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{ "abstract": "MALT1 mutations impair normal NF-κB activation and paracaspase activity to cause a novel combined immunodeficiency. The clinical and immunological phenotype of MALT1 deficiency can be successfully treated with hematopoietic stem cell transplantation following reduced intensity conditioning.", "affiliations": "Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.;Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.;Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.;Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.;Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.;Pathology and Laboratory Medicine, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.;Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.;Medical Genetics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.;Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.;Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada. Electronic address: sturvey@cw.bc.ca.", "authors": "Rozmus\|Jacob\|J\|;McDonald\|Rachel\|R\|;Fung\|Shan-Yu\|SY\|;Del Bel\|Kate L\|KL\|;Roden\|Juliana\|J\|;Senger\|Christof\|C\|;Schultz\|Kirk R\|KR\|;McKinnon\|Margaret L\|ML\|;Davis\|Jeffrey\|J\|;Turvey\|Stuart E\|SE\|", "chemical_list": "D016328:NF-kappa B; D009363:Neoplasm Proteins; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein", "country": "United States", "delete": false, "doi": "10.1016/j.clim.2016.04.011", "fulltext": null, "fulltext_license": null, "issn_linking": "1521-6616", "issue": "168()", "journal": "Clinical immunology (Orlando, Fla.)", "keywords": "CARD11–BCL10–MALT1 (CBM) signalosome complex; Combined immunodeficiency; Hematopoietic stem cell transplantation (HSCT); MALT1 mutations; NF-κB; Paracaspase", "medline_ta": "Clin Immunol", "mesh_terms": "D000293:Adolescent; D020169:Caspases; D002478:Cells, Cultured; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D007963:Leukocytes, Mononuclear; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D016328:NF-kappa B; D009363:Neoplasm Proteins; D015398:Signal Transduction; D016896:Treatment Outcome", "nlm_unique_id": "100883537", "other_id": null, "pages": "1-5", "pmc": null, "pmid": "27109639", "pubdate": "2016-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Successful clinical treatment and functional immunological normalization of human MALT1 deficiency following hematopoietic stem cell transplantation.", "title_normalized": "successful clinical treatment and functional immunological normalization of human malt1 deficiency following hematopoietic stem cell transplantation" }	[ { "companynumb": "CA-SA-2016SA109594", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, ...
{ "abstract": "We report an unusual case of intermittent episodes of cholestasis in a young patient. The cholestatic attacks were preceded in each case by an infection and subsequent antibiotic therapies. After ruling out many possible causes of cholestatic hepatitis, the differential diagnoses were a benign recurrent intrahepatic cholestasis or a drug-induced liver injury. We discuss here the diagnostic approach and interpretation of the genetic analysis.", "affiliations": "Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.;Division of Clinical Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.;Swiss Pediatric Liver Center, University Hospitals Geneva, Geneva, Switzerland.;Diagnostic Department, Division of Clinical Pathology, University Hospitals Geneva, Geneva, Switzerland.;Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.", "authors": "Schreiner\|Philipp\|P\|0000-0003-1610-1925;Stieger\|Bruno\|B\|;McLin\|Valérie\|V\|;Rougemont\|Anne-Laure\|AL\|;Keitel\|Verena\|V\|;Dröge\|Carola\|C\|;Müllhaupt\|Beat\|B\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1111/liv.14122", "fulltext": null, "fulltext_license": null, "issn_linking": "1478-3223", "issue": "39(11)", "journal": "Liver international : official journal of the International Association for the Study of the Liver", "keywords": "benign recurrent intrahepatic cholestasis; drug induced liver injury", "medline_ta": "Liver Int", "mesh_terms": "D000293:Adolescent; D056486:Chemical and Drug Induced Liver Injury; D002780:Cholestasis, Intrahepatic; D003937:Diagnosis, Differential; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D041781:Jaundice, Obstructive; D008297:Male; D012008:Recurrence", "nlm_unique_id": "101160857", "other_id": null, "pages": "2036-2041", "pmc": null, "pmid": "31021034", "pubdate": "2019-11", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A rare cause of a cholestatic jaundice in a North African teenager.", "title_normalized": "a rare cause of a cholestatic jaundice in a north african teenager" }	[ { "companynumb": "CH-TEVA-2020-CH-1175173", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CODEINE" }, "drugadditional": "3", "d...
{ "abstract": "Active antibody-mediated rejection (AMR) is a potentially devastating complication and consistently effective treatment remains elusive. We hypothesized that the reversal of acute AMR requires rapid elimination of antibody-secreting plasma cells (PC) with a proteasome inhibitor, bortezomib, followed by the sustained inhibition of PC generation with CTLA4-Ig or belatacept (B/B). We show in mice that B/B therapy selectively depleted mature PC producing donor-specific antibodies (DSA) and reduced DSA, when administered after primary and secondary DSA responses had been established. A pilot investigation was initiated to treat six consecutive patients with active AMR with B/B. Compassionate use of this regimen was initiated for the first patient who developed early, severe acute AMR that did not respond to steroids, plasmapheresis, and intravenous immunoglobulin after his third kidney transplant. B/B treatment resulted in a rapid reversal of AMR, leading us to treat five additional patients who also resolved their acute AMR episode and had sustained disappearance of circulating DSA for ≤30 months. This study provides a proof-of-principle demonstration that mouse models can identify mechanistically rational therapies for the clinic. Follow-up investigations with a more stringent clinical design are warranted to test whether B/B improves on the standard of care for the treatment of acute AMR.", "affiliations": "Section of Transplantation, Department of Surgery, University of Chicago, Chicago, Illinois, USA.;Department of Surgery, The Ohio State University, Columbus, Ohio, USA.;Section of Transplantation, Department of Surgery, University of Chicago, Chicago, Illinois, USA.;Section of Transplantation, Department of Surgery, University of Chicago, Chicago, Illinois, USA.;Department of Pathology, The Ohio State University, Columbus, Ohio, USA.;Section of Transplantation, Department of Surgery, University of Chicago, Chicago, Illinois, USA.;Department of Surgery, The Ohio State University, Columbus, Ohio, USA.", "authors": "Jain\|Dharmendra\|D\|0000-0002-8741-1288;Rajab\|Amer\|A\|;Young\|James S\|JS\|;Yin\|Dengping\|D\|;Nadasdy\|Tibor\|T\|;Chong\|Anita S\|AS\|0000-0003-0460-0196;Pelletier\|Ronald P\|RP\|0000-0001-6128-8333", "chemical_list": "D007518:Isoantibodies; D000069286:Bortezomib; D000069594:Abatacept", "country": "United States", "delete": false, "doi": "10.1111/ajt.15881", "fulltext": null, "fulltext_license": null, "issn_linking": "1600-6135", "issue": "20(10)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": "B cell biology; alloantibody; costimulation; desensitization; immunobiology; immunosuppression/immune modulation; kidney transplantation/nephrology; translational research/science", "medline_ta": "Am J Transplant", "mesh_terms": "D000069594:Abatacept; D000818:Animals; D000917:Antibody Formation; D000069286:Bortezomib; D006084:Graft Rejection; D006801:Humans; D007518:Isoantibodies; D016030:Kidney Transplantation; D051379:Mice", "nlm_unique_id": "100968638", "other_id": null, "pages": "2675-2685", "pmc": null, "pmid": "32243663", "pubdate": "2020-10", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "1335362;25833397;8386518;31658991;21690252;26187412;29296858;23027924;23855587;26928966;26416270;29292861;29767445;27362308;27355541;28608550;29509295;29573335;29315141;25534446;31550069;31595669;21753709;22577514;30102844;22370719;28092129;29242250", "title": "Reversing donor-specific antibody responses and antibody-mediated rejection with bortezomib and belatacept in mice and kidney transplant recipients.", "title_normalized": "reversing donor specific antibody responses and antibody mediated rejection with bortezomib and belatacept in mice and kidney transplant recipients" }	[ { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP015505", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditiona...
{ "abstract": "BACKGROUND\nCapillary hemangioma can be found in many organs, but rarely in pleura. Previously, only localized pleural capillary hemangioma cases have been reported. Corticosteroids are the most commonly recommended drugs in capillary hemangioma.\n\n\nMETHODS\nHere, we present a case of a young woman with recurrent hemorrhagic pleural effusion. Despite repeatedly thoracentesis, the routine examinations, including chest computed tomography (CT) scan, pleural effusion biochemical test, and cytology all failed to make a definite diagnosis. Thus, single port video-assisted thoracoscopy (VATS) was then performed. Numerous nodules arising from the parietal pleura were found, and biopsies showed multifocal pleural capillary. However, recurrent pleural effusion was successfully managed by oral azathioprine, after failure of dexamethasone treatment.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case of a patient with recurrent hemorrhagic pleural effusion masquerading as malignant pleurisy, but in fact caused by multifocal pleural capillary hemangioma.", "affiliations": "Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China.;Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China.;Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China.;Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China.;Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China. cgq1963@163.com.", "authors": "Nie\|Naifu\|N\|;Liu\|Zhulin\|Z\|;Kang\|Jun\|J\|;Li\|Li\|L\|;Cao\|Guoqiang\|G\|", "chemical_list": "D001379:Azathioprine", "country": "England", "delete": false, "doi": "10.1186/s12890-021-01507-5", "fulltext": "\n==== Front\nBMC Pulm Med\nBMC Pulm Med\nBMC Pulmonary Medicine\n1471-2466\nBioMed Central London\n\n1507\n10.1186/s12890-021-01507-5\nCase Report\nMultifocal pleural capillary hemangioma: a rare cause of hemorrhagic pleural effusion-case report\nNie Naifu\nLiu Zhulin\nKang Jun\nLi Li\nCao Guoqiang cgq1963@163.com\n\ngrid.410570.7 0000 0004 1760 6682 Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042 China\n10 5 2021\n10 5 2021\n2021\n21 15627 2 2021\n20 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nCapillary hemangioma can be found in many organs, but rarely in pleura. Previously, only localized pleural capillary hemangioma cases have been reported. Corticosteroids are the most commonly recommended drugs in capillary hemangioma.\n\nCase presentation\n\nHere, we present a case of a young woman with recurrent hemorrhagic pleural effusion. Despite repeatedly thoracentesis, the routine examinations, including chest computed tomography (CT) scan, pleural effusion biochemical test, and cytology all failed to make a definite diagnosis. Thus, single port video-assisted thoracoscopy (VATS) was then performed. Numerous nodules arising from the parietal pleura were found, and biopsies showed multifocal pleural capillary. However, recurrent pleural effusion was successfully managed by oral azathioprine, after failure of dexamethasone treatment.\n\nConclusions\n\nTo our knowledge, this is the first case of a patient with recurrent hemorrhagic pleural effusion masquerading as malignant pleurisy, but in fact caused by multifocal pleural capillary hemangioma.\n\nKeywords\n\nMultifocal pleural\nCapillary hemangioma\nHemorrhagic pleural effusion\nAzathioprine\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nCapillary hemangioma is a neoplasm of vascular proliferation, which is benign but may be multifocal. Capillary hemangioma is commonly found in facial skin, subcutaneous tissue and oral mucosa, although it can be found in any organs [1, 2]. In the current study, we described a case of multifocal capillary hemangioma in a young female with recurrent hemorrhagic pleural effusion and undertake a literature review of such unusual tumors. As far as we know, this is the first report of hemorrhagic pleural effusion caused by multifocal pleural capillary hemangioma.\n\nCase presentation\n\nWe report the case of a 32-year-old non-smoker female, who presented with mild dyspnea for two weeks. She denied cough, hemoptysis, fever and weight loss. Serologic tumor markers, including carcinoembryonic antigen (CEA) and α-fetoprotein (AFP), did not reveal any abnormalities. Tuberculin purified protein derivative (PPD) test of the patient was negative. A computed tomography scan (CT) of the chest revealed left pleural effusion, and there was no evidence of mediastinal lymphadenopathy and the lung fields were clear (Fig. 1a, b). Although undergoing repeatedly thoracentesis, the hemorrhagic pleural effusion was recurrent refilling. The routine biochemical test of pleural effusion showed that it was exudative, while no malignancy was detected on cytology examination. Thus, single port video-assisted thoracoscopy (VATS) was then performed. Thoracoscope showed a large number of nodules arising from the parietal pleura, with a tenacious texture and a clear margin. Biopsy was performed on multiple nodules, with a little bleeding (Fig. 2). Microscopic examination revealed the nodules comprised a conglomerate of capillary vessels, and some of the vascular spaces lined by proliferating endothelial cells. No significant atypia was found in the lining endothelial cells (Fig. 3a). Immunohistochemical (IHC) analysis showed CD31 and erythroblast transformation specific regulated gene-1(ERG) positive, and Ki-67 proliferation index was 2% (Fig. 3b–d). The biopsy was suggestive of capillary hemangioma. Dexamethasone (10 mg/day)was injected into the thoracic cavity for three consecutive days, and then the patient began to receive prednisone acetate (30 mg/day). Unfortunately, both topical and systemic dexamethasone were failure to control pleural effusion. The chest CT scan showed that medium-volume still exist after 4 weeks of oral corticosteroids (Fig. 1c, d). Hence, the patient stopped corticosteroids and switched to oral azathioprine 100 mg ever day. No side effect associated with azathioprine occurred. The patient was followed up regularly and the pleural effusion was gradually reduced. At the 12 months of follow up, reexamination with CT scan revealed no pleural effusion (Fig. 1e, f).Fig. 1 a, b CT scans revealed that left pleural effusion without any nodule in the lung fields. c, d The pleural effusion did not absorb well after 4 weeks of oral corticosteroids. e, f CT scan revealed no pleural effusion after 12 months of oral azathioprine\n\nFig. 2 Single port video-assisted thoracoscopy (VATS) showing a large number of nodules on parietal pleura, and biopsy was performed on multiple sites\n\nFig. 3 a Microscopically, the tumor was composed of capillary-sized vessels filled with red blood cells, and the lining endothelial cells showed no significant atypia (hematoxylin–eosin staining; × 100). b–d Immunohistochemical analysis on CD31 and ERG, and Ki-67, respectively\n\nDiscussion and conclusions\n\nCapillary hemangioma is an even rare congenital disease, which is thought to be associated with the imbalance between proangiogenic factors and angiogenesis inhibitors [3, 4]. Pleural capillary hemangioma was extremely rare, and all of the reported cases previously are the localized lesion [5]. As far as we know, multifocal pleural capillary hemangioma has not been reported in the literature.\n\nMultifocal pleural capillary hemangioma is more like a localized capillary hemangioma with multiple lesions, which was different from the diffuse neonatal hemangiomatosis [6]. Most previous reports describe pleural hemangiomas as being asymptomatic, and a few presenting with cough or short of breath. They are usually diagnosed incidentally or when spontaneous rupture causing hemorrhage or hemorrhagic pleural effusion [7]. As might be expected, the patient in our case presented with recurrent accumulation of one-sided pleural effusion masquerading as malignant pleurisy. Although the precise cause of pleural effusion remains unclear, the capillary tumor vessels might play a causative role in increasing microvascular permeability or pleural inflammatory processes [8].\n\nDiagnosis of hemangioma mainly depends on imaging and pathological examinations. Multifocal capillary hemangiomas may present numerous nodules on the pleural surface with pleural thickening on CT scan [9]. However, chest CT doesn’t always reveal findings suggestive of hemangiomas, especially those characterized by small pleural nodules. Medical thoracoscopy is an important method for the diagnosis of pleural hemangioma. Histopathological examination and IHC are essential. Microscopically, capillary hemangiomas consisted of vascular spaces lined by proliferating endothelial cells, with few dilated channels. The sparse inflammatory cells and fibrocollagenous stroma were found in the vascular spaces. The neoplasm showed no cellular atypia or mitosis [3, 10]. In our case, numerous nodules of pleura can found through thoracoscopy, which were biopsied and diagnosed as pleural capillary hemangioma.\n\nThe majority of hemangiomas are harmless cutaneous lesions, but approximately 10% of hemangiomas need a therapeutic approach because of their location, size, or behavior [11]. The treatments were mainly based on the location and quantity of the lesions [12].Besides, neoplasm size and adjacent structures, the age should also be considered [13]. For localized hemangioma, surgical resection is the most common approach. While for multifocal pleural capillary hemangioma, individualized and multimodal treatment approach may be necessary, including dry ice cryotherapy, sclerosing agent injection, radiotherapy, vascular embolism, surgical excision and drugs therapy [14, 15]. Drugs used include corticosteroids, interferon-alfa, propranolol and immunosuppressive agents [6, 15].\n\nSteroid hormones are most commonly used in the treatment of hemangioma, which may promote regression of the proliferating hemangioma by inhibition of cytokines, regulating of hemangioma proliferation and involution [15]. High doses of systemic or intralesional steroids are the first-line treatment [11]. In vitro studies, dexamethasone may be the best choice for treating hemangioma [14]. Local use of dexamethasone can reduce capillary permeability and relieve exudation. Immunosuppressive agents can be used in cases which did not respond to corticosteroids [16]. In our case, dexamethasone was not effective. However, after oral application of azathioprine, pleural effusion was reduced gradually and completely disappeared at the 12 months of follow up. Hence, azathioprine may be one of choice for multiple pleural hemangiomas.\n\nTo conclude, capillary hemangioma in the pleura is extremely rare, for recurrent hemorrhagic pleural effusion, the possibility of benign tumor such as hemangioma should be considered. Thoracoscopy is an important method for diagnosis. Due to the rarity of multifocal plural capillary hemangioma, the treatment still needs to be further explored. In addition to corticosteroids, immunosuppressive agents may also be potential therapeutic drugs. Hence, reporting of our case and sharing the treatment experiences may be helpful to improve for clinical therapeutic strategy.\n\nAbbreviations\n\nCT Computed tomography\n\nVATS Video-assisted thoracoscopy\n\nPPD Purified protein derivative\n\nCEA Carcinoembryonic antigen\n\nAFP α-Fetoprotein\n\nIHC Immune- histochemical\n\nERG Erythroblast transformation specific regulated gene-1\n\nAcknowledgements\n\nThe authors thank the patient and his family. We also thank the investigators, study coordinators, operation staff, and the whole project team who worked on this study.\n\nAuthors' contributions\n\nNNF and CGQ analyzed and interpreted the patient data regarding the pleural capillary hemangioma disease. NNF and LZL were major contributors in writing the manuscript. KJ and LL collected clinical data, pictures, and collated data. All authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the Daping Hospital, Army Medical University. Written informed consent was obtained from the patient.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient. Copy of the consent form is available for review.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNaifu Nie and Zhulin Liu have contributed equally to this work\n==== Refs\nReferences\n\n1. Chang MW Updated classification of hemangiomas and other vascular anomalies Lymphat Res Biol 2003 1 4 259 265 10.1089/153968503322758067 15624554\n2. Papagiannopoulos K Sheppard MN Goldstraw P Thymic Hemangioma Presenting With Recurrent Pleural Effusion Ann Thorac Surg 2000 70 1 297 299 10.1016/S0003-4975(00)01273-X 10921733\n3. Nanaware S Gothi D Joshi JM Hemorrhagic pleural effusion due to pleural hemangioma J Assoc Physicians India 2003 51 623 625 15266938\n4. Nagasaka M Naganuma H Satoh E Growth potential of orbital cavernous hemangioma suggested by vascular endothelial growth factor and its receptor flk-1 Neurol Med Chir (Tokyo) 2007 47 1 5 10 10.2176/nmc.47.5 17245007\n5. Sota Yoldi LA Vigil Vigil L Arceo SR Pleural effusion caused by a capillary hemangioma in the pleural cavity Arch Bronconeumol 2016 52 10 537 10.1016/j.arbres.2016.02.018 27087237\n6. Gottschling S Schneider G Meyer S Reinhard H Dill-Mueller D Graf N Two infants with life-threatening diffuse neonatal hemangiomatosis treated with cyclophosphamide Pediatr Blood Cancer 2006 46 2 239 242 10.1002/pbc.20522 16369922\n7. Zhi X Qiao Z Changzheng W Guoming W Guansong W Wei Y A 21-year-old male with right chest pain, dyspnoea on exertion and bloody pleural effusion Thorax 2010 65 9 769, 836 10.1136/thx.2010.137992 20805168\n8. Hashimoto N Takenaka S Akimoto Y Capillary hemangioma in a rib presenting as large pleural effusion Ann Thorac Surg 2011 91 4 e59 61 10.1016/j.athoracsur.2010.11.074 21440110\n9. Kim EY Kim TS Han J Recurrent pulmonary capillary hemangioma:dynamic contrast-enhanced CT and histopathologic findings Korean J Radiol 2012 13 3 350 354 10.3348/kjr.2012.13.3.350 22563274\n10. Abrahams NA Colby TV Pearl RH Pulmonary hemangiomas of infancy and childhood: report of two cases and review of the literature Pediatr Dev Pathol 2002 5 3 283 292 10.1007/s10024-001-0151-x 12007021\n11. Mulliken JB, Boon LM, Takahashi K, et al. Pharmacologic therapy for endangering hemangiomas. Curr Opin Dermatol 1995;109–113.\n12. Dionzon-Serra CA Salonga R Dizon R Cavernous pleural hemangioma: a rare cause of nonhemorrhagic pleural effusion Chest 2014 146 4 475A 10.1378/chest.1989638\n13. Sindhwani G Khanduri R Nadia S Pleural hemangioma: A rare cause of recurrent pleural effusion Respir Med Case Rep 2015 17 24 26 27222779\n14. Ogino I Torikai K Kobayasi S Radiation therapy for life- or function-threatening infant hemangioma Radiology 2001 218 3 834 839 10.1148/radiology.218.3.r01mr04834 11230664\n15. Hasan Q Tan ST Gush J Steroid therapy of a proliferating hemangioma: histochemical and molecular changes Pediatrics 2000 105 1 Pt 1 117 120 10.1542/peds.105.1.117 10617714\n16. Hurvitz CH Greenberg SH Song CH Hemangiomatosis of the pleura with hemorrhage and disseminated intravascular coagulation J Pediatr Surg 1982 17 1 73 75 10.1016/S0022-3468(82)80332-1 7077482\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2466", "issue": "21(1)", "journal": "BMC pulmonary medicine", "keywords": "Azathioprine; Capillary hemangioma; Hemorrhagic pleural effusion; Multifocal pleural", "medline_ta": "BMC Pulm Med", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D001379:Azathioprine; D001706:Biopsy; D005260:Female; D018324:Hemangioma, Capillary; D006491:Hemothorax; D006801:Humans; D016066:Pleural Effusion, Malignant; D010997:Pleural Neoplasms; D012008:Recurrence; D013906:Thoracoscopy; D016896:Treatment Outcome", "nlm_unique_id": "100968563", "other_id": null, "pages": "156", "pmc": null, "pmid": "33971849", "pubdate": "2021-05-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "7077482;10921733;15266938;20805168;21440110;27087237;10617714;11230664;15624554;12007021;22563274;27222779;16369922;17245007", "title": "Multifocal pleural capillary hemangioma: a rare cause of hemorrhagic pleural effusion-case report.", "title_normalized": "multifocal pleural capillary hemangioma a rare cause of hemorrhagic pleural effusion case report" }	[ { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-320118", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drug...
{ "abstract": "A 2-year-old boy had a severe cytomegalovirus (CMV) infection with multi-organ involvement, while on maintenance therapy for acute lymphoblastic leukemia. The patient was treated with intravenous gancyclovir, with a marked improvement in his clinical status, with the exception of a progressive deterioration of the renal function. He also developed hemolytic anemia and thrombocytopenia, suggesting a diagnosis of atypical hemolytic uremic syndrome (HUS). A percutaneous renal biopsy showed lesions consistent with HUS, but no evidence of CMV infection. The patient had a good clinical outcome with no evidence of renal sequelae. We report a rare association of CMV infection and HUS in the pediatric age-group, which suggests a possible cause-effect relationship that deserves further evaluation.", "affiliations": "Department of Pediatrics, Catholic University School of Medicine, Santiago, Chile. feavagna@med.puc.cl", "authors": "Cavagnaro\|F\|F\|;Barriga\|F\|F\|", "chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir", "country": "Germany", "delete": false, "doi": "10.1007/s004670000402", "fulltext": null, "fulltext_license": null, "issn_linking": "0931-041X", "issue": "14(12)", "journal": "Pediatric nephrology (Berlin, Germany)", "keywords": null, "medline_ta": "Pediatr Nephrol", "mesh_terms": "D000998:Antiviral Agents; D001706:Biopsy; D002675:Child, Preschool; D003586:Cytomegalovirus Infections; D015774:Ganciclovir; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D007668:Kidney; D007678:Kidney Glomerulus; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma", "nlm_unique_id": "8708728", "other_id": null, "pages": "1118-20", "pmc": null, "pmid": "11045399", "pubdate": "2000-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hemolytic uremic syndrome in a child with leukemia and cytomegalovirus infection.", "title_normalized": "hemolytic uremic syndrome in a child with leukemia and cytomegalovirus infection" }	[ { "companynumb": "CL-PFIZER INC-2018427443", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3",...
{ "abstract": "Rectal cancer metastasis to the breast is rare with around 19 cases reported in literature. It signifies diffuse disseminated disease or highly aggressive tumour, such that surgical intervention other than palliation has a limited role. We report a case of a 43-year-old with the above presentation. As the management differs and because of its rarity the importance of the diagnosis between primary and the metastatic breast cancer is imperative.", "affiliations": "Department of Surgery, Letterkenny University Hospital Letterkenny, County Donegal, Ireland.;Department of Surgery, Letterkenny University Hospital Letterkenny, County Donegal, Ireland.;Department of Surgery, Letterkenny University Hospital Letterkenny, County Donegal, Ireland.;Department of Surgery, Letterkenny University Hospital Letterkenny, County Donegal, Ireland.", "authors": "Ahmad\|Syed Sohail\|SS\|;Khalilullah\|Kaleem\|K\|;McGowan\|Katherine\|K\|;Dillon\|Katrina\|K\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/jscr/rjz036", "fulltext": "\n==== Front\nJ Surg Case RepJ Surg Case RepjscrJournal of Surgical Case Reports2042-8812Oxford University Press 10.1093/jscr/rjz036rjz036Case ReportUnexpected destination! Rectal carcinoma metastasis to breast Ahmad Syed Sohail Khalilullah Kaleem McGowan Katherine Dillon Katrina Department of Surgery, Letterkenny University Hospital Letterkenny, County Donegal, IrelandCorrespondence address. Department of Surgery, Letterkenny University Hospital Letterkenny, County Donegal, Ireland. E-mail: ahmad_sohail5@yahoo.com3 2019 14 3 2019 14 3 2019 2019 3 rjz03607 1 2019 03 3 2019 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2019.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nRectal cancer metastasis to the breast is rare with around 19 cases reported in literature. It signifies diffuse disseminated disease or highly aggressive tumour, such that surgical intervention other than palliation has a limited role. We report a case of a 43-year-old with the above presentation. As the management differs and because of its rarity the importance of the diagnosis between primary and the metastatic breast cancer is imperative.\n==== Body\nINTRODUCTION\nNineteen percent of patients newly diagnosed with colorectal cancer present with distant metastasis at the time of diagnosis and patients treated for cure develop metastatic disease in nearly 40%. Metastases from rectal cancer to multiple organs have been reported either as synchronous or metachronous lesions [1]. Regardless, metastatic disease from the rectum to unusual sites carries substantially poor prognosis.\n\nCASE REPORT\nA 43-year-old female, 10 weeks postpartum, underwent colonoscopy for bleeding per rectum showing a bulky tumour (Fig. 1) in the rectum at 5 cm. Histologically poorly differentiated adenocarcinoma of the rectum (Fig. 2) T3N1Mo. Underwent laparoscopic loop ileostomy formation for impending bowel obstruction. Bloods showed Hemoglobin13.6 g/dL, Bilirubin 10umol/L, CEA 3.6 ng/mL. MRI pelvis (Fig. 3a and b) showed locally advanced annular neoplasm of mid and upper rectum. CT TAP (Fig. 4) reported no distant metastasis. She had neoadjuvant chemoradiothreapy with poor response. Post chemotherapy she noticed a lump in her right breast and axilla. Breast mammogram (Fig. 5a) showed 26 mm lesion in the right breast at 10 o'clock position and ultrasound showed 27 mm lesion in right axilla. Core biopsy (Fig. 6) reported signet ring morphology. The tumour stained positive with CK20, CDX-2 and CEA. There was no staining with CK7, ER, PR or Her-2. The rectal biopsy specimen, also analysed for KRAS status, was KRAS/NRAS/BRAF negative. She is being followed up by oncology with FOLFOX+Panitumumab.\n\nFigure 1: Rectal cancer annular obstructing 5 cm from anal verge.\n\nFigure 2: Primary rectal biopsy showing mucinous poorly differentiated adenocarcinoma with signet cells KRAS/BRAS/NRAF negative.\n\nFigure 3: (a) MRI pelvis showing rectal tumour 7.3 cm two lymph nodes. (b) MRI pelvis Mucinous component within 5 mm of the right meso-rectum.\n\nFigure 4: Staging CT TAP showing no distant metastasis.\n\nFigure 5: (a) Mammogram post-neoadjuvant chemoradiothreapy showing right breast mass. (b) CT TAP pos-tneoadjuvant chemoradiothreapy showing enlarged right axillary lymph node.\n\nFigure 6: Breast core biopsy showing features similar to the primary rectal cancer.\n\nDISCUSSION\nMost breast metastases originate from the contra lateral breast [2]. Metastases to the breast from extra-mammary malignancies are rare 0.43%. Lymphoma, melanoma, sarcoma, lung carcinoma and ovarian tumour are common extra-mammary primary malignancies metastasizing to breast. Metastases from colon to breast was first reported by McIntosh and from rectum by Lal in 1999 [3]. A handful of cases of CRC metastasis to the breast have been reported, with two largest studies presenting two new cases each [4].\n\nThese metastatic lesions must be differentiated from primary breast tumours on the basis of history, clinical, radiological features, morphology of tumour and immune-histochemistry [5]. Most metastases present as palpable breast masses, occasionally adherent to the skin with slight left predominance, most common being upper outer quadrant. Rarely are there multiple or bilateral lesions [4]. Schaekelford et al. reported 55% to the left, 30% to the right and only 3% with bilateral breast metastasis. Toombs and Kalisher reported pain, tenderness or discharge is distinctly unusual. Nipple retraction has not been described, although adherence to the skin has been reported in 25%. Axillary node involvement was frequently encountered. Rumana, Rakesh Kumar, Ruiz, et al. [6, 7] reported cases of bilateral breast metastasis in young patients. Suganthi Krishnamurthy reported the youngest patient age 23 years old with rectal cancer metastasis to the breast. Hisham et al. [2] reported an unusual case of rectal carcinoma metastasis to the breast along with ocular involvement. Mihai et al. [8] reported a 53-year-old woman who post chemotherapy developed breast metastasis and later cutaneous metastasis similar in disease progression to our patient (Table 1).\nTable 1 Few reported cases of rectal cancer metastasis to breast.\n\nReferences\tAge\tSex\tPrimary cancer\tMetastasis\tLocation of breast metastasis\tRadiology\tHistology\tManagement\tOPD\t\nMy patient\t43\tF\tRectal cancer\tBreast\tRt upper quadrant/rt axilla\tMRI/CT TAP/Mammogram/US\tPoorly differentiated adenocarcinoma\tChemoradiothreapy,oncology follow-up\tOncology\t\nLal and Joffe [3]\t69\tF\tRectal cancerT3N2R0Mo\tBreast, liver, lung, brain, skin\tLeft upper outer quadrant\tCT TAP, FNA, wide local excision, elevated CEA, CA19.9\tModerately differentiated mucin secreting adenocarcinoma breast histology moderately differentiated adenocarcinoma, ER negative\tRadical anterior resectional wide local excision Poor response to chemotherapy\tRIP 4/12 after breast diagnosis\t\nSanchez et al. [1]\t36\tF\tRectal cancer\tBreast metastasis\tLeft outer upper quadrant 6 cm in size\t\t\t\t\t\nHisham et al. [2]\t32\tF\tRectal cancer\t10 months after APR, breast, spine, left eye, orbit\tLeft breast metastasis\tColonoscopy, CT abdomenpelvis Lumbosacral x-ray, MRI brain\tPoorly differentiated mucinous adenocarcinoma of the rectum, Breast Bx similar\tAPR and total mesorectal excision, excision of posterior vaginal wall, cuff of the tissue in the lateral pelvic wall\tRIP 2/12\t\nMihai et al. [8]\t53\tF\tRectal cancer\tLung, breast metastasis, skin metastasis\tBreast lump\tUltrasound, mammogram, FNA, core biopsies, local excision\t\tChemothreapy, local excision, Post op chemothreapy\tRIP\t\nWakeham et al. [4]\t43\tF\tRectal Cancer\tBilateral breast\tBreast lump 2×2.2 cm2\t\tDukes C rectal cancer\t\t\t\nLi et al. [5]\t51\tF\tPerforated rectal cancer\tBreast, lung, soft tissue\t3 cm mass in the right upper quadrant\tCT abdomen pelvis,Mammogram,US breast,axilla\tInvasive poorly differentiated adenocarcinoma rectal carcinoma T4N0M0, Core Bx breast and axilla triple negative similar to rectal histology\tLaparotomy colostomy, preop radichemothreapy\tRIP 12 months\t\nRumana Makhdomi [6]\t28\tF\tRectal cancer 4 cm away from anal verge\tBilateral breast metastasis\tLargest 3×2 cm2 and smallest 2×1 cm2\tSigmoidoscopy, colonoscopy, contrast enhanced computed tomography, mamamography, FNAC\tMucus secreting adenocarcinoma with signet-ring differentiation, metastatic mucinous adenocarcinoma of the breast,ER/PR negative\tAnteroperineal resection, adjuvant chemothreapy\tOPD follow up\t\nSingh et al. [10]\t42\tF\tRectal cancerT4 N1M0\tRight Breast lump\tOuter upper quadrant 5×4 cm2\tMammogram, FNAC, pleural fluid cytology, core needle biopsy, CEA mildly elevated\tMucin secreting adenocarcinoma with signet ring cell Signet cell carcinoma CK20 positive, CK7, ER/PR negative\tAnterior resection, chemoradiation, chemothreapy\tRIP 2/12 after breast metastasis\t\nHasukic et al. [9]\t63\tF\tRectal cancer T3N1M0\tRight breast mass 3×2 cm\tRight upper outer quadrant\tMammography, Ultrasound\tRectal adenocarcinoma T3N1M0, breast biopsy, Adenocarcinoma ER/PR neg\tAPR, Adjuvant chemoradiothreapy, open excisional breast biopsy\tRIP post 4/12 breast pathology\t\nRuiz et al. [7]\t36\tF\tRectal cancer\tBilateral breast left axilla right groin\tBilateral breast\tCT abdomen pelvis, Mammogram Ultrasound\tPoorly differentiated rectal carcinoma with signet ring cellT3N1M0\tAPR with hysterectomy, adjuvant radiochemotherapy exploratory laparotomy, incisional bx of both breast, chemothreapy nine cycles\tRIP 6 /12 after breast mets diagnosis\t\nTing Wang et al. [11]\t38\tM\tRectal cancer\tRight mammary mass 7 years after surgery\t\t\t\tAnterior resection, core needle bx, neoadjuvant chemotherapy, modified radical mastectomy\t\t\nSuganthi Krishnamurthy et al. [12]\t23\tF\tRectal cancer\tBreast/axillary metastasis two 1/2 months later\tRight upper outer quadrant\tColonoscopy, CT TAP, FNAC, Core Bx\tPoorly differentiated adenocarcinoma with signet cell\tEmergency laparotomy, loop colostomy, palliative chemotherapy\t\t\n\n\nThe time from initial diagnosis to metastasis to the breast varies between 1 month and 15 years, average between 1 and 5 years. Hasukic et al. [9] reported a 69 year old patient who had breast metastasis 30 months after the APR. Ting Wang et al. reported a 38 year old male who underwent anterior resection developing breast metastasis after 7 years.\n\nDifferentiating primary from metastatic breast neoplasms is not always easy. Mammograms help in settling doubts. The classic mammographic finding is a rounded, well-circumscribed mass no speculation, microcalcification or thickening of the skin [1, 4]. Typical ultrasound (US) features of haematogenous metastases include single or multiple, round to oval shaped, well-circumscribed hypo-echoic masses without spiculations, calcifications, or architectural distortion located superficially in subcutaneous tissue or immediately adjacent to the breast parenchyma.\n\nHistologically, the metastatic tumours show the morphological characteristics of the primary tumours. Excisional or incisional biopsy is the most commonly used procedure for the differential diagnosis [10]. There is increasing use of needle core biopsy rather than fine needle aspiration cytology. Silverman in his study reported 2529 FNA breast biopsies, 666 were malignant, only 18 of these were from extra-mammary malignancies. Alvardo et al. in his series of 10 650 breast biopsies in Mexican population, reported 24 extra-mammary cases.\n\nIn majority cases, immune-histochemistry can help to make an accurate diagnosis. Testing for expression of CK7 and CK20 is considered to be most beneficial. The great majority of primary breast cancers are CK7-positive and CK20-negative, while colorectal carcinomas are usually CK7-negative and CK20-positive. Mucinous differentiation of colorectal cancer is associated with poor outcome. In our patient, rectal tumour showed mucinous differentiation with features of signet ring cell subtype which explains the poor response to the neoadjuvant chemotherapy.\n\nMost patients succumb to the aggressive course of the disease within a year after the diagnosis of the primary tumour. Surgical treatment of secondary breast cancer is usually palliative. Mastectomy has no significant role, systemic chemotherapy is necessary in these patients. Metastasectomy with effective systemic chemotherapy can prolong survival of these patients [1, 4]. However, its role is mostly palliative.\n\nTreatment options for patients with metastatic colorectal cancer (mCRC) have changed considerably with the introduction of antiepidermal growth factor receptor (EGFR) therapies targeting EGFR transduction cascade. KRAS genotyping is mandatory in mCRC treatment prior to undertaking (EGFR) monoclonal antibody therapy. KRAS mutations have been identified as a reliably strong negative predictive factor to anti-EGFR monoclonal antibody therapies in mCRC patients.\n\nIn conclusion, a new breast mass in a patient with a known primary rectal tumour has to be considered as a breast metastasis until proven otherwise despite its rare occurrence!\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 \nSanchez LD , Chelliah T , Meisher I , Niranjan S \nRare case of breast tumor secondary to rectal adenocarcinoma . South Med J 2008 ;101 :1062 –4 .18791504 \n2 \nHisham RB , Thuaibah H , Gul YA \nMucinous adenocarcinoma of the rectum with breast and ocular metastases . Asian J Surg 2006 ;29 :95 –7 .16644510 \n3 \nLal RL , Joffe JK \nRectal carcinoma metastatic to the breast . Clin Oncol (R Coll Radiol) 1999 ;11 :422 –3 .10663337 \n4 \nWakeham NR , Satchithananda K , Svensson WE , Barrett NK , Comitis S , Zaman N , et al \nColorectal breast metastases presenting with atypical imaging features . Br J Radiol 2008 ;81 :e149 –53 .18440938 \n5 \nLi HC , Patel P , Kapur P , Huerta S \nMetastatic rectal cancer to the breast . Rare Tumors 2009 ;1 :e22 10.4081/rt.2009.e22 .21139894 \n6 \nMakhdoomi R , Mustafa F , Ahmad R , Malik S , Sheikh S , Baba KM \nBilateral breast metastasis from mucinous adenocarcinoma of the rectum: a case report and review of the literature . Turkish J Pathol 2013 ;29 :231 –4 .\n7 \nCalderillo-Ruiz GERMÁN , Herrera-Goepfert ROBERTO , Romero CD , Lopez-Basave HN , García EBR , Duran ET , et al \nRectal cancer-associated metastasis to the breast; a case report . J Cancerol 2014 ;1 :36 –40 .\n8 \nMihai R , Christie-Brown J , Bristol J \nBreast metastases from colorectal carcinoma . Breast 2004 ;13 :155 –8 .15019699 \n9 \nHasukic SI , Iljazovic ES , Odobasic AH , Matovic EA \nA rare case of primary rectal adenocarcinoma metastatic to the breast . Saudi Med J 2012 ;33 :1014 –7 .22964815 \n10 \nSingh T , Premalatha CS , Satheesh CT , Lakshmaiah KC , Suresh TM , Babu KG , et al \nRectal carcinoma metastasizing to the breast: a case report and review of literature . J Cancer Res Threaupetics 2009 ;5 :321 –3 .\n11 \nWang T , Lv Y-G , Yan Q-G , Yuan S-F , Ling R , Chen J-H , et al \nRectal carcinoma metastatic to the male breast after 7 years: case report . Onkologie 2011 ;34 :544 –6 .21985854 \n12 \nKrishnamurthy S , Rout P , Girish Mohanty S. , Huerta S \nPrimary adenocarcinoma of rectum metastasis to the breast – a Case report . J Biosci Tech 2015 ;6 :664 –6 10.4081/rt.2009.e22 .\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2042-8812", "issue": "2019(3)", "journal": "Journal of surgical case reports", "keywords": null, "medline_ta": "J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101560169", "other_id": null, "pages": "rjz036", "pmc": null, "pmid": "30891171", "pubdate": "2019-03", "publication_types": "D002363:Case Reports", "references": "10663337;15019699;16644510;18440938;18791504;20160374;21139894;21985854;22964815;24022315", "title": "Unexpected destination! Rectal carcinoma metastasis to breast.", "title_normalized": "unexpected destination rectal carcinoma metastasis to breast" }	[ { "companynumb": "IE-AMGEN-IRLSP2020183454", "fulfillexpeditecriteria": "2", "occurcountry": "IE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, ...
{ "abstract": "A 14-year-old child treated with valproic acid over several years for a seizure disorder developed abdominal pain with radiological evidence of acute pancreatitis. The association with valproic acid was not recognized, and the child continued to take the drug. The patient eventually developed steatorrhea and weight loss that improved with pancreatic enzyme replacement. Radiological evaluation showed an atrophic pancreas. Without evidence of other etiological factors, valproic acid by itself appeared to be the cause of chronic pancreatitis with exocrine pancreatic insufficiency in this patient.", "affiliations": "Sunnybrook and Women's College Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Suite HG64, Toronto, Ontario M4N 3M5, Canada.", "authors": "Cooper\|M A\|MA\|;Groll\|A\|A\|", "chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid", "country": "Canada", "delete": false, "doi": "10.1155/2001/687087", "fulltext": null, "fulltext_license": null, "issn_linking": "0835-7900", "issue": "15(2)", "journal": "Canadian journal of gastroenterology = Journal canadien de gastroenterologie", "keywords": null, "medline_ta": "Can J Gastroenterol", "mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002908:Chronic Disease; D010188:Exocrine Pancreatic Insufficiency; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D010195:Pancreatitis; D012640:Seizures; D014635:Valproic Acid", "nlm_unique_id": "8807867", "other_id": null, "pages": "127-30", "pmc": null, "pmid": "11240383", "pubdate": "2001-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case of chronic pancreatic insufficiency due to valproic acid in a child.", "title_normalized": "a case of chronic pancreatic insufficiency due to valproic acid in a child" }	[ { "companynumb": "CA-MYLANLABS-2018M1049130", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "1", ...
{ "abstract": "Chronic hepatitis C virus (HCV) infection carries increased risks for morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) but has become curable through the advent of directly acting antiviral compounds. Current guidelines of the American Society for Blood and Marrow Transplantation (ASBMT) recommend that HCV-infected HSCT candidates preferably start and complete therapy prior to transplant. However, this is often not feasible due to time constraints or treatment-limiting comorbidities, conditions and treatments. For these reasons, data on the safety of antiviral treatment, its efficacy to achieve durable eradication of the virus until full immune recovery, and late effects of former HCV infection in patients receiving HSCT are unknown. Here, we report the course of two paediatric patients with chronic HCV infection who received a full course of directly acting antivirals prior to allogeneic HSCT and achieved and maintained viral eradication throughout transplantation until complete immune recovery.", "affiliations": "Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.;Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.;Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.;Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.;Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.;Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany.;Department of Medical Microbiology, University Hospital Münster, Münster, Germany.;Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.;Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.;Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.", "authors": "Rauwolf\|Kerstin\|K\|;Herbrüggen\|Heidi\|H\|;Zöllner\|Stefan\|S\|;Thorer\|Heike\|H\|;Makarova\|Olga\|O\|;Kaiser\|Thomas\|T\|;Pettke\|Aleksandra\|A\|;Rossig\|Claudia\|C\|;Burkhardt\|Birgit\|B\|;Groll\|Andreas H\|AH\|http://orcid.org/0000-0003-1188-393X", "chemical_list": "D000998:Antiviral Agents", "country": "England", "delete": false, "doi": "10.1111/jvh.13046", "fulltext": null, "fulltext_license": null, "issn_linking": "1352-0504", "issue": "26(4)", "journal": "Journal of viral hepatitis", "keywords": "Hepatitis C; acute leukaemia; bone marrow failure; children; transplantation", "medline_ta": "J Viral Hepat", "mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D002648:Child; D004359:Drug Therapy, Combination; D018380:Hematopoietic Stem Cell Transplantation; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome", "nlm_unique_id": "9435672", "other_id": null, "pages": "454-458", "pmc": null, "pmid": "30516856", "pubdate": "2019-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Durable control of hepatitis C through interferon-free antiviral combination therapy immediately prior to allogeneic haematopoietic stem cell transplantation.", "title_normalized": "durable control of hepatitis c through interferon free antiviral combination therapy immediately prior to allogeneic haematopoietic stem cell transplantation" }	[ { "companynumb": "DE-ADIENNEP-2019AD000168", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOTEPA" }, "drugadditional": "3", ...
{ "abstract": "A 57-year-old man had been suffering from dermatomyositis and systemic sclerosis presenting interstitial pneumonia since Jan, 2004. On February 2, 2005, he was admitted to our hospital because of thrombocytopenia, hematuria and proteinuria continuing from January, 2005. Hemolytic anemia and thrombocytopenia progressed, and fragmented red cells were present in peripheral blood on the 11th hospital day. Thrombotic microangiopathy (TMA) was diagnosed and he was treated with plasma infusion and methylprednisolone pulse therapy. Bloody sputum and hypoxia were observed, and HRCT of the chest on the 12th hospital day revealed multiple infiltrates and consolidations throughout all lung fields. His hypoxia was exacerbated and he was placed on a ventilator on the 13th hospital day. Bronchoscopic examination showed bleeding from both bronchi and he was diagnosed with complicating diffuse alveolar hemorrhage. He died of progressive respiratory failure. TMA and diffuse alveolar hemorrhage are rare but important complications of dermatomyositis and systemic sclerosis and need special care.", "affiliations": "First Department of Internal Medicine, Osaka Medical College.", "authors": "Shoda\|Takeshi\|T\|;Kotani\|Takuya\|T\|;Takeuchi\|Tohru\|T\|;Makino\|Shigeki\|S\|;Hanafusa\|Toshiaki\|T\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1343-3490", "issue": "47(3)", "journal": "Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society", "keywords": null, "medline_ta": "Nihon Kokyuki Gakkai Zasshi", "mesh_terms": "D003882:Dermatomyositis; D006470:Hemorrhage; D006801:Humans; D008171:Lung Diseases; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D011650:Pulmonary Alveoli; D012595:Scleroderma, Systemic; D013927:Thrombosis", "nlm_unique_id": "9808802", "other_id": null, "pages": "227-31", "pmc": null, "pmid": "19348271", "pubdate": "2009-03", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A fulminant case of systemic sclerosis/dermatomyositis complicating thrombotic microangiopathy and diffuse alveolar hemorrhage.", "title_normalized": "a fulminant case of systemic sclerosis dermatomyositis complicating thrombotic microangiopathy and diffuse alveolar hemorrhage" }	[ { "companynumb": "JP-PFIZER INC-2018352834", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "druga...
{ "abstract": "To describe a potential drug interaction between warfarin and the combination of remdesivir with dexamethasone.\nTwo male patients, a 71-year-old and 62-year-old presented to the emergency department for symptoms of coronavirus disease 2019 (COVID-19). Both patients were on long-term warfarin therapy with their most recent international normalized ratio (INR) prior to admission within their patient specific goal as managed by their outpatient Pharmacist. In both instances, the patients denied any changes in diet, lifestyle, or missed doses of medications upon admission interview. During admission, both patients experienced a marked elevation in INR within 24 to 48 hours of the initiation of remdesivir with dexamethasone for COVID-19 pneumonia directed therapy. The patients were both eventually stable and were instructed to continue warfarin monitoring and management under the direction of their outpatient Pharmacist upon discharge.\nThe underrecognized but probable interaction between warfarin in conjunction with remdesivir and dexamethasone warrants further analysis.", "affiliations": "19994Miami VA Healthcare System, Miami, FL, USA.;3239Lake Erie College of Osteopathic Medicine, USA.;3463University of Florida, USA.", "authors": "Landayan\|Ronald Patrick\|RP\|https://orcid.org/0000-0001-8931-2008;Saint-Felix\|Sampson\|S\|;Williams\|Ashley\|A\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/08971900211008623", "fulltext": null, "fulltext_license": null, "issn_linking": "0897-1900", "issue": null, "journal": "Journal of pharmacy practice", "keywords": "COVID-19; anticoagulation; case report; coronavirus; dexamethasone; drug interaction; remdesivir; warfarin", "medline_ta": "J Pharm Pract", "mesh_terms": null, "nlm_unique_id": "8900945", "other_id": null, "pages": "8971900211008623", "pmc": null, "pmid": "33853438", "pubdate": "2021-04-15", "publication_types": "D016428:Journal Article", "references": null, "title": "Probable Interaction Between Warfarin and the Combination of Remdesivir With Dexamethasone for Coronavirus Disease 2019 (COVID-19) Treatment: A 2 Case Report.", "title_normalized": "probable interaction between warfarin and the combination of remdesivir with dexamethasone for coronavirus disease 2019 covid 19 treatment a 2 case report" }	[ { "companynumb": "US-CIPLA LTD.-2021US03380", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "REMDESIVIR" }, "drugadditional": null, ...
{ "abstract": "Sweet's syndrome is a neutrophilic dermatosis associated with many different underlying conditions but only rarely is it triggered by environmental factors such as ultraviolet (UV) exposure. We present two cases of photoinduced Sweet syndrome. Our first patient, who was taking hydrochlorothiazide, presented photodistributed lesions, pathological phototest and neutrophilic dermatosis histopathology. The phototest normalized after drug withdrawal, suggesting that both UV light and hydrochlorothiazide were necessary to cause the lesions. Our second case presented lesions clearly induced by UV light and histologically consistent with Sweet's syndrome. The MED was decreased and the lesions were reproduced with nbUVB, suggesting the diagnosis of photoinduced Sweet's syndrome. In conclusion, we report a case of neutrophilic dermatosis induced by hydrochlorothiazide and UV light and a case of photoinduced Sweet's syndrome with reproduction of the lesions after nbUVB. Both patients had a pathologic photobiological study. Our report emphasizes the need to perform phototests in patients with photodistributed Sweet's syndrome.", "affiliations": "Department of Dermatology, University Clinical Hospital of Santiago de Compostela, Spain. Electronic address: patriciaperezfeal@gmail.com.;Department of Dermatology, University Clinical Hospital of Santiago de Compostela, Spain.;Department of Dermatology, University Clinical Hospital of Santiago de Compostela, Spain.;Department of Dermatology, University Clinical Hospital of Santiago de Compostela, Spain.;Department of Pathology, University Clinical Hospital of Santiago de Compostela, Spain.;Department of Dermatology, University Clinical Hospital of Santiago de Compostela, Spain.", "authors": "Pérez-Feal\|Patricia\|P\|;Pita da Veiga\|Gabriela\|G\|;Moreiras-Arias\|Noelia\|N\|;Buján-Bonino\|Cecilia\|C\|;Suárez-Peñaranda\|José Manuel\|JM\|;Rodríguez-Granados\|M T\|MT\|", "chemical_list": "D017319:Photosensitizing Agents", "country": "Netherlands", "delete": false, "doi": "10.1016/j.pdpdt.2021.102258", "fulltext": null, "fulltext_license": null, "issn_linking": "1572-1000", "issue": "34()", "journal": "Photodiagnosis and photodynamic therapy", "keywords": "Neutrophilic dermatosis; Photodistributed; Photoinduced; Photosensitivity; Phototriggered; Sweet syndrome", "medline_ta": "Photodiagnosis Photodyn Ther", "mesh_terms": "D006801:Humans; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D016463:Sweet Syndrome; D014466:Ultraviolet Rays", "nlm_unique_id": "101226123", "other_id": null, "pages": "102258", "pmc": null, "pmid": "33737218", "pubdate": "2021-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Sweet's syndrome triggered by ultraviolet light.", "title_normalized": "sweet s syndrome triggered by ultraviolet light" }	[ { "companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-289620", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, ...
