt treatment with plateletpheresis is life-saving. Patients with ET should undergo routine testing with the VWF ristocetin cofactor assay. The findings in our patient indicate that clinicians should have a high degree of suspicion of AVWS if patients with ET present with bleeding in addition to, or instead of, clotting.\n\nDepartment and Institution where work was done\n\nDepartment of Internal Medicine, UPMC Pinnacle, Harrisburg, PA, U.S.A.; and Department of Hematology/Oncology, UPMC Hillman Cancer Center, Camp Hill, PA, U.S.A.\n\nConflict of interest\n\nNone.\n\nFigure 1. EKG on admission, demonstrating ST segment elevation in V2, V3 and V4, consistent with an anterior myocar-dial infarction in the left anterior descending artery.\n\nFigure 2. Diagram representing the patient’s condition before cardiac catheterization, showing 100% occlusion of the left anterior descending artery (black).\n\nFigure 3. Diagram representing the patient’s condition after cardiac catheterization, showing revascularization of the left anterior descending artery, indicated as a mesh denoting a stent with 0% occlusion.\n==== Refs\nReferences:\n1. Beer PA Erber WN Campbell PJ Green AR How I treat essential thrombocythemia Blood 2011 117 1472 82 21106990 \n2. Akcan T Strati P Yan M Idowu M A rare case of triple-negative essential thrombocythemia in a young postsplenectomy patient: A diagnostic challenge Case Rep Hematol 2018 2018 9079462 30647982 \n3. Arber DA Orazi A Hasserjian R The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Blood 2016 127 2391 405 27069254 \n4. Hehlmann R Jahn M Baumann B Köpcke W Essential thrombocythemia. Clinical characteristics and course of 61 cases Cancer 1988 61 2487 96 3365670 \n5. Yokus O Gedik H Jak-2 mutation frequency in patients with thrombocytosis Caspian J Intern Med 2018 9 189 93 29732039 \n6. Cetin G Özkan T Turgut S Evaluation of clinical and laboratory findings with JAK2 V617F mutation as an independent variable in essential thrombocytosis Mol Biol Rep 2014 41 6737 42 25012914 \n7. Cervantes F Management of essential thrombocythemia Hematology Am Soc Hematol Educ Program 2011 2011 215 21 22160037 \n8. Karkucak M Yakut T Ozkocaman V Evaluation of the JAK2-V617F gene mutation in Turkish patients with essential thrombocythemia and polycythemia vera Mol Biol Rep 2012 39 8663 67 22722988 \n9. National Organisation of Rare Disorders (NORD) Tefferi A Essential thrombocythemia Updated 2018https://rarediseases.org/rare-diseases/essential-thrombocythemia/ \n10. Kralovics R Passamonti F Buser AS A gain-of-function mutation of JAK2 in myeloproliferative disorders N Engl J Med 2005 352 1779 90 15858187 \n11. Baxter EJ Scott LM Campbell PJ Cancer Genome Project Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders Lancet 2005 365 1054 61 15781101 \n12. Langabeer S Ni Ainle F Conneally E Lawler M Incidence and significance of the JAK2 V617F mutation in patients with chronic myeloproliferative disorders Ir J Med Sci 2007 176 105 9 17440677 \n13. Basquiera AL Soria NW Ryser R Clinical significance of V617F mutation of the JAK2 gene in patients with chronic myeloproliferative disorders Hematology 2009 14 323 30 19941738 \n14. Van Genderen PJJ Budde U Michiels JJ The reduction of large von Willebrand factor multimers in plasma in essential thrombocythaemia is related to the platelet count Br J Haematol 1996 93 962 65 8703834 \n15. Mital A Prejzner W Bieniaszewska M Hellmann A Prevalence of acquired von Willebrand syndrome during essential thrombocythemia: A retrospective analysis of 170 consecutive patients Pol Arch Med Wewn 2015 125 914 20 26658493 \n16. Rottenstreich A Kleinstern G Krichevsky S Factors related to the development of acquired von Willebrand syndrome in patients with essential thrombocythemia and polycythemia vera Eur J Intern Med 2017 41 49 54 27919526 \n17. Federici AB Rand JH Bucciarelli P Subcommittee on von Willebrand Factor: Acquired von Willebrand syndrome: Data from an international registry Thromb Haemost 2000 84 345 49 10959711 \n18. Franchini M Lippi G Acquired von Willebrand syndrome: An update Am J Hematol 2007 82 368 75 17133419 \n19. Tefferi A Vannucchi AM Barbui T Essential thrombocythemia treatment algorithm 2018 Blood Cancer J 2018 8 2 29321520 \n20. Cazzola M Kralovics R From Janus kinase 2 to calreticulin: The clinically relevant genomic landscape of myeloproliferative neoplasms Blood 2014 123 3714 19 24786775 \n21. Harrison CN Bareford D Butt N British Committee for Standards in Haematology: Guideline for investigation and management of adults and children presenting with a thrombocytosis Br J Haematol 2010 149 352 75 20331456 \n22. Tefferi A Guglielmelli P Larson DR Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis Blood 2014 124 2507 13 25037629 \n23. Wolanskyj AP Schwager SM McClure RF Essential thrombocythemia beyond the first decade: Life expectancy, long-term complication rates, and prognostic factors Mayo Clin Proc 2006 81 159 66 16471068 \n24. Ueki T Takeshige K Sumi M [Successful management of intraperitoneal bleeding with platelet apheresis and von Willebrand factor supplementation in a patient with essential thrombocythemia and acquired von Willebrand syndrome] Rinsho Ketsueki 2017 58 922 26 [in Japanese] 28883275 \n25. Carobbio A Finazzi G Guerini V Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status Blood 2007 109 2310 13 17110452 \n26. Budde U Schaefer G Mueller N Acquired von Willebrand’s disease in the myeloproliferative syndrome Blood 1984 64 981 85 6333259 \n27. Budde U Dent JA Berkowitz SD Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome Blood 1986 68 1213 17 3535924 \n28. Fabris F Casonato A Grazia del Ben M Abnormalities of von Willebrand factor in myeloproliferative disease: A relationship with bleeding diathesis Br J Haematol 1986 63 75 83 3085704 \n29. van Genderen PJJ Prins FJ Lucas IS Decreased half-life time of plasma von Willebrand factor collagen binding activity in essential thrombocythaemia: Normalization after cytoreduction of the increased platelet count Br J Haematol 1997 99 832 36 9432029 \n30. Van Genderen PJJ Leenknegt H Michiels JJ Budde U Acquired von Willebrand disease in myeloproliferative disorders Leuk Lymphoma 1996 22 Suppl. 1 79 82 8951776 \n31. Zaidi U Shahid S Fatima N Genomic profile of a patient with triple negative essential thrombocythemia, unresponsive to therapy: A case report and literature review J Adv Res 2017 8 375 78 28560052 \n32. Ju M Fu R Li H Mutation profiling by targeted sequencing of “triple-negative” essential thrombocythaemia patients Br J Haematol 2018 181 857 60 28466600\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D006801:Humans; D008297:Male; D009196:Myeloproliferative Disorders; D013920:Thrombocythemia, Essential; D013922:Thrombocytosis; D013927:Thrombosis; D014842:von Willebrand Diseases",
"nlm_unique_id": "101489566",
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"pubdate": "2020-08-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17110452;6333259;29732039;26658493;3085704;17440677;3535924;17133419;28466600;22160037;15781101;25037629;30647982;28560052;27919526;20331456;24786775;8951776;25012914;29321520;9432029;16471068;27069254;3365670;22722988;28883275;21106990;10959711;19941738;8703834;15858187",
"title": "Triple-Negative Essential Thrombocythemia Complicated by Thrombosis and Acquired von Willebrand Disease in a Young Man.",
"title_normalized": "triple negative essential thrombocythemia complicated by thrombosis and acquired von willebrand disease in a young man"
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"abstract": "Methotrexate, a folate antimetabolite and one of the first few anti-neoplastic drugs, is now a commonly used drug in the treatment of many inflammatory disorders ranging from diseases like rheumatoid arthritis to psoriasis. The life-threatening toxicity of methotrexate in inflammatory diseases is not commonly encountered. Here we report a case of life-threatening multiorgan failure from methotrexate toxicity, which was given for skin lesions suspected to be psoriasis.",
"affiliations": "General Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND.;Pathology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND.;Dermatology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND.;Internal Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND.;Internal Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND.",
"authors": "Tiewsoh|Iadarilang|I|;Dey|Biswajit|B|;Chhangte|Mary|M|;Lyngdoh|Monaliza|M|;Sathees|Varsha|V|",
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"doi": "10.7759/cureus.18069",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.18069\nInternal Medicine\nInfectious Disease\nRheumatology\nMethotrexate-Induced Septicemia With Severe Pancytopenia and Diffuse Cutaneous Ulcerative Lesions\nMuacevic Alexander\nAdler John R\nTiewsoh Iadarilang 1\nDey Biswajit 2\nChhangte Mary 3\nLyngdoh Monaliza 4\nSathees Varsha 4\n1 General Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND\n2 Pathology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND\n3 Dermatology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND\n4 Internal Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, IND\nIadarilang Tiewsoh iadarilang@yahoo.com\n17 9 2021\n9 2021\n13 9 e1806917 9 2021\nCopyright © 2021, Tiewsoh et al.\n2021\nTiewsoh et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/70197-methotrexate-induced-septicemia-with-severe-pancytopenia-and-diffuse-cutaneous-ulcerative-lesions\nMethotrexate, a folate antimetabolite and one of the first few anti-neoplastic drugs, is now a commonly used drug in the treatment of many inflammatory disorders ranging from diseases like rheumatoid arthritis to psoriasis. The life-threatening toxicity of methotrexate in inflammatory diseases is not commonly encountered. Here we report a case of life-threatening multiorgan failure from methotrexate toxicity, which was given for skin lesions suspected to be psoriasis.\n\npsoriasis\nsepticemia\nulcerative lesions\npancytopenia\ntoxicity\nmethotrexate\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nMethotrexate is a folate antimetabolite and the first few anti-neoplastic drugs that were administered for diseases like lymphoma and leukemia in high doses [1]. However, with the evolving evidence of its anti-inflammatory and immunomodulation properties, it has become one of the drugs of choice in many diseases like rheumatoid arthritis, small vessel vasculitis, and psoriasis [2-4]. The toxicity of methotrexate has been reported with both high and low doses and some risk factors are known to contribute to the toxicity [5-7].\n\nHere we report a case of methotrexate toxicity with life-threatening multiorgan failure given to a patient with suspected cutaneous psoriasis.\n\nCase presentation\n\nA middle-aged male of 46 years old, who is a chronic alcoholic, presented to the emergency department with multiple blisters and hemorrhagic crusting involving both upper and lower limbs and trunk for the last two months. The lesions started on the upper limbs as blisters and erosions following which the patient consulted a dermatologist (Figure 1). With a clinical suspicion of psoriasis, the patient was prescribed oral methotrexate weekly and topical steroids by a private practitioner. However after two weeks of the medication, the lesions increased resulting in multiple necrotic ulcers and hyperpigmented papules, macules distributed on the chest, the lower limbs and upper limbs bilaterally and erosions and necrotic ulcers on the back, some covered with crusts (Figure 2). This was followed by high-grade fever and difficulty in breathing. There was also a history of bleeding from the gums, mouth, and nasal cavity five days prior to admission. The patient went into a stage of altered sensorium and was rushed to our center for further management. On examination, the patient had mucositis of the buccal mucosa, active bleeding from the gums and nasal cavity. Examination of the skin lesions revealed multiple blisters and erythematous to hyperpigmented, scaly, and crusts on the neck, trunk, and limbs. There were multiple ulcers over these lesions with some of them were showing hemorrhagic crusts (Figure 3).\n\nFigure 1 Initial lesion showing a blister on the upper part of the forearm and few vesicles with surrounding erythema and oedema on the lower part of the forearm.\n\nFigure 2 Few erythematous macules and scaly plaques with oedema on the lower limb.\n\nFigure 3 Multiple necrotic ulcers and hyperpigmented papules and macules distributed on the chest, the lower limbs and upper limbs bilaterally. Multiple erosions and necrotic ulcers on the back, some covered with crusts. Some of the lesions are healing with hyperpigmentation.\n\nHis baseline saturation was 60% at room air and 91% with high flow oxygen therapy. Systemic examination revealed basal crepitations on respiratory examination and Glasgow Coma score of 5/15 with no focal neurological deficits. A CT brain was down to rule out any intracranial hemorrhage which did not show any obvious abnormality. Laboratory investigations revealed severe pancytopenia with hemoglobin of 6 gm%, total leucocyte count (TLC) of 300/cumm, platelets of 5000/cumm, and a reticulocyte count of 0.08%. Peripheral blood smear showed macrocytic anemia with target cells, leukocytopenia with lymphocytosis, and severe thrombocytopenia. Biochemical parameter like serum lactate dehydrogenase (LDH) was raised (475 IU/L) and serum procalcitonin was elevated (25.24 ng/mL). His serum creatinine was 2.5 mg/dL and serum urea was 150 mg/dL. Bone marrow study revealed hypocellular marrow with marked suppression of erythroid, myeloid, and megakaryocytic cell lineages favoring myelosuppression. Residual erythroid and myeloid cell lineages also showed megaloblastic changes (Figure 4). His bone marrow culture and blood culture had significant growth of methicillin-resistant Staphylococcus aureus (MRSA) which was sensitive to vancomycin. His chest X-ray was suggestive of a right lower lobe consolidation (Figure 5). His skin biopsy taken from an intact lesion on the medial aspect of the left foot showed features of psoriasis (Figure 6). With the background history of worsening symptoms after the intake of methotrexate, the multiorgan dysfunction was suspected to be due to methotrexate toxicity, however, serum methotrexate estimation could not be carried out. All the investigations are tabulated in Table 1 and Table 2. Since low doses of methotrexate are unlikely to cause severe life-threatening complications a detailed history of the doses taken by the patient was obtained and it was found that the patient had consumed methotrexate daily at the dose of 10 mg for two weeks which was then followed by the increase of the cutaneous lesions and other complications. Based on the above clinical and laboratory findings with no other contributing factors, a diagnosis of methotrexate toxicity was made. Naranjo Algorithm-Adverse Drug Reaction Probability scale was 1 to 4.\n\nFigure 4 Bone marrow aspirate showing hypocellular particle with fat (arrows) replacing marrow particles (Leishman, 40x).\n\nFigure 5 Chest X-ray showing right lower zone consolidation\n\nFigure 6 Skin biopsy showing parakeratosis of stratum corneum (blue arrow), psoriasiform hyperplasia (black arrow), and dilated capillaries in dermal papillae (red arrow) with suprapapillary thinning (H & E, 40x).\n\nTable 1 Haemotological and biochemical reports\n\nTLC: Total leucocyte count; DLC: Differential leukocyte count; ESR: Erythrocyte sediment rate; AST: Aspartate aminotransferase; ALT: Alanine transaminase; ALP: Alkaline phosphatase.\n\n \t1st day of admission\t5th day of admission\t10th day of admission\tOn discharge\t\nHb (gm %)\t6.2\t4.7\t9.1\t9.2\t\nTLC (per cumm)\t300\t2300\t4900\t5.7 x 10³\t\nDLC (N/L/M/E)\t38/50/06/06\t70/24/05/01\t73/18/08/01\t70/23/04/03\t\nPlatelets (per cumm)\t5000\t23,000\t30,000\t250,000\t\nPeripheral blood smear\tMacrocytic anemia with target cells, leucocytopenia, lymphocytosis and severe thrombocytopenia\t \t \t \t\nESR at the end of 1st hour\t66\t \t \t \t\nReticulocytes\t0.08\t \t \t \t\nProthrombin time (sec)\t16.3\t \t \t \t\nActivated partial thromboplastin time (aPTT) (sec)\t40.8\t \t \t \t\nFibrinogen levels (mg/dl)\t267\t \t \t \t\nD-Dimer (ng/dL)\t<250\t \t \t \t\nInternational normalized ratio (sec)\t1.41\t \t \t \t\nUrea (mg/dL)\t84\t150\t63\t13\t\nCreatinine (mg/dl)\t2.5\t2.3\t1.3\t0.9\t\nSodium (mmol/dL)\t154.6\t168.9\t155.1\t137\t\nPotassium (mmol/dL)\t3.79\t3.69\t4.59\t3.66\t\nChloride (mmol/dL)\t123.2\t125.9\t117.8\t102\t\nTotal bilirubin (mg/dL)\t2.5\t1.0\t1.5\t0.7\t\nDirect bilirubin (mg/dL)\t1.4\t0.4\t0.7\t0.2\t\nAST (U/L)\t59\t35\t43\t19\t\nALT (U/L)\t34\t15\t16\t13\t\nALP (U/L)\t98\t102\t162\t141\t\nTotal protein (g/dL)\t5.3\t5.2\t6.5\t6.5\t\nAlbumin (g/dL)\t2.4\t2.2\t2.1\t3.4\t\nLDH (IU/L)\t \t475\t \t \t\nProcalcitonin (ng/mL)\t \t25.24\t5.04\t1\t\n\nTable 2 Biopsy and serology reports\n\nHCV: Hepatitis C virus; VDRL: Venereal disease research laboratory test; ANA: Antinuclear antibody; RT-PCR: Reverse transcription-polymerase chain reaction.\n\nBone marrow study\tHypocellular marrow with marked suppression of erythroid, myeloid, and megakaryocytic cell lineages favoring myelosuppression. Residual erythroid and myeloid cell lineages also showed megaloblastic changes.\t\nBone marrow culture\tStaphylococcus aureus (methicillin-resistant)\t\nSkin biopsy from the medial aspect of left foot\tPsoriasiform hyperplasia with hypogranulosis and dilated capillaries with suprapapillary thinning confirming psoriasis\t\nHBsAg / Anti-HCV\tNegative\t\nAnti-HCV\tNon-reactive\t\nVDRL\tNegative\t\nHIV\tNon-reactive\t\nANA\tNegative\t\nRT-PCR for SARS-CoV-2\tNegative\t\n\nThe patient was intubated and ventilated on the day of admission. He was managed on the line of severe sepsis with acute kidney injury, pneumonia, and pancytopenia with supportive skincare of the ulcerated lesions. The patient was started on intravenous leucovorin calcium, 25 mg every 6 hours on day 1, followed by 10 mg every 6 hours on days 2 and 3. Apart from intravenous antibiotic therapy and intravenous fluid, he received 2 units of packed red blood cells and 16 units of platelet concentrate due to upper gastrointestinal bleeding and bleeding from gums, nasal cavity, and buccal mucosa. Total parental therapy was continued for seven days. He responded to the medical treatment and on the 10th day of intensive care therapy, he was extubated and continued with supportive care. His lesions healed with the continuation of antibiotic therapy and daily dressing with povidone-iodine followed by the application of silver sulfadiazine cream. He was discharged on the 28th day of his hospital stay.\n\nDiscussion\n\nThere have been case reports of methotrexate toxicities in the form of cutaneous skin lesions, acute renal failure, pancytopenia, pneumonitis, neurotoxicity [5-13]. Here we report methotrexate toxicity following over-dosage of methotrexate by the patient resulting in life-threatening multiorgan failure with severe pancytopenia, septicemia, acute kidney injury, and diffuse cutaneous skin lesions. Toxicities like myelosuppression, pancytopenia, acute renal failure, interstitial pneumonitis, hepatitis, gastrointestinal mucositis, leukoencephalopathy are severe forms usually associated with high doses and risk factors. The severity of methotrexate toxicity can vary from mild to severe forms.\n\nMethotrexate is a folate antagonist and inhibitor of cellular proliferation. Cells with the highest turnover such as oral mucosa, gastrointestinal tract, and bone marrow cells are the most susceptible to its effect. Thus, mucositis develops when a patient's oral epithelial cells are affected. Myelosuppression in patients with methotrexate toxicity is explained by the same mechanism [14]. As a result, pancytopenia develops, which leads to increased bleeding, easy bruising, macrocytic red blood cells, and an increased risk of infections [15].\n\nA varied range of skin disorders has been reported with methotrexate in high to low doses. These include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme, erythroderma, papular rash, photodermatitis reaction, epidermal necrosis, and cutaneous ulceration [7-9,16].\n\nUlceration of the psoriatic plaques in the skin due to methotrexate toxicity is uncommon. Two patterns of skin ulceration have been described in psoriasis patients, who are treated with methotrexate. In type I ulcers, the psoriatic plaques begin to erode shortly after commencing methotrexate treatment. Type II ulcers affect uninvolved skin observed with higher dose. The pathogenic mechanism was believed to be the direct toxicity of the drug in both types. Psoriatic plaques are initially painful and red, and then they develop superficial erosions [17].\n\nWhen methotrexate is given to patients in high or low doses all preventive measures are to be taken before administering the drug. High doses of methotrexate are administered with maintaining a good urine output, urinary alkalinization, monitoring serum creatinine, electrolytes, pharmacokinetically guided leucovorin rescue therapy and serum methotrexate estimation. Toxicities from low doses of methotrexate are stomatitis, nausea, hepatitis, cutaneous eruptions, fever, macrocytosis, and myelosuppression which can be prevented by educating and monitoring the patient from time to time along with co-administration of weekly folic acid. Immediate withdrawal of methotrexate when toxicity is encountered is an important intervention with supportive therapy. Education about the proper dosage and the related toxicity should be explained to patients before administrating the drug.\n\nIn the present case, the patient had an overdose of the drug following which he suffered a severe form of bone marrow suppression, acute renal failure, and diffuse cutaneous ulcerative lesions with septicemia. Pancytopenia could have also been contributed by folate deficiency which might have persisted before the event with the patient being a chronic alcoholic. The skin lesions of the patient could be attributed to the direct toxicity of the methotrexate therapy.\n\nConclusions\n\nMethotrexate is a commonly used drug for many systemic inflammatory diseases and cutaneous lesions in clinical practice. The toxicity that our patient suffered was due to overdosage and resulted in life-threatening complications which if not timely managed the mortality is known to be very high. Hence the toxicities that can result from methotrexate should always be considered before initiating the drug therapy. It is important for all clinicians to carry out a detailed laboratory evaluation prior to initiation of the therapy, adequate education and close monitoring during the course of therapy to avoid the adverse drug events from methotrexate.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (Aminopterin) N Engl J Med Farber S Diamond LK Mercer RD Sylvester RF Jr Wolff JA 787 793 238 1948 18860765\n2 Methotrexate in rheumatoid arthritis: a quarter century of development Trans Am Clin Climatol Assoc Weinblatt ME 16 25 124 2013 https://pubmed.ncbi.nlm.nih.gov/23874006/ 23874006\n3 Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatment J Eur Acad Dermatol Venereol Haustein UF Rytter M 382 388 14 2000 11305380\n4 Non-cancer uses of methotrexate (Article in French) Presse Med Brion N Paule B 1929 1234 25 1996 https://pubmed.ncbi.nlm.nih.gov/9033614/ 9033614\n5 High dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients Br J Clin Pharmacol Holmboe L Andersen AM Mørkrid L Slørdal L Hall KS 106 114 73 2012 21707700\n6 Factors associated with myelosuppression related to low-dose methotrexate therapy for inflammatory rheumatic diseases PLoS One Mori S Hidaka M Kawakita T 0 11 2016\n7 Acute severe methotrexate toxicity in patients with psoriasis: a case series and discussion Dermatology Yélamos O Català A Vilarrasa E Roe E Puig L 306 309 229 2014 25401478\n8 Methotrexate-induced epidermal necrosis: a case series of 24 patients J Am Acad Dermatol Chen TJ Chung WH Chen CB 247 255 77 2017 28499754\n9 Methotrexate-induced toxic epidermal necrolysis in a patient with psoriasis J Am Acad Dermatol Primka EJ 3rd Camisa C 815 818 36 1997 9146556\n10 Understanding and managing methotrexate nephrotoxicity Oncologist Widemann BC Adamson PC 694 703 11 2006 16794248\n11 Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review Arthritis Rheum Kremer JM Alarcón GS Weinblatt ME 1829 1837 40 1997 9336418\n12 Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia J Clin Oncol Bhojwani D Sabin ND Pei D 949 959 32 2014 24550419\n13 Methotrexate induced pancytopenia Case Rep Rheumatol Gonzalez-Ibarra F Eivaz-Mohammadi S Surapaneni S 679580 2014 2014 25006519\n14 Methotrexate-induced pancytopenia and mucositis caused by medication error Ghana Med J Amissah-Arthur MB Baah W 68 71 54 2020 https://pubmed.ncbi.nlm.nih.gov/32863415/ 32863415\n15 Stevens-Johnson syndrome associated with methotrexate treatment for non-Hodgkin's lymphoma Ulster Med J Cuthbert RJ Craig JI Ludlam CA 95 97 62 1993 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2449034/ 7685956\n16 Two patterns of skin ulceration induced by methotrexate in patients with psoriasis J Am Acad Dermatol Lawrence CM Dahl MG 1059 1065 11 1984 6512051\n17 Cutaneous ulceration caused by methotrexate J Am Acad Dermatol Kazlow DW Federgrun D Kurtin S Lebwohl MG 197 198 49 2003\n\n",
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"title": "Methotrexate-Induced Septicemia With Severe Pancytopenia and Diffuse Cutaneous Ulcerative Lesions.",
"title_normalized": "methotrexate induced septicemia with severe pancytopenia and diffuse cutaneous ulcerative lesions"
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"dru... |
{
"abstract": "Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of ∼2%. In AA, the immune system targets the hair follicle, resulting in clinical hair loss. The prognosis of AA is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common γ-chain cytokine and IFN pathways. Because these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors. In preclinical trials in mice, tofacitinib successfully prevented AA development and reversed established disease. In our tofacitinib trial in 12 patients with moderate to severe AA, 11 patients completed a full course of treatment with minimal adverse events. Following limited response to the initial dose (5 mg b.i.d.), the dose was escalated (10 mg b.i.d.) for nonresponding subjects. Eight of 12 patients demonstrated ≥50% hair regrowth, while three patients demonstrated <50% hair regrowth, as measured by Severity in Alopecia Tool scoring. One patient demonstrated no regrowth. Gene expression profiles and Alopecia Areata Disease Activity Index scores correlated with clinical response. Our open-label studies of ruxolitinib and tofacitinib have shown dramatic clinical responses in moderate to severe AA, providing strong rationale for larger clinical trials using JAK inhibitors in AA. ClinicalTrials.gov ID NCT02299297.",
"affiliations": "Department of Dermatology, Columbia University, New York, New York, USA; Department of Dermatology and Interdisciplinary Program in Immunology, University of Iowa, Iowa City, Iowa, USA.;Department of Dermatology, Columbia University, New York, New York, USA.;Department of Dermatology, Columbia University, New York, New York, USA.;Department of Dermatology, Columbia University, New York, New York, USA.;Department of Dermatology, Columbia University, New York, New York, USA.;Department of Dermatology, Columbia University, New York, New York, USA.;Department of Dermatology, Columbia University, New York, New York, USA.;Department of Dermatology, Columbia University, New York, New York, USA; Department of Genetics, Columbia University, New York, New York, USA; Department of Pathology, Columbia University, New York, New York, USA; Department of Medicine, Columbia University, New York, New York, USA.;Department of Dermatology, Columbia University, New York, New York, USA.;Department of Dermatology, Columbia University, New York, New York, USA. Electronic address: jc299@columbia.edu.",
"authors": "Jabbari|A|A|;Sansaricq|F|F|;Cerise|J|J|;Chen|J C|JC|;Bitterman|A|A|;Ulerio|G|G|;Borbon|J|J|;Clynes|R|R|;Christiano|A M|AM|;Mackay-Wiggan|J|J|",
"chemical_list": "D000075242:Janus Kinase Inhibitors; D009570:Nitriles; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; C540383:ruxolitinib; C479163:tofacitinib; D053612:Janus Kinases",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jid.2018.01.032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-202X",
"issue": "138(7)",
"journal": "The Journal of investigative dermatology",
"keywords": null,
"medline_ta": "J Invest Dermatol",