{ "abstract": "Cast nephropathy is the most common manifestation of renal injury in patients with multiple myeloma but is rarely reported in other conditions. We are reporting our experience in caring for a teenager with a metastatic neuroendocrine carcinoma who developed rapidly progressive kidney injury that advanced to end-stage renal disease. On renal biopsy extensive tubular necrosis and intratubular eosinophilic casts were noted. This previously unreported finding should prompt oncologists to closely monitor for such a complication in patients with secretory tumors. Whether early plasmapheresis could be of benefit, as has been tried in multiple myeloma, remains to be determined.", "affiliations": "Departments of *Pediatrics, Section of Pediatric Nephrology †Pediatrics, Division of Pediatric Hematology and Oncology, University of California Davis Medical Center, Sacramento, CA.", "authors": "Butani\|Lavjay\|L\|;Ducore\|Jonathan\|J\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000000556", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "38(5)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D000293:Adolescent; D000818:Animals; D001706:Biopsy; D018278:Carcinoma, Neuroendocrine; D018450:Disease Progression; D006801:Humans; D007668:Kidney; D007676:Kidney Failure, Chronic; D008297:Male; D009362:Neoplasm Metastasis", "nlm_unique_id": "9505928", "other_id": null, "pages": "e177-9", "pmc": null, "pmid": "26989910", "pubdate": "2016-07", "publication_types": "D016428:Journal Article", "references": null, "title": "End-Stage Renal Disease From Cast Nephropathy in a Teenager With Neuroendocrine Carcinoma.", "title_normalized": "end stage renal disease from cast nephropathy in a teenager with neuroendocrine carcinoma" }	[ { "companynumb": "US-BAXTER-2017BAX036083", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, ...
{ "abstract": "To identify factors associated with the prognosis in Pythium keratitis.\nThe medical records of 25 patients (26 eyes) diagnosed with Pythium keratitis at a referral institution were reviewed. The demographic and clinical characteristics, treatment, microbiological diagnosis, histopathological features, and outcomes were recorded. The histopathological specimens were reviewed. The patients were divided into a globe removal group and a globe salvage group. Univariate analysis was used to identify factors associated with poor outcomes.\nFifteen eyes (57.7%) were removed. Patients in the globe removal group were on average 16.4 years older (95% CI 6.98 to 25.88) than those in the globe salvage group, received the first medication (either topical antifungals or antibiotics) later than one day after the onset of symptoms (RR = 2.75, 95% CI 1.18 to 6.42), and had a maximal diameter of the infiltration area ≥6 mm (RR = 3.14, 95% CI 1.17 to 8.45). The globe removal group showed satellite, multifocal, or total corneal infiltration patterns (RR = 2.82, 95% CI 1.03 to 7.74) and a hypopyon (RR = 3.43, 95% CI 1.26 to 9.35) as risk factors. The histopathological examination showed a higher density of Pythium in the globe removal group than the globe salvage group (median 376 (interquartile range 323, 620) versus 107 (interquartile range 16, 260) hyphae per high power field; P = 0.035).\nThe risk of globe removal in patients with Pythium keratitis increased with age, delayed initial topical antifungal or antibiotic treatment, advanced disease at presentation, and dense Pythium hyphae infiltration of the cornea. Early recognition and treatment are critical to successfully eradicate the infection.", "affiliations": "Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Center of Excellence for Cornea and Stem Cell Transplantation, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.;Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Center of Excellence for Cornea and Stem Cell Transplantation, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.;Center of Excellence for Cornea and Stem Cell Transplantation, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.;Center of Excellence for Cornea and Stem Cell Transplantation, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.;Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Center of Excellence for Cornea and Stem Cell Transplantation, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.;Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.", "authors": "Puangsricharern\|Vilavun\|V\|0000-0002-0725-456X;Chotikkakamthorn\|Patraramon\|P\|0000-0003-1638-3176;Tulvatana\|Wasee\|W\|0000-0002-5421-5619;Kittipibul\|Thanachaporn\|T\|;Chantaren\|Patchima\|P\|0000-0002-8321-2628;Reinprayoon\|Usanee\|U\|;Kasetsuwan\|Ngamjit\|N\|;Satitpitakul\|Vannarut\|V\|0000-0002-1020-6833;Worasilchai\|Navaporn\|N\|;Chindamporn\|Ariya\|A\|0000-0002-9761-1670", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/OPTH.S303721", "fulltext": "\n==== Front\nClin Ophthalmol\nClin Ophthalmol\nopth\nclinop\nClinical Ophthalmology (Auckland, N.Z.)\n1177-5467\n1177-5483\nDove\n\n303721\n10.2147/OPTH.S303721\nOriginal Research\nClinical Characteristics, Histopathology, and Treatment Outcomes of Pythium Keratitis: A Retrospective Cohort Study\nPuangsricharern et al\nPuangsricharern et al\nhttp://orcid.org/0000-0002-0725-456X\nPuangsricharern Vilavun 12\nhttp://orcid.org/0000-0003-1638-3176\nChotikkakamthorn Patraramon 2\nhttp://orcid.org/0000-0002-5421-5619\nTulvatana Wasee 1\nKittipibul Thanachaporn 2\nhttp://orcid.org/0000-0002-8321-2628\nChantaren Patchima 2\nReinprayoon Usanee 2\nKasetsuwan Ngamjit 12\nhttp://orcid.org/0000-0002-1020-6833\nSatitpitakul Vannarut 2\nWorasilchai Navaporn 34\nhttp://orcid.org/0000-0002-9761-1670\nChindamporn Ariya 3\n1 Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand\n2 Center of Excellence for Cornea and Stem Cell Transplantation, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand\n3 Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand\n4 Department of Transfusion Medicine and Clinical Microbiology, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand\nCorrespondence: Vilavun Puangsricharern Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, 1873 Rama IV Road, Pathumwan, Bangkok, Thailand, 10330Tel +66 83-012-2999 Email vilavun@hotmail.com\n23 4 2021\n2021\n15 16911701\n25 1 2021\n25 3 2021\n© 2021 Puangsricharern et al.\n2021\nPuangsricharern et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nPurpose\n\nTo identify factors associated with the prognosis in Pythium keratitis.\n\nPatients and Methods\n\nThe medical records of 25 patients (26 eyes) diagnosed with Pythium keratitis at a referral institution were reviewed. The demographic and clinical characteristics, treatment, microbiological diagnosis, histopathological features, and outcomes were recorded. The histopathological specimens were reviewed. The patients were divided into a globe removal group and a globe salvage group. Univariate analysis was used to identify factors associated with poor outcomes.\n\nResults\n\nFifteen eyes (57.7%) were removed. Patients in the globe removal group were on average 16.4 years older (95% CI 6.98 to 25.88) than those in the globe salvage group, received the first medication (either topical antifungals or antibiotics) later than one day after the onset of symptoms (RR = 2.75, 95% CI 1.18 to 6.42), and had a maximal diameter of the infiltration area ≥6 mm (RR = 3.14, 95% CI 1.17 to 8.45). The globe removal group showed satellite, multifocal, or total corneal infiltration patterns (RR = 2.82, 95% CI 1.03 to 7.74) and a hypopyon (RR = 3.43, 95% CI 1.26 to 9.35) as risk factors. The histopathological examination showed a higher density of Pythium in the globe removal group than the globe salvage group (median 376 (interquartile range 323, 620) versus 107 (interquartile range 16, 260) hyphae per high power field; P = 0.035).\n\nConclusion\n\nThe risk of globe removal in patients with Pythium keratitis increased with age, delayed initial topical antifungal or antibiotic treatment, advanced disease at presentation, and dense Pythium hyphae infiltration of the cornea. Early recognition and treatment are critical to successfully eradicate the infection.\n\nKeywords\n\neye evisceration\neye infections\nkeratoplasty\npenetrating\noomycetes\nprognostic factors\n==== Body\nIntroduction\n\nPythium keratitis is a sight-threatening ocular disease caused by Pythium insidiosum, an aquatic oomycete. Incidence of Pythium keratitis were primarily reported in the tropical, subtropical area especially Thailand and India.1–4 Direct exposure of the cornea to the zoospores, the infectious form of P.insidiosum, can result in the development of the disease.5 According to previous reports, a history of exposure to contaminated water or vegetative material was an important risk factor for acquiring the infection.1,2,6–8 Various patterns of infiltration are described in Pythium keratitis, for example, multiple tentacle-like infiltrations, dot-like lesions, and reticular infiltrations.1,2,6,7,9–13\n\nPythium keratitis usually progresses rapidly and is unresponsive to common antifungal treatment. The reason is that the oomycetes lack ergosterol, the main target of commonly used antifungal medications, in their cytoplasmic membrane.14 Recently, some Pythium keratitis cases were successfully treated with antibiotics, such as minocycline, azithromycin, chloramphenicol, and linezolid.1,15,16 There is no standard treatment regimen for Pythium keratitis to date, but most of the patients undergo early therapeutic penetrating keratoplasty (TPK).11 Pythium antigen immunotherapy (PIAI) has also been studied, but its efficacy remains controversial.3,8,11 The evisceration and enucleation rates in Pythium keratitis range from 53.3% to 91% in Thailand.3,4,8,17\n\nSome risk factors of Pythium keratitis were previously evaluated, but their effect on the treatment outcome is still inconclusive.1,8 In this study, we retrospectively reviewed a series of Pythium keratitis patients and their clinical and histopathological characteristics and treatment outcomes to identify factors associated with globe removal.\n\nMaterials and Methods\n\nWe retrospectively reviewed the medical records of patients consecutively diagnosed with Pythium keratitis who received treatment at King Chulalongkorn Memorial Hospital (KCMH), Bangkok, Thailand, between 2006 and 2019. The diagnosis of Pythium keratitis was confirmed by either a positive microbial culture or a positive polymerase chain reaction (PCR) from a corneal scraping or corneal button part after biopsy or TPK. Patients whose document was missing were excluded from this study. The demographic data, clinical characteristics, microbiological diagnosis, treatment details, and outcome of each patient were extracted from the medical records. We divided the eyes into two groups based on the treatment outcome: a globe removal group (enucleation or evisceration) and a globe salvage group.\n\nThe study protocol was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (Certificate of approval no. 1368/2019, IRB No. 695/62). The requirement for informed consent was waived because of the nature of the study as a retrospective file review. All patient data was maintained with confidentiality. All procedures of the study adhered to the guidelines and principles laid out in the Declaration of Helsinki 1964 and its later amendments.\n\nBaseline and Clinical Characteristics and Outcomes\n\nThe following data were collected: age, sex, comorbidity, occupation, a history of ocular injury, contamination of the eye with water or natural substances (i.e., soil or plant materials), duration from the onset of symptoms to the first medical treatment (either topical antifungals or antibiotics) and from the onset of symptoms to the first TPK, follow-up time, surgical interventions and treatment outcome.\n\nData on visual acuity and the clinical characteristics described during slit-lamp examination (Topcon SL-D701 with DC4, Topcon Corporation, Tokyo, Japan) were retrieved from the patients’ first visit to our hospital. After admission, as part of our treatment protocol, all patients suspected of having Pythium keratitis were immediately treated with either topical natamycin or amphotericin B. The infectious disease unit was consulted subsequently to assess the need for PIAI, oral terbinafine, or voriconazole. One milliliter of a 2 mg/mL PIA (a crude antigen) solution, prepared according to the protocol by Mendoza et al18 was injected subcutaneously in laboratory-proven cases. Subsequently, six booster doses were scheduled at 0.5, 1, 1.5, 3, 6, and 12 months. For some cases, treatment with PIAI was continued for a year as an adjunct therapy. Complete vaccination varied depending on the hospital course, follow-up period, and the specialist’s discretion.\n\nTPK was planned in patients, who had a poor response to optimal medical therapy, those showing advanced keratitis that extended to the limbus or posterior segment, or those with perforation.17 If the infection could not be controlled with these measures, or the patient developed endophthalmitis, evisceration or enucleation was performed.\n\nThe following parameters were analyzed: the maximal diameter of the area of corneal infiltration, depth of infiltration, patterns of infiltration, and presence of an epithelial defect or hypopyon. The maximal diameter of the infiltration area and depth of infiltration were classified according to the modified Jones’ criteria19 to grade the severity of keratitis: diameter (<2 mm, 2–6 mm, >6 mm), and depth (anterior 1/3 of the cornea, middle stroma, or extension to the posterior 1/3 of the cornea).\n\nMicrobiological Examination\n\nAt the patients’ initial assessment, a microbiological examination was performed for all eyes by scraping the corneal lesions using a sterile surgical blade No.15. Specimens were sent for gram staining, 10% potassium hydroxide preparation, and cultivation on blood agar, chocolate agar, and Sabouraud dextrose agar. The cornea specimens harvested during TPK were also sent for microbiological examination as described above. P. insidiosum was diagnosed by using culture or a PCR-based assay that amplified the internal transcribed spacer region and cytochrome oxidase II gene. The PCR-product was subsequently subjected to DNA-sequencing analysis.20,21\n\nHistopathological Examination\n\nAll specimens were obtained from corneal biopsies, TPK, evisceration, or enucleation. They were fixed in 10% neutral buffered formalin and sent for histopathological examination. The paraffin-embedded tissues were stained with hematoxylin and eosin, Gomori methenamine silver, and periodic acid-Schiff. As part of this retrospective study, slides were re-evaluated by one pathologist who was unaware of the patient’s treatment outcome. The density of the infiltration with the organism was manually and separately counted in the first corneal specimen that was taken out from infected eye either the corneal button or corneal biopsy, as hyphae per high power field (400x) within the field with the highest organism density. The depths of the invasion for both organisms and inflammatory cells were also recorded. Descemet’s membranes were classified as intact or involved, perforated, or detached.\n\nData Management and Statistical Analysis\n\nData were collected from patients’ case record forms and converted to electronic files using the double-entry technique. The source documents and the electronic data were later cross-checked by two investigators to ensure the accuracy of the data. Demographic data and clinical characteristics were reported using descriptive statistics. Univariate analysis was performed for each variable. Multivariate analysis was not performed because of the small sample size.\n\nCategorical data were compared using Fisher’s exact test. The risk ratio (RR) was calculated and reported with the 95% confidence interval (95% CI). Continuous data were compared with the Student’s t-test and Mann–Whitney U-test. Data analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, N.Y., USA). A P-value < 0.05 was considered to be statistically significant.\n\nResults\n\nFrom 2006 to 2019, 26 eyes of 25 patients (14 males, 11 females) were diagnosed with Pythium keratitis at KCMH. All cases had been treated at other hospitals before they were referred to KCMH. The mean age at presentation was 46.1±14.0 (range 21–73) years. All except one patient were admitted to the hospital. None of patients had alpha-thalassemia. The mean length of hospital stay was 30.9±11.9 (range 15–54) days. The mean follow-up time was 3.08 years (ranging from 2 months to 13.5 years). Ten patients were referred from the East of Thailand. Demographic data of patients are summarized in Table 1. The demographic details, clinical features, treatment, and outcome of each patient are described in Supplementary Table 1.Table 1 Demographic Data and Possible Predisposing Factors\n\nDemographic Data\tNo. of Eyes (%) (n = 26)\t\nAge group\t\t\n <40 years\t8 (30.7)\t\n 40–60 years\t12 (46.2)\t\n >60 years\t6 (23.1)\t\nComorbidity\t\t\n Type 2 Diabetes mellitus\t1 (3.8)\t\n Hemoglobin E trait\t1 (3.8)\t\nAgriculturist\t15 (57.7)\t\nHistory of water contamination\t12 (46.2)\t\nHistory of eye contamination with natural substances (ie, soil or plant materials)\t13 (50.0)\t\nHistory of ocular injury\t10 (38.5)\t\n\nClinical Characteristics\n\nAll patients except one had unilateral involvement. The patient with bilateral involvement had a history of wastewater contact of both eyes. The patterns of corneal infiltration were examined and classified into four distinct patterns: Reticular infiltration: single faint lesion in the center with reticular (or tentacle-like) spreading (Figure 1A);\n\nSatellite infiltration: single dense infiltration surrounded by multiple small infiltrations, indistinct edge (Figure 1B);\n\nMultifocal infiltration: scattered multi-focal dense infiltrations (Figure 1C);\n\nTotal infiltration: dense infiltration of the total cornea (Figure 1D).\n\nFigure 1 Diagrams of infiltration pattern and clinical slit-lamp photographs. (A1 and A2) Diagram of a reticular infiltration pattern and a photograph of a 21-year-old student who had a history of contact-lens wearing and presented at KCMH two days after left eye irritation (Case#21); (B1 and B2) diagram of a satellite infiltration pattern and a photograph of a 55-year-old farmer who had a trauma to the right eye from grass leaves (Case#15); (C1 and C2) diagram of a multifocal infiltration pattern and a photograph of a 58-year-old farmer who had a trauma of the right eye with soil contamination (Case#24); (D1 and D2) diagram of a total infiltration pattern and a photograph of the right eye of a 61-year-old female without a significant history of ocular trauma (Case#10).\n\nThe baseline characteristics, laboratory results, and the clinical course of all patients are summarized in Table 2.Table 2 Clinical and Diagnostic Data\n\nOcular Features\tNo. of Eyes (%)\t\nBest corrected visual acuity (BCVA)\t\t\n Worse than 20/200\t24/26 (92.3)\t\n 20/40 to 20/200\t2/26 (7.7)\t\nPattern of infiltration\t\t\n Reticular\t11/24 (45.8)\t\n Satellite\t10/24 (41.7)\t\n Multifocal\t2/24 (8.3)\t\n Total infiltration\t1/24 (4.2)\t\nMaximal diameter of infiltration area (mm) (mean ± SD)\t5.56 ± 1.94\t\nDepth of infiltration\t\t\n Anterior to mid stroma\t11/23 (47.8)\t\n Posterior stroma\t12/23 (52.2)\t\nPresence of epithelial defect\t23/26 (88.5)\t\nPresence of hypopyon\t14/26 (53.8)\t\nDiagnostic laboratory\t\t\n Positive culture\t1/25 (4)\t\n Positive PCR\t4/25 (16)\t\n Positive culture, genus and species confirmed by PCR\t20/25 (80)\t\nPIAI injection\t17/26 (65.4)\t\n In globe salvage case\t7/17 (41.2)\t\n In globe removal case\t10/17 (58.8)\t\nSurgical interventions\t\t\n Corneal biopsy\t10/26 (38.5)\t\n TPK\t21/26 (80.7)\t\n Evisceration or enucleation\t15/26 (57.7)\t\nTreatment outcome\t\t\n Globe salvage\t11/26 (42.3)\t\n Globe removal\t15/26 (57.7)\t\n\nTreatment and Outcomes\n\nMost patients received a combination of at least two antifungal agents either at KCMH or at outside clinics, prior to referral. The most commonly used topical regimen was 5% natamycin and 1% voriconazole (14 eyes; 53.8%), followed by 5% natamycin and 0.17% amphotericin B (11 eyes; 42.3%). Topical antibiotics, such as 0.5% moxifloxacin (15 eyes), 1% azithromycin (5 eyes), and 0.2% linezolid (3 eyes) were also used. The treatment of 15 eyes (57.7%) also included oral terbinafine and itraconazole. Two eyes (7.7%) in two patients responded well to medical treatment alone (cases 6 and 25), and the treatment regimens in these cases are described in Supplementary Table 1.\n\nThe infection progressed in 24 eyes (92.3%) despite drug treatment. Twenty-one eyes underwent TPK, and three eyes had to be eviscerated because of uncontrollable disease. The average duration from disease onset to the first TPK was 28.9±14.6 days. After the first TPK, 6 of 21 eyes (28.6%) improved, and no subsequent surgery was needed until the patients’ discharge. Recurrence was observed in 15 of 21 eyes (71.4%). In seven of these (46.7%), we performed evisceration or enucleation and in the other eight (53.3%), a second TPK. Three eyes improved after the second TPK, while another five eyes had to undergo evisceration or enucleation.\n\nOverall, globe salvage was possible in 11 eyes (42.3%), whereas the globe had to be removed in 15 (57.7%) eyes. Seventeen eyes had received at least one dose of PIAI (Table 2).\n\nThe anatomy was preserved in all globe salvage patients, but the visual outcomes were mostly poor (the best corrected visual acuity (BCVA) ranged from hand movements to 20/25). The BCVA of 20/25 achieved in a patient with anterior stromal reticular infiltration who had BCVA of 20/50 at presentation. The details of the clinical characteristics, medical, surgical, and adjunctive management, and treatment outcomes are shown in Supplementary Table 1.\n\nFactors Affecting the Treatment Outcome\n\nWe compared the demographic data, ocular features, and histopathological characteristics between the globe salvage group and the globe removal group in Tables 3 and 4. The box plot analysis showed that there was a statistically significant difference in the duration of the disease from onset to the first medical treatment between the two groups (P = 0.02) (Figure 2). Nine of 11 cases in the globe salvage group received their first medical treatment on day one after the onset of symptoms.Table 3 Demographic Data and histopathology of Globe Salvage Group versus Globe Removal Group (Categorical Variables)\n\nA. Assessment of Predisposing Factors\tGlobe Salvage n(%), N=11\tGlobe Removal n (%), N=15\tRisk Ratio for Globe Removal\t95% CI of Risk Ratio\t\nHistory of water contamination\t\t\t\t\t\n Presence\t3 (27.3)\t9 (60.0)\t1.75\t0.88 to 3.48\t\n Absence\t8 (72.7)\t6 (40.0\t\t\t\nHistory of eye contamination with natural substances (ie, soil or plant materials)\t\t\t\t\t\n Presence\t2 (18.2)\t11 (73.3)\t2.75\t1.18 to 6.42\t\n Absence\t9 (81.8)\t4 (26.7)\t\t\t\nHistory of ocular injury\t\t\t\t\t\n Presence\t1 (9.1)\t9 (60.0)\t2.40\t1.23 to 4.67\t\n Absence\t10 (90.9)\t6 (40.0)\t\t\t\nDuration from onset of symptoms to 1st medical treatment\t\t\t\t\t\n > 1 day\t2 (18.2)\t11 (73.3)\t2.75\t1.18 to 6.42\t\n ≤ 1 day\t9 (81.8)\t4 (26.7)\t\t\t\nB. Clinical Characteristics\tGlobe Salvage n (%)\tGlobe Removal n (%)\tRisk Ratio for Globe Removal\t95% CI of Risk Ratio\t\nPattern of infiltration\tN=11\tN=13\t\t\t\n Satellite/Multifocal/Total\t3 (27.3)\t10 (76.9)\t2.82\t1.03 to 7.74\t\n Reticular\t8 (72.7)\t3 (23.1)\t\t\t\nMaximal diameter of infiltration area\tN=10\tN=15\t\t\t\n ≥ 6 mm diameter\t2 (20.0)\t12 (80.0)\t3.14\t1.17 to 8.45\t\n < 6 mm diameter\t8 (80.0)\t3 (20.0)\t\t\t\nDepth of infiltration\tN=11\tN=12\t\t\t\n Posterior stroma\t3 (27.3)\t9 (75.0)\t2.75\t0.99 to 7.62\t\n Anterior-middle stroma\t8 (72.7)\t3 (25.0)\t\t\t\nEpithelial defect\tN=11\tN=15\t\t\t\n Presence\t9 (81.8)\t14 (93.3)\t1.83\t0.36 to 9.35\t\n Absence\t2 (18.2)\t1 (6.7)\t\t\t\nHypopyon\tN=11\tN=15\t\t\t\n Presence\t2 (18.2)\t12 (80.0)\t3.43\t1.26 to 9.35\t\n Absence\t9 (81.8)\t3 (20.0)\t\t\t\nC. Histopathological Features\tGlobe Salvage n (%)\tGlobe Removal n (%)\tRisk Ratio for Globe Removal\t95% CI of Risk Ratio\t\nDescemet membrane\tN=7\tN=11\t\t\t\n Involved/Perforated/Detached\t3 (42.9)\t6 (54.5)\t1.20\t0.57 to 2.53\t\n Intact\t4 (57.1)\t5 (45.5)\t\t\t\nDepth of organism invasion\tN=6\tN=12\t\t\t\n Posterior stroma\t3 (50.0)\t9 (75.0)\t1.5\t0.63 to 3.56\t\n Anterior to mid stroma\t3 (50.0)\t3 (25.0)\t\t\t\nDepth of inflammatory cell presence\tN=8\tN=11\t\t\t\n Posterior stroma\t7 (87.5)\t8 (72.7)\t0.71\t0.34 to 1.49\t\n Anterior to mid stroma\t1 (12.5)\t3 (27.3)\t\t\t\nNotes: Boldface type highlights a significant risk ratio as determined by 95% confidence interval (CI).\n\nTable 4 Demographic Data and Histopathology of Globe Salvage Group versus Globe Removal Group (Continuous Variables)\n\nCharacteristics\tGlobe Salvage N=11\tGlobe Removal N=15\tMean Difference\t95% CI of Mean Difference\tP value\t\nDemographic data\t\nAge at onset [mean ±SD; years]\t36.6 ±13.1\t53.1 ±10.3\t16.43\t6.98 to 25.88\t0.00a\t\nDuration from onset of symptoms to 1st medical treatment [median; days (IQR†)]\t1 (1,2)\t5 (3,11)\t\t\t0.02b\t\n\tN=9\tN=12\t\t\t\t\nDuration from onset of symptoms to 1st TPK [mean ±SD; days]\t28.6 ±14.0\t29.1 ±15.6\t0.53\t−13.28 to 14.34\t0.94a\t\nHistopathological features\t\n\tN=7\tN=11\t\t\t\t\nEstimated density of organism (Median; filament per HPF‡ (IQR))\t107 (16,260)\t376 (323,620)\t\t\t0.03b\t\nNotes: †IQR, Interquartile range. ‡HPF, High-power field. P <0.05 are highlighted in boldface. aP value of independent t-test. bP value of Mann–Whitney U-test.\n\nFigure 2 Box plot demonstrates that almost all of the cases from the globe salvage group received their first medical treatment on day 1 after onset of symptoms (asterisks indicate extreme outliers).\n\nHistopathological Features\n\nExtensive infiltration of the cornea with acute inflammatory cells, extensive cellular necrosis, and stromal collagen lamellar fragmentation was found in all specimens. The most common microscopic characteristics of P. insidiosum were rarely branching and sparsely septate short hyphae that varied in size and diameter. In every specimen, P. insidiosum hyphae showed intense positive staining with Gomori methenamine silver. Pythium hyphae were much denser in the globe removal group (Figure 3–5).Figure 3 Histopathology of Pythium keratitis in a globe salvage case (Case#19). (A) Histopathology section shows an ulcerated corneal lesion with numerous acute inflammatory cells and necrotic cells primarily located at the anterior stroma (Hematoxylin-Eosin); (B) special stain shows varying sizes of short hyphae at the posterior stroma and pre-Descemet’s membrane area (Gomori Methenamine Silver).\n\nFigure 4 Histopathology of Pythium keratitis in globe salvage case (Case#05). (A) Histopathology section shows numerous acute inflammatory cells and necrotic cells in the corneal stroma (Hematoxylin-Eosin); (B) special stain shows varying-sized short hyphae at the mid stroma (Gomori Methenamine Silver).\n\nFigure 5 Histopathology of Pythium keratitis in globe removal case (Case#23). (A) Histopathology section shows numerous acute inflammatory cells and necrotic cells in the corneal stroma (Hematoxylin-Eosin); (B) special stain shows numerous varying-sized short hyphae with rare septation (Gomori Methenamine Silver).\n\nDiscussion\n\nIn this retrospective study, we aimed to identify the predictive factors for treatment outcomes in patients with Pythium keratitis. We found that the risk of globe removal increased with age, delayed initial topical antifungal or antibiotic treatment, advanced disease at presentation, and dense Pythium hyphae infiltration. All previous studies of Pythium keratitis were either small or large case series. A retrospective study from South India reported a series of 71 patients with microbiologically proven Pythium keratitis.1 The authors concluded that there was still a knowledge gap regarding the best treatment because conventional antifungal agents are not effective against P. insidiosum. Newer treatments such as linezolid, azithromycin, and PIAI were reported to be successful in healing the infection in small case series8,16 and in vitro susceptibility testing.22 Currently, TPK remains the most effective treatment but has to be done as early as possible. However, recurrence of the infection and graft failure are still problematic, frequently necessitating regrafting. In our series, we reported 42.3% of globe salvage, which is higher than in previous reports in Thailand.3,4,17 The exception was a 2019 report from Permpalung et al8 who achieved globe salvage in 53% of patients. The authors found that patients in whom the globe was salvaged were significantly younger and showed a shorter period from the onset of disease to first ocular surgery than those in whom the globe had to be removed. However, their study focused on PIAI treatment and the profile of biologic markers after treatment.\n\nClinical Characteristics\n\nMost patients were referred to KCMH from hospitals in the Eastern region of Thailand. According to previous reports from other regions in Thailand (ie, North,23 Northeast,2 and South4), the organism is widespread across the country. Although the natural habitat of P. insidiosum is soil and water, only 58% of the patients in our study were agriculturist, 46% had a history of water contamination, and 50% had a history of environmental exposure to natural substances, such as soil or plant material. This implies that Pythium keratitis may occur in patients who do not have a history of exposure to water. Most of the patients in our report had advanced disease: 92% had a visual acuity of less than 20/200, and 52.2% had deep stromal infiltration. Considering that, the globe salvage rate of 42% in our study is acceptable compared to other reports from Thailand, where it ranged from 21% to 53.3%.3,4,8\n\nFactors Affecting the Treatment Outcome\n\nPatients who had to have their globe removed were significantly older than those in whom it could be preserved (mean 53.1 vs 36.6 years). This finding was consistent with previous reports.3,8 Regarding impaired natural immune responses in older patients, infectious condition tends to cause more morbidity in this group. We also found a higher risk of globe removal in patients who had a history of ocular injury or contamination of their eyes with natural substances. It is possible that these two characteristics are confounding factors because infection in patients whose eyes were exposed to natural substances mostly involved a traumatic mechanism. This finding is consistent with reports from India1 describing that the majority of their patients had environmental exposures not involving water. Considering these data, we suggest that Pythium keratitis should be suspected in patients with findings suggestive of P. insidiosum who had disease persisting despite antifungal treatment even though there is no clear history of exposure to water.\n\nWe also found that patients who received treatment late had an approximately 2.75-times higher risk of globe removal. Contrary to a recent report,8 we did not find that patients who received early ocular surgery, especially TPK, had better outcomes. One reason may be differences in the study populations. All of our patients were referred to us from other hospitals, meaning they already had advanced disease at their first presentation. It is difficult to eradicate the infection in an advanced clinical stage with TPK.\n\nPythium keratitis is recognized for its progressive course. Within a few days, the infection may spread all over the cornea and invade the posterior stroma, causing corneal perforation. The unique histopathological patterns of Pythium keratitis were previously described as multiple tentacle-like or reticular infiltrations originating from the central lesion. Hence, we distinguished four specific patterns of corneal lesions in our patients and used these to investigate a potential association with the treatment outcome. We found that there was a significantly higher risk for globe removal in patients who had a large lesion (diameter ≥ 6 mm). Interestingly, the risk of globe removal also increased by 2.8-times in patients who had satellite, multifocal, or total corneal infiltration patterns compared to those that had a reticular pattern. In spite of not statistically significant, our result showed the risk of globe removal increased 2.75-times in eyes with posterior stromal infiltration. We conclude that a large lesion and satellite, multifocal, and total corneal infiltration patterns represent an advanced stage of disease, and these were associated with a poor treatment outcome in our study. A hypopyon is common in Pythium keratitis, ranging from 25% to 54% in previous studies,1 where it was found to be a factor for a poor prognosis. In our study, a hypopyon was associated with a 3.4-times higher risk for evisceration or enucleation compared to that in patients without a hypopyon. To date, the origin of the hypopyon in Pythium keratitis, ie, whether it comes from inflammation or infection, is unclear.\n\nHistopathology\n\nOur observations correspond to a previous report24 that found that the risk of globe removal increases with the density of fungal hyphae in the cornea specimens as an indication of advanced disease. Other histopathological parameters, such as the discontinuation of Descemet’s membrane and the depth of P. insidiosum invasion and inflammatory cell infiltration in the first corneal specimen of patients diagnosed with Pythium keratitis, were not statistically significantly associated with the treatment outcome.\n\nTreatment and Outcome\n\nIn our patients, only two (7.7%) patients were successfully treated with medication only. Both patients had good initial visual acuity (20/40 and 20/50) and received treatment within one day after the onset of symptoms.\n\nIn our study, 28.6% of patients had a successful outcome, defined as globe preservation, after the first TPK, whereas previous studies reported a success rate of 30–80%.1,3,9,11,25 Our comparably low success rate might result from the advanced stage of disease with which patients in our study presented initially.\n\nSince PIAI was administered at various points in time to our patients, we refrained from the statistical analysis of this variable and are not able to gauge the effects of this treatment. Furthermore, treatment with PIAI may not be effective in eradicating the infection in patients with advanced disease, as reported by Permpalung et al.8 In our patients, this treatment was safe and well-tolerated with no severe adverse events.\n\nOur results need to be interpreted within the limitations of our study. First, this was a retrospective file review. Some data were missing in patients’ documents. Further, our center is a referral center so that most of the patients presented with advanced stages of disease. Hence, our findings may not be representative of the presentation of Pythium keratitis in Thailand. Finally, Pythium keratitis has a low incidence. Even though we were able to identify some prognostic factors, our sample size was not large enough to allow for multivariable analysis. Prospective studies in larger populations are required to obtain more accurate information on the prognosis and identify the most effective treatment for this severe infection.\n\nConclusion\n\nPythium keratitis is a sight-threatening disease that frequently requires globe removal. Early recognition and treatment of the disease, particularly among elderly patients, are critical to successfully eradicate the infection. Advanced stages of disease and delay of drug therapy result in a high risk of globe removal. The histopathological analysis may provide important prognostic information.\n\nAcknowledgments\n\nWe would like to acknowledge Assist. Prof. Lalida Pariyakanok MD, Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, for her assistance, and Prof. Stephen John Kerr, PhD., Biostatistics Excellence Center, Department of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, and Assoc. Prof. Dr. Jaranit Kaewkungwal, Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, for their guidance in the study design, statistics and interpretation of the results.\n\nDisclosure\n\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1. Hasika R, Lalitha P, Radhakrishnan N, Rameshkumar G, Prajna NV, Srinivasan M. 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Vanittanakom N, Supabandhu J, Khamwan C, et al. Identification of emerging human-pathogenic Pythium insidiosum by serological and molecular assay-based methods. J Clin Microbiol. 2004;42 (9 ):3970–3974. doi:10.1128/JCM.42.9.3970-3974.2004 15364977\n24. Vemuganti GK, Garg P, Gopinathan U, et al. Evaluation of agent and host factors in progression of mycotic keratitis: a histologic and microbiologic study of 167 corneal buttons. Ophthalmology. 2002;109 (8 ):1538–1546. doi:10.1016/S0161-6420(02)01088-6 12153808\n25. Agarwal S, Iyer G, Srinivasan B, et al. Clinical profile, risk factors and outcome of medical, surgical and adjunct interventions in patients with Pythium insidiosum keratitis. Br J Ophthalmol. 2019;103 (3 ):296–300. doi:10.1136/bjophthalmol-2017-311804 30206158\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1177-5467", "issue": "15()", "journal": "Clinical ophthalmology (Auckland, N.Z.)", "keywords": "eye evisceration; eye infections; keratoplasty; oomycetes; penetrating; prognostic factors", "medline_ta": "Clin Ophthalmol", "mesh_terms": null, "nlm_unique_id": "101321512", "other_id": null, "pages": "1691-1701", "pmc": null, "pmid": "33935486", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "28025573;32015039;29545414;25630647;14962441;22902492;32117626;12798620;30805615;25535313;25738236;30574890;31289761;19116305;12153808;30206158;19730096;28903964;28207431;7322500;16886148;8263182;20818919;15364977", "title": "Clinical Characteristics, Histopathology, and Treatment Outcomes of Pythium Keratitis: A Retrospective Cohort Study.", "title_normalized": "clinical characteristics histopathology and treatment outcomes of pythium keratitis a retrospective cohort study" }	[ { "companynumb": "TH-ASTELLAS-2021US022423", "fulfillexpeditecriteria": "1", "occurcountry": "TH", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VORICONAZOLE" }, "drugadditional": null, ...
{ "abstract": "Olanzapine is a potent atypical antipsychotic drug used for the treatment of schizophrenia and bipolar disorder with approved efficiency. Olanzapine is superior to the typical antipsychotic drugs with low incidence of extrapyramidal side effects, especially tardive dyskinesia. The most common side effects associated with olanzapine are constipation, dyspepsia, weight gain, somnolence, asthenia, dry mouth and dizziness. Peripheral edema associated with olanzapine is rarely reported and as far as we know there is no report in the literature about peripheral edema concomitant with pericardial effusion related to olanzapine. The mechanism of these side effects associated with olanzapine is still unclear and there are different hypotheses in the literature. Herein we report the first case that developed both peripheral edema and pericardial effusion after olanzapine administration. Although very rarely encountered, clinicians should be aware of these possible side-effects.", "affiliations": "Department of Psychiatry, Kırklareli Babaeski State Hospital, Kırklareli, Turkey.;Department of Cardiology, Kırklareli Babaeski State Hospital, Kırklareli, Turkey.;Department of Cardiology, Medipol University Faculty of Medicine, İstanbul, Turkey.", "authors": "Arslan\|Mehmet\|M\|;Bulut\|Ümit\|Ü\|;Naki\|Deniz Dilan\|DD\|", "chemical_list": null, "country": "Turkey", "delete": false, "doi": "10.29399/npa.22860", "fulltext": null, "fulltext_license": null, "issn_linking": "1300-0667", "issue": "56(1)", "journal": "Noro psikiyatri arsivi", "keywords": "Olanzapine; adverse reaction; atypical antipsychotic; edema; pericardial effusion", "medline_ta": "Noro Psikiyatr Ars", "mesh_terms": null, "nlm_unique_id": "9426194", "other_id": null, "pages": "79-81", "pmc": null, "pmid": "30911243", "pubdate": "2019-03", "publication_types": "D002363:Case Reports", "references": "12490777;17669575;19620851;21632800;22452653;26934282;27335511;28062268;28360618;7249508;9885782", "title": "Olanzapine Associated Acute Peripheral Edema and Pericardial Effusion: A Case Report.", "title_normalized": "olanzapine associated acute peripheral edema and pericardial effusion a case report" }	[ { "companynumb": "TR-JUBILANT CADISTA PHARMACEUTICALS-2019JUB00259", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugad...
{ "abstract": "Significant impairment of left ventricular function causes low cardiac output syndrome in the immediate postoperative period in 3-14% of patients undergoing surgery, increasing the mortality 15-fold.\nTo assess the use of levosimendan in patients undergoing cardiac surgery in 2016.\nThe analysis included 14 patients: 3 (21.4%) women and 11 (78.6%) men aged 65.4 ±11.8 years. The mean value of left ventricular ejection fraction amounted to 20 ±6.25%. In 11 patients, levosimendan infusion was started immediately after the induction of anesthesia. Three patients received the agent during the early postoperative period due to low cardiac output syndrome refractory to conventional therapy. The dosage was modified within the range of 0.05-0.2 μg/kg/min. On the day of the surgery, all patients received continuous infusion of adrenaline and levonor.\nThe cardiac index amounted to 2.8 ±0.71 l/m2 after several hours of infusion and 2.9 ±0.1 l/m2 the next morning. The first examination showed that the mean systemic vascular resistance was 1010 dyn/s-5 and the second: 940 ±100 dyn/s-5; mixed venous blood saturation amounted to 66 ±7.5% and 65.5 ±8%, respectively. Respectively, the mean concentration of lactates was 2.0 ±0.96 mmol/l and 1.8 ±0.24 mmol/l. Mechanical lung ventilation lasting more than 48 hours was required in 50% of the patients. Two patients with chronic kidney disease required bedside renal replacement therapy before the procedure. Two (14.3%) patients died. Nine (64.3%) patients were discharged home, and three were transferred to cardiac wards.\nLevosimendan therapy proved safe in the study group. The nature of the study and the small sample size preclude the formulation of detailed conclusions.", "affiliations": "Chair and Clinic of Anesthesiology and Intensive Care, Medical University of Silesia, Katowice, Poland.;Department of Anesthesiology and Intensive Care with Cardiac Monitoring, Upper Silesian Medical Center, Katowice, Poland.;Department of Anesthesiology and Intensive Care with Cardiac Monitoring, Upper Silesian Medical Center, Katowice, Poland.;Department of Anesthesiology and Intensive Care with Cardiac Monitoring, Upper Silesian Medical Center, Katowice, Poland.;Department of Anesthesiology and Intensive Care with Cardiac Monitoring, Upper Silesian Medical Center, Katowice, Poland.;Department of Anesthesiology and Intensive Care with Cardiac Monitoring, Upper Silesian Medical Center, Katowice, Poland.", "authors": "Kucewicz-Czech\|Ewa M\|EM\|;Maciejewski\|Tomasz\|T\|;Budziarz\|Barbara\|B\|;Kołodziej\|Tadeusz\|T\|;Kiermasz\|Kazimierz\|K\|;Machej\|Leszek\|L\|", "chemical_list": null, "country": "Poland", "delete": false, "doi": "10.5114/kitp.2018.74673", "fulltext": "\n==== Front\nKardiochir Torakochirurgia PolKardiochir Torakochirurgia PolKITPKardiochirurgia i Torakochirurgia Polska = Polish Journal of Cardio-Thoracic Surgery1731-55301897-4252Termedia Publishing House 3237110.5114/kitp.2018.74673Original PaperLevosimendan in patients with low ejection fraction undergoing cardiac surgery Kucewicz-Czech Ewa M. 1Maciejewski Tomasz 2Budziarz Barbara 2Kołodziej Tadeusz 2Kiermasz Kazimierz 2Machej Leszek 21 Chair and Clinic of Anesthesiology and Intensive Care, Medical University of Silesia, Katowice, Poland2 Department of Anesthesiology and Intensive Care with Cardiac Monitoring, Upper Silesian Medical Center, Katowice, PolandAddress for correspondence: Prof. Ewa M. Kucewicz-Czech MD, PhD, Chair and Clinic of Anesthesiology and Intensive Care, Medical University of Silesia, 15 Medyków St, 40-752 Katowice, Poland. phone: +48 604 451 880. e-mail: j.ciesla@sccs.pl28 3 2018 3 2018 15 1 31 37 20 11 2017 05 12 2017 Copyright © 2018 Polish Society of Cardiothoracic Surgeons (Polskie Towarzystwo KardioTorakochirurgów) and the editors of the Polish Journal of Cardio-Thoracic Surgery (Kardiochirurgia i Torakochirurgia Polska)2018This 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.Introduction\nSignificant impairment of left ventricular function causes low cardiac output syndrome in the immediate postoperative period in 3–14% of patients undergoing surgery, increasing the mortality 15-fold.\n\nAim\nTo assess the use of levosimendan in patients undergoing cardiac surgery in 2016.\n\nMaterial and methods\nThe analysis included 14 patients: 3 (21.4%) women and 11 (78.6%) men aged 65.4 ±11.8 years. The mean value of left ventricular ejection fraction amounted to 20 ±6.25%. In 11 patients, levosimendan infusion was started immediately after the induction of anesthesia. Three patients received the agent during the early postoperative period due to low cardiac output syndrome refractory to conventional therapy. The dosage was modified within the range of 0.05–0.2 μg/kg/min. On the day of the surgery, all patients received continuous infusion of adrenaline and levonor.\n\nResults\nThe cardiac index amounted to 2.8 ±0.71 l/m2 after several hours of infusion and 2.9 ±0.1 l/m2 the next morning. The first examination showed that the mean systemic vascular resistance was 1010 dyn/s–5 and the second: 940 ±100 dyn/s–5; mixed venous blood saturation amounted to 66 ±7.5% and 65.5 ±8%, respectively. Respectively, the mean concentration of lactates was 2.0 ±0.96 mmol/l and 1.8 ±0.24 mmol/l. Mechanical lung ventilation lasting more than 48 hours was required in 50% of the patients. Two patients with chronic kidney disease required bedside renal replacement therapy before the procedure. Two (14.3%) patients died. Nine (64.3%) patients were discharged home, and three were transferred to cardiac wards.\n\nConclusions\nLevosimendan therapy proved safe in the study group. The nature of the study and the small sample size preclude the formulation of detailed conclusions.\n\nWstęp\nIstotne upośledzenie funkcji lewej komory serca jest przyczyną zespołu małego rzutu w bezpośrednim okresie pooperacyjnym. Dotyczy 3–14% operowanych chorych, śmiertelność w takich przypadkach wzrasta 15-krotnie.\n\nCel\nOceniono zastosowanie lewosimendanu u chorych poddawanych zabiegom kardiochirurgicznym w 2016 roku.\n\nMateriał i metody\nAnalizą objęto 14 pacjentów, w tym 3 (21,4%) kobiety i 11 (78,6%) mężczyzn w wieku 65,4 ±11,8 roku. Średnia wartość frakcji wyrzutowej lewej komory serca wynosiła 20 ±6,25%. U 11 pacjentów infuzję lewosimendanu rozpoczęto bezpośrednio po indukcji znieczulenia. Trzech chorych otrzymało lek we wczesnym okresie pooperacyjnym z powodu zespołu małego rzutu, niepoddającego się konwencjonalnej terapii. Dawkę lewosimendanu modyfikowano w zakresie wartości 0,05–0,2 μg/kg/min. W pierwszej dobie operacji wszyscy chorzy otrzymywali wlew ciągły adrenaliny i lewonoru.\n\nWyniki\nIndeks sercowy w kilka godzin po rozpoczęciu infuzji wynosił 2,8 ±0,71 l/m2, w kolejnej dobie rano 2,9 ±0,1 l/m2. Naczyniowe opory systemowe w pierwszym badaniu wyniosły średnio 1010 dyn/s–5, a w kolejnym badaniu 940 ±100 dyn/s–5. Saturacja mieszanej krwi żylnej w pierwszym punkcie czasowym wyniosła 66 ±7,5%, a w kolejnym 65,5 ±8%. Średnie stężenie mleczanów wynosiło w pierwszym punkcie czasowym 2,0 ±0,96 mmol/l, a w kolejnym 1,8 ±0,24 mmol/l. Połowa pacjentów wymagała wentylacji mechanicznej płuc powyżej 48 godzin. Dwóch chorych z przewlekłą niewydolnością nerek przed operacją wymagało przyłóżkowej terapii nerkozastępczej. Dwóch (14,3%) chorych zmarło. Dziewięciu (64,3%) chorych wypisano do domu, 3 pacjentów przekazano na oddziały kardiologii.\n\nWnioski\nW badanej grupie terapia lewosimendanem okazała się bezpieczna. Charakter badania i mała liczba pacjentów nie pozwala na formułowanie szczegółowych wniosków.\n\nlevosimendancardiac surgerylow cardiac output syndrome\n==== Body\nIntroduction\nCardiac surgery procedures are an established method of treating cardiac diseases. The popularity of this form of therapy is reflected by the number of procedures performed each year; in Europe and the USA, this number amounts to over a million [1]. Patients referred for cardiac surgery are increasingly older and burdened with numerous comorbidities. Just a few years ago, such patients were being disqualified from surgical treatment. Today, older patients with comorbidities can benefit from surgical heart repair; nevertheless the risk of postoperative complications and mortality in such patients is higher.\n\nSignificant impairment of left ventricular function is one of the causes of low cardiac output syndrome during the immediate postoperative period. This complication occurs in 3–14% of patients undergoing surgery; the mortality in this group increases 15-fold. The patients require extra doses of agents to improve cardiac function, which generates a dramatic increase in side effects, vasoconstriction and ischemia, tachycardia and increased myocardial demand of oxygen, arrhythmias, limited coronary perfusion, anaerobic cellular metabolism, increased lactate concentration and maximal oxygen extraction with low venous saturation, resulting in multiple organ dysfunction syndrome. Clinical studies (single center studies, meta-analyses) suggest that the use of catecholamines, especially those acting through β-receptors, may be associated with worse long-term outcomes [2]. The inodilator milrinon, used in low cardiac output syndrome, has many side effects; some authors also point out that it may increase the risk of death in patients undergoing therapy with phosphodiesterase III inhibitors [3]. Another therapeutic option for postoperative heart failure is to provide mechanical support with intra-aortic counterpulsation. However, clinical practice often shows that the increase in cardiac output by approximately 0.5 l/min that can be achieved with an intra-aortic balloon proves insufficient. Other methods of mechanical support (like post-cardiotomy AV-ECMO) are usually contraindicated in patients older than 70 and are burdened with 50% mortality. Transesophageal echo results indicate that right ventricular dysfunction occurs in 40% of patients in whom symptoms of cardiogenic shock develop after the procedure [4].\n\nThe optimal management consists in preventing postoperative low cardiac output syndrome. This may perhaps be achieved with levosimendan as its pharmacokinetic characteristics offer some hope for success in this regard. The drug has been classified as an “inoprotector”.\n\nLevosimendan induces calcium to bond with troponin C, sensitizing myofilaments to calcium. Its mechanism of action also includes the activation of ATP-dependent potassium channels, which results in improved myocardial contractility, vasodilation, and cardioprotection. Levosimendan does not increase mycoardial demand for oxygen. Its combined inotropic and vasodilatory effects increase the strength of contraction, at the same time reducing both preload and afterload in both ventricles. Its cardioprotective action limits mitochondrial pathway apoptosis [5]. The metabolism of levosimendan is complex. After many biochemical reactions, a part of its dose forms an active form, QR-1896, with properties similar to those of the original form, but with better clinical potential. Its maximum concentration in patients with heart failure is observed 2–4 days after the start of a 24-hour infusion. In patients after cardiac surgery involving extracorporeal circulation, the formation of this active metabolite is delayed, and its maximum concentration is observed 5–6 days after the start of the infusion. The drug’s action persists for 1–1.3 weeks [6]. The beneficial effect of levosimendan could potentially be compromised by the drug’s vasodilatory properties, which result in hypotension and an increased demand for vasopressors [7]. Abandoning the use of a loading dose and controlling the dosage of the continuous infusion largely reduced the problem of hypotension. Levosimendan may increase bleeding and the risk of cardiac arrhythmias.\n\nData from small randomized studies and meta-analyses indicate that levosimendan is effective in preventing and treating low cardiac output syndrome. The results of large randomized studies published in 2016 and 2017 offer less optimism [1, 8, 9]. The current debate on the effectiveness of levosimendan focuses on the time of its administration, which may prove to be a key element of the therapy. Beyond all doubt, all researchers unanimously report that the agent is safe.\n\nMaterial and methods\nThis retrospective analysis included 14 patients who received levosimendan in 2016 and were postoperatively hospitalized at the Department of Intensive Care with Cardiac Monitoring of the Upper Silesian Center of Cardiology in Katowice. Due to its retrospective character, the study did not require the approval of the local Bioethics Committee. The analysis included 3 (21.4%) women and 11 (78.6%) men aged 65.4 ±11.8 years. Five patients underwent elective surgery, the others were operated on urgently. Thirteen patients had impaired cardiac function before the surgery (cardiomyopathy). One female patient was operated on urgently after a percutaneous coronary intervention; prior to the incident, her cardiac function was normal. The average value of left ventricular ejection fraction in the analyzed group amounted to 20 ±6.25%. In 50% of the patients, the primary cardiac rhythm was atrial fibrillation. The average value of Euroscore II was 5.4 ±1.68 points (Table I). Three patients underwent coronary artery bypass grafting (CABG); in 7 patients, CABG was combined with valve repair or replacement; valve procedures were performed in further 3 patients; 1 patient underwent decompression of cardiac tamponade and repair of the bleeding site. One patient was operated on without extracorporeal circulation (iatrogenic tamponade after the removal of endocavitary electrodes). The average time of extracorporeal circulation was 98.4 ±53.95 minutes, the average aortic cross-clamping time was 58.4 ±31.35 minutes (Table II). Five patients had concomitant chronic kidney disease.\n\nTable I Characteristics of patients receiving levosimendan\n\nPatient\tAge [years]\tGender\tComorbidity\tMode of admission\tChronic AF\tEURO score\tEF (%)\t\n1\t72\tF\tSevere pulmonary hypertension\tElective\tYes\t8.5\t20\t\n2\t48\tM\tCardiomyopathy\tUrgent\t\t25.6\t14\t\n3\t77\tM\tCardiomyopathy\tElective\t\t5.33\t25\t\n4\t64\tF\tDiastolic failure\tUrgent\tYes\t3.78\t40\t\n5\t66\tM\tCardiomyopathy\tElective\tYes\t2.52\t20\t\n6\t81\tM\tCardiomyopathy\tUrgent\tYes\t42.94\t15\t\n7\t50\tM\tSTEMI\tUrgent\t\t4.99\t20\t\n8\t56\tM\tCardiomyopathy\tUrgent\tYes\t5.25\t30\t\n9\t70\tM\tCardiomyopathy\tUrgent\tYes\t5.25\t20\t\n10\t76\tF\tUnsuccessful PCI RCA\tUrgent\t\t8.13\t50\t\n11\t68\tM\tDiastolic failure\tElective\tYes\t10.27\t37\t\n12\t44\tM\tCardiomyopathy\tElective\t\t4.14\t20\t\n13\t78\tM\tCardiomyopathy\tUrgent\t\t6\t15\t\n14\t65\tM\tCardiomyopathy\tUrgent\t\t5.49\t15\t\nMean ± SD\t65.4 ±11.8\tF: n = 3; 21.4%M: n = 11; 78.6%\txxx\txxx\t\nn = 7 (50%)\t5.41 ±1.68\t20 ±6.25\t\n* Median ± quartile deviation, F – female, M – male, STEMI – ST-elevation myocardial infarction, PCI – prcutaneous coronary intervention, RCA – right coronary artery, AF – atrial fibrillation, EURO score – modified score for the risk of death in cardiac surgery patients, EF – left ventricular ejection fraction.\n\nTable II Types of procedures performed in the study group\n\nPatient\tTypes of procedures\tGroup\tExtracorporeal circulation time [min]\tCross-clamping time [min]\t\n1\tMVpl, TVpl\tValve surgery\t34\t15\t\n2\tTamponade after pacemaker implantation\tTamponade\tN/A\tn/a\t\n3\tCABG\tBypass grafting\t186\t60\t\n4\tTVpl, MVpl, ablation\tValve surgery\t128\t101\t\n5\tAVR, ablation\tValve surgery\t92\t72\t\n6\tAVR, CABG\tComplex surgery\t96\t76\t\n7\tMVpl, CABG\tComplex surgery\t101\t74\t\n8\tPericardiectomy, CABG\tComplex surgery\t50\t30\t\n9\tCABG, MVpl\tComplex surgery\t189\t104\t\n10\tCABG\tBypass grafting\t37\t15\t\n11\tAAA, CABG\tComplex surgery\t113\t89\t\n12\tCABG, MVpl\tComplex surgery\t125\t78\t\n13\tCABG\tBypass grafting\t35\t15\t\n14\tCABG, MVpl\tComplex surgery\t96\t73\t\n\t\tMean ± SD\t98.4 ±53.95\t58.4 ±31.35\t\nMVpl – mitral valvuloplasty, TVpl – tricuspid valvuloplasty, CABG – coronary artery bypass grafting, AVR – aortic valve replacement, AAA – ascending aorta replacement due to an aneurysm, N/A – not applicable.\n\nLevosimendan, Simdax (Orion) was administered via continuous intravenous infusion. A 12.5-mg ampule was dissolved in 250 ml; the infusion was planned for 24 hours, starting with a rate of 10 ml/h. The rate of infusion was adjusted to the values of arterial blood pressure and systemic vascular resistance. The dosage was modified within the range of 0.05–0.2 μg/kg/min. In 11 patients, levosimendan infusion was started immediately after the induction of anesthesia. Three patients received the agent during the early postoperative period due to low cardiac output syndrome refractory to conventional therapy. In all patients except for the patient with tamponade, cardiac function received additional mechanical support with intra-aortic counterpulsation. The function of the circulatory system was monitored using a Swan-Ganz catheter. Due to technical considerations, one of the patients was not monitored for cardiac output and mixed venous blood saturation. Replenishment of the vascular bed and the dosage of catecholamines were adjusted to the hemodynamic profile in accordance with the principles of goal-directed therapy. The goal was to maintain the cardiac index (CI) at ≥ 2.4 l/min/m2; mixed venous blood saturation at > 60%; mean systemic pressure at > 65 mm Hg; and lactate concentration at ≤ 2 mmol/l. Hemodynamic measurements were taken 4 times per day. Cardiac output measurements were not compared to values from before the administration of levosimendan as 11 patients received the drug preoperatively due to significantly reduced ejection fraction, regardless of the postoperative development of low cardiac output syndrome. The patients received continuous infusion of noradrenaline and/or adrenaline dosed in accordance with the principles of goal-directed therapy.\n\nStatistical analysis\nStatistical analysis was conducted using Microsoft Office Excel 2010 and Statistica 12.0.® The Shapiro-Wilk W test was used to determine the dataset. Data with normal distribution were presented as arithmetic mean ± standard deviation; data with non-normal distribution were presented as median ± quartile deviation. To compare percentages, a test for the significance of the difference between two structure indices was used. For difference tests, statistical significance was set at p < 0.05.\n\nResults\nHemodynamic profiles and oxygen balance were analyzed based on mixed venous blood saturation a few hours after the start of the levosimendan infusion and on the next morning. On the day of the surgery, all patients received continuous infusion of adrenaline and noradrenaline. Three patients required adrenaline and/or noradrenaline in doses exceeding 0.1 μg/kg/min. One patient received both amines in a dose exceeding 0.1 μg/kg/min. The cardiac index amounted to 2.8 ±0.71 l/m2 after several hours of infusion and 2.9 ±0.1 l/m2 the next morning. The mean systemic vascular resistance in the first examination was 1010 dyn/s–5 and in the second examination: 940 ±100 dyn/s–5; respectively, mixed venous blood saturation amounted to 66 ±7.5% and 65.5 ±8%. Respectively, the mean concentration of lactates was 2.0 ±0.96 mmol/l and 1.8 ±0.24 mmol/l (Table III). Mechanical lung ventilation lasting more than 48 hours was required in 50% of the patients.\n\nTable III Hemodynamic profile, oxygen balance, and pharmacological and mechanical support for cardiac function on the day of the surgery and the first postoperative day\n\nPatient\tCI1\n\tSVR1\n\tsatV1\n\tIABP\tLactates1\n\tAdrenaline1\n\tLeonor1\n\tCI1a\n\tSVR1a\n\tSatV1a\n\tLactates1a\n\t\n1\t1.6\t2380\t72\tYes\t2\t≤ 0.1\t≤ 0.1\t2.8\t1400\t69\t2.1\t\n2\t2.5\t1335\t60\tNo\t1.5\t> 0.1\t≤ 0.1\t3\t840\t69\t1.7\t\n3\t3\t1140\t58\tYes\t3.6\t≤ 0.1\t≤ 0.1\t2.9\t1100\t58\t1.7\t\n4\t2.3\t823\t65\tYes\t1.3\t≤ 0.1\t≤ 0.1\t2.6\t826\t58\t1.7\t\n5\t4\t830\t78\tYes\t2.4\t≤ 0.1\t≤ 0.1\t4\t900\t74\t1.7\t\n6\t2.8\t1600\t73\tYes\t1.7\t≤ 0.1\t≤ 0.1\t3.6\t1000\t76\t1.8\t\n7\t3.9\t1100\t57\tYes\t1.6\t≤ 0.1\t≤ 0.1\t3.5\t910\t53\t1.8\t\n8\tn/a\tn/a\tn/a\tYes\t1.9\t≤ 0.1\t> 0.1\tN/A\tn/a\tn/a\t2.2\t\n9\t2.35\t970\t57\tYes\t3.4\t≤ 0.1\t≤ 0.1\t2.9\t940\t58\t1.9\t\n10\t2.6\t850\t67\tYes\t5\t≤ 0.1\t≤ 0.1\t2.9\t1100\t65\t3.1\t\n11\t2.7\t1050\t56\tYes\t1.8\t≤ 0.1\t> 0.1\t2.8\t1050\t63\t1.6\t\n12\t2.4\t900\t64\tYes\t5.2\t> 0.1\t≤ 0.1\t3\t1000\t68\t3.4\t\n13\t2.3\t1100\t75\tYes\t1.3\t≤ 0.1\t≤ 0.1\t2.5\t850\t80\t2.3\t\n14\t3.8\t950\t76\tYes\t7.5\t> 0.1\t> 0.1\t3\t750\t61\t1.5\t\nMean ± SD\t2.8 ±0.71\t1010 ±120\t66 ±7.50\txxx\t2.0 ±0.96\txxx\txxx\t2.9 ±0.10\t940 ±100\t65.5 ±8.04\t1.8 ±0.24\t\n* Median ± quartile deviation. CI1 – cardiac index in l/m2 measured on the day of the surgery after hemodynamic stabilization, SVR1 – systemic vascular resistance in dyn/s–5 measured on the day of the surgery after hemodynamic stabilization, satV1 – mixed venous blood saturation measured on the day of the surgery after hemodynamic stabilization, IABP – intra-aortic balloon pump, lactates1 – lactate concentration in mmol/l measured on the day of the surgery after hemodynamic stabilization, adrenaline1 – dose of adrenaline in μg/kg/min administered on the day of the surgery after hemodynamic stabilization, levonor1 – dose in μg/kg/min administered on the day of the surgery after hemodynamic stabilization; CI1a, SVR1a, satV1a, lactates1a – parameters assessed in the morning of the day following the surgery; N/A – not available.\n\nAtrial fibrillation occurred in 5 patients with sinus rhythm. Two patients with chronic kidney disease required bedside renal replacement therapy before the procedure. Two (14.3%) patients died. Nine (64.3%) patients were discharged home, and three were transferred to cardiac wards (Table IV).\n\nTable IV Postoperative complications and outcomes of patients receiving levosimendan\n\nPatient\tRRT\tVentilation > 48 hours\tPost-op AF\tDischarge\tDeath\t\n1\t\t\t\tHome\t\t\n2\tYes\t\tYes\tAnother hospital\t\t\n3\t\tYes\t\tHome\t\t\n4\tYes\tYes\t\t\tYes\t\n5\t\t\t\tHome\t\t\n6\t\tYes\t\tAnother hospital\t\t\n7\t\t\t\tHome\t\t\n8\t\tYes\t\tHome\t\t\n9\t\tYes\t\tHome\t\t\n10\t\tYes\tYes\t\tYes\t\n11\t\t\t\tHome\t\t\n12\t\tYes\tYes\tHome\t\t\n13\t\t\tYes\tAnother hospital\t\t\n14\t\t\tYes\tHome\t\t\n\nN\n\t2\t7\t5\tHome: 9 Another hospital: 3\t2\t\n%\t14.3\t50\t35.7\t64.3 21.4\t14.3\t\nRRT – renal replacement therapy, AF – atrial fibrillation in patients with preoperative sinus rhythm.\n\nDiscussion\nThe ambivalent reports on the use of levosimendan to improve the results of heart failure treatment prompted researchers to conduct large randomized trials on the use of this agent in cardiac surgery patients. Considering the agent’s pharmacokinetic properties, the research hypothesis was that it would reduce mortality after cardiac surgery in patients with concomitant heart failure or heart failure developing in the perioperative period. The results of the CHEETAH study were published in print in April 2017 [8]. Its participants received the agent at different times of the perioperative period, in doses that were significantly smaller than the recommended dose. The duration of infusion was increased to 48 hours. Only 4.3% of the patients received levosimendan preoperatively; these were patients with low initial left ventricular function. The remaining patients were included in the study at various stages of treatment due to the necessity of mechanical cardiac support with intra-aortic counterpulsation. The study’s methodology did not include the measurement of cardiac output. The analysis did not confirm the agent’s influence on reducing 30-day mortality in patients after cardiac surgery procedures. However, in view of the most recent guidelines, it seems that high-risk patients, which include patients with significantly impaired cardiac function (EF ≤ 25%), require therapy based on hemodynamic monitoring with cardiac output measurements. Such management enables optimal vascular bed filling and individual selection of the types and doses of medications increasing contractility and correct vascular resistances. Scientists from the Vanderbilt University conducted a study that encompassed over 6,000 patients undergoing cardiac surgery procedures. The study demonstrated that hemodynamic monitoring using a Swan-Ganz catheter reduces the incidence of heart failure, lung failure, and bleeding; it has no bearing on mortality, length of hospitalization, or unplanned readmissions; and it increases the incidence of bacteremia and urinary tract infections [10].\n\nIn our material, 3 patients received levosimendan postoperatively. One female patient suffered from concomitant carcinoid syndrome. She underwent mitral and tricuspid valvuloplasty. Due to the carcinoid syndrome, she did not receive catecholamines after the surgery. On the 2nd postoperative day, a decision was made to introduce levosimendan therapy due to symptoms of low cardiac output syndrome. The patient died on the 14th postoperative day, having presented signs of multiple organ dysfunction syndrome and infectious complications (pneumonitis). Renal replacement therapy was used during the treatment, as the patient was burdened with chronic kidney disease. Another patient who received levosimendan postoperatively was a woman with good left ventricular function who was operated on urgently due to unstable ischemic heart disease. Intraoperatively, after the pericardial sac was opened, an extensive infarct was observed in the wall of the right ventricle and the right atrium, resulting from unsuccessful right coronary arterioplasty. Low cardiac output syndrome, high lactate concentration, and symptoms of ischemia in the organs of the abdominal cavity were observed during the early postoperative period. Heart failure was initially treated with intra-aortic counterpulsation. Due to persisting heart failure, levosimendan infusion was included in the therapy on the 2nd postoperative day. The patient died due to intestinal ischemia despite undergoing right-sided hemicolectomy and partial resection of the ileum. It appears that the administration of a full dose of heparin before extracorporeal circulation may have caused further expansion of the hematoma and resulted in irreversible heart failure. The third patient received levosimendan after a sudden cardiac arrest; its most probable etiology was cholesterol embolization. In view of evident signs of heart failure and dramatic left ventricular hypertrophy accompanied by pulmonary edema, agents stimulating β-receptors were not used, and levosimendan and noradrenaline were administered. Five days prior, the patient underwent a surgical procedure involving the replacement of the ascending aorta and aortic valve and coronary artery bypass grafting (CABG). He remained in the ICU for 27 days; ultimately, he was discharged home.\n\nAnother multicenter study, dubbed with the acronym LICORN, was conducted in 13 hospitals in France to assess the efficacy of levosimendan in preventing low cardiac output syndrome after CABG [9]. Levosimendan was administered after anesthesia, dosed at 0.1 μg/kg/min, to patients with left ventricular ejection fraction ≤ 35%. Its efficacy was assessed based on the requirement of positive inotropes after 24 hours from surgery, mechanical support, and renal replacement therapy. Early and 6-month mortality was recorded. The detailed results of the study were published in July 2017. The authors were not able to demonstrate a significant reduction in mortality in the group treated with levosimendan. Notwithstanding, cases of low cardiac output syndrome and requirement of additional agents supporting cardiac function were significantly less frequent.\n\nEleven of our patients received levosimendan, dosed at 0.05–0.2 μg/kg/min, after the induction of anesthesia or after the end of extracorporeal circulation. All patients except one (operated on due to iatrogenic heart injury and tamponade after a pacemaker implantation) received mechanical support with intra-aortic counterpulsation. Pharmacotherapy for heart failure was provided on the basis of hemodynamic parameters measured using a Swan-Ganz catheter. Additional monitored parameters influencing the selection of treatment were lactate concentration and mixed venous blood saturation. Hypotension was treated with continuous infusion of norepinephrine, its dose adjusted to the established goal, i.e., maintaining mean arterial blood pressure above 65 mm Hg. In 5 patients with initially normal sinus rhythm, atrial fibrillation occurred during their stay at the ICU. No anaphylactic reaction to the agent was observed in any of the patients. One patient required resternotomy due to bleeding from the wall of the right atrium. He underwent surgery on the previous day due to constrictive pericarditis and coronary atherosclerosis.\n\nThe third multicenter study devoted to the analysis of the outcomes of heart failure treatment with levosimendan in patients after cardiac surgery procedures, with impaired left ventricular function (EF ≤ 35%), was LEVO-CTS [1]. Its results did not confirm a reduction in its composite endpoint (mortality, perioperative myocardial infarction, use of mechanical support, necessity of renal replacement therapy) during the early postoperative period in the group of patients receiving levosimendan. In the discussion, the authors suggested that benefits from the therapy may be limited to patients with severe impairment of heart function. They also consider the question of increasing the dose to > 0.2 μg/kg/min during the initial stage of treatment. The study reported a trend towards a reduction in 90-day mortality (no statistical significance), which was interpreted as a potential possibility of prolonging the life of high-risk patients qualified for cardiac surgery procedures. At the same time, the authors estimated that achieving adequate power for assessing the effect of levosimendan on mortality in a group of such heterogeneity would require the enrollment of 3,000 patients.\n\nThe prevalence of heart failure in the population continues to rise, and the number of heart failure patients referred for surgery by cardiologists continues to increase. Optimizing the preoperative condition of patients from this challenging group may have the greatest potential in reducing the risks associated with cardiac surgery [11]. Strategies aiming to achieve this goal include mechanical and pharmacological support of cardiac function. A meta-analysis comparing preoperative treatment with dobutamine, phosphodiesterase inhibitors, levosimendan, and placebo reported a decrease in mortality in the group treated with levosimendan [11]. It should be underscored that positive inotropes should not be used routinely. This type of treatment should be reserved for patients with low cardiac output syndrome, in shock with disturbances of organ perfusion. In such cases, it is worthwhile to adhere to the principles of goal-directed therapy and monitor the hemodynamic parameters using a Swan-Ganz catheter. Optimizing the preoperative clinical condition of patients with severe heart failure requires teamwork and must be treated as a package of actions; single interventions offer little benefit. Levosimendan therapy has been placed on the list of 11 probable non-surgical interventions limiting perioperative mortality. This verdict came in 2016 based on the analysis of literature and the opinions of experts and clinicians (the discussion involved 500 participants) from 61 countries [12].\n\nIn our study, levosimendan was added to mechanical support and continuous infusions of adrenaline and noradrenaline. Three patients required more than 0.1 μg/kg/min of adrenaline during the first postoperative day. Only one patient did not receive intra-aortic counterpulsation (iatrogenic pericardial tamponade). Two patients required renal replacement therapy before the procedure due to chronic kidney disease. Mechanical lung ventilation lasting more than 48 hours was required in 50% of the patients treated with levosimendan. The duration of ICU stay was long, 10 days on average, which to some degree can be attributed to the organizational scheme of the hospital. Nine patients were discharged directly home. Mortality in the discussed group amounted to 14.3%. Mortality associated with postoperative low cardiac output syndrome is estimated at 13–24% [9].\n\nLevosimendan’s protective action in ischemia and reperfusion indicates that it may be justified to use it in advance (preoperatively) in patients with severe impairment of cardiac function undergoing cardiac surgery (preconditioning) [13]. The agent can also be applied in patients requiring pharmacotherapy with catecholamines, in whom mechanical support is planned to be discontinued. A meta-analysis published in 2015 reported shorter ICU stays among patients treated with levosimendan [14]. The demand for an agent with levosimendan’s pharmacokinetic properties is enormous, particularly in the context of patients undergoing cardiac surgery procedures. In 2017, the journal “Critical Care” published a meta-analysis of randomized studies involving cardiac surgery patients who were administered levosimendan [15]. The results showed reduced mortality in patients with significant preoperative impairments of systolic function. Additionally, levosimendan therapy is associated with a reduced requirement of renal replacement therapy and shorter ICU stays.\n\nOne significant limitation of the present study is the lack of a control group of patients in a similar clinical situation (significantly impaired left ventricular function) who would not receive levosimendan infusions to treat postoperative low cardiac output syndrome.\n\nConclusions\nIn the studied group, therapy with levosimendan proved safe. The patient sample was too small to justify the formulation of more detailed conclusions.\n\nDisclosure\nAuthors report no conflict of interest.\n==== Refs\nReferences\n1 Mehta RH Leimberger JD van Diepen S Meza J Wang A Jankowich R Harrison RW Hay D Fremes S Duncan A Soltesz EG Luber J Park S Argenziano M Murphy E Marcel R Kalavrouziotis D Nagpal D Bozinovski J Toller W Herlinglake M Goodman SG Levy JH Harrington RA Anstrom KJ Alexander JH Levosimendan in patients wiyh left ventricular dysfunction undergoing cardiac surgery N Engl J Med 2017 376 2032 2042 28316276 \n2 Landoni G Biondi-Zoccai G Greco M Greco T Bignami E Morelli A Guarracino F Zangrillo A Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies Crit Care Med 2012 40 634 646 21963578 \n3 Majure DT Greco T Greco M Ponschab M Biondi-Zoccai G Zangrillo A Landoni G Meta-analysis of randomized trials of effect of milrinone on mortality in cardiac surgery: an update J Cardiothorac Anesth 2013 27 220 229 \n4 Mebaza A Pitsis AA Rudiger A Toller W Longrois D Ricksten SE Bobek I De Hert S Wieseithaler G Schrime U von Segesser LK Sander M Poldermans D Ranucci M Karpati PCJ Wouters P Seeberger M Schmid ER Weder W Follath F Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery Crit Care 2010 14 201 20497611 \n5 Farmakis D Alvarez J Ben Gal T Brito D Fedele F Fonseca C Gordon AC Gotsman I Grossini E Guarracino F Harjola V Hellman Y Heunks L Ivancan V Karavidas A Kivikko M Lomivorotov V Longrois D Masip J Metra M Morelli A Nikolaou M Papp Z Parkhomenko A Poelzl G Pollesello P Berg Ravn H Rex S Riha H Ricksten S Schwinger RHG Vrtovec B Yilmaz MB Zielinska M Parissis J Levosimendan beyond inotropy and acute heart failure: evidence of pleiotropic effects on the heart and other organs: an expert panel position paper Int J Cardiol 2016 222 303 312 27498374 \n6 Pisano A Monti G Landoni G Levosimendan: new indications and evidence for reduction in perioperative mortality? Curr Opin Anesthesiol 2016 29 454 461 \n7 Distelmaier K Roth C Schrutka L Binder C Steinlechner B Heinz G Lang IM Maurer G Koinig H Niessner A Hulsmann M Speidl W Goliasch G Beneficial effect of levosimendan on survival in patients undergoing extracorporeal membrane oxygenation after cardiovascular surgery Br J Anaesth 2016 117 52 58 27317704 \n8 Landoni G Lomivorotov VV Alvaro G Lobregilo R Pisano A Guarracino F Calabro MG Grigoryev EV Likhvatsev VV Salgado-Filho MF Bianchi A Pasyuga VV Baiocchi M Pappalardo F Monaco F Boboshko VA Abubakirov MN Amantea B Lembo R Brazzi L Verniero L Bertini P Scandroglio AM Bove T Belletti A Michienzi MG Shukevich DL Zabelina TS Bellomo R Zangrillo A Levosimendan for hemodynamic support after cardiac surgery N Engl J Med 2017 376 2021 2031 28320259 \n9 Caruba T Hourton D Sabatier B Rousseau D Tibi A Hoffart-Jourdain C Souag A Freitas N Yjjou M Almeida C Gomes N Aucouturier P Djadi-Prat J Menasche P Chatellier G Cholley B Rationale and design of the multicenter randomized trial investigating the effects of levosimendan pretreatment in patients with low ejection fraction (≤ 40%) undergoing CABG with cardiopulmonary bypass (LINCORN study) J Cardiothorac Surg 2016 11 127 134 27496105 \n10 Heringlake M Goal-directed therapy – evidence based or wishful thinking? 2017 Berlin EACTA PL 39 Plenary Lecture \n11 Pichette M Liszkowski M Ducharme A Preoperative optimization of the heart failure patient undergoing cardiac burgery Can J Cardiol 2017 33 72 79 27876563 \n12 Landoni G Pisano A Lomivorotov V Alvaro G Hajjar L Paternoster G Neto CN Latronici N Fominskiy E Pasin L Finco G Lobregilo R Azzolini ML Buscaglia G Castella A Comis M Conte A Conte M Corradi F Dal Checco E De Vuono G Ganzaroli M Garofalo E Gazivoda G Lembo R Marianello D Baiardo Redaelli M Monaco F Tarzia V Mucchetti M Belletti A Mura P Musu M Pala G Paltenghi M Pasyuga V Piras D Riefolo C Roasio A Ruggeri L Santini F Székely A Verniero L Vezzani A Zangrillo A Bellomo R Randomized evidence for reduction of perioperative mortality: an updated consensus process J Cardiothorac Vasc Anesth 2017 31 719 730 27693206 \n13 Greco T Calabro MG Covello RD Greco M Pasin L Morelli A Landoni G Zangrillo A A Bayesian network meta-analysis on the effect of inodilatatory agents on mortality Br J Anaesth 2015 114 746 756 25652947 \n14 Lim JY Deo SV Rababah A Altarabsheh SE Cho YH Hang D McGraw M Avery EG Markowitz AH Park SJ Levosimendan reduces mortality in adults with left ventricular dysfunction undergoing cardiac surgery: a systemic review and meta-analysis J Card Surg 2015 30 547 554 25989324 \n15 Chen Q Zheng R Lin H Yu J Wang H Effect of levosimendan on prognosis in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials Critical Care 2017 21 253 264 29041948\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "1731-5530", "issue": "15(1)", "journal": "Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery", "keywords": "cardiac surgery; levosimendan; low cardiac output syndrome", "medline_ta": "Kardiochir Torakochirurgia Pol", "mesh_terms": null, "nlm_unique_id": "101279148", "other_id": null, "pages": "31-37", "pmc": null, "pmid": "29681959", "pubdate": "2018-03", "publication_types": "D016428:Journal Article", "references": "27496105;27693206;28316276;23063100;20497611;27317704;25989324;28320259;27876563;27498374;29041948;25652947;21963578;27168089", "title": "Levosimendan in patients with low ejection fraction undergoing cardiac surgery.", "title_normalized": "levosimendan in patients with low ejection fraction undergoing cardiac surgery" }	[ { "companynumb": "PL-MYLANLABS-2018M1050716", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, ...
{ "abstract": "A 73-year-old male suffers a type-2 inferior myocardial infarction and is found unconscious, hypotensive and centrally cyanotic. His arterial blood gas analysis shows a chocolate-brown discoloration, with pO2 45.1 kPa, HbO2 48.9%, MetHb 51%, BE -9 and a lactate of 3.7 mmol/l. Administration of 200 mg of methylene blue intravenously, normalizes the patient's abnormalities. His life-threatening acquired methaemoglobinaemia appears secondary to under-the-counter viagra.", "affiliations": "Department of Intensive Care Medicine, Maastricht University Medical Centre, the Netherlands l.mommers@mumc.nl.;Department of Intensive Care Medicine, Maastricht University Medical Centre, the Netherlands.;Department of Intensive Care Medicine, Maastricht University Medical Centre, the Netherlands.", "authors": "Mommers\|Lars\|L\|;Delnoij\|Thijs Sr\|TS\|;Strauch\|Ulrich\|U\|", "chemical_list": "D000068677:Sildenafil Citrate; D008751:Methylene Blue", "country": "England", "delete": false, "doi": "10.1177/2048872615579394", "fulltext": null, "fulltext_license": null, "issn_linking": "2048-8726", "issue": "5(8)", "journal": "European heart journal. Acute cardiovascular care", "keywords": "Methaemoglobinaemia; acute coronary syndrome; under-the-counter medication; viagra", "medline_ta": "Eur Heart J Acute Cardiovasc Care", "mesh_terms": "D054058:Acute Coronary Syndrome; D000368:Aged; D006801:Humans; D008297:Male; D008708:Methemoglobinemia; D008751:Methylene Blue; D000068677:Sildenafil Citrate", "nlm_unique_id": "101591369", "other_id": null, "pages": "549-550", "pmc": null, "pmid": "25838438", "pubdate": "2016-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Under-the-counter acquired acute coronary syndrome: Methaemoglobinaemia.", "title_normalized": "under the counter acquired acute coronary syndrome methaemoglobinaemia" }	[ { "companynumb": "NL-PFIZER INC-2017222504", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LOSARTAN" }, "drugadditional": null, ...
{ "abstract": "We carried out a study aiming to determine the renal effect of ibuprofen treatment for patent ductus arteriosus (PDA) in very preterm infants during the first month of life. Infants aged 27-31 weeks gestation were enrolled from October 2004 to August 2006. They were assigned to two different groups according to ibuprofen exposure during care of their PDA status assessed by echocardiography. Infants of both groups were matched based on gestational age, Clinical Risk Index for Babies score, birth weight and inclusion center. Renal function was evaluated at baseline and weekly for 1 month. One hundred and forty-eight infants were enrolled. Glomerular filtration rate (GFR) was significantly decreased in the ibuprofen group after treatment withdrawal (GFR on day 7, ibuprofen versus no ibuprofen: 12.8 +/- 6.2 vs. 18.1 +/- 12.1 ml/min/1.73 m(2); P < 0.001). Adjusted analysis proved this decrease to be sustained during the first month of life. Tubular function was also impaired during the first month in ibuprofen-treated infants. Ibuprofen administered for PDA is associated with a decreased GFR during the first month of life. Renal function of infants receiving ibuprofen should be carefully monitored and drugs that are eliminated by glomerular filtration handled cautiously during this period.", "affiliations": "Maternite Regionale, Neonatal Department, Nancy-University, Nancy, France. r.vieux@maternite.chu-nancy.fr", "authors": "Vieux\|Rachel\|R\|;Desandes\|Roxane\|R\|;Boubred\|Farid\|F\|;Semama\|Denis\|D\|;Guillemin\|Francis\|F\|;Buchweiller\|Marie-Christine\|MC\|;Fresson\|Jeanne\|J\|;Hascoet\|Jean-Michel\|JM\|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D003404:Creatinine; D007052:Ibuprofen", "country": "Germany", "delete": false, "doi": "10.1007/s00467-009-1349-9", "fulltext": null, "fulltext_license": null, "issn_linking": "0931-041X", "issue": "25(2)", "journal": "Pediatric nephrology (Berlin, Germany)", "keywords": null, "medline_ta": "Pediatr Nephrol", "mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D003404:Creatinine; D016861:Cyclooxygenase Inhibitors; D004374:Ductus Arteriosus, Patent; D005260:Female; D005865:Gestational Age; D005919:Glomerular Filtration Rate; D006801:Humans; D007052:Ibuprofen; D007231:Infant, Newborn; D007234:Infant, Premature; D007668:Kidney; D007677:Kidney Function Tests; D008297:Male", "nlm_unique_id": "8708728", "other_id": null, "pages": "267-74", "pmc": null, "pmid": "19902266", "pubdate": "2010-02", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": "19067286;6343572;9175948;16773403;10103341;8100927;7050860;15811164;16550364;17136231;16113155;5902430;15567009;9279181;7472835;820994;15567010;12014386;490263;10586177;19078973;10974130;7877873;15930213;950959;3588043;16585305;5048712;8323361;19048246;18254020", "title": "Ibuprofen in very preterm infants impairs renal function for the first month of life.", "title_normalized": "ibuprofen in very preterm infants impairs renal function for the first month of life" }	[ { "companynumb": "US-JNJFOC-20150219573", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "...
{ "abstract": "We report the first case of renal antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis treated with autologous mesenchymal stromal cells (MSCs). A 73-year-old man was admitted to the hospital for malaise, weight loss, and oliguria. His serum creatinine level was 2.7 mg/dL but it rapidly increased to 7.8 mg/dL; urinalysis showed proteinuria and hematuria, and the ANCA to myeloperoxidase with a perinuclear pattern (pANCA) titer was high (132 IU/mL). Renal biopsy showed necrotizing crescentic glomerulonephritis. Standard immunosuppressive therapy (cyclophosphamide and corticosteroids) was ineffective. Rituximab therapy was started, but it was discontinued after the third dose to minimize the risk of systemic spread of a severe oral Candida infection and to prevent superinfections that were facilitated by leukopenia. The patient received autologous MSCs, 1.5 × 10(6) cells/kg body weight, intravenously. After 7 days, his serum creatinine level decreased to 2.2 mg/dL, pANCA titer decreased to 75 IU/mL, and urinalysis findings normalized. Eight months later, he received a second MSC infusion because his serum creatinine level increased. In 1 week, his creatinine level decreased to 1.9 mg/dL and his pANCA titer decreased to 14 IU/mL. Immunosuppressive therapy was subsequently withdrawn. At the last follow-up visit, 12 months after the second MSC infusion, the patient remained in clinical remission without any therapy. Infusion of MSCs induced expansion of the T-lymphocyte subset expressing a regulatory T-cell phenotype (CD4(+)CD25(+)Foxp3(+)) and a notable reduction in interferon-γ, interleukin 6, and tumor necrosis factor serum levels.", "affiliations": "Unità Complessa di Nefrologia Dialisi e Trapianto, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo e Università di Pavia, Pavia, Italy.", "authors": "Gregorini\|Marilena\|M\|;Maccario\|Rita\|R\|;Avanzini\|Maria Antonietta\|MA\|;Corradetti\|Valeria\|V\|;Moretta\|Antonia\|A\|;Libetta\|Carmelo\|C\|;Esposito\|Pasquale\|P\|;Bosio\|Francesca\|F\|;Dal Canton\|Antonio\|A\|;Rampino\|Teresa\|T\|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0025-6196", "issue": "88(10)", "journal": "Mayo Clinic proceedings", "keywords": "AAV; ANCA; ANCA with a perinuclear staining pattern; ANCA-associated vasculitis; BVAS; Birmingham Vasculitis Activity Score; CTL; CYC; IL; MSC; NK; PBMC; PHA; RTX; TNF; Treg; antineutrophil cytoplasmic antibody; cyclophosphamide; cytotoxic T lymphocyte; interleukin; mesenchymal stromal cell; natural killer; pANCA; peripheral blood mononuclear cell; phytohemagglutin; regulatory T cell; rituximab; tumor necrosis factor", "medline_ta": "Mayo Clin Proc", "mesh_terms": "D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D014182:Transplantation, Autologous", "nlm_unique_id": "0405543", "other_id": null, "pages": "1174-9", "pmc": null, "pmid": "24079687", "pubdate": "2013-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Antineutrophil cytoplasmic antibody-associated renal vasculitis treated with autologous mesenchymal stromal cells: evaluation of the contribution of immune-mediated mechanisms.", "title_normalized": "antineutrophil cytoplasmic antibody associated renal vasculitis treated with autologous mesenchymal stromal cells evaluation of the contribution of immune mediated mechanisms" }	[ { "companynumb": "IT-BAXTER-2015BAX000267", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, ...
{ "abstract": "Venous thromboembolism (VTE) prophylaxis, also known as thromboprophylaxis, reduces the risk of deep vein thrombosis, pulmonary embolism, and associated complications, including death, in high-risk patients. VTE prophylaxis is recommended for acutely ill, hospitalized medical patients at risk of thrombosis. Anticoagulants, the pharmacologic agents of choice to prevent VTE, are considered high-alert medications. By definition, therefore, anticoagulants bear a hightened risk of causing significant patient harm when they are used in error. As part of ongoing collaboration with a provincial death investigation service, ISMP Canada received a report of a fatal incident that involved continuation of VTE prophylaxis with enoxaparin for a patient discharge to a long-term care (LTC) facility from an acute care setting. The findings and recommendations from this case are charged to highlight the need to build routine reassessment of VTE prophylaxis into the process for discharging patients from the acute care setting and upon transfer to another facility or to primary care.\n\n\nCONCLUSIONS\nThe incident described in this bulletin highlights the importance of continually reassessing the need for VTE prophylaxis, especially at transitions of care, such as discharge from an acute care setting. Evidence and guidelines confirm the benefits of VTE prophylaxis in certain patients during a hospital stay for an acute illness, but the balance of benefits and risks may become unfavourable once the patient is discharged. Clear documentation from the acute care facility can assist the receiving facility and health-care providers, as well as family caregivers, when determining whether thromboprophylaxis is still warranted. Until clear guidance to continue thromboprophylaxis after acute care is available, health-care organizations and practitioners across the spectrum of care are urged to share and consider the strategies presented in this bulletin to ensure the safe use of VTE prophylaxis and improved communication among health-care providers. ISMP Canada will be integrating the learning from this case in an update of the Hospital-Self-Assessment for Anticoagulant Safety. This assessment is available on a complimentary basis to all facilities across Canada after sign up at HTTPS://mssa.ismp-canada.org/hsasas/.", "affiliations": null, "authors": null, "chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin", "country": "Canada", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1481-9988", "issue": "71(3)", "journal": "Alberta RN", "keywords": null, "medline_ta": "Alta RN", "mesh_terms": "D000368:Aged; D000925:Anticoagulants; D002170:Canada; D017984:Enoxaparin; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D009732:Nursing Care; D010360:Patient Transfer; D017410:Practice Guidelines as Topic; D012307:Risk Factors; D054556:Venous Thromboembolism; D020246:Venous Thrombosis", "nlm_unique_id": "100883278", "other_id": null, "pages": "26-8", "pmc": null, "pmid": "26638268", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Death Associated with Inadequate Reassessment of Venous Thromboembolism Prophylaxis at and after Hospital Discharge.", "title_normalized": "death associated with inadequate reassessment of venous thromboembolism prophylaxis at and after hospital discharge" }	[ { "companynumb": "PHHY2015CA169525", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugad...
{ "abstract": "Tardive oculogyric crisis (OGC) is a dystonic syndrome that starts after long-term use of dopamine receptor antagonists. Atypical antipsychotics have reduced liability for inducing tardive dystonia and show antidystonic properties in patients with pre-existing tardive dystonia. Clozapine is an atypical antipsychotic drug, and there have been case reports that clozapine may be an effective treatment for tardive dystonia. Surprisingly, we found that three patients appeared to develop tardive OGC while taking clozapine. The relationship between tardive OGC and clozapine is still unknown. However, it is possible that the previous antipsychotic exposure could have created a sensitising or priming effect on the striatum. Also, there are some suggestions of an underlying susceptibility and possibly a genetic predisposition, at least in some patients.", "affiliations": "Department of Psychiatry, Gulhane School of Medicine, Ankara, Turkey. ouzun@gata.edu.tr", "authors": "Uzun\|Ozcan\|O\|;Doruk\|Ali\|A\|", "chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine", "country": "New Zealand", "delete": false, "doi": "10.2165/00044011-200727120-00009", "fulltext": null, "fulltext_license": null, "issn_linking": "1173-2563", "issue": "27(12)", "journal": "Clinical drug investigation", "keywords": null, "medline_ta": "Clin Drug Investig", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D004409:Dyskinesia, Drug-Induced; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D015835:Ocular Motility Disorders; D012559:Schizophrenia", "nlm_unique_id": "9504817", "other_id": null, "pages": "861-4", "pmc": null, "pmid": "18020545", "pubdate": "2007", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "8861192;2573005;6128697;8935815;10495056;1671793;6122714;7969212;1298936;7913739;1362053;8071284;12210290;10667744;16532448;8526237;17308236", "title": "Tardive oculogyric crisis during treatment with clozapine: report of three cases.", "title_normalized": "tardive oculogyric crisis during treatment with clozapine report of three cases" }	[ { "companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-145434", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "CLOZAPINE" }, "druga...
{ "abstract": "A73 -year-old man underwent a sigmoidectomy for sigmoid colon cancer with liver metastasis. After the operation, he received CapeOX combined with bevacizumab therapy. After 6 courses, the liver metastasis was undetectable on computed tomography scans. After 15 courses, computed tomography revealed ascites, and chemotherapy was discontinued. Two months later, computed tomography revealed portal vein thrombosis. Owing to the chronic nature of the thrombosis, thrombolytic therapy was not initiated. However, preservation therapy using antiplatelet drugs for 1 month resolved the ascites and the thrombosis. The risk of serious thrombosis must be considered when using bevacizumab.", "affiliations": "Dept. of Surgery, Nagoya Memorial Hospital.", "authors": "Uno\|Yasuo\|Y\|;Tsuboi\|Kenji\|K\|;Shimizu\|Mitsuya\|M\|;Tomosugi\|Toshihide\|T\|;Shoka\|Michita\|M\|;Hibino\|Soki\|S\|;Matsushita\|Hidenobu\|H\|;Takahashi\|Takuji\|T\|;Okochi\|Osamu\|O\|;Kawase\|Yoshihisa\|Y\|", "chemical_list": "D009944:Organoplatinum Compounds; D010975:Platelet Aggregation Inhibitors; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine; D001241:Aspirin", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "43(7)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001241:Aspirin; D000068258:Bevacizumab; D000069287:Capecitabine; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010975:Platelet Aggregation Inhibitors; D011169:Portal Vein; D012811:Sigmoid Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D020246:Venous Thrombosis", "nlm_unique_id": "7810034", "other_id": null, "pages": "905-7", "pmc": null, "pmid": "27431639", "pubdate": "2016-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A Case of Portal Vein Thrombosis Occurring during CapeOX and Bevacizumab Combination Therapy for Liver Metastasis.", "title_normalized": "a case of portal vein thrombosis occurring during capeox and bevacizumab combination therapy for liver metastasis" }	[ { "companynumb": "JP-PFIZER INC-2016521801", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "1", ...
{ "abstract": "OBJECTIVE\nTo determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory noninfectious scleritis.\n\n\nMETHODS\nProspective, dose-ranging, randomized, double-masked phase I/II clinical trial.\n\n\nMETHODS\nTwelve patients with noninfectious scleritis refractory to systemic corticosteroid and ≥1 other systemic immunosuppressive agent were enrolled from January 2007 to March 2010.\n\n\nMETHODS\nSubjects were randomly assigned to 500 (n = 5) or 1000 mg (n = 7) dosing arms of rituximab intravenous infusions (500 or 1000 mg), given at study days 1 and 15. Initial responders with breakthrough inflammation after study week 24 were offered treatment with an additional cycle of 2 open-label rituximab 1000 mg infusions.\n\n\nMETHODS\nPrimary outcomes were reduction of inflammation, as measured with a validated scleritis disease grading scale (SGS) and reduction in corticosteroid dose by ≥50%. Patients were characterized as responders to study therapy if ≥1 of these endpoints showed improvement and neither showed evidence of worsening. Secondary outcomes were improvement in visual acuity, reduction in pain, and improvement in patient and physician-reported global health assessment.\n\n\nRESULTS\nOf 12 enrolled patients, 9 met the SGS endpoint at or before week 24, and 4 additionally were able to reduce corticosteroid dose by ≥50%. With regard to secondary outcome measures, 11 and 9 patients showed improvement in patient and physician global health scores, respectively, and 7 patients had reduction in pain. Of 9 initial responders, 7 experienced breakthrough inflammation after 24 weeks and were treated with a second cycle of rituximab infusions. Four patients had significant objective or subjective worsening within 8 weeks of receiving rituximab; this event was averted in subsequent patients by treatment with peri-infusional oral corticosteroid. No other significant adverse events were noted. No differences in efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms.\n\n\nCONCLUSIONS\nRituximab was effective treatment for 9 of 12 enrolled patients with refractory, noninfectious scleritis at 24 weeks, although 7 required reinfusion with rituximab to maintain inflammatory control. The treatment was well-tolerated, and peri-infusional inflammatory exacerbations were managed successfully with oral corticosteroids. Further long-term studies are warranted to determine the safety and efficacy of rituximab in treating noninfectious scleritis and other ocular inflammatory diseases.", "affiliations": "Portland Veterans Administration Medical Center, Portland, Oregon; Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon; Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, Oregon. Electronic address: suhlere@ohsu.edu.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon; Department of Developmental Biology, Oregon Health & Science University, Portland, Oregon; Clinical and Molecular Medicine, Flinders University, Adelaide, Australia.;Oregon Health & Science University, Department of Ophthalmology/Casey Eye Institute, Portland, Oregon; Department of Medicine, and Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon; Department of Developmental Biology, Oregon Health & Science University, Portland, Oregon; Devers Eye Institute, Portland, Oregon.", "authors": "Suhler\|Eric B\|EB\|;Lim\|Lyndell L\|LL\|;Beardsley\|Robert M\|RM\|;Giles\|Tracy R\|TR\|;Pasadhika\|Sirichai\|S\|;Lee\|Shelly T\|ST\|;de Saint Sardos\|Alexandre\|A\|;Butler\|Nicholas J\|NJ\|;Smith\|Justine R\|JR\|;Rosenbaum\|James T\|JT\|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0161-6420", "issue": "121(10)", "journal": "Ophthalmology", "keywords": null, "medline_ta": "Ophthalmology", "mesh_terms": "D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069283:Rituximab; D015423:Scleritis; D012720:Severity of Illness Index; D055815:Young Adult", "nlm_unique_id": "7802443", "other_id": null, "pages": "1885-91", "pmc": null, "pmid": "24953794", "pubdate": "2014-10", "publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Rituximab therapy for refractory scleritis: results of a phase I/II dose-ranging, randomized, clinical trial.", "title_normalized": "rituximab therapy for refractory scleritis results of a phase i ii dose ranging randomized clinical trial" }	[ { "companynumb": "US-JNJFOC-20150716238", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nTreatment of chronic hepatitis C (HCV) with newer direct acting antiviral (DAA) agents has been highly effective. Unfortunately, patients over 70 years old are underrepresented in studies. Given current recommendations to screen patients born between 1945 and 1965 for HCV, it is essential to determine the efficacy and safety of DAAs within the elderly population. This study aims to evaluate clinical outcomes of patients aged 70 years or older treated for HCV with DAAs at a single tertiary care center.\n\n\nMETHODS\nWe identified 25 patients aged 70 years or older who were treated for HCV with a sofosbuvir-based regimen. Baseline demographics, prior HCV treatment history, HCV treatment regimen, adverse effects, and interruption or discontinuation of therapy were collected. The primary endpoint was sustained virologic response at 12 weeks after end of treatment (SVR12). Secondary outcomes were self-reported side effects, drug interactions, and changes in medical regimen of treated patients.\n\n\nRESULTS\nAll patients were genotype 1 (13 1a, 9 1b, 3 unspecified). Seventeen (68%) had cirrhosis including 1 Child's Pugh class B. Fifteen patients were treatment-naïve and 10 previously failed treatment with interferon. Seventeen patients were on ledipasvir/sofosbuvir, 4 on simeprevir/sofosbuvir/ribavirin, and 4 on simeprevir/sofosbuvir. Of 25 patients included, 96% (24/25) patients achieved SVR12. Two patients had a greater than 2 g/dL drop in hemoglobin from baseline and both were on ribavirin. Ribavirin was discontinued in 1 patient. One patient required a change in proton pump inhibitor. No patients discontinued therapy due to side effects.\n\n\nCONCLUSIONS\nPatients aged 70 years or older with genotype 1 achieved high rates of sustained virologic response with treatment with newer sofosbuvir-based DAAs without any undue adverse events.", "affiliations": "Department of Pharmacy, Methodist University Hospital, 1265 Union Ave, Memphis, TN 38104, USA.;Department of Surgery, Methodist University Hospital Transplant Institute, 1211 Union Ave, Suite 340, Memphis, TN 38104, USA.;Department of Surgery, Methodist University Hospital Transplant Institute, 1211 Union Ave, Suite 340, Memphis, TN 38104, USA.;Department of Surgery, Methodist University Hospital Transplant Institute, 1211 Union Ave, Suite 340, Memphis, TN 38104, USA.;Department of Surgery, Methodist University Hospital Transplant Institute, 1211 Union Ave, Suite 340, Memphis, TN 38104, USA.", "authors": "Snyder\|Heather S\|HS\|;Ali\|Bilal\|B\|;Gonzalez\|Humberto C\|HC\|;Nair\|Satheesh\|S\|;Satapathy\|Sanjaya K\|SK\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.1016/j.jceh.2017.03.009", "fulltext": null, "fulltext_license": null, "issn_linking": "0973-6883", "issue": "7(2)", "journal": "Journal of clinical and experimental hepatology", "keywords": "DAA, direct acting antiviral; HCV, hepatitis C virus; SVR, sustained virologic response; direct acting antivirals; elderly; hepatitis C", "medline_ta": "J Clin Exp Hepatol", "mesh_terms": null, "nlm_unique_id": "101574137", "other_id": null, "pages": "93-96", "pmc": null, "pmid": "28663671", "pubdate": "2017-06", "publication_types": "D016428:Journal Article", "references": "11434622;22910836;27789224;26704693;24737271;10895431;12682882;24291324;23172780", "title": "Efficacy and Safety of Sofosbuvir-Based Direct Acting Antivirals for Hepatitis C in Septuagenarians and Octogenarians.", "title_normalized": "efficacy and safety of sofosbuvir based direct acting antivirals for hepatitis c in septuagenarians and octogenarians" }	[ { "companynumb": "US-JNJFOC-20170714083", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nProton-pump inhibitors (PPIs) are one of the most prescribed drugs. Their dermatological adverse reactions are multiple and vary in severity.\n\n\nOBJECTIVE\nThis review discusses all reported cutaneous side effects of PPIs in order to help physicians understand them and provide appropriate management.\n\n\nMETHODS\nA thorough search of PubMed, Embase, and FDAAQ8 drugs websites was conducted. 56 articles including case reports, case series, and review articles of PPI-induced cutaneous adverse reactions were selected. Data were recorded regarding patient age, gender, history, clinical manifestations, diagnostic tests, management, and clinical outcomes.\n\n\nRESULTS\nPPI-induced adverse skin reactions are mostly immunological and include both immediate and delayed-type hypersensitivity reactions. These reactions are sometimes life-threatening. All PPIs can induce immediate IgE-mediated reactions. Most of previously published cases of delayed-type hypersensitivity reactions have involved esomeprazole, omeprazole, and lansoprazole. Skin tests are helpful in confirming PPI-induced hypersensitivity reactions and diagnosing potential cross-reactivities. PPIs should also be added to our list of usual suspects when considering possible culprits for a new presentation of drug-induced subacute lupus erythematosus. PPI-related occupational contact dermatitis has also been numerously reported.\n\n\nCONCLUSIONS\nPPIs should be considered in our list of culprits when considering a patient with a cutaneous drug reaction, taking into account that these drugs can cause severe immunological manifestations.", "affiliations": "Department of Dermatology, Saint Georges Hospital University Medical Center, Beirut, Lebanon.;Faculty of Medicine, University of Balamand, Beirut, Lebanon.;Department of Dermatology, Saint Georges Hospital University Medical Center, Beirut, Lebanon.", "authors": "Salloum\|Antoine\|A\|https://orcid.org/0000-0002-7184-9859;Nasr\|Dayana\|D\|;Maalouf\|Diane\|D\|", "chemical_list": "D054328:Proton Pump Inhibitors", "country": "England", "delete": false, "doi": "10.1111/jocd.13763", "fulltext": null, "fulltext_license": null, "issn_linking": "1473-2130", "issue": "20(4)", "journal": "Journal of cosmetic dermatology", "keywords": "adverse reaction; allergy; hypersensitivity; proton-pump inhibitors; rash", "medline_ta": "J Cosmet Dermatol", "mesh_terms": "D004342:Drug Hypersensitivity; D006801:Humans; D054328:Proton Pump Inhibitors; D012867:Skin; D012882:Skin Tests", "nlm_unique_id": "101130964", "other_id": null, "pages": "1073-1079", "pmc": null, "pmid": "33031621", "pubdate": "2021-04", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Dermatologic adverse reactions to proton-pump inhibitors: A synthetized review.", "title_normalized": "dermatologic adverse reactions to proton pump inhibitors a synthetized review" }	[ { "companynumb": "SA-ALKEM LABORATORIES LIMITED-SA-ALKEM-2020-07468", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "dru...