"mesh_terms": "D000328:Adult; D000506:Alopecia Areata; D001327:Autoimmune Diseases; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D018859:Hair Follicle; D006801:Humans; D000075242:Janus Kinase Inhibitors; D053612:Janus Kinases; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010781:Photography; D010865:Pilot Projects; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0426720",
"other_id": null,
"pages": "1539-1545",
"pmc": null,
"pmid": "29452121",
"pubdate": "2018-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15337988;16723010;17637376;18795920;1884604;21689242;22147632;25129481;25303533;26633291;27119625;27699252;27816293;7791384",
"title": "An Open-Label Pilot Study to Evaluate the Efficacy of Tofacitinib in Moderate to Severe Patch-Type Alopecia Areata, Totalis, and Universalis.",
"title_normalized": "an open label pilot study to evaluate the efficacy of tofacitinib in moderate to severe patch type alopecia areata totalis and universalis"
} | [
{
"companynumb": "US-PFIZER INC-2018083294",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOFACITINIB CITRATE"
},
"drugadditional": null... |
{
"abstract": "This is a case report involving a patient who was treated with topical 5-FU cream and subsequently developed a severe case of angioedema. This case presents the possibility of anaphylaxis to topical 5-FU treatments and/or the interaction with angiotensin converting enzyme inhibitors. To our knowledge there has been no prior reported case of this reaction. We present this unusual case along with a review of the current literature on angioedema.",
"affiliations": "Silver Falls Dermatology, Salem, OR, USA.",
"authors": "Maughan|Cory|C|;Lear|William|W|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "19(3)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D000964:Antimetabolites, Antineoplastic; D004342:Drug Hypersensitivity; D004347:Drug Interactions; D005145:Face; D005472:Fluorouracil; D006225:Hand; D006801:Humans; D055623:Keratosis, Actinic; D008297:Male",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": "13",
"pmc": null,
"pmid": "23552010",
"pubdate": "2013-03-15",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Acute angioedema response to topical 5-fluorouracil therapy.",
"title_normalized": "acute angioedema response to topical 5 fluorouracil therapy"
} | [
{
"companynumb": "US-APOTEX-2018AP017385",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": "1",
... |
{
"abstract": "Sustained-release calcium channel blocker (CCB SR) overdoses are potentially life-threatening ingestions. These patients may not become hemodynamically unstable until many hours after ingestion. On theoretical grounds, some have suggested that whole bowel irrigation (WBI) with polyethylene glycol electrolyte lavage solution may be of value in the management of these cases. We report two cases with poor outcome (including one fatality) that were complicated by the use of WBI. Both cases were treated with WBI beginning before and continuing after developing hypotension. WBI should be avoided in the setting of the hemodynamically unstable CCB SR overdose.",
"affiliations": "The Toxikon Consortium at Cook County Hospital, Chicago, Illinois 60612, USA.",
"authors": "Cumpston|Kirk L|KL|;Aks|Steven E|SE|;Sigg|Todd|T|;Pallasch|Erin|E|",
"chemical_list": "D002121:Calcium Channel Blockers",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2007.11.100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "38(2)",
"journal": "The Journal of emergency medicine",
"keywords": null,
"medline_ta": "J Emerg Med",
"mesh_terms": "D001291:Attitude of Health Personnel; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D006439:Hemodynamics; D006801:Humans; D007422:Intestines; D008297:Male; D008875:Middle Aged; D013406:Suicide, Attempted; D007507:Therapeutic Irrigation",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "171-4",
"pmc": null,
"pmid": "18614321",
"pubdate": "2010-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Whole bowel irrigation and the hemodynamically unstable calcium channel blocker overdose: primum non nocere.",
"title_normalized": "whole bowel irrigation and the hemodynamically unstable calcium channel blocker overdose primum non nocere"
} | [
{
"companynumb": "US-TEVA-2010R0403202",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALCOHOL"
},
"drugadditional": null,
"dru... |
{
"abstract": "Apalutamide, a competitive inhibitor of the androgen receptor, is being increasingly used for the treatment of prostate cancer. There have been few reports of interstitial lung disease in clinical trials of apalutamide. However, two cases of apalutamide-induced interstitial lung disease with respiratory failure in Japanese males, who were successfully treated with high-dose corticosteroids, are presented here. These cases suggest that clinicians should be alert to the potentially life-threatening risk of pulmonary toxicity associated with apalutamide treatment.",
"affiliations": "Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minaminachi, Kobe City, Hyogo, 650-00047, Japan; Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital, Kurashiki City, Okayama, 710-8602, Japan. Electronic address: hk16554@kchnet.or.jp.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minaminachi, Kobe City, Hyogo, 650-00047, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minaminachi, Kobe City, Hyogo, 650-00047, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minaminachi, Kobe City, Hyogo, 650-00047, Japan.;Department of Urology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minaminachi, Kobe City, Hyogo, 650-00047, Japan.;Department of Urology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minaminachi, Kobe City, Hyogo, 650-00047, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minaminachi, Kobe City, Hyogo, 650-00047, Japan.",
"authors": "Kobe|Hiroshi|H|;Tachikawa|Ryo|R|;Masuno|Yoshitsugu|Y|;Matsunashi|Atsushi|A|;Murata|Shiori|S|;Hagimoto|Hiroki|H|;Tomii|Keisuke|K|",
"chemical_list": "D000970:Antineoplastic Agents; D013867:Thiohydantoins; C572045:apalutamide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.resinv.2021.05.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2212-5345",
"issue": "59(5)",
"journal": "Respiratory investigation",
"keywords": "Apalutamide; Interstitial lung disease; Methylprednisolone; Refractory",
"medline_ta": "Respir Investig",
"mesh_terms": "D000970:Antineoplastic Agents; D006801:Humans; D007564:Japan; D017563:Lung Diseases, Interstitial; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D013867:Thiohydantoins",
"nlm_unique_id": "101581124",
"other_id": null,
"pages": "700-705",
"pmc": null,
"pmid": "34144936",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Apalutamide-induced severe interstitial lung disease: A report of two cases from Japan.",
"title_normalized": "apalutamide induced severe interstitial lung disease a report of two cases from japan"
} | [
{
"companynumb": "JP-DSJP-DSJ-2021-137296",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A 39-year-old man who had received cadaveric renal transplantation (RT) 1 month previously presented with rash and pain on his left lower extremity. Initially, bacterial cellulitis was suspected, and ampicillin/sulbactam was initiated; however, 3 days later, skin necrosis occurred and pain increased. Ampicillin/sulbactam was replaced with imipenem+ciprofloxacin, and surgical debridement was performed. Escherichia coli was identified in the wound culture, urine culture, and blood culture. After repeated debridement, wound care, and appropriate antimicrobial treatment, wounds began to heal and skin grafting was planned at the 4th month of therapy. However, the patient died of viral pneumonia. To date, 20 cases of necrotizing fasciitis (NF) after RT have been reported (including our case), and, as far as we know, this is the second E coli-related NF case. An analysis of all 20 cases showed that the most common infection site was the extremities (90%) and that 45% of pathogens were fungus. The mortality rate was 30%. NF is a rare but rapidly developing and life-threatening soft-tissue infection in RT patients. To reduce mortality rates, early diagnosis, recurrent surgical debridement, and aggressive therapy are mandatory.",
"affiliations": "Goztepe Medical Park Hospital, Organ Transplantation Center, Istanbul, Turkey. Electronic address: drturunc@hotmail.com.;Goztepe Medical Park Hospital, Organ Transplantation Center, Istanbul, Turkey.;Department of Plastic, Reconstructive, and Aesthetic Surgery, Bahcesehir University, Istanbul, Turkey.;Department of General Surgery, Bahcesehir University, Istanbul, Turkey.;Department of General Surgery, Bahcesehir University, Istanbul, Turkey.;Goztepe Medical Park Hospital, Organ Transplantation Center, Istanbul, Turkey.",
"authors": "Turunç|V|V|;Eroğlu|A|A|;Cihandide|E|E|;Tabandeh|B|B|;Oruğ|T|T|;Güven|B|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D003646:Debridement; D004927:Escherichia coli Infections; D019115:Fasciitis, Necrotizing; D017809:Fatal Outcome; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016038:Skin Transplantation",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1518-21",
"pmc": null,
"pmid": "26093756",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Escherichia Coli-Related Necrotizing Fasciitis After Renal Transplantation: A Case Report.",
"title_normalized": "escherichia coli related necrotizing fasciitis after renal transplantation a case report"
} | [
{
"companynumb": "PHHY2015TR077336",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Diseases in end stage typically occur with hypothalamic-pituitary-ovarian axis disorders, with consequent anovulation and infertility. The solid organ transplantation increased survival of patients with end-stage organs disease and the vast majority of women improve their reproductive capacity after transplantation. Although adoption can always be a possibility, the transplanted infertile woman has the right to self-reproductive determination using assisted reproductive techniques. While it is known that pregnancies in transplantedwomen are at high risk, there is no evidence of differences in pregnancy outcome in pregnant transplanted subject to technical, compared with spontaneous pregnancies. The use of assisted reproductive techniques in transplanted women is a medical, ethical and psychosocial challenge, whose approach must be multidisciplinary, to ensure reproductive success without compromising the function of the transplanted organ or maternal health, allowing the birth of a healthy child. The literature remains scarce. Three clinical cases are presented.",
"affiliations": "Serviço de Ginecologia e Obstetrícia. Hospital de Braga. Braga. Portugal.;Unidade de Medicina da Reprodução. Serviço de Ginecologia e Obstetrícia. Centro Hospitalar de S. João, EPE. Porto. Portugal.;Unidade de Medicina da Reprodução. Serviço de Ginecologia e Obstetrícia. Centro Hospitalar de S. João, EPE. Porto. Portugal.;Unidade de Medicina da Reprodução. Serviço de Ginecologia e Obstetrícia. Centro Hospitalar de S. João, EPE. Porto. Portugal.;Unidade de Medicina da Reprodução. Serviço de Ginecologia e Obstetrícia. Centro Hospitalar de S. João, EPE. Porto. Portugal.;Unidade de Medicina da Reprodução. Serviço de Ginecologia e Obstetrícia. Centro Hospitalar de S. João, EPE. Porto. Portugal.;Serviço de Ginecologia e Obstetrícia. Centro Hospitalar de São João, EPE. Porto. Portugal.;Serviço de Ginecologia e Obstetrícia. Centro Hospitalar de São João, EPE. Porto. Portugal. Faculdade de Medicina. Universidade do Porto. Porto. Portugal. Unidade de Investigação em Epidemiologia - EPIUnit. Instituto de Saúde Pública. Universidade do Porto. Porto. Portugal.",
"authors": "Vale-Fernandes|Emídio|E|;Póvoa|Ana Margarida|AM|;Soares|Sandra|S|;Calejo|Lucinda|L|;Xavier|Pedro|P|;Sousa|Sónia|S|;Beires|Jorge|J|;Montenegro|Nuno|N|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.6349",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": "29(1)",
"journal": "Acta medica portuguesa",
"keywords": null,
"medline_ta": "Acta Med Port",
"mesh_terms": "D005260:Female; D006801:Humans; D011247:Pregnancy; D011256:Pregnancy Outcome; D018456:Reproductive Medicine; D027724:Reproductive Techniques, Assisted; D012307:Risk Factors; D066027:Transplant Recipients",
"nlm_unique_id": "7906803",
"other_id": null,
"pages": "73-8",
"pmc": null,
"pmid": "26926902",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Assisted Reproductive Technology in Female Transplant Recipients: Experience of a Reproductive Medicine Unit and Literature Review.",
"title_normalized": "assisted reproductive technology in female transplant recipients experience of a reproductive medicine unit and literature review"
} | [
{
"companynumb": "PT-ASTELLAS-2016US005397",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Bladder cancer (BC) is the second most common cancer involving the urinary system. In non-muscle-invading BC, transurethral resection of a bladder tumor followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) is the usual treatment. Disseminated (or systemic) BCG infection (BCGitis) represents the most severe adverse effect of intravesical BCG therapy, presenting with high-grade fever, with or without symptoms in the urinary tract, leading to severe sepsis and death if left untreated. The treatment of choice consists of isoniazid, rifampicin, and ethambutol (with or without corticosteroids) for 6 months, and the recovery rate is extremely high. Given the fact that these drugs are hepatotoxic, treating a patient with liver cirrhosis is challenging. CASE REPORT We present a patient with a medical history of BC treated with transurethral resection and intravesical BCG therapy, presenting with fever, transaminasemia, and generalized weakness. Liver and bone marrow biopsies revealed liver cirrhosis and granulomas in both organs. A diagnose of BCGitis was made and the patient was treated with isoniazid, rifampicin, and ethambutol; rifampicin was substituted with moxifloxacin after 1 month due to worsening of liver laboratory results, and moxifloxacin was substituted with levofloxacin later on due to tonic-clonic seizures. The patient was treated for 4 more months with levofloxacin and for 7 more months with isoniazid and ethambutol, with no other adverse effects, preserving liver function and achieving cure of BCGitis. CONCLUSIONS We present the case of a cirrhotic patient presenting with fever and deterioration of liver laboratory results, found to have BCGitis, and discuss possible difficulties in diagnosing and treating such patients.",
"affiliations": "Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Department of Gastroenterology, Sismanoglio General Hospital, Athens, Greece.;Department of Pathology, Evangelismos General Hospital, Athens, Greece.;First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Department of Internal Medicine, Nicosia General Hospital, Nicosia, Cyprus.;Thalassemia and Sickle Cell Disease Center, Laiko General Hospital, Athens, Greece.;First Department of Internal Medicine, Laiko General Hospital, Athens, Greece.;Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athnes, Greece.",
"authors": "Vallilas|Christos|C|;Zachou|Maria|M|;Dolkiras|Philippos|P|;Sakellariou|Stratigoula|S|;Constantinou|Costas A|CA|;Flevari|Pagona|P|;Anastasopoulou|Amalia|A|;Androutsakos|Theodoros|T|",
"chemical_list": "D001500:BCG Vaccine",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.933006",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n10.12659/AJCR.933006\n933006\nArticles\nDifficulties in Diagnosing and Treating Disseminated Bacillus Calmette-Guérin (BCG) Infection After Intravesical BCG Therapy in a Patient with Liver Cirrhosis: A Case Report\nVallilas Christos * B C D E 1\nZachou Maria * B C D E 2\nDolkiras Philippos B D E 3\nSakellariou Stratigoula B D E 4\nConstantinou Costas A. B C D E 5\nFlevari Pagona D E 6\nAnastasopoulou Amalia C D E F 7\nAndroutsakos Theodoros A B C D E F 1\n1 Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece\n2 Department of Gastroenterology, Sismanoglio General Hospital, Athens, Greece\n3 Department of Pathology, Evangelismos General Hospital, Athens, Greece\n4 First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece\n5 Department of Internal Medicine, Nicosia General Hospital, Nicosia, Cyprus\n6 Thalassemia and Sickle Cell Disease Center, Laiko General Hospital, Athens, Greece\n7 First Department of Internal Medicine, Laiko General Hospital, Athens, Greece\nCorresponding Author: Theodoros Androutsakos, e-mail: T_Androutsakos@yahoo.gr\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n* Christos Vallilas and Maria Zachou are Co-authors\n\nFinancial support: None declared\n\nConflict of interest: None declared\n\n2021\n16 10 2021\n22 e933006-1e933006-7\n04 5 2021\n27 8 2021\n14 9 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 62-year-old\n\nFinal Diagnosis: BCGitis\n\nSymptoms: Fever • general fatigue\n\nMedication: —\n\nClinical Procedure: Bone marrow biopsy • liver biopsy\n\nSpecialty: Infectious Diseases • General and Internal Medicine\n\nObjective:\n\nRare coexistence of disease or pathology\n\nBackground:\n\nBladder cancer (BC) is the second most common cancer involving the urinary system. In non-muscle-invading BC, transurethral resection of a bladder tumor followed by intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) is the usual treatment. Disseminated (or systemic) BCG infection (BCGitis) represents the most severe adverse effect of intravesical BCG therapy, presenting with high-grade fever, with or without symptoms in the urinary tract, leading to severe sepsis and death if left untreated. The treatment of choice consists of isoniazid, rifampicin, and ethambutol (with or without corticosteroids) for 6 months, and the recovery rate is extremely high. Given the fact that these drugs are hepatotoxic, treating a patient with liver cirrhosis is challenging.\n\nCase Report:\n\nWe present a patient with a medical history of BC treated with transurethral resection and intravesical BCG therapy, presenting with fever, transaminasemia, and generalized weakness. Liver and bone marrow biopsies revealed liver cirrhosis and granulomas in both organs. A diagnose of BCGitis was made and the patient was treated with isoniazid, rifampicin, and ethambutol; rifampicin was substituted with moxifloxacin after 1 month due to worsening of liver laboratory results, and moxifloxacin was substituted with levofloxacin later on due to tonic-clonic seizures. The patient was treated for 4 more months with levofloxacin and for 7 more months with isoniazid and ethambutol, with no other adverse effects, preserving liver function and achieving cure of BCGitis.\n\nConclusions:\n\nWe present the case of a cirrhotic patient presenting with fever and deterioration of liver laboratory results, found to have BCGitis, and discuss possible difficulties in diagnosing and treating such patients.\n\nKeywords:\n\nBCG and Salmonella Infection, Disseminated\nIsoniazid\nLiver Cirrhosis\nRifampin\n==== Body\npmcBackground\n\nBladder cancer (BC) is the ninth most common malignancy worldwide and the second most common one involving the urinary system; however, in middle-aged and elderly men, BC is the second most common malignancy, after only prostate cancer [1–4]. The majority (75–80%) of BCs are non-muscle-invasive (NMIBC) and the treatment strategy includes transurethral resection of bladder tumor (TURBT), usually followed by intravesical immunotherapy with Bacillus Calmette-Guérin (BCG), which is an attenuated strain of Mycobacterium bovis, leading to eradication of residual tumor, delay of disease progression, reduction in need for cystectomy, and prolonging survival [5–8].\n\nDespite the efficacy of intravesical BCG therapy, most patients report local, mild, early complications after instillation, like cystitis (81%), macroscopic hematuria (15%), and urination frequency [9–13]. Although BCG therapy is usually well-tolerated, local and systemic complications can occur [9,10,13]. Local complications involve the genitourinary tract in the form of epididymitis and granulomatous prostatitis, while systemic ones include short-term fever in 5–30% of patients, as well as allergic reactions, reactive arthritis, drug-induced liver injury, granulomatous hepatitis, and nephritis, all with a prevalence of less than 1% [10,12–15].\n\nDisseminated (or systemic) BCG infection (BCGitis) is the most severe adverse effect of intravesical BCG therapy. BCGitis has an incidence of 3% to 7% and presents with high-grade fever and/or various organ involvement with or without symptoms from the urinary tract, leading to severe sepsis and death if left untreated [9,10,16–19]. BCGitis should be suspected in any patient who develops moderate-to-severe genitourinary or systemic symptoms following ≥1 instillation of intravesical BCG when no alternative diagnosis can be established. Microbiological documentation of the infection is required for definitive diagnosis; however, it has low sensitivity, and when histopathology is available, granulomas are commonly found [17]. Due to the aforementioned difficulties, empirical treatment is commonly started upon suspicion; in this setting, improvement of symptoms after treatment initiation is mandatory for establishing the diagnosis [9,14,17]. The treatment of choice for BCGitis consists of isoniazid, rifampicin, and ethambutol (alone or in combination with corticosteroids) for 6 months, and the recovery rate is extremely high [17,20–24]. Unfortunately, all of the above-mentioned drugs are hepatotoxic and can cause liver dysfunction, a problem most often encountered in cirrhotic patients [25]. Here, we report the first case of a cirrhotic patient diagnosed with BCGitis with liver and bone marrow involvement, and we discuss potential therapeutic challenges related to the co-existence of BCGitis and liver cirrhosis.\n\nCase Report\n\nA 62-year-old non-smoker, male patient was admitted to Laiko General Hospital in Athens, Greece, due to a 6-month history of fever and generalized weakness. He had a medical history of non-muscle-invading BC, diagnosed 2 years before presentation and treated with transurethral resection (TURBT) followed by 6 weeks of intravesical therapy with BCG. His medical anamnesis was also notable for coronary artery disease and dyslipidemia. He reported consuming moderate amounts of alcohol daily for the past 20 years, stopping about 4 months ago.\n\nApproximately 2 months before presentation, the patient was hospitalized in another hospital due to fever up to 38.5°C, anemia, and generalized weakness. During his stay there, a cystoscopy was performed that revealed BC recurrence and he received a second course of 6 weekly intravesical BCG infusions. His fever was attributed to BC recurrence, so no further diagnostic evaluation was performed at that time. Due to fever persistence and generalized weakness after treatment completion, he was admitted to our hospital for further evaluation and management.\n\nUpon admission, the patient had an axillary temperature of 37.5°C, a blood pressure of 110/80 mmHg, a heart rate of 93 beats per minute, an oxygen saturation of 89% on ambient air, and a respiratory rate of 22 breaths per minute. On physical examination, he was mildly lethargic with no focal neurological deficits or signs. Lung auscultation revealed bilateral crackles and abdomen examination revealed hepato-splenomegaly with no pain during palpation. The rest of his clinical examination was unremarkable.\n\nRoutine laboratory blood results showed mild pancytopenia, elevated serum gamma glutamyl-transferase (GGT) and alkaline phosphatase (ALP) levels, as well as mildly elevated serum C-reactive protein (CRP) aspartate (AST) and normal alanine (ALT) aminotransferases levels (Table 1). Urinary testing revealed pyuria and mild hematuria, whereas the urine culture was sterile.\n\nA chest X-ray was performed that demonstrated bilateral pleural fluid accumulation, while abdominal ultrasound revealed a cirrhotic liver, splenomegaly, and mild ascites. No focal hepatic lesions were found. Computed tomography (C/T) scans of the chest and abdomen confirmed the aforementioned findings, without revealing portal or hepatic veins thrombosis.\n\nAscitic fluid analysis was consistent with portal hypertension-induced ascites (serum-to-ascites albumin gradient of 2.1 g/dl), with no signs of infection or malignancy. Testing for hepatitis B and hepatitis C infections, Leishmaniasis, Q fever, and Brucellosis were negative, as were anti-nuclear, anti-smooth muscle, and anti-mitochondrial antibodies in serum. Serum iron studies, ferritin, ceruloplasmin level, and 24-h urine copper excretion were within normal limits. Quantiferon testing was negative and an echocardiogram was also normal.\n\nDue to pancytopenia, a bone marrow biopsy was performed. Additionally, a liver biopsy was performed due to progressive deterioration of liver biochemistry results. The bone marrow biopsy revealed non-caseating granulomas and Langhans giant cells (Figure 1A, 1B), whereas the liver biopsy showed bridging fibrosis along with multiple, small, non-caseating granulomas and mild portal and lobular inflammation (Figure 2A, 2B).\n\nGiven the recent history of intravesical BCG therapy and the histological findings of liver and bone marrow biopsies, a diagnosis of BCGitis was made. The patient was started on isoniazid, rifampicin, and ethambutol, had a rapid resolution of symptoms, and was discharged from the hospital 4 days after treatment initiation.\n\nOne month after discharge, the patient had further deterioration of GGT and ALP serum levels (Table 1), so rifampicin was discontinued and moxifloxacin was initiated instead. Four weeks after treatment modification, the patient experienced an episode of loss of consciousness with gaze fixation that resolved spontaneously a few minutes later. A brain magnetic resonance imaging (MRI) was ordered, which revealed no pathology, and moxifloxacin was substituted for levofloxacin.\n\nDuring his next visits, the patient had a slow improvement of liver biochemistry and overall status, so levofloxacin was continued for 4 additional months and isoniazid and ethambutol was continued for 7 additional months (9 months in total). Three months after treatment completion, the patient was afebrile, in good overall status, with normal levels of serum AST, ALT, and ALP, and only mildly elevated GGT levels, with no progression of liver cirrhosis status as defined by MELD and CTP scores.\n\nDiscussion\n\nWe present the case of a patient with a history of BC treated with intravesical BCG who was concurrently diagnosed with disseminated BCGitis (with bone marrow and liver involvement).\n\nBCGitis is a well-known adverse effect of intravesical BCG infusions. Incorrect instillation of BCG with iatrogenic trauma or concurrent urinary infection, previous urinary interventions, and the presence of breaches in the bladder are the most common risk factors [11,16,17,26–29]. Since the attenuated Mycobacterium bovis is a live strain preserving a degree of virulence, instillation of BCG in a patient with immunosuppression also carries a risk of BCGitis [30–33]. In our case, the patient was diagnosed with liver cirrhosis, a condition in which reduction in the reticuloendothelial system cell mass (Kupffer cells and sinusoidal endothelial cells) and porto-systemic shunts lead to immune system dysfunction, making BCGitis a possible complication [34–37].\n\nBCGitis should be suspected in every patient having received intravesical BCG infusions, presenting with fever and/or organ involvement, with or without symptoms in the genitourinary tract. However, establishing the diagnosis can be quite challenging, needing, apart from the history of BCG exposure, exclusion of all other causes of fever, as well as clinical improvement after treatment initiation, since microbiological and/or histopathological documentation is rarely feasible. Nevertheless, in our patient, the clinical suspicion was supported by liver and bone marrow histology, which found noncaseating granulomas. Interestingly, unlike tuberculosis, infection with M. bovis leads to non-caseating granulomas [38,39]. Moreover, Quantiferon testing is not helpful, since interferon-gamma release assays use stimulating antigens that are present in M. tuberculosis and pathogenic M. bovis strains but absent in M. bovis BCG [40].\n\nInitial treatment for BCGitis consists of isoniazid, rifampicin, and ethambutol, alone or in combination with corticosteroids, for 6 months, and the infection usually resolves with no sequelae. Corticosteroid use is controversial and is usually reserved for severe cases of miliary involvement and respiratory failure. Treating a cirrhotic patient poses many challenges, since anti-tuberculosis treatment is accompanied with significant hepatotoxicity. Isoniazid is metabolized in the liver, leading to hepatotoxic metabolites in the form of acetyl hydrazine and hydrazine, which cause hepatocellular steatosis and necrosis [25,41,42], with an incidence of 0.6% when used as mono-therapy [25,43], although severe isoniazid-induced hepatotoxicity seems to be heavily under-reported [44]. Rifampicin usually causes transient transaminitis that is thought to be benign; however, it has also been associated with centrilobular parenchymal necrosis and elevation of conjugated bilirubin due to cholestasis [45,46], leading to a 4-fold higher incidence of hepatotoxicity when used in combination with isoniazid [47]. Interestingly, according to Park et al, this incidence increases to 17% when a liver disease coexists, irrespective of the presence or absence of cirrhosis [48]. In contrast, ethambutol is not associated with clinically important hepatotoxic effects [25,49].\n\nDue to these adverse effects, treating a patient with liver cirrhosis for BCGitis involves the risk of decompensation or even acute-on-chronic liver failure [25]. According to WHO guidelines, the number of hepatotoxic agents that can be used in a cirrhotic patient depends on the severity of liver disease [50]. Regarding anti-tuberculosis (TB) drugs, some authors propose the use of isoniazid and rifampicin for patients with Child-Pugh ≤7, isoniazid or rifampicin for Child-Pugh 8–10, and none of the hepatotoxic anti-TB drugs for patients with Child-Pugh ≥11 [51,52]. Since hepatotoxicity usually occurs during the first 2 months of treatment, close monitoring of transaminases’ levels is mandatory in that period [42,51,52].\n\nDue to the aforementioned problems, our patient was started on isoniazid, rifampicin, and ethambutol, according to guidelines. The patient had a deterioration of liver enzymes serum levels during his first follow-up visit, so rifampicin was changed to moxifloxacin.\n\nWith regards to fluoroquinolones (FQs), which are the most commonly used second-line agents, a large case-control safety study showed no significant association between moxifloxacin and levofloxacin exposure and hepatotoxicity risk, while Ho et al found that introduction of FQ in patients with hepatitis induced by first-line agents did not cause additional hepatotoxicity [53,54]. On the contrary, Paterson et al found increased risk of acute liver injury among older patients [55]. Given these results, FQs may be a reasonable option in patients with hepatitis after exposure to first-line anti-TB agents.\n\nEven though this regimen was considered to be safe for a cirrhotic patient, our patient developed seizures attributed to moxifloxacin treatment, which resolved after discontinuation of the medication. Although levofloxacin, ofloxacin, and moxifloxacin have the lowest potential of inducing central nervous system adverse events among the FQ available, case reports exist attributing episodes of seizures to moxifloxacin treatment [56–59]. Our patient’s regimen was once more changed and levofloxacin was initiated instead of moxifloxacin, without other significant toxicities.\n\nAlthough the usual treatment duration for BCGitis is 6 months, no treatment recommendations exist regarding immunocom-promised patients, since most data come from children with primary immunodeficiency syndromes for which regimens with various durations were used [60–62]. In a case report presented by Winger et al [63], a 16-year-old patient with systemic lupus erythematosus, diagnosed with intestinal M. bovis infection was treated for a total of 9 months, with symptoms resolution. We opted to use a commonly used 3-drug regimen for 6 months and prolonged isoniazid-ethambutol for 3 more months. The levofloxacin treatment was discontinued to diminish the risk of hepatotoxicity.\n\nDuring his last visit, 3 months after treatment completion (12 months after treatment initiation), the patient was stable, with no fever or deterioration of cirrhosis status.\n\nConclusions\n\nWe report a unique case of concurrent diagnosis of BCGitis and liver cirrhosis in a patient with previous intravesical BCG administration for BC and discuss the difficulties in diagnosing and treating such a patient for BCGitis.\n\nFigure 1. Bone marrow biopsy. (A) Langhans-type giant cell in a paratrabecular position (arrow) (HE ×400). (B) A collection of histiocytes forming a non-caseating granuloma in the center (arrow) (HE ×100).\n\nFigure 2. Liver biopsy. (A) Small histiocytic granuloma with a Langhans-type giant cell in a portal tract (arrow). Mild portal inflammation is also evident (HE ×200). (B) Small histiocytic granuloma with a Langhans-type giant cell located in the parenchyma (arrow) (HE ×400).\n\nTable 1. Laboratory results on admission and throughout the follow-up period. Time-points of follow-up as follows: “First follow-up” at one month after hospital discharge, “second follow-up” at one month after levofloxacin initiation and “end of follow-up” at 3 months after treatment completion.\n\n\tAdmission\tHospital exit\tFirst follow-up\tSecond follow-up\tEnd of follow-up\tNormal range\t\nHb (g/dl)\t13\t13\t14.2\t13\t14.3\t14–18\t\nWBC (neut/lymph/mono)\t3540 (62/27/0.3)\t2960 (55/30/0.4)\t3510 (72/19/8)\t3200 (56/31/12)\t5300 (51/40/6)\t4500–11000\t\nPLT (K/μL)\t119\t72\t94\t107\t165\t140–440\t\nINR\t1.13\t1.1\t1.4\t1.3\t1.02\t0.85–1.15\t\nAST (IU/ml)\t59\t35\t50\t46\t22\t11–38\t\nALT (IU/ml)\t31\t22\t30\t24\t17\t11–43\t\nGGT (IU/ml)\t258\t473\t810\t262\t75\t10–60\t\nALP (IU/ml)\t285\t401\t409\t124\t52\t25–129\t\nSodium (mEq/L)\t134\t131\t133\t140\t142\t137–150\t\nPotassium (mEq/L)\t3.9\t3.6\t4.2\t4\t4.4\t3.5–5.1\t\nUrea (mg/dl)\t48\t30\t36\t26\t37\t10–50\t\nCreatinine (mg/dl)\t0.82\t0.49\t0.79\t0.80\t0.98\t0.6–1.4\t\nCRP (IU/ml)\t25\t14\t18\t6\t2\t<5\t\nTotal bilirubin (mg/dl)\t0.96\t1.2\t0.9\t1.02\t0.4\t0.1–1.2\t\nDirect bilirubin (mg/dl)\t0.45\t0.63\t0.4\t0.6\t0.18\t0.1–0.3\t\nHgb – hemoglobin; Hct – hematocrit; PLT – platelets; INR – International Normalized Ratio; AST – aspartate aminotransferase; ALT – alanine aminotransferase; GGT – gamma glutamyl-transferase; ALP – alkaline phosphatase; CRP – C-reactive protein.\n\nStatement\n\nThe patient was hospitalized in the Internal Medicine Clinic of the Pathophysiology Department of Athens Medical School, in Laiko General Hospital, and was then followed up by the Hepatology and Infectious Outpatient Clinics of the same department.\n\nDeclaration of Figures’ Authenticity\n\nAll figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.\n==== Refs\nReferences:\n\n1. 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Qiao L Cui X Li Y Status epilepticus attributed to moxifloxacin in an adolescent patient with spina bifida occulta Eur J Clin Pharmacol 2011 67 1 103 4 20809082\n60. Bernatowska EA Wolska-Kusnierz B Pac M Disseminated bacillus Calmette-Guérin infection and immunodeficiency Emerg Infect Dis 2007 13 5 799 801 18044052\n61. Fekrvand S Yazdani R Olbrich P Primary immunodeficiency diseases and bacillus Calmette-Guérin (BCG)-vaccine-derived complications: A systematic review J Allergy Clin Immunol Pract 2020 8 4 1371 86 32006723\n62. Hassanzad M Valinejadi A Darougar S Disseminated bacille Calmette-Guérin infection at a glance: A mini review of the literature Adv Respir Med 2019 87 4 239 42 31476012\n63. Winger BA Foy E Sud SR Mycobacterium bovis enterocolitis in an immunocompromised host J Pediatr Gastroenterol Nutr 2016 63 1 e17 19 26020480\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000283:Administration, Intravesical; D001500:BCG Vaccine; D006801:Humans; D008103:Liver Cirrhosis; D009163:Mycobacterium bovis; D014376:Tuberculosis; D001749:Urinary Bladder Neoplasms",
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"pages": "e933006",
"pmc": null,
"pmid": "34654796",
"pubdate": "2021-10-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8248067;25220842;20670648;32285440;19400686;1824929;12404239;20808293;24679470;28168135;12522745;2231917;18044052;25724701;22891208;29668641;25398060;11254624;31476012;24048121;32278732;23351086;32099909;6693068;21296855;30984262;25941429;27370177;1066353;11549784;26773235;26020480;16813873;27516382;10476764;24914337;1538436;25135860;33079050;32006723;2744050;8631702;10575271;30997355;10633963;20809082;24352180;19969411;23856256;26095833;8411436;25987681;31711964;25755442;30473130;29168333;24224546;28396542;23372864",
"title": "Difficulties in Diagnosing and Treating Disseminated Bacillus Calmette-Guérin (BCG) Infection After Intravesical BCG Therapy in a Patient with Liver Cirrhosis: A Case Report.",
"title_normalized": "difficulties in diagnosing and treating disseminated bacillus calmette gu rin bcg infection after intravesical bcg therapy in a patient with liver cirrhosis a case report"
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"activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN"
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"abstract": "Background: This study aimed to measure the association of various H1-antihistamines (H1A) with Torsade de Pointes (TdP), and present a comprehensive overview of H1A-induced TdP cases reported to the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: All H1A-induced TdP cases (n = 406) were retrieved from the FAERS database using the preferred term 'Torsade de Pointes' of MedDRA version-22 from 1990 to 2019. Four data-mining algorithms were used for disproportionality analysis: Reporting Odds Ratio (ROR); Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Content (IC). H1A with >3 TdP cases were included. Results: A total of 12 signals (Astemizole, cetirizine, chlorpheniramine, clemastine, desloratadine, diphenhydramine, hydroxyzine, loratadine, meclizine, promethazine, terfenadine, and trimeprazine) were identified including six new signals (cetirizine, chlorpheniramine, clemastine, desloratadine, loratadine, and meclizine). The number of risk factors (p = 0.031) and concomitant QT-prolonging drugs (p = <0.001) were significantly lower among new signals vs old signals. Moreover, new signals were strongly associated with QT-prolongation, cardiac reactions, and electrolyte abnormalities as compared with old signals. Conclusions: Our study found the increased torsadogenic potential of new signals compared with previously known old signals, hence necessitating clinical studies to determine the actual torsadogenic potential of newly identified signals.",
"affiliations": "Department of Pharmacy, University of Peshawar , Peshawar, Khyber Pakhtunkhwa, Pakistan.;Department of Pharmacy, University of Peshawar , Peshawar, Khyber Pakhtunkhwa, Pakistan.;Department of Pharmacy, University of Peshawar , Peshawar, Khyber Pakhtunkhwa, Pakistan.;Department of Pharmacy, University of Peshawar , Peshawar, Khyber Pakhtunkhwa, Pakistan.",
"authors": "Ali|Zahid|Z|;Ismail|Mohammad|M|https://orcid.org/0000-0001-7227-3399;Khan|Fahadullah|F|https://orcid.org/0000-0003-3497-0278;Sajid|Hira|H|",
"chemical_list": "D006634:Histamine H1 Antagonists",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2021.1846717",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "20(1)",
"journal": "Expert opinion on drug safety",
"keywords": "FAERS; H1-antihistamines; Torsade de Pointes; disproportionality analysis; new signal; pharmacovigilance",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000465:Algorithms; D002648:Child; D002675:Child, Preschool; D057225:Data Mining; D016208:Databases, Factual; D005260:Female; D006634:Histamine H1 Antagonists; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D012307:Risk Factors; D016171:Torsades de Pointes; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "101-107",
"pmc": null,
"pmid": "33141610",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association of H1-antihistamines with torsade de pointes: a pharmacovigilance study of the food and drug administration adverse event reporting system.",
"title_normalized": "association of h1 antihistamines with torsade de pointes a pharmacovigilance study of the food and drug administration adverse event reporting system"
} | [
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"companynumb": "PK-JNJFOC-20201125084",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
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"abstract": "Background: Mucosal melanomas including melanomas of the urogenital tract represent a rare type of melanoma characterized by low mutational burden and poor prognosis. Immune checkpoint inhibition has so far only been assessed in a limited number of mucosal melanoma patients and, in contrast to response in cutaneous melanoma, was associated with disappointing response rates. The oncolytic viral immunotherapy Talimogene laherparepvec (T-VEC) has recently been approved for treatment of locally advanced or unresectable melanoma. T-VEC combines direct oncolytic effects with local and systemic immune-mediated anti-tumor response. Our rationale to use T-VEC in this case was an expected augmentation of immunogenicity by tumor lysis to overcome primary resistance of a mucosal melanoma to immune checkpoint blockade. Objective: To report the first case of an advanced mucosal melanoma of the urethra treated with intralesional application of Talimogene laherparepvec. Case Report: A 78-years old female patient was diagnosed with an advanced mucosal melanoma of the urethra with inguinal lymph node metastases and intravaginal mucosal metastases. Shortly after surgical resection of the tumor mass, intravaginal mucosal metastases, and new nodal metastases in proximity of the left iliac vessels were diagnosed. The patient was treated with the anti-PD1 antibody pembrolizumab and obtained a stable disease lasting for 30 weeks. However, upon checkpoint inhibition the patient developed a loco-regional progressive disease featuring bleeding intravaginal metastases, while nodal metastases remained stable. We stopped treatment with pembrolizumab and administered T-VEC directly into the intravaginal mucosal metastases. After five injections T-VEC yielded a partial response with clinical regression of the injected mucosal metastases. Disease remained stable for 16 weeks under biweekly T-VEC treatment. Thereafter the patient showed disease progression in nodal metastases. T-VEC was discontinued. Immunotherapy with pembrolizumab was restarted but failed to achieve a response. Finally, targeted therapy with imatinib was induced in presence of a druggable c-KIT mutation, leading to a considerable response of all tumor sites that is still ongoing. Conclusion: T-VEC represents an effective and well-tolerated treatment option for patients with loco-regionally advanced mucosal melanoma. In combination with immunotherapy, T-VEC bears the potential of synergistic effects to overcome the specific primary resistance of mucosal melanoma to immune checkpoint blockade.",
"affiliations": "Department of Dermatology and Allergy, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.;Department of Dermatology and Allergy, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.;Department of Dermatology and Allergy, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.;Department of Gynaecology, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.;Department of Radiology, Kantonsspital Graubünden, Chur, Switzerland.;Department of Pathology University Hospital Bonn, Rheinische-Friedrich-Wilhelms -Universität Bonn, Bonn, Germany.;Department of Dermatology and Allergy, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.;Department of Dermatology and Allergy, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.;Department of Dermatology and Allergy, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.",
"authors": "Fröhlich|Anne|A|;Hoffmann|Friederike|F|;Niebel|Dennis|D|;Egger|Eva|E|;Kukuk|Guido M|GM|;Toma|Marieta|M|;Sirokay|Judith|J|;Bieber|Thomas|T|;Landsberg|Jennifer|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.00611",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00611\nOncology\nCase Report\nTalimogene Laherparepvec in Advanced Mucosal Melanoma of the Urethra Upon Primary Resistance on Immune Checkpoint Inhibition: A Case Report\nFröhlich Anne 1* Hoffmann Friederike 1 Niebel Dennis 1 Egger Eva 2 Kukuk Guido M. 3 Toma Marieta 4 Sirokay Judith 1 Bieber Thomas 1 Landsberg Jennifer 1 1Department of Dermatology and Allergy, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany\n2Department of Gynaecology, Rheinische-Friedrich-Wilhelms-Universität Bonn, Bonn, Germany\n3Department of Radiology, Kantonsspital Graubünden, Chur, Switzerland\n4Department of Pathology University Hospital Bonn, Rheinische-Friedrich-Wilhelms -Universität Bonn, Bonn, Germany\nEdited by: Kalijn Fredrike Bol, Herlev Hospital, Denmark\n\nReviewed by: Ioana Cosgarea, Newcastle University, United Kingdom; Ashley M. Holder, Houston Methodist Hospital, United States\n\n*Correspondence: Anne Fröhlich anne.froehlich@ukbonn.deThis article was submitted to Skin Cancer, a section of the journal Frontiers in Oncology\n\n\n08 5 2020 \n2020 \n10 61103 3 2020 03 4 2020 Copyright © 2020 Fröhlich, Hoffmann, Niebel, Egger, Kukuk, Toma, Sirokay, Bieber and Landsberg.2020Fröhlich, Hoffmann, Niebel, Egger, Kukuk, Toma, Sirokay, Bieber and LandsbergThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: Mucosal melanomas including melanomas of the urogenital tract represent a rare type of melanoma characterized by low mutational burden and poor prognosis. Immune checkpoint inhibition has so far only been assessed in a limited number of mucosal melanoma patients and, in contrast to response in cutaneous melanoma, was associated with disappointing response rates. The oncolytic viral immunotherapy Talimogene laherparepvec (T-VEC) has recently been approved for treatment of locally advanced or unresectable melanoma. T-VEC combines direct oncolytic effects with local and systemic immune-mediated anti-tumor response. Our rationale to use T-VEC in this case was an expected augmentation of immunogenicity by tumor lysis to overcome primary resistance of a mucosal melanoma to immune checkpoint blockade.\n\nObjective: To report the first case of an advanced mucosal melanoma of the urethra treated with intralesional application of Talimogene laherparepvec.\n\nCase Report: A 78-years old female patient was diagnosed with an advanced mucosal melanoma of the urethra with inguinal lymph node metastases and intravaginal mucosal metastases. Shortly after surgical resection of the tumor mass, intravaginal mucosal metastases, and new nodal metastases in proximity of the left iliac vessels were diagnosed. The patient was treated with the anti-PD1 antibody pembrolizumab and obtained a stable disease lasting for 30 weeks. However, upon checkpoint inhibition the patient developed a loco-regional progressive disease featuring bleeding intravaginal metastases, while nodal metastases remained stable. We stopped treatment with pembrolizumab and administered T-VEC directly into the intravaginal mucosal metastases. After five injections T-VEC yielded a partial response with clinical regression of the injected mucosal metastases. Disease remained stable for 16 weeks under biweekly T-VEC treatment. Thereafter the patient showed disease progression in nodal metastases. T-VEC was discontinued. Immunotherapy with pembrolizumab was restarted but failed to achieve a response. Finally, targeted therapy with imatinib was induced in presence of a druggable c-KIT mutation, leading to a considerable response of all tumor sites that is still ongoing.\n\nConclusion: T-VEC represents an effective and well-tolerated treatment option for patients with loco-regionally advanced mucosal melanoma. In combination with immunotherapy, T-VEC bears the potential of synergistic effects to overcome the specific primary resistance of mucosal melanoma to immune checkpoint blockade.\n\nimmune checkpoint blockadeintralesional treatmentmucosal melanomaprimary resistancetalimogene laherparepvecDeutsche Forschungsgemeinschaft10.13039/501100001659EXC 1023\n==== Body\nBackground\nMucosal melanomas including melanomas located in the urogenital tract represent a rare phenotype. Primary melanomas of the urethra make up <1% of all melanomas and 4% of urethral cancers (1). Melanomas of the urogenital tract form a group of aggressive malignancies and due to hidden anatomical localization the diagnosis is often delayed, leading to poor prognosis (2). The approval of the immune checkpoint inhibitors anti-CTLA4 and anti-PD1 as well as the targeted therapy against BRAF and MEK have remarkably improved overall survival for patients with cutaneous melanoma. Since mucosal melanoma is quite uncommon, the efficacy of these therapeutic options has only been assessed in a limited series of patients and data from clinical trials is scarce. Preliminary reports suggest lower response rates of mucosal melanoma to immunotherapy compared to cutaneous melanoma, the reasons being unclear. Mucosal melanoma is characterized by a higher number of chromosomal structural aberrations and a lower mutational burden than cutaneous melanoma (3). Accordingly, mutations in BRAF and NRAS are less prevalent in mucosal melanoma, targeted therapy is only available for a small subset of patients. Some mucosal melanoma harbor c-KIT mutations targetable by imatinib or nilotinib (4).\n\nTumor infiltrating lymphocytes can be detected less frequently in mucosal melanoma than in cutaneous melanoma (5). Therefore, it has been hypothesized that mucosal melanomas tend to be less immunogenic and are consequently often primarily resistant to immune checkpoint blockade.\n\nIn patients with locally advanced or unresectable cutaneous melanoma the oncolytic viral immunotherapy Talimogene laherparepvec (T-VEC) represents an additional therapeutic option. Approval was granted by FDA and EMA in 2016 for the local injection in cutaneous, subcutaneous and nodal metastases in unresectable stage IIIB-IVM1a melanoma patients. T-VEC is a genetically modified herpes simplex virus type 1 combining direct oncolytic effects with local and systemic, immune-mediated anti-tumor response (6, 7). The phase III trial (OPTiM) which led to approval of T-VEC demonstrated an overall response rate of 26,4 %, including 10.8% complete responses (8). Patients with mucosal melanoma were excluded from the trial. To our knowledge there is no published data about intralesional treatment of mucosal melanoma or mucosal metastases with T-VEC so far. Here we report the case of a patient with intravaginal metastases of a melanoma of the urethra responding to intralesional treatment with T-VEC.\n\nCase Report\nA 78-years old female patient was diagnosed with a mucosal melanoma of the urethra (patient characteristics: see Table 1).\n\nTable 1 Medical history, clinical, histological, and molecular characteristic of the patient.\n\nHistory of primary diagnosis and medical history\t\t\nGender, age\tFemale, 78 years\t\nStaging of primary and lymph node status\tMucosal melanoma of the urethra; Tumor thickness 10 mm (Breslow); Ulceration UN; LN (4/8 ece-); pT4, N3c, M1a, stage IV (AJCC 2017);\t\nMutational profile\tBRAF wt\n\nNRAS wt\n\nKIT mutation exon 11, c.1672_1674dup\n p.K558dup\t\nAdjuvant therapy\tNone\t\nMedical history\tHysterectomy due to myomas\n Arterial hypertonia\n Hypercholesterolemia\t\nFamily history\tNegative family history of melanoma\t\nPsychosocial history\tWidowed, 2 children and grandchildren\t\nUN, unknown; LN, lymph node status; ece, extracapsular lymph node extension; wt, wild type.\n\nAt the time of primary diagnosis, inguinal lymph node metastases were detected. A complete resection of the urethra and a radical dissection of the left inguinal lymph nodes was performed concomitantly in our surgical department. Only 1 month after the intervention intravaginal mucosal metastases were diagnosed and histologically confirmed (Figure 1). Computed tomography (CT) scans showed nodal metastases in proximity of the left iliac vessels with no option to obtain a complete resection of the tumor masses. Molecular analyses of the tumor showed wild types in the BRAF- and NRAS gene and a p.K558dup mutation of c-KIT on exon 11. In view of the locally advanced, inoperable melanoma a systemic therapy with the PD-1 inhibitor pembrolizumab was induced and temporary obtained stable disease. After administration of 10 cycles of pembrolizumab the patient started to suffer from recurrent vaginal bleeding, which significantly restricted the patient's quality of life. Clinical examinations revealed ulcerated pigmented intravaginal metastases. Imaging confirmed loco-regional progress without distant metastases (Figure 2). Hence, 4 weeks after the last dose anti-PD1 antibody and in agreement with our patient, we initiated treatment with the oncolytic virus T-VEC (first administration 106 PFU/ml, followed by 108 PFU/ml at week 3 and followed Q2W, 1–3 mL). In cooperation with our department of gynecology T-VEC was injected directly into the intravaginal mucosal metastases. The injections provoked moderate local bleeding of the mucosa, and the patient suffered from flu-like symptoms a few hours after injections. The patient did not show any signs of a herpes infection at any time. Our patient reported that the T-VEC applications were tolerable and that the side effects did not restrict her daily life. Laboratory investigations did not reveal any significant pathologic findings. After the first injections, metastases slightly seemed to increase in size, but vaginal bleeding remarkably ameliorated. After five injections T-VEC yielded a partial response with substantial regression of the injected mucosal metastases and cessation of intravaginal bleedings (Figure 2). Overall nine cycles of T-VEC were administered. The uninjected iliac lymph node metastases did not respond to oncolytic virus therapy. CT scans revealed a progression of the left inguinal nodal metastases and development of retroperitoneal nodal metastases after 16 weeks upon T-VEC. Consequently, T-VEC was discontinued and immunotherapy with pembrolizumab (2 mg/kg Q3W) was restarted. After three cycles pembrolizumab, para-aortic and mesenteric nodal metastases were diagnosed and there was a progression of the iliac and inguinal nodal metastases. The intravaginal metastases remained stable. A combined immunotherapy with PD-1- and CTLA-4-inhibition was refused by the patient due to higher risk of treatment related toxicities. With regards to the druggable c-KIT mutation (p.K558dup in Exon 11) we started treatment with the tyrosine kinase inhibitor imatinib (400 mg once a day). Treatment with imatinib achieved a considerable regression of all metastatic tumor sites with a still ongoing response (summary of the sequential therapies: see Figure 3).\n\nFigure 1 Representative histopathologic images of the ulcerated primary pigmented mucosal melanoma of the Urethra. (A) Overview image of the histopathologic sample, H&E stained in 2,5-fold magnification. (B) Detailed view, H&E stained in 10-fold magnification.\n\nFigure 2 Clinical and MR image of intravaginal mucosal metastasis of a malignant melanoma of the urethra. A/B: Visual appraisal with speculum. (A) Target lesion before injection of T-VEC. Baseline image shows a pigmented ulcerated mucosal tumor (arrow). (B) Target lesion after seven injections of T-VEC: partial response with substantial regression of the injected mucosal metastasis (arrow) and cessation of intravaginal bleeding. C/D MR image. (C) Transverse T2-weighted fat suppressed MR image shows labial metastasis (arrow) before injection of T-VEC. (D) Transverse T2-weighted fat suppressed MR image 2 months upon T-VEC therapy shows complete disappearance of labial metastasis (arrow indicating the original location).\n\nFigure 3 Summary of the sequential treatment in our case of advanced mucosal melanoma.\n\nDiscussion\nHere, we present the case of a 78-years old female patient with a primary pigmented melanoma of the distal urethra. Melanoma of the urinary tract are extremely rare. The distal urethra is the most common site of occurrence of melanoma in the urinary tract. It is more common in females and elderly patients (9). In contrast to increasing incidence of cutaneous melanoma, the incidence of mucosal melanoma has remained fairly stable (10) which reflects the distinct UV-independent biology of mucosal melanoma. Due to the rarity of mucosal melanoma and its anatomic location diagnosis is often delayed and patients commonly present with advanced disease. Therefore, patients with mucosal melanoma generally have a worse prognosis than patients with cutaneous melanoma with the lowest 5-years survival (11%) for women with urogenital-tract melanoma (2, 10). First-line therapeutic strategy in primary mucosal melanoma is surgery, which is recommended to be performed early and in an aggressive manner. However, primary surgery ranges from conservative surgery with wide local excision to radical surgery with urethrocystectomy and total exenteration. It has been stated that survival after radical surgery does not differ from survival after conservative surgery (2). Therefore, in our patient no urethrocystectomy or total exenteration was performed.