{ "abstract": "OBJECTIVE\nTo present two cases of delayed acetaminophen absorption in abdominal trauma patients with concomitant acetaminophen overdose.\n\n\nMETHODS\nCase 1. A 25-year-old female arrived to the emergency department with multiple stab wounds. She had ingested an unknown amount of acetaminophen and was then stabbed by her boyfriend in a suicide pact. Initial acetaminophen concentration was 211.7 mcg/mL and the patient was started on N-Acetylcysteine (NAC) therapy. She was found to have injuries and was taken for operative repair. Acetaminophen concentrations were down trending and nearly undetectable until 58 h post-presentation when concentrations began to rise again.\nA 41-year-old female ingested approximately 500 tablets of acetaminophen prior to jumping from a four-story building in a suicide attempt. She was found to have multiple traumatic injuries as well as an initial acetaminophen concentration of 225 mcg/mL and was started on NAC therapy. The patient underwent multiple interventions to treat her traumatic injuries. Despite receiving no acetaminophen while inpatient, the patient's acetaminophen concentrations peaked a second time on her third hospital day.\n\n\nCONCLUSIONS\nIn this case series, two patients with abdominal trauma and coexistent massive acetaminophen ingestions were described. Both cases demonstrated a delayed rise in serum acetaminophen concentrations and required extended NAC therapy.", "affiliations": "Department of Emergency Medicine, Division of Medical Toxicology, University of Southern California, Los Angeles, CA, USA.;Department of Emergency Medicine, Division of Medical Toxicology, University of Southern California, Los Angeles, CA, USA.;Department of Emergency Medicine, Regions Hospital, Saint Paul, MN, USA.;Department of Emergency Medicine, University of California, Los Angeles, CA, USA.;Department of Emergency Medicine, Regions Hospital, Saint Paul, MN, USA.", "authors": "Crow\|Elizabeth M\|EM\|;Spyres\|Meghan B\|MB\|;Boley\|Sean P\|SP\|https://orcid.org/0000-0003-1340-6416;Levine\|Michael\|M\|;Stellpflug\|Samuel J\|SJ\|https://orcid.org/0000-0002-2378-5280", "chemical_list": "D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D000082:Acetaminophen; D000111:Acetylcysteine", "country": "England", "delete": false, "doi": "10.1080/15563650.2020.1749278", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3650", "issue": "59(1)", "journal": "Clinical toxicology (Philadelphia, Pa.)", "keywords": "Acetaminophen; N-Acetylcysteine; delayed peak; trauma", "medline_ta": "Clin Toxicol (Phila)", "mesh_terms": "D000007:Abdominal Injuries; D000082:Acetaminophen; D000111:Acetylcysteine; D000328:Adult; D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D013406:Suicide, Attempted; D016896:Treatment Outcome; D014949:Wounds, Nonpenetrating; D014951:Wounds, Stab", "nlm_unique_id": "101241654", "other_id": null, "pages": "65-68", "pmc": null, "pmid": "32349551", "pubdate": "2021-01", "publication_types": "D002363:Case Reports", "references": null, "title": "Delayed peaks of acetaminophen in overdose patients with concomitant abdominal trauma.", "title_normalized": "delayed peaks of acetaminophen in overdose patients with concomitant abdominal trauma" }	[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-308957", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "d...
{ "abstract": "Telestroke services have been shown to increase stroke therapy access in rural areas. The implementation of advanced CT imaging for patient assessment may improve patient selection and detection of stroke mimics in conjunction with telestroke. We implemented a telestroke service supported by multimodal CT imaging in a rural hospital in Australia. Over 21months we conducted an evaluation of service activation, thrombolysis rates and use of multimodal imaging to assess the feasibility of the service. Rates of symptomatic intracranial haemorrhage and 90-day modified Rankin Score were used as safety outcomes. Fifty-eight patients were assessed using telestroke, of which 41 were regarded to be acute ischemic strokes and 17 to be stroke mimics on clinical grounds. Of the 41 acute stroke patients, 22 patients were deemed eligible for thrombolysis. Using multimodal CT imaging, 8 more patients were excluded from treatment because of lack of treatment target. Multimodal imaging failed to be obtained in one patient. For the 14 treated patients, median door-imaging time was 38min. Median door-treatment time was 91min. A 90-day mRS ⩽2 was achieved in 40% of treated patients. We conclude that a telestroke service using advanced CT imaging for therapy decision assistance can be successfully implemented in regional Australia and can be used to guide acute stroke treatment decision-making and improve access to thrombolytic therapy. Efficiency and safety is comparable to established telestroke services.", "affiliations": "John Hunter Hospital, Newcastle, NSW, Australia.;School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia.;Manning Rural Referral Hospital, Taree, NSW, Australia.;John Hunter Hospital, Newcastle, NSW, Australia.;Hunter Stroke Service, Hunter New England Health, Newcastle, NSW, Australia.;Manning Rural Referral Hospital, Taree, NSW, Australia.;John Hunter Hospital, Newcastle, NSW, Australia.;John Hunter Hospital, Newcastle, NSW, Australia.;John Hunter Hospital, Newcastle, NSW, Australia.;John Hunter Hospital, Newcastle, NSW, Australia; University of Newcastle, Callaghan, NSW, Australia.;Hunter Medical Research Institute, Newcastle, NSW, Australia.;Hunter Medical Research Institute, Newcastle, NSW, Australia.;John Hunter Hospital, Newcastle, NSW, Australia; University of Newcastle, Callaghan, NSW, Australia.;John Hunter Hospital, Newcastle, NSW, Australia; University of Newcastle, Callaghan, NSW, Australia. Electronic address: christopher.levi@hnehealth.nsw.gov.au.", "authors": "Demeestere\|Jelle\|J\|;Sewell\|Claire\|C\|;Rudd\|Jennifer\|J\|;Ang\|Timothy\|T\|;Jordan\|Louise\|L\|;Wills\|James\|J\|;Garcia-Esperon\|Carlos\|C\|;Miteff\|Ferdinand\|F\|;Krishnamurthy\|Venkatesh\|V\|;Spratt\|Neil\|N\|;Lin\|Longting\|L\|;Bivard\|Andrew\|A\|;Parsons\|Mark\|M\|;Levi\|Christopher\|C\|", "chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator", "country": "Scotland", "delete": false, "doi": "10.1016/j.jocn.2016.10.018", "fulltext": null, "fulltext_license": null, "issn_linking": "0967-5868", "issue": "37()", "journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia", "keywords": "CT perfusion; Reperfusion therapy; Telemedicine; Telestroke; Thrombectomy; Thrombolysis", "medline_ta": "J Clin Neurosci", "mesh_terms": "D000368:Aged; D001315:Australia; D002545:Brain Ischemia; D000066491:Clinical Decision-Making; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D018579:Patient Selection; D020521:Stroke; D017216:Telemedicine; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "9433352", "other_id": null, "pages": "1-5", "pmc": null, "pmid": "27887976", "pubdate": "2017-03", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "The establishment of a telestroke service using multimodal CT imaging decision assistance: \"Turning on the fog lights\".", "title_normalized": "the establishment of a telestroke service using multimodal ct imaging decision assistance turning on the fog lights" }	[ { "companynumb": "AU-ROCHE-1917444", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugad...
{ "abstract": "OBJECTIVE\nThe management of nonhealing corneal ulcers, particularly in patients with neurotrophic corneas, remains a challenging problem today. Some patients may fail to respond to conventional therapy, making new alternative agents necessary to treat these resistant cases. In this article, we aim to present six challenging cases of refractory corneal ulcers that revealed healing response to the adjuvant treatment with coenzyme Q10 (CoQ10) eye drops and to review the literature examining of new therapeutic agents.\n\n\nMETHODS\nOur study was designed as a descriptive case series demonstrating the use of novel coenzyme Q10 eye drops in refractory corneal ulcers. In our case series, CoQ10 eye drops were added to the existing therapies as an adjuvant agent in six cases: three cases with neurotrophic corneal ulcers, two cases with postinfectious corneal ulcers (one unknown etiology+one Acanthamoeba keratitis), and 1 case with Stevens-Johnson syndrome. All cases were monitored regularly and corneal images were taken at all visits.\n\n\nRESULTS\nAll nonhealing corneas with conventional therapy revealed recovery after the addition of CoQ10 eye drops. Except for two cases that responded to the CoQ10 eye drops more rapidly (within 1 to 2 weeks), complete corneal healing was observed in four cases between weeks 4 and 8. No adverse events were reported in these cases throughout the follow-up period.\n\n\nCONCLUSIONS\nCoenzyme Q10 eye drops can be considered as an important adjuvant therapeutic agent promoting corneal epithelial wound healing in challenging cases.", "affiliations": "Ocular Surface and Contact Lens Section, Department of Ophthalmology, Erciyes University School of Medicine, Kayseri, Turkey; Currently Ocular Surface Center and Alkek Eye Center, Baylor College of Medicine, Houston, TX.", "authors": "Gumus\|Koray\|K\|", "chemical_list": "D009883:Ophthalmic Solutions; D014815:Vitamins; D014451:Ubiquinone; C024989:coenzyme Q10", "country": "United States", "delete": false, "doi": "10.1097/ICL.0000000000000229", "fulltext": null, "fulltext_license": null, "issn_linking": "1542-2321", "issue": "43(2)", "journal": "Eye & contact lens", "keywords": null, "medline_ta": "Eye Contact Lens", "mesh_terms": "D000328:Adult; D000368:Aged; D017024:Chemotherapy, Adjuvant; D002648:Child; D003320:Corneal Ulcer; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D016896:Treatment Outcome; D014451:Ubiquinone; D014815:Vitamins", "nlm_unique_id": "101160941", "other_id": null, "pages": "73-80", "pmc": null, "pmid": "26783983", "pubdate": "2017-03", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Topical Coenzyme Q10 Eye Drops as an Adjuvant Treatment in Challenging Refractory Corneal Ulcers: A Case Series and Literature Review.", "title_normalized": "topical coenzyme q10 eye drops as an adjuvant treatment in challenging refractory corneal ulcers a case series and literature review" }	[ { "companynumb": "TR-DEXPHARM-20170688", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CHLORHEXIDINE" }, "drugadditional": "1", ...
{ "abstract": "The Toxicology Investigators Consortium (ToxIC) Registry was established by the American College of Medical Toxicology (ACMT) in 2010. The Registry collects data from participating sites with the agreement that all bedside medical toxicology consultation will be entered. The objective of this ninth annual report is to summarize the Registry's 2018 data and activity with its additional 7043 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2018. Detailed data was collected from these cases and aggregated to provide information which included demographics, reason for medical toxicology evaluation, agent and agent class, clinical signs and symptoms, treatments and antidotes administered, mortality, and whether life support was withdrawn. A total of 51.5% of cases were female, 48% were male, and 0.6% transgender. Non-opioid analgesics were the most commonly reported agent class, followed by antidepressants and opioids. Acetaminophen was once again the most common agent reported. There were 106 fatalities, comprising 1.5% of all registry cases. Major trends in demographics and exposure characteristics remained similar to past years' reports. Sub-analyses were conducted to describe exposures in elderly patients, addiction consultation practices, and risk factors for bupropion-induced seizures. The launch of the ToxIC Qualified Clinical Data Registry (TQCDR) is also described.", "affiliations": "Department of Emergency Medicine, Division of Medical Toxicology, University of Southern California, 1200 N State St. Rm 1011, Los Angeles, CA, 90033, USA. mspyres@gmail.com.;Hartford Hospital and University of Connecticut School of Medicine, 80 Seymour Street, Hartford, CT, 06102, USA.;Departments of Medicine and Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.;New Jersey Medical School, Rutgers, The State University of New Jersey, 140 Bergen Street, Suite G1600, Newark, NJ, 07101-1709, USA.;American College of Medical Toxicology, 10645 N Tatum Blvd., Suite 200-111, Phoenix, AZ, 85028, USA.;University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.;University of Rochester Medical Center and Strong Memorial Hospital, 601 Elmwood Ave, Rochester, NY, 14642, USA.;Indiana university school of medicine, 340 West 10th Street, Suite 6200, Indianapolis, IN, 46202, USA.;Michigan State University College of Human Medicine, 100 Michigan NE MC49, Grand Rapids, MI, 49503, USA.;American College of Medical Toxicology, 10645 N Tatum Blvd., Suite 200-111, Phoenix, AZ, 85028, USA.;University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.;University of Colorado School of Medicine, 13001 E 17th Pl, Aurora, CO, 80045, USA.", "authors": "Spyres\|Meghan B\|MB\|;Farrugia\|Lynn A\|LA\|;Kang\|A Min\|AM\|;Calello\|Diane P\|DP\|;Campleman\|Sharan L\|SL\|;Pizon\|Anthony\|A\|;Wiegand\|Timothy\|T\|;Kao\|Louise\|L\|;Riley\|Brad D\|BD\|;Li\|Shao\|S\|;Wax\|Paul M\|PM\|;Brent\|Jeffery\|J\|;\|\|\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1007/s13181-019-00736-9", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-9039", "issue": "15(4)", "journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology", "keywords": "Epidemiology; Medical Toxicology; Overdose; Poisoning; Surveillance", "medline_ta": "J Med Toxicol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance; D012042:Registries; D014116:Toxicology; D014481:United States; D055815:Young Adult", "nlm_unique_id": "101284598", "other_id": null, "pages": "228-254", "pmc": null, "pmid": "31642014", "pubdate": "2019-10", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.", "references": "24178902;25119250;28766237;26602099;30094774;22068919;27517280;31279256;30430638;22528591;30846215;31112123;23055123", "title": "The Toxicology Investigators Consortium Case Registry-the 2018 Annual Report.", "title_normalized": "the toxicology investigators consortium case registry the 2018 annual report" }	[ { "companynumb": "US-ALLERGAN-1949537US", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": nu...
{ "abstract": "Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission.\n\n\n\nThe present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants.\n\n\n\nTrial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001).\n\n\n\nIn community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended.\n\n\n\nThe Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.", "affiliations": "Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada. Electronic address: jean-claude.tardif@icm-mhi.org.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Ecogene-21, Université de Montréal, Montreal, QC, Canada; Department of Medicine, Université de Montréal, Montreal, QC, Canada.;New York University Grossman School of Medicine, New York, NY, USA.;New York University Grossman School of Medicine, New York, NY, USA.;H La Paz, IdiPaz, UAM, Ciber-CV, Madrid, Spain.;Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada.;Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Mayo Clinic, Rochester, MN, USA.;San Francisco General Hospital, San Francisco, CA, USA.;San Francisco General Hospital, San Francisco, CA, USA.;Cedars-Sinai Heart Institute, Geffen School of Medicine-UCLA, Los Angeles, CA, USA.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, QC, Canada.;Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, QC, Canada.;Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.;Université Laval, Quebec City, QC, Canada.;Second Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.;Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.;Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada.", "authors": "Tardif\|Jean-Claude\|JC\|;Bouabdallaoui\|Nadia\|N\|;L'Allier\|Philippe L\|PL\|;Gaudet\|Daniel\|D\|;Shah\|Binita\|B\|;Pillinger\|Michael H\|MH\|;Lopez-Sendon\|Jose\|J\|;da Luz\|Protasio\|P\|;Verret\|Lucie\|L\|;Audet\|Sylvia\|S\|;Dupuis\|Jocelyn\|J\|;Denault\|André\|A\|;Pelletier\|Martin\|M\|;Tessier\|Philippe A\|PA\|;Samson\|Sarah\|S\|;Fortin\|Denis\|D\|;Tardif\|Jean-Daniel\|JD\|;Busseuil\|David\|D\|;Goulet\|Elisabeth\|E\|;Lacoste\|Chantal\|C\|;Dubois\|Anick\|A\|;Joshi\|Avni Y\|AY\|;Waters\|David D\|DD\|;Hsue\|Priscilla\|P\|;Lepor\|Norman E\|NE\|;Lesage\|Frédéric\|F\|;Sainturet\|Nicolas\|N\|;Roy-Clavel\|Eve\|E\|;Bassevitch\|Zohar\|Z\|;Orfanos\|Andreas\|A\|;Stamatescu\|Gabriela\|G\|;Grégoire\|Jean C\|JC\|;Busque\|Lambert\|L\|;Lavallée\|Christian\|C\|;Hétu\|Pierre-Olivier\|PO\|;Paquette\|Jean-Sébastien\|JS\|;Deftereos\|Spyridon G\|SG\|;Levesque\|Sylvie\|S\|;Cossette\|Mariève\|M\|;Nozza\|Anna\|A\|;Chabot-Blanchet\|Malorie\|M\|;Dubé\|Marie-Pierre\|MP\|;Guertin\|Marie-Claude\|MC\|;Boivin\|Guy\|G\|;\|\|\|", "chemical_list": "D000893:Anti-Inflammatory Agents; D003078:Colchicine", "country": "England", "delete": false, "doi": "10.1016/S2213-2600(21)00222-8", "fulltext": "\n==== Front\nLancet Respir Med\nLancet Respir Med\nThe Lancet. Respiratory Medicine\n2213-2600\n2213-2619\nElsevier\n\nS2213-2600(21)00222-8\n10.1016/S2213-2600(21)00222-8\nArticles\nColchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial\nTardif Jean-Claude Prof MD jean-claude.tardif@icm-mhi.org\na\nBouabdallaoui Nadia MD a\nL'Allier Philippe L MD a\nGaudet Daniel MD bc\nShah Binita MD d\nPillinger Michael H Prof MD d\nLopez-Sendon Jose Prof MD e\nda Luz Protasio Prof MD f\nVerret Lucie MSc a\nAudet Sylvia MSc a\nDupuis Jocelyn Prof MD a\nDenault André Prof MD a\nPelletier Martin PhD g\nTessier Philippe A PhD g\nSamson Sarah BSN a\nFortin Denis BSN a\nTardif Jean-Daniel BSc a\nBusseuil David PhD a\nGoulet Elisabeth RN a\nLacoste Chantal DEC a\nDubois Anick PhD a\nJoshi Avni Y Prof MD h\nWaters David D Prof MD i\nHsue Priscilla Prof MD i\nLepor Norman E Prof MD j\nLesage Frédéric Prof PhD a\nSainturet Nicolas PhD k\nRoy-Clavel Eve MSc, BSc k\nBassevitch Zohar k\nOrfanos Andreas MBBS k\nStamatescu Gabriela MD k\nGrégoire Jean C MD a\nBusque Lambert MD l\nLavallée Christian MD l\nHétu Pierre-Olivier PhD m\nPaquette Jean-Sébastien MD n\nDeftereos Spyridon G Prof MD o\nLevesque Sylvie MSc k\nCossette Mariève MSc k\nNozza Anna MSc k\nChabot-Blanchet Malorie MSc k\nDubé Marie-Pierre Prof PhD a\nGuertin Marie-Claude PhD k\nBoivin Guy MD g\nfor the COLCORONA Investigators\na Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada\nb Ecogene-21, Université de Montréal, Montreal, QC, Canada\nc Department of Medicine, Université de Montréal, Montreal, QC, Canada\nd New York University Grossman School of Medicine, New York, NY, USA\ne H La Paz, IdiPaz, UAM, Ciber-CV, Madrid, Spain\nf Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil\ng Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada\nh Mayo Clinic, Rochester, MN, USA\ni San Francisco General Hospital, San Francisco, CA, USA\nj Cedars-Sinai Heart Institute, Geffen School of Medicine-UCLA, Los Angeles, CA, USA\nk Montréal Health Innovations Coordinating Center, Montreal, QC, Canada\nl Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, QC, Canada\nm Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada\nn Université Laval, Quebec City, QC, Canada\no Second Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece\n* Correspondence to: Prof Jean-Claude Tardif, Montreal Heart Institute, H1T1C8 Montreal, QC, Canada jean-claude.tardif@icm-mhi.org\n* Members listed in the appendix\n\n1 8 2021\n8 2021\n9 8 924932\n© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nSummary\n\nBackground\n\nEvidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission.\n\nMethods\n\nThe present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants.\n\nFindings\n\nTrial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0–61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61–1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57–0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001).\n\nInterpretation\n\nIn community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended.\n\nFunding\n\nThe Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.\n==== Body\nIntroduction\n\nAccumulating evidence suggests that some patients with COVID-19 have excessive inflammation.1 Treatment of this exaggerated inflammatory response has been advocated to address the immediate need to reduce the risk of complications.1, 2 The steroid dexamethasone reduces mortality in patients admitted to hospital with COVID-19, but only if they receive mechanical ventilation or supplemental oxygen.3 In the open-label STOIC trial,4 the inhaled steroid budesonide decreased the requirement for urgent medical care in patients with early COVID-19. In addition, the anti-interleukin (IL)-6-receptor antibody tocilizumab was shown to reduce the likelihood of progression to mechanical ventilation in patients admitted and treated in hospital for COVID-19 pneumonia.5 The IL-1 receptor antagonist anakinra might also be effective in some patients with COVID-19.6\n\nSARS-CoV, which is closely related to the SARS-CoV-2 virus responsible for COVID-19, has been shown to activate the NLR-family pyrin domain-containing 3 (NLRP3) inflammasome.7 Activation of the NLRP3 inflammasome by SARS-CoV-2 has been shown in lung tissues of patients with COVID-19.8 This intracellular complex activates several ILs, which then trigger an inflammatory cascade. Given that elevated concentrations of IL-1β and IL-6 are associated with adverse clinical outcomes in COVID-19,9, 10 targeting the NLRP3 inflammasome (which is responsible for the maturation and secretion of IL-1β) might reduce related complications in patients at risk of cytokine activation.\n\nResearch in context\n\nEvidence before this study\n\nWe searched MEDLINE (PubMed), Embase, and Cochrane central to identify studies investigating the role of the host inflammatory response in COVID-19 complications and randomised controlled trials (RCTs) of anti-inflammatory agents aimed at preventing this response, from inception until April 12, 2021. To maximise sensitivity, we also searched for citations in Google Scholar, Scopus, and Web of Science. Search terms included “COVID-19”, “coronavirus”, “inflammation”, “inflammatory storm”, “cytokine”, “cytokine storm”, “anti-inflammatory agents”, and “colchicine”, either separately or in combination. The inhaled steroid budesonide was shown in the open-label STOIC trial to reduce the requirement for urgent medical care in patients with early COVID-19. Activation of the NLRP3 inflammasome by SARS-CoV-2 was observed in lung tissues of patients with COVID-19. Prevention of COVID-19 complications in an outpatient setting ideally requires a clinically approved, orally administered, and inexpensive medication targeting the inflammasome with a known favourable safety profile.\n\nAdded value of this study\n\nPotential clinical benefits of colchicine have been reported in observational studies and two small RCTs (including GRECCO) of patients admitted to hospital with COVID-19. In our COLCORONA double-blinded, placebo-controlled, randomised trial of 4488 non-hospitalised patients, including the 327 (7%) without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among the 4159 (93%) of patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo.\n\nImplications of all the available evidence\n\nGiven the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients, the burden on health-care systems caused by hospital admissions, and the benefit of colchicine in patients with PCR-proven COVID-19, we propose that colchicine is a safe and inexpensive anti-inflammatory agent that could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of patients who have positive PCR tests and have been treated in the community (such as the PRINCIPLE trial) is recommended. Additional trials such as the AGILE-ACCORD might enrich our therapeutic armamentarium to prevent COVID-19-related complications in ambulatory patients.\n\nPrevention of COVID-19 complications in an outpatient setting ideally requires a clinically available, orally administered, and inexpensive medication targeting the inflammasome with a known favourable safety and tolerability profile. Colchicine is a potent anti-inflammatory agent used to treat gout, viral pericarditis, coronary disease, and familial Mediterranean fever.11, 12, 13, 14 Its mechanism of action is through the inhibition of tubulin polymerisation, with effects on the inflammasome, cellular adhesion molecules, and inflammatory chemokines.15, 16, 17 In an experimental model of acute respiratory-distress syndrome, colchicine was shown to reduce inflammatory lung injury and respiratory failure by interfering with leukocyte activation and recruitment.18 Substantial clinical benefits of colchicine have also been reported in observational studies and two randomised controlled trials of patients admitted to hospital with COVID-19.19, 20, 21, 22\n\nWe did the COLchicine CORONAvirus SARS-CoV-2 (COLCORONA) trial in community-treated patients with COVID-19 to establish the effects of colchicine on complications, including hospital admission and death, as well as its safety and tolerability.\n\nMethods\n\nStudy design\n\nCOLCORONA was a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre, investigator-initiated trial comparing orally administered colchicine (0·5 mg twice per day for the first 3 days and then once per day for 27 days thereafter) with placebo in a 1:1 ratio. We have described the rationale for the treatment regimen (appendix p 8). COLCORONA was done in six countries (Brazil, Canada, Greece, South Africa, Spain, and the USA) and was led by the Montreal Heart Institute (Montreal, QC, Canada). The trial protocol was designed by the study steering committee. The protocol was approved by the institutional review board at all centres involved in the six countries that participated in the trial (appendix pp 4–7). All study support activities, including project coordination, data management, site monitoring, and statistical oversight and analyses, were done at the Montreal Health Innovations Coordinating Center (MHICC). The trial was overseen by a data-safety monitoring board of independent experts.\n\nTrial population\n\nPatients were eligible if they were at least 40 years of age, had received a diagnosis of COVID-19 within 24 h of enrolment, were not currently being treated in hospital and not under immediate consideration for hospital treatment or admission, and presented at least one of the following high-risk criteria: age of 70 years or older, obesity (body-mass index of 30 kg/m2 or more), diabetes, uncontrolled hypertension (systolic blood pressure ≥150 mm Hg), known respiratory disease, known heart failure, known coronary disease, fever of at least 38·4°C within the last 48 h, dyspnoea at the time of presentation, bicytopenia, pancytopenia, or the combination of high neutrophil and low lymphocyte counts. The diagnosis of COVID-19 was made by local laboratories using PCR testing on a nasopharyngeal swab specimen. Given the restrictions in laboratory testing early in the pandemic, a diagnosis was also accepted as an epidemiological link with a household member who had a positive nasopharyngeal test result for patients with symptoms compatible with COVID-19, or by a clinical algorithm in a symptomatic patient without an obvious alternative cause, as per official guidelines (appendix p 9).23 Women were either not of childbearing potential or practicing adequate contraception.\n\nPatients were excluded if they had inflammatory bowel disease or chronic diarrhoea or malabsorption, pre-existent progressive neuromuscular disease, an estimated glomerular filtration rate of less than 30 mL per min per 1·73 m2, severe liver disease, current treatment with colchicine, current chemotherapy for cancer, or a history of substantial sensitivity to colchicine. Further details regarding eligibility criteria are provided (appendix).\n\nWritten informed consent was obtained electronically or on paper from all patients before enrolment following a telemedicine or in-person visit.\n\nRandomisation and masking\n\nMasked randomisation was centralised and done electronically through an automated interactive web-response system (IWRS). Participants were randomly assigned (1:1) to either colchicine treatment or placebo, using an allocation sequence that was computer-generated using a blocking schema with block sizes of six. Allocation sequence was not stratified. Eligible patients were randomly assigned by research nurses through the IWRS system that provided the bottle number to send to patients. The randomisation list was computer-generated by an unmasked biostatistician and uploaded to an interactive web response system (Dacima). The database was a validated electronic-data-capture system (eCRF) using InForm 6.0 provided by Oracle. The eCRF was developed by the MHICC as per their internal standard-operating procedures. All eCRF users were trained as per completion guidelines and the data entry was done directly by the study staff during phone calls with the patients. The data cleaning activities were done as per the MHICC data-management plan. All staff involved, including study investigators, nurses, and patients were masked to the treatment received.\n\nProcedures\n\nAll patients received either 0·5 mg colchicine orally administered twice per day for the first 3 days and then once per day for 27 days thereafter, or matching placebo. Study medication was delivered at the patient's house within 4 h of enrolment. The study medication and matching placebo were provided by Pharmascience (Montreal, Canada), which had no role in the design or conduct of the trial or the preparation or review of this manuscript.\n\nClinical evaluations occurred by telephone at 15 days and 30 days following randomisation for evaluation of the occurrence of any trial endpoints or other adverse events.\n\nEndpoints\n\nThe primary efficacy endpoint was a composite of death or hospital admission because of COVID-19 infection in the 30 days after randomisation. The secondary endpoints consisted of the components of the composite primary endpoint, and the need for mechanical ventilation in the 30 days after randomisation. Pneumonias, other serious adverse events, and non-serious adverse events were also collected.\n\nStatistical analysis\n\nAssuming a primary endpoint event rate of 7% in the placebo group, we estimated that a sample size of approximately 6000 patients randomly allocated to treatment with 3000 patients in each treatment group would be required to detect a target 25% relative-risk reduction with colchicine (corresponding to a primary endpoint event rate of 5·25% with colchicine, for an absolute difference of 1·75%) with a power of 80% and a two-sided test at the 0·05 significance level. Because the efficacy interim analyses were done with the conservative O'Brien-Fleming approach, their impact on final significance was deemed to be minimal and no sample-size adjustment was done for interim analyses.\n\nEfficacy analyses were done according to the intention-to-treat principle. The primary endpoint was compared between the two treatment groups using a χ2 test, and the odds ratio (OR) along with the 95·1% CI was provided. Secondary endpoints were analysed similarly. Because of potential limitations to the specificity of COVID-19 diagnosis made on clinical or epidemiological criteria alone, a pre-specified subgroup analysis of the primary endpoint examined patients who were enrolled based on a positive PCR test. Pre-specified subgroup analyses of the primary endpoint were done using logistic-regression models including the treatment group, the subgroup factor, and the treatment x subgroup-factor interaction. Investigation of secondary endpoints in subgroups were done as post-hoc analyses. A pre-specified sensitivity analysis of the primary endpoint was done by imputing a primary event in event-free patients who did not complete the study (ie, discontinued before day 30 or for whom no information was available at end of study).\n\nThree formal interim efficacy analyses on the primary endpoint were planned after 25%, 50%, and 75% of the primary endpoint events had occurred. The prespecified stopping rule for efficacy was based on the Lan-DeMets procedure with the O'Brien-Fleming α-spending function to determine the significance level. Futility was assessed by computing the conditional power under the original alternative and judged at 15%. Results of the interim analyses were generated by an unmasked biostatistician and were provided only to the data-safety monitoring board members. During the entire duration of the trial, the study team, including the biostatisticians who wrote the statistical analysis plan and generated the final results, remained masked to treatment allocation.\n\nFollowing its review of the first two interim results, the monitoring board recommended that the trial should continue as planned (appendix p 10). On Dec 11, 2020, the steering committee chairman informed the data-safety monitoring board that the investigators had decided to terminate the study once 75% of the planned patients were recruited and had completed the 30 day follow-up. This decision was made due to substantial logistical, personnel, and budgetary issues related to maintaining the central study call centre active 24 h per day for a prolonged period of time, which were compounded by the inability to reliably model the additional time required to reach the target number of patients through the successive waves of the pandemic. To account for the two interim analyses that were done, the final statistical significance level was calculated as 0·049 for the final analysis of the primary endpoint. No other statistical adjustment for bias was made. All other statistical tests were two-sided and done at the 0·05 significance level.\n\nStatistical analyses were done using SAS version 9.4. There was no prespecified plan to adjust for multiple comparisons across the multiple methods used to analyse the primary outcome and secondary endpoints; results of these analyses are reported with point estimates and 95% CI, without p values. 95% CIs are not adjusted for multiple comparisons, and inferences drawn from them might not be reproducible. The statistical analysis plan was approved on Nov 25, 2020. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682).\n\nRole of the funding source\n\nThe funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.\n\nResults\n\nTrial enrolment began in March 23, 2020, and was completed in Dec 22, 2020; the last trial visit was in Jan 19, 2021. A total of 4488 patients were randomly assigned to either colchicine (2235 patients) or placebo (2253 patients) and were followed up for 30 days. At the time of database lock and unblinding on Jan 20, 2021, vital and primary-endpoint event status were available for all except 93 (2·1%) of 4488 patients (figure).Figure Trial profile\n\nOf a sample of 5536 patients screened in Canada, 775 (14%) patients were randomly assigned to treatment, because 2392 (43%) patients did not have at least one high-risk characteristic (which was an inclusion criterion) or met at least one exclusion criterion, and 2369 (43%) patients declined participation. Note that information on screened individuals is only available for those recruited in Canada.\n\nWe present the baseline characteristics of the patients (table 1, appendix p 12). Patients were enrolled a mean of 5·3 days (SD 4·4) after the onset of COVID-19 symptoms. The median age of participants was 54·0 years (IQR 47·0–61·0), 53·9% of the patients were women, mean body-mass index was 30·0 kg per m2 (SD 6·2), and 19·9% had diabetes. The mean treatment duration with the trial medication was 26·2 days (SD 9·6).Table 1 Characteristics of the patients at randomisation in the intent-to-treat population\n\n\t\tColchicine (n=2235)\tPlacebo (n=2253)\t\nAge (years), median (IQR)\t53·0 (47·0–61·0)\t54·0 (47·0–61·0)\t\nWomen\t1238 (55·4%)\t1183 (52·5%)\t\nMen\t997 (44·6%)\t1070 (47·5%)\t\nWhite\t2086 (93·3%)\t2096 (93·2%)\t\nBlack\t114 (5·1%)\t119 (5·3%)\t\nBMI (kg/m2), mean (SD)\t30·0 (6·2)\t30·0 (6·3)\t\nSmoking\t217 (9·7%)\t212 (9·4%)\t\nHypertension\t781 (34·9%)\t848 (37·6%)\t\nDiabetes\t444 (19·9%)\t450 (20·0%)\t\nRespiratory disease\t583 (26·1%)\t605 (26·9%)\t\nPrior MI\t65 (2·9%)\t72 (3·2%)\t\nPrior heart failure\t24 (1·1%)\t18 (0·8%)\t\nConcomitant medication use\t\n\tHydroxychloroquine\t12 (0·5%)\t11 (0·5%)\t\n\tOral anticoagulant\t48 (2·1%)\t65 (2·9%)\t\n\tAspirin\t195 (8·7%)\t235 (10·4%)\t\n\tOther platelet agents\t32 (1·4%)\t43 (1·9%)\t\nCountries\t\n\tCanada\t1817 (81·3%)\t1830 (81·2%)\t\n\tUSA\t244 (10·9%)\t244 (10·8%)\t\n\tOther countries\t174 (7·8%)\t179 (7·9%)\t\nData are n (%) unless otherwise specified. BMI=body-mass index. MI=myocardial infarction.\n\n Data on race were missing for some patients; the denominator in the placebo group was 2248.\n\nA primary endpoint event occurred in 104 (4·7%) of 2235 patients in the colchicine group, as compared with 131 (5·8%) of 2253 patients in the placebo group (table 2). Components of the primary endpoint included death and hospital admission due to COVID-19, and for the secondary efficacy endpoint included the need for mechanical ventilation. Although not a prespecified endpoint, the rate of hospital admissions due to any cause was 110 (4·9%) of 2235 patients in the colchicine group and 138 (6·1%) of 2253 patients in the placebo group (OR 0·79, 95% CI 0·61–1·03; p=0·078).Table 2 Rates and odds ratios for major clinical outcomes in the intent-to-treat population\n\n\t\tColchicine (n=2235)\tPlacebo (n=2253)\tOdds ratio (95% CI)\tp value\t\nPrimary composite endpoint\t104 (4·7%)\t131 (5·8%)\t0·79 (0·61–1·03)\t0·081\t\nComponents of primary endpoint\t\n\tDeath\t5 (0·2%)\t9 (0·4%)\t0·56 (0·19–1·67)\t..\t\n\tHospitalisation for COVID-19\t101 (4·5%)\t128 (5·7%)\t0·79 (0·60–1·03)\t..\t\nSecondary endpoint, mechanical ventilation\t11 (0·5%)\t21 (0·9%)\t0·53 (0·25–1·09)\t..\t\nData are n (%).\n\n Odds ratio (95·1% CI) for the primary composite endpoint.\n\nIn a prespecified sensitivity analysis of the primary endpoint to account for missing data where an event was imputed in all patients who were event free and who did not complete the study (32 patients in the colchicine group and 49 patients in the placebo group), the primary-endpoint event rate was 136 (6·1%) of 2235 patients in the colchicine group and 180 (8·0%) of 2253 patients in the placebo group (OR 0·75, 95% CI, 0·59–0·94; p=0·013).\n\nIn the prespecified analysis of the 4159 patients with COVID-19 confirmed by PCR (appendix p 13), the primary endpoint was shown in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 in the placebo group (table 3). Among the patients with confirmed COVID-19, ORs were 0·75 (95% CI 0·57–0·99) for hospital admission due to the infection and 0·56 (0·19–1·66) for death. Results for the secondary endpoints in this group of patients represented a post-hoc analysis. The secondary efficacy endpoint of the need for mechanical ventilation occurred in ten (0·5%) of 2075 patients in the colchicine group, as compared with 20 (1·0%) of 2084 patients in the placebo group (table 3). Although not a prespecified endpoint, the rate of hospital admission due to any cause was 101 (4·9%) of 2075 patients in the colchicine group versus 132 (6·3%) of 2084 patients in the placebo group (OR 0·76, 95% CI 0·58–0·99; p=0·040).Table 3 Rates and odds ratios for major clinical outcomes in the subgroup of patients with PCR-confirmed COVID-19 in the intent-to-treat population\n\n\t\tColchicine (n=2075)\tPlacebo (n=2084)\tOdds ratio (95% CI)\tp value\t\nPrimary composite endpoint\t96 (4·6%)\t126 (6·0%)\t0·75 (0·57–0·99)\t0·042\t\nComponents of primary endpoint\t\n\tDeath\t5 (0·2%)\t9 (0·4%)\t0·56 (0·19–1·66)\t..\t\n\tHospitalisation for COVID-19\t93 (4·5%)\t123 (5·9%)\t0·75 (0·57–0·99)\t..\t\nSecondary endpoint mechanical ventilation\t10 (0·5%)\t20 (1·0%)\t0·50 (0·23–1·07)\t..\t\nData are n (%). Evaluation of the primary endpoint in the subgroup of patients with PCR-confirmed COVID-19 was prespecified and that of components of the primary endpoint and the secondary endpoints were done as post-hoc analyses.\n\nAmong the patients with diabetes, the primary endpoint occurred in 27 (6·1%) of the 444 patients in the colchicine group and 43 (9·6%) of the 450 in the placebo group. The primary endpoint event rate in men was 58 (5·8%) of 997 in the colchicine group and 90 (8·4%) of 1070 in the placebo group, whereas the corresponding values in women were 46 (3·7%) of 1238 in the colchicine group and 41 (3·5%) of 1183 in the placebo group (table 4). The primary-event rate in the placebo group was 126 (6·0%) of 2084 when diagnosis was done by PCR, and five (3·0%) of 169 when clinical criteria were used for diagnosis.Table 4 Primary-efficacy composite endpoint in prespecified subgroups of the intent-to-treat population\n\n\tColchicine\tPlacebo\tOdds ratio (95% CI)\t\nPCR-confirmed COVID-19\t\nYes\t96 (4·6%) of 2075\t126 (6·0%) of 2084\t0·75 (0·57–0·99)\t\nNo\t8 (5·1%) of 158\t5 (3·0%) of 169\t1·75 (0·56–5·46)\t\nHistory of diabetes\t\nYes\t27 (6·1%) of 444\t43 (9·6%) of 450\t0·61 (0·37–1·01)\t\nNo\t77 (4·3%) of 1791\t88 (4·9%) of 1803\t0·88 (0·64–1·20)\t\nHistory of hypertension\t\nYes\t48 (6·1%) of 781\t64 (7·5%) of 848\t0·80 (0·54–1·18)\t\nNo\t56 (3·9%) of 1454\t67 (4·8%) of 1405\t0·80 (0·56–1·15)\t\nSmoking\t\nNon-smoker\t59 (4·6%) of 1279\t71 (5·6%) of 1270\t0·82 (0·57–1·16)\t\nPrevious smoker\t38 (5·1%) of 738\t56 (7·3%) of 770\t0·69 (0·45–1·06)\t\nActive smoker\t7 (3·2%) of 217\t4 (1·9%) of 212\t1·73 (0·50–6·01)\t\nAge\t\n≥70 years\t18 (9·5%) of 190\t27 (12·7%) of 213\t0·72 (0·38–1·36)\t\n<70 years\t86 (4·2%) of 2045\t104 (5·1%) of 2040\t0·82 (0·61–1·09)\t\nSex\t\nMen\t58 (5·8%) of 997\t90 (8·4%) of 1070\t0·67 (0·48–0·95)\t\nWomen\t46 (3·7%) of 1238\t41 (3·5%) of 1183\t1·07 (0·70–1·65)\t\nRace\t\nBlack\t3 (2·6%) of 114\t6 (5·0%) of 119\t0·51 (0·12–2·09)\t\nNon-black\t101 (4·8%) of 2121\t125 (5·9%) of 2129\t0·80 (0·61–1·05)\t\nBody-mass index\t\n≥30 kg/m2\t53 (5·2%) of 1012\t70 (6·7%) of 1040\t0·77 (0·53–1·11)\t\n<30 kg/m2\t50 (4·1%) of 1216\t61 (5·1%) of 1205\t0·80 (0·55–1·18)\t\nRespiratory disease\t\nYes\t35 (6·0%) of 583\t48 (7·9%) of 605\t0·74 (0·47–1·16)\t\nNo\t69 (4·2%) of 1652\t83 (5·0%) of 1647\t0·82 (0·59–1·14)\t\nCardiovascular disease\t\nYes\t6 (5·0%) of 119\t11 (9·0%) of 122\t0·54 (0·19–1·50)\t\nNo\t98 (4·6%) of 2116\t120 (5·6%) of 2131\t0·81 (0·62–1·07)\t\nUse of ACEi or ARB\t\nYes\t37 (6·1%) of 602\t53 (7·8%) of 676\t0·77 (0·50–1·19)\t\nNo\t67 (4·1%) of 1633\t78 (4·9%) of 1577\t0·82 (0·59–1·15)\t\nData are n (%) of N. ACEi=angiotensin-converting enzyme inhibitor. ARB=angiotensin-receptor blocker.\n\nSerious adverse events occurred in 4·9% in the colchicine group and 6·3% in the placebo group (table 5), and pneumonia occurred in 2·9% in the colchicine group and 4·1% in the placebo group. Pulmonary embolism was diagnosed in 0·5% of patients in the colchicine group and 0·1% in the placebo group (appendix p 14). These pulmonary emboli did not lead to the need for mechanical ventilation or to death, were all considered to be unrelated to the study medication by the physician in charge, and were included as hospital admissions due to COVID-19 in the analysis of the primary efficacy endpoint. No deep venous thrombosis was reported. Dehydration was reported in three (0·1%) of 2195 patients in the colchicine group and six (0·3%) of 2217 patients in the placebo group.Table 5 Proportions of patients with adverse events in the safety population\n\n\tColchicine (n=2195)\tPlacebo (n=2217)\t\nDeath\t5 (0·2%)\t9 (0·4%)\t\nAny SAE\t108 (4·9%)\t139 (6·3%)\t\nPneumonia SAE\t63 (2·9%)\t92 (4·1%)\t\nPulmonary embolism\t11 (0·5%)\t2 (0·1%)\t\nDeep venous thrombosis\t0\t0\t\nMyocardial infarction\t0\t1 (<0·1%)\t\nDehydration SAE\t3 (0·1%)\t6 (0·3%)\t\nAny related AE\t532 (24·2%)\t344 (15·5%)\t\nGastrointestinal AE\t524 (23·9%)\t328 (14·8%)\t\nGastrointestinal SAE\t6 (0·3%)\t3 (0·1%)\t\nDiarrhoea AE\t300 (13·7%)\t161 (7·3%)\t\nNausea AE\t43 (2·0%)\t47 (2·1%)\t\nGastrointestinal haemorrhage AE\t1 (<0·1%)\t0\t\nRash AE\t4 (0·2%)\t13 (0·6%)\t\nData are n (%). The safety population refers to the patients who took at least one dose of trial medication. AE=adverse event. SAE=serious adverse event. NA=not applicable.\n\nThe percentage of adverse events that were considered to be related to trial medication was 24·2% in the colchicine group and 15·5% in the placebo group (table 5). At least one treatment-emergent gastrointestinal adverse event occurred in 524 (23·9%) of 2195 patients in the colchicine group, as compared with 328 (14·8%) of the 2217 patients in the placebo group. Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group.\n\nDiscussion\n\nIn COLCORONA, the risk of the primary composite efficacy endpoint of death or hospital admission due to COVID-19 infection in the 30 days following randomisation was not statistically significantly lower among the patients who were randomly assigned to receive colchicine than in those who received placebo.\n\nBecause of the shortage of reagents for PCR tests and the restriction in the use of such testing early in the pandemic, diagnosis of probable COVID-19 through an epidemiological link or compatible symptoms was initially allowed in the study. These patients had a primary event rate that was half (3%) that observed in those with confirmed diagnosis by PCR testing (6%).\n\nWhen the patients who had a confirmed diagnosis of COVID-19 are considered, the benefit of colchicine on the primary-efficacy endpoint was more marked and statistically significant. The relative-risk reduction that we observed was similar to the one planned in the sample-size calculation. Treatment with colchicine was associated with concordant effects on hospital admissions, use of mechanical ventilation, and deaths in patients with a diagnosis of COVID-19 confirmed by PCR testing.\n\nThe effect of colchicine on the primary endpoint was consistent across subgroups of patients on the basis of various clinical characteristics. Although the benefits of colchicine appeared to be more marked in patients with diabetes and men, there was no statistically significant heterogeneity in the results. Because the event rates were higher in patients with these characteristics, the effect of colchicine might have been more readily detectable. Diabetes is a pro-inflammatory state, which might explain the greater risk of complications of COVID-19 in patients with diabetes than in those without. Despite the link between weight, insulin resistance, and type 2 diabetes, the effects of colchicine did not differ whether the body-mass index was higher or lower than 30 kg per m2. Sex-related differences in immune responses against SARS-CoV-2 exist. Men have higher plasma concentrations of IL-18 and IL-8, whereas women have stronger T-cell activation.24 These differences might at least in part explain the apparent difference in response to colchicine in COVID-19. Of note, the concomitant use of an inhibitor of the renin-angiotensin system did not appear to modify the clinical response to colchicine.\n\nThe most common adverse events that we observed were gastrointestinal. Diarrhoea was reported by 13·7% of patients in the colchicine group and 7·3% in the placebo group. Dehydration was reported in three (0·1%) patients in the colchicine group and six (0·3%) patients in the placebo group. Deleterious effects of COVID-19 are numerous and can affect among others the lungs, heart, and brain. The seriousness of the disease is reflected by the high incidence of serious adverse events in patients of the placebo group in the COLCORONA trial. The number of patients with any serious adverse event was smaller in the colchicine group than in the placebo group, which might reflect the benefits of systemic-inflammation reduction in this disease. Pneumonia was reported less frequently in patients of the colchicine group than those of the placebo group. This is concordant with the statistically significant reduction of hospital admissions in patients with confirmed COVID-19 treated with colchicine, and the numerically lower number of patients requiring mechanical ventilation, although this was not significant. Our results are supported by the results of two smaller clinical trials showing reductions in the need for oxygen supplementation, the duration of hospital treatment, and the deterioration of clinical status.19, 20 Colchicine has previously been shown to reduce acute lung injury in an experimental model of acute respiratory-distress syndrome.18 The risk of viral inflammatory pneumonitis therefore appears to be lowered by colchicine in patients with COVID-19. Reassuringly, there was no evidence of an increased risk of bacterial pneumonia in COLCORONA.\n\nThe number of reported cases of pulmonary embolism was higher in patients of the colchicine group than in patients in the placebo group in COLCORONA. The 13 cases of pulmonary embolism were included in the analysis of the primary composite endpoint as hospital admissions due to COVID-19. Despite this apparent imbalance, the numbers of hospital admissions, use of mechanical ventilation, and deaths were numerically lower in the colchicine group than in the placebo group. Additionally, the pulmonary emboli did not lead to the need for mechanical ventilation or to death in these 13 patients. By contrast, there was no imbalance in other reported thrombotic or embolic events such as deep venous thrombosis or myocardial infarction. A systematic review and meta-analysis of randomised controlled trials involving more than 10 000 patients with coronary disease followed for approximately 2 years has not shown a statistically significant difference in the rate of pulmonary embolism or deep venous thrombosis between the colchicine and placebo groups.25 In addition, a significant reduction in the concentration of D dimer, a plasma biomarker used for the diagnostic investigation of pulmonary embolism, was observed with colchicine compared with the control in the GRECCO study.19 Furthermore, colchicine has previously been shown in murine models to lower the release of α defensin associated with large thrombus burdens and in clinical studies to reduce the aggregation between neutrophils and platelets.26, 27, 28 Thus, there is no known potential biological basis to suggest a causal link between colchicine therapy and thromboembolic disease. The incidence of pulmonary embolism is high in COVID-19, and occurs in up to 25% of patients with associated pneumonia.29 More than 57% of patients dying from COVID-19 have evidence of deep venous thrombosis or pulmonary embolus at autopsy.30 In COLCORONA, the incidence of pulmonary embolism in patients requiring hospital admission was 11 (10·9%) of 101 patients in the colchicine group and two (1·6%) of 128 in the placebo group. The totality of the evidence suggests that the low rate of pulmonary embolisms in the placebo group represents an anomaly. The more common presence and greater severity of COVID-19 pneumonia infiltrates in patients receiving placebo might have reduced the clinical suspicion for pulmonary embolism in symptomatic patients.\n\nOur trial has certain limitations. The study was stopped when 75% of the planned patients were recruited and had completed the 30 day follow-up. We nevertheless believe that our results are clinically persuasive. The duration of follow-up was relatively short at approximately 30 days. We did not investigate the evolution of persistent COVID-19 symptoms and the effects of longer-term treatment with colchicine. The benefit of a shorter course of colchicine therapy for less than 30 days is also not entirely known, although the results of two smaller trials showed benefits of treatment administered for 10–21 days.19, 20 Finally, our results apply to patients who have a proven diagnosis of COVID-19, are at risk of clinical complications, and are not admitted to hospital at the time of treatment initiation. The number needed to treat with colchicine to prevent one primary endpoint event was 70 (95% CI 36–1842) for patients with PCR-proven COVID-19, 29 (14 to not defined) for those with diabetes, 31 (11 to not defined) for patients aged 70 years and older, 39 (21–259) in men, 52 (21 to not defined) in patients with respiratory disease, and 25 (10 to not defined) in those with cardiovascular disease.\n\nIn conclusion, in community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo.\n\nData sharing\n\nThe anonymised patient data will be shared, while safeguarding the privacy of participants, via the Vivli data repository (https://vivli.org/).\n\nSupplementary Material\n\nSupplementary appendix\n\nAcknowledgments\n\nThe authors acknowledge the expert secretarial assistance of Lucie Lefebvre in the preparation and submission of this manuscript.\n\nContributors\n\nJ-CT and lead statistician M-CG had full access to the trial database, generated statistical analyses, made the decision to submit the manuscript for publication, and assume responsibility for the accuracy and completeness of the data and analyses and for the fidelity to the protocol. Concept and design was done by J-CT, NB, PLL'A, JD, AD, MP, PAT, and GB. Acquisition, analysis, or interpretation of data was done by J-CT, NB, PLL'A, DG, BS, MHP, JL-S, PdL, JD, SS, DF, J-DT, DB, EG, CL, AD, AYJ, DDW, PH, NEL, FL, NS, ER-C, ZB, AO, GS, JCG, LB, CL, P-OH, SL, MC, AN, MC-B, M-PD, M-CG, and GB. Drafting of the manuscript was done by J-CT and M-CG. Critical revision of the manuscript for important intellectual content was done by J-CT, NB, SGD, PLL'A, DG, BS, MHP, JL-S, PdL, LV, SA, JD, AD, MP, PAT, SS, DF, J-DT, DB, EG, CL, AD, AYJ, DDW, PH, NEL, FL, NS, ER-C, ZB, AO, GS, JCG, LB, CL, P-OH, J-SP, SL, MC, AN, M-CB, M-PD, M-CG, and GB. Statistical analysis was done by SL, MC, AN, M-CB, and M-CG. J-CT obtained funding. Administrative, technical, or material support was offered by J-CT, LV, SA, DB, EG, CL, AD, FL, NS, ER-C, ZB, AO, GS, LB, CL, and P-OH. Supervision was provided by J-CT, NB, PLL'A, BS, MHP, JL-S, PdL, LV, ZB, AO, and GB. SS, DF, and EG had the role of research nurses.\n\nDeclaration of interests\n\nJ-CT reports grants from Government of Quebec, the National Heart, Lung, and Blood Institute of the US National Institutes of Health (NIH), the Montreal Heart Institute Foundation, the Bill & Melinda Gates Foundation, Amarin, Esperion, Ionis, Servier, and RegenXBio, along with grants and personal fees from AstraZeneca, Sanofi, and Servier, and grants, personal fees, and minor equity interests from Dalcor. In addition, J-CT's institution has submitted a pending patent for a method of treating a coronavirus infection using colchicine, and a pending patent on early administration of low-dose colchicine after myocardial infarction. J-CT has waived his rights in all patents related to colchicine and does not stand to benefit financially if colchicine becomes used as a treatment for COVID-19. M-PD and J-CT have a patent method for treating or preventing cardiovascular disorders and lowering risk of cardiovascular events issued to Dalcor, no royalties received, a patent genetic markers for predicting responsiveness to therapy with HDL-raising or HDL mimicking agent issued to Dalcor, no royalties received, and a patent method for using low-dose colchicine after myocardial infarction with royalties paid to invention assigned to the Montreal Heart Institute. NB reports personal fees from AstraZeneca. BS reports grants from NIH NHLBI; MHP reports grants from Hikma Pharmaceuticals and Horizon Therapeutics, and personal fees from Horizon Therapeutics. JL-S reports grants from Bayer, Pfizer, Amgen, and Boheringer Ingelheim, and personal fees from Menarini. AD reports personal fees from CAE Healthcare and Masimo and grants from Edwards. POH reports grants from NIH, Montreal Heart Institute, Gilead, and other types of support from Merck. AO reports grants from the COVID-19 Therapeutics Accelerator. J-SP reports personal fees from Université Laval. M-PD reports personal fees and other types of support from Dalcor and personal fees from GlaxoSmithKline, AstraZeneca, Pfizer, Servier, and Sanofi. All other authors declare no competing interests.\n==== Refs\nReferences\n\n1 Faigenbaum DC June CH Cytokine storm N Engl J Med 383 2020 2255 2273 33264547\n2 Fedson DS Treating the host response: an alternative way to manage Ebola in Africa and the next influenza pandemic J Glob Health 9 2019 010322\n3 The RECOVERY collaborative group Dexamethasone in hospitalized patients with Covid-19 - Preliminary report N Engl J Med 384 2021 693 704 32678530\n4 Ramakrishnan S Nicolau DV Jr Langford B Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial Lancet Respir Med 2021 published online April 9. 10.1016/S2213-2600(21)00160-0\n5 Salama C Han J Yau L Tocilizumab in patients hospitalized with Covid-19 pneumonia N Engl J Med 384 2021 20 30 33332779\n6 Cavalli G De Luca G Campochiaro C Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study Lancet Rheumatol 2 2020 e325 e331 32501454\n7 Nieto-Torres JL Verdiá-Báguena C Jimenez-Guardeno JM Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome Virology 485 2015 330 339 26331680\n8 Rodrigues TS de Sa KSG Ishimoto AY Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients J Exp Med 218 2020 e20201707\n9 Coomes EA Haghbayan H Interleukin-6 in Covid-19: A systematic review and meta-analysis Rev Med Virol 30 2020 1 9\n10 Thwaites RS Sevilla Uruchurtu AS Siggins M Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19 Sci Immunol 6 2021 9873\n11 Imazio M Bobbio M Cecchia E Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial Circulation 112 2005 2012 2016 16186437\n12 Tardif JC Kouz S Waters DD Efficacy and safety of low-dose colchicine after myocardial infarction N Engl J Med 381 2019 2497 2505 31733140\n13 Nidorf SM Fiolet ATL Mosterd A Colchicine in patients with chronic coronary disease N Engl J Med 383 2020 1831 1847\n14 Cerquaglia C Diaco M Nucera G La Regina M Montalto M Manna R Pharmacological and clinical basis of treatment of familial Mediterranean fever (FMF) with colchicine or analogues: an update Curr Drug Targ Inflamm Allergy 4 2005 117 124\n15 Ravelli RBG Gigant B Curmi PA Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain Nature 428 2004 198 202 15014504\n16 Pope RM Tschopp J The role of interleukin-1 and the inflammasome in gout: implications for therapy Arthritis Rheumat 56 2007 3183 3188 17907163\n17 Perico N Ostermann D Bontempeill M Colchicine interferes with L-selectin and leukocyte function associated antigen-1 expression on human T lymphocytes and inhibits T cell activation J Am Soc Nephrol 7 1996 594 601 8724893\n18 Dupuis J Sirois MG Rhéaume E Colchicine reduces lung injury in experimental acute respiratory distress syndrome PLoS One 15 2020 e0242318\n19 Deftereos SG Giannopoulos G Vrachatis DA Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial JAMA Network Open 3 2020 e2013136\n20 Lopes MA Bonjomo LP Giannini MC Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial RMD Open 7 2021 e001455\n21 Zavaleta MH Corzo CAC Silva FB Characteristics and risk factors for mortality in patients hospitalized by COVID-19 in a public hospital in Tacna SciFlo 2021 published online Jan 26. 10.1590/SciELOPreprints.1764 (preprint).\n22 Scarsi M Piantoni S Colombo E Association between treatment with colchicine and improved survival in a single-center cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome Ann Rheum Dis 79 2020 1286 1289 32732245\n23 European Centre for Disease Prevention and Control Case definition for coronavirus disease 2019 (COVID-19) https://www.ecdc.europa.eu/en/covid-19/surveillance/case-definition\n24 Takahashi T Ellingson MK Wong P Sex differences in immune responses that underlie COVID-19 disease outcomes Nature 588 2020 315 320 32846427\n25 Samuel M Tardif JC Bouabdallaoui N Colchicine for secondary prevention of cardiovascular disease: A systematic review and meta-analysis of randomized controlled trials Can J Cardiol 2020 published online Oct 17. 10.1016/j.cjca.2020.10.006\n26 Abu-Fanne R Stepanova V Litvinov RI Neutrophil defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability Blood 133 2019 481 493 30442678\n27 Leichman AK Hadassah researchers pinpoint source of corona blood clots. ISRAEL21c (internet) https://www.israel21c.org/hadassah-researchers-find-source-of-corona-blood-clots/ 2020\n28 Shah B Allen N Harchandani B Effect of colchicine on platelet-platelet and platelet-leukocyte interactions: a pilot study in healthy subjects Inflammation 39 2016 182 189 26318864\n29 Bompard F Monnier H Saab I Pulmonary embolism in patients with COVID-19 pneumonia Eur Respir J 56 2020 2001365\n30 Wichmann D Sperhake JP Lutgehetmann M Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study Ann Intern Med 173 2020 268 277 32374815\n\n", "fulltext_license": "CC BY", "issn_linking": "2213-2600", "issue": "9(8)", "journal": "The Lancet. Respiratory medicine", "keywords": null, "medline_ta": "Lancet Respir Med", "mesh_terms": "D000284:Administration, Oral; D000553:Ambulatory Care; D000893:Anti-Inflammatory Agents; D000086382:COVID-19; D003078:Colchicine; D004311:Double-Blind Method; D016903:Drug Monitoring; D005260:Female; D006760:Hospitalization; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D018570:Risk Assessment; D000086402:SARS-CoV-2", "nlm_unique_id": "101605555", "other_id": null, "pages": "924-932", "pmc": null, "pmid": "34051877", "pubdate": "2021-08", "publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "32678530;33231615;33264547;32374815;17907163;33075455;16186437;33542047;32845568;33332779;32501454;31733140;30442678;33844996;31217958;26331680;33264297;32865380;15720245;32579195;8724893;32398297;26318864;32846427;15014504;32732245;33692097", "title": "Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.", "title_normalized": "colchicine for community treated patients with covid 19 colcorona a phase 3 randomised double blinded adaptive placebo controlled multicentre trial" }	[ { "companynumb": "CA-TAKEDA-2021TUS045794", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "COLCHICINE" }, "drugadditional": "3", ...