\n\nFor unresectable or metastatic melanoma, immune checkpoint blockade with anti-CTLA4 and anti-PD1 and targeted therapy against BRAF and MEK improved the overall survival for cutaneous melanoma. The efficacy of anti-CTLA-4 and anti-PD1 antibodies has not been specifically evaluated in larger cohorts of patients with mucosal melanoma. Yet, response rates seem to be lower than in cutaneous melanoma. A recent pooled analysis evaluated PD-1 blockade alone (86 patients) or in combination with ipilimumab (35 patients) in mucosal melanoma patients (11). Response rate for anti-PD1 monotherapy was 23.3% with a progression-free survival (PFS) of 3.0 months. For combination of nivolumab with ipilimumab response rate was 37.1% with a PFS of 5.9 months. This identifies patients who suffer from metastatic mucosal melanoma as high medical need subgroup as corresponding response rates in cutaneous melanoma were 40.9% for monotherapy and 60.4% for the combined immunotherapy with a PFS of 6.2 months in monotherapy and 11.7 months in patients treated with combined immunotherapy. Another recent retrospective study including 35 patients with mucosal melanoma produced comparable PFS of 3.9 months and a median overall survival of 12.4 months (12). The lower response rate of mucosal melanoma in comparison to cutaneous melanoma might be explained by the different genomic landscape of mucosal melanoma. Whole genome sequencing data from mucosal melanoma demonstrated a low single nucleotide mutation burden without any evidence of UV signature, but numerous large-scale copy number changes and whole chromosome gains and losses (3). A high somatic tumor mutational burden is associated with improved survival in patients receiving immune checkpoint blockade across a wide variety of cancer, including melanoma (13). Beyond, density of tumor infiltrating lymphocytes is decreased in mucosal compared to cutaneous melanoma (5), supporting the hypothesis that mucosal melanoma are less immunogenic and consequently frequently primarily resistant to immune checkpoint blockade. Our patient initially obtained a stable disease which lasted for 30 weeks. However, upon anti-PD1 therapy our patient developed a loco-regional resistance with disease progression.\n\nThe disappointing results of immune checkpoint blockade in mucosal melanoma demonstrate the need for alternative or additional treatment strategies preferentially enhancing immunogenicity of mucosal melanoma. In vulvovaginal mucosal melanoma radiotherapy has been approved to be appropriate in the (neo-)adjuvant setting (14). Beyond, combined radiotherapy and checkpoint inhibition bear the potential to create a synergistic anti-tumor response. We found one retrospective case series investigating on the so called abscopal effect in mucosal melanoma of the lower genital tract including four patients treated with combined ipilimumab and radiotherapy. In three of the four patients this therapy was followed by surgery. The study showed favorable responses suggesting further trials to follow up on this observation (15).\n\nThe vaginal mucosa constitutes a tissue with distinct inflammatory and tolerogenic properties, which are tailored to the physiologic functions as barrier tissue on the one hand and tolerance to fetal antigens in pregnancy on the other hand (16). In an experimental model, vaginal antigen exposure was followed by mucosa induced tolerance (17). However, these specific tolerogenic qualities have not been demonstrated to render the vaginal mucosa more susceptible to malignancies. The latter phenomenon has been suggested in organs with limited regenerative capacity such as the eye or the brain, a mechanism for reducing the risk of immune-mediated inflammation, also referred to as “immune privilege” (18). A recent study showed that vaginal type-II mucosa itself is an inductive site for primary CD8+ memory T-cells (19). In a mouse model the authors demonstrated vaginal antigen-specific CD8+ T-cell immune responses in the absence of lymph node involvement. The ability of vaginal mucosa to induce local immunity supports the rational for a local immunotherapy like T-VEC. During treatment with T-VEC our patient initially showed an increase of size of the intravaginal, mucosal metastases. We interpreted the initial growth of the metastases as a pseudoprogression, caused by reactive infiltration of immune cells. Median time to response among the 78 responding patients in the OPTiM approval trial was 4.1 months (range, 1.2 to 16.7 months) in the T-VEC arm. In more than half of the responding patients a pseudoprogression with appearance of new lesions or 25% initial increase of metastatic lesions was observed before response to T-VEC was achieved (8). The phenomenon of pseudoprogression has also been described in immunotherapies including anti-PD-1 antibodies and the CTLA-4 inhibitor Ipilimumab and remains a challenging task for radiologic work up and treatment evaluation (20, 21).\n\nSeveral recent clinical studies have focused on treatment with T-VEC alone and in combination with other systemic treatments, specifically immunotherapy. These trials excluded patients with mucosal melanoma (8, 22–25). The published data support the idea that combining checkpoint inhibitors with oncolytic therapy may provide a synergistic efficacy by priming the tumor microenvironment (23). In our case the sequentially initiated therapies with anti-PD1 antibodies, T-VEC and re-induction of anti-PD1 antibodies occurred consecutively. Our patient did not respond to anti-PD1 therapy after T-VEC therapy systemically but showed stable mucosal melanoma metastases. It can be assumed that treatment with T-VEC might help to overcome locally acquired resistance, which is in line with the approval of the oncolytic therapy.\n\nTargeted therapy is only suitable for a small subset of patients with mucosal melanoma, as BRAF or NRAS mutations are less common than in cutaneous melanoma. Nevertheless, 14% to 39% of mucosal melanomas harbor mutations of the KIT gene, which are only rarely observed in cutaneous melanomas (26, 27). In our patient the KIT mutation p.K558dup in Exon 11 was detected via molecular pathologic analysis. This mutation is targetable by imatinib, a tyrosine kinase inhibitor which has shown efficacy in melanoma harboring KIT gene mutations in exon 11 and 13. Our patient showed a good response to imatinib after intensive pretreatment with anti-PD1 and T-VEC therapy. Successful treatment with imatinib after resistance to immunotherapy has recently been shown in a patient suffering from vaginal melanoma with KIT p.Val559Gly mutation (4). We are aware of the limitation of this work being a single case report, which does not allow to draw general conclusions. To what extent T-VEC or targeted therapy can induce an immune response that may help to overcome primary resistance to immune checkpoint blockade should therefore be investigated in clinical trials for the rare subtype of mucosal melanoma. Recruiting a sufficient number of individuals suffering from mucosal melanoma for a clinical trial is presumed to be time-consuming. This emphasizes the great necessity of publication of case-series and case reports about this rare tumor type.\n\nTaken together, treatment of locally advanced metastatic mucosal melanoma with T-VEC represents a therapeutic option, which should be addressed in interventional trials. Furthermore, our case underlines the rationale for the combination of T-VEC with systemic immunotherapies.\n\nEthics Statement\nWe obtained written informed consent from the patient presented in our case report in accordance with the Helsinki Declaration of 1975. The patient consented to the treatment and the use of her data, including photos, for research, and publication.\n\nAuthor Contributions\nAF and JL were involved in the study design and concept. FH, DN, EE, GK, MT, and JS were involved in data acquisition. TB revised the manuscript for critical intellectual content. All authors read and approved the final manuscript and were involved in the review and editing of the manuscript.\n\nConflict of Interest\nAF has received speaker's honoraria or travel expsense reimbursements from the following companies: Novartis, BMS, Almirall, and Eli Lilly Pharma. DN has received speakers' honoraria or travel expense reimbursements from the following companies: BMS, Novartis, GSK, Celgene and MSD. JS received speaker's honoraria from Novartis, BMS, MSD, and Roche. MT has received speaker's honoraria or travel expense reimbursements from the following companies: Ipsen, Roche, Astra Zeneca. JL was a consultant/advisory board member of Bristol-Myers Squibb, Merck, Novartis, and Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe abstract of this manuscript was previously published as an ePoster at the congress 29. Deutscher Hautkrebskongress (Arbeitsgemeinschaft Dermatologische Onkologie, ADO). The case report was presented as a talk at the 22nd meeting of the DWFA (Dermatologische Wissenschafts- und Fortbildungsakademie) and the abstract was published in the corresponding, DWFA internal conference paper “Fälle, Fakten, Pharmaka.” The first author AF holds the copyright. We thank the BioBank Bonn of the Bonn University Medical Faculty and the University Hospital Bonn for the support of this case report.\n\nFunding. AF was funded by the Deutsche Krebshilfe through a Mildred Scheel Nachwuchszentrum Grant (Grant number 70113307) Köln/Bonn. JS was funded by the Deutsche Dermatologische Gesellschaft (DDG). DN was funded in part by DFG Cluster of Excellence ImmunoSensation (EXC 1023).\n==== Refs\nReferences\n1. Robutti F Betta PG Bellingeri M Bellingeri D . Primary malignant melanoma of the female urethral meatus\n. Eur Urol. (1986 ) 12 :62 –3\n. 10.1159/000472579 3512273 \n2. Piura B . Management of primary melanoma of the female urogenital tract\n. Lancet Oncol. (2008 ) 9 :973 –81\n. 10.1016/S1470-2045(08)70254-7 19071254 \n3. Hayward NK Wilmott JS Waddell N Johansson PA Field MA Nones K . Whole-genome landscapes of major melanoma subtypes\n. Nature . (2017 ) 545 :175 –80\n. 10.1038/nature22071 28467829 \n4. Komatsu-Fujii T Nomura M Otsuka A Ishida Y Doi K Matsumoto S . Response to imatinib in vaginal melanoma with KIT p.Val559Gly mutation previously treated with nivolumab, pembrolizumab and ipilimumab\n. J Dermatol. (2019 ) 46 :e203 –4\n. 10.1111/1346-8138.14763 30614559 \n5. Kaunitz GJ Cottrell TR Lilo M Muthappan V Esandrio J Berry S . Melanoma subtypes demonstrate distinct PD-L1 expression profiles\n. Lab Investig J Tech Methods Pathol. (2017 ) 97 :1063 –71\n. 10.1038/labinvest.2017.64 28737763 \n6. Hu JCC Coffin RS Davis CJ Graham NJ Groves N Guest PJ . A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor\n. Clin Cancer Res Off J Am Assoc Cancer Res. (2006 ) 12 :6737 –47\n. 10.1158/1078-0432.CCR-06-0759 17121894 \n7. Fountzilas C Patel S Mahalingam D . Review: oncolytic virotherapy, updates and future directions\n. Oncotarget. (2017 ) 8 :102617 –39\n. 10.18632/oncotarget.18309 29254276 \n8. Andtbacka RHI Kaufman HL Collichio F Amatruda T Senzer N Chesney J . Talimogene laherparepvec improves durable response rate in patients with advanced melanoma\n. J Clin Oncol Off J Am Soc Clin Oncol. (2015 ) 33 :2780 –8\n. 10.1200/JCO.2014.58.3377 26014293 \n9. DiMarco DS DiMarco CS Zincke H Webb MJ Keeney GL Bass S . Outcome of surgical treatment for primary malignant melanoma of the female urethra\n. J Urol. (2004 ) 171 :765 –7\n. 10.1097/01.ju.0000104671.20863.47 14713806 \n10. Chang AE Karnell LH Menck HR . The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society\n. Cancer. (1998 ) 83 :1664 –78\n. 10.1002/(SICI)1097-0142(19981015)83:8<1664::AID-CNCR23>3.0.CO;2-G 9781962 \n11. D'Angelo SP Larkin J Sosman JA Lebbé C Brady B Neyns B . Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis\n. J Clin Oncol Off J Am Soc Clin Oncol. (2017 ) 35 :226 –35\n. 10.1200/JCO.2016.67.9258 28056206 \n12. Shoushtari AN Munhoz RR Kuk D Ott PA Johnson DB Tsai KK . The efficacy of anti-PD-1 agents in acral and mucosal melanoma\n. Cancer. (2016 ) 122 :3354 –62\n. 10.1002/cncr.30259 27533633 \n13. Samstein RM Lee C-H Shoushtari AN Hellmann MD Shen R Janjigian YY . Tumor mutational load predicts survival after immunotherapy across multiple cancer types\n. Nat Genet. (2019 ) 51 :202 –6\n. 10.1038/s41588-018-0312-8 30643254 \n14. Leitao MM Cheng X Hamilton AL Siddiqui NA Jurgenliemk-Schulz I Mahner S . Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas\n. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. (2014 ) 24 :S117 –22\n. 10.1097/IGC.0000000000000198 24987924 \n15. Schiavone MB Broach V Shoushtari AN Carvajal RD Alektiar K Kollmeier MA . Combined immunotherapy and radiation for treatment of mucosal melanomas of the lower genital tract\n. Gynecol Oncol Rep. (2016 ) 16 :42 –6\n. 10.1016/j.gore.2016.04.001 27331137 \n16. Zhou JZ Way SS Chen K . Immunology of the uterine and vaginal mucosae\n. Trends Immunol. (2018 ) 39 :302 –14\n. 10.1016/j.it.2018.01.007 29433961 \n17. Black CA Rohan LC Cost M Watkins SC Draviam R Alber S . Vaginal mucosa serves as an inductive site for tolerance\n. J Immunol Baltim Md. (2000 ) 165 :5077 –83\n. 10.4049/jimmunol.165.9.5077 11046038 \n18. Niederkorn JY . Ocular Immune Privilege and Ocular Melanoma: Parallel Universes or Immunological Plagiarism? Front Immunol (2012 ). Available online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3@@374415/ (accessed November 1, 2019). \n19. Wang Y Sui Y Kato S Hogg AE Steel JC Morris JC . Vaginal type-II mucosa is an inductive site for primary CD8+ T-cell mucosal immunity\n. Nat Commun. (2015 ) 6 :6100 . 10.1038/ncomms7100 25600442 \n20. 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\n. Clin Cancer Res. (2009 ) 15 :7412 –20\n. 10.1158/1078-0432.CCR-09-1624 19934295 \n21. 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\n. Clin Cancer Res Off J Am Assoc Cancer Res. (2017 ) 23 :4671 –9\n. 10.1158/1078-0432.CCR-17-0114 28592629 \n22. Chesney J Puzanov I Collichio F Singh P Milhem MM Glaspy J . Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma\n. J Clin Oncol Off J Am Soc Clin Oncol. (2017 ) 36 :1658 –67\n. 10.1200/JCO.2017.73.7379 28981385 \n23. Ribas A Dummer R Puzanov I VanderWalde A Andtbacka RHI Michielin O . Oncolytic virotherapy promotes intratumoral t cell infiltration and improves anti-PD-1 immunotherapy\n. Cell. (2017 ) 170 :1109 –19.e10\n. 10.1016/j.cell.2017.08.027 28886381 \n24. Blackmon JT Dhawan R Viator TM Terry NL Conry RM . Talimogene laherparepvec for regionally advanced merkel cell carcinoma: a report of 2 cases\n. JAAD Case Rep. (2017 ) 3 :185 –9\n. 10.1016/j.jdcr.2017.02.003 28443305 \n25. Sun L Funchain P Song JM Rayman P Tannenbaum C Ko J . Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series\n. J Immunother Cancer. (2018 ) 6 :36 . 10.1186/s40425-018-0337-7 29764498 \n26. Curtin JA Busam K Pinkel D Bastian BC . Somatic activation of KIT in distinct subtypes of melanoma\n. J Clin Oncol Off J Am Soc Clin Oncol. (2006 ) 24 :4340 –6\n. 10.1200/JCO.2006.06.2984 16908931 \n27. Tacastacas JD Bray J Cohen YK Arbesman J Kim J Koon HB . Update on primary mucosal melanoma\n. J Am Acad Dermatol. (2014 ) 71 :366 –75\n. 10.1016/j.jaad.2014.03.031 24815565\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "immune checkpoint blockade; intralesional treatment; mucosal melanoma; primary resistance; talimogene laherparepvec",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "611",
"pmc": null,
"pmid": "32457834",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26014293;24815565;28443305;29254276;27533633;28056206;28592629;17121894;29764498;16908931;19071254;28981385;27331137;28737763;19934295;25600442;14713806;9781962;22707951;30614559;28886381;29433961;3512273;24987924;28467829;11046038;30643254",
"title": "Talimogene Laherparepvec in Advanced Mucosal Melanoma of the Urethra Upon Primary Resistance on Immune Checkpoint Inhibition: A Case Report.",
"title_normalized": "talimogene laherparepvec in advanced mucosal melanoma of the urethra upon primary resistance on immune checkpoint inhibition a case report"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2019153140",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TALIMOGENE LAHERPAREPVEC"
},
"drugadditional":... |
{
"abstract": "The narrow therapeutic window of polymyxin B constrains its clinical use against the multidrug-resistant organisms (MDRO). A 45-year-old patient was suffering with bloodstream infection with high fever and received a combined treatment with polymyxin B and tigecycline. Therapeutic drug monitoring (TDM) was applied to polymyxin B to develop a personalized medication against MDRO. The dose adjustment of polymyxin B with TDM successfully alleviated the infection and reduced the incident of acute kidney injury as caused in case of the original doses of polymyxin B. TDM of polymyxin B represents a valid treatment to ensure the efficiency and safety.",
"affiliations": "Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.;Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.;Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.;Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, China.;Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.;Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.;Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. zch760217@163.com.",
"authors": "Yu|Xuben|X|;Pan|Jingye|J|;Zhou|Ziye|Z|;Wen|Xin|X|;Dai|Ying|Y|;Lin|Guanyang|G|;Jiao|Zheng|Z|;Zhang|Chunhong|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015780:Carbapenems; D011112:Polymyxin B",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-020-03945-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-9723",
"issue": "40(1)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": "Acute kidney injury; Bloodstream infection; Carbapenem-resistant Klebsiella pneumoniae; Polymyxin B",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D015780:Carbapenems; D003937:Diagnosis, Differential; D004334:Drug Administration Schedule; D024881:Drug Resistance, Bacterial; D005334:Fever; D006801:Humans; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D008875:Middle Aged; D011112:Polymyxin B",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "201-204",
"pmc": null,
"pmid": "32661810",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28011614",
"title": "TDM-guided medication of polymyxin B in a patient with CRKP-induced bloodstream infection: a case report.",
"title_normalized": "tdm guided medication of polymyxin b in a patient with crkp induced bloodstream infection a case report"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK202102442",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "POLYMYXIN B"
},
"drugadditional": "1",
... |
{
"abstract": "The authors present a case of a patient with multiple episodes of perioperative anaphylaxis. The incidence and the most common causes of perioperative anaphylaxis are reviewed. The most common causes can vary by country and the type of perioperative medications used. The unique environment and the multiple medications and substances used in the anesthesia and surgical setting that make a definitive diagnosis challenging are outlined. A systematic strategy to recognize the reaction, identify the culprit, and direct future management are demonstrated. Management of the patient experiencing perioperative anaphylaxis requires close collaboration between the anesthesia, surgical, and allergy teams.",
"affiliations": "Division of Allergic Diseases, Department of Medicine, Mayo Medical School, Mayo Clinic, Rochester, Minn. Electronic address: Volcheck.gerald@mayo.edu.;Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.",
"authors": "Volcheck|Gerald W|GW|;Hepner|David L|DL|",
"chemical_list": "D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D001993:Bronchodilator Agents; D003102:Colloids; D004396:Coloring Agents; D005938:Glucocorticoids; D006993:Hypnotics and Sedatives; D009466:Neuromuscular Blocking Agents; D013566:Sympathomimetics; D001414:Bacitracin; D000077122:Sugammadex; D007073:Immunoglobulin E; D011206:Povidone-Iodine; D053802:Tryptases; D002710:Chlorhexidine; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2019.05.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "7(7)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Anaphylaxis; Anesthesia; Hypersensitivity reactions; Intraoperative; Perioperative period",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000368:Aged; D058109:Airway Management; D000701:Analgesics, Opioid; D000707:Anaphylaxis; D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D019072:Antibiotic Prophylaxis; D001414:Bacitracin; D001993:Bronchodilator Agents; D002710:Chlorhexidine; D003102:Colloids; D004396:Coloring Agents; D004342:Drug Hypersensitivity; D004837:Epinephrine; D005440:Fluid Therapy; D005938:Glucocorticoids; D006801:Humans; D006993:Hypnotics and Sedatives; D007073:Immunoglobulin E; D007428:Intradermal Tests; D020315:Latex Hypersensitivity; D008297:Male; D009466:Neuromuscular Blocking Agents; D010102:Oxygen Inhalation Therapy; D059035:Perioperative Period; D011206:Povidone-Iodine; D012008:Recurrence; D012882:Skin Tests; D000077122:Sugammadex; D013566:Sympathomimetics; D065227:Transfusion Reaction; D053802:Tryptases",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "2134-2142",
"pmc": null,
"pmid": "31154032",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Identification and Management of Perioperative Anaphylaxis.",
"title_normalized": "identification and management of perioperative anaphylaxis"
} | [
{
"companynumb": "US-BECTON DICKINSON-2019BDN00354",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CHLORHEXIDINE"
},
"drugadditional": nu... |
{
"abstract": "Carvedilol is a non-selective beta-adrenoreceptor antagonist that is also an antagonist at the alpha(1)-adrenoreceptor. This unique pharmacological effect may produce a different toxicodynamic profile compared to other beta-adrenoreceptor antagonists. Only one previous case of carvedilol overdose has been reported. Here, we report massive carvedilol ingestion confirmed by quantitative analysis. The case report deals with an 84-year-old man who chewed a total of 60 (6.25 mg) tablets and rapidly developed symptoms. Vital signs on presentation were systolic blood pressure 70 mmHg; heart rate 45 beats/min.; respirations 18 breaths/min.; temperature 37 degrees . The electrocardiogram showed a junctional rhythm at 49 beats/min. The patient was treated with normal saline boluses, repeated glucagon boluses (2-3 mg each) and a dopamine infusion. At 14 hr after ingestion, he was weaned off vasopressors and was in a normal sinus rhythm. Quantitative confirmation showed a carvedilol serum concentration of 472 ng/ml (steady-state concentration 8.5 ng/ml during 6.25 mg twice daily dosing). Despite its unique pharmacological properties, the clinical manifestations of carvedilol overdose appear similar to other beta-adrenoreceptor antagonists.",
"affiliations": "New York City Poison Control Center; and Columbia University Medical Center/New York-Presbyterian Hospital, New York, NY, USA. nb2233@columbia.edu",
"authors": "Bouchard|Nicole C|NC|;Forde|Jenice|J|;Hoffman|Robert S|RS|",
"chemical_list": "D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D005934:Glucagon; D004298:Dopamine",
"country": "England",
"delete": false,
"doi": "10.1111/j.1742-7843.2008.00269.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-7835",
"issue": "103(1)",
"journal": "Basic & clinical pharmacology & toxicology",
"keywords": null,
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": "D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000369:Aged, 80 and over; D002227:Carbazoles; D000077261:Carvedilol; D004298:Dopamine; D062787:Drug Overdose; D005934:Glucagon; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011412:Propanolamines",
"nlm_unique_id": "101208422",
"other_id": null,
"pages": "102-3",
"pmc": null,
"pmid": "18598302",
"pubdate": "2008-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Carvedilol overdose with quantitative confirmation.",
"title_normalized": "carvedilol overdose with quantitative confirmation"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2021-040107",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drugadditional": "4",
... |
{
"abstract": "Cryosurgery using liquid nitrogen is a method for treating benign- and low-malignant skeletal tumors. The advantage of preserving the supportive function of bone should be compared to the risk for its complications; postoperative fracture is well known, but less so the occurrence of intraoperative venous gas embolism. This paper describes 17 patients: 2 patients who had serious hemodynamic complications during cryosurgery and a study of 15 patients in whom end-tidal N2 tension was measured in an attempt to investigate the clinical incidence of venous gas embolism during cryosurgery. In the 15 cases analyzed, we did not detect any exhaled N2 during cryosurgery.",
"affiliations": "Department of Orthopaedics, University Hospital of St. Radboud, University of Nijmegen, The Netherlands.",
"authors": "Schreuder|H W|HW|;van Beem|H B|HB|;Veth|R P|RP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jso.2930600311",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-4790",
"issue": "60(3)",
"journal": "Journal of surgical oncology",
"keywords": null,
"medline_ta": "J Surg Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D017824:Bone Cysts, Aneurysmal; D001859:Bone Neoplasms; D002648:Child; D002675:Child, Preschool; D002813:Chondrosarcoma; D003452:Cryosurgery; D004618:Embolism, Air; D005260:Female; D005266:Femoral Neoplasms; D006439:Hemodynamics; D006801:Humans; D006811:Humerus; D015994:Incidence; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D014680:Veins",
"nlm_unique_id": "0222643",
"other_id": null,
"pages": "196-200",
"pmc": null,
"pmid": "7475071",
"pubdate": "1995-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Venous gas embolism during cryosurgery for bone tumors.",
"title_normalized": "venous gas embolism during cryosurgery for bone tumors"
} | [
{
"companynumb": "NL-ALSI-201700316",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VECURONIUM BROMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The prognosis of hematologic malignancies has improved over the past three decades. However, the prognosis in hematologic malignancies with severe acute respiratory distress syndrome has remained poor. Initial reports regarding the utility of extracorporeal membrane oxygenation in hematologic malignancies have been controversial, with limited evaluations of acute leukemia patients supported by extracorporeal membrane oxygenation.\nWe conducted a retrospective review of patients with acute leukemia who developed acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation support at our facility from July 2015 through August 2017.\nFour cases of acute myelogenous leukemia with respiratory failure and acute respiratory distress syndrome treated with veno-venous extracorporeal membrane oxygenation while undergoing induction chemotherapy were identified. All patients completed induction therapy with addition of extracorporeal membrane oxygenation support, with two patients dying secondary to their acute leukemia and the other two surviving to allogeneic hematopoietic stem cell transplant. Overall, 75% (three of four) survived to decannulation with a 1-year survival rate following extracorporeal membrane oxygenation of 50% (two of four).\nCurrently, the use of extracorporeal membrane oxygenation in patients with hematologic malignancies who develop severe acute respiratory distress syndrome remains controversial. Although extracorporeal membrane oxygenation in post-allogeneic hematopoietic stem cell transplant is associated with poorer outcomes, our data suggest that salvage extracorporeal membrane oxygenation support is a viable option to manage moderate to severe acute respiratory distress syndrome while completing therapeutic chemotherapy and following in the peri-induction phase of acute leukemia.",
"affiliations": "1 Pulmonary/Critical Care Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.;2 Hematology/Oncology Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.;1 Pulmonary/Critical Care Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.;3 Trauma/Critical Care Surgery Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.;3 Trauma/Critical Care Surgery Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.;1 Pulmonary/Critical Care Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.;2 Hematology/Oncology Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.;3 Trauma/Critical Care Surgery Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.;3 Trauma/Critical Care Surgery Service, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX, USA.",