{ "abstract": "After kidney transplantation, immunosuppressive therapy increases risk of BK polyomavirus-associated nephropathy (BKPyVAN). Outcomes of BKPyV viremia are various and prognostic markers are missing. The impact of different immunosuppressive regimens on BKPyV infections is currently under discussion.\n\n\n\nWe analyzed immunosuppressive therapy and BKPyV-specific cellular immunity to distinguish patients at risk of BKPyVAN from those with self-limiting viremia for purposes of risk-stratified BKPyV management. In a retrospective analysis, 46 pediatric kidney recipients with BKPyV viremia were analyzed with regard to duration of BKPyV viremia and immunosuppressive therapy; in addition, in 37/46 patients, BKPyV-specific CD4 and CD8 T cells were measured.\n\n\n\nNine patients showed persistent BKPyV viremia and BKPyVAN, and required therapeutic intervention, while 37 patients had asymptomatic, self-limiting viremia. At onset of viremia, 78% of patients with persistent viremia and BKPyVAN were treated with tacrolimus, whereas tacrolimus therapy was significantly less frequent in patients with self-limiting viremia (14%). The majority of patients with transient, self-limiting viremia received cyclosporine A (81%) and/or mTOR inhibitors (81%). Patients with persistent BKPyV viremia and BKPyVAN showed lack of BKPyV-specific CD4 and CD8 T cells (6/6), whereas the majority of patients with self-limiting viremia (27/31) had detectable BKPyV-specific CD4 and/or CD8 T cells ≥ 0.5 cells/μl (p < 0.001).\n\n\n\nThese results indicate that tacrolimus enhances risk of BKPyVAN with need of therapeutic intervention, whereas under cyclosporine A and mTOR inhibitors, the majority of pediatric kidney recipients showed self-limiting viremia. In patients at risk of BKPyV infections, combination of cyclosporine A and mTOR inhibitor may be advantageous.", "affiliations": "Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany. Ahlenstiel.Thurid@mh-hannover.de.;Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.", "authors": "Ahlenstiel-Grunow\|Thurid\|T\|;Pape\|Lars\|L\|http://orcid.org/0000-0002-3635-6418", "chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus", "country": "Germany", "delete": false, "doi": "10.1007/s00467-019-04408-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0931-041X", "issue": "35(4)", "journal": "Pediatric nephrology (Berlin, Germany)", "keywords": "BK polyomavirus-associated nephropathy; Cyclosporine A; Immunomonitoring; Immunosuppression; Kidney transplantation; Tacrolimus; Virus-specific T cells; mTOR inhibitors", "medline_ta": "Pediatr Nephrol", "mesh_terms": "D000293:Adolescent; D001739:BK Virus; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007223:Infant; D016030:Kidney Transplantation; D008137:Longitudinal Studies; D008297:Male; D027601:Polyomavirus Infections; D012189:Retrospective Studies; D016559:Tacrolimus; D066027:Transplant Recipients; D014766:Viremia", "nlm_unique_id": "8708728", "other_id": null, "pages": "625-631", "pmc": null, "pmid": "31858227", "pubdate": "2020-04", "publication_types": "D016428:Journal Article", "references": "30539254;12858417;19434930;6302172;19295303;12181403;24408118;16164661;14522260;15912088;23137180;19352121;19207187;15707414;27600985;20455882;10793163;23465010;17700158;21371220;15575913;12846764;16858282;21733554;21114642;17908275;18431228;24476010;30476254;12138148;21831150;24279642;17359507;16734631;27391197;24726000;21804444;20840473;25127887;26639422;22466913;19935369;26590390;24088187;21585634", "title": "Immunosuppression, BK polyomavirus infections, and BK polyomavirus-specific T cells after pediatric kidney transplantation.", "title_normalized": "immunosuppression bk polyomavirus infections and bk polyomavirus specific t cells after pediatric kidney transplantation" }	[ { "companynumb": "NVSC2019DE077996", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "dru...
{ "abstract": "BACKGROUND\nDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe toxidermia that can lead to death from multivisceral failure. We report a case of DRESS associated with febrile agranulocytosis in a child.\n\n\nMETHODS\nAn 8-year-old child was hospitalized for diffuse maculopapular exanthema with edema of the extremities and face associated with cheilitis and febrile agranulocytosis. This symptomatology began 1month after the introduction of carbamazepine for partial epilepsy. The clinical picture was a multisystemic disease with colitis, interstitial pneumonitis, hepatic cytolysis, and hepatocellular insufficiency. HHV7 viral reactivation and increased eosinophils (20%) in the myelogram were demonstrated, providing the diagnosis of DRESS. The progression was favorable after carbamazepine therapy was stopped and systemic corticosteroids were administered.\n\n\nCONCLUSIONS\nDRESS syndrome is a disorder that is unfamiliar to pediatricians. Its association with agranulocytosis is rare and the absence of hypereosinophilia contributed to diagnostic difficulties in this case. The multisystemic failure, the reactivation of HHV7, the increase of eosinophils in the myelogram, and the favorable progression under systemic corticosteroid therapy contributed greatly to the diagnosis. A cutaneous biopsy was not considered necessary for the diagnosis in the case reported herein.\n\n\nCONCLUSIONS\nDRESS syndrome is rarely associated with agranulocytosis, but its diagnosis must be quickly raised so that the incriminated drug can be interrupted.", "affiliations": "Pôle de la femme, de la mère et de l'enfant, centre hospitalier universitaire, 2, avenue Foch, 29609 Brest, France.;Pôle de la femme, de la mère et de l'enfant, centre hospitalier universitaire, 2, avenue Foch, 29609 Brest, France; EA4685 (laboratoire de neurosciences de Brest), faculté de médecine et des sciences de la santé, université de Bretagne occidentale, 22, rue Camille-Desmoulins, 29200 Brest, France.;Service de dermatologie, centre hospitalier universitaire, 2, avenue Foch, 29609 Brest, France.;Service de dermatologie, centre hospitalier universitaire, 2, avenue Foch, 29609 Brest, France.;EA4685 (laboratoire de neurosciences de Brest), faculté de médecine et des sciences de la santé, université de Bretagne occidentale, 22, rue Camille-Desmoulins, 29200 Brest, France; Service de dermatologie, centre hospitalier universitaire, 2, avenue Foch, 29609 Brest, France.;Pôle de la femme, de la mère et de l'enfant, centre hospitalier universitaire, 2, avenue Foch, 29609 Brest, France; EA4685 (laboratoire de neurosciences de Brest), faculté de médecine et des sciences de la santé, université de Bretagne occidentale, 22, rue Camille-Desmoulins, 29200 Brest, France. Electronic address: stephane.rioualen@chu-brest.fr.", "authors": "Lavenant\|P\|P\|;Roue\|J-M\|JM\|;Huet\|F\|F\|;Abasq\|C\|C\|;Misery\|L\|L\|;Rioualen\|S\|S\|", "chemical_list": "D000927:Anticonvulsants; D005938:Glucocorticoids; D002220:Carbamazepine", "country": "France", "delete": false, "doi": "10.1016/j.arcped.2017.05.010", "fulltext": null, "fulltext_license": null, "issn_linking": "0929-693X", "issue": "24(8)", "journal": "Archives de pediatrie : organe officiel de la Societe francaise de pediatrie", "keywords": null, "medline_ta": "Arch Pediatr", "mesh_terms": "D000380:Agranulocytosis; D000927:Anticonvulsants; D002220:Carbamazepine; D002648:Child; D063926:Drug Hypersensitivity Syndrome; D004828:Epilepsies, Partial; D005334:Fever; D005938:Glucocorticoids; D006801:Humans; D016896:Treatment Outcome", "nlm_unique_id": "9421356", "other_id": null, "pages": "752-756", "pmc": null, "pmid": "28669649", "pubdate": "2017-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "DRESS syndrome and agranulocytosis, a rare combination.", "title_normalized": "dress syndrome and agranulocytosis a rare combination" }	[ { "companynumb": "FR-ZYDUS-016093", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "1", "dru...
{ "abstract": "BACKGROUND\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug reactions considered to be part of the spectrum of a single pathological process.\n\n\nOBJECTIVE\nTo describe the clinical and epidemiological characteristics of SJS/TEN in children attended at our hospital.\n\n\nMETHODS\nRetrospective study of children diagnosed with SJS/TEN between 1999 and 2009 in a University Hospital provided with regional-level burn and paediatric intensive care units.\n\n\nRESULTS\nWe found 14 paediatric patients (eight SJS and six TEN). They presented an average of 60% of the body surface area affected and 31% of epidermal sloughing. The average of suspected drugs was 1.7 per patient, anticonvulsants (carbamazepine, phenytoin and lamotrigine) and antibiotics (penicillin and macrolides) being the most frequent ones. Silver sulfadiazine was the topical treatment most frequently used, 86% of patients received systemic steroids and 28.5% intravenous immunoglobulins. One patient died.\n\n\nCONCLUSIONS\nThe SJS/TEN complex is a true dermatological critical condition that also affects children. Any drug can be the causative agent, more frequently anticonvulsants and antibiotics. Depending on the extension of the affected body surface, patients should be rapidly admitted to a critical care area with experience in the care of burn patients. Discontinuation of the suspected offending drugs is mandatory. Optimal supportive care and management of denuded skin areas are still the mainstay of treatment. The use of specific therapies remains controversial. Compared with adults, the disease in children seems to be milder with lower mortality.", "affiliations": "Department of Dermatology Paediatric Intensive Care Unit, Universitary Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. 40879cfp@comb.cat", "authors": "Ferrándiz-Pulido\|C\|C\|;García-Fernández\|D\|D\|;Domínguez-Sampedro\|P\|P\|;García-Patos\|V\|V\|", "chemical_list": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants", "country": "England", "delete": false, "doi": "10.1111/j.1468-3083.2010.03935.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0926-9959", "issue": "25(10)", "journal": "Journal of the European Academy of Dermatology and Venereology : JEADV", "keywords": null, "medline_ta": "J Eur Acad Dermatol Venereol", "mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D013262:Stevens-Johnson Syndrome; D015996:Survival Rate", "nlm_unique_id": "9216037", "other_id": null, "pages": "1153-9", "pmc": null, "pmid": "21198948", "pubdate": "2011-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a review of the experience with paediatric patients in a university hospital.", "title_normalized": "stevens johnson syndrome and toxic epidermal necrolysis in children a review of the experience with paediatric patients in a university hospital" }	[ { "companynumb": "ES-RANBAXY-2011RR-50775", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METAMIZOLE" }, "drugadditional": null, ...
{ "abstract": "One goal of precision medicine is to identify mutations within individual tumors to design targeted treatment approaches. This report details the use of genomic testing to select a targeted therapy regimen of erlotinib and rapamycin for a pediatric anaplastic oligodendroglioma refractory to standard treatment, achieving a 33-month sustained response. Immunohistochemical analysis of total and phosphorylated protein isoforms showed abnormal signaling consistent with detected mutations, while revealing heterogeneity in per-cell activation of signaling pathways in multiple subpopulations of tumor cells throughout the course of disease. This case highlights molecular features that may be relevant to designing future targeted treatments.", "affiliations": "Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.;Departments of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.;Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.;Monroe Carell Jr. Children's Hospital at Vanderbilt, Division of Pediatric Hematology-Oncology, Nashville, Tennessee.;Monroe Carell Jr. Children's Hospital at Vanderbilt, Division of Pediatric Hematology-Oncology, Nashville, Tennessee.;Departments of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.;Monroe Carell Jr. Children's Hospital at Vanderbilt, Division of Pediatric Hematology-Oncology, Nashville, Tennessee.", "authors": "Geben\|Laura C\|LC\|;Mobley\|Bret C\|BC\|;Brockman\|Asa A\|AA\|;Pastakia\|Devang\|D\|;Naftel\|Rob\|R\|;Ihrie\|Rebecca A\|RA\|;Esbenshade\|Adam J\|AJ\|0000-0002-0154-4996", "chemical_list": "D000069347:Erlotinib Hydrochloride; D020123:Sirolimus", "country": "United States", "delete": false, "doi": "10.1002/pbc.28750", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "68(1)", "journal": "Pediatric blood & cancer", "keywords": "EGFR; brain tumor; mTOR; neuro-oncology; pediatric oncology; targeted therapy", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D009837:Oligodendroglioma; D011379:Prognosis; D012074:Remission Induction; D020123:Sirolimus", "nlm_unique_id": "101186624", "other_id": null, "pages": "e28750", "pmc": null, "pmid": "33001573", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.", "references": null, "title": "Sustained response to erlotinib and rapamycin in a patient with pediatric anaplastic oligodendroglioma.", "title_normalized": "sustained response to erlotinib and rapamycin in a patient with pediatric anaplastic oligodendroglioma" }	[ { "companynumb": "US-PFIZER INC-2021392180", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROCARBAZINE" }, "drugadditional": null, ...
{ "abstract": "Acute ischemic stroke (AIS) during pregnancy is a rare but serious complication. Intravenous alteplase is the only medication approved for hyperacute treatment of AIS; however, it has not been evaluated prospectively in pregnancy. Pregnancy was an exclusion criterion in prospective AIS studies and was only recently removed as a relative contraindication in the 2018 American Heart Association/American Stroke Association Stroke guidelines. Due to the exclusion of pregnant women from randomized controlled trials, the safety of fibrinolytic therapy in pregnant patients is not well established. In this review, we report the use of intravenous alteplase for AIS in two pregnant patients, with temporally associated clinical improvement and without complications to either the mother or fetus. Additionally, we summarize a systematic review of the literature for both intravenous and intra-arterial alteplase use for AIS in pregnant patients. A total of 31 cases met inclusion criteria for this review of assessment of safety and efficacy of alteplase use in pregnancy. Existing case reports and guidelines support the use of alteplase for AIS in pregnant patients without contraindications.", "affiliations": "Department of Pharmacy, Intermountain Medical Center, Murray, Utah.;Department of Pharmacy, Intermountain Medical Center, Murray, Utah.;Department of Neurology, Intermountain Medical Center, Murray, Utah.;Department of Pharmacy, Intermountain Medical Center, Murray, Utah.", "authors": "Ryman\|Klayton M\|KM\|0000-0002-7309-9289;Pace\|Wilson D\|WD\|;Smith\|Shawn\|S\|;Fontaine\|Gabriel V\|GV\|0000-0003-4680-5720", "chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator", "country": "United States", "delete": false, "doi": "10.1002/phar.2278", "fulltext": null, "fulltext_license": null, "issn_linking": "0277-0008", "issue": "39(7)", "journal": "Pharmacotherapy", "keywords": "acute ischemic stroke; alteplase; pregnancy; stroke", "medline_ta": "Pharmacotherapy", "mesh_terms": "D000328:Adult; D002545:Brain Ischemia; D005260:Female; D005343:Fibrinolytic Agents; D005865:Gestational Age; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D020521:Stroke; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome", "nlm_unique_id": "8111305", "other_id": null, "pages": "767-774", "pmc": null, "pmid": "31077601", "pubdate": "2019-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Alteplase Therapy for Acute Ischemic Stroke in Pregnancy: Two Case Reports and a Systematic Review of the Literature.", "title_normalized": "alteplase therapy for acute ischemic stroke in pregnancy two case reports and a systematic review of the literature" }	[ { "companynumb": "US-BAYER-2019-140417", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "dr...
{ "abstract": "BACKGROUND\nReduced blood pressure is commonly seen associated to spinal anaesthesia for Caesarean section and efforts to reduce its occurrence and its magnitude is common practice. Cardiovascular collapse requiring cardio-pulmonary resuscitation after putting the spinal/epidural block for Caesarean section is however a rare but most dramatic event.\n\n\nMETHODS\nWe describe a case with sudden short loss of circulation, circulatory collapse, short after start of emergency Caesarean section in top up epidural anaesthesia (3+12ml ropivaciane 7.5mg/ml), requiring CPR. The neonate was delivered during CPR with Apgar 1, 10, 10 at 1, 5 and 10min. Circulation was restored following 60-90s of CPR and administration of 0.5mg adrenaline. No cardioversion was administered sinus rhythm was regained spontaneously. The mother and child had a further uncomplicated course. No signs of cardiac damage/anomaly, emboli, septicaemia, pereclampisa or local anaesthetic toxicity was found. The patient had prior to the decision about Caesarean section had fever and was subsequently relatively dehydrated.\n\n\nCONCLUSIONS\nThe patient had a fast return of sinus rhythm following birth of the child, without cardioversion. None of common causes for cardiac arrest was found and the patient an uncomplicated post Caesarean section course. The combination of epidural induced sympathetic block and reduced preload possibly triggered a Bezold-Jarisch reflex with a profound vasovagal reaction.\nA structured plan for the handling of cardiovascular crisis must be available wherever Caesarean section are performed. Adequate volume loading, left tilt and vigilant control of circulation following regional block performance is of outmost importance.", "affiliations": "Department of Anaesthesia & Intensive Care, Institution for Clinical Science, Karolinska Institutet, Danderyds University Hospital, SE 182 88 Stockholm, Sweden. Electronic address: evaoddby-muhrbeck@ds.se.;Department of Anaesthesia & Intensive Care, Institution for Clinical Science, Karolinska Institutet, Danderyds University Hospital, SE 182 88 Stockholm, Sweden. Electronic address: anette.hein@ds.se.;Department of Anaesthesia & Intensive Care, Institution for Clinical Science, Karolinska Institutet, Danderyds University Hospital, SE 182 88 Stockholm, Sweden. Electronic address: jan.jakobsson@ki.se.", "authors": "Oddby\|Eva\|E\|;Hein\|Anette\|A\|;Jakobsson\|Jan G\|JG\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": null, "fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(16)30075-X10.1016/j.ijscr.2016.04.016Case ReportCirculatory collapse following epidural bolus for Caesarean section a profound vasovagal reaction? A case report Oddby Eva evaoddby-muhrbeck@ds.seHein Anette anette.hein@ds.seJakobsson Jan G. jan.jakobsson@ki.se⁎Department of Anaesthesia & Intensive Care, Institution for Clinical Science, Karolinska Institutet, Danderyds University Hospital, SE 182 88 Stockholm, Sweden⁎ Corresponding author. jan.jakobsson@ki.se12 4 2016 2016 12 4 2016 23 74 76 4 4 2016 8 4 2016 © 2016 Published by Elsevier Ltd. on behalf of IJS Publishing Group Ltd.2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Secure adequate hydration before putting a regional block.\n\n• Prepare vaso-active medication, phenylephrine and have ephedrine and atropine readily available.\n\n• Secure adequate lift tilt after block placement.\n\n• Measure blood pressure and heart rate every 3 min.\n\n• React readily to decrease in blood pressure and/or heart rate.\n\n\n\nIntroduction\nReduced blood pressure is commonly seen associated to spinal anaesthesia for Caesarean section and efforts to reduce its occurrence and its magnitude is common practice. Cardiovascular collapse requiring cardio-pulmonary resuscitation after putting the spinal/epidural block for Caesarean section is however a rare but most dramatic event.\n\nPresentation of case\nWe describe a case with sudden short loss of circulation, circulatory collapse, short after start of emergency Caesarean section in top up epidural anaesthesia (3 + 12 ml ropivaciane 7.5 mg/ml), requiring CPR. The neonate was delivered during CPR with Apgar 1, 10, 10 at 1, 5 and 10 min. Circulation was restored following 60–90 s of CPR and administration of 0.5 mg adrenaline. No cardioversion was administered sinus rhythm was regained spontaneously. The mother and child had a further uncomplicated course. No signs of cardiac damage/anomaly, emboli, septicaemia, pereclampisa or local anaesthetic toxicity was found. The patient had prior to the decision about Caesarean section had fever and was subsequently relatively dehydrated.\n\nDiscussion\nThe patient had a fast return of sinus rhythm following birth of the child, without cardioversion. None of common causes for cardiac arrest was found and the patient an uncomplicated post Caesarean section course. The combination of epidural induced sympathetic block and reduced preload possibly triggered a Bezold-Jarisch reflex with a profound vasovagal reaction.\n\nConcluiosn\nA structured plan for the handling of cardiovascular crisis must be available wherever Caesarean section are performed. Adequate volume loading, left tilt and vigilant control of circulation following regional block performance is of outmost importance.\n\nKeywords\nCaesarean sectionSpinal anaesthesiaCardiovascular collapse\n==== Body\n1 Introduction\nCardiac arrest may be seen on rare occasions during pregnancy associated to cardiac disease, severe bleeding, pulmonary embolism and amnion fluid emboli. Cardiac arrest requiring CPR associated to spinal or epidural anaesthesia is also a known but likewise a most uncommon event. Circulatory collapse following spinal or epidural block for Caesarean section is a rare and most dramatic event putting mother and child at risk.\n\n2 Case presentation\nThe patient described has provided explicit informed consent for this presentation. A 37-year old healthy Asian female, BMI 32 before pregnancy (weight 80 kg, length 158 cm), nulli-parous was admitted for induction of vaginal delivery in gestation week 42+ 0 two days. Several doses of misoprostol, dinoprostin and oxytocin were administered with limited effect. The patient was instructed not to eat or drink from the second day of induction. She received a well functioning epidural analgesia. At the same time a temperature of 39.2C was detected and antibiotics were administered. Three hours later Caesarean section was decided due to slow progress. The temperature had declined and the patient was brought to the operating theatre. An infusion with Ringer lactate 1 000 ml was started and infused rapidly, an epidural top up bolus of 3 + 12 ml ropivacaine 7.5 mg/ml with 50 μg fentanyl added was administered. Patient was placed in supine position and tilted to the left side. Heart rate and blood pressure was recorded each minute. Heart rate was around 120 beats/min. Repeated doses of phenylephrine 0.05 mg were provided as blood pressure was instable and systolic pressure was hard to maintain above 100 mmHg. Approximately 20 min after top up of the epidural the block reached Th 3–4. The WHO checklist was done and operation started. The patient complained about hard to breathe. Bradycardia was seen and Atropine 0.5 mg was given at a heart rate of 43 beats/min but heart rate continued to fall accompanied by a sudden drop in blood pressure. The patient became unresponsive, ECG and pulsoximetry showed no pulse. CPR was rapidly initiated, patient was intubated, 0.5 mg adrenalin i.v. was given and the baby was delivered instantaneously. Heart beats and blood pressure was restored within 60–90 s, return of circulation was confirmed 90 s after the pulse arrest. Sinus rhythm was spontaneously regained without further interventions, no cardioversion. A high initial heart rate around 160 beats per minute and systolic blood pressure first measured 166 mmHg and oxygen saturation 97% was observed. The neonate had Apgar scores 1, 10, 10 at 1, 5 and 10 min. No signs of increased bleed (peroperative bleed was 800 ml) or intra-uterine abnormalities were observed. Twelve lead ECG and blood tests showed no signs of myocardial damage and echocardiography tight after the section was normal. CT scan performed right after end of surgery did not show any signs of pulmonary embolism or aortic dissection. No septicaemia was found, blood cultures were negative, the infection was assessed as an endometritis and antibiotics continued. No signs of local anaesthetic toxicity was noticed. Mother and child had an uncomplicated postoperative course.\n\n3 Discussion\nUS figures describing cardiac arrest during in-patient care for delivery being 1 in 12000 admissions and that there is a slow increase. Globally it is estimated that there are some 800 maternal death daily. The American Heart Association has recently issued an update around the handling of the pregnant mother experiencing cardiac arrest [1]. Montufar-Rueda and Gei published a comprehensive review around cardiac arrest in pregnancy in 2015 stating that most common causes were associated to profound bleed, eclampsia and infection, sepsis [2]. Indeed common causes for sudden cardiac arrest associated to pregnancy and delivery should be early and systematically considered as stated in Advanced Life Support resuscitation guide lines, Reversible Causes of Collapse the 4H’s and the 4T’s) [3].\n\nThere is a study from Thailand reporting the incidence of cardiac arrest associated to spinal anaesthesia. There were 11 cardiac arrests among 40,271 cases of spinal anaesthesia corresponding to an incidence of 2.73 per 10,000 anaesthetics. Among 11 patients who arrested, there were 5 cases of caesarean delivery; 5 cardiac arrest among 11,291 spinals for caesarean section [4]. All blocks where performed with bupivacaine and 3 of 5 to a level of Th 4, 1 to Th 2 and 1 to an unknown height. There are also several case reports around circulatory collapse during regional block for caesarean section. In 1996 Scull and Carli presented a case where a 31-year-old Afro-Caribbean woman (weight 76 kg, height 1.68 m), ASA I, presented at term in spontaneous labour [5]. There was a slow progress and the child showed 2 episodes of distress and it was decided to have a Caesarean section. She had a spinal block with 0.75% hyperbaric bupivacaine 2 ml and preservative-free morphine 0.25 mg providing a sensory block to temperature from T2 to S5. After an uncomplicated procedure and delivery of a healthy neonate perioperative bleed 700 ml she became unresponsive and without pulse on arrival in the recovery room. She was rapidly and successfully resuscitated. ECG and lab tests where normal. The authors comment that cardiac arrest may occur following regional anaesthesia. The combination of sympathetic block and reduced venous return may activate a so called Benzold–Jarish reflex with resultant profound bradycardia and circulatory collapse. Ou et al. described a similar case, a 35-year-old parturient with gestational diabetes mellitus history that developed a circulatory collapse, sustained nearly fatal Bezold-Jarisch reflex during Caesarean section under spinal anaesthesia [6].\n\nJang et al. describes a 39-year-old pregnant woman with episodes of non-sustained ventricular arrhythmia and newly developed vasovagal syncope during pregnancy. She was undergoing section in spinal block in week 38 and immediately after the placental expulsion, a sudden severe bradycardia, followed by a cardiac arrest occurred. The patient fully recovered after prompt cardiopulmonary resuscitation with chest compression, manual ventilation with oxygen, rapid injection of epinephrine and hydration. The event was assessed as vasovagal reaction caused by combination of spinal sympathetic inhibition and the placenta expulsion [7].\n\nOur patient had rapid return of circulation following delivery of the neonate and thus restoration of preload. Adrenalin was also provided although small dose. There was a direct return of sinus rhythm and no need for defibrillation. Ecocardiography, ECG and blood tests where unremarkable. No signs of myocardial damage, arrhythmias, pulmonary emboli, amnion fluid emboli or sepsis were identified. There was no excessive blood loss, no signs of preeclampsia or allergic reaction, thus common causes for cardiac arrest were excluded [8]. There were no signs of local anaesthetic toxicity, no involuntary movements of signs of seizures. Thus most common causes were excluded and taking in consideration the rapid restoration of sinus rhythm and circulation made us suspect a profound vaso-vagal reaction.\n\nThe Bezold reflex has a long history, described initially already in 1867 by von Bezold in 1867 and was later revived by Jarisch [9]. Kinsella and Tuckey provided a comprehensive review around Perioperative bradycardia and asystole in 2001 [10]. Reflex cardiovascular depression with vasodilation and bradycardia has been variously termed vasovagal syncope, the Bezold-Jarisch reflex and neurocardiogenic syncope. The circulatory response changes from the normal maintenance of arterial pressure, to parasympathetic activation and sympathetic inhibition, causing hypotension. This change is triggered by reduced cardiac venous return as well as through affective mechanisms such as pain or fear. It is probably mediated in part via afferent nerves from the heart, but also by various non-cardiac baroreceptors which may become paradoxically active. This response may occur during regional anaesthesia, haemorrhage or supine inferior vena cava compression in pregnancy; these factors are additive when combined. Also Tsai et al. describes pathophysiology, mechanism of action and treatment in a review from 2006 [11]. Regional anesthesia, decreased venous return, hemorrhage and abnormal fetal presentation cumulatively increase the risk of vasovagal syncope in cesarean section patients. When a vasovagal response occurs, ephedrine is the drug of first choice because of its combined action on the heart and peripheral blood vessels. Epinephrine must be used early in established cardiac arrest, especially after high regional anesthesia.\n\nFluid loading and vasoconstriction for prevention and treatment of low blood pressure is standard of care [12]. There is clear evidence in favour for phenylephrine for the management of hypotension associated to Caesarean section spinal anaesthesia by means of better foetal pH and less increase in Base Excess with similar or better blood pressure control [13]. However ephedrine is associated to less bradycardia [14]. One may argue whether general anaesthesia should have been preferred technique because of the fever. Top-up epidural was however considered adequate as the fever had settled. The volume of epidural bolus dose can be argued, considered huge and have without doubt contributed to the sympathetic block.\n\nWe consider a reasonable cause for the short lasting but dramatic circulatory collapse in our patient to be a profound vasovagal response elicited by the combination of the epidural bolus sympathetic blockade in combination hypovolemia. Hypovolemic due to fever and reduced preload associated to her supine position, even though left lateral tilt. A vasovagal reaction caused by a Bezold-Jarisch reflex. It seems of importance to have in mind whenever regional blocks are provided in the pregnant female that adequate preload should be secured by thoroughly left tilt and adequate volume load. Phenylephrine should be administered to maintain a systolic blood pressure above 90 mmHg. Ephedrine and atropine should readily available and early administered when signs of hypotension and bradycardia is seen.\n\nNo external funding and all authors confirm no competing interests.\n\nThe patients is informed and has provided full consent to the publication/presentation of an anonymous case report around the event.\n\nConflicts of interest\nNone.\n\nFunding\nThe paper is supported by the department no external funding has been received for the preparation of this case report.\n\nEthical approval\nNot applicable, the patient has been informed and provided explicit consent to the presentation of this case report.\n\nConsent\nThe patient has provided consent for an anonymous presentation of the event.\n\nAuthor contribution\nAll authors have contributed equal to the writing/preparation of this case report.\n\nGuarantor\nNone.\n==== Refs\nReferences\n1 Jeejeebhoy F.M. Zelop C.M. Lipman S. Carvalho B. Joglar J. Mhyre J.M. Katz V.L. Lapinsky S.E. Einav S. Warnes C.A. Page R.L. Griffin R.E. Jain A. Dainty K.N. Arafeh J. Windrim R. Koren G. Callaway C.W. American heart association emergency cardiovascular care committee, council on cardiopulmonary, critical care, perioperative and resuscitation, council on cardiovascular diseases in the young, and council on clinical cardiology. cardiac arrest in pregnancy: a scientific statement from the american heart association Circulation 132 2015 1747 1773 26443610 \n2 Montufar-Rueda C. Gei A. Cardiac arrest during pregnancy Clin. Obstet. Gynecol. 57 2014 871 881 25314090 \n3 Ann Harper, Rowan Wilson on behalf of the MBRRACE-UK AFE chapter writing group. In Knight M., Kenyon S., Brocklehurst P., Neilson J., Shakespeare J., Kurinczuk J.J. (Eds.) on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care − Lessons learned to inform future maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009–12. Oxford : National Perinatal Epidemiology Unit, University of Oxford 2014: p 60–61.\n4 Charuluxananan S. Thienthong S. Rungreungvanich M. Chanchayanon T. Chinachoti T. Kyokong O. Punjasawadwong Y. Cardiac arrest after spinal anesthesia in Thailand: a prospective multicenter registry of 40,271 anesthetics Anesth. Analg. 107 2008 1735 1741 18931240 \n5 Scull T.J. Carli F. Cardiac arrest after Caesarean section under subarachnoid block Br. J. Anaesth. 77 1996 274 276 8881641 \n6 Ou C.H. Tsou M.Y. Ting C.K. Chiou C.S. Chan K.H. Tsai S.K. Occurrence of the Bezold-Jarisch reflex during Cesarean section under spinal anesthesia—a case report Acta Anaesthesiol. Taiwan. 42 2004 175 178 15551897 \n7 Jang Y.E. Do S.H. Song I.A. Vasovagal cardiac arrest during spinal anesthesia for Cesarean section—a case report- Korean J. Anesthesiol. 64 2013 77 81 23372892 \n8 Jones R. Baird S.M. Thurman S. Gaskin I.M. Maternal cardiac arrest: an overview J. Perinat. Neonatal Nurs. 26 2012 117 123 22551858 \n9 Mark A.L. The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart J. Am. Colloid Cardiol. 1 1983 90 102 \n10 Kinsella S.M. Tuckey J.P. Perioperative bradycardia and asystole: relationship to vasovagal syncope and the Bezold-Jarisch reflex Br. J. Anaesth. 86 2001 859 868 11573596 \n11 Tsai P.S. Chen C.P. Tsai M.S. Perioperative vasovagal syncope with focus on obstetric anesthesia Taiwan J. Obstet Gynecol. 45 2006 208 214 17175465 \n12 Cyna A.M. Andrew M. Emmett R.S. Middleton P. Simmons S.W. Techniques for preventing hypotension during spinal anesthesia for caesarean section Cochrane Database Syst. Rev. 18 October (4) 2006 (CD002251. Review) \n13 Lin F.Q. Qiu M.T. Ding X.X. Fu S.K. Li Q. Ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean section: an updated meta-analysis CNS Neurosci. Ther. 18 2012 591 597 22759268 \n14 Veeser M. Hofmann T. Roth R. Klöhr S. Rossaint R. Heesen M. Vasopressors for the management of hypotension after spinal anesthesia for elective caesarean section Systematic review and cumulative meta-analysis Acta Anaesthesiol. Scand. 56 2012 810 816 22313496\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2210-2612", "issue": "23()", "journal": "International journal of surgery case reports", "keywords": "Caesarean section; Cardiovascular collapse; Spinal anaesthesia", "medline_ta": "Int J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101529872", "other_id": null, "pages": "74-6", "pmc": null, "pmid": "27100952", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "22759268;25314090;8881641;18931240;6826948;15551897;17175465;26443610;22313496;23372892;22551858;11573596;17054153", "title": "Circulatory collapse following epidural bolus for Caesarean section a profound vasovagal reaction? A case report.", "title_normalized": "circulatory collapse following epidural bolus for caesarean section a profound vasovagal reaction a case report" }	[ { "companynumb": "SE-BIODELIVERY SCIENCES INTERNATIONAL-2016BDSI0078", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ROPIVACAINE" }, "dru...
{ "abstract": "Low-grade gliomas (LGG) represent the most common form of primary central nervous system tumor arising in childhood. There is growing evidence to support the role of the mitogen-activated protein kinase pathway in driving tumor growth and MEK inhibitors are being investigated in clinical trials for refractory and unresectable LGGs. As MEK inhibitors progress through clinical trials, drug toxicities have been identified. We report on 2 pediatric patients with LGG and known diabetes insipidus who developed severe hyponatraemia associated with significant decreases in desmopressin doses after starting trametinib. We review potential mechanisms for this sodium imbalance by examining the interaction between MEK inhibition and aquaporin channel physiology. We recommend close monitoring of serum sodium levels and clinical status in patients with diabetes insipidus who have optic-hypothalamic gliomas and are started on treatment with MEK inhibitors.", "affiliations": "Division of Haematology/Oncology.;Division of Endocrinology, The Hospital for Sick Children.;Division of Haematology/Oncology.;Division of Haematology/Oncology.;Division of Haematology/Oncology.;Divison of Neurosurgery, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.;Division of Haematology/Oncology.", "authors": "Egan\|Grace\|G\|;Hamilton\|Jill\|J\|;McKeown\|Tara\|T\|;Bouffet\|Eric\|E\|;Tabori\|Uri\|U\|;Dirks\|Peter\|P\|;Bartels\|Ute\|U\|", "chemical_list": "D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib", "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000001427", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "42(4)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D002648:Child; D003919:Diabetes Insipidus; D005134:Eye Neoplasms; D005260:Female; D005910:Glioma; D006801:Humans; D007029:Hypothalamic Neoplasms; D011728:Pyridones; D011744:Pyrimidinones", "nlm_unique_id": "9505928", "other_id": null, "pages": "e248-e250", "pmc": null, "pmid": "30676433", "pubdate": "2020-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Trametinib Toxicities in Patients With Low-grade Gliomas and Diabetes Insipidus: Related Findings?", "title_normalized": "trametinib toxicities in patients with low grade gliomas and diabetes insipidus related findings" }	[ { "companynumb": "CA-TOLMAR, INC.-20CA024219", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DESMOPRESSIN ACETATE" }, "drugadditional": "...
{ "abstract": "The first aim of this article is to analyze the risk/benefit ratio of using psychotropic drugs approved in some countries for treating fibromyalgia syndrome (FMS) during pregnancy. Assessing the effectiveness of non-pharmacological interventions is the second scope of this article, in order to help clinicians to manage FMS in pregnancy in those countries were no drugs are approved for treating the disease. Following the PRISMA guidelines for systematic reviews, a literature search was conducted on PubMed and Google Scholar. Separate literature searches were performed for the three psychotropic drugs approved in the USA for treating FMS, psychotherapy, and transcranial magnetic stimulation (TMS). Perinatal duloxetine exposure is associated with increased risk of gestational and perinatal complications. With regards pregabalin, available information suggests that the drug is not devoid of structural teratogenicity potential. No data are available for milnacipran. Duloxetine and pregabalin should be only given to pregnant women diagnosed with severe forms of FMS after carefully weighing the benefits and risks for the mother-fetus dyad. On the other hand, we have to consider that the proportion of women who discontinue psychotropic drugs during pregnancy is as high as 85.4%. This figure raises further questions about adequate alternative treatment of FMS during the perinatal period. Moreover, neither duloxetine nor milnacipran or pregabalin have been approved by the EMEA for the treatment of FMS. Unfortunately, psychological treatment of FMS in perinatal women are not yet tested and data on TMS are conflicting.", "affiliations": "ASL Salerno -Department of Mental Health, Mental Health Center Cava de' Tirreni Vietri sul Mare, Piazza Galdi, 1, 841013, Cava de' Tirreni, (Salerno), Italy. salvatore_gentile@alice.it.;Developmental Psychologist, Mental Health Institute, Torre Annunziata, (Naples), Italy.", "authors": "Gentile\|Salvatore\|S\|;Fusco\|Maria Luigia\|ML\|", "chemical_list": "D014151:Anti-Anxiety Agents; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000069583:Pregabalin; D000068736:Duloxetine Hydrochloride; D000078764:Milnacipran", "country": "Austria", "delete": false, "doi": "10.1007/s00737-018-0933-z", "fulltext": null, "fulltext_license": null, "issn_linking": "1434-1816", "issue": "22(6)", "journal": "Archives of women's mental health", "keywords": "Cognitive behavioral therapy; Duloxetine; Fibromyalgia; Milnacipran; Pregabalin; Transcranial magnetic stimulation", "medline_ta": "Arch Womens Ment Health", "mesh_terms": "D014151:Anti-Anxiety Agents; D000068736:Duloxetine Hydrochloride; D005060:Europe; D005260:Female; D005356:Fibromyalgia; D006801:Humans; D000078764:Milnacipran; D000069583:Pregabalin; D011247:Pregnancy; D011248:Pregnancy Complications; D018570:Risk Assessment; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D014481:United States", "nlm_unique_id": "9815663", "other_id": null, "pages": "711-721", "pmc": null, "pmid": "30607517", "pubdate": "2019-12", "publication_types": "D016428:Journal Article; D000078182:Systematic Review", "references": null, "title": "Managing fibromyalgia syndrome in pregnancy no bridges between USA and EU.", "title_normalized": "managing fibromyalgia syndrome in pregnancy no bridges between usa and eu" }	[ { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-00773", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, ...
{ "abstract": "Three to seven percent of non-small cell lung cancer (NSCLC) patients show anaplastic lymphoma kinase (ALK)-translocation and could be treated with ALK-inhibitors. However, under crizotinib, a first-generation ALK-inhibitor, patients develop drug resistance after a median of 12 months. To overcome crizotinib resistance, several next-generation ALK inhibitors have been developed. In NSCLC, liquid biopsy allowed important improvements in the detection of the epidermal growth factor receptor (EGFR) mutation. The ability of liquid biopsy to detect oncogenic gene/protein fusions is a newly investigated field, and is not routinely applied yet. We here present two NSCLC patients, both rearranged for echinoderm microtubule associated-protein like 4-anaplastic lymphoma kinase (EML4-ALK) and treated accordingly, who differed in the clinical outcome. We analyzed the predictive value of the liquid biopsy components, namely epithelial cellular adhesion molecule (EpCAM)+ circulating tumor cells (CTCs), EpCAM low/neg CTCs, EML4-ALK rearranged CTCs, and cell-free mRNA (cfmRNA), during ALK-inhibitors treatment. This analysis showed a potential association between the liquid biopsy biomarkers, patients' outcome and response to treatment, thus suggesting their combined use in the clinical practice, as proposed here. This approach would allow longitudinal monitoring and consequent identification of putative drug-resistance mechanisms, in the light of improving high-risk patient management.", "affiliations": "IOV-IRCCS, Padova, Italy.;IOV-IRCCS, Padova, Italy.;Department of Onco-Hematology, Division of Medical Oncology, Centro di Riferimento Oncologico della Basilicata, IRCCS, Rionero in Vulture, PZ, Italy.;IOV-IRCCS, Padova, Italy.;Department of Onco-Hematology, Division of Medical Oncology, Centro di Riferimento Oncologico della Basilicata, IRCCS, Rionero in Vulture, PZ, Italy.;Department of Onco-Hematology, Division of Medical Oncology, Centro di Riferimento Oncologico della Basilicata, IRCCS, Rionero in Vulture, PZ, Italy.;IOV-IRCCS, Padova, Italy.;IOV-IRCCS, Padova, Italy.", "authors": "Manicone\|Mariangela\|M\|;Scaini\|Maria Chiara\|MC\|;Rodriquenz\|Maria Grazia\|MG\|;Facchinetti\|Antonella\|A\|;Tartarone\|Alfredo\|A\|;Aieta\|Michele\|M\|;Zamarchi\|Rita\|R\|;Rossi\|Elisabetta\|E\|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/jtd.2017.08.151", "fulltext": null, "fulltext_license": null, "issn_linking": "2072-1439", "issue": "9(Suppl 13)", "journal": "Journal of thoracic disease", "keywords": "Non-small cell lung cancer (NSCLC); anaplastic lymphoma kinase (ALK); cell-free mRNA (cfmRNA); circulating tumor cells (CTCs); liquid biopsy", "medline_ta": "J Thorac Dis", "mesh_terms": null, "nlm_unique_id": "101533916", "other_id": null, "pages": "S1391-S1396", "pmc": null, "pmid": "29184678", "pubdate": "2017-10", "publication_types": "D016428:Journal Article; D016454:Review", "references": "25220842;25016063;20978147;28461563;27397482;26184843;27283993;27354477;28415744;15317891;27573756;26142544;28578501;25322323", "title": "Liquid biopsy for monitoring anaplastic lymphoma kinase inhibitors in non-small cell lung cancer: two cases compared.", "title_normalized": "liquid biopsy for monitoring anaplastic lymphoma kinase inhibitors in non small cell lung cancer two cases compared" }	[ { "companynumb": "IT-MYLANLABS-2018M1071410", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": "3", ...
{ "abstract": "Idiopathic cytopenia is a condition where there is a decrease in peripheral blood counts causing either anaemia, leucopoenia and thrombocytopaenia. Most cases of cytopenia reveal a cause on further workup. But very rarely, in some cases, a definitive cause could not be identified. Unexplained cytopenia becomes challenging and poses difficulty in diagnosis and management. Discriminating these groups of bone marrow failure disorders from myelodysplastic syndrome (MDS) becomes an important clinical question. We describe a case of a middle-aged Hispanic woman who presented with pancytopenia and on extensive workup did not reveal any specific cause. Her bone marrow examination revealed severely reduced megakaryocytes but with normal haemopoiesis of other lineages. Cytogenetics, flow cytometry, comprehensive next-generation whole genomic analysis did not reveal any abnormalities. She fit the criteria for idiopathic cytopenia of undetermined significance rather than MDS. She remained asymptomatic and her counts never improved with immunosuppressives or thrombopoietin mimetics.", "affiliations": "Hematology/Oncology, Brookdale University Hospital Medical Center, Brooklyn, New York, USA drpreethiram@hotmail.com.;Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, New York, USA.;Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, New York, USA.;Hematology/Oncology, Brookdale University Hospital Medical Center, Brooklyn, New York, USA.", "authors": "Ramachandran\|Preethi\|P\|http://orcid.org/0000-0003-3032-8886;Erdinc\|Burak\|B\|;Sahni\|Sonu\|S\|;Avezbakiyev\|Boris\|B\|", "chemical_list": "D007166:Immunosuppressive Agents", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-231323", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(10)", "journal": "BMJ case reports", "keywords": "Haematology (incl blood transfusion); Medical management", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000740:Anemia; D001803:Blood Transfusion; D001856:Bone Marrow Examination; D002908:Chronic Disease; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D009190:Myelodysplastic Syndromes; D010198:Pancytopenia; D013001:Somatoform Disorders; D013921:Thrombocytopenia", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31630129", "pubdate": "2019-10-18", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "26429975;21920601;23233623;3780888;17257673;28832236", "title": "Unexplained chronic cytopenia: is it idiopathic cytopenia of undetermined significance or myelodysplastic syndrome.", "title_normalized": "unexplained chronic cytopenia is it idiopathic cytopenia of undetermined significance or myelodysplastic syndrome" }	[ { "companynumb": "US-TEVA-2019-US-1142721", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", ...
{ "abstract": "Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .", "affiliations": "Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.;Julie R. Brahmer, Johns Hopkins Kimmel Cancer Center; Jennifer S. Mammen, Johns Hopkins University, Baltimore, MD; Christina Lacchetti, American Society of Clinical Oncology, Alexandria; Alexander Spira, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA; Bryan J. Schneider, University of Michigan Health System, Ann Arbor, MI; Michael B. Atkins, Georgetown Lombardi Comprehensive Cancer Center; Cristina A. Reichner, Georgetown University; Laura D. Porter, Colon Cancer Alliance; Washington, DC; Kelly J. Brassil, Aung Naing, Loretta J. Nastoupil, Maria E. Suarez-Almazor, and Yinghong Wang, MD Anderson Cancer Center, Houston, TX; Jeffrey M. Caterino, The Ohio State University Wexner Medical Center, Columbus, OH; Ian Chau, The Royal Marsden Hospital and Institute of Cancer Research, London and Surrey, United Kingdom; Marc S. Ernstoff and Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Bianca D. Santomasso and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center; Jeffrey S. Weber, New York University Langone Medical Center, New York, NY; Pamela Ginex, Oncology Nursing Society, Pittsburgh, PA; Jennifer M. Gardner, Seattle Cancer Care Alliance and University of Washington, Seattle, WA; Sigrun Hallmeyer, Oncology Specialists SC, Park Ridge, IL; Jennifer Holter Chakrabarty, University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; David F. McDermott, Beth Israel Deaconess Medical Center; Carole Seigel, Massachusetts General Hospital Cancer Center, Boston, MA; John A. Thompson, Seattle Cancer Care Alliance, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and Tanyanika Phillips, CHRISTUS St Frances Cabrini Cancer Center, Alexandria, LA.", "authors": "Brahmer\|Julie R\|JR\|;Lacchetti\|Christina\|C\|;Schneider\|Bryan J\|BJ\|;Atkins\|Michael B\|MB\|;Brassil\|Kelly J\|KJ\|;Caterino\|Jeffrey M\|JM\|;Chau\|Ian\|I\|;Ernstoff\|Marc S\|MS\|;Gardner\|Jennifer M\|JM\|;Ginex\|Pamela\|P\|;Hallmeyer\|Sigrun\|S\|;Holter Chakrabarty\|Jennifer\|J\|;Leighl\|Natasha B\|NB\|;Mammen\|Jennifer S\|JS\|;McDermott\|David F\|DF\|;Naing\|Aung\|A\|;Nastoupil\|Loretta J\|LJ\|;Phillips\|Tanyanika\|T\|;Porter\|Laura D\|LD\|;Puzanov\|Igor\|I\|;Reichner\|Cristina A\|CA\|;Santomasso\|Bianca D\|BD\|;Seigel\|Carole\|C\|;Spira\|Alexander\|A\|;Suarez-Almazor\|Maria E\|ME\|;Wang\|Yinghong\|Y\|;Weber\|Jeffrey S\|JS\|;Wolchok\|Jedd D\|JD\|;Thompson\|John A\|JA\|;\|\|\|", "chemical_list": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor", "country": "United States", "delete": false, "doi": "10.1200/JCO.2017.77.6385", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "36(17)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D006801:Humans; D009369:Neoplasms; D017410:Practice Guidelines as Topic; D061026:Programmed Cell Death 1 Receptor", "nlm_unique_id": "8309333", "other_id": null, "pages": "1714-1768", "pmc": null, "pmid": "29442540", "pubdate": "2018-06-10", "publication_types": "D016428:Journal Article; D017065:Practice Guideline", "references": "28499515;28239462;28651328;25918278;26783344;28296676;24991413;26748223;26501224;24610577;22541997;28652812;27401894;28869988;26874776;12755552;27367787;25918658;28973656;26867832;26952546;28220466;27532025;21325604;26944362;27307501;28915085;26752406;20525992;28064139;26513491;28719841;27534573;19955205;23741070;16224277;27472273;28085999;19018089;26079306;25795410;27138582;28076715;25901283;26583635;28076863;28550712;18974373;27806233;26765102;25538262;28892432;26071885;28068177;25840693;24590637;26633184;28360039;28830882;27733243;25897158;26981948;27687304;28426103;27517638;28368458;16087944;27566797;28425751;27622997;22456429;28031822;28894725;28315541;28401456;24600203;26962927;25078147;25993145;28524159;28822650;29048973;27271951;27051297;25891174;26837003;28841387;20354889;29297009;25891304;26988410;28600350;27540850;28228726;22256820;26065611;28797029;23357570;26446948;26371282;29045547;27092830;28503645;20686117;28446641;28843363;27539137;20004617;28315552;26885708;28124291;23460165;23669224;26027431;19198837;24831977;26715621;19814739;28204866;28000525;25605840;27908801;27998041;26951628;22047582;27282937;28973343;22614989;28373768;27977496;28416507;25891173;25784681;28873125;27646942;27157227;23045571;26760044;26100356;27736313;28821685;28881921;26629425;27442668;27291635;28155012", "title": "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline.", "title_normalized": "management of immune related adverse events in patients treated with immune checkpoint inhibitor therapy american society of clinical oncology clinical practice guideline" }	[ { "companynumb": "US-JNJFOC-20201138328", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VEDOLIZUMAB" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nThe prognosis in advanced biliary carcinoma has remained poor. The purpose of this study was to investigate the efficacy of intraarterial 5-fluorouracil and interferon therapy against unresectable biliary carcinoma.\n\n\nMETHODS\nPatients with unresectable biliary carcinoma with performance status 0 or 1 were enrolled between January 2002 and September 2012. They received pegylated interferon-α 2a and intraarterial 5-FU every 4 weeks. The therapy was either terminated at the end of the first cycle for the patients with progressive disease or continued for at least three cycles. Patients' characteristics (physical, laboratory and radiographic) at the time of starting intraarterial 5-FU therapy were investigated. The relationship between the patients' characteristics and outcome, i.e., survival time and radiographic therapeutic evaluation of patients, was statistically analyzed.\n\n\nRESULTS\nTumor sites were the intrahepatic bile ducts in 23 patients and gallbladder in 2 patients. Previous treatment had been administered in ten patients. The overall response rate was 24% (6 partial responses in 25 patients). Stable disease was observed in 13 patients. The median overall survival was 358 days. Among the six partial responses, three patients received surgery, and one patient received radiofrequency ablation because clinical downstaging was obtained. The treatment was well tolerated. The survival analyses revealed that two factors (serum albumin ≥ 3.5 and hypovascular tumor) were significantly associated with overall survival.\n\n\nCONCLUSIONS\nCombination therapy with 5-FU and interferon-α was safe and may improve the prognosis of advanced biliary carcinomas.", "affiliations": "Department of Hepatology and Gastroenterology, Kyoundo Hospital, Tokyo, Japan, yashimay@gmail.com.", "authors": "Yashima\|Yoko\|Y\|;Sato\|Shinpei\|S\|;Kawai\|Toshihiro\|T\|;Sugimoto\|Takafumi\|T\|;Sato\|Takahisa\|T\|;Kanda\|Miho\|M\|;Obi\|Shuntaro\|S\|", "chemical_list": "D016898:Interferon-alpha; D011994:Recombinant Proteins; D012709:Serum Albumin; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a; D005472:Fluorouracil", "country": "United States", "delete": false, "doi": "10.1007/s12072-014-9583-z", "fulltext": null, "fulltext_license": null, "issn_linking": "1936-0533", "issue": "9(1)", "journal": "Hepatology international", "keywords": null, "medline_ta": "Hepatol Int", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma; D005260:Female; D005472:Fluorouracil; D005706:Gallbladder Neoplasms; D006801:Humans; D007261:Infusions, Intra-Arterial; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012709:Serum Albumin; D015996:Survival Rate; D016896:Treatment Outcome", "nlm_unique_id": "101304009", "other_id": null, "pages": "142-8", "pmc": null, "pmid": "25788388", "pubdate": "2015-01", "publication_types": "D016428:Journal Article", "references": "20375404;22044786;19548033;8633917;21063134;19896103;23023701;12445422;8047893;15726542;19287994;17523311;19958061;18704990;19750567;16565970;16214602;12377661;22072099", "title": "Intraarterial 5-fluorouracil and interferon therapy is safe and effective for nonresectable biliary tract adenocarcinoma.", "title_normalized": "intraarterial 5 fluorouracil and interferon therapy is safe and effective for nonresectable biliary tract adenocarcinoma" }	[ { "companynumb": "JP-ROCHE-1529666", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "dr...
{ "abstract": "Anti-Hu antibodies (Hu-Abs) are the most frequent onconeural antibodies associated with paraneoplastic neurologic syndromes (PNS). PNS include a variety of neurological syndromes, affecting less than 1/10,000 patients with cancer. In the majority of cases, PNS will manifest before the malignancy is diagnosed. We found a case in which PNS was diagnosed without finding a primary malignancy after extensive work-up and even post-mortem autopsy.\n\n\n\nWe present a case report of a 58-year-old man. This article includes extensive clinical work-up, full-body autopsy and brain autopsy with classical histochemical and myelin stainings and immunohistochemistry was performed.\n\n\n\nThe patient developed a progressive trigeminal neuropathy over a period of 5 years, in combination with cerebellar degeneration, asymmetrical brainstem and limbic encephalitis. Serum showed repeatedly high anti-Hu antibodies. Comprehensive cancer screening could not demonstrate any primary malignancy. Therapy with corticosteroids, plasma exchange, cyclophosphamide and rituximab showed no beneficial effect. He died from the complications of enteric ganglionitis 5 years after onset of the first symptoms. A postmortem autopsy could not detect a primary malignancy either. Brain morphology is described in detail.\n\n\n\nParaneoplastic anti-Hu encephalitis cases associated with SCLC or other primary neoplasms are well known. An adult with a progressive multifocal neurological syndrome in the presence of positive anti-Hu antibodies, but without any primary neoplasm after a follow-up over 5 years is unusual.", "affiliations": "Neurology Department, Gent University Hospital, Gent, Belgium. Electronic address: Elien.Deschamphelaere@uzgent.be.;Neurology Department, Gent University Hospital, Gent, Belgium; Institute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of Antwerp, Antwerp, Belgium.;Neurology Department, Gent University Hospital, Gent, Belgium.;Pathology Department, Antwerp University Hospital, Antwerp, Belgium.;Pathology Department, Gent University Hospital, Gent, Belgium.;Neurology Department, Gent University Hospital, Gent, Belgium; Neurology Department, St Lucas General Hospital Gent, Belgium.", "authors": "De Schamphelaere\|E\|E\|;Sieben\|A\|A\|;Heyndrickx\|S\|S\|;Lammens\|M\|M\|;Geboes\|K\|K\|;De Bleecker\|J L\|JL\|", "chemical_list": "D000974:Antibodies, Antinuclear", "country": "Netherlands", "delete": false, "doi": "10.1016/j.clineuro.2020.105849", "fulltext": null, "fulltext_license": null, "issn_linking": "0303-8467", "issue": "194()", "journal": "Clinical neurology and neurosurgery", "keywords": "Hu-antibodies; Limbic encephalitis; Trigeminal neuropathy", "medline_ta": "Clin Neurol Neurosurg", "mesh_terms": "D015746:Abdominal Pain; D000974:Antibodies, Antinuclear; D001327:Autoimmune Diseases; D001344:Autopsy; D001921:Brain; D017809:Fatal Outcome; D006801:Humans; D020363:Limbic Encephalitis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020361:Paraneoplastic Syndromes, Nervous System; D049268:Positron-Emission Tomography; D020433:Trigeminal Nerve Diseases", "nlm_unique_id": "7502039", "other_id": null, "pages": "105849", "pmc": null, "pmid": "32388246", "pubdate": "2020-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Long lasting trigeminal neuropathy, limbic encephalitis and abdominal ganglionitis without primary cancer: An atypical case of Hu-antibody syndrome.", "title_normalized": "long lasting trigeminal neuropathy limbic encephalitis and abdominal ganglionitis without primary cancer an atypical case of hu antibody syndrome" }	[ { "companynumb": "BE-PFIZER INC-2021777629", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", ...
{ "abstract": "Sarcoidosis is a pleomorphic disease that can present with pulmonary hypertension (PH). What little information is available about the association of these two diseases comes mainly from small series of patients scheduled for transplant. We present 4 cases of mild pulmonary involvement in whom right catheterisation was performed and PH-specific therapy was administered. After obtaining written consent, a genetic study was performed that showed mutations in PH-related genes in 3 of the patients. This is the first study of its kind to yield genetic information for this type of PH.", "affiliations": "Servicio de Neumología, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, España. Electronic address: adolfo.baloira.villar@sergas.es.;Departamento de Genética, Bioquímica e Inmunología, Facultad de Biología, Universidad de Vigo, Vigo, Pontevedra, España.;Servicio de Neumología, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, España.;Departamento de Genética, Bioquímica e Inmunología, Facultad de Biología, Universidad de Vigo, Vigo, Pontevedra, España.", "authors": "Baloira Villar\|Adolfo\|A\|;Pousada Fernández\|Guillermo\|G\|;Núñez Fernández\|Marta\|M\|;Valverde Pérez\|Diana\|D\|", "chemical_list": "C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D010666:Phenylpropionates; D011724:Pyridazines; D012333:RNA, Messenger; D013449:Sulfonamides; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D011464:Epoprostenol; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; C467894:ambrisentan; D000077300:Bosentan; C427248:treprostinil", "country": "Spain", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0300-2896", "issue": "51(4)", "journal": "Archivos de bronconeumologia", "keywords": "Hipertensión pulmonar; Mutaciones; Mutations; Pulmonary hypertension; Sarcoidosis", "medline_ta": "Arch Bronconeumol", "mesh_terms": "D052006:Bone Morphogenetic Protein Receptors, Type II; D000077300:Bosentan; D018450:Disease Progression; D011464:Epoprostenol; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D051666:Kv1.5 Potassium Channel; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010666:Phenylpropionates; D017354:Point Mutation; D011724:Pyridazines; D012333:RNA, Messenger; D012129:Respiratory Function Tests; D012507:Sarcoidosis; D000068677:Sildenafil Citrate; D013449:Sulfonamides; D000068581:Tadalafil; D016896:Treatment Outcome", "nlm_unique_id": "0354720", "other_id": null, "pages": "e19-21", "pmc": null, "pmid": "24950668", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Clinical and molecular study of 4 cases of pulmonary hypertension associated with sarcoidosis.", "title_normalized": "clinical and molecular study of 4 cases of pulmonary hypertension associated with sarcoidosis" }	[ { "companynumb": "ES-ACTELION-A-CH2016-129952", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SILDENAFIL" }, "drugadditional": null, ...
{ "abstract": "This case describes the incidental finding of a massive and persistent elevation of troponin T in a patient with end-stage renal disease. This high troponin T value was not consistent with the patient's clinical condition and the laboratory was called in to investigate this discrepancy. After exclusion of analytical interference and discovery of a discordance between troponin T and troponin I, a clinical investigation including cardiac and whole-body magnetic resonance imaging was performed. Magnetic resonance imaging results allowed us to exclude a cardiac origin of troponin elevation but revealed a skeletal muscle pathology. This case constitutes the first description of high-sensitivity cardiac troponin T elevation due to musculoskeletal pathology without cardiac involvement in a patient with end-stage renal disease.", "affiliations": "Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium. Electronic address: matthieu.deltombe@uclouvain.be.;Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.;Department of Clinical Biochemistry, Cliniques Saint-Pierre, Ottignies, Belgium.;Department of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium; Pôle de recherche en Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.", "authors": "Deltombe\|Matthieu\|M\|;Nevraumont\|Arnaud\|A\|;Bayart\|Jean-Louis\|JL\|;Pouleur\|Anne-Catherine\|AC\|;Labriola\|Laura\|L\|;Gruson\|Damien\|D\|", "chemical_list": "D015415:Biomarkers; D019210:Troponin I; D020107:Troponin T", "country": "Netherlands", "delete": false, "doi": "10.1016/j.cca.2021.06.018", "fulltext": null, "fulltext_license": null, "issn_linking": "0009-8981", "issue": "520()", "journal": "Clinica chimica acta; international journal of clinical chemistry", "keywords": "Discrepancy; Interference; Skeletal muscle; Troponin I; roponin T", "medline_ta": "Clin Chim Acta", "mesh_terms": "D015415:Biomarkers; D006801:Humans; D008279:Magnetic Resonance Imaging; D019210:Troponin I; D020107:Troponin T; D051598:Whole Body Imaging", "nlm_unique_id": "1302422", "other_id": null, "pages": "214-216", "pmc": null, "pmid": "34126066", "pubdate": "2021-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A colossal, enigmatic, and long-lasting high-sensitivity cardiac troponin T elevation.", "title_normalized": "a colossal enigmatic and long lasting high sensitivity cardiac troponin t elevation" }	[ { "companynumb": "BE-CELLTRION INC.-2022BE000743", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", ...
{ "abstract": "Takotsubo cardiomyopathy, apical ballooning syndrome or stress-induced cardiomyopathy is characterised by transient left ventricular dysfunction, mimicking myocardial infarction in the absence of obstructive coronary artery disease or acute plaque rupture on coronary angiography. The exact mechanism of myocardial dysfunction in Takotsubo cardiomyopathy is unknown; however, due to its association with physical and emotional stress, it is postulated that catecholamines play a central role in its pathogenesis. We present a case of a patient who was admitted with acute asthma exacerbation and was treated with β-2 agonist nebulisation and intravenous aminophylline. During her hospital stay she developed Takotsubo cardiomyopathy.", "affiliations": "Department of Medicine, The Aga Khan University Hospital, Karachi, Pakistan.;Department of Medicine, The Aga Khan University Hospital, Karachi, Pakistan.", "authors": "Khwaja\|Yousuf Hasan\|YH\|;Tai\|Javed Majid\|JM\|", "chemical_list": "D001993:Bronchodilator Agents; D000628:Aminophylline; D000420:Albuterol", "country": "England", "delete": false, "doi": "10.1136/bcr-2016-217364", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2016()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000208:Acute Disease; D000280:Administration, Inhalation; D000420:Albuterol; D000628:Aminophylline; D001249:Asthma; D001993:Bronchodilator Agents; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D054549:Takotsubo Cardiomyopathy", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "27793870", "pubdate": "2016-10-28", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "20561882;22456259;18094670;25071891;16344237;18294473;13990605;20689475;25855605;20038421;22732314;24554679;15889197;1841907;19513776;19106400;24855502;18945727;11343413;22795284;24944763;19628289;17395683;21931096;19561716;12063255;18842143;19838460;19544675;20541719;25743867;26246918;12690430;17052786;16720686;23882408;20486954;25522887;26548803;27638018;15703419;22761975", "title": "Takotsubo cardiomyopathy with use of salbutamol nebulisation and aminophylline infusion in a patient with acute asthma exacerbation.", "title_normalized": "takotsubo cardiomyopathy with use of salbutamol nebulisation and aminophylline infusion in a patient with acute asthma exacerbation" }	[ { "companynumb": "PK-MYLANLABS-2016M1054714", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null...
{ "abstract": "Femoral neck stress fractures in young healthy individuals are rare and occur in those who take part in physical training with repetitive loading and those with osteoporosis. Bone density is related to sex hormone status, which is artificially manipulated during gender reassignment. Conflicting evidence currently exists on the effect of cross sex hormone treatment on bone density, with no literature suggesting a link between hormone treatment in gender reassignment and stress fractures. Our aim is to highlight the potential risk of stress fractures amongst transsexual patients receiving cross sex hormones as part of gender reassignment. The patient presented with groin pain after competing in a running event. Despite a number of risk factors, there was a delay in diagnosis, which could have led to complications compromising outcome. Femoral neck stress fractures should be considered in the differential diagnosis of transsexual patients receiving hormone treatment with non-specific groin/thigh pain following exercise.", "affiliations": "Department of Trauma and Orthopaedics, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, Cheshire, UK.;Department of Trauma and Orthopaedics, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, Cheshire, UK.;Department of Trauma and Orthopaedics, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, Cheshire, UK.", "authors": "Richardson\|Tom\|T\|;Grant\|Michael\|M\|;Chandran\|Prakash\|P\|", "chemical_list": "D012739:Gonadal Steroid Hormones", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2016()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D001265:Athletic Injuries; D005260:Female; D005265:Femoral Neck Fractures; D015775:Fractures, Stress; D012739:Gonadal Steroid Hormones; D006801:Humans; D008297:Male; D012307:Risk Factors; D012420:Running; D014189:Transsexualism", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "27033288", "pubdate": "2016-03-31", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19213509;10782361;2252096;22970643;8742125;12594565;17414993;15521957;3733811;9205638;7769130;12145125;20205723;2521824;22222419;17141015;11120762;17986639;15502960;9434047;12050121;8837613;9578826;12665184;11981604", "title": "A curious case of stress fracture in a transsexual athlete.", "title_normalized": "a curious case of stress fracture in a transsexual athlete" }	[ { "companynumb": "GB-MYLANLABS-2017M1013824", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TESTOSTERONE" }, "drugadditional": "3", ...
{ "abstract": "Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (CDI) and is considered as a treatment for other gastrointestinal (GI) diseases. We followed up the relief of symptoms and long-term, over-a-year microbiota stabilization in a 46-year-old man, who underwent FMT for antibiotic-induced, non-CDI colitis nine months after being treated for CDI by FMT. Fecal and mucosal microbiota was analyzed before the second FMT and during 14 months after FMT by using a high-throughput phylogenetic microarray. FMT resolved the symptoms and restored normal GI-function. Microbiota analysis revealed increased bacterial diversity in the rectal mucosa and a stable fecal microbiota up to three months after FMT. A number of mucosa-associated bacteria increased after FMT and some of these bacteria remained increased in feces up to 14 months. Notably, the increased bacteria included Bifidobacterium spp. and various representatives of Clostridium clusters IV and XIVa, such as Clostridium leptum, Oscillospira guillermondii, Sporobacter termitidis, Anaerotruncus colihominis, Ruminococcus callidus, R. bromii, Lachnospira pectinoschiza, and C. colinum, which are presumed to be anti-inflammatory. The presented case suggests a possible role of microbiota in restoring and maintaining normal GI-functionality and improves our knowledge on the etiology of antibiotic-induced, noninfectious colitis.", "affiliations": "Department of Veterinary Biosciences, University of Helsinki, P.O. Box 66, 00014 Helsinki, Finland.;Laboratory of Microbiology, Wageningen University, Dreijenplein 10, 6703 HB Wageningen, The Netherlands.;Department of Infectious Diseases, Helsinki University Central Hospital, P.O. Box 348, 00029 Helsinki, Finland.;Department of Veterinary Biosciences, University of Helsinki, P.O. Box 66, 00014 Helsinki, Finland.;Department of Veterinary Biosciences, University of Helsinki, P.O. Box 66, 00014 Helsinki, Finland ; Laboratory of Microbiology, Wageningen University, Dreijenplein 10, 6703 HB Wageningen, The Netherlands ; Haartman Institute, University of Helsinki, P.O. Box 21, 00014 Helsinki, Finland.;Department of Gastroenterology, Helsinki University Central Hospital, P.O. Box 372, 00029 Helsinki, Finland.", "authors": "Satokari\|Reetta\|R\|0000-0002-4258-3414;Fuentes\|Susana\|S\|0000-0003-2275-4500;Mattila\|Eero\|E\|;Jalanka\|Jonna\|J\|;de Vos\|Willem M\|WM\|;Arkkila\|Perttu\|P\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2014/913867", "fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/913867Case ReportFecal Transplantation Treatment of Antibiotic-Induced, Noninfectious Colitis and Long-Term Microbiota Follow-Up http://orcid.org/0000-0002-4258-3414Satokari Reetta \n1\n\n\nhttp://orcid.org/0000-0003-2275-4500Fuentes Susana \n2\nMattila Eero \n3\nJalanka Jonna \n1\nde Vos Willem M. \n1\n\n2\n\n4\nArkkila Perttu \n5\n1Department of Veterinary Biosciences, University of Helsinki, P.O. Box 66, 00014 Helsinki, Finland2Laboratory of Microbiology, Wageningen University, Dreijenplein 10, 6703 HB Wageningen, The Netherlands3Department of Infectious Diseases, Helsinki University Central Hospital, P.O. Box 348, 00029 Helsinki, Finland4Haartman Institute, University of Helsinki, P.O. Box 21, 00014 Helsinki, Finland5Department of Gastroenterology, Helsinki University Central Hospital, P.O. Box 372, 00029 Helsinki, FinlandReetta Satokari: reetta.satokari@helsinki.fiAcademic Editor: Ron Rabinowitz\n\n2014 19 11 2014 2014 91386727 8 2014 2 11 2014 Copyright © 2014 Reetta Satokari et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (CDI) and is considered as a treatment for other gastrointestinal (GI) diseases. We followed up the relief of symptoms and long-term, over-a-year microbiota stabilization in a 46-year-old man, who underwent FMT for antibiotic-induced, non-CDI colitis nine months after being treated for CDI by FMT. Fecal and mucosal microbiota was analyzed before the second FMT and during 14 months after FMT by using a high-throughput phylogenetic microarray. FMT resolved the symptoms and restored normal GI-function. Microbiota analysis revealed increased bacterial diversity in the rectal mucosa and a stable fecal microbiota up to three months after FMT. A number of mucosa-associated bacteria increased after FMT and some of these bacteria remained increased in feces up to 14 months. Notably, the increased bacteria included Bifidobacterium spp. and various representatives of Clostridium clusters IV and XIVa, such as Clostridium leptum, Oscillospira guillermondii, Sporobacter termitidis, Anaerotruncus colihominis, Ruminococcus callidus, R. bromii, Lachnospira pectinoschiza, and C. colinum, which are presumed to be anti-inflammatory. The presented case suggests a possible role of microbiota in restoring and maintaining normal GI-functionality and improves our knowledge on the etiology of antibiotic-induced, noninfectious colitis.\n==== Body\n1. Introduction\nThe intestinal tract harbors an extremely diverse microbiota, which is crucial in maintaining immunological and physiological homeostasis of the mucosa [1]. Dysbiosis of microbiota (aberrant composition) can lead to loss of normal, regulatory immune effects in the gut mucosa, and dysbiotic microbiota has been associated with a number of inflammatory and immune-mediated diseases [2, 3]. A recent hypothesis presents that, after epithelial insult by a pathogen or an injury, specific symbiotic bacteria are needed to restore mucosal homeostasis back to a basal level by ceasing the acute inflammation [3]. In support of the hypothesis, a community of 17 intestinal strains attenuated intestinal inflammation by stimulating regulatory T cells in a mouse colitis model [4]. Fecal microbiota transplantation (FMT) is effective in treating recurrent Clostridium difficile infection (CDI) [5, 6], and it is increasingly considered also for the treatment of noninfectious colitis [7]. This report describes treatment of antibiotic-induced, noninfectious colitis by FMT nine months after the first FMT treatment for CDI and the stabilization of intestinal microbiota in a 46-year-old man during 14 months after the second FMT.\n\n2. Materials and Methods\n2.1. The Case Presentation\nThe patient was a 46-year-old man with history of hypertension and ventricular extrasystolia, which were being controlled by medication. He had no known allergies, and he had travelled only in Western Europe. He smoked. He had had several sinusitis episodes. Two years before the onset of refractory Clostridium difficile infection, he had septic infection due to the axillar bursitis. His uncle has Crohn's disease.\n\nThe patient had Clostridium difficile infection (CDI), after amoxicillin clavulanate treatment for otitis media. CDI was verified by cultivation of C. difficile and positive toxin test of feces (VIDAS C. difficile Toxin A & B CDAB, BioMerieux, France). No resolution of symptoms was achieved with oral metronidazole (400 mg thrice a day) or vancomycin (first 120 mg four times a day and later 250 mg four times a day). Because of refractory situation, patient was hospitalized and the treatment was switched to meropenem (1 g thrice a day intravenously) and rifaximin (400 mg twice a day). In addition, he got one dose of immunoglobulin 27.5 g intravenously. After six days of treatment, the patient was discharged with ten days of rifaximin (400 mg twice a day) treatment. Three days after stopping the rifaximin treatment, the symptoms reappeared including 10 diarrhea episodes per day. The patient restarted rifaximin treatment and continued it until colonoscopy and FMT were done three weeks later. Mild nonspecific proctitis was found in colonoscopy. The histology showed postinfectious inflammation and no typical signs of chronic inflammatory bowel disease. FMT was performed by infusing fecal suspension into the caecum. The diarrhea disappeared within two days after FMT.\n\nSeven months after FMT, the patient got clarithromycin for sinusitis and diarrhea reappeared. Symptoms were not as severe as earlier; that is, he had 5-6 diarrhea episodes per day and urgency of defecation. No C. difficile or toxins were found in feces by cultivation or toxin tests, respectively. The symptoms did not resolve spontaneously during 8 weeks after the cessation of clarithromycin. Colonoscopy was reassessed to exclude chronic inflammatory bowel disease. The macroscopic and microscopic findings were similar as seen previously, that is, mild inflammation. Fecal calprotectin was also tested and was 12 μg/g. The patient received the second FMT and thereafter he has had no GI-symptoms (two and a half years by the time of submitting this report). The patient had three antibiotic courses during the follow-up period between 10 and 12 months after the second FMT.\n\n2.2. The Donor and Fecal Microbiota Transplantation (FMT)\nThe donor of fecal material in both transplantations was the patient's 35-year-old wife, who was pregnant at the time of the second FMT. She had not received antimicrobial therapy for the past 6 months and did not have any intestinal symptoms. She was tested by the protocol for fecal donors as described previously [5]. Thirty grams of the donor's feces were suspended into 150 mL of tap water and the suspension was infused into the caecum through colonoscopy as described previously [5].\n\n2.3. Samples and Microbiota Analysis\nRectal biopsies were taken from the patient at the time of the second FMT and one month later in proctoscopy and stored in −80°C until further processing. The patient and donor collected fecal samples after the second FMT according to the sampling scheme presented in Figure 1. The fecal samples were placed in a home freezer at −20°C immediately after defecation and stored in the home freezer for maximally 4 months until transfer to laboratory for further analysis. Six healthy adult volunteers (3 males and 3 females, mean age 67 years), who underwent diagnostic colonoscopy and were found to have a healthy intestine, were included as a comparison group for mucosa-associated microbiota. DNA extraction was done as described previously by using mechanical disruption of bacterial cells by bead-beating followed by DNA purification [8]. Microbiota analysis was done by using the HITChip high-throughput bacterial phylogenetic microarray as described previously [8–11].\n\n2.4. Ethical Considerations\nThe study was approved by the Ethics Committee of Hospital District of Helsinki and Uusimaa (HUS), Finland (Dnro HUS 124/13/03/01/11). The patient was informed about the experimental nature and possible risks of FMT. Written informed consent was obtained from the patient and donor for publication of this case report. The healthy volunteers who donated biopsies signed informed consent.\n\n3. Results\n3.1. Resolution of GI-Symptoms by FMT\nThe patient's recurrent Clostridium difficile infection was successfully treated by FMT. Seven months later, he got antibiotic-induced diarrhea, which was not as severe as earlier. Also, no C. difficile or toxins were found in feces. The symptoms did not resolve spontaneously within eight weeks after stopping the antibiotic. Colonoscopy excluded inflammatory bowel disease, but mild inflammation was observed. The patient received FMT again and the GI-symptoms were resolved within few days. The patient had three antibiotic courses during the follow-up period between 10 and 12 months after the second FMT, but these antibiotic treatments did not induce diarrhea.\n\n3.2. Fecal Microbiota of the Donor\nIn general, fecal microbiota of the donor was found to be stable during the 14-month follow-up period, but a decrease in stability was observed between 2-day and 2-week and 4- and 7-month samples, that is, approximately one month before and three months after the delivery, respectively (Figure 2). The most predominating phylum was Firmicutes, where Clostridium clusters IV and XIVa and uncultured Clostridiales were the largest groups (Figure 1). Phylum Bacteroidetes constituted 2–13% and Actinobacteria and Proteobacteria less than 4% of the total microbiota in the donor (Figure 1). In the enterotype (ET) profiling, the donor's fecal microbiota represented ET3, that is, the Ruminococcus enterotype (Figure 1). The diversity and richness of fecal microbiota were higher in the donor than in the patient throughout the follow-up period (Figure 3).\n\n3.3. Mucosal and Fecal Microbiota of the Patient during 14 Months after the FMT\nIntestinal microbiota composition was followed up with frequent sampling during 14 months after the FMT. In the patient, a shift from a Bacteroidetes-rich fecal microbiota to a microbiota, where Firmicutes constitute over 87% of the bacterial community, was observed from two weeks after FMT onwards (Figure 1). Particularly, the relative proportion of Clostridium cluster XIVa increased by 20% in feces after FMT. However, in mucosa, the relative abundance of the phylum Bacteroidetes increased and Firmicutes decreased after FMT. Fecal microbiota two days after FMT resembled the pre-FMT microbiota and may reflect an adaptation stage. Also, fecal microbiota enterotype (ET) profiling analysis showed a shift at 2 days after FMT. Fecal microbiota represented enterotype 3 (ET3), that is, the Ruminococcus enterotype at all other sampling points except at 2 days after FMT. In contrast, mucosal microbiota represented enterotype 2 (ET2), that is, the Prevotella enterotype (Figure 1). Consistently, both the phylum level and enterotype profiling, that is, genus level analysis, showed that the composition of mucosa-associated microbiota is different from that of the fecal microbiota. The patient's fecal microbiota was stable from 2 weeks to 3 months after FMT, but then stability decreased slightly between 3 and 7 months and more notably between 7 and 14 months (Figure 2). From 7- to 14-month fecal samples, a shift back to a Bacteroidetes-rich fecal microbiota was seen (Figure 1). The shift cooccurred with the administration of three antibiotic courses between these sampling points.\n\nFurther, the analysis of mucosa-associated microbiota revealed a marked increase in the diversity and richness of bacterial species in post-FMT rectal biopsy as compared to the pre-FMT biopsy (Figure 3). The increase in diversity and richness in the patient's rectal mucosa exceeded the interindividual variability of rectal biopsies from six healthy controls (Figure 3). The increase in diversity also exceeded intraindividual variability between ileal and rectal biopsies from the same individual (Figure 3). The results indicate that the increase in diversity and richness of the patient's mucosal microbiota is beyond the natural variability. Thus, the mucosal microbiota of the patient seemed to be strongly affected by FMT. However, in the luminal contents (feces), the increase in bacterial diversity and richness was modest (Figure 3). Interestingly, the post-FMT biopsy of the patient clustered with fecal samples of the donor in hierarchical clustering of the microbiota profiles (Supplementary Figure 1 available online at http://dx.doi.org/10.1155/2014/913867). A number of bacterial groups in the mucosa showed either a decrease or an increase in their relative abundance after FMT (Table 1). Most of these bacterial groups (46 out of 49) showed a similar difference between the donor and the pre-FMT patient fecal samples. Further, specific bacterial groups in post-FMT mucosal sample showed the same direction of change in their relative abundance in the fecal sample at 14 months after FMT and during the follow-up period from 2 weeks to 7 months (in average) as compared to the pre-FMT feces (Table 1). The increased bacterial groups include Bifidobacterium spp. (Actinobacteria), Clostridium leptum et rel., Oscillospira guillermondii et rel., Sporobacter termitidis et rel., Anaerotruncus colihominis et rel., Ruminococcus callidus et rel., R. bromii et rel. (Clostridium cluster IV), Dialister spp. (Clostridium cluster IX), Lachnospira pectinoschiza et rel., C. colinum et rel. (Clostridium cluster XIVa), uncultured Clostridiales I, and Oxalobacter formigenes et rel. (Proteobacteria) (Table 1). We assume that these bacterial groups have established themselves stably from the donor's microbiota or have successfully and stably recovered from the patient's own microbiota after FMT. On the other hand, four groups belonging to Bacteroidetes and Clostridium ramosum et rel. (Clostridium cluster XVIII) decreased after FMT both in mucosa and in feces.\n\n4. Discussion\nThe case described herein presents an expansion of the use of FMT to treat antibiotic-induced, non-CDI colitis. FMT restored normal GI-function and the patient has not had GI-symptoms thereafter, that is, two and a half years at the time of writing this report.\n\nInterestingly, the patient did not seem to have perturbed fecal microbiota prior to FMT. The relative proportion of Bacteroidetes was rather high, but within the normal variation in healthy Europeans adults [9]. Also, the microbiota composition of the donor was typical to healthy adults [9] and showed high stability during the last month of pregnancy and three months postpartum, which is in line with the results from a recent study [12]. In the patient, the proportion of Bacteroidetes still increased two days after the FMT, but later a clear shift to a Firmicutes-dominating microbiota was observed. It seems that a period ranging from few days to two weeks is needed before the establishment of post-FMT microbiota. The temporary shift of the microbiota enterotype at 2d after FMT also indicates a transition period. At the phylum level, fecal microbiota was relatively stable from two weeks up to three months after FMT. Recently, a stable phylum level microbiota composition was reported in three patients, who were followed up for 3-4 months after FMT for recurrent C. difficile infection [13]. In our patient, the diversity of microbiota decreased and the total microbiota was less stable after three months after FMT. The result indicates that microbiota evolution may continue for a considerable period of time after FMT and underlines the need for long-term post-FMT follow-up studies of microbiota stabilization.\n\nIn the patient, fecal and mucosal microbiota showed different compositions at both bacterial phylum and genus levels. In the enterotype profiling, fecal microbiota was found to be enterotype 3 (ET3) and mucosal microbiota enterotype 2 (ET2). The three enterotypes are each characterized by a discriminating genus, Bacteroides (ET1), Prevotella (ET2), or Ruminococcus (ET3), whose abundance correlates with the abundance of other genera [11]. Thus, the enterotypes are driven by groups of bacteria that together contribute to the preferred microbiota composition, which is a result of adaption to the particular environment. Interestingly, the bacterial diversity and richness were higher in the mucosal biopsies as compared to feces. Similarly, higher bacterial richness was observed in the mucosa as compared to matched fecal samples in a recent study comprising four individuals [14]. Clearly, intestinal lumen and mucosa represent different environments and, consequently, harbor different microbiota.\n\nWe observed a shift back to a Bacteroidetes-rich fecal microbiota in the patient at 14 months after FMT. The shift was associated with the administration of three antibiotic courses, which, however, did not induce diarrhea this time. Thus, at the phylum level composition, the patient's microbiota at 14 months resembled microbiota before FMT, but apparently he maintained some key bacterial species that could support gut functionality even when challenged by antibiotics. Indeed, we observed a drastic increase in the diversity and richness of mucosal microbiota after FMT indicating either the strong engraftment of donor's microbiota or the recovery of patient's own microbiota particularly in the mucosal lining. Specific mucosa-associated bacteria, which increased in abundance, showed an increase also in feces up to 14 months after FMT. The increased bacterial groups include Bifidobacterium and Dialister spp., bacteria related to Clostridium leptum, Oscillospira guillermondii, Sporobacter termitidis, Anaerotruncus colihominis, Ruminococcus callidus, R. bromii, Lachnospira pectinoschiza, C. colinum, and Oxalobacter formigenes, as well as uncultured Clostridiales I. We assume that these bacterial groups have established themselves stably after FMT and may have a crucial role in maintaining gut homeostasis. Previously, Bifidobacterium, C. leptum, Sporobacter, Oscillospira, Anaerotruncus, R. bromii, Dialister, and uncultured Clostridiales have been found to be increased in healthy individuals as compared to inflammatory bowel disease (IBD) patients [10, 15]. Further, a combination of 17 strains of intestinal bacteria, belonging to the genera Ruminococcus, Anaerotruncus, Lachnospiraceae, Clostridium, Eubacterium, and Blautia, has been shown to attenuate inflammation in a mouse colitis model by stimulating regulatory T cells [4]. As an exception, O. formigenes has no reported anti-inflammatory effects but is associated with a reduced risk of calcium oxalate stone disease [16]. Collectively, our patient showed constantly increased levels of intestinal bacteria, which seem to have anti-inflammatory effects and possibly ceased the mild, on-going inflammation.\n\nIn the presented case, FMT resolved the symptoms in an antibiotic-induced, noninfectious colitis. The post-FMT bacterial community restored normal GI-function possibly by ceasing the mild, on-going inflammation. The microbiota analysis suggests that specific members of microbiota may have a role in restoring and maintaining normal GI-functionality. Interestingly, the 17 strains in the study by Atarashi et al. [4] exerted an anti-inflammatory effect as a community, but not as individual strains. Thus, it seems that an assembly of bacterial species, rather than a specific single species, is essential in preventing or treating intestinal diseases. Today, FMT is the most straightforward way of introducing the necessary combination of bacteria to a patient, but there is an increasing need to identify the crucial bacterial species that are able to control infection or inflammation in the intestine. The first two cases on the use of an “artificial stool” consisting of pure cultures of intestinal bacterial have shown promising results in the treatment of recurrent CDI [17]. Clinical FMT-studies linked with microbiota analysis can greatly advance these efforts and improve our understanding of the etiology of diseases, where dysbiosis of the microbiota is considered to play a role.\n\n5. Conclusions\nThe antibiotic-induced, noninfectious colitis of a 46-year-old man was successfully treated with FMT. The results suggest a possible role of intestinal microbiota and its specific members in restoring and maintaining normal GI-functionality.\n\nSupplementary Material\nSupplementary figure 1. Hierarchical clustering based of the HITChip phylogenetic microarray profiles of the patient (P) and donor (D) fecal samples and patient biopsy samples (P_B). The samples are coded by the time of collection, where 0 represents the pre-FMT sample and d, wk and m represent days, weeks or months after the FMT, respectively. The color intensity represents microarray probe signal level, which corresponds to the bacterial abundance in the sample. The highest phylogenetic level of probes' specificity is depicted on the side of the profiles. Pearson correlation and Ward's clustering method were used.\n\n Acknowledgments\nThe authors thank the patient and donor for collecting the follow-up samples and the healthy volunteers for donating biopsies. They also thank the HITChip team, from University of Wageningen, for their excellent technical assistance. This work was partly funded by the Academy of Finland Grants (138902, 258439, and 137389) and the unrestricted Spinoza Award from the Netherlands Organization for Scientific Research.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nAuthors’ Contribution\nReetta Satokari and Susana Fuentes contributed equally to this work; Reetta Satokari, Eero Mattila, Willem M. de Vos, and Perttu Arkkila designed the research. Reetta Satokari, Eero Mattila, and Perttu Arkkila performed the clinical work and collection of samples; Reetta Satokari, Susana Fuentes, and Jonna Jalanka analysed the data; all authors interpreted data; Reetta Satokari, Susana Fuentes, and Perttu Arkkila wrote the paper; all authors revised the paper for important intellectual content; all authors approved the final version of the paper to be published.\n\nFigure 1 Microbiota composition at the phylum level and bacterial genus level enterotype (ET) status before FMT and during the 14-month follow-up period.\n\nFigure 2 Stability of the fecal microbiota determined as Pearson correlation of the microbiota profiles between the subsequent sampling points.\n\nFigure 3 Diversity and richness of microbiota in the fecal samples (a and c) and in mucosal biopsies from the patient and six healthy controls (b and d). 0 d: pre-FMT sample; 2 wk to 14 mo: post-FMT samples. Line connects the rectal and ileal samples from the same individual.\n\nTable 1 Mucosal bacteria with >2-fold change in relative abundance after FMT and constituting >0.01% of the microbiota. \n\nPhylum/cluster\tIncreased bacterial groups\nin colonic mucosa1\n\tFold-change \nB0 to B1\tIncreased in feces\nF14?m and F2?w–7?m3\n\t\nActinobacteria\t\nBifidobacterium spp.\t2.2\tYes\t\n\n\n\t\nBacteroidetes\t\nPrevotella melaninogenica et rel. \n\t5.6\tNo\t\n\nPrevotella oralis et rel. \n\t5.7\tNo\t\n\n\n\t\nFirmicutes/Clostridium cl. IV\t\nClostridium leptum et rel. \n\t2.5\tYes\t\n\nOscillospira guillermondii et rel. \n\t4.8\tYes\t\n\nSporobacter termitidis et rel. \n\t2.7\tYes\t\n\nAnaerotruncus colihominis et rel. \n\t3.4\tYes\t\n\nRuminococcus callidus et rel. \n\t4.1\tYes\t\n\nRuminococcus lactaris et rel. \n\t15.4\tNo\t\n\nRuminococcus bromii et rel. \n\t12.0\tYes\t\n\nSubdoligranulum variabile et rel. \n\t7.9\tNo\t\n\n\n\t\nFirmicutes/Clostridium cl. IX\t\nDialister spp.\t3.6\tYes\t\n\n\n\t\nFirmicutes/Clostridium cl. XIVa\t\nLachnospira pectinoschiza et rel. \n\t2.3\tYes\t\n\nRuminococcus lactaris et rel. \n\t15.4\tNo\t\n\nButyrivibrio crossotus et rel. \n\t2.5\tNo\t\n\nClostridium colinum et rel. \n\t3.3\tYes\t\n\n\n\t\nUncult. Clostridiales\tUncult. ClostridialesI\t10.2\tYes\t\n\n\n\t\nProteobacteria\t\nOxalobacter formigenes \n\t3.5\tYes\t\n\n\n\t\nPhylum/cluster\tDecreased bacterial groups\nin colonic mucosa2\n\tFold-change\nB0 to B1\tDecreased in feces\nF14 m and F2 w–7 m3\n\t\n\n\n\t\nBacteroidetes\t\nAlistipes et rel. \n\t2.0\tNo\t\n\nBacteroides stercoris et rel. \n\t2.4\tNo\t\n\nBacteroides vulgatus et rel. \n\t9.6\tYes\t\n\nBacteroides fragilis et rel. \n\t2.1\tYes\t\n\nBacteroides ovatus et rel. \n\t3.4\tYes\t\n\nBacteroides intestinalis et rel. \n\t3.4\tNo\t\n\nBacteroides plebeius et rel. \n\t2.5\tNo\t\n\nPrevotella tannerae et rel. \n\t6.2\tYes\t\n\nTannerella et rel. \n\t2.4\tNo\t\n\nParabacteroides distasonis et rel. \n\t4.0\tNo\t\nUncult. Bacteroidetes\t5.9\tNo\t\n\n\n\t\nFirmicutes/Clostridium cl. I\tClostridia\t5.8\tNo\t\n\n\n\t\nFirmicutes/Clostridium cl. XIVa\t\nCoprococcus eutactus et rel. \n\t2.4\tNo\t\n\nDorea formicigenerans et rel. \n\t4.0\tNo\t\n\nEubacterium rectale et rel. \n\t2.0\tNo\t\n\nRuminococcus gnavus et rel. \n\t7.0\tNo\t\n\nRuminococcus obeum et rel. \n\t4.4\tNo\t\n\nClostridium nexile et rel. \n\t5.3\tNo\t\nOutgr. Clostridium cl. XIVa\t6.2\tNo\t\n\n\n\t\nFirmicutes/Clostridium cl. IX\t\nVeillonella spp.\t2.7\tNo\t\n\nMegasphaera elsdenii et rel. \n\t3.4\tNo\t\n\n\n\t\nFirmicutes/Clostridium cl. XI\t\nClostridium difficile et rel. \n\t23.1\tNo\t\n\n\n\t\nFirmicutes/Clostridium cl. XVI\t\nBulleidia moorei et rel. \n\t2.1\tNo\t\n\nEubacterium cylindroides et rel. \n\t2.2\tNo\t\n\n\n\t\nFirmicutes/Clostridium cl. XVIII\t\nClostridium ramosum et rel. \n\t8.1\tYes\t\n\n\n\t\nFirmicutes/Bacilli\t\nStreptococcus bovis et rel. \n\t2.3\tNo\t\n\nStreptococcus intermedius et rel. \n\t2.3\tNo\t\n\nStreptococcus mitis et rel. \n\t2.1\tNo\t\n\n\n\t\nProteobacteria\t\nSutterella wadsworthia et rel. \n\t2.7\tNo\t\n\nEscherichia coli et rel. \n\t3.7\tNo\t\n\nKlebsiella pneumonia et rel. \n\t2.2\tNo\t\n\n1Higher abundance also in the donor's feces as compared to the patient's pre-FMT feces; 2lower abundance also in the donor's feces as compared to the patient's pre-FMT feces, with the exception of C. eutactus et rel., E. rectale et rel., and S. bovis et rel.; 3increased/decreased abundance in 14 mo and in 2 w to 7 mo (average) post-FMT samples as compared to the pre-FMT fecal sample; Uncult.: uncultured; cl.: cluster; Outgr.: outgrouping.\n==== Refs\n1 Maynard C. L. Elson C. O. Hatton R. D. Weaver C. T. Reciprocal interactions of the intestinal microbiota and immune system Nature 2012 489 7415 231 241 10.1038/nature11551 2-s2.0-84866167497 22972296 \n2 Ivanov I. I. Honda K. Intestinal commensal microbes as immune modulators Cell Host & Microbe 2012 12 4 496 508 10.1016/j.chom.2012.09.009 2-s2.0-84867658789 23084918 \n3 Manichanh C. Borruel N. Casellas F. Guarner F. The gut microbiota in IBD Nature Reviews Gastroenterology and Hepatology 2012 9 10 599 608 10.1038/nrgastro.2012.152 2-s2.0-84867208167 22907164 \n4 Atarashi K. Tanoue T. Oshima K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota Nature 2013 500 7461 232 236 10.1038/nature12331 2-s2.0-84881477044 23842501 \n5 Mattila E. Uusitalo-Seppälä R. Wuorela M. Lehtola L. Nurmi H. Ristikankare M. Moilanen V. Salminen K. Seppälä M. Mattila P. S. Anttila V. Arkkila P. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection Gastroenterology 2012 142 3 490 496 10.1053/j.gastro.2011.11.037 2-s2.0-84857640098 22155369 \n6 van Nood E. Vrieze A. Nieuwdorp M. Duodenal infusion of donor feces for recurrent clostridium difficile The New England Journal of Medicine 2013 368 5 407 415 10.1056/NEJMoa1205037 2-s2.0-84873019302 23323867 \n7 Smits L. P. Bouter K. E. C. de Vos W. M. Borody T. J. Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation Gastroenterology 2013 145 5 946 953 10.1053/j.gastro.2013.08.058 2-s2.0-84886782819 24018052 \n8 Nylund L. Heilig H. G. H. J. Salminen S. de Vos W. M. Satokari R. Semi-automated extraction of microbial DNA from feces for qPCR and phylogenetic microarray analysis Journal of Microbiological Methods 2010 83 2 231 235 10.1016/j.mimet.2010.09.003 2-s2.0-77957885233 20849891 \n9 Rajilić-Stojanović M. Heilig H. G. H. J. Tims S. Zoetendal E. G. de Vos W. M. Long-term monitoring of the human intestinal microbiota composition Environmental Microbiology 2013 15 4 1146 1159 10.1111/1462-2920.12023 2-s2.0-84875904427 \n10 Rajilić-Stojanović M. Shanahan F. Guarner F. de Vos W. M. Phylogenetic analysis of dysbiosis in ulcerative colitis during remission Inflammatory Bowel Diseases 2013 19 3 481 488 10.1097/MIB.0b013e31827fec6d 2-s2.0-84876375062 23385241 \n11 Arumugam M. Raes J. Pelletier E. Le Paslier D. Yamada T. Mende D. R. Fernandes G. R. Tap J. Bruls T. Batto J.-M. Bertalan M. Borruel N. Casellas F. Fernandez L. Gautier L. Hansen T. Hattori M. Hayashi T. Kleerebezem M. Kurokawa K. Leclerc M. Levenez F. Manichanh C. Nielsen H. B. Nielsen T. Pons N. Poulain J. Qin J. Sicheritz-Ponten T. Tims S. Torrents D. Ugarte E. Zoetendal E. G. Wang J. Guarner F. Pedersen O. de Vos W. M. Brunak S. Doré J. Consortium M. Weissenbach J. Ehrlich S. D. Bork P. Antolín M. Artiguenave F. Blottiere H. M. Almeida M. Brechot C. Cara C. Chervaux C. Cultrone A. Delorme C. Denariaz G. Dervyn R. Foerstner K. U. Friss C. van de Guchte M. Guedon E. Haimet F. Huber W. van Hylckama-Vlieg J. Jamet A. Juste C. Kaci G. Knol J. Lakhdari O. Layec S. Le Roux K. Maguin E. Mérieux A. Melo Minardi R. M'rini C. Muller J. Oozeer R. Parkhill J. Renault P. Rescigno M. Sanchez N. Sunagawa S. Torrejon A. Turner K. Vandemeulebrouck G. Varela E. Winogradsky Y. Zeller G. Enterotypes of the human gut microbiome Nature 2011 473 174 180 10.1038/nature09944 2-s2.0-79955076622 21508958 \n12 Jost T. Lacroix C. Braegger C. Chassard C. Stability of the maternal gut microbiota during late pregnancy and early lactation Current Microbiology 2014 68 4 419 427 10.1007/s00284-013-0491-6 2-s2.0-84893925578 24258611 \n13 Hamilton M. J. Weingarden A. R. Unno T. Khoruts A. Sadowsky M. J. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria Gut Microbes 2013 4 2 125 135 10.4161/gmic.23571 2-s2.0-84874737205 23333862 \n14 Gorkiewicz G. Thallinger G. G. Trajanoski S. Lackner S. Stocker G. Hinterleitner T. Gülly C. Högenauer C. Alterations in the colonic microbiota in response to osmotic diarrhea PLoS ONE 2013 8 2 e55817 10.1371/journal.pone.0055817 2-s2.0-84873629791 \n15 Joossens M. Huys G. Cnockaert M. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives Gut 2011 60 5 631 637 10.1136/gut.2010.223263 2-s2.0-79953748870 21209126 \n16 Siener R. Bangen U. Sidhu H. Hönow R. von Unruh G. Hesse A. The role of Oxalobacter formigenes colonization in calcium oxalate stone disease Kidney International 2013 83 6 1144 1149 10.1038/ki.2013.104 2-s2.0-84882268800 23536130 \n17 Petrof E. O. Gloor G. B. Vanner S. J. Weese S. J. Carter D. Daigneault M. C. Brown E. M. Schroeter K. Allen-Vercoe E. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: “RePOOPulating” the gut Microbiome 2013 1, article 3 10.1186/2049-2618-1-3\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2014()", "journal": "Case reports in medicine", "keywords": null, "medline_ta": "Case Rep Med", "mesh_terms": null, "nlm_unique_id": "101512910", "other_id": null, "pages": "913867", "pmc": null, "pmid": "25548572", "pubdate": "2014", "publication_types": "D016428:Journal Article", "references": "20849891;21508958;22155369;24467987;24258611;23385241;23323867;23286720;24018052;22907164;21209126;23333862;23842501;23536130;23084918;22972296;23409050", "title": "Fecal transplantation treatment of antibiotic-induced, noninfectious colitis and long-term microbiota follow-up.", "title_normalized": "fecal transplantation treatment of antibiotic induced noninfectious colitis and long term microbiota follow up" }	[ { "companynumb": "FI-MYLANLABS-2015M1000556", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nTo present the case of a patient who developed bleb-related endophthalmitis after an intravitreal injection using the InVitria injection guide, alongside a review of the literature on bleb-related endophthalmitis.\n\n\nMETHODS\nOur case is presented in context of the current literature on bleb-related endophthalmitis.\n\n\nRESULTS\nBleb-related endophthalmitis occurs in up to 2% of eyes within 5 years of filtering glaucoma surgery. Risk factors include bleb leakage, use of anti-fibrinolytic agents, blepharitis, hypotony, and nasolacrimal duct obstruction. Our patient presented with a bleb leak and bleb-related endophthalmitis 2 weeks after an intravitreal injection using the InVitria injection guide.\n\n\nCONCLUSIONS\nInjection guides can cause bleb trauma and resulting bleb leakage. They should be avoided in patients with filtering glaucoma surgery.", "affiliations": "Ophthalmology Department, The Royal Free Hospital, London, United Kingdom; and.;Ophthalmology Department, The Royal Free Hospital, London, United Kingdom; and.;Ophthalmology Department, The Royal Free Hospital, London, United Kingdom; and.;Ophthalmology Department, The Royal Free Hospital, London, United Kingdom; and.", "authors": "Baneke\|Alex J\|AJ\|;Vakros\|Georgios\|G\|;Sharma\|Vik\|V\|;Wong\|Sui Chien\|SC\|", "chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor", "country": "United States", "delete": false, "doi": "10.1097/ICB.0000000000000631", "fulltext": null, "fulltext_license": null, "issn_linking": "1935-1089", "issue": "14(1)", "journal": "Retinal cases & brief reports", "keywords": null, "medline_ta": "Retin Cases Brief Rep", "mesh_terms": "D000369:Aged, 80 and over; D020256:Choroidal Neovascularization; D009877:Endophthalmitis; D015818:Eye Infections, Bacterial; D005260:Female; D018463:Filtering Surgery; D005901:Glaucoma; D006801:Humans; D058449:Intravitreal Injections; D009301:Nasolacrimal Duct; D011183:Postoperative Complications; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins", "nlm_unique_id": "101298744", "other_id": null, "pages": "33-34", "pmc": null, "pmid": "28858192", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "BLEB-RELATED ENDOPHTHALMITIS AFTER USE OF THE INVITRIA INJECTION GUIDE.", "title_normalized": "bleb related endophthalmitis after use of the invitria injection guide" }	[ { "companynumb": "GB-REGENERON PHARMACEUTICALS, INC.-2020-25921", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AFLIBERCEPT" }, "drugaddi...