"authors": "Huprikar|Nikhil A|NA|;Peterson|Matthew R|MR|;DellaVolpe|Jeffrey D|JD|;Sams|Valerie G|VG|;Lantry|James H|JH|;Walter|Robert J|RJ|;Osswald|Michael B|MB|;Chung|Kevin K|KK|;Mason|Phillip E|PE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0391398818799160",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-3988",
"issue": "42(1)",
"journal": "The International journal of artificial organs",
"keywords": "Acute respiratory distress syndrome; acute myelogenous leukemia; extracorporeal membrane oxygenation; leukemia",
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D000328:Adult; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012128:Respiratory Distress Syndrome; D012189:Retrospective Studies; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "49-54",
"pmc": null,
"pmid": "30223700",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Salvage extracorporeal membrane oxygenation in induction-associated acute respiratory distress syndrome in acute leukemia patients: A case series.",
"title_normalized": "salvage extracorporeal membrane oxygenation in induction associated acute respiratory distress syndrome in acute leukemia patients a case series"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201905503",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IDARUBICIN HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "A case of disseminated nocardiosis caused by Nocardia elegans in a 72-year-old man with rheumatoid arthritis, treated with tacrolimus and prednisolone, is reported herein. The patient had impaired vision and was diagnosed with endophthalmitis and an abdominal skin abscess. He was started on trimethoprim-sulfamethoxazole treatment, followed by cefepime. The patient was then switched to a combination of imipenem-cilastatin and minocycline. Although the patient survived as a result of surgery and prolonged antibiotic treatment, he eventually lost vision after the infection became resistant to antibiotic treatment. Molecular analysis of samples from the abscess and vitreous fluid confirmed the extremely rare pathogen N. elegans, which accounts for only 0.3-0.6% of infections caused by Nocardia species. This organism is almost always associated with pulmonary infection, and disseminated infections are rare. As with previously reported norcardial infections, the current case was treated successfully with trimethoprim-sulfamethoxazole, carbapenems, and aminoglycosides. However, the clinical characteristics of this organism remain unclear. Further studies are therefore required to develop more effective treatment protocols for disseminated nocardiosis caused by this problematic pathogen.",
"affiliations": "Department of Infection Control and Prevention, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Electronic address: task300@tokyo-med.ac.jp.;Department of Anesthesiology, Tokyo Medical University, Tokyo, Japan.;Department of Infection Control and Prevention, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Infection Control and Prevention, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Microbiology, Tokyo Medical University, Tokyo, Japan.",
"authors": "Nakamura|Itaru|I|;Nagakura|Tomoki|T|;Fujita|Hiroaki|H|;Fukusima|Shinji|S|;Gonoi|Tohru|T|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2016.10.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "54()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Disseminated; Endophthalmitis; Nocardia elegans; Pneumonia; β-d-Glucan",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D006801:Humans; D008297:Male; D009615:Nocardia; D009617:Nocardia Infections; D016896:Treatment Outcome",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "15-17",
"pmc": null,
"pmid": "27826114",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Nocardia elegans infection: a case report and literature review.",
"title_normalized": "nocardia elegans infection a case report and literature review"
} | [
{
"companynumb": "JP-BAUSCH-BL-2017-001216",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Cabergoline has been shown to have some effect in the treatment of moderate Cushing's disease, but its effectiveness in Cushing's syndrome of ectopic or occult origin remains to be investigated.\nIn this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing's syndrome of ectopic or occult origin. Cabergoline's effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases.\nIn the literature, we found only 11 cases of ectopic or occult Cushing's syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded.\nAlthough limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing's syndrome.",
"affiliations": "Endocrinology Department, 'Groupement Hospitalier Est' Hospices Civils de Lyon, Lyon, France.;Biochemistry Laboratory Department, 'Groupement Hospitalier Est' Hospices Civils de Lyon, Lyon, France.;Lyon 1 University, Lyon, France.;Lyon 1 University, Lyon, France.;Endocrinology Department, 'Groupement Hospitalier Est' Hospices Civils de Lyon, Lyon, France.;Endocrinology Department, 'Groupement Hospitalier Est' Hospices Civils de Lyon, Lyon, France.",
"authors": "Ilie|Mirela Diana|MD|;Raverot|Véronique|V|;Tronc|François|F|;Vasiljevic|Alexandre|A|;Borson-Chazot|Françoise|F|;Raverot|Gérald|G|",
"chemical_list": "D018491:Dopamine Agonists; D065088:Steroid Synthesis Inhibitors; D000077465:Cabergoline; D007654:Ketoconazole; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0804-4643",
"issue": "181(1)",
"journal": "European journal of endocrinology",
"keywords": null,
"medline_ta": "Eur J Endocrinol",
"mesh_terms": "D000182:ACTH Syndrome, Ectopic; D000328:Adult; D000368:Aged; D000077465:Cabergoline; D002276:Carcinoid Tumor; D003480:Cushing Syndrome; D018491:Dopamine Agonists; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007654:Ketoconazole; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D000077779:Pancreatic Intraductal Neoplasms; D012004:Rectal Neoplasms; D065088:Steroid Synthesis Inhibitors; D013953:Thymus Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9423848",
"other_id": null,
"pages": "K1-K9",
"pmc": null,
"pmid": "31048558",
"pubdate": "2019-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cabergoline in severe ectopic or occult Cushing's syndrome.",
"title_normalized": "cabergoline in severe ectopic or occult cushing s syndrome"
} | [
{
"companynumb": "FR-PFIZER INC-2019295405",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "KETOCONAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nImmunosuppressant medications (ISPs) increase the occurrence of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients. The prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) for PCP is effective but has serious adverse effects and so should be selectively used for patients at high risk. The aims of this study were to clarify the risk factors for PCP in RA patients and to establish the indications for administering TMP/SMX.\n\n\nMETHODS\nThis retrospective cohort study analyzed data from 2640 patients (2010-2014) diagnosed as having RA who had not received a prophylactic administration of TMP/SMX. The risk factors for PCP were evaluated by comparing the clinical parameters between patients with PCP (PCP group, n = 19) and those without (non-PCP group, n = 2621).\n\n\nRESULTS\nThe PCP group was older (70 vs. 64 years), received higher doses of prednisolone (6.2 vs. 2.4 mg/d) and methotrexate (7.7 vs. 5.2 mg/wk), and had a greater number of ISPs (1.3 vs. 0.8) (p < 0.05). We stratified the PCP risk using a scoring system based on odds ratios (ORs) calculated for these parameters (methotrexate ≥6 mg/wk OR = 4.5, 1 point; age ≥65 years, OR = 3.7, 1 point; ≥2 ISPs, OR = 3.7, 1 point; prednisolone ≥5 mg/d, OR = 12.4, 3 points). The incidence of PCP among patients scoring 0 to 2 points was 0.04%; 3 to 4 points, 2.3%; and 5 points or more, 5.8%.\n\n\nCONCLUSIONS\nThe prophylactic administration of TMP/SMX for PCP is recommended for RA patients who score at least 5 points with our system.",
"affiliations": "Division of Cardiology, Tsuchiya General Hospital, Hiroshima, Japan.",
"authors": "Yukawa|Kazutoshi|K|;Nagamoto|Yasutsugu|Y|;Watanabe|Hirofumi|H|;Funaki|Masamoto|M|;Iwahashi|Mitsuhiro|M|;Yamana|Jiro|J|;Sasaki|Rie|R|;Yamana|Seizo|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "United States",
"delete": false,
"doi": "10.1097/RHU.0000000000000731",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-1608",
"issue": "24(7)",
"journal": "Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases",
"keywords": null,
"medline_ta": "J Clin Rheumatol",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9518034",
"other_id": null,
"pages": "355-360",
"pmc": null,
"pmid": "29664819",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk Factors for Pneumocystis jirovecii Pneumonia in Patients With Rheumatoid Arthritis and a Prophylactic Indication of Trimethoprim/Sulfamethoxazole.",
"title_normalized": "risk factors for pneumocystis jirovecii pneumonia in patients with rheumatoid arthritis and a prophylactic indication of trimethoprim sulfamethoxazole"
} | [
{
"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2018EDE000371",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE"
... |
{
"abstract": "We present a case of a 7-year-old boy with a history of multiple mitral valve interventions and subsequent Melody valve placement in the mitral position, who presented with acute mitral stenosis due to complete fracture of the Melody stent. He was born early with severe mitral and tricuspid insufficiency due to valvular dysplasia, and ended up with 4 sternotomies before the age of 2 due to mitral valve dysfunction and recurrent prosthetic valve thrombosis. He then developed mixed stenosis and regurgitation at age 6, and to avoid another sternotomy, valve-in-valve therapy with off-label use of a 20-mm Melody valve was done with hybrid procedure via trans-apical approach. Eight months later he presented with acutely worsened mitral stenosis (mean gradient 20 mm Hg), due to fracture of the proximal stent. While the safety and efficacy of the Melody valve has been well established especially in the pulmonary position, stent fracture is a known and potentially serious complication. As with any novel valve therapy, close follow-up and frequent imaging may be warranted to watch for loss of stent integrity, particularly if clinical symptoms of valve dysfunction occur.",
"affiliations": "Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota.;Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota.;Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota.",
"authors": "Morrical|Brandon D|BD|0000-0002-9310-4989;Dearani|Joseph A|JA|;Cabalka|Allison K|AK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ccd.27683",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-1946",
"issue": "93(2)",
"journal": "Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions",
"keywords": "congenital; intervention; transcatheter",
"medline_ta": "Catheter Cardiovasc Interv",
"mesh_terms": "D000208:Acute Disease; D001705:Bioprosthesis; D002648:Child; D020878:Device Removal; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008297:Male; D008943:Mitral Valve; D008944:Mitral Valve Insufficiency; D008946:Mitral Valve Stenosis; D011474:Prosthesis Design; D011475:Prosthesis Failure; D020127:Recovery of Function; D012086:Reoperation; D016896:Treatment Outcome",
"nlm_unique_id": "100884139",
"other_id": null,
"pages": "E101-E104",
"pmc": null,
"pmid": "30380204",
"pubdate": "2019-02-01",
"publication_types": "D002363:Case Reports; D059040:Video-Audio Media",
"references": null,
"title": "Melody valve in mitral position: Complete fracture causing acute mitral stenosis in a child.",
"title_normalized": "melody valve in mitral position complete fracture causing acute mitral stenosis in a child"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US01386",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
... |
{
"abstract": "Hydroxyurea is a chemotherapeutic agent that is used in the treatment of various hematological diseases including chronic myelogenous leukemia, polycythemia vera, and sickle cell anemia. Hydroxyurea is also used to treat psoriasis. Drug-induced hyperpigmentation is a known cutaneous side effect of hydroxyurea along with xerosis, dermal ulcers, and dermatomyositis-like eruptions. Hyperpigmentation has been observed in the oral mucosa, nails, and in a generalized or a diffuse pattern. The mechanism of hyperpigmentation related to hydroxyurea is believed to be correlated with increased melanin. Classically, clinical types of diffuse hyperpigmentation owing to iron deposition in the dermis have been associated with minocycline and not with hydroxyurea. We report a novel case in which hydroxyurea hyperpigmentation is associated with iron deposition.",
"affiliations": "McGovern Medical School, Houston, TX. kevin.p.lee@uth.tmc.edu.",
"authors": "Lee|Kevin P|KP|;Vangipuram|Ramya K|RK|;Klimas|Natasha K|NK|;Sanyal|Soma|S|;Koshelev|Misha V|MV|",
"chemical_list": "D019384:Nucleic Acid Synthesis Inhibitors; D007501:Iron; D006918:Hydroxyurea",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "25(10)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000368:Aged; D006801:Humans; D006918:Hydroxyurea; D017495:Hyperpigmentation; D007501:Iron; D008297:Male; D064347:Microscopy, Electrochemical, Scanning; D019384:Nucleic Acid Synthesis Inhibitors; D012867:Skin",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31735009",
"pubdate": "2019-10-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydroxyurea-induced hyperpigmentation with iron deposition.",
"title_normalized": "hydroxyurea induced hyperpigmentation with iron deposition"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-115544",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "HYDROXYUREA"
},
"drugad... |
{
"abstract": "Dinitrogen (N2) has been increasingly connected to suicidal deaths. The analysis of N2 in post-mortem cases still represents a major challenge in forensic toxicology and circumstantial data has so far played a major role for the determination of the cause of death. In this paper, after presenting a review of cases of N2 intoxication described in forensic literature, we report the application of two approaches in order to quantify an excess of N2 in post-mortem whole blood collected from a case of suicide by nitrogen inhalation. N2 analyses were performed by GC-MS on the suicidal case and on controls taken from 10 autopsy cases with similar PMI (5 traumatic deaths and 5 deaths by asphyxia). The percentage of N2 was estimated by building a five-point N2 peak area calibration curve (0, 15.6 %, 62.4 % 78.1 %, 100 %) and through an external QC, assessing linearity, accuracy and precision, LLOQ, specificity and stability of N2 in the sample vial. Percentage of N2 of the case was significantly higher than the post-mortem controls (p<0.05). The N2/O2 ratio of the case and controls was also calculated as an additional indicator, and was significantly higher in the case (p<0.05). The strengths and the limitation of both methods are reported in the paper. Toxicological confirmation for N2 are rarely performed when the cause of death is evident, probably due to the lack of validated methods and the complexity of the interpretation of N2 concentration in biological fluids. The presented methods can be rapidly and profitably applied with instrumentation normally available in forensic laboratories.",
"affiliations": "Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address: arianna.giorgetti@unibo.it.;Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address: guidopelletti@gmail.com.;Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address: rossella.barone3@unibo.it.;Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address: marco.garagnani@unibo.it.;Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address: francesca.rossi@unibo.it.;Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address: gianni.guada@gmail.com.;Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address: paolo.fais@unibo.it.;Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address: susi.pelotti@unibo.it.",
"authors": "Giorgetti|Arianna|A|;Pelletti|Guido|G|;Barone|Rossella|R|;Garagnani|Marco|M|;Rossi|Francesca|F|;Guadagnini|Gianni|G|;Fais|Paolo|P|;Pelotti|Susi|S|",
"chemical_list": "D002245:Carbon Dioxide; D009584:Nitrogen; D010100:Oxygen",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2020.110548",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "317()",
"journal": "Forensic science international",
"keywords": "Asphyxiant gas; Forensic toxicology; GC–MS; Nitrogen inhalation",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D001237:Asphyxia; D002245:Carbon Dioxide; D016022:Case-Control Studies; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D009584:Nitrogen; D010100:Oxygen; D000081013:Suicide, Completed",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "110548",
"pmc": null,
"pmid": "33129047",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Deaths related to nitrogen inhalation: Analytical challenges.",
"title_normalized": "deaths related to nitrogen inhalation analytical challenges"
} | [
{
"companynumb": "IT-ALSI-202000466",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NITROGEN"
},
"drugadditional": null,
"drug... |
{
"abstract": "To evaluate outcome and toxicity of High-dose methotrexate (HDMTX)-based induction therapy followed by consolidation with conventional systemic chemotherapy and facultative intraventricular therapy (modified Bonn protocol) in patients with primary CNS lymphoma (PCNSL).\nBetween 01/2005 and 12/2013 113 patients with newly diagnosed PCNSL presented at our center; 98 of those qualified for HDMTX based chemotherapy, received a modified Bonn protocol and were included in the analysis. The treatment regimen was based on the \"Bonn protocol\", but modified by omission of systemic drugs not able to cross the intact blood brain barrier. Intraventricular therapy was postponed until completion of three induction chemotherapy cycles or was replaced by intrathecal liposomal AraC and rituximab was added to induction from 2010 onwards.\nMedian patient age was 67 years (range 38-83). Complete response/complete response unconfirmed (CR/CRu) was achieved in 59/98 patients (60%), partial response (PR) in 9/98 patients (9%). Twenty-four patients (23%) had progressive disease (PD), 6 (6%) died on therapy. Median progression-free survival (PFS) for all patients was 11.4 months, median overall survival (OS) 29.1 months. A trend to better outcome for intraventricular therapy versus intrathecal liposomal AraC was found in patients < 65 years (HR 0.53 [0.19-1.47] for OS and 0.46 [0.21-1.02] for PFS. Ommaya reservoir infection occurred in 3/33 patients (9%).\nThe data of this single center experience suggest that the outcome with a modified Bonn protocol was comparable to that of the previous regimen, showed fewer Ommaya reservoir infections and may have a trend for better outcome with intraventricular therapy.",
"affiliations": "Department of Neurology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 - 25, D-44892 Bochum, Germany.;Department of Hematology and Oncology, Charité Berlin, University of Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.;Department of Neurology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 - 25, D-44892 Bochum, Germany.;Department of Neurology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 - 25, D-44892 Bochum, Germany.;Department of Neurology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 - 25, D-44892 Bochum, Germany.;Department of Hematology and Oncology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 - 25, D-44892 Bochum, Germany.;Department of Hematology and Oncology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 - 25, D-44892 Bochum, Germany.;Department of Neurology, Hospital Barmherzige Brüder, Prüfeninger Straße 86, 93049 Regensburg, Germany.;Department of Biostatistics and Clinical Epidemiology, University of Tübingen, Silcherstr. 5, D-72076 Tübingen, Germany.;Department of Neurology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 - 25, D-44892 Bochum, Germany.",
"authors": "Seidel|Sabine|S|0000-0002-1671-3297;Korfel|Agnieszka|A|;Kowalski|Thomas|T|;Margold|Michelle|M|;Ismail|Fatme|F|;Schroers|Roland|R|;Baraniskin|Alexander|A|;Pels|Hendrik|H|;Martus|Peter|P|;Schlegel|Uwe|U|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s42466-019-0024-2",
"fulltext": "\n==== Front\nNeurol Res Pract\nNeurol Res Pract\nNeurological Research and Practice\n2524-3489 BioMed Central London \n\n24\n10.1186/s42466-019-0024-2\nResearch Article\nHDMTX-based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy (modified Bonn protocol) in primary CNS lymphoma: a monocentric retrospective analysis\nhttp://orcid.org/0000-0002-1671-3297Seidel Sabine sabine.seidel@kk-bochum.de 1 Korfel Agnieszka agnieszka.korfel@charite.de 2 Kowalski Thomas thomas.kowalski@kk-bochum.de 1 Margold Michelle michelle.margold@kk-bochum.de 1 Ismail Fatme FatmeSeval.Ismail@kk-bochum.de 1 Schroers Roland roland.schroers@kk-bochum.de 3 Baraniskin Alexander alexander.baraniskin@ruhr-uni-bochum.de 3 Pels Hendrik Hendrik-Johannes.Pels@barmherzige-regensburg.de 4 Martus Peter peter.martus@med.uni-tuebingen.de 5 Schlegel Uwe uwe.schlegel@kk-bochum.de 1 1 0000 0004 0490 981Xgrid.5570.7Department of Neurology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 – 25, D-44892 Bochum, Germany \n2 Department of Hematology and Oncology, Charité Berlin, University of Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany \n3 0000 0004 0490 981Xgrid.5570.7Department of Hematology and Oncology, Knappschaftskrankenhaus University of Bochum, In der Schornau 23 – 25, D-44892 Bochum, Germany \n4 Department of Neurology, Hospital Barmherzige Brüder, Prüfeninger Straße 86, 93049 Regensburg, Germany \n5 0000 0001 2190 1447grid.10392.39Department of Biostatistics and Clinical Epidemiology, University of Tübingen, Silcherstr. 5, D-72076 Tübingen, Germany \n20 6 2019 \n20 6 2019 \n2019 \n1 1729 3 2019 26 4 2019 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTo evaluate outcome and toxicity of High-dose methotrexate (HDMTX)-based induction therapy followed by consolidation with conventional systemic chemotherapy and facultative intraventricular therapy (modified Bonn protocol) in patients with primary CNS lymphoma (PCNSL).\n\nMethods\nBetween 01/2005 and 12/2013 113 patients with newly diagnosed PCNSL presented at our center; 98 of those qualified for HDMTX based chemotherapy, received a modified Bonn protocol and were included in the analysis. The treatment regimen was based on the “Bonn protocol”, but modified by omission of systemic drugs not able to cross the intact blood brain barrier. Intraventricular therapy was postponed until completion of three induction chemotherapy cycles or was replaced by intrathecal liposomal AraC and rituximab was added to induction from 2010 onwards.\n\nResults\nMedian patient age was 67 years (range 38–83). Complete response/complete response unconfirmed (CR/CRu) was achieved in 59/98 patients (60%), partial response (PR) in 9/98 patients (9%). Twenty-four patients (23%) had progressive disease (PD), 6 (6%) died on therapy. Median progression-free survival (PFS) for all patients was 11.4 months, median overall survival (OS) 29.1 months. A trend to better outcome for intraventricular therapy versus intrathecal liposomal AraC was found in patients < 65 years (HR 0.53 [0.19–1.47] for OS and 0.46 [0.21–1.02] for PFS. Ommaya reservoir infection occurred in 3/33 patients (9%).\n\nConclusions\nThe data of this single center experience suggest that the outcome with a modified Bonn protocol was comparable to that of the previous regimen, showed fewer Ommaya reservoir infections and may have a trend for better outcome with intraventricular therapy.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s42466-019-0024-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nPCNSLMethotrexateConsolidation chemotherapyIntraventricular therapyBonn protocolissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nPrimary CNS lymphoma (PCNSL) accounts for about 3% of primary brain cancers [1]. It is a highly aggressive tumor and optimal treatment is not yet defined [2]. PCNSL is highly responsive to radiation, however, whole-brain radiotherapy (WBRT) cannot control the disease if given alone [3]. High-dose methotrexate (HDMTX) is the most active drug in PCNSL. Thus, in the 1990ies, the combination of HDMTX based chemotherapy with WBRT given for consolidation became treatment of choice in PCNSL, but was associated with a high rate of delayed neurotoxicity, particularly in the elderly [4]. No overall survival prolongation was found by adding 45 Gy-WBRT to HDMTX-based primary chemotherapy in a randomized phase III-study [5]. To avoid late neurocognitive decline radiation-free treatment protocols were developed, combining HDMTX with other drugs given systemically and intrathecally. The “Bonn protocol” first published in 2003 [6] resulted in durable responses in a substantial fraction of patients, particularly in the younger, when evaluated in a single arm phase II-trial [6–8]. Systemic HDMTX- and High-dose cytarabine (HDAraC)-based chemotherapy was applied sequentially and combined in each of six treatment cycles with intraventricular therapy (MTX, prednisolone, AraC) via an Ommaya reservoir. Median overall survival (OS) was 50 months and failure free survival (FFS) 21 month [6] without neurotoxicity at long-term follow-up [8]. This protocol has not found broad acceptance due to a 19% rate of Ommaya reservoir infections. On the other hand, a phase II-trial of our group was prematurely stopped, when young patients treated with systemic therapy alone according to the Bonn protocol suffered from early and leptomeningeal relapses [9].\n\nClinical research in PCNSL is currently focused on defining the optimal consolidation treatment after HDMTX-based induction. With studies exploiting conventional non-cross resistant systemic chemotherapy [10], high dose chemotherapy with autologous stem cell transplantation (HD-ASCT) [11] or dose-reduced WBRT [12], 2-years PFS of 37–77% and 2-years OS of 42–90% have been reported. Two randomized studies compared standard-dose WBRT and HD-ASCT for consolidation in younger patients. No significant difference in 2-years PFS between WBRT and ASCT (80% vs 69%, p = 0,17) was found in the IELSG-32 trial [13], but a 24% better 2-years PFS: 86.8% vs. 63.2% was found with HD-ASCT in the French PRECIS trial [14] which, however, was not designed for a direct comparison. In conclusion, an optimal consolidation after HDMTX-based induction therapy has not been established thus far.\n\nChemotherapy in this series is based on the Bonn protocol [6, 8] and the goal was to preserve its efficacy while reducing its acute toxicity: Cyclophosphamide was replaced by ifosfamide for its better CNS penetration [15]; vincristine und vindesine which are not able to cross the intact blood-brain barrier (BBB) were omitted, and the duration of HDMTX infusion was reduced from 24 to 4 h according to pharmacokinetic considerations [16]. Rituximab was given to all patients treated from September 2010 onwards based on retrospective analyses on its role in PCNSL [17, 18]. However, due to its limited CNS penetration [19] the application of rituximab was restricted to the induction phase where an open BBB is assumed [20]. Most notably, the frequent (4x/week) intraventricular injections were started after three full cycles of induction with initiation of the consolidation phase or were replaced by intrathecal liposomal cytarabine given every 2 weeks. We thus avoided intraventricular therapy during induction, when patients` general condition frequently is compromised due to the higher tumor burden, reduced mobility and concomitant (immunosuppressant) steroids. However, after a Scandinavian consortium had failed to achieve good results with a regimen based on the Bonn protocol for elderly patients, when intraventricular therapy was replaced by intrathecal liposomal AraC [21], we did not apply liposomal AraC in the following. While high dose intravenous MTX application leads to cytotoxic drug concentrations in the cerebrospinal fluid for up to 48 h [22], more sustained drug concentrations for up to 1 week can be achieved with repeated daily intraventricular injections [23].\n\nThus, depending on patient age and treatment phase, patients were treated differently in this series and a heterogeneously treated group is analyzed. Here we present treatment results obtained with a modified Bonn protocol in 98 patients with a median follow up of more than 7 years. With this report we want to document results achievable in everyday practice with a modified chemotherapy alone regimen in PCNSL.\n\nPatients and methods\nAll HIV-negative patients, 18 years and older, presenting at this tertiary care center with newly diagnosed and histologically confirmed PCNSL are offered a modified Bonn protocol if they are able to tolerate HDMTX defined by lack of severe organ dysfunction, in particular renal insufficiency with a glomerular filtration rate below 50 ml/min. Between January 2005 and December 2013 113 patients with newly diagnosed PCNSL presented at our center. In December 2013 an arbitrary cut-off was made to report a minimum follow up of 4 years. Of 113 patients, 7 patients (6%) were unable to receive HDMTX-based chemotherapy due to the following reasons: renal insufficiency (n = 4), high age and significant comorbidities (n = 2), toxic hepatitis with liver dysfunction, infection (peritonitis) and patient’s refusal in one patient each. Two of these patients were treated with radiotherapy and five patients received best supportive care alone. Four patients received individualized MTX-based protocols for the following reasons: One patient had a ventriculoperitoneal shunt because of subarachnoid hemorrhage years before diagnosis of PCNSL and could not receive intraventricular chemotherapy via an Ommaya reservoir. One patient was admitted in a critically ill status and received only 1 cycle HDMTX monotherapy. Four patients received the original Bonn protocol [6]. Therefore, 98 patients received chemotherapy with a modified Bonn protocol and were included in this analysis. As this was a retrospective analysis on data obtained from the archives of the clinic no written informed consent was obtained. The ethics committee of faculty of medicine of the University of Bochum approved the study.\n\nPre-therapy evaluation was performed according to International PCNSL Collaborative Group (IPCG) recommendations [24]. Systemic HDMTX was administered as a 4 h infusion under vigorous hydration and urine alkalization at a dosage of 3–5 g/m2 body-surface area. From 2005 to 2009 patients < 65 years were given 5 g/m2 and patients ≥65 years received 3 g/m2 as in the original Bonn protocol. From 2010 to 2013 patients in general received 4 g/m2, which was adjusted individually according to glomerular filtration rate. After completion of HDMTX infusion, an intensified leucovorin rescue was performed in case of delayed MTX-clearance. Ifosfamide was given at a dose of 800 mg/m2 body-surface area as a 1 h infusion with sodium 2-mercaptoethane sulfonate protection. AraC was given in a dose of 3000 mg/m2 body-surface area as a 3 h infusion. Rituximab was given at a dosage of 500 mg/m2 body-surface area, a dosage higher than in systemic lymphoma for its poor blood brain barrier penetrance [19]. Intraventricular or intrathecal therapy was applied depending on time of diagnosis as presented in Table 1. From 2005 to 2009 all patients received intrathecal therapy. From 2010 to 2013 only patients < 65 years and 8 “biologically young” patients ≥65 years received intraventricular therapy. Treatment course in all 98 patients is presented in Fig. 1. Response was assessed by contrast-enhanced cMRI scans after 2 to 3 courses and 4 to 6 weeks after completion of treatment and categorized according to the IPCG-criteria (CR = complete response, PR = partial response, PD = progressive disease) with the additional response category “complete response unconfirmed (CRu)”, which allows small enhancing abnormalities in the original tumor localization related to biopsy or focal hemorrhage [24].Table 1 Overview of the intended chemotherapy protocol (* patients treated 2009–2013, ** patients treated 2005–2008, i.v. = intravenous, MTX = methotrexate, AraC = cytarabine, i.th. = intrathecal)\n\n\tDay 0\tDay 1\tDay 2\tDay 3\tDay 4\tDay 5\tDay 6\t\nCycle 1–3 (1 cycle = 2 weeks)\t\n- Rituximab 500 mg/m2 i.v.*\tx\t\t\t\t\t\t\t\n- MTX 3000–5000 mg/m2 i.v.\t\tx\t\t\t\t\t\t\n- Ifosfamide 800 mg/m2 i.v.\t\t\tx\tx\tx\t\t\t\n- Liposomal AraC 50 mg i.th.**\t\t\tx\t\t\t\t\t\nCycle 4 + 6 (1 cycle = 3 weeks)\t\n- Cytarabine 3000 mg/m2 i.v\t\tx\tx\t\t\t\t\t\n- Liposomal AraC 50 mg i.th.**\t\t\t\tx\t\t\t\t\n- MTX 2,5 mg + prednisolone 3 mg intraventricular (patients < 65 ys)*\t\t\t\tx\tx\tx\t\t\n- AraC 10 mg intraventricular (patients < 65 ys)*\t\t\t\t\t\t\tx\t\nCycle 5 (1 cycle = 2 weeks)\t\n- MTX 3000–5000 mg/m2 i.v.\t\tx\t\t\t\t\t\t\n- Ifosfamide i.v. 800 mg/m2 i.v.\t\t\tx\tx\tx\t\t\n- Liposomal AraC 50 mg i.th.**\t\t\tx\t\t\t\t\n- MTX 2,5 mg + prednisolone 3 mg intraventricular (patients < 65 ys)*\t\t\tx\tx\tx\t\t\n- AraC10 mg intraventricular (patients < 65 ys)*\t\t\t\t\t\tx\t\nCycle 5 was repeated for patients < 65 ys\t\t\t\t\t\t\t\nFig. 1 Course of therapy for n = 98 patients (group A (< 65 ys 2005–2008) and group C (≥65 ys 2005–2008) received intrathecal liposomal Ara C; group B (< 65 ys 2009–2013) received intraventricular therapy via Ommaya reservoir [25/26 patients]; group D (≥ 65 ys 2009–2013) received no intrathecal therapy [27/35 patients])\n\n\n\nData concerning toxicity was classified according to the WHO system [25]. All patients were included in a follow up-program. Within the first 2 years clinical controls, MRI controls and ophthalmological controls were carried out every 3 months, afterwards every 6 months for 3 years and in the following annually. Additional examinations were performed on clinical suspicion only.\n\nOverall survival (OS) was calculated from the date of histologic diagnosis to death of any cause or last date of follow up. Progression free survival (PFS) was defined as the time from date of histologic diagnosis to progression, death of any cause (if progression was not determined) or last date of follow up. OS and PFS were estimated by the Kaplan-Meier method. Log-rank tests were used to compare OS and PFS between groups. Additionally, simple and multiple Cox proportional hazard regression models were calculated and hazard ratios, two-sided 95% confidence intervals, and p-values were presented. For each of the non-significant variables results refer to the model in which significant variables and a single non-significant variable was included. The level of significance was 0,05 (two-sided). Analyses were conducted using SPSS version 23.0, SPSS Inc., Chicago, IL.\n\nResults\nPatients` characteristics and treatment\nPretherapeutic characteristics are summarized in Table 2. Three patients (3%) were considered immunocompromised due to long-term oral steroid therapy for an autoimmune disease (polyarthritis n = 2, alveolitis n = 1). Thirty-seven patients (12 patients < 65 years [group A] and 25 patients ≥65 [group C]) treated between 2005 and 2008, received 50 mg intrathecal liposomal AraC on day 2 or 3 of each chemotherapy course instead of intraventricular therapy. Of 61 patients treated thereafter, 26 patients were < 65 years (group B). 25/26 patients in group B received intraventricular chemotherapy via an Ommaya reservoir during consolidation (starting with cycle 4 of all cycles). 35 patients treated from 2009 to 2013 were ≥ 65 years (group D), 8 of these patients were treated with intraventricular therapy starting with cycle 4 (since they were considered “biologically younger”) and 27 patients received no intrathecal therapy at all.Table 2 Pretherapeutic patients` characteristics\n\nAge\t\n- Median (range 38–83)\t67\t\t\n- < 65\t38\t39%\t\n- ≥ 65\t60\t61%\t\nSex\t\n- Male\t45\t46%\t\n- Female\t53\t54%\t\nSurgery\t\n- Stereotactic biopsy\t60\t61%\t\n- Open biopsy\t19\t19%\t\n- Partial resection\t5\t5%\t\n- Complete resection\t11\t11%\t\n- Vitreal cytology\t2\t2%\t\n- CSF cytology\t1\t1%\t\nNeuropathologial Diagnosis\t\n- Diffuse large-cell B-cell lymphoma\t92\t94%\t\n- Lymphoma, not specified\t6\t6%\t\n- Other\t0\t\t\nCSF diagnostic\t\n- elevated cell count\t26/82\t32%\t\n- elevated CSF protein\t45/80\t56%\t\n- lymphoma cells in CSF cytology\t10/74\t14%\t\n- lymphoma cells in flow cytometry\t3/53\t6%\t\nKarnofsky-Performance Score\t\n- median (range 20–100)\t60\t\t\n- ≥ 70\t45\t46%\t\n- < 70\t53\t54%\t\nMSKCC Score\t\n- ≤ 50 years\t9\t9%\t\n- > 50 years/KPS ≥ 70\t39\t40%\t\n- > 50 years/KPS ≥ 70\t50\t51%\t\nIELSG Score\t\n- score 0–1\t11/74\t15%\t\n- score 2–3\t40/74\t54%\t\n- score 4–5\t23/74\t31%\t\n\n\nAll patients treated after September 2010 (25/26 = 96% in group B and 26/35 = 74% in group D) received rituximab. Sixty-one patients (62%) received the complete protocol as planned. Reasons for premature termination were: toxicity in 20 patients (20%), lymphoma progression in 9 (9%), toxicity-related death in 6 (6%), treating physician’s decision (patient’s incompliance) and patient’s decision in 1 patient each (1%).\n\nTreatment outcome\nAfter completion of therapy CR/CRu was achieved in 59 patients (60%) and PR in 9 patients (9%) accounting for an overall response rate of 69%. Twenty-four patients (23%) had progressive disease (PD) and 6 (6%) died on therapy. Median follow up was 84,4 months (range 4.8–135.9 months). Two patients were lost to follow up.\n\nMedian PFS for all patients was 11.4 months, median OS was 29.1 months.\n\nGroup A hat a median PFS of 11.2 months (95% CI 3.5–18.8), group B 30.3 months (95% CI 8.7–51.9), group C 9.8 months (95% CI 2.7–11.1) and group D 6.4 months (95% CI 2.1–10.7) (Fig. 2). Median OS was 54 months (95% CI 0–154) in group A, was not reached in group B, 17.9 months (95% CI 10.1–25.7) in group C and 14.6 months (95% CI 5.4–23.9) in group D (Fig. 3).Fig. 2 Progression free survival according to age and treatment period (group A: < 65 ys 2005–2008 received intrathecal liposomal Ara C; group B: < 65 ys 2009–2013 received intraventricular therapy via Ommaya reservoir [25/26 patients]; group C: ≥ 65 ys 2005–2008 received intrathecal liposomal Ara C; group D: ≥ 65 ys 2009–2013 received no intrathecal therapy [27/35 patients])\n\nFig. 3 Overall survival according to age and treatment period (group A: < 65 ys 2005–2008 received liposomal Ara C i.th.; group B: < 65 ys 2009–2013 received i.c.v. therapy via Ommaya reservoir (25/26 patients); group C: ≥ 65 ys 2005–2008 received liposomal Ara C i.th; group D: ≥ 65 ys 2009–2013 received no i.th. therapy (27/35 patients)\n\n\n\nToxicity\nGrade 3/4 toxicity is summarized in Additional file 1. Anemia, leucopenia, thrombopenia, infections and transaminases elevation were the most frequent grade 3/4 toxic side effects, occurring in 37, 54, 51, 41 and 44%, respectively. Of 37 patients treated with liposomal AraC intrathecally 7 (19%) developed grade 3 arachnoiditis. Of 33 patients treated with intraventricular chemotherapy via Ommaya reservoirs, reservoir infection occurred in three (9%) patients. In one patient the reservoir infection occurred immediately after implantation prior to application of intraventricular chemotherapy: the reservoir was removed, antibiotics were given, and after recovering a new reservoir was implanted and chemotherapy was continued as planned. In the two other patients the infection occurred 5 days after 1st cycle of intraventricular therapy and 6 days after 2nd cycle, respectively. In both the reservoir was removed, systemic antibiotics were given and chemotherapy was continued without intraventricular therapy. In one patient misplacement with extravasation of chemotherapy into the surrounding brain tissue occurred. In this patient, the reservoir was removed and the treatment was continued with systemic therapy only incl. HD-ASCT for consolidation. This patient experienced psychomotor slowing and disorientation, but fully recovered within 6 weeks. Six patients died on therapy, 4 of whom were ≥ 65 years. Reasons of death were myocardial infarction in one patient and infection in 5. Three of these patients suffered from pneumonia and for 2 patients the focus of infection could not be determined, but meningitis was ruled out.\n\nPrognostic factors\nThe following factors were tested: age, Karnofsky performance score (KPS), lactate dehydrogenase (LDH) in serum, cerebrospinal fluid (CSF) protein, involvement of deep brain structures, International Extranodal Lymphoma Study Group (IELSG) score and type of protocol (Additional files 2 and 3). On univariate analysis, younger age, higher KPS and lower IELSG score were associated with longer OS as were younger age and higher KPS with longer PFS. On multivariate analysis younger age and higher KPS were associated with longer PFS but only younger age was associated with longer OS: patients ≥65 years had a median PFS of 7.8 months (95% CI 4.4–11.2) and median OS of 16 months (95% CI 8.9–23.1), patients < 65 years had a median of PFS 17.9 months (95% CI 1.7–34.2) and median OS of 110 months (53.8–166.5). No significant influence on survival was found for LDH elevation in serum, protein elevation in the CSF and for involvement of deep brain structures.\n\nWhen the influence of therapy on outcome was analyzed, a trend to better outcome for intraventricular therapy vs. intrathecal liposomal AraC was found in patients < 65 years: on univariate analysis HR was 0.53 (0.19–1.47) for OS and 0.46 (0.21–1.02) for PFS. No influence of rituximab on outcome was found.\n\nTreatment at relapse is summarized in Additional file 4.\n\nDiscussion\nThe current series represents a retrospective monocentric analysis. Yet the patient population analyzed in this series presumably reflects every day clinical practice of PCNSL treatment better than patient series treated within formal clinical trials, where patient selection is determined by stringent exclusion criteria. Except for severe organ dysfunction, representing contraindications to basic treatment elements, no such selection was carried out in the patient cohort presented here, such that 98/113 patients (87%) could be treated as intended. This is reflected by a relatively high median age of 67 years with 60% of patients ≥65 years in this series, which is in contrast to other studies using induction followed by consolidation with a median age of 51 to 60 years and 19 to 42% of patients > 60 years [10–13, 26–28]. Moreover, the KPS of patients in the present study was rather low with a median of 60 and 54% of patients with KPS < 70%, as compared to a median KPS of 70–90% and a percentage of 18 to 50 of patients with KPS < 70% in other studies [11, 12, 26, 27, 29]. This is to be considered when interpreting the current results.\n\nAs the Bonn protocol has proven to preserve neurocognitive function in long-term survivors [8, 30], since 2005 all patients with newly diagnosed PCNSL able to tolerate HDMTX at our center were treated with a protocol combining the elements of the Bonn protocol with the concept of induction-consolidation. In contrast to the original Bonn protocol, a 24 h infusion of HDMTX was replaced by a 4 h infusion, systemic drugs not able to cross the intact blood brain barrier (BBB) were omitted, cyclophosphamide was replaced by ifosfamide and intraventricular therapy was modified. Since several retrospective analyses suggested that rituximab could improve therapeutic efficacy in PCNSL [17, 18], rituximab was added to induction therapy in 2010.\n\nWhen the results are compared to that achieved with the original Bonn protocol [6] similar response rates are found: CR/CRu of 60% vs. 61%, PR 9% vs. 10% and PD 23% vs. 19%. Moreover, similar 2-years OS was achieved: in patients < 61 years: 78% vs. 80% and in patients > 60 years: 41% versus 59%. When acute toxicity is compared, less grade 3–4 leukopenia and thrombocytopenia were found in the current analysis: 55% vs. 94 and 52% vs. 89%, respectively. The frequency of Ommaya reservoir infections which occurred in 19% of patients treated with the original Bonn protocol [6], was only 9% in the current series. This difference is not significant due to the small number of patients analyzed, but may reflect the fact, that intraventricular therapy is better tolerated in patients devoid of steroid treatment and in a good clinical condition. However, the frequency of grade 3 to 4 infections of 41% was higher than in the Bonn study with 26% [6], most likely as a consequence of a more frequently reduced general condition in the current series. The rate of toxic death was 6% in the current study as compared to 9% in the Bonn study. In our view, with the modifications made, the practicability of the Bonn protocol is improved, while the effectivity was preserved. When comparing the results achieved in this series with results of the original protocol it should be considered, that pre-therapeutic prognostic factors of the 65 patients included in the Bonn study were better than in the present study: the median age in the original Bonn study was 62 years with 54% of patients > 60 years, and median KPS was 70% with 25% of patients with KPS < 70%.\n\nA particular emphasis of this analysis was put on the role of intrathecal therapy, with a focus on that of intraventricular treatment via an Ommaya reservoir. Comparing the results achieved with intrathecal therapies in patients < 65 years, our data suggest a higher efficacy of intraventricular therapy than of intrathecal liposomal AraC: On univariate analysis, an almost significant PFS difference was found benefitting intraventricular therapy with a HR of 0.46 (0.21–1.02), whereas the HR for OS was 0.53 (0.19–1.47). The number of patients presumably was too low to detect a difference of statistical significance. A potentially higher efficacy of intraventricular treatment with MTX, prednisolone and AraC in our view is not surprising. Liposomal AraC may well have advantageous pharmacokinetics in comparison to other formula, however, it has never been suggested, that MTX for systemic treatment in PCNSL may be replaced by AraC and this might be true for intrathecal therapy as well.\n\nA high proportion of 91% of patients received salvage treatment at progression/relapse with systemic chemotherapy being the most frequent treatment, which is summarized in Additional file 4.\n\nWhen the results of the present analysis are compared to other studies using the therapeutic concept of induction followed by consolidation, comparable results can be found at least. In those studies, CR-rates of 30–81% and PR-rates of 11–14% after completion of therapy were achieved despite younger age and better KPS as compared to this cohort [5, 10–13, 26–28]. Also, long term outcome in our series is in the higher range of the 2-years OS rates compared to other studies including elderly patients with 32–90% [5, 12, 26–28]. From our treatment benefitted particularly patients < 61 years whose 2-years PFS was 69%, 2-years OS 78% and 5-years OS 57%. This is in accordance to results by Morris et al. with 2-years PFS of 64% and DeAngelis et al. with 2-years PFS and –OS of approximately 75% each.\n\nConclusions\nThis study has several limitations as it represents a retrospective monocentric analysis of a heterogeneously treated patient population with rather small subgroups.\n\nNevertheless, we considered the following possible therapeutic perspectives: HDMTX based induction followed by consolidation with intensive conventional chemotherapy plus intraventricular treatment can be applied to the vast majority of PCNSL patients with no upper age limit besides that set by possible comorbidity.\n\nIntraventricular treatment via an Ommaya reservoir is associated with manageable complications of low frequency, if started with consolidation.\n\nPCNSL treatment in elderly patients not qualifying for HD-ASCT is still extremely unsatisfying [29, 31–33]. Therefore, we currently apply intraventricular treatment as part of first-line therapy in every elderly patient beginning with consolidation as a valuable option of treatment intensification with no risk of additional systemic toxicity.\n\nAdditional files\n\nAdditional file 1: CTC Grade 3–4 toxicity. (DOCX 15 kb)\n\n \nAdditional file 2: Influence of prognostic factors on Progression free survival. (DOCX 13 kb)\n\n \nAdditional file 3: Influence of prognostic factors on Overall survival. (DOCX 13 kb)\n\n \nAdditional file 4: Treatment at first relapse or in case of progressive disease during therapy (n = 68). (DOCX 13 kb)\n\n \n\n\nAbbreviations\nBBBBlood brain barrier\n\nCRComplete remission\n\nCRuComplete remission\n\nCSFCerebrospinal fluid\n\nHD AraCHigh-dose cytarabine\n\nHDMTXHigh-dose methotrexate\n\nHD-SCTHigh dose chemotherapy with autologous stem cell transplantation\n\nIELSGInternational Extranodal Lymphoma Study Group score\n\nKPSKarnofsky performance score\n\nLDHLactate dehydrogenase\n\nOSOverall survival\n\nPCNSLPrimary central nervous system lymphoma\n\nPDProgressive disease\n\nPFSProgression free survival\n\nPRPartial remission\n\nWBRTWhole brain radiation therapy\n\nAcknowledgements\nNot applicable\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article and its additional files.\n\nAuthors’ contributions\nS.S. and U.S. conceived of the presented idea. S.S. collected data with the help of T.K., M.M., F.I. and wrote the manuscript with support from A.K., P.M. and U.S.. P.M. performed statistical analyses. U.S. and A.K. supervised the project. H.P. provided critical feedback. All authors discussed the results and commented on the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nAs this was a retrospective analysis on data obtained from the archives of the clinic no written informed consent was obtained. The ethics committee of faculty of medicine of the University of Bochum approved the study (reference number 18–6472).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nU.S. has received honoraria as a speaker from Novartis, GSK, medac and as an Advisory Board member from Roche and Optune. M.M. has received an SIO grant from medac.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ostrom QT Gittleman H Liao P Rouse C Chen Y Dowling J Wolinsky Y Kruchko C Barnholtz-Sloan J CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2007-2011 Neuro-Oncology 2014 16 Suppl 4 iv1 i63 10.1093/neuonc/nou223 25304271 \n2. Korfel A Schlegel U Diagnosis and treatment of primary CNS lymphoma Nature Reviews Neurology 2013 9 6 317 327 10.1038/nrneurol.2013.83 23670107 \n3. Nelson DF Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL) Journal of Neuro-Oncology 1999 43 241 247 10.1023/A:1006206602918 10563430 \n4. Abrey LE Yahalom J DeAngelis LM Treatment for primary CNS lymphoma: The next step Journal of Clinical Oncology 2000 18 519 526 10.1200/JCO.2000.18.17.3144 10653867 \n5. 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Pels H Juergens A Glasmacher A Schulz H Engert A Linnebank M Schackert G Reichmann H Kroschinsky F Vogt-Schaden M Egerer G Bode U Schaller C Lamprecht M Hau P Deckert M Fimmers R Bangard C Schmidt-Wolf IG Schlegel U Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: Results of a phase II study Journal of Neuro-Oncology 2009 91 3 299 305 10.1007/s11060-008-9712-4 18931887 \n10. Rubinstein JL His ED Johnson JL Jung SH Nakashima MO Grant B Cheson BD Kaplan LD Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202) Journal of Clinical Oncology 2013 31 25 3061 3068 10.1200/JCO.2012.46.9957 23569323 \n11. Illerhaus G Kasenda B Ihorst G Egerer G Lamprecht M Keller U Wolf HH Hirt C Stilgenbauer S Binder M Hau P Edinger M Frickhofen N Bentz M Möhle R Röth A Pfreundschuh M von Baumgarten L Deckert M Hader C Fricker H Valk E Schorb E Fritsch K Finke J High-dose chemotherapy with autologous haematopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: A prospective, single-arm, phase 2 trial Lancet Haematology 2016 3 8 e388 e397 10.1016/S2352-3026(16)30050-3 27476790 \n12. Morris PG Correa DD Yahalom J Raizer JJ Schiff D Grant B Grimm S Lai RK Reiner AS Panageas K Karimi S Curry R Shah G Abrey LE DeAngelis LM Omuro A Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome Journal of Clinical Oncology 2013 31 31 3971 3979 10.1200/JCO.2013.50.4910 24101038 \n13. Ferreri AJM Cwynarski K Pulczynski E Fox CP Schorb E La Rosée P Binder M Fabbri A Torri V Minacapelli E Falautano M Ilariucci F Ambrosetti A Roth A Hemmaway C Johnson P Linton KM Pukrop T Sønderskov Gørløv J Balzarotti M Hess G Keller U Stilgenbauer S Panse J Tucci A Orsucci L Pisani F Levis A Krause SW Schmoll HJ Hertenstein B Rummel M Smith J Pfreundschuh M Cabras G Angrilli F Ponzoni M Deckert M Politi LS Finke J Reni M Cavalli F Zucca E Illerhaus G Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial Lancet Haematology 2017 4 11 e510 e523 10.1016/S2352-3026(17)30174-6 29054815 \n14. Houillier C Taillandier L Lamy T Chinot O Molucon-Chabrot C Soubeyran P Gressin R Choquet S Damaj G Thyss A Jaccard A Delwail V Gyan E Sanhes L Cornillon J Garidi R Delmer A Savignoni A Jijakli A Morel P Bourquard P Moles M Deconinck E Morel P Gastinne T Constans J Langer A Lacomblez L Delgadillo D Dureau S Turbiez I Plissonnier A Cassoux N Touitou V Ricard D Hoang-Xuan K Soussain C Whole brain radiotherapy (WBRT) versus intensive chemotherapy with Haematopoietic stem cell rescue (IC + HCR) for primary central nervous system lymphoma (PCNSL) in young patients: An intergroup Anocef-Goelams randomized phase II trial (PRECIS) Blood 2016 128 22 782 \n15. Yule SM Price L Pearson AD Boddy AV Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children Clinical Cancer Research 1997 3 11 1985 1992 9815588 \n16. Ferreri AJ Guerra E Regazzi M Pasini F Ambrosetti A Pivnik A Gubkin A Calderoni A Spina M Brandes A Ferrarese F Rognone A Govi S Dell'Oro S Locatelli M Villa E Reni M Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas British Journal of Cancer 2004 90 2 353 358 10.1038/sj.bjc.6601472 14735176 \n17. Birnbaum T Stadler EA von Baumgarten L Straube A Rituximab significantly improves complete response rate in patients with primary CNS lymphoma Journal of Neuro-Oncology 2012 109 2 285 291 10.1007/s11060-012-0891-7 22570142 \n18. Holdhoff M Ambady P Abdelaziz A Sarai G Bonekamp D Blakeley J Grossman SA Ye X High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma Neurology 2014 83 3 235 239 10.1212/WNL.0000000000000593 24928128 \n19. Rubinstein JL Fridlyand J Abrey L Shen A Karch J Wang E Issa S Damon L Prados M McDermott M O'Brien J Haqq C Shuman M Phase 1 study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma Journal of Clinical Oncology 2007 25 11 1350 1356 10.1200/JCO.2006.09.7311 17312328 \n20. Ott RJ Brada M Flower MA Babich JW Cherry SR Deehan BJ Measurements of blood-brain barrier permeability in patients undergoing radiotherapy and chemotherapy for primary cerebral lymphoma European Journal of Cancer 1991 27 11 1356 1361 10.1016/0277-5379(91)90009-3 1835848 \n21. Pulczynski EJ Kuittinen O Erlanson M Hagberg H Fosså A Eriksson M Nordstrøm M Østenstad B Fluge Ø Leppä S Fiirgaard B Bersvendsen H Fagerli UM Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-escalating induction and introducing temozolomide maintenance: results from a phase II study by the Nordic Lymphoma Group Haematologica 2015 100 4 534 540 10.3324/haematol.2014.108472 25480497 \n22. Glantz MJ Cole BF Recht L Akerley W Mills P Saris S Hochberg F Calabresi P Egorin MJ High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: Is intrathecal chemotherapy necessary? Journal of Clinical Oncology 1998 16 4 1561 1567 10.1200/JCO.1998.16.4.1561 9552066 \n23. Bleyer WA Poplack DG Simon RM \"Concentration x time\" methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms Blood 1978 51 5 835 842 638249 \n24. Küker W Nägele T Thiel E Weller M Herrlinger U Primary central nervous system lymphomas (PCNSL): MRI response criteria revised Neurology 2005 65 7 1129 1131 10.1212/01.wnl.0000178894.51436.54 16217075 \n25. World Health Organization. (1979) WHO Handbook for Reporting Results of Cancer Treatment. WHO offset publication no. 48 Geneva, Switzerland.\n26. DeAngelis LM Seiferheld W Schold SC Fisher B Schultz CJ Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation therapy oncology group study 93-10 Journal of Clinical Oncology 2002 20 24 4643 4648 10.1200/JCO.2002.11.013 12488408 \n27. Poortmans PM Kluin-Nelemans HC Haaxma-Reiche H Van't Veer M Hansen M Soubeyran P Taphoorn M Thomas J Van den Bent M Fickers M Van Imhoff G Rozewicz C Teodorovic I van Glabbeke M High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962 Journal of Clinical Oncology 2003 21 24 4483 4488 10.1200/JCO.2003.03.108 14597741 \n28. Ferreri AJ Reni M Foppoli M Martelli M Pangalis GA Frezzato M Cabras MG Fabbri A Corazzelli G Ilariucci F Rossi G Soffietti R Stelitano C Vallisa D Zaja F Zoppegno L Aondio GM Avvisati G Balzarotti M Brandes AA Fajardo J Gomez H Guarini A Pinotti G Rigacci L Uhlmann C Picozzi P Vezzulli P Ponzoni M Zucca E Caligaris-Cappio F Cavalli F High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: A randomised phase 2 trial Lancet 2009 374 1512 1520 10.1016/S0140-6736(09)61416-1 19767089 \n29. Omuro A Chinot O Taillandier L Ghesquieres H Soussain C Delwail V Lamy T Gressin R Choquet S Soubeyran P Huchet A Benouaich-Amiel A Lebouvier-Sadot S Gyan E Touitou V Barrié M del Rio MS Gonzalez-Aguilar A Houillier C Delgadillo D Lacomblez L Tanguy ML Hoang-Xuan K Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial Lancet Haematology 2015 2 6 e251 e259 10.1016/S2352-3026(15)00074-5 26688235 \n30. Doolittle ND Korfel A Lubow MA Schorb E Schlegel U Rogowski S Fu R Dósa E Illerhaus G Kraemer DF Muldoon LL Calabrese P Hedrick N Tyson RM Jahnke K Maron LM Butler RW Neuwelt EA Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma Neurology 2013 81 1 84 92 10.1212/WNL.0b013e318297eeba 23685932 \n31. Roth P Martus P Kiewe P Möhle R Klasen H Rauch M Röth A Kaun S Thiel E Korfel A Weller M Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial Neurology 2012 2012 79 9 890 896 10.1212/WNL.0b013e318266fcb2 \n32. Fritsch K Kasenda B Schorb E Hau P Bloehdorn J Möhle R Löw S Binder M Atta J Keller U Wolf HH Krause SW Heß G Naumann R Sasse S Hirt C Lamprecht M Martens U Morgner A Panse J Frickhofen N Röth A Hader C Deckert M Fricker H Ihorst G Finke J Illerhaus G High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study) Leukemia 2017 31 4 846 852 10.1038/leu.2016.334 27843136 \n33. Mendez JS Ostrom QT Gittleman H Kruchko C DeAngelis LM Barnholtz-Sloan JS Grommes C The elderly left behind-changes in survival trends of primary central nervous system lymphoma over the past 4 decades Neuro-Oncology 2018 20 5 687 694 10.1093/neuonc/nox187 29036697\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2524-3489",