{ "abstract": "Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.", "affiliations": "Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;NextCure Inc, Beltsville, Maryland, USA.;Department of Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.;Department of Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA nllosa1@jhmi.edu.", "authors": "Cheung\|Laurene S\|LS\|;Chen\|Lingling\|L\|;Oke\|Teniola F\|TF\|;Schaffer\|Thomas B\|TB\|;Boudadi\|Karim\|K\|;Ngo\|Jillian T\|JT\|;Gross\|John McMahon\|JM\|;Kemberling\|Holly\|H\|;Diaz\|Luis A\|LA\|;Lipson\|Evan\|E\|0000-0003-2976-0911;Sidhom\|John-WIlliam\|JW\|0000-0002-5575-0285;Taube\|Janis\|J\|;Anders\|Robert\|R\|;Pardoll\|Drew M\|DM\|;Le\|Dung T\|DT\|;Meyer\|Christian F\|CF\|;Llosa\|Nicolas\|N\|0000-0001-7047-0858", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/jitc-2021-002345", "fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34103354\njitc-2021-002345\n10.1136/jitc-2021-002345\nCase Report\n1506\n2518\n1619\nAnti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures\nCheung Laurene S 12\nChen Lingling 12\nOke Teniola F 12\nSchaffer Thomas B 3\nBoudadi Karim 2\nNgo Jillian T 1\nGross John McMahon 4\nKemberling Holly 2\nDiaz Luis A 5\nhttp://orcid.org/0000-0003-2976-0911\nLipson Evan 12\nhttp://orcid.org/0000-0002-5575-0285\nSidhom John-WIlliam 12\nTaube Janis 124\nAnders Robert 124\nPardoll Drew M 12\nLe Dung T 12\nMeyer Christian F 2\nhttp://orcid.org/0000-0001-7047-0858\nLlosa Nicolas 12\n1 Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA\n2 Department of Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA\n3 NextCure Inc, Beltsville, Maryland, USA\n4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA\n5 Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA\nCorrespondence to Dr Nicolas Llosa; nllosa1@jhmi.edu\n2021\n8 6 2021\n9 6 e00234518 4 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.\n\nUndifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.\n\nImmunotherapy\nsarcoma\ntumor biomarkers\nhttp://dx.doi.org/10.13039/100000043 American Association for Cancer Research Bloomberg-Kimmel Institute for Immunotherapy Johns Hopkins Hospital http://dx.doi.org/10.13039/100015283 Bloomberg Philanthropies MERCK Pharmaceuticals http://dx.doi.org/10.13039/100009730 Stand Up To Cancer Giant Food http://dx.doi.org/10.13039/100002491 Bristol-Myers Squibb special-featureunlocked\n==== Body\nBackground\n\nSoft-tissue sarcomas (STS) comprise a heterogeneous group of cancers that arise from mesenchymal tissue and represent ~1% of adult malignancies. Undifferentiated pleomorphic sarcomas (UPS) are typically deep-seated lesions that enlarge rapidly and painlessly, frequently located in the limbs followed by the trunk, while superficial lesions are rare. The pathogenesis is unknown, although some tumors occur in a previously irradiated field.1 Surgery plus radiotherapy remain the cornerstone of treatment of non-metastatic tumors. Relapse is common, with a 5-year overall survival rate of ~64%, and prognosis for patients with metastatic disease is poor, with a median survival of ~12 months.2\n\nTreatment options for advanced UPS remain limited. Although PD-1 blockade has triggered tumor regressions in some patients, clinical trial results have been mixed. While Tawbi and colleagues reported a 40% (4/10) objective response rate to anti-PD-1, other trials have reported fewer responders or none at all, suggesting that a subset of UPS patients may respond to immune checkpoint blockade.3–5 Emerging evidence reveals an association between increased tumor-infiltrating immune cells and tumor regressions.6 Recent clinical trials have shown efficacy of PD-1 blockade in high tumor mutational burden (TMB) tumors, across many solid tumor types, leading to approval of the drug for treatment of high TMB tumors, regardless of tumor type.7 Additionally, >1% intratumoral PD-L1 expression in other tumor types is often associated with antitumor response to anti-PD-1, however, UPS generally have low TMB and the majority do not express high PD-L1.8–11 Further studies to determine how UPS patients who respond to immunotherapy differ from non-responders are necessary for prospectively identifying patients who may benefit from checkpoint blockade and to understand what aspects of the tumor and tumor immune microenvironment can promote response in UPS patients. Here, we report two patients with relapsed and metastatic UPS of the scalp who were found to have unusually high TMB, but were microsatellite stable. Both patients were treated with checkpoint blockade and experienced clinical improvement. We analyzed the mutational signatures and tumor microenvironment of these and other UPS tumors to determine if UPS of the head and neck have distinct characteristics relevant to response to checkpoint blockade.\n\nMethods\n\nPatients and tumor samples\n\nBoth patients’ primary UPS tumors were not associated with previous radiation therapy. Tumor tissues and blood were collected at Johns Hopkins Hospital (Baltimore, Maryland, USA) from patients with UPS. All samples were obtained in accordance with the Health Insurance Portability and Accountability Act. Immunohistochemical analysis was performed on samples from the two patients detailed in the case report and 36 unique patients with UPS obtained from the Johns Hopkins Hospital surgical pathology archives from 2005 to 2017. All radiation-induced UPS tumors were excluded. Further details regarding patient treatment and demographics are provided in online supplemental table 1. Whole-exome sequencing (WES) data of head and neck UPS samples was obtained from the two case report patients, three patients from the Johns Hopkins Hospital surgical pathology archives, one patient from the Cancer Genome Atlas (TCGA) and one patient from MSK-IMPACT clinical sequencing cohort(online supplemental table 2).12 13 Genomic data for 48 non-head and neck UPS samples were from TCGA.\n\n10.1136/jitc-2021-002345.supp1 Supplementary data\n\nImmunohistochemistry\n\nFormalin-fixed paraffin-embedded tissue blocks from tumor specimens were annotated by a pathologist, cut into 5 um sections and mounted onto plus-charge glass slides. For each specimen, staining was performed according to standard protocol.\n\nResults\n\nCase presentation number 1\n\nA male in his late 60s with Fitzpatrick skin type II and a history of basal cell and cutaneous squamous cell carcinoma presented with a scalp lesion confirmed to be high grade UPS and was initially treated with surgical wide excision of the lesion, followed by radiation therapy. Over the next 18 months, the patient presented with multiple recurrences of scalp lesions, which were resected. He received gemcitabine and docetaxel, which was discontinued due to toxicities, and additional doses of radiation to his scalp but continued to develop new scalp lesions. Targeted DNA sequencing of his lesions revealed a microsatellite stable high TMB tumor. From the time of diagnosis, the patient underwent six total surgical resections and two cycles of radiation, but due to progression of his disease and high TMB of his tumor, he was enrolled on a phase 2 clinical trial with anti-PD-1 therapy for high TMB neoplasms (ClinicalTrials.gov number, NCT01876511). The largest scalp lesion measured 20 mm in diameter with several additional satellite lesions. After 4 months of anti-PD-1 treatment, the patient had a complete response (defined by Response Evaluation Criteria in Solid Tumors, RECIST V.1.1) of his dominant scalp lesion and satellite scalp lesions.14 One month later, a new scalp lesion emerged. However, given that the dominant scalp lesion was still undetectable and there was no evidence of metastatic disease, the new lesion was resected and the patient continued on anti-PD-1 after surgical recovery. The patient has now been treated with anti-PD-1 for 22 months and continues to have no evidence of local or distant disease for the past 16 months (figure 1A, B).\n\nFigure 1 Clinical timeline and response to checkpoint blockade in two patients with ups of the scalp. Day 0 represents initiation of immunotherapy treatment. Events in red occurred while patients were treated with immunotherapy. (A) Clinical timeline of treatment for patient 1. (B) Images of patient 1 scalp lesions from before (left) and after achieving a CR of the target lesion 4 months after initiation of immunotherapy (right). (C) Clinical timeline of treatment for patient 2. (D) CT imaging of chest and MRI of brain from patient 2 before (top) and during (bottom) immunotherapy treatment exhibiting resolution of lung metastatic lesion and stabilization of brain metastatic mass. UPS, undifferentiated pleomorphic sarcoma.; CR, complete response.\n\nCase presentation number 2\n\nA man in his late 70s with Fitzpatrick skin type II and a history of cutaneous squamous cell carcinoma presented with a high grade UPS of his occipital scalp. Targeted DNA sequencing of the tumor found it to be microsatellite stable with a high TMB. He underwent wide excision but experienced disease relapse 7 months later requiring a radical resection, followed by adjuvant radiation therapy. Despite undergoing several surgical resections, the patient developed brain, osseous, and lung metastases. The patient received radiation to the brain lesion and to a new scalp lesion. One month later on follow-up CT, several lung nodules were noted to be increasing in size. The lung mass measured 13 mm and the brain lesion was 7 mm in diameter pretreatment. Immunotherapy with combination anti-PD-1 and anti-CTLA-4 was started. After 1 month of anti-PD-1, the patient had regression of lung nodules with stabilization of the brain lesion. At month 2 of anti-PD-1 and anti-CTLA-4, the patient developed hypophysitis requiring administration of replacement hydrocortisone therapy and immunotherapy was halted. Imaging demonstrated new osseous metastases, but pulmonary nodules continued to shrink and the brain lesion remained stable and anti-PD-1 monotherapy was restarted 3 months later. The patient has had complete resolution of pulmonary nodules, with stable brain and bone lesions for the last 18 months after 23 months of anti-PD-1 therapy (figure 1C, D).\n\nWES and mutational signature\n\nAs targeted sequencing uses a panel of commonly mutated genes and can only provide an estimated TMB, WES was performed to determine the exact TMB for each tumor. High TMB is generally defined as ≥10 mutations/MB.15 TMB was 33 and 43 mutations/MB for the patients, respectively, while the average TMB of UPS tumors in the TCGA is 2.7 mutations/MB, indicating these scalp tumors were likely subjected to a different mutational process. To assess mutational signatures of these tumors, we compared the frequencies of single nucleotide variants to reference signatures in the COSMIC database. We found that for both tumors, COSMIC signature 7 was the dominant signature, with a prevalence of C>T mutations in a dipyrimidine context, which is characteristic of UV-induced DNA damage and repair and is frequently found in melanoma (online supplemental figures 1A, 2A).16 This finding is interesting as a previous study characterizing genomics of STS identified only one out of 44 UPS tumors with high TMB due to a mutation in DNA mismatch repair machinery, rather than being due to UV exposure.8\n\nTo determine whether UV damage is common in head and neck UPS tumors, we analyzed mutational signatures of UPS tumors in publically available databases as well as tumors from three patients who underwent surgical resection at Johns Hopkins Hospital. Of three head and neck UPS tumors resected from Johns Hopkins patients that we sequenced, one patient also had high TMB at 68 mutations/MB with a UV mutational signature, while the other two patients had less than 10 mutations/MB. Additionally, we found two patients with primary UPS tumors arising from the head and neck in the TCGA and MSK-IMPACT databases and both tumors had high TMB (53 and 62 mutations/MB) with a UV mutational signature (online supplemental figures 2, 3, online supplemental table 2).12 13 In the TCGA dataset, one non head and neck UPS tumor had high TMB, located at the thigh/knee with a UV signature (data not shown), however, 26 other UPS tumors located on the leg were low TMB. In summary, of seven head and neck UPS tumors for which sequencing data was available, five tumors had high TMB due to UV exposure.\n\nT cell infiltration and PD-L1 expression in the tumor microenvironment\n\nCD8 +T cell infiltration and PD-L1 expression have been found to correlate with anti-PD-1 response, independently of TMB.17 While UPS tumors generally have a paucity of T cells and low expression of PD-L1, tumors from patient 1 and 2 had high levels of infiltrating CD8 +T cells and expression of PD-L1 (online supplemental figure 1B).11 We analyzed 36 additional UPS samples from the Johns Hopkins Hospital archive, comparing the levels of CD8 +T cells and PD-L1 expression in head and neck UPS tumors to those arising from other sites in the body (online supplemental table 1). Head and neck UPS tumors had increased CD8 +T cell infiltration and expression of PD-L1 versus UPS tumors from other sites of the body (figure 2A, B). High TMB did not predict the level of CD8+ T cells or PD-L1 in the tumor.\n\nFigure 2 CD8+ T cell infiltration and PD-L1 expression in UPS tumors of head and neck compared with other sites. (A) Representative images and quantitation of IHC staining of UPS tumors for CD8. The number of CD8+ T cells mm2 of tumor tissue is shown. (B) Representative images and quantifation of IHC staining of ups tumors for PD-L1. Per cent PD-L1 expression of tumor tissue is shown. Ι bars show the SE. P values were calculated using a two-tailed t-test. UPS, undifferentiated pleomorphic sarcoma; IHC, immunohistochemistry.\n\nDiscussion\n\nWe report two patients with recurrent scalp UPS tumors with high TMB and UV mutational signatures who experienced clinical benefit with anti-PD-1 therapy. Together with analysis of additional head and neck UPS samples, our findings suggest that UPS tumors arising in this location may represent a distinct genetic subgroup of UPS with predominantly UV-induced mutations that confer susceptibility to checkpoint blockade. Both patients had developed frequent locally recurrent tumors, and in one case, metastatic lesions before starting immunotherapy. Additionally, patients were unable to continue with standard chemotherapy due to treatment failure or intolerable toxicities. On treatment with anti-PD-1, both patients derived clinical benefit from checkpoint blockade. Further analysis of head and neck UPS tumors revealed additional cases with a UV mutational signature and a T-cell-inflamed immune signature as compared with UPS tumors arising from other sites of the body.\n\nUPS tumors have been previously reported to respond to immunotherapy, however, the majority are not sensitive to anti-PD-1 treatment.3–5 In these trials, the location of the primary tumors (ie, head and neck vs elsewhere) were not reported. UPS generally has low TMB, and therefore, generates fewer tumor neoantigens, decreasing the likelihood of T cell recognition of the tumor.18 High TMB can occur due to environmental factors such as exposure to carcinogens or mutations in DNA repair pathways that allow for the accrual of errors during DNA replication.19 20 UV rays only penetrate the epidermis and dermis, causing DNA damage in tumors such as melanoma and squamous cell carcinoma. While most UPS tumors originate in the deep tissues, a subset of tumors arise in the dermis, making these tumors more likely to have UV-induced high TMB.21 Our data suggest that UV damage can cause high TMB in UPS tumors of the head and neck, due to increased sun exposure of these sites, making these tumors more likely to be sensitive to checkpoint blockade than tumors arising from other sites. Of seven head and neck UPS tumors for which we obtained WES data, five tumors had high TMB with a UV signature, suggesting this may be a frequent phenomenon. Additionally, 1 of 26 leg UPS tumors also had high TMB, indicating that although non-head and neck tumors are less frequently high TMB, some UPS tumors arising in other sun-exposed sites may also be amenable to checkpoint blockade. Steele et al have also identified a subset of high TMB UPS tumors due to DNA repair pathway defects associated with IFN gamma response pathway enrichment, suggestive of increased immune infiltration, which mirrors our observations in UPS tumors with UV mutational signatures.20\n\nPreviously, studies of UPS immune infiltrates have shown low levels of CD8+ T cells and PD-L1 expression, despite being more inflamed when compared with other STS.10 22 We found that head and neck UPS tumors had increased CD8+ T cell infiltration and intratumoral PD-L1 expression as compared with UPS tumors located in other sites. This T-cell-inflamed phenotype could indicate a pre-existing anti-tumor immune response that has subsequently become exhausted, making these tumors more likely to respond to anti-PD-1 therapy.23\n\nIn conclusion, we describe two patients with high TMB scalp UPS tumors who experienced an anti-tumor immune response to checkpoint blockade. Head and neck UPS showed a higher frequency of UV-induced high TMB and a T-cell inflamed phenotype compared with UPS arising from other sites. Taken together, these findings support the screening of head and neck UPS tumors for high TMB and consideration for treatment with PD-1 blockade.\n\nEthics statements\n\nPatient consent for publication\n\nObtained.\n\nEthics approval\n\nThis study was conducted in accordance with the ethical principles stated in the Belmont Report and the US Common Rule. It was approved by the Johns Hopkins Institutional Review Board and all samples were obtained in accordance with the Health Insurance and Accountability Act. This study was conducted under an Institutional Review Board approved protocol with a waiver of consent for archived tissues and patients gave written informed consent for prospective tumor collection.\n\nContributors: LSC and NL conceptualized and designed the study. LSC, LC, and TBS analyzed data. LSC, LC, TFO, JT and HK collected clinical data. LSC, LC and NL interpreted data. LAD, EL, J-WS, JT, RA, DMP, DTL and CFM provided insight and assisted in interpretation of data. DTL, KB and CFM treated the cases. LSC and NL wrote the manuscript. NL supervised the study. All authors reviewed and edited manuscript.\n\nFunding: This work was supported by Johns Hopkins Hospital, Bloomberg-Kimmel Institute for Immunotherapy; Bloomberg Philanthropies, BMS II-ON, MERCK Pharmaceuticals, Giant Food, and a Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.\n\nCompeting interests: LC is employed by Janssen Research and Development at the time of this submission. LAD is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics. He is a paid consultant to PGDx, 4Paws (PetDx), Innovatus CP and Neophore. He is an uncompensated consultant for Merck but has received research support for clinical trials from Merck. LAD is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and LAD. He holds equity in PGDx, Jounce Therapeutics, Thrive Earlier Detection and Neophore. His spouse holds equity in Amgen. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. EJL has received institutional research grant funding from Bristol-Myers Squibb, Merck, and Regeneron. EJL is a consultant for Array BioPharma, Bristol-Myers Squibb, EMD Serono, MacroGenics, Novartis, Merck, Regeneron, Sanofi Genzyme. JMT serves on advisory boards for BMS, Merck, Akoya Biosciences, Astra Zeneca and has received research funding from BMS, Akoya Biosciences. RAA serves on advisory boards for Merck, Bristol Myers Squibb and FLX bio and has received research funding from Merck, Bristol Myers Squibb, and FLX bio. DMP serves on advisory boards for Merck, Bristol Myers Squibb and Compugen and has received research funding from Bristol Myers Squibb and Compugen. DTL serves on advisory boards for Merck and Bristol Myers Squibb and has received research funding from Merck, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, and Nouscom. She has received speaking honoraria from Merck and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. The terms of these arrangements are being managed by Johns Hopkins. CFM was a paid consultant for Bayer and has received speakers bureau honoraria from Novartis. NJL has received funding support from Bristol Myers Squibb.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 Widemann BC , Italiano A . Biology and management of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and malignant peripheral nerve sheath tumors: state of the art and perspectives. J Clin Oncol 2018;36 :160–7. 10.1200/JCO.2017.75.3467 29220302\n2 Italiano A , Mathoulin-Pelissier S , Cesne AL , et al . Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer 2011;117 :1049–54. 10.1002/cncr.25538 20945333\n3 Tawbi HA , Burgess M , Bolejack V , et al . Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. 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Ann Oncol 2019;30 :v477–8. 10.1093/annonc/mdz253.018\n8 Abeshouse A , Adebamowo C , Adebamowo SN . Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell 2017;171 :950–65. 10.1016/j.cell.2017.10.014 29100075\n9 Borghaei H , Paz-Ares L , Horn L , et al . Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373 :1627–39. 10.1056/NEJMoa1507643 26412456\n10 Park HK , Kim M , Sung M , et al . Status of programmed death-ligand 1 expression in sarcomas. J Transl Med 2018;16 :1–11. 10.1186/s12967-018-1658-5 29316942\n11 Boxberg M , Steiger K , Lenze U , et al . Pd-L1 and PD-1 and characterization of tumor-infiltrating lymphocytes in high grade sarcomas of soft tissue – prognostic implications and rationale for immunotherapy. Oncoimmunology 2018;7 :e1389366–11. 10.1080/2162402X.2017.1389366 29399389\n12 Gao J , Aksoy BA , Dogrusoz U , et al . Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6 :pl1–20. 10.1126/scisignal.2004088 23550210\n13 Zehir A , Benayed R , Shah RH , et al . Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 2017;23 :703–13. 10.1038/nm.4333 28481359\n14 Eisenhauer EA , Therasse P , Bogaerts J , et al . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45 :228–47. 10.1016/j.ejca.2008.10.026 19097774\n15 Hellmann MD , Ciuleanu T-E , Pluzanski A , et al . Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018;378 :2093–104. 10.1056/NEJMoa1801946 29658845\n16 Tate JG , Bamford S , Jubb HC , et al . Cosmic: the Catalogue of somatic mutations in cancer. Nucleic Acids Res 2019;47 :D941–7. 10.1093/nar/gky1015 30371878\n17 Yarchoan M , Albacker LA , Hopkins AC , et al . Pd-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight 2019;4 . 10.1172/jci.insight.126908. [Epub ahead of print: 21 Mar 2019].\n18 Rizvi NA , Hellmann MD , Snyder A , et al . Cancer immunology. mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348 :124–8. 10.1126/science.aaa1348 25765070\n19 Chalmers ZR , Connelly CF , Fabrizio D , et al . Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017;9 :1–14. 10.1186/s13073-017-0424-2 28081715\n20 Steele CD , Tarabichi M , Oukrif D , et al . Undifferentiated sarcomas develop through distinct evolutionary pathways. Cancer Cell 2019;35 :441–56. 10.1016/j.ccell.2019.02.002 30889380\n21 D'Orazio J , Jarrett S , Amaro-Ortiz A , et al . Uv radiation and the skin. Int J Mol Sci 2013;14 :12222–48. 10.3390/ijms140612222 23749111\n22 Keung EZ , Tsai J-W , Ali AM , et al . Analysis of the immune infiltrate in undifferentiated pleomorphic sarcoma of the extremity and trunk in response to radiotherapy: rationale for combination neoadjuvant immune checkpoint inhibition and radiotherapy. Oncoimmunology 2018;7 :e1385689. 10.1080/2162402X.2017.1385689 29308306\n23 Trujillo JA , Sweis RF , Bao R , et al . T Cell-Inflamed versus non-T Cell-Inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection. Cancer Immunol Res 2018;6 :990–1000. 10.1158/2326-6066.CIR-18-0277 30181337\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2051-1426", "issue": "9(6)", "journal": "Journal for immunotherapy of cancer", "keywords": "Immunotherapy; sarcoma; tumor biomarkers", "medline_ta": "J Immunother Cancer", "mesh_terms": null, "nlm_unique_id": "101620585", "other_id": null, "pages": null, "pmc": null, "pmid": "34103354", "pubdate": "2021-06", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "29220302;19097774;30371878;25765070;29370992;31942077;30889380;28420421;29100075;29399389;29308306;26412456;20945333;29658845;23550210;28988646;28662235;23749111;30400799;28481359;30181337;30895946", "title": "Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures.", "title_normalized": "anti pd 1 elicits regression of undifferentiated pleomorphic sarcomas with uv mutation signatures" }	[ { "companynumb": "US-DRREDDYS-SPO/USA/21/0139853", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, ...
{ "abstract": "Purpose.To investigate image intensity histograms as a potential source of useful imaging biomarkers in both a clinical example of detecting immune-related colitis (irColitis) in18F-FDG PET/CT images of immunotherapy patients and an idealized case of classifying digital reference objects (DRO).Methods.Retrospective analysis of bowel18F-FDG uptake in N = 40 patients receiving immune checkpoint inhibitors was conducted. A CNN trained to segment the bowel was used to generate the histogram of bowel18F-FDG uptake, and percentiles of the histogram were considered as potential metrics for detecting inflammation associated with irColitis. A model of the colon was also considered using cylindrical DRO. Classification of DRO with different intensity distributions was undertaken under varying geometry and noise settings.Results.The most predictive biomarker of irColitis was the 95th percentile of the bowel SUV histogram (SUV95%). Patients later diagnosed with irColitis had a significantly higher increase in SUV95%from baseline to first on-treatment PET than patients who did not experience irColitis (p = 0.02). An increase in SUV95%> + 40% separated pre-irColitis change from normal variability with a sensitivity of 75% and specificity of 88%. Furthermore, histogram percentiles were ideal metrics for classifying 'hot center' and 'cold center' DRO, and were robust to varying DRO geometry and noise, and to the presence of spoiler volumes unrelated to the detection task.Conclusions.The 95th percentile of the bowel SUV histogram was the optimal metric for detecting irColitis on18F-FDG PET/CT. Image intensity histograms are a promising source of imaging biomarkers for clinical tasks.", "affiliations": "Department of Medical Physics, University of Wisconsin-Madison, Madison WI, United States of America.;Department of Medical Physics, University of Wisconsin-Madison, Madison WI, United States of America.;Department of Medical Physics, Nuclear Diagnostic Center Foundation, Buenos Aires, Argentina.;University of Wisconsin Carbone Cancer Center, Madison WI, United States of America.;University of Wisconsin Carbone Cancer Center, Madison WI, United States of America.;Department of Medical Physics, University of Wisconsin-Madison, Madison WI, United States of America.", "authors": "Huff\|Daniel T\|DT\|0000-0001-9792-4119;Ferjancic\|Peter\|P\|0000-0001-9604-9439;Namías\|Mauro\|M\|0000-0001-5808-4102;Emamekhoo\|Hamid\|H\|0000-0002-8506-8703;Perlman\|Scott B\|SB\|0000-0001-9744-7105;Jeraj\|Robert\|R\|0000-0002-2192-2931", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1088/2057-1976/ac27c3", "fulltext": null, "fulltext_license": null, "issn_linking": "2057-1976", "issue": "7(6)", "journal": "Biomedical physics & engineering express", "keywords": "18F-FDG PET/CT; adverse event; immunotherapy; segmentation", "medline_ta": "Biomed Phys Eng Express", "mesh_terms": null, "nlm_unique_id": "101675002", "other_id": null, "pages": null, "pmc": null, "pmid": "34534974", "pubdate": "2021-09-30", "publication_types": "D016428:Journal Article", "references": null, "title": "Image intensity histograms as imaging biomarkers: application to immune-related colitis.", "title_normalized": "image intensity histograms as imaging biomarkers application to immune related colitis" }	[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2022-017547", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugaddi...
{ "abstract": "Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.", "affiliations": "Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany, johanna.hammersen@uk-erlangen.de.;Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.;Department of Pediatrics, Hospital St. Elisabeth, Neuburg an der Donau, Germany.;Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany.", "authors": "Hammersen\|Johanna\|J\|;Neuner\|Andrea\|A\|;Wild\|Florian\|F\|;Schneider\|Holm\|H\|", "chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins", "country": "Switzerland", "delete": false, "doi": "10.1159/000499906", "fulltext": null, "fulltext_license": null, "issn_linking": "1018-8665", "issue": "235(4)", "journal": "Dermatology (Basel, Switzerland)", "keywords": "Gentamicin; Premature termination codon; Read-through; Severe generalized junctional epidermolysis bullosa", "medline_ta": "Dermatology", "mesh_terms": "D000900:Anti-Bacterial Agents; D016109:Epidermolysis Bullosa, Junctional; D005260:Female; D005839:Gentamicins; D006801:Humans; D007223:Infant; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D012189:Retrospective Studies; D016896:Treatment Outcome", "nlm_unique_id": "9203244", "other_id": null, "pages": "315-322", "pmc": null, "pmid": "31132778", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": null, "title": "Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin.", "title_normalized": "attenuation of severe generalized junctional epidermolysis bullosa by systemic treatment with gentamicin" }	[ { "companynumb": "PHHY2019DE204449", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "GENTAMICIN" }, "drugadditional": null, "drug...
{ "abstract": "A 71-year-old man who had undergone an ileorectal anastomosis some years earlier, developed fulminant fatal Clostridium difficile pseudomembranous enteritis and proctitis after a prostatectomy. This case and three reports of C. difficile involvement of the small bowel in adults emphasize that the small intestine can be affected. No case like ours, of enteritis after colectomy from C. difficile, has hitherto been reported.", "affiliations": "Department of Medicine, University of California, San Francisco, 94143-0538, USA.", "authors": "Yee\|H F\|HF\|;Brown\|R S\|RS\|;Ostroff\|J W\|JW\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/00004836-199601000-00013", "fulltext": null, "fulltext_license": null, "issn_linking": "0192-0790", "issue": "22(1)", "journal": "Journal of clinical gastroenterology", "keywords": null, "medline_ta": "J Clin Gastroenterol", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D003082:Colectomy; D004761:Enterocolitis, Pseudomembranous; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D011183:Postoperative Complications; D011468:Prostatectomy; D011471:Prostatic Neoplasms", "nlm_unique_id": "7910017", "other_id": null, "pages": "45-7", "pmc": null, "pmid": "8776096", "pubdate": "1996-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Fatal Clostridium difficile enteritis after total abdominal colectomy.", "title_normalized": "fatal clostridium difficile enteritis after total abdominal colectomy" }	[ { "companynumb": "US-PFIZER INC-2019191562", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nTo characterize pregnancy outcomes following maternal and paternal exposure to abatacept, using clinical trial and post-marketing data available to the manufacturer.\n\n\nMETHODS\nAll confirmed cases of pregnancy with outcome data reported to the manufacturer up to September 1, 2014 were included. Sources included clinical trials, spontaneously reported (unsolicited) post-marketing cases, and the Organization of Teratology Information Specialists registry. Details recorded included number of live births, spontaneous abortions and terminations, pregnancy complications, and congenital anomalies.\n\n\nRESULTS\nA total of 161 pregnancies with known outcomes were identified between 1995 and September 2014: 151 were following maternal exposure to abatacept and 10 were following paternal exposure. Seven of 86 (8.1%) live births following maternal exposure had congenital anomalies (cleft lip/cleft palate, congenital aortic anomaly, meningocele, pyloric stenosis, skull malformation, ventricular septal defect/congenital arterial malformation, and Down׳s syndrome with premature rupture of membranes at 17 weeks that resulted in a live birth via cesarean section and subsequent infant death). In addition, 59 of the 151 (39.0%) cases with maternal exposure resulted in abortions (40 spontaneous and 19 elective). Of the 10 pregnancies with paternal exposure, there were nine live births and one elective abortion, with no congenital abnormalities identified and no fetal deaths.\n\n\nCONCLUSIONS\nBased on these data, there does not appear to be a pattern of congenital anomalies following maternal or paternal exposure to abatacept. No cases of vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, or limb abnormalities (VACTERL) were noted. Spontaneous abortion rates were within expected range. Abatacept should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.", "affiliations": "Bristol-Myers Squibb, Princeton, NJ.;Bristol-Myers Squibb, Princeton, NJ.;Bristol-Myers Squibb, Plainsboro, NJ.;Bristol-Myers Squibb, Princeton, NJ. Electronic address: Teresa.Simon@bms.com.", "authors": "Kumar\|Monica\|M\|;Ray\|Laura\|L\|;Vemuri\|Sudha\|S\|;Simon\|Teresa A\|TA\|", "chemical_list": "D000069594:Abatacept", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0049-0172", "issue": "45(3)", "journal": "Seminars in arthritis and rheumatism", "keywords": "Abatacept; Biological disease-modifying antirheumatic drugs; Congenital anomalies; Exposure; Pregnancy", "medline_ta": "Semin Arthritis Rheum", "mesh_terms": "D000069594:Abatacept; D000014:Abnormalities, Drug-Induced; D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies", "nlm_unique_id": "1306053", "other_id": null, "pages": "351-6", "pmc": null, "pmid": "26210783", "pubdate": "2015-12", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Pregnancy outcomes following exposure to abatacept during pregnancy.", "title_normalized": "pregnancy outcomes following exposure to abatacept during pregnancy" }	[ { "companynumb": "PHHY2015US093915", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "dr...
{ "abstract": "There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.", "affiliations": "Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.;Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.;Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.;Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.;Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.;Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.;Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.;Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.;Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.;Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany.;Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany.;iFIT Cluster of Excellence (EXC 2180), University of Tübingen, Tübingen, Germany.;Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.;Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.;Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.", "authors": "Forschner\|Andrea\|A\|;Sinnberg\|Tobias\|T\|;Mroz\|Gabi\|G\|;Schroeder\|Christopher\|C\|;Reinert\|Christian Philipp\|CP\|;Gatidis\|Sergios\|S\|;Bitzer\|Michael\|M\|;Eigentler\|Thomas\|T\|;Garbe\|Claus\|C\|;Niessner\|Heike\|H\|;Röcken\|Martin\|M\|;Roggia\|Cristiana\|C\|;Armeanu-Ebinger\|Sorin\|S\|;Riess\|Olaf\|O\|;Mattern\|Sven\|S\|;Nann\|Dominik\|D\|;Bonzheim\|Irina\|I\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fonc.2021.643156", "fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.643156\nOncology\nCase Report\nCase Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma\nForschner Andrea 1 \n\nSinnberg Tobias 1 2\n\nMroz Gabi 1\n\nSchroeder Christopher 3\nReinert Christian Philipp 4\n\nGatidis Sergios 4\nBitzer Michael 5\nEigentler Thomas 1\n\nGarbe Claus 1\nNiessner Heike 1\n\nRöcken Martin 1 2\nRoggia Cristiana 3\nArmeanu-Ebinger Sorin 3\nRiess Olaf 2 6\n\nMattern Sven 7\nNann Dominik 7\nBonzheim Irina 7\n\n1 Department of Dermatology, University Hospital Tübingen, Tübingen, Germany\n2 iFIT Cluster of Excellence (EXC 2180), University of Tübingen, Tübingen, Germany\n3 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany\n4 Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany\n5 Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany\n6 German Deutsche Forschungsgemeinschaft (DFG) Next Generation Sequencing (NGS) Competence Center, NGS Competence Center Tübingen (NCCT), Tübingen, Germany\n7 Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany\nEdited by: Nihal Ahmad, University of Wisconsin-Madison, United States\n\nReviewed by: Sanjay Premi, Moffitt Cancer Center & Research Institute, United States; Jasmine George, Medical College of Wisconsin, United States; Gagan Chhabra, University of Wisconsin-Madison, United States\n\nCorrespondence: Andrea Forschner, andrea.forschner@med.uni-tuebingen.de\nThis article was submitted to Skin Cancer, a section of the journal Frontiers in Oncology\n\n01 3 2021\n2021\n11 64315617 12 2020\n25 1 2021\nCopyright © 2021 Forschner, Sinnberg, Mroz, Schroeder, Reinert, Gatidis, Bitzer, Eigentler, Garbe, Niessner, Röcken, Roggia, Armeanu-Ebinger, Riess, Mattern, Nann and Bonzheim\n2021\nForschner, Sinnberg, Mroz, Schroeder, Reinert, Gatidis, Bitzer, Eigentler, Garbe, Niessner, Röcken, Roggia, Armeanu-Ebinger, Riess, Mattern, Nann and Bonzheim\nThis 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.\nThere are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.\n\nmelanoma\nCDKN2A\nNRAS\nribociclib\nbinimetinib\n==== Body\nIntroduction\n\nIn addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.\n\nMethods\n\nThe patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .\n\nCase Report\n\nA 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.\n\nAs the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.\n\nNext generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.\n\nFigure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.\n\nImmunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).\n\nAccording to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.\n\nImmediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.\n\nFigure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, p < 0.05, **p < 0.01).\n\nSupporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).\n\nThe slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).\n\nIn order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).\n\nApart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.\n\nLDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).\n\nFigure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.\n\nFigure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.\n\nHowever, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.\n\nThoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).\n\nAs 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.\n\nDiscussion\n\nThis case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).\n\nPET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).\n\nThe severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.\n\nThis case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.\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/ Supplementary Material .\n\nEthics Statement\n\nLocal Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nDrafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nAF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.\n\nThe 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\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Genomic Classification of Cutaneous Melanoma. Cancer Genome Atlas Network. Cell (2015) 161 :1681–96. 10.1016/j.cell.2015.05.044\n2 Dummer R Schadendorf D Ascierto PA Arance A Dutriaux C Di Giacomo AM . Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol (2017) 18 :435–45. 10.1016/S1470-2045(17)30180-8\n3 Kwong LN Costello JC Liu H Jiang S Helms TL Langsdorf AE . Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med (2012) 18 :1503–10. 10.1038/nm.2941\n4 Posch C Sanlorenzo M Ma J Kim ST Zekhtser M Ortiz-Urda S . MEK/CDK4,6 co-targeting is effective in a subset of NRAS, BRAF and ‘wild type’ melanomas. Oncotarget (2018) 9 :34990–5. 10.18632/oncotarget.26204\n5 Ruscetti M Morris JPT Mezzadra R Russell J Leibold J Romesser PB . Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer. Cell (2020) 181 :424–41.e21. 10.1016/j.cell.2020.03.008 32234521\n6 Schuler MH Ascierto PA Vos FYFLD Postow MA Herpen CML-V Carlino MS . Phase 1b/2 trial of ribociclib+binimetinib in metastatic NRAS-mutant melanoma: Safety, efficacy, and recommended phase 2 dose (RP2D). J Clin Oncol (2017) 35 :9519–. 10.1200/JCO.2017.35.15_suppl.9519\n7 Bendell JC Javle M Bekaii-Saab TS Finn RS Wainberg ZA Laheru DA . A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer (2017) 116 :575–83. 10.1038/bjc.2017.10\n8 Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V . A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas. Clin Cancer Res an Off J Am Assoc Cancer Res (2016) 22 :5696–705. 10.1158/1078-0432.CCR-16-1248\n9 Brenner E Schorg BF Ahmetlic F Wieder T Hilke FJ Simon N . Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours. Nat Commun (2020) 11 :1335. 10.1038/s41467-020-14987-6 32165639\n10 Seith F Forschner A Schmidt H Pfannenberg C Guckel B Nikolaou K . 18F-FDG-PET detects complete response to PD1-therapy in melanoma patients two weeks after therapy start. Eur J Nucl Med Mol Imaging (2018) 45 :95–101. 10.1007/s00259-017-3813-2 28831583\n11 Schmitt RJ Kreidler SM Glueck DH Amaria RN Gonzalez R Lewis K . Correlation between early 18F-FDG PET/CT response to BRAF and MEK inhibition and survival in patients with BRAF-mutant metastatic melanoma. Nucl Med Commun (2016) 37 :122–8. 10.1097/MNM.0000000000000406\n12 Forschner A Weißgraeber S Hadaschik D Schulze M Kopp M Kelkenberg S . Circulating Tumor DNA Correlates with Outcome in Metastatic Melanoma Treated by BRAF and MEK Inhibitors - Results of a Prospective Biomarker Study. Onco Targets Ther (2020) 13 :5017–32. 10.2147/OTT.S248237\n13 Eggersmann TK Degenhardt T Gluz O Wuerstlein R Harbeck N . CDK4/6 Inhibitors Expand the Therapeutic Options in Breast Cancer: Palbociclib, Ribociclib and Abemaciclib. BioDrugs Clin Immunother Biopharm Gene Ther (2019) 33 :125–35. 10.1007/s40259-019-00337-6\n14 Hortobagyi GN Stemmer SM Burris HA Yap YS Sonke GS Paluch-Shimon S . Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. New Engl J Med (2016) 375 :1738–48. 10.1056/NEJMoa1609709\n\n", "fulltext_license": "CC BY", "issn_linking": "2234-943X", "issue": "11()", "journal": "Frontiers in oncology", "keywords": "CDKN2A; NRAS; binimetinib; melanoma; ribociclib", "medline_ta": "Front Oncol", "mesh_terms": null, "nlm_unique_id": "101568867", "other_id": null, "pages": "643156", "pmc": null, "pmid": "33732653", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "32581559;27717303;26440571;26091043;30847853;22983396;27542767;32234521;28831583;28152546;32165639;30405888;28284557", "title": "Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.", "title_normalized": "case report combined cdk4 6 and mek inhibition in refractory cdkn2a and nras mutant melanoma" }	[ { "companynumb": "DE-PFM-2022-03898", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BINIMETINIB" }, "drugadditional": "3", "dru...