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"journal": "Neurological research and practice",
"keywords": "Bonn protocol; Consolidation chemotherapy; Intraventricular therapy; Methotrexate; PCNSL",
"medline_ta": "Neurol Res Pract",
"mesh_terms": null,
"nlm_unique_id": "101767802",
"other_id": null,
"pages": "17",
"pmc": null,
"pmid": "33324883",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "17312328;24928128;20225195;10963643;24101038;9552066;14597744;16217075;638249;25480497;22895585;25304271;23670107;14597741;19767089;29054815;23569323;14597745;27843136;29036697;23685932;14735176;20970380;22570142;27476790;18931887;9815588;10563430;1835848;26688235;12488408",
"title": "HDMTX-based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy (modified Bonn protocol) in primary CNS lymphoma: a monocentric retrospective analysis.",
"title_normalized": "hdmtx based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy modified bonn protocol in primary cns lymphoma a monocentric retrospective analysis"
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"abstract": "Aspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis, and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may select for compensatory mutations in the A. flavus genome, resulting in azole resistance. Here, we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole-susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole-genome sequencing revealed the high genetic relatedness of all isolates, indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. The whole-genome sequencing of susceptible and azole-resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene, which corresponds to the Y121F mutation found in A. fumigatus. One azole-resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter (AFLA 083950).",
"affiliations": "Department of Medical Microbiology, Radboud University Medical Center, 6525 GANijmegen, The Netherlands.;Westerdijk Fungal Biodiversity Institute, 3584 CT Utrecht, The Netherlands.;Center of Expertise in Mycology Radboudumc/CWZ, 6525 GA Nijmegen, The Netherlands.;Department of Medical Microbiology, Radboud University Medical Center, 6525 GANijmegen, The Netherlands.;Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.;Department of Medical Microbiology, Radboud University Medical Center, 6525 GANijmegen, The Netherlands.;Department of Medical Microbiology, Radboud University Medical Center, 6525 GANijmegen, The Netherlands.;Department of Medical Microbiology, Radboud University Medical Center, 6525 GANijmegen, The Netherlands.",
"authors": "Buil|Jochem B|JB|;Houbraken|Jos|J|0000-0003-4893-4438;Reijers|Monique H|MH|0000-0002-4401-5103;Zoll|Jan|J|0000-0003-2155-7935;Sanguinetti|Maurizio|M|0000-0002-9780-7059;Meis|Jacques F|JF|0000-0003-3253-6080;Verweij|Paul E|PE|0000-0002-8600-9860;Melchers|Willem J G|WJG|0000-0002-5446-2230",
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"doi": "10.3390/jof7030164",
"fulltext": "\n==== Front\nJ Fungi (Basel)\nJ Fungi (Basel)\njof\nJournal of Fungi\n2309-608X\nMDPI\n\n33668871\n10.3390/jof7030164\njof-07-00164\nArticle\nGenetic and Phenotypic Characterization of in-Host Developed Azole-Resistant Aspergillus flavus Isolates\nBuil Jochem B. 12*\nhttps://orcid.org/0000-0003-4893-4438\nHoubraken Jos 3\nhttps://orcid.org/0000-0002-4401-5103\nReijers Monique H. 24\nhttps://orcid.org/0000-0003-2155-7935\nZoll Jan 12\nhttps://orcid.org/0000-0002-9780-7059\nSanguinetti Maurizio 56\nhttps://orcid.org/0000-0003-3253-6080\nMeis Jacques F. 127\nhttps://orcid.org/0000-0002-8600-9860\nVerweij Paul. E. 12\nhttps://orcid.org/0000-0002-5446-2230\nMelchers Willem J.G. 12\nPerlin David Academic Editor\n1 Department of Medical Microbiology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Jan.Zoll@radboudumc.nl (J.Z.); jacques.meis@gmail.com (J.F.M.); Paul.Verweij@radboudumc.nl (P.E.V.); Willem.Melchers@radboudumc.nl (W.J.G.M.)\n2 Center of Expertise in Mycology Radboudumc/CWZ, 6525 GA Nijmegen, The Netherlands; Monique.Reijers@radboudumc.nl\n3 Westerdijk Fungal Biodiversity Institute, 3584 CT Utrecht, The Netherlands; j.houbraken@wi.knaw.nl\n4 Department of Pulmonology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands\n5 Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; maurizio.sanguinetti@unicatt.it\n6 Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy\n7 Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital (CWZ), 6532 SZ Nijmegen, The Netherlands\n* Correspondence: jochem.buill@radboudumc.nl\n25 2 2021\n3 2021\n7 3 16420 1 2021\n22 2 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nAspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis, and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may select for compensatory mutations in the A. flavus genome, resulting in azole resistance. Here, we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole-susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole-genome sequencing revealed the high genetic relatedness of all isolates, indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. The whole-genome sequencing of susceptible and azole-resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene, which corresponds to the Y121F mutation found in A. fumigatus. One azole-resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter (AFLA 083950).\n\nCyp51A\nazole resistance\nchronic pulmonary aspergillosis\naspergillosis\nY119F\nacquired resistance\n==== Body\n1. Introduction\n\nChronic pulmonary aspergillosis (CPA) is a relatively uncommon pulmonary disease, occurring in apparently nonimmunocompromised patients. The disease often affects patients with other respiratory disorders such as chronic obstructive pulmonary disease, tuberculosis, nontuberculous mycobacteria (NTM) infection, prior pneumothorax or treated lung cancers [1,2]. Aspergillus fumigatus is the causative species of CPA in the majority of patients, but other species such as A. niger, A. terreus and A. flavus may also be cultured from patients with CPA [3]. Subacute invasive aspergillosis (SAIA) is another clinical presentation of pulmonary aspergillosis occurring in mild immunocompromised patients. The clinical and radiological features are very similar to CPA, but the progression of the disease is more rapid. In contrast to CPA, serum galactomannan is often positive in SAIA. However, SAIA has a slower course of progression (one to three months) compared to acute invasive aspergillosis [1]. Symptomatic or progressive CPA is treated primarily with itraconazole, but voriconazole and posaconazole are potential alternative agents [1,4]. Patients with SAIA should always be treated with antifungals according to the CPA guideline. Voriconazole and isavuconazole are regarded as first-line agents for these patients [1,4].\n\nAzole resistance in A. fumigatus is reported in many countries worldwide and challenges the treatment of Aspergillus diseases [5,6]. Although azole resistance has also been described in A. flavus isolates, the mechanism of azole resistance has been less extensively studied in A. flavus compared to A. fumigatus. Azole-resistant infections may be due to the direct inhalation of resistant spores present in the environment. Alternatively, azole resistance may develop during azole treatment, characterized by a phenotype switch from drug susceptible to drug resistant [7,8]. The latter occurs primarily in patients with chronic forms of aspergillosis receiving long-term therapy and especially in those with pulmonary cavities [9,10].\n\nHere, we describe a patient who was treated for SAIA. During antifungal treatment, several A. flavus isolates were cultured. The sequentially cultured isogenic isolates in this study showed a highly variable macroscopic morphology. The first two isolates appeared to be azole susceptible, and the following nine isolates had increased MICs for voriconazole and itraconazole. Azole resistance generally comes with a fitness cost, which may become apparent through growth variation when resistant isolates are cultured in the absence of azole pressure under laboratory conditions [11]. In A. fumigatus, similar variations in colony morphology were observed in sequential cultures [12]. To further understand in-host adaptation dynamics of A. flavus during antifungal treatment, we performed genetic analysis of 11 cultured A. flavus isolates from consecutive cultures obtained from a single patient during azole treatment for SAIA.\n\n2. Materials and Methods\n\n2.1. Origin of Strains and Antifungal Treatment\n\nThe 11 strains used in this study were cultured from a 66-year-old female with COPD Gold IIA. One and a half years prior to the first A. flavus culture, computed tomography (CT) of the lungs showed a cavity, and subsequent biopsy culture showed Mycobacterium intracellulare, which was treated with clarithromycin. Eight months later, CT showed an aspergilloma in the pre-existing cavity, and the patient was treated with voriconazole for six weeks. As the patient’s condition worsened, with progressive weight loss and recurrent hemoptysis, she was referred to the University Medical Centre (Nijmegen, the Netherlands) for the optimization of nontuberculosis mycobacterial treatment. Her antimycobacterial therapy was changed to clarithromycin, rifampicin and ethambutol. No clinical improvement was observed, and two sputum cultures showed A. flavus (Isolates 1 and 2), which prompted a diagnostic work-up for CPA (Figure 1 and Figure 2). The serum galactomannan (GM) index (2.0), Aspergillus IgG (43 mg/L) (ImmunoCap) and IgE antibodies (0.44 kU/L) were positive, which, together with her CT scan abnormalities, were consistent with SAIA. Antifungal treatment was again started with liposomal amphotericin B (L-AmB). Although A. flavus may be less susceptible to L-AmB treatment, the concurrent use of rifampicin precluded azole therapy, and L-AmB was chosen as the second-best option. After six weeks, both L-AmB and rifampicin were stopped due to side effects. The serum GM index had declined to 0.6. The patient was subsequently treated with voriconazole, which was changed to itraconazole after two weeks due to visual disturbances. During this therapy, A. flavus was cultured from sputum, which now showed an azole-resistant phenotype (Isolate 3), and antifungal treatment was changed to anidulafungin. In addition, terbinafine was started as the terbinafine MICs were low, and the combination was aimed to prevent or delay further resistance selection. As symptoms worsened and serum GM increased to 3, L-AmB was restarted after five weeks. As no improvement was observed despite continued antifungal and tuberculostatic agents, antifungal treatment was stopped, and the patient was discharged. The patient remained stable for some time after discharge but eventually died after 12 months.\n\nOver a six-month period, 11 isolates were cultured from the patient, and all were morphologically identified as A. flavus at the Centre of Expertise in Mycology Radboudumc/CWZ. Isolates were stored at −80 ℃ in 10% glycerol. In vitro susceptibility testing of the isolates was performed according to the EUCAST broth microdilution reference method for molds (E.def 9.2) [13]. Isolates were tested at a final drug concentration range of 0.032–16 mg/L for itraconazole, voriconazole and posaconazole. The endpoint defined as no growth was visually determined. Susceptibility testing was performed at the time the isolates were cultured, and the results were confirmed by reviving the isolates and repeating the susceptibility testing. Short tandem repeat (STR) typing was performed as described previously using three sets of three markers (AflaSTR2, AflaSTR3 and AflaSTR4) [14,15]. The isolates were phenotyped by studying the colony morphology on agar media (creatine agar (CREA), Czapek yeast extract agar (CYA) incubated at 25, 37 and 40 °C, CYA supplemented with 5% NaCl (CYAS), dichloran 18% glycerol agar (DG18), malt extract agar (MEA), Sabouraud dextrose agar (SAB) and yeast extract sucrose (YES) agar). The agar media were inoculated in a three-point position and incubated for 7 days at 25 °C (unless stated otherwise) in darkness. The composition of the media is according to Samson et al. [16]. Partial β-tubulin (BenA), calmodulin (CaM) and RNA polymerase II second largest subunit (RPB2) sequencing were performed as previously described [17].\n\n2.2. Whole-Genome Sequencing and Analysis\n\nGenomic DNA was extracted from conidia. Conidia were suspended in Tris–EDTA buffer (pH 8, supplemented with 1% SDS, 2% Triton × 100 and 100 mM NaCl). The suspension was shaken for 30 min at 70 °C. DNA was extracted using phenol/chloroform and purified using the QIAamp DNA Blood Mini kit (Qiagen, Aarhus, Denmark). A fragmented genomic DNA library was prepared using a Nextera XT DNA sample preparation kit (Illumina, San Diego, USA). Subsequent sequencing was conducted in a paired-end 2 × 150 bp mode using an Illumina NextSeq500 machine. Reads were mapped to the Aspergillus flavus NRRL3357 (Assembly GCA_000006275.2, EnsemblFungi) and Aspergillus oryzae RIB40 (ASM18445v3) (Assembly GCA_000184455.3, EnsemblFungi) reference genomes using CLC Genomics Workbench 12 (Qiagen, Aarhus, Denmark). Single-nucleotide polymorphism (SNP) detection and variant comparisons were conducted using CLC Genomics Workbench 12 (Qiagen) and the Basic Variant Detection method with ploidy 1, a minimum coverage of 5 and a minimum probability of 0.8.\n\nWhole-genome sequencing data from 14 A, flavus and A. oryzae strains were obtained from the NCBI SRA database (Appendix A Table A1). Contigs were generated by de novo assembly using sequencing reads from all clinical samples and reference strains. Whole-genome alignment was performed on sets of contigs with a minimum size of 10 kb. Whole-genome alignment and pairwise comparison were performed using the Whole-Genome Alignment tool implemented in CLC Genomic Workbench version 20.0.4 with default settings [18]. The generated distance matrix, based on the average nucleotide identity (ANI), was used to calculate the neighbor-joining phylogenetic relationships (Figure 3).\n\nSNP-calling on the various clinical samples was done by mapping reads of individual strains to contigs obtained from strain V159-40 as a reference genome. Variants were determined by the Basic Variant Detection tool in CLC Genomics Workbench version 20. The ploidy number was set to one and the minimum frequency filter to 95%. Default values were used for all other parameters and variant filters. Sequences containing SNPs present in a total of 177 positions were aligned using MAFFT [19]. A maximum-likelihood phylogenetic tree was calculated using CLC Genomics Workbench version 20.\n\n3. Results\n\n3.1. Strains, Phenotypical Analysis and Genotyping\n\nPartial BenA, CaM and RPB2 sequencing confirmed the morphological species identification as A. flavus. All isolates had identical BenA, CaM and RPB2 sequences. The results of the susceptibility testing are shown in Table 1. Isolates 1 and 2 had low MICs for the azoles, and the azole MICs of Isolates 3–11 were increased compared to Isolates 1 and 2. Repeated testing of isolates showed similar MICs (within two dilution steps) for all isolates, except Isolate 4. For Isolate 4, the increased MICs could not be reproduced, even after subculturing the isolate on azole-containing agar first. The MIC of amphotericin B was either 1 or 2 mg/L for all isolates, and the MIC of anidulafungin ranged from 0.016 to 0.025 mg/L (Table 1).\n\nGrowth analysis of the isolates at eight different conditions revealed a diverse colony morphology (Figure 4 and Figure A1), and none of the isolates were phenotypically identical. Isolates 1 and 2 showed typical spreading A. flavus colonies, with abundant sclerotia production on CYA incubated at 25 °C and yellow-green-colored conidia. Isolate 5 resembled Isolates 1 and 2, though sporulation was absent on most agar media, and growth was reduced on DG18. Isolates 3, 6, 8 and 11 had similar colony diameters, and of those isolates, 6 and 11 had a similar degree of sporulation. Compared to Isolates 1 and 2, these isolates had smaller colony diameters on CYAS and DG18. Isolate 4 was unique in producing greenish-brown-colored conidia, and Isolate 9 had very restricted growth, unlike all other isolates. Isolates 7 and 10 resembled each other in colony diameters, though Isolate 7 sporulated more strongly. Short tandem repeat genotyping revealed full genetic relatedness between all isolates, suggesting that the isolates originate from the same parent strain. The tandem repeat numbers are shown in Table 1.\n\n3.2. Whole-Genome Sequence Analysis\n\nAspergillus flavus NRRL3357 and A. oryzae RIB40 were used as reference genomes for read mapping based on an assessment of mapping quality and coverage statistics; a mean coverage of approximately 40 and a mean mapping quality score of 40 were found across the sequenced isolates. A total of 31 nonsynonymous SNPs, absent in early Isolates 1 and 2, were identified in later isolates (Table 2). The cyp51A mutation Y119F (corresponding to the Y121F mutation in A. fumigatus) was found in Isolates 3 and 5-11 but not in Isolate 4. Isolates 3, 5, 6, 8, 9 and 11 had a mutation in a gene with putative C-4 methyl sterol oxidase function, resulting in a stop codon at Locus 35. Isolate 4 did have a point mutation in a putative major facilitator superfamily (MFS) transporter (AFLA_083950). Phylogenetic relationship analysis based on whole-genome sequencing data confirmed the results based on short tandem repeat genotyping. All sequential cultured strains showed a genetic relationship (Figure 3). Phylogenetic relationship analyses of the 11 cultured A. flavus strain showed that Isolates 2, 7 and 10 were genetically highly similar to each other. Isolates 3, 6, 8, 9 and 11 were more genetically related to each other (Figure A2).\n\n4. Discussion\n\nHere, we describe the characteristics of 11 A. flavus isolates that were cultured during the treatment of SAIA in a patient with chronic lung disease. All isolates were identified as A. flavus and had identical partial BenA, CaM and RPB2 gene sequences, showing high genetic similarity. STR analysis and whole-genome sequencing further confirmed the isogeneity of all isolates. The isolates were macroscopically very diverse and later isolates showed decreased in vitro susceptibility to azoles.\n\nAzole resistance is an increasing problem worldwide, especially in A. fumigatus. [20]. However, reports on azole resistance in A. flavus are sparse, and the resistance mechanisms are generally unknown. Several single-nucleotide polymorphisms (SNPs) have been reported in the A. flavus Cyp51 genes encoding lanosterol 14 alpha-demethylase. This protein is the target of azoles, and the A. flavus genome contains three orthologs of this gene. One study demonstrated S196F, A324P, N423D and V465M polymorphisms in the Cyp51C gene in an azole-resistant isolate [21]. However, another study identified the same SNPs in both azole-susceptible and azole-resistant isolates, arguing against the association of these mutations for azole resistance [22]. Another study suggested the role of the S240A SNP in the Cyp51C gene. They found an S240A SNP in an isolate with increased voriconazole MICs and confirmed its role in voriconazole tolerance by transformations [23]. However, again, this SNP was also found in many azole-susceptible isolates [21,22,24]. The last SNP in Cyp51C that was suggested to play a role in azole susceptibility is Y319H [24]. In laboratory-selected resistant isolates using voriconazole stress, both Cyp51A and Cyp51B mutations were identified compared to the parental strain. K197N, Y132N+T469S and K197N+D282E+M288L SNPs were found in the Cyp51A of isolates with increased voriconazole MICs, and H399P+D411N and T454P+T486P were observed in the Cyp51B of 2 other isolates [25]. However, a direct relationship with azole resistance was not established. In addition, other non-cyp51-mediated mechanisms, such as azole efflux, due to the overexpression of ATP-binding cassettes (ABC) and MFS transporters, have been suggested to play a role in azole resistance in A. flavus. [26].\n\nWe identified a novel Y119F substitution in the cyp51A gene, which seemed to be the cause of the azole resistance phenotype in eight of nine azole-resistant isolates. Although the relation of the Y119F mutations and azole resistance is not formally proven, strong indirect evidence is available. First, the mutation was observed in azole-resistant strains, and the genetically identical parental isolates without this mutation were susceptible. Secondly, in A. fumigatus, the homolog Y121F mutation is directly linked to increased voriconazole MICs, and this phenotype is supported by a CYP51A homology protein model [27,28]. Furthermore, Y119F-corresponding homologous mutations in other fungal species have similar effects on azole susceptibility. For example, the homolog Y132F mutation has been described in azole-resistant Candida albicans and was also found in azole-resistant C. auris and C. parapsilosis isolates [29,30,31]. The homolog Y145F mutation in C. neoformans [32] and the Y136F mutation in the Histoplasma capsulatum cyp51A gene [33] were associated with reduced voriconazole susceptibility. Furthermore, the homolog Y137F mutation in Mycosphaerella graminicola [34] and the Y136F mutation in Uncinula necator [35] are associated with resistance to triadimenol, a triazole that shows structurally more resemblance to voriconazole than to the long-tailed triazole itraconazole and posaconazole. Interestingly, the C. neoformans and H. capsulatum strains with Y145F and Y136F mutations remained susceptible to itraconazole and posaconazole [32,33]. Thus, the increased MICs of voriconazole observed in our isolates are likely explained by the Y119F mutation in the Cyp51A gene. However, itraconazole showed paradoxical growth (eagle effect) in our clinical isolates, where significant growth inhibition was seen at relatively low concentration but only minimal growth inhibition at higher concentrations of itraconazole. Whether the Y119F substitution is causing this phenomenon and whether itraconazole remains clinical effective is not clarified.\n\nAnother mutation resulting in a stop codon at Locus 35 found in six of nine azole-resistant isolates might also be involved in adaptation to azole stress. Orthologs of the AFLA_115530 gene, which has a putative C-4 methyl sterol oxidase function, are involved in sterol biosynthesis. The orthologs ERG25 and ERG25b in A. fumigatus are upregulated during azole stress [36]. Furthermore, in vitro itraconazole selection was pressure-selected for a mutation in the ERG25 gene of A. fumigatus. [37]. Although the precise function and its effect on azole susceptibility are largely unknown, azole stress may have resulted in the selection of this mutation. In addition to azole treatment, the patient was treated with L-AmB and anidulafungin, which may select for mutations in the ERG genes or FKS gene. However, none of the isolates had increased L-AmB MICs and SNPs in the FKS gene were not identified.\n\nIsolate 4 did not harbor the Y119F Cyp51A mutation or the mutation putative C-4 methyl sterol oxidase. Initial testing showed increased MICs for itraconazole and voriconazole, but after reviving the stored isolate, repeated testing could not confirm the initially observed phenotype. It could be that this isolate harbored a nonstable resistance mechanism that was lost during storage and subculturing. However, growing the isolate under azole pressure did not reproduce the increased MICs (data not shown). Alternatively, the stored isolate might not have been a pure culture, and reviving and subculturing may have resulted in the selection of a faster-growing nonresistant isolate. Whole-genome sequencing revealed a mutation in the putative MFS transporter (AFLA_083950) gene of this isolate. In A. fumigatus, azole stress increases the expression of the ortholog AFU1G15490 gene, and thus this gene may be involved in the development of azole tolerance [38]. However, further studies would be required to confirm this observation.\n\nIsolates 3, 5, 6, 8 and 11 share a similar mutation pattern and also have similar growth rates (Table A2). Compared to isolates 1 and 2 (wild-type phenotype), all strains grow slower on DG18 and, with the exception of Isolate 5, slower on CYAS (Figure 4). These two agar media have a lowered water activity due to the presence of glycerol (DG18) and NaCl (CYAS). It can be speculated that the evolution of the isolate in the patient led to reduced stress resistance against lowered water activity, a condition not present in the human lung. In contrast, A. fumigatus isolates obtained from humans with suspected invasive pulmonary aspergillosis and dogs with sino-orbital aspergillosis have a higher growth rate on DG18 compared with environmental strains [39]. Isolate 4 has four mutations (R52G, V99A, A561T, T159I) that are not observed in the other isolates. The production of greenish-brown-colored conidia is a unique macro-morphological feature of this isolate and might be linked to one or a combination of these mutations. The function of two genes with mutations is unknown; the other two are an MSF transporter and a global gene regulator VeA. Isolates 7 and 10 resemble each other and these two strains only have the Y119F mutation. These strains have similar growth rates as Isolates 1 and 2 but lack the production of sclerotia and acid production on CREA.\n\nPhylogenetic analysis of the isolates showed that Isolates 2, 7 and 10 were highly similar, indicating these isolates were from the same subpopulation. Isolate 2 was isolated at the beginning of the infections, whereas Isolate 10 was cultured six months later. However, several less-related A. flavus isolates were cultured between Isolates 2 and 10, which possibly represent different subpopulations in the lungs of the patient. This indicates that the patient was initially infected with a single A. flavus strain, which resulted in several subpopulations. Furthermore, it also indicates that these subpopulations of A. flavus were present in the lungs of the patient at the same time. The first azole-resistant isolates were cultured already after one week of voriconazole treatment. It could be that the resistant isolates acquired the resistance-associated mutations during the earlier six weeks’ voriconazole treatment and thus were already present in the lung of the patient. It could be that these resistant isolates were selected during the second treatment with voriconazole. This would explain how the resistant strains could be isolated after a very short course of voriconazole treatment. The clinical samples did not grow strains from every population in every culture that was taken from this patient. Thus, even when a culture from a patient with aspergillosis is positive, it could be that another isogenic population of Aspergillus is present in the lung with a different susceptibility phenotype if SNPs conferring resistance were selected in this subpopulation. Accordingly, as not all subpopulations will be detected in a single culture, patients with CPA treated with antifungal agents should be cultured repeatedly, especially if a pulmonary cavity is present in the lungs or the patient does not improve clinically.\n\nThe sequentially cultured isolates in this study were morphologically very diverse. Interestingly, STR and genomic analysis showed that all isolates were isogenic, indicating that the patient was infected with one single isolate. Only few SNPs were found in later isolates compared to the first two cultured isolates. The variable colony morphology may be due to fitness costs associated with resistance development, nutrient availability or adaptation to other host stressors [9,40]. In vitro studies indicate that azole stress may result in morphological variation. The in vitro selection of azole resistance using posaconazole resulted in apparent morphological changes in A. fumigatus colonies [41]. Similar morphological changes were observed in azole-resistant isolates exposed to itraconazole selection pressure [11]. Morphological variation was also seen in consecutive A. fumigatus isolates cultured from a patient with recurrent invasive aspergillosis extensively treated with several antifungals [12]. It is possible that the observed mutations in our isolates underlie the variable phenotypes, but other underlying (epi)genetic mechanisms may be undiscovered. The precise role of the mutations observed in our study regarding the morphological variation remains unknown and could not be explained by the function of the mutated genes alone. Further transformation studies would be needed to further elaborate on the role of these genes. Our observations show that genetically related isolates can be very different morphologically, and genetic relatedness cannot be excluded based on morphology alone [42].\n\nAuthor Contributions\n\nConceptualization, P.E.V. and W.J.G.M.; validation, J.B.B. and J.Z.; formal analysis, J.B.B., J.F.M., J.H. and J.Z.; writing—original draft preparation, J.B.B. and J.H.; writing—review and editing, M.H.R., J.Z., M.S., J.F.M., P.E.V. and W.J.G.M.; supervision, P.E.V. and W.J.G.M. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInformed Consent Statement\n\nPatient consent was waived as the patients was deceased.\n\nData Availability Statement\n\nThe datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nAppendix A\n\nFigure A1 Overview of the phenotypic diversity of A. flavus isolates (all reverse, 7 days at 25 °C, unless stated otherwise). Columns, left to right: CYA, CYA incubated 37 °C, CYA incubated 40 °C, CYAS, YES, MEA, CREA, DG18, SAB. Rows, top to bottom: Isolates 1–11.\n\nFigure A2 Maximum-likelihood phylogenetic tree of the 11 A. flavus isolates.\n\njof-07-00164-t0A1_Table A1 Table A1 Strain information including accession numbers of the strains used for phylogenetic analysis based on whole-genome sequencing data.\n\n\tAccession Number\tOrganism\tStrain\tOrigin\t\n1\tSRR4142427\tA. flavus\t3357 wt parent\tUnknown\tUSA\t\n2\tSRR5906257\tA. flavus\tWRRL1519\tAlmond nut\tCal. USA\t\n3\tSRR6914138\tA. flavus\tATCC200026\tPeanut\tUSA\t\n4\tSRR7615260\tA. flavus\tNRRL21882\tPeanut\tUSA\t\n5\tSRR8554744\tA. flavus\tfrom corn (Miss. USA)\tCorn\tMiss. USA\t\n6\tSRR8556699\tA. flavus\tfrom corn (Miss. USA)\tCorn\tMiss. USA\t\n7\tSRR11596600\tA. flavus\t07-S-2-5-7\tCorn\tLouis. USA\t\n8\tSRR11596612\tA. flavus\t07-S-2-5-4\tCorn\tLouis. USA\t\n9\tSRR12001143\tA. flavus\tTX-B-1-1-1\tSoil\tUSA\t\n10\tSRR12001155\tA. flavus\tPA-B-20-3-1\tSoil\tUSA\t\n12\tSRR7615261\tA. oryzae\tM2040\tIndustrial strain\tSouth Korea\t\n13\tSRR1835311\tA. oryzae\tRIB40\tIndustrial strain\tunknown\t\n15\tDRR163532\tA. oryzae\tTK-82 replicate 2\tIndustrial strain\tunknown\t\n16\tDRR163631\tA. oryzae\tTK-82 replicate 1\tIndustrial strain\tunknown\t\n17\tSAMN14278081\tA. flavus\tV152-39\tClinical sample\tThe Netherlands\t\n18\tSAMN14278082\tA. flavus\tV152-49\tClinical sample\tThe Netherlands\t\n19\tSAMN14278083\tA. flavus\tV156-58\tClinical sample\tThe Netherlands\t\n20\tSAMN14278084\tA. flavus\tV158-11\tClinical sample\tThe Netherlands\t\n21\tSAMN14278085\tA. flavus\tV158-20\tClinical sample\tThe Netherlands\t\n22\tSAMN14278086\tA. flavus\tV158-70\tClinical sample\tThe Netherlands\t\n23\tSAMN14278087\tA. flavus\tV158-75\tClinical sample\tThe Netherlands\t\n24\tSAMN14278088\tA. flavus\tV158-76\tClinical sample\tThe Netherlands\t\n25\tSAMN14278089\tA. flavus\tV158-77\tClinical sample\tThe Netherlands\t\n26\tSAMN14278090\tA. flavus\tV159-40\tClinical sample\tThe Netherlands\t\n27\tSAMN14278091\tA. flavus\tV159-56\tClinical sample\tThe Netherlands\t\n\njof-07-00164-t0A2_Table A2 Table A2 Overview of the amino acid changes of nine A. flavus isolates and the unique macromorphological characteristics.\n\nIsolate\tAmino Acid Change\tColony Diameter (mm, after 7 d, 25 °C)\tUnique Macromorphological Characters Compared to Isolates 1–2 a\t\n\tI997N\tR52G\tA221T\tV99A\tH25Q\tP38L\tA561T\tY119F\tK1757R\tI570T\tT159I\tR669Q\tE35*\tP445L\tCYAS\tDG18\t\t\n3\tx\t\tx\t\tx\tx\t\tx\tx\tx\t\tx\tx\tx\t36–38\t32–34\tColony diameters smaller on DG18 and CYAS, sporulation variable\t\n4\t\tx\t\tx\t\t\tx\t\t\t\tx\t\t\t\t50–53\t>60\tColony diameters slightly smaller on CYAS; greenish-brown-colored conidia\t\n5\tx\t\tx\t\tx\tx\t\tx\tx\tx\t\t\tx\t\t54–58\t36–38\tColony diameters smaller on DG18, slightly smaller on CYAS; sporulation generally absent or weak\t\n6\tx\t\tx\t\tx\tx\t\tx\tx\tx\t\tx\tx\t\t26–30\t32–34\tColony diameters smaller on DG18 and CYAS; sporulation variable\t\n7\t\t\t\t\t\t\t\tx\t\t\t\t\t\t\t>60\t>60\tColony diameters similar as Isolates 1–2; abundant sporulation on all agar media, except creatine agar\t\n8\tx\t\tx\t\tx\tx\t\tx\tx\tx\t\tx\tx\t\t36–38\t29–32\tColony diameters smaller on DG18 and CYAS; sporulation variable\t\n9\t\t\t\t\tx\t\t\tx\tx\tx\t\tx\tx\t\t8–10\t16–18\tColony diameters restricted on all agar media; sporulation absent\t\n10\t\t\t\t\t\t\t\tx\t\t\t\t\t\t\t54–58\t>60\tGrowth diameters slightly smaller on CYAS, sporulation generally moderate or good\t\n11\tx\t\t\t\tx\tx\t\tx\tx\tx\t\tx\tx\t\t35–38\t30–33\tColony diameters smaller on DG18 and CYAS; sporulation variable\t\na Isolates 3–11 are compared to isolates 1 and 2; the latter two isolates present a typical A. flavus phenotype with a high growth rate on most media (CYAS: >60 mm, DG18: >60 mm), production of yellow-green-colored conidia and black sclerotia. Isolates 3–11 do not produce sclerotia or acid on creatine agar.\n\nFigure 1 Chest computed tomography image showing a large pulmonary cavity in the left upper lobe with a mass lying in the cavity.\n\nFigure 2 Timeline of the antifungal treatment and A. flavus culture morphology. VCZ, voriconazole; ICZ, itraconazole; L-AMB, liposomal amphotericin B; TRB, terbinafine; ANI, anidulafungin. The dates that clinical samples were obtained from the patient are indicated in the Figure, and the numbering of the isolates is based on the date the cultures became positive. Isolates 7 and 9 were cultured from the same clinical material but showed different morphologies. Isolate 8 was cultured from a clinical sample obtained 2 days after Isolates 7 and 9. This culture was earlier positive than the cultures of Isolate 9.2.2. Strains, phenotypic analysis, antifungal susceptibility and typing.\n\nFigure 3 Neighbor-joining phylogenetic relationships of sequential isolated A. flavus strains and 14 A. flavus and A. oryzae strains obtained from the NCBI SRA database based on whole-genome sequencing data. The phylogenetic relationship was calculated from a distance matrix based on the average nucleotide identity.\n\nFigure 4 Overview of the phenotypic diversity of A. flavus isolates (all obverse, 7 days at 25 °C, unless stated otherwise). Columns, left to right: Czapek yeast extract agar (CYA), CYA incubated 37 °C, CYA incubated 40 °C, CYA supplemented with 5% NaCl (CYAS), yeast extract sucrose (YES), malt extract agar (MEA), creatine agar (CREA), dichloran 18% glycerol agar (DG18), Sabouraud dextrose agar (SAB). Rows, top to bottom: Isolates 1–11.\n\njof-07-00164-t001_Table 1 Table 1 Overview susceptibility and short tandem repeat (STR) typing of 11 sequentially cultured A. flavus isolates MIC minimal inhibitory concentration.\n\nStrain Number\tIsolation Date\t\tMIC (mg/L)\t\t\t\tSTR Numbers\t\n\t\tITC\tVOR\tPOSA\tAMB\tANI c\t2\t3\t4\t\n1 V152-39\t8-8-2013\t0.5\t1\t0.5\t1\t0.063\t23-14-17\t8-22-12\t5-7-2011\t\n2 V152-49\t12-8-2013\t1\t4\t0.25\t2\t0.031\t23-14-17\t8-22-12\t5-7-2011\t\n3 V156-58\t22-11-2013\t16 a\t>16\t0.5\t2\t0.031\t23-14-17\t8-22-12\t5-7-2011\t\n4 V158-11\t31-12-2013\t>16 a,b\t>16 b\t1\t2\t0.063\t23-14-17\t8-22-12\t5-7-2011\t\n5 V158-20\t3-1-2014\t16 a\t16\t0.5\t1\t0.016\t23-14-17\t8-22-12\t5-7-2011\t\n6 V158-70\t17-1-2014\t2\t>16\t0.5\t2\t0.016\t23-14-17\t8-22-12\t5-7-2011\t\n7 V158-75\t21-1-2014\t>16 a\t>16\t1\t2\t0.125\t23-14-17\t8-22-12\t5-7-2011\t\n8 V158-76\t23-1-2014\t>16 a\t>16\t1\t2\t0.125\t23-14-17\t8-22-12\t5-7-2011\t\n9 V158-77\t21-1-2014\t1\t16\t0.25\t2\t0.25\t23-14-17\t8-22-12\t5-7-2011\t\n10 V159-40\t3-2-2014\t>16 a\t>16\t2\t2\t0.031\t23-14-17\t8-22-12\t5-7-2011\t\n11 V159-56\t7-2-2014\t1\t>16\t0.5\t2\t0.016\t24-14-17\t8-22-12\t5-7-2011\t\nSTR, short tandem repeats; ITC, itraconazole; VOR, voriconazole; POSA, posaconazole; AMB, amphotericin B; ANI, anidulafungin. a Isolates showed paradoxical growth (eagle effect). Significant growth inhibition was seen at a relatively low concentration but only minimal growth inhibition at higher concentrations of itraconazole. b The MIC results could not be reproduced. Repeated testing showed a MIC of 0.25 mg/L for itraconazole and a MIC of 2 mg/L for voriconazole. c Repeating the MIC of anidulafungin resulted in a MIC of 0.016–0.032 mg/L for all isolates.\n\njof-07-00164-t002_Table 2 Table 2 Nonsynonymous mutations in azole-resistant A. flavus isolates compared to two isogenic azole-susceptible isolates.\n\n\t\t\tAmino Acid Change\t\t\t\t\nChr.-Pos. a\tAllele\t\tIsolate b\tA. oryzae Gene c (RefSeq Accession Numbers)\tA. flavus Gene d\tFunction\t\n\t\t\t3\t4\t5\t6\t7\t8\t9\t10\t11\t\t\t\t\n1-498965\tT\tA\tI997N\t\tI997N\tI997N\t\tI997N\t\t\tI997N\tAO090009000185 (XM_001816630)\tAFLA_052710\tGTPase activating protein\t\n1-561401\tA\tG\t\tR52G\t\t\t\t\t\t\t\tAO090009000208 (XM_023234211)\tAFLA_052490\tunknown\t\n1-1099800\tC\tT\tA221T\t\tA221T\tA221T\t\tA221T\t\t\t\tAO090009000417 (XM_001816830)\tAFLA_050600\tAldehyde dehydrogenase\t\n1-3360498\tT\tC\t\tV99A\t\t\t\t\t\t\t\tAO090005001154 (XM_023232984)\tAFLA_083950\tMSF transporter\t\n1-3370761\tT\tA\tH25Q\t\tH25Q\tH25Q\t\tH25Q\tH25Q\t\tH25Q\tAO090005001151 (XM_023232999)\tAFLA_083930\tDnaJ domain protein\t\n2-578295\tC\tT\tP38L\t\tP38L\tP38L\t\tP38L\t\t\tP38L\tAO090001000237 (XM_001818728)\t\tGlobal gene regulator VeA\t\n2-579927\tG\tA\t\tA561T\t\t\t\t\t\t\t\tAO090001000237 (XM_001818728)\t\tGlobal gene regulator VeA\t\n2-2642838\tT\tA\tY119F\t\tY119F\tY119F\tY119F\tY119F\tY119F\tY119F\tY119F\tAO090003000205 (XM_001819367)\tAFLA_036130\t14-alpha sterol demethylase\t\n2-3253116\tT\tC\tK1757R\t\tK1757R\tK1757R\t\tK1757R\tK1757R\t\tK1757R\tAO090003000437 (XM_001819566)\tAFLA_033810\tNPC protein An-Mlp1\t\n3-851374\tA\tG\tI570T\t\tI570T\tI570T\t\tI570T\tI570T\t\tI570T\tAO090023000332 (XM_023235544)\tAFLA_107440\tSla1\t\n4-1887254\tC\tT\t\tT159I\t\t\t\t\t\t\t\tAO090012000739 (XM_023236608)\t\tunknown\t\n4-4726184\tC\tT\tR669Q\t\t\tR669Q\t\tR669Q\tR669Q\t\tR669Q\tAO090166000062 (XM_023237067)\t\tunknown\t\n7-2588623\tC\tA\tE35*\t\tE35*\tE35*\t\tE35*\tE35*\t\tE35*\tAO090206000001 (XM_023233185)\tAFLA_115530\tC-4 methylsterol oxidase\t\n8-891870\tG\tA\tP445L\t\t\t\t\t\t\t\t\tAO090103000145 (XM_023233427)\tAFLA_010830\tunknown\t\nMutations are described based on mapping to the A. oryzae RIB40 reference genome. A. flavus equivalent genes are indicated. a Mutations are indicated by the chromosome number and nucleotide position in the A. oryzae RIB40 reference genome. b Subsequent isolates are indicated by their numbers: 3: V156-58, 4: V158-11, 5: V158-20, 6: V158-70, 7: V158-75, 8: V158-76, 9: V158-77, 10: 159-40, and 11: 159-56. c Annotated gene names based on the A. oryzae RIB40 reference genome. d Annotated gene names based on from the A. flavus NRRL3357 reference genome. If no annotation was available, the row was left empty.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Denning D.W. Cadranel J. Beigelman-Aubry C. Ader F. Chakrabarti A. Blot S. Ullmann A.J. Dimopoulos G. Lange C. European Society of Clinical Microbiology Chronic pulmonary aspergillosis: Rationale and clinical guidelines for diagnosis and management Eur. Respir. J. 2016 47 45 68 10.1183/13993003.00583-2015 26699723\n2. Smith N.L. Denning D.W. Underlying conditions in chronic pulmonary aspergillosis including simple aspergilloma Eur. Respir. J. 2011 37 865 872 10.1183/09031936.00054810 20595150\n3. Juan Aguilar-CompanyMartin M.T. Goterris-Bonet L. Martinez-Marti A. Sampol J. Roldan E. Almirante B. Ruiz-Camps I. Chronic pulmonary aspergillosis in a tertiary care centre in Spain: A retrospective, observational study Mycoses 2019 62 765 772 10.1111/myc.12950 31162731\n4. Ullmann A.J. Aguado J.M. Arikan-Akdagli S. Denning D.W. Groll A.H. Lagrou K. Lass-Florl C. Lewis R.E. Munoz P. Verweij P.E. Diagnosis and management of Aspergillus diseases: Executive summary of the 2017 ESCMID-ECMM-ERS guideline Clin. Microbiol. Infect. 2018 24 Suppl. S1 e1 e38 10.1016/j.cmi.2018.01.002 29544767\n5. Verweij P.E. Ananda-Rajah M. Andes D. Arendrup M.C. Bruggemann R.J. Chowdhary A. Cornely O.A. Denning D.W. Groll A.H. Izumikawa K. International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus Drug Resist. Updates 2015 21–22 30 40 10.1016/j.drup.2015.08.001\n6. Meis J.F. Chowdhary A. Rhodes J.L. Fisher M.C. Verweij P.E. Clinical implications of globally emerging azole resistance in Aspergillus fumigatus Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2016 371 10.1098/rstb.2015.0460\n7. Tashiro M. Izumikawa K. Hirano K. Ide S. Mihara T. Hosogaya N. Takazono T. Morinaga Y. Nakamura S. Kurihara S. Correlation between triazole treatment history and susceptibility in clinically isolated Aspergillus fumigatus Antimicrob. Agents Chemother. 2012 56 4870 4875 10.1128/AAC.00514-12 22751542\n8. Chen J. Li H. Li R. Bu D. Wan Z. Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma J. Antimicrob. Chemother. 2005 55 31 37 10.1093/jac/dkh507 15563516\n9. Verweij P.E. Zhang J. Debets A.J.M. Meis J.F. van de Veerdonk F.L. Schoustra S.E. Zwaan B.J. Melchers W.J.G. In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: A dilemma for clinical management Lancet Infect. Dis. 2016 16 e251 e260 10.1016/S1473-3099(16)30138-4 27638360\n10. Howard S.J. Cerar D. Anderson M.J. Albarrag A. Fisher M.C. Pasqualotto A.C. Laverdiere M. Arendrup M.C. Perlin D.S. Denning D.W. Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure Emerg. Infect. Dis. 2009 15 1068 1076 10.3201/eid1507.090043 19624922\n11. Chen P. Liu M. Zeng Q. Zhang Z. Liu W. Sang H. Lu L. Uncovering new mutations conferring azole resistance in the Aspergillus fumigatus cyp51A gene Front. Microbiol. 2019 10 3127 10.3389/fmicb.2019.03127 32038564\n12. Ballard E. Melchers W.J.G. Zoll J. Brown A.J.P. Verweij P.E. Warris A. In-host microevolution of Aspergillus fumigatus: A phenotypic and genotypic analysis Fungal Genet. Biol. 2018 113 1 13 10.1016/j.fgb.2018.02.003 29477713\n13. Arendrup M.C. Cuenca-Estrella M. Lass-Flörl C. Hope W.W. Howard S.J. EUCAST Definitive Document, E.Def 9.2 Method for the Determination of Broth Dilution Minimum Inhibitory Concentrations of Antifungal Agents for Conidia Forming Moulds EUCAST Växjö, Sweden 2014\n14. Rudramurthy S.M. de Valk H.A. Chakrabarti A. Meis J.F. Klaassen C.H. High resolution genotyping of clinical Aspergillus flavus isolates from India using microsatellites PLoS ONE 2011 6 e16086 10.1371/journal.pone.0016086 21264229\n15. Khodavaisy S. Badali H. Rezaie S. Nabili M. Moghadam K.G. Afhami S. Hagen F. Aala F. Hashemi S.J. Meis J.F. Genotyping of clinical and environmental Aspergillus flavus isolates from Iran using microsatellites Mycoses 2016 59 220 225 10.1111/myc.12451 26756650\n16. Samson R.A. Houbraken J. Thrane U. Frisvad J.C. Andersen B. Food and Indoor Fungi Westerdijk Fungal Biodiversity Institute Utrecht, The Netherlands 2019\n17. Samson R.A. Visagie C.M. Houbraken J. Hong S.B. Hubka V. Klaassen C.H. Perrone G. Seifert K.A. Susca A. Tanney J.B. Phylogeny, identification and nomenclature of the genus Aspergillus Stud. Mycol. 2014 78 141 173 10.1016/j.simyco.2014.07.004 25492982\n18. Lee I. Ouk Kim Y. Park S.C. Chun J. OrthoANI: An improved algorithm and software for calculating average nucleotide identity Int. J. Syst. Evol. Microbiol. 2016 66 1100 1103 10.1099/ijsem.0.000760 26585518\n19. Katoh K. Standley D.M. MAFFT multiple sequence alignment software version 7: Improvements in performance and usability Mol. Biol. Evol. 2013 30 772 780 10.1093/molbev/mst010 23329690\n20. Lestrade P.P.A. Meis J.F. Melchers W.J.G. Verweij P.E. Triazole resistance in Aspergillus fumigatus: Recent insights and challenges for patient management Clin. Microbiol. Infect. 2019 25 799 806 10.1016/j.cmi.2018.11.027 30580035\n21. Sharma C. Kumar R. Kumar N. Masih A. Gupta D. Chowdhary A. Investigation of multiple resistance mechanisms in voriconazole-resistant Aspergillus flavus clinical isolates from a Chest hospital surveillance in Delhi, India Antimicrob. Agents Chemother. 2018 62 e01928-17 10.1128/AAC.01928-17 29311090\n22. Choi M.J. Won E.J. Joo M.Y. Park Y.J. Kim S.H. Shin M.G. Shin J.H. Microsatellite typing and tesistance mechanism analysis of voriconazole-resistant Aspergillus flavus isolates in South Korean hospitals Antimicrob. Agents Chemother. 2019 63 e01610-18 10.1128/AAC.01610-18 30397064\n23. Liu W. Sun Y. Chen W. Liu W. Wan Z. Bu D. Li R. The T788G mutation in the cyp51C gene confers voriconazole resistance in Aspergillus flavus causing aspergillosis Antimicrob. Agents Chemother. 2012 56 2598 2603 10.1128/AAC.05477-11 22314539\n24. Paul R.A. Rudramurthy S.M. Meis J.F. Mouton J.W. Chakrabarti A. A Novel Y319H Substitution in CYP51C Associated with Azole Resistance in Aspergillus flavus Antimicrob. Agents Chemother. 2015 59 6615 6619 10.1128/AAC.00637-15 26248359\n25. Krishnan-Natesan S. Chandrasekar P.H. Alangaden G.J. Manavathu E.K. Molecular characterisation of cyp51A and cyp51B genes coding for P450 14alpha-lanosterol demethylases A (CYP51Ap) and B (CYP51Bp) from voriconazole-resistant laboratory isolates of Aspergillus flavus Int. J. Antimicrob. Agents 2008 32 519 524 10.1016/j.ijantimicag.2008.06.018 18775650\n26. Rudramurthy S.M. Paul R.A. Chakrabarti A. Mouton J.W. Meis J.F. Invasive Aspergillosis by Aspergillus flavus: Epidemiology, Diagnosis, Antifungal Resistance, and Management J. Fungi 2019 5 55 10.3390/jof5030055\n27. Snelders E. Camps S.M. Karawajczyk A. Rijs A.J. Zoll J. Verweij P.E. Melchers W.J. Genotype-phenotype complexity of the TR46/Y121F/T289A cyp51A azole resistance mechanism in Aspergillus fumigatus Fungal Genet. Biol. 2015 82 129 135 10.1016/j.fgb.2015.06.001 26092193\n28. Lescar J. Meyer I. Akshita K. Srinivasaraghavan K. Verma C. Palous M. Mazier D. Datry A. Fekkar A. Aspergillus fumigatus harbouring the sole Y121F mutation shows decreased susceptibility to voriconazole but maintained susceptibility to itraconazole and posaconazole J. Antimicrob. Chemother. 2014 69 3244 3247 10.1093/jac/dku316 25125676\n29. Perea S. Lopez-Ribot J.L. Kirkpatrick W.R. McAtee R.K. Santillan R.A. Martinez M. Calabrese D. Sanglard D. Patterson T.F. Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients Antimicrob. Agents Chemother. 2001 45 2676 2684 10.1128/AAC.45.10.2676-2684.2001 11557454\n30. Chowdhary A. Prakash A. Sharma C. Kordalewska M. Kumar A. Sarma S. Tarai B. Singh A. Upadhyaya G. Upadhyay S. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009–17) in India: Role of the ERG11 and FKS1 genes in azole and echinocandin resistance J. Antimicrob. Chemother. 2018 73 891 899 10.1093/jac/dkx480 29325167\n31. Singh A. Singh P.K. de Groot T. Kumar A. Mathur P. Tarai B. Sachdeva N. Upadhyaya G. Sarma S. Meis J.F. Emergence of clonal fluconazole-resistant Candida parapsilosis clinical isolates in a multicentre laboratory-based surveillance study in India J. Antimicrob. Chemother. 2019 74 1260 1268 10.1093/jac/dkz029 30753525\n32. Sionov E. Chang Y.C. Garraffo H.M. Dolan M.A. Ghannoum M.A. Kwon-Chung K.J. Identification of a Cryptococcus neoformans cytochrome P450 lanosterol 14alpha-demethylase (Erg11) residue critical for differential susceptibility between fluconazole/voriconazole and itraconazole/posaconazole Antimicrob. Agents Chemother. 2012 56 1162 1169 10.1128/AAC.05502-11 22155829\n33. Wheat L.J. Connolly P. Smedema M. Durkin M. Brizendine E. Mann P. Patel R. McNicholas P.M. Goldman M. Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole J. Antimicrob. Chemother. 2006 57 1235 1239 10.1093/jac/dkl133 16627592\n34. Leroux P. Walker A.S. Multiple mechanisms account for resistance to sterol 14alpha-demethylation inhibitors in field isolates of Mycosphaerella graminicola Pest Manag. Sci. 2011 67 44 59 10.1002/ps.2028 20949586\n35. Delye C. Laigret F. Corio-Costet M.F. A mutation in the 14 alpha-demethylase gene of Uncinula necator that correlates with resistance to a sterol biosynthesis inhibitor Appl. Environ. Microbiol. 1997 63 2966 2970 10.1128/AEM.63.8.2966-2970.1997 9251183\n36. Hokken M.W.J. Zoll J. Coolen J.P.M. Zwaan B.J. Verweij P.E. Melchers W.J.G. Phenotypic plasticity and the evolution of azole resistance in Aspergillus fumigatus; an expression profile of clinical isolates upon exposure to itraconazole BMC Genom. 2019 20 28 10.1186/s12864-018-5255-z\n37. Losada L. Sugui J.A. Eckhaus M.A. Chang Y.C. Mounaud S. Figat A. Joardar V. Pakala S.B. Pakala S. Venepally P. Genetic analysis using an isogenic mating pair of Aspergillus fumigatus identifies azole resistance genes and lack of MAT locus's role in virulence PLoS Pathog. 2015 11 e1004834 10.1371/journal.ppat.1004834 25909486\n38. Da Silva Ferreira M.E. Malavazi I. Savoldi M. Brakhage A.A. Goldman M.H. Kim H.S. Nierman W.C. Goldman G.H. Transcriptome analysis of Aspergillus fumigatus exposed to voriconazole Curr. Genet. 2006 50 32 44 10.1007/s00294-006-0073-2 16622700\n39. Valdes I.D. van den Berg J. Haagsman A. Escobar N. Meis J.F. Hagen F. Haas P.J. Houbraken J. Wösten H.A.B. de Cock H. Comparative genotyping and phenotyping of Aspergillus fumigatus isolates from humans, dogs and the environment BMC Microbiol. 2018 18 118 10.1186/s12866-018-1244-2 30223790\n40. Hokken M.W.J. Zwaan B.J. Melchers W.J.G. Verweij P.E. Facilitators of adaptation and antifungal resistance mechanisms in clinically relevant fungi Fungal Genet. Biol. 2019 132 103254 10.1016/j.fgb.2019.103254 31326470\n41. Faria-Ramos I. Farinha S. Neves-Maia J. Tavares P.R. Miranda I.M. Estevinho L.M. Pina-Vaz C. Rodrigues A.G. Development of cross-resistance by Aspergillus fumigatus to clinical azoles following exposure to prochloraz, an agricultural azole BMC Microbiol. 2014 14 155 10.1186/1471-2180-14-155 24920078\n42. Howard S.J. Pasqualotto A.C. Anderson M.J. Leatherbarrow H. Albarrag A.M. Harrison E. Gregson L. Bowyer P. Denning D.W. Major variations in Aspergillus fumigatus arising within aspergillomas in chronic pulmonary aspergillosis Mycoses 2013 56 434 441 10.1111/myc.12047 23369025\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2309-608X",
"issue": "7(3)",
"journal": "Journal of fungi (Basel, Switzerland)",
"keywords": "Cyp51A; Y119F; acquired resistance; aspergillosis; azole resistance; chronic pulmonary aspergillosis",
"medline_ta": "J Fungi (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101671827",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33668871",
"pubdate": "2021-02-25",
"publication_types": "D016428:Journal Article",
"references": "15563516;26585518;19624922;30580035;27638360;29544767;16622700;25125676;30626317;9251183;22751542;11557454;16627592;26248359;24920078;26756650;30397064;18775650;28080986;23329690;22314539;23369025;25909486;26282594;25492982;26092193;29477713;29311090;21264229;31266196;20595150;29325167;31162731;30753525;31326470;26699723;20949586;30223790;22155829;32038564",
"title": "Genetic and Phenotypic Characterization of in-Host Developed Azole-Resistant Aspergillus flavus Isolates.",
"title_normalized": "genetic and phenotypic characterization of in host developed azole resistant aspergillus flavus isolates"
} | [
{
"companynumb": "NL-PFIZER INC-2021340735",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
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{
"abstract": "OBJECTIVE\nMost patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years).\n\n\nMETHODS\nWe enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed.\n\n\nRESULTS\nThe median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response.\n\n\nCONCLUSIONS\nIR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.",
"affiliations": "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Hemato-pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Hemato-pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Gastroenterology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Hemato-pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Hemato-pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Hemato-pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.",
"authors": "Jain|Preetesh|P|0000-0003-2735-168X;Zhao|Shuangtao|S|0000-0002-8624-7834;Lee|Hun Ju|HJ|0000-0001-7219-5562;Hill|Holly A|HA|0000-0003-3642-1897;Ok|Chi Young|CY|0000-0002-6822-7880;Kanagal-Shamanna|Rashmi|R|0000-0001-7829-5249;Hagemeister|Fredrick B|FB|;Fowler|Nathan|N|;Fayad|Luis|L|;Yao|Yixin|Y|0000-0002-8439-6043;Liu|Yang|Y|0000-0002-1910-8076;Moghrabi|Omar B|OB|;Navsaria|Lucy|L|;Feng|Lei|L|;Nogueras Gonzalez|Graciela M|GM|;Xu|Guofan|G|;Thirumurthi|Selvi|S|;Santos|David|D|0000-0001-7636-7077;Iliescu|Cezar|C|;Tang|Guilin|G|0000-0002-9482-4806;Medeiros|L Jeffrey|LJ|0000-0001-6577-8006;Vega|Francisco|F|0000-0001-5956-452X;Avellaneda|Michelle|M|;Badillo|Maria|M|;Flowers|Christopher R|CR|0000-0002-9524-3990;Wang|Linghua|L|0000-0001-9380-0266;Wang|Michael L|ML|0000-0001-9748-5486",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.21.01797",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": null,
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "JCO2101797",
"pmc": null,
"pmid": "34797699",
"pubdate": "2021-11-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma.",
"title_normalized": "ibrutinib with rituximab in first line treatment of older patients with mantle cell lymphoma"
} | [
{
"companynumb": "US-CELLTRION INC.-2021US016035",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to clarify the outcomes of preoperative CDDP/5-FU chemotherapy (FP therapy) followed by surgery for patients with clinical Stage II/III thoracic esophageal cancer.\n\n\nMETHODS\nSeventeen patients with clinical Stage II/III thoracic esophageal cancer who underwent FP therapy followed by esophagectomy were investigated with regard to the perioperative clinical results and postoperative outcomes.\n\n\nRESULTS\nGrade 3 or 4 adverse effects associated with FP therapy were recognized in 2 of the 17 (11.8%) cases, and 16 patients completed 2 cycles of FP therapy (94.1%). Complications after surgery occurred in 7 cases (41.2%). There were 7 patients with postoperative recurrences (41.2%), 6 of whom had clinical Stage III disease. Similarly, 4 out of the 5 patients who died of cancer had clinical Stage III disease. All recurrences and cancer-related deaths were recognized in histological effectiveness of Grade 0/1 cases.\n\n\nCONCLUSIONS\nPreoperative FP therapy was found to be safe for patients with clinical Stage II/III thoracic esophageal cancer. However, the treatment seemed to be less beneficial for Stage III patients than for Stage II patients, thus suggesting that a more powerful preoperative treatment may be necessary for clinical Stage III patients.",
"affiliations": null,
"authors": "Kasagi|Yuta|Y|;Saeki|Hiroshi|H|;Ando|Koji|K|;Hiyoshi|Yukiharu|Y|;Ito|Shuhei|S|;Sugimachi|Keishi|K|;Yamashita|Yo-Ichi|Y|;Oki|Eiji|E|;Uchiyama|Hideaki|H|;Kawanaka|Hirofumi|H|;Morita|Masaru|M|;Ikeda|Tetsuo|T|;Maehara|Yoshihiko|Y|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-254X",
"issue": "104(12)",
"journal": "Fukuoka igaku zasshi = Hukuoka acta medica",
"keywords": null,
"medline_ta": "Fukuoka Igaku Zasshi",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D004938:Esophageal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9423321",
"other_id": null,
"pages": "523-9",
"pmc": null,
"pmid": "24693680",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical results of preoperative CDDP/5-FU chemotherapy followed by surgery for patients with clinical stage II/III thoracic esophageal cancer.",
"title_normalized": "clinical results of preoperative cddp 5 fu chemotherapy followed by surgery for patients with clinical stage ii iii thoracic esophageal cancer"
} | [
{
"companynumb": "JP-ACCORD-038017",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
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