{ "abstract": "After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.", "affiliations": "Department of Hematology, Hopital Universitaire Henri Mondor, Assistance Publique-Hôpitaux de Paris (APHP) and Paris 12 University, Creteil, France.;Assistance Publique-Hopitaux de Paris, Hopital Cochin, Laboratory of Hematology and Paris Descartes University, Paris, France.;Biostatistics Team (ECSTRA), UMR1153, Inserm, Hopital Saint Louis, APHP and Paris 7 University, Paris, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Henri Becquerel, Rouen, France.;Department of Hematology, Hopital Saint Vincent de Paul, Lomme, France.;Department of Hematology, Centre Hospitalier Universitaire, Purpan, France.;Department of Hematology, Centre Hospitalier Universitaire, Strasbourg, France.;Department of Hematology, Centre Hospitalier Universitaire, Nancy, France.;Department of Hematology, Centre Hospitalier Universitaire, Nimes, France.;Department of Hematology, Centre Hospitalier Universitaire, Dijon, France.;Department of Hematology, Centre Hospitalier, Le Mans, France.;Department of Hematology, Centre Hospitalier Universitaire, Clermont Ferrand, France.;Department of Hematology, Centre Hospitalier Universitaire, Limoges, France.;Department of Hematology, Hopital Avicenne, APHP, and Paris 13 University Bobigny, Bobigny, France.;Department of Hematology, Centre Hospitalier, Avignon, France.;Department of Hematology, Centre Hospitalier, Perpignan, France.;Department of Hematology, Hopital Universitaire Amiens, Amiens, France.;Department of Hematology, Centre Hospitalier Annecy-Genevois, Prigny, France.;Department of Hematology, Centre Hospitalier, Boulogne sur Mer, France.;Department of Hematology, Centre Hospitalier, Corbeil, France.;Department of Hematology, Centre Hospitalier, Pontoise, France.;Department of Hematology, Centre Hospitalier Universitaire, Nice, France.;Department of Hematology, Centre Hospitalier Edouard Herriot, Lyon, France.;Department of Hematology, Hopital Kremlin Bicetre, APHP, Kremlin Bicetre, France.;Department of Hematology, Centre Hospitalier Universitaire, Bordeaux, France.;Department of Hematology, Centre Hospitalier Jean Bernard, Poitiers, France.;Department of Hematology, Centre Hospitalier, Versailles, France.;Department of Hematology, Centre Hospitalier Universitaire, Caen, France.;Department of Hematology, Hopital Pitie Salpetriere, APHP and Paris 6 University Paris, Paris, France.;Department of Hematology, Centre Hospitalier Universitaire, Rennes, France.;Department of Oncology, Centre Rene Huguenin, Saint Cloud, France.;Department of Hematology, Hopital Saint Antoine, APHP, and Paris 6 University Paris, Paris, France.;Department of Hematology, Centre Hospitalier Universitaire, Tours, France.;Departement de Recherche Clinique, Hopital Saint Louis, APHP, Paris, France.;Biostatistics Team (ECSTRA), UMR1153, Inserm, Hopital Saint Louis, APHP and Paris 7 University, Paris, France.;Assistance Publique-Hopitaux de Paris, Hopital Cochin, Laboratory of Hematology and Paris Descartes University, Paris, France.;Department of Biology, Centre Hospitalier Universitaire, Lille, France.;Department of Biology, Centre Hospitalier Universitaire, Lille, France.;Assistance Publique-Hopitaux de Paris, Hopital Cochin, Laboratory of Hematology and Paris Descartes University, Paris, France.;Department of Hematology, Service Hematologie Seniors, Hopital Saint Louis, APHP, and Paris 7 University Paris, Paris, France.;Department of Hematology, Hopital Cochin, APHP, and Paris 5 University Paris, Paris, France.", "authors": "Toma\|A\|A\|;Kosmider\|O\|O\|;Chevret\|S\|S\|;Delaunay\|J\|J\|;Stamatoullas\|A\|A\|;Rose\|C\|C\|;Beyne-Rauzy\|O\|O\|;Banos\|A\|A\|;Guerci-Bresler\|A\|A\|;Wickenhauser\|S\|S\|;Caillot\|D\|D\|;Laribi\|K\|K\|;De Renzis\|B\|B\|;Bordessoule\|D\|D\|;Gardin\|C\|C\|;Slama\|B\|B\|;Sanhes\|L\|L\|;Gruson\|B\|B\|;Cony-Makhoul\|P\|P\|;Chouffi\|B\|B\|;Salanoubat\|C\|C\|;Benramdane\|R\|R\|;Legros\|L\|L\|;Wattel\|E\|E\|;Tertian\|G\|G\|;Bouabdallah\|K\|K\|;Guilhot\|F\|F\|;Taksin\|A L\|AL\|;Cheze\|S\|S\|;Maloum\|K\|K\|;Nimuboma\|S\|S\|;Soussain\|C\|C\|;Isnard\|F\|F\|;Gyan\|E\|E\|;Petit\|R\|R\|;Lejeune\|J\|J\|;Sardnal\|V\|V\|;Renneville\|A\|A\|;Preudhomme\|C\|C\|;Fontenay\|M\|M\|;Fenaux\|P\|P\|;Dreyfus\|F\|F\|", "chemical_list": "D020533:Angiogenesis Inhibitors; D004921:Erythropoietin; D013792:Thalidomide; D000077269:Lenalidomide", "country": "England", "delete": false, "doi": "10.1038/leu.2015.296", "fulltext": null, "fulltext_license": null, "issn_linking": "0887-6924", "issue": "30(4)", "journal": "Leukemia", "keywords": null, "medline_ta": "Leukemia", "mesh_terms": "D000368:Aged; D000740:Anemia; D020533:Angiogenesis Inhibitors; D001803:Blood Transfusion; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D004359:Drug Therapy, Combination; D004921:Erythropoietin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D013792:Thalidomide", "nlm_unique_id": "8704895", "other_id": null, "pages": "897-905", "pmc": null, "pmid": "26500139", "pubdate": "2016-04", "publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "17021321;19605847;16609072;25469886;17893227;25185242;22211483;23980065;17940203;19357394;23434730;19564636;9639501;21887679;21527522;24656536;4027319;10384139;22936658;22740453;15054036;24608733;9058730;15703420;18413642;18265982;25480830;19470455;18559873;21041705", "title": "Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion.", "title_normalized": "lenalidomide with or without erythropoietin in transfusion dependent erythropoiesis stimulating agent refractory lower risk mds without 5q deletion" }	[ { "companynumb": "FR-CELGENE-FRA-2014124234", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, ...
{ "abstract": "The Toxicology Investigators Consortium (ToxIC) Case Registry was established by the American College of Medical Toxicology in 2010. The Registry contains data from participating sites with the agreement that all bedside medical toxicology consultations will be entered. Currently, 83% of accredited medical toxicology fellowship programs in the USA participate. The Registry continues to grow each year, and as of 31 December 2016, a new milestone was reached, with more than 50,000 cases reported since its inception. The objective of this seventh annual report is to summarize the Registry's 2016 data and activity with its additional 8529 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2016. Detailed data was collected from these cases and aggregated to provide information which includes the following: demographics (age, gender, race, ethnicity, HIV status), reason for medical toxicology evaluation (intentional pharmaceutical exposure, envenomation, withdrawal from a substance), agent and agent class, clinical signs and symptoms (vital sign abnormalities, organ system dysfunction), treatments and antidotes administered, fatality and life support withdrawal data. Fifty percent of cases involved females, and adults aged 19-65 were the most commonly reported. There were 86 patients (1.0%) with HIV-positive status known. Non-opioid analgesics were the most commonly reported agent class, with acetaminophen the most common agent reported. There were 126 fatalities reported in 2016 (1.5% of cases). Major trends in demographics and exposure characteristics remained similar overall with past years' reports. While treatment interventions were commonly required, fatalities were rare.", "affiliations": "Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA. Lynn.Farrugia@hhchealth.org.;Saint Francis Hospital and Medical Center, 114 Woodland St., Hartford, CT, 06105, USA.;New Jersey Medical School, Rutgers, the State University of New Jersey, 140 Bergen Street, Suite G1600, Newark, NJ, 07101-1709, USA.;American College of Medical Toxicology, 10645 N. Tatum Blvd., Suite 200-111, Phoenix, AZ, 85028, USA.;American College of Medical Toxicology, 10645 N. Tatum Blvd., Suite 200-111, Phoenix, AZ, 85028, USA.;University of Arizona College of Medicine, Banner University Medical Center, 1012 E. Willetta Ave, Phoenix, AZ, 85006, USA.;University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.;University of Rochester Medical Center, Strong Memorial Hospital, 601 Elmwood Avenue, Rochester, NY, 14642, USA.;American College of Medical Toxicology, 10645 N. Tatum Blvd., Suite 200-111, Phoenix, AZ, 85028, USA.;University of Colorado School of Medicine, 13001 E 17th Pl., Aurora, CO, 80045, USA.", "authors": "Farrugia\|Lynn A\|LA\|;Rhyee\|Sean H\|SH\|;Calello\|Diane P\|DP\|;Campleman\|Sharan L\|SL\|;Riederer\|Anne M\|AM\|;Malashock\|Hannah R\|HR\|;Pizon\|Anthony\|A\|;Wiegand\|Timothy\|T\|;Wax\|Paul M\|PM\|;Brent\|Jeffrey\|J\|;\|\|\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1007/s13181-017-0627-3", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-9039", "issue": "13(3)", "journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology", "keywords": "Epidemiology; Medical toxicology; Overdose; Poisonings", "medline_ta": "J Med Toxicol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D062787:Drug Overdose; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007557:Israel; D008297:Male; D008875:Middle Aged; D011041:Poisoning; D011379:Prognosis; D015397:Program Evaluation; D012017:Referral and Consultation; D012042:Registries; D013997:Time Factors; D014116:Toxicology; D014481:United States; D055815:Young Adult", "nlm_unique_id": "101284598", "other_id": null, "pages": "203-226", "pmc": null, "pmid": "28766237", "pubdate": "2017-09", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": "26275996;25384489;26013746;28188147;27339062;25280925;25119250;24838013;24580062;23736069;27517280;23076090;21956161;24178902;22068919;24199643;27480352;27413997;28033313;27470579;28256996;23055123;26602099;25592250", "title": "The Toxicology Investigators Consortium Case Registry-the 2016 Experience.", "title_normalized": "the toxicology investigators consortium case registry the 2016 experience" }	[ { "companynumb": "US-LANNETT COMPANY, INC.-US-2018LAN001134", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, ...
{ "abstract": "Paracetamol anaphylaxis is a very rare event, with only a few cases described in literature and even less reported in children. We report the case of a 15-year-old boy, referred to Immunoallergy Department due to four reproducible episodes of anaphylaxis after paracetamol administration, since the age of 8 years. The most severe episode occurred at 12 years, characterized by glottis edema with respiratory distress, hypotension, generalized urticaria and facial edema, immediately after intravenous administration of paracetamol during a post-operatory recovery. He had always and still tolerates ibuprofen; an oral challenge test with meloxicam was negative. Skin prick and intradermal tests with paracetamol were negative. Serum-specific IgE and CAST to paracetamol were also negative. This report provides an alert to health-care professionals regarding the potential severity of reactions occurring within the therapeutic range of this widely used drug.", "affiliations": "Immunoallergy Department, CUF-Descobertas Hospital, Lisbon, Portugal.", "authors": "Couto\|M\|M\|;Gaspar\|A\|A\|;Morais-Almeida\|M\|M\|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D007073:Immunoglobulin E", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1764-1489", "issue": "44(4)", "journal": "European annals of allergy and clinical immunology", "keywords": null, "medline_ta": "Eur Ann Allergy Clin Immunol", "mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D018712:Analgesics, Non-Narcotic; D000707:Anaphylaxis; D004342:Drug Hypersensitivity; D006801:Humans; D007073:Immunoglobulin E; D008297:Male", "nlm_unique_id": "101466614", "other_id": null, "pages": "163-6", "pmc": null, "pmid": "23092003", "pubdate": "2012-08", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Selective anaphylaxis to paracetamol in a child.", "title_normalized": "selective anaphylaxis to paracetamol in a child" }	[ { "companynumb": "PT-MYLANLABS-2020M1088536", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "1", ...
{ "abstract": "We report the case of an 18-year-old gentleman who presented to the emergency department following a large overdose of amitriptyline. He was comatose on admission but his neurology further deteriorated to global loss of brainstem reflexes. He made a full but slow neurological recovery. First signs of improving neurology were seen on day 3 of admission; he was extubated on day 6 and discharged home on day 9. There is limited recent literature to help guide prognostication in this group of patients.", "affiliations": "Department of Anaesthetics, Musgrove Park Hospital, Taunton, UK.;Department of Intensive Care, Derriford Hospital, Plymouth, UK.;Department of Intensive Care, Derriford Hospital, Plymouth, UK.", "authors": "Webster\|Deborah\|D\|;Datar\|Priya\|P\|;Waddy\|Sam\|S\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/1751143718765408", "fulltext": null, "fulltext_license": null, "issn_linking": "1751-1437", "issue": "19(4)", "journal": "Journal of the Intensive Care Society", "keywords": "Amitriptyline; brain stem; brainstem reflex; neurological recovery; overdose; poisoning; prognosis", "medline_ta": "J Intensive Care Soc", "mesh_terms": null, "nlm_unique_id": "101538668", "other_id": null, "pages": "365-367", "pmc": null, "pmid": "30505347", "pubdate": "2018-11", "publication_types": "D002363:Case Reports", "references": "7196546;2009762;7114819;7224376;21614669;3390781", "title": "Full neurological recovery following tricyclic overdose associated with absent brainstem reflexes.", "title_normalized": "full neurological recovery following tricyclic overdose associated with absent brainstem reflexes" }	[ { "companynumb": "GB-ACCORD-066142", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorization...
{ "abstract": "We report the clinical course and outcome of primary varicella infection in six children with systemic juvenile idiopathic arthritis (sJIA) receiving tocilizumab. None had disseminated or fatal varicella infection, but one patient developed macrophage activation syndrome (MAS) and another had an arthritis relapse. All patients had a significant elevation of serum IL-6 levels, and the two children who developed MAS or arthritis relapse showed high serum IL-18 levels, which could cause a sJIA flare-up.", "affiliations": "a Department of Pediatrics , Yokohama City University Graduate School of Medicine , Yokohama City , Japan.;a Department of Pediatrics , Yokohama City University Graduate School of Medicine , Yokohama City , Japan.;a Department of Pediatrics , Yokohama City University Graduate School of Medicine , Yokohama City , Japan.;a Department of Pediatrics , Yokohama City University Graduate School of Medicine , Yokohama City , Japan.;a Department of Pediatrics , Yokohama City University Graduate School of Medicine , Yokohama City , Japan.", "authors": "Nozawa\|Tomo\|T\|;Nishimura\|Kenichi\|K\|;Ohara\|Asami\|A\|;Hara\|Ryoki\|R\|;Ito\|Shuichi\|S\|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000589760:IL18 protein, human; D007166:Immunosuppressive Agents; D020382:Interleukin-18; C502936:tocilizumab", "country": "England", "delete": false, "doi": "10.1080/14397595.2016.1254314", "fulltext": null, "fulltext_license": null, "issn_linking": "1439-7595", "issue": "29(3)", "journal": "Modern rheumatology", "keywords": "IL-6; Macrophage activation syndrome; Systemic juvenile idiopathic arthritis; Tocilizumab; Varicella", "medline_ta": "Mod Rheumatol", "mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001171:Arthritis, Juvenile; D002644:Chickenpox; D002648:Child; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D020382:Interleukin-18; D055501:Macrophage Activation Syndrome; D008297:Male", "nlm_unique_id": "100959226", "other_id": null, "pages": "558-562", "pmc": null, "pmid": "27846755", "pubdate": "2019-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Primary varicella infection in children with systemic juvenile idiopathic arthritis under tocilizumab therapy.", "title_normalized": "primary varicella infection in children with systemic juvenile idiopathic arthritis under tocilizumab therapy" }	[ { "companynumb": "PHHY2019JP125403", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "dr...
{ "abstract": "Dabigatran, directly targeting thrombin, is widely used for the prevention of stroke in nonvalvular atrial fibrillation (NVAF). We reported a rare case of left atrial appendage thrombus formation in a persistent NVAF patient despite the 31 months uninterrupted treatment with dabigatran 110 mg twice daily. The patient is a carrier of ABCB1 variant alleles with 7 heterozygote single nucleotide polymorphisms (SNPs: rs4148738, rs2235046, rs1128503, rs10276036, rs1202169, rs1202168, rs1202167) as well as CES-1 variant alleles with 2 homozygote SNPs (rs2244613 and rs4122238) and 2 heterozygote SNPs (rs8192935 and rs4580160), which may contribute to the changes of dabigatran plasma concentration. In addition, Drug-drug interaction with atorvastatin may also play a role to decrease dabigatran plasma concentration. There are only four such cases till date, of which had thrombus in the left atrium, reported in the literature. We firstly reported the documented case in a Chinese patient carrying multiple alleles of ABCB1 and CES-1, who suffered from thrombus in the left atrial appendage despite long-term anticoagulation with dabigatran. More clinical data are required to elucidate the impact of CES-1 and ABCB1 polymorphism on dabigatran pharmacokinetics, especially for Asian.", "affiliations": "Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.;Department of Clinical Laboratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.;Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, China.;Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.;Department of Pharmacy, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China.", "authors": "Gu\|Zhi-Chun\|ZC\|;Ma\|Xiao-Wei\|XW\|;Zheng\|Xiao-Yuan\|XY\|;Shen\|Long\|L\|;Shi\|Fang-Hong\|FH\|;Li\|Hao\|H\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fphar.2018.00491", "fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2018.00491PharmacologyCase ReportLeft Atrial Appendage Thrombus Formation in a Patient on Dabigatran Therapy Associated With ABCB1 and CES-1 Genetic Defect Gu Zhi-Chun 1†Ma Xiao-Wei 2†Zheng Xiao-Yuan 3†Shen Long 4Shi Fang-Hong 1Li Hao 51Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China2Department of Clinical Laboratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China3Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, China4Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China5Department of Pharmacy, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaEdited by: Colin H. Macphee, GlaxoSmithKline (United States), United States\n\nReviewed by: Milica S. Prostran, University of Belgrade, Serbia; Claudio de Lucia, Temple University, United States\n\nCorrespondence: Hao Li lihao19880810@hotmail.comThis article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology\n\n†These authors have contributed equally to this work as first authors.\n\n15 5 2018 2018 9 49109 3 2018 25 4 2018 Copyright © 2018 Gu, Ma, Zheng, Shen, Shi and Li.2018Gu, Ma, Zheng, Shen, Shi and LiThis 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 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.Dabigatran, directly targeting thrombin, is widely used for the prevention of stroke in nonvalvular atrial fibrillation (NVAF). We reported a rare case of left atrial appendage thrombus formation in a persistent NVAF patient despite the 31 months uninterrupted treatment with dabigatran 110 mg twice daily. The patient is a carrier of ABCB1 variant alleles with 7 heterozygote single nucleotide polymorphisms (SNPs: rs4148738, rs2235046, rs1128503, rs10276036, rs1202169, rs1202168, rs1202167) as well as CES-1 variant alleles with 2 homozygote SNPs (rs2244613 and rs4122238) and 2 heterozygote SNPs (rs8192935 and rs4580160), which may contribute to the changes of dabigatran plasma concentration. In addition, Drug-drug interaction with atorvastatin may also play a role to decrease dabigatran plasma concentration. There are only four such cases till date, of which had thrombus in the left atrium, reported in the literature. We firstly reported the documented case in a Chinese patient carrying multiple alleles of ABCB1 and CES-1, who suffered from thrombus in the left atrial appendage despite long-term anticoagulation with dabigatran. More clinical data are required to elucidate the impact of CES-1 and ABCB1 polymorphism on dabigatran pharmacokinetics, especially for Asian.\n\ndabigatranleft atrial appendage thrombusgenetic polymorphismABCB1CES-1drug-drug interaction\n==== Body\nIntroduction\nWarfarin, one of the vitamin K-dependent antagonists (VKAs), is the most commonly used oral anticoagulant (Mega and Simon, 2015). Although warfarin has been used clinically for more than 60 years, several challenges including bleeding complications have been noted, which are one of the primacy causes of severe adverse drug events (Crowther et al., 2000; Wysowski et al., 2007). The inherent limitations of warfarin, comprising narrow therapeutic window, intra-patient variability, and numerous food-drug interaction and drug-drug interaction, lead to a need for more elaborative anticoagulation monitoring (Johnson et al., 2011; Pirmohamed et al., 2013). Different from warfarin, non-VKA oral anticoagulants (NOACs), which directly target thrombin or Xa factor, have been approved for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation without necessary of routine blood monitoring (López-López et al., 2017). Dabigatran etexilate, the prodrug of dabigatran, has the lowest bioavailability of present NOACs of 3~7% (Mega and Simon, 2015), which is rapidly converted by esterases-1 (CES-1) to dabigatran after administration (Stangier and Clemens, 2009; Laizure et al., 2014). In addation, dabigatran etexilate is a substrate of the P-glycoprotein intestinal efflux transporter (P-gp), which also known as ATP-binding cassette sub-family B member 1 (ABCB1) (Paré et al., 2013). P-gp is one of the drug transporters expressed in gastrointestinal tract which involves in the efflux of various kinds of drugs into lumen (Ambudkar et al., 2003). Thus, strong P-gp inhibitors can increase dabigatran bioavailability by 12–23% (Liesenfeld et al., 2011; Paré et al., 2013; Kishimoto et al., 2014). Unlike Xa factor inhibitors, oxidoreductases or cytochrome P450 enzymes are not involved in the metabolism of dabigatran (Blech et al., 2008). As the renal clearance of dabigatran is 80%, renal function should be monitored regularly in patients taking dabigatran (Mega and Simon, 2015). Accordingly, changes in the process of absorption or elimination could have a great effect on dabigatran plasma concentrations (Antonijevic et al., 2017; Favaloro et al., 2017). We reported a dabigatran-treated patient who presented with severe left atrial appendage thrombus formation, of whom ABCB1 and CES1 genetic polymorphism and drug-drug interaction may have been the contributing factors. The patient gave his written informed consent for publication of this report.\n\nCase presentation\nThe present patient is a 70-year-old Chinese male with paroxysmal atrial fibrillation, complicating hypertension, type 2 diabetes mellitus, coronary heart disease, cerebral infarction, and lost binocular vision. The patient had received dabigatran etexilate 110 mg twice daily since April 30th, 2015 for the prevention of stroke and systemic embolism. Before the introduction of dabigatran, several drugs, including atorvastatin, have been taking for years (Table 1). The patient was admitted to the department of cardiology on November 9th 2017 due to the recurrence of cardio-embolic stroke. Vital signs were normal with blood pressure of 133/73 mmHg and heart rate of 73 rates per minute. Transesophageal echocardiography on admission showed a large thrombus in the left atrial appendage (Figure 1, Video 1), the enlarged left atrial diameter of 46 mm (reference: 30–40 mm) as well as depressed left ventricular function with left ventricular ejection fraction of 52% (reference: 55%) (Table 2). Laboratory data on admission were within normal limits expect for serum creatinine of 115 umol/L (reference: 45–104 umol/L) and B type natriuretic peptide (BNP) of 188 pg/mL (reference: 0.0~100 pg/mL) (Table 2). Dabigatran was stopped at admission, and enoxaparin was administrated with the combination of warfarin since November 8th, 2017 for 20 days till November 28th, 2017. Finally, the patient was treated with coronary artery bypass grafting (CABG), atrial fibrillation ablation, left atrial appendage excision and pericardial drainage plus cardiac temporary pacemaker implantation in November 29th, 2017. He was discharged day 15 post-operation on treatment with warfarin 2.5 mg daily. At 3 months follow up, the patient has been doing well without any evidence of recurrent thrombotic events.\n\nTable 1 Drugs administration during 3 years.\n\nStarting Time\tJune 21st, 2014\tNov. 30th, 2014\tApr. 4th, 2015\tNov. 11th, 2017\t\nStop Time\tNov. 29th, 2014\tApr. 3rd, 2015\tNov. 8th, 2017\tDec. 20th, 2017\t\nFosinopril Sodium Tablets\tNK\t–\t–\t–\t\nAmlodipine Besylate Tablets\t5 mg bid\t5 mg bid\t5 mg bid\t–\t\nMetoprolol Tartrate Tablets\tNK\t25 mg bid\t25 mg bid\t–\t\nClopidogrel Hydrogen Sulphate Tablets\t–\t75 mg qd\t–\t–\t\nAtorvastatin Tablets\t–\t20 mg qd\t20 mg qd\t–\t\nMetformin Hydrochloride Tablets\t–\t500 mg qd\t500 mg qd\t–\t\nDabigatran Etexilate Capsules\t–\t–\t110 mg bid\t–\t\nClonidine Hydrochloride Tablets\t–\t–\t75 μg qd\t–\t\nOlmesartan Medoxomil\t–\t–\t20 mg qd\t–\t\nWarfarin Tablets\t–\t–\t–\t2.5 mg qn\t\nNK, not known.\n\nFigure 1 Transesophageal echocardiogram showed the large left atrial thrombus.\n\nTable 2 Results of main laboratory test.\n\nIndex (normal range)\tNov. 8th\t10th\t12th\t14th\t16th\t20th\t23th\t27th\t29th\t30th\t\nREGULAR BLOOD ANALYSIS\t\nWhite blood cell count (3.97~9.15 × 10∧9/L)\t8.53\t–\t–\t–\t–\t–\t–\t–\t15.65\t24.86\t\nNeutrophils% (50~70%)\t54.8\t–\t–\t–\t–\t–\t–\t–\t85.0\t89.9\t\nPlatelet count (85~303 × 10∧9/L)\t200\t–\t–\t–\t–\t–\t–\t–\t133\t121\t\nRed blood cell count (4.09~5.74 × 10∧12/L)\t5.56\t–\t–\t–\t–\t–\t–\t–\t3.85\t3.61\t\nTriglyceride (<1.7 mmol/L)\t2.75\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nTotal cholesterol (<5.72 mmol/L)\t3.38\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nTotal bilirubin (3.4~17.1 umol/L)\t13.5\t–\t–\t–\t–\t–\t–\t–\t36.0\t–\t\nHigh density lipoprotein (0.9~2.0 mmol/L)\t0.61\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nLow density lipoprotein (0.9~2.0 mmol/L)\t1.70\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nNon high density lipoprotein (1.8~4.1 mmol/L)\t2.77\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nCreatinine (45~104 umol/L)\t115.0\t–\t119.0\t–\t144.0\t144.0\t150.0\t–\t138.0\t157.0\t\nBlood ketone body (negative)\tNegative\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nBlood ammonia (9~30 umol/L)\t72.48\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nErythrocyte sedimentation rate (0.0~15.0 mm/h)\t29\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nGlycosylated hemoglobin Hba1C (4~6%)\t7.0\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\n2 h blood glucose (<7.8 mmol/l)\t8.32\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nHigh sensitive C reactive protein (0~3 mg/L)\t2.9\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nB type natriuretic peptide (0.0~100 pg/mL)\t188.00\t160.0\t–\t–\t–\t–\t–\t–\t–\t–\t\nMYOCARDIAL INFARCTION MARKERS\t\nTroponin (<0.04 ng/mL)\t0.01\t–\t–\t–\t–\t–\t–\t–\t10.65\t4.01\t\nCreatine kinase (0.6~6.3 ng/mL)\t0.7\t–\t–\t–\t–\t–\t–\t–\t639\t–\t\nMyoglobin (17.4~105.7 ng/mL)\t33.10\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nBLOOD COAGULATION ANALYSIS\t\nFibrin degradation product (0~5 μg/ml)\t5.90\t10.10\t–\t–\t–\t–\t–\t–\t–\t–\t\nThrombin time (14~21 s)\t20.50\t20.70\t–\t–\t–\t–\t–\t–\t–\t–\t\nProthrombin time (9.4~12.5 s)\t12.00\t14.70\t–\t13.5\t18.50\t36.00\t37.30\t11.4\t–\t–\t\nFibrinogen (2.00~4.00 g/L)\t3.75\t3.67\t–\t–\t–\t–\t–\t–\t–\t–\t\nActivated partial prothrombin time (25~33.8 s)\t28.20\t30.10\t–\t–\t–\t–\t–\t–\t–\t–\t\nProthrombin INR (0.8~1.15)\t1.01\t1.23\t–\t1.13\t1.65\t2.99\t3.10\t1.03\t–\t–\t\nD–Dimer (0~0.5 μg/mL)\t0.95\t1.48\t–\t–\t–\t–\t–\t–\t–\t–\t\nECHOCARDIOGRAPHY\t\nInternal diameter of the aortic root (28~40 mm)\t37\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nLeft atrial diameter (30~40 mm)\t46\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nThe left ventricular ejection fraction (55%)\t52\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nLeft ventricular end diastolic diameter (38~52 mm)\t48\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nData were collected from Nov. 8th 2017 to Nov. 30th 2017. Nov., November; -, No tested.\n\nInvestigations\nClinical investigations were performed to assess the causes of potential decreased dabigatran effects at therapeutic doses. They included patient's characteristic, co-administrated drugs, and genotyping of ABCB1 and CES1.\n\nABCB1 and CES1 genotyping\nGenomic DNA was extracted from whole blood (200 μl) using the QIAamp DNA blood mini kit (QIAGEN, Hombrechtikon, Switzerland). ABCB1 (rs4148738, rs2235046, rs1128503, rs10276036, rs1202169, rs1202168, and rs1202167) and CES1 (rs8192935, rs2244613, and rs4122238) and CES1P2 (rs4580160 and rs4784563) polymorphisms were determined by Sanger sequencing. The polymerase chain reaction primers were presented in Table 3. Sequencing was performed on 1 μl of the purified mixture using the BigDye Terminator v1.1 Cycle Sequencing kit (Life Technologies, Warsaw, Poland) and an ABI 3130 Automatic Capillary DNA Sequencer.\n\nTable 3 The polymerase chain reaction primers of ABCB1 and CES1.\n\nSNP\tForward\tReverse\t\nrs4148738\tTGCTGTTTGTGAGGCCC\nTTTGCC\tTTTTGGTACATTAAAGAATTT\nGCCATC\t\nrs2235046\tAATTAGAAAATGCAGCTG\tTCTTGTCAGGTTCTGAGTACC\t\nrs1128503\tGAGTTTCTGATGTTTTCTTG\tGACCCTGCGGTGATCAGCAG\t\nrs10276036\tTTGTGGAGAGCTGGATAAAGTG\tAGCCCAGGAGGTAGAGGTTATG\t\nrs1202169\tAGTGGTCTCTTTGGAAAAGG\tGTAGAAACTTCTACCCTGC\t\nrs1202168\tAGTGGTCTCTTTGGAAAAGG\tGTAGAAACTTCTACCCTGC\t\nrs1202167\tTCTGTCACCCAGGCTGGAGT\tTGGTGGGTCTTACCTGATGC\t\nrs8192935\tTTATATTATTAAAAACATC\tCATTGTTCTCCTCAGGAAT\t\nrs4580160\tCCATGCTAAGTATGTAGGGG\tCATCCTTCTGAGATTTTCTG\t\nrs4784563\tACTGCCACAGCTTCTCCAC\tTCACCTACCTCCCAGCATA\t\nrs2244613\tATCAGCCTTTGAGGCCTGAC\tCTGCTAAAAAAAAAAAAAAGT\t\nrs4122238\tGAGTGGAGGCGTGGTGGGAG\tCCTTCACCCACAACATGCCC\t\nSNP, single nucleotide polymorphism.\n\nResults\nSeveral reasons that contributed to treatment failure with dabigatran should be considered in this case: (1) the patient is a 70-year-old Chinese male and had a moderate renal insufficiency (estimated glomerular filtration rate of 55 mL/min); (2) the drug-drug interaction between dabigatran and atorvastatin was present; (3) as shown in Table 4, The patient is a heterozygote carrier of ABCB1 variant alleles with 7 heterozygote single nucleotide polymorphisms (SNPs: rs4148738, rs2235046, rs1128503, rs10276036, rs1202169, rs1202168, rs1202167) as well as CES-1 variant alleles with 2 homozygote SNPs (rs2244613 and rs4122238) and 2 heterozygote SNPs (rs8192935 and rs4580160).\n\nTable 4 The results of ABCB1 and CES1 Genotyping.\n\nSNP\tChromosome\tPosition, bp\tLocus\tFunction\tResults\tMAF(allel)\tMAF in china\t\nrs4148738\t7\t87000985\tABCB1\tIntron\tGA\t0.38 (A)\t0.41\t\nrs2235046\t7\t87012002\tABCB1\tIntron\tAG\t0.44 (G)\t0.69\t\nrs1128503\t7\t87017537\tABCB1\tSynonymous\tTC\t0.42 (C)\t0.69\t\nrs10276036\t7\t87018134\tABCB1\tIntron\tCT\t0.43 (T)\t0.69\t\nrs1202169\t7\t87033786\tABCB1\tIntron\tAG\t0.43 (G)\t0.69\t\nrs1202168\t7\t87033898\tABCB1\tIntron\tCT\t0.43 (T)\t0.69\t\nrs1202167\t7\t87034995\tABCB1\tIntron\tGA\t0.43 (A)\t0.69\t\nrs8192935\t16\t54419295\tCES1\tIntron\tAG\t0.42 (G)\t0.76\t\nrs4580160\t16\t54326141\tCES1P2\tIntron\tTC\t0.50 (C)\t0.42\t\nrs4784563\t16\t54333986\tCES1P2\tIntron\tGG\t0.42 (A)\t0.24\t\nrs2244613\t16\t54402110\tCES1\tIntron\tTT\t0.33 (T)\t0.62\t\nrs4122238\t16\t54414218\tCES1\tIntron\tGG\t0.27 (G)\t0.52\t\nSNP, single nucleotide polymorphism; MAF, minor allele frequency.\n\nDiscussion\nWe described the case of an old dabigatran-treated patient who presented with left atrial appendage thrombus formation despite the 31 months uninterrupted dabigatran therapy. Laboratory investigations showed a serum creatinine of 115 μmol/L and estimated glomerular filtration rate of 55 mL/min, which indicated a moderate renal insufficiency. Given that more than 80% of dabigatran is eliminated via urine, renal insufficiency was probably a contributing factor to increase the susceptibility of dabigatran. Furthermore, dabigatran may not suitable for elderly person due to insufficient renal function and correspondingly increased risk of bleeding. However, the mutation of both ABCB1 and CES-1 alleles may lead to a significant decrease of dabigatran blood concentration. The ABCB1 gene encodes for P-gp, and P-gp is an ATP-dependent drug efflux pump (Verhalen et al., 2017). Dabigatran etexilate, but not dabigatran, is a P-gp substrate. P-gp inhibitors increase dabigatran bioavailability by 10–20% (Stangier and Clemens, 2009). As compared to the homozygotes for ABCB1 SNP rs4148738 (G allele), patients carrying 1 or 2 A alleles showed 5% lower trough concentration (Dimatteo et al., 2016). CES-1 gene, which encodes for the liver carboxylesterase 1 enzyme, is responsible for the biotransformation of dabigatran etexilate into the active metabolite, namely, dabigatran (Wadkins et al., 2001; Redinbo et al., 2003). Paré et al. (2013) conducted a genome-wide association study, and found that the association of ABCB1 and CES-1 SNPs was consistent with its effect on dabigatran blood concentration. Of which, CES-1 SNP rs2244613 is associated at genome-wide significance with trough concentration, while rs8192935 and rs4148738 are associated with peak concentration modestly (Paré et al., 2013; Ross and Paré, 2013). The minor allele of the CES-1 SNP rs8192935 is associated with a 12% decrease in adjusted peak concentration (Paré et al., 2013). The CES-1 SNP rs2244613 is associated with a 15% decrease in adjusted trough concentration per minor allele (Paré et al., 2013). Thus, the subject carrying 2 minor alleles of rs2244613 are expected to have 28% lower concentration than no-carriers (Paré et al., 2013). In agreement with genome-wide association study, Gouin-Thibault I et al. (Gouin-Thibault et al., 2016) indicated that the heterozygous and homozygous of rs2244613 (CES-1) mutated groups had 14 and 26% lower AUC values as well as 13 and 43% lower Cmax values than the wild-type groups. Of note, the frequency of the T allele of rs2244613 (CES-1) is 33% in overall populations, but affects up to over 60% in Asians. Also, the frequency of the A allele of rs8192935 affects up to 76% in Asians while that is 42% in overall populations (Table 3). Therefore, the impacts on dabigatran concentrations related to rs2244613 and rs8192935 may be greater than previously postulated especially in Asians. Regretfully, no studies that focused on the relationship between CES-1 SNP and ischemic events have been carried out. The present case indicated the presence of ABCB1 heterozygotes in all tested allele. Meanwhile, there is a homozygous mutation of CES-1 rs2244613 and rs4122238 as well as heterozygote mutation of CES-1 rs8192935 and rs4580160. Presumably, patient carrying all these alleles may bring about the relatively low dabigatran blood concentration, subsequently leading to thrombus in the left atrial appendage. In addition, the presence of drug interaction with atorvastatin was probably another contributing factor to increase the risk of thrombosis. Atorvastatin is known as a moderate inhibitors of P-gp, which leads to an approximate 20% decrease in dabigatran concentrations (Wessler et al., 2013; Stöllberger and Finsterer, 2015). According to a large retrospective cohort study of 91,330 Taiwanese patients with non-valvular atrial fibrillation who were treated with dabigatran (49.65% of subjects) or another NOACs, concurrent use of atorvastatin was associated with a 29% decrease in the incidence rate ratio of major bleeding (Chang et al., 2017).\n\nAt present, there are limited data on the thrombosis in atrial fibrillation with the management of dabigatran. Luis et al. (2013) firstly reported the images which demonstrated the documented case of thrombosis in atrial fibrillation with coexistent valvular heart disease after 4 months anticoagulation with dabigatran. Sharma et al. (2014) report 2 cases of development of large left atrial thrombus in spite of the continuous treatment with dabigatran. Shah et al. (2015) reported another patient with thrombus formation in the left atrium. In all four cases, the formation of thrombus were in the left atrium but not in the left atrial appendage (Shah et al., 2015). Several proposed mechanisms might explain the reason of left atrial thrombus formation on dabigatran therapy. Firstly, dabigatran therapy is a single level downstream inhibition of thrombin, which could lead to a compensatory increase in upstream clotting factors. Secondly, incomplete inhibition of all available coagulation factors leaves some thrombin activity uninhibited or active. Thirdly, potential drug-drug interactions or inadequate absorption may lead to the unachieved therapeutic levels. Currently, the best strategy of anticoagulation in patients who develop thrombus on dabigatran therapy is uncertain, and a tried therapy with warfarin or left atrial appendage closure should be considered in such patients.\n\nOur report had a few potential limitations. Firstly, our study was underpowered to detect the dabigatran plasma concentration. Secondly, we did not investigate ABCB2 gene polymorphism, which may also impact the blood concentration of dabigatran. Moreover, we did not evaluate P-gp and CES activity in vivo.\n\nConcluding remarks\nWe suggest that the presence of ABCB1 variant alleles and CES-1 variant alleles and drug-drug interaction with atorvastatin are possibly contributing factors for dabigatran therapy failure in this case. Indeed, dabigatran may not suitable for elderly person owing to insufficient renal function and potential drug-drug interaction. Regarding optimal strategy, the treatment with warfarin or left atrial appendage closure may be the viable regimens in such patients suffering dabigatran therapy failure.\n\nMore clinical data are required to elucidate the impact of genetic polymorphism on dabigatran pharmacokinetics and thrombosis formation in atrial atrium or left atrial appendage. The impact of ABCB1 and CES-1 gene polymorphism on dabigatran pharmacokinetics should be investigated in a phase 1 clinical study in healthy volunteers based on different races.\n\nAuthor contributions\nLS was in charge of the treatment of patient. X-YZ was responsible for collecting the patient's information. X-WM was performed the phenotyping test of ABCB1 and CES-1 gene. Z-CG was involved in the care of the patient and interpreted the results, and wrote the manuscript. HL supervised the investigations and interpreted the results, and wrote the manuscript. F-HS was redacted of the manuscript. All authors read and approved the manuscript.\n\nConflict of interest statement\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\nThe authors would like to thank the patient for allowing publication of this case.\n\nFunding. This work was supported by the Science Fund of Hospital Pharmacy of Shanghai Jiaotong University School of Medicine (JDYX2016ZD003), Program for Key Discipline of Clinical Pharmacy of Shanghai (2016-40044-002), Program for Key but Weak Discipline of Shanghai Municipal Commission of Health and Family Planning (2016ZB0304), and the Fundamental Research Funds for the Central Universities (No.17JCYB11).\n\nSupplementary material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2018.00491/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\nAmbudkar S. V. Kimchi-Sarfaty C. Sauna Z. E. Gottesman M. M. (2003 ). P-glycoprotein: from genomics to mechanism . Oncogene \n22 , 7468 –7485 . 10.1038/sj.onc.1206948 14576852 \nAntonijevic N. M. Zivkovic I. D. Jovanovic L. M. Matic D. M. Kocica M. J. Mrdovic I. B. . (2017 ). 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Med. \n167 , 1414 –1419 . 10.1001/archinte.167.13.1414 17620536\n\n", "fulltext_license": "CC BY", "issn_linking": "1663-9812", "issue": "9()", "journal": "Frontiers in pharmacology", "keywords": "ABCB1; CES-1; dabigatran; drug-drug interaction; genetic polymorphism; left atrial appendage thrombus", "medline_ta": "Front Pharmacol", "mesh_terms": null, "nlm_unique_id": "101548923", "other_id": null, "pages": "491", "pmc": null, "pmid": "29867495", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "27893182;12773168;23696587;24212379;25616425;27261537;11075768;18006647;28289287;23467860;28460624;24088127;29183961;28413976;24212378;21900891;14576852;24251363;25777662;17620536;25793127;23803980;11455023;28973247;19696042;21972820;23563132", "title": "Left Atrial Appendage Thrombus Formation in a Patient on Dabigatran Therapy Associated With ABCB1 and CES-1 Genetic Defect.", "title_normalized": "left atrial appendage thrombus formation in a patient on dabigatran therapy associated with abcb1 and ces 1 genetic defect" }	[ { "companynumb": "CN-LANNETT COMPANY, INC.-CN-2018LAN000778", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLMESARTAN MEDOXOMIL" }, "dru...
{ "abstract": "Viral hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT) can be devastating. Standard treatment modalities have not been well established, but immune reconstitution may be necessary for sustained viral clearance. We studied five pediatric patients who developed viral HC after haplo-identical HSCT. All patients developed virus-specific CD4- and CD8-positive T cells, and the emergence of these viral-specific T cells was temporally associated with successful viral clearance.", "affiliations": "Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Section for Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.", "authors": "Apiwattanakul\|Nopporn\|N\|http://orcid.org/0000-0003-1833-5127;Hongeng\|Suradej\|S\|;Anurathapan\|Usanarat\|U\|;Pakakasama\|Samart\|S\|;Srisala\|Supanart\|S\|;Techasaensiri\|Chonnamet\|C\|;Andersson\|Borje S\|BS\|", "chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents", "country": "Denmark", "delete": false, "doi": "10.1111/tid.12775", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "19(6)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "pediatric; post-transplant hemorrhagic cystitis; stem cell transplantation; viral-specific T cells", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000256:Adenoviridae; D000257:Adenoviridae Infections; D000293:Adolescent; D000998:Antiviral Agents; D001739:BK Virus; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D002648:Child; D002675:Child, Preschool; D003556:Cystitis; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006470:Hemorrhage; D006801:Humans; D007111:Immunity, Cellular; D007166:Immunosuppressive Agents; D008297:Male; D027601:Polyomavirus Infections; D011183:Postoperative Complications; D014184:Transplantation, Homologous; D014412:Tumor Virus Infections; D019562:Viral Load", "nlm_unique_id": "100883688", "other_id": null, "pages": null, "pmc": null, "pmid": "28865164", "pubdate": "2017-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Viral-specific T-cell response in hemorrhagic cystitis after haploidentical donor stem cell transplantation.", "title_normalized": "viral specific t cell response in hemorrhagic cystitis after haploidentical donor stem cell transplantation" }	[ { "companynumb": "TH-TEVA-2018-TH-861100", "fulfillexpeditecriteria": "1", "occurcountry": "TH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIDOFOVIR" }, "drugadditional": "1", "...
{ "abstract": "A 47-year-old Hispanic woman presented to a pulmonology clinic with 2 weeks of cough productive of white sputum and worsening dyspnea on exertion, requiring increasing supplemental oxygen. In addition, she reported fatigue, night sweats, diffuse myalgias, and extremity weakness. She denied hemoptysis, fevers, chills, weight loss, or rash. Her medical history is significant for undifferentiated rapidly progressive hypoxemic respiratory failure 2 years before her current presentation. At that time, she presented to the ED with 3 weeks of progressive shortness of breath and cough. Chest CT imaging showed bilateral infiltrates concerning for infection, and she was treated empirically for community-acquired pneumonia. She developed worsening hypoxemic respiratory failure despite broadening of her antibiotics and subsequently required intubation. Her course was further complicated by pulseless electrical activity arrest with return of spontaneous circulation and development of shock requiring multiple vasopressors. Because of difficulty with oxygenation, she was referred to our center for extracorporeal membrane oxygenation evaluation and was ultimately started on venous-arterial extracorporeal membrane oxygenation. Bronchoscopy with BAL was negative for bacterial, viral, and fungal origins, and initial autoimmune evaluation (antinuclear antibody and rheumatoid factor) was negative, except an elevated creatine kinase (CK) to 3,000. Her course was complicated by heparin-induced thrombocytopenia, and as a result she suffered limb ischemia requiring amputation of her left lower extremity. Elevated CK at that time was attributed to compartment syndrome before amputation. The patient recovered clinically with supportive care and was ultimately discharged on 2 L supplemental oxygen, with a diagnosis of acute respiratory failure of unclear origin. The patient had stability in her clinical symptoms until this current presentation.", "affiliations": "Department of Internal Medicine, Rush University Medical Center, Chicago, IL. Electronic address: samuel_c_fox@rush.edu.;Division of Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, IL.", "authors": "Fox\|Samuel C\|SC\|;Trivedi\|Abhaya P\|AP\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.chest.2020.08.2119", "fulltext": null, "fulltext_license": null, "issn_linking": "0012-3692", "issue": "159(2)", "journal": "Chest", "keywords": null, "medline_ta": "Chest", "mesh_terms": "D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D009220:Myositis; D012131:Respiratory Insufficiency", "nlm_unique_id": "0231335", "other_id": null, "pages": "e69-e73", "pmc": null, "pmid": "33563457", "pubdate": "2021-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A 47-Year Old Woman With Rapidly Progressive Hypoxemic Respiratory Failure.", "title_normalized": "a 47 year old woman with rapidly progressive hypoxemic respiratory failure" }	[ { "companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-53650", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, ...
{ "abstract": "Nephrogenic systemic fibrosis (NSF) is a severe iatrogenic disease that affect patients with impaired renal function exposed to gadolinium-based contrast agents. Clinically, symptoms develop within days or weeks after the exposure and mimic a scleromyxedema. The causal relationship between use of gadolinium-based contrast agents and NSF led to develop clinical guidelines aiming to limit the use of this contrast medium in high risk patients. These guidelines decreased the incidence of NSF in the last years. Unfortunately there is no specific treatment for NSF yet. Thus, strict adherence to current guidelines is key to prevent new cases. Renal dysfunction is increasingly common in our population. Therefore, practicing physicians should be aware of this potential complication of the use of gadolinium based contrast media.", "affiliations": null, "authors": "Varela\|Cristian U\|CU\|;Prieto-Rayo\|Juan Carlos\|JC\|", "chemical_list": "D003287:Contrast Media; D005682:Gadolinium", "country": "Chile", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0034-9887", "issue": "142(12)", "journal": "Revista medica de Chile", "keywords": null, "medline_ta": "Rev Med Chil", "mesh_terms": "D003287:Contrast Media; D005682:Gadolinium; D006801:Humans; D054989:Nephrogenic Fibrosing Dermopathy; D012307:Risk Factors", "nlm_unique_id": "0404312", "other_id": null, "pages": "1565-74", "pmc": null, "pmid": "25693439", "pubdate": "2014-12", "publication_types": "D004740:English Abstract; D016428:Journal Article; D016454:Review", "references": null, "title": "Causal relationship between the use of gadolinium based contrast media and nephrogenic systemic fibrosis.", "title_normalized": "causal relationship between the use of gadolinium based contrast media and nephrogenic systemic fibrosis" }	[ { "companynumb": "CL-GE HEALTHCARE MEDICAL DIAGNOSTICS-OSCN-PR-1504L-0081", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GADODIAMIDE" }, ...
{ "abstract": "BACKGROUND\nAdverse Drug Reactions (ADR) are a major cause of morbidity and mortality worldwide. In spite of this, ADR are largely underreported and unrecognized.\n\n\nOBJECTIVE\nIdentify and characterize ADR related admissions to our internal medicine ward using a proactive multidisciplinary pharmacovigilance approach.\n\n\nMETHODS\nWithin 24 hrs of admission 1045 patients admitted to the Internal Medicine Ward between August 2010 and February 2012 were screened for possible or probable ADR related admissions.\n\n\nRESULTS\nProbable ADR accounted for 112 of 1045 admissions (10.7%, 95% Confidence Interval [CI]: 8.8-12.6%), of which only 16 (14.3%) were classified as unavoidable. NSAIDs were the drug group more commonly implicated in probable ADR-related admissions (17.0%), followed by antiplatelets (16.1%). In-hospital mortality of patients admitted due to probable ADR was 8.0% (95% CI: 2.9-13.1%). During this study period, 6% of internal medicine ward and 4% of critical care unit beds were occupied by patients with probable ADR. The estimated cost of care of these patients was 641,000 US dollars (USD).\n\n\nCONCLUSIONS\nADR are a frequent reason for admission to an Internal Medicine Ward in Argentina. The culprit drugs and interactions are similar to those reported in the literature. The cost is substantial and most of the ADR are potentially avoidable.", "affiliations": "Department of Medicine, Centro de Educación Médica e Investigación Clínica (CEMIC) \"Norberto Quirno\", Buenos Aires, Argentina.", "authors": "Alvarez\|Paulino A\|PA\|;Bril\|Fernando\|F\|;Castro\|Verónica\|V\|;Meiville\|Itati\|I\|;Gonzalez\|Claudio D\|CD\|;Centurion\|Ignacio Gomez\|IG\|;Parejas\|Griselda\|G\|;Riera\|Cristina Soler\|CS\|;Saubidet\|Cristian Lopez\|CL\|;Di Girolamo\|Guillermo\|G\|;Keller\|Guillermo A\|GA\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.3233/JRS-130596", "fulltext": null, "fulltext_license": null, "issn_linking": "0924-6479", "issue": "25(3)", "journal": "The International journal of risk & safety in medicine", "keywords": null, "medline_ta": "Int J Risk Saf Med", "mesh_terms": "D000368:Aged; D001118:Argentina; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006760:Hospitalization; D006801:Humans; D007902:Length of Stay; D008297:Male", "nlm_unique_id": "9100907", "other_id": null, "pages": "185-92", "pmc": null, "pmid": "24047689", "pubdate": "2013", "publication_types": "D016428:Journal Article", "references": null, "title": "Adverse drug reactions as a reason for admission to an internal medicine ward in Argentina.", "title_normalized": "adverse drug reactions as a reason for admission to an internal medicine ward in argentina" }	[ { "companynumb": "AR-PFIZER INC-2018341946", "fulfillexpeditecriteria": "1", "occurcountry": "AR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", ...
{ "abstract": "Neoadjuvant PD-(L)1 inhibitors may be promising for locally advanced non-small cell lung cancer (NSCLC) with potential pathological and survival benefits. But severe immune-related adverse events (irAEs) may cause fatal consequences which require early identification and timely intervention. The basis for most of these adverse events is a reactive hyperactivated T-cell response to normal tissues that results in the production of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells in normal tissues. It is recommended that all patients receiving PD-(L)1 inhibitors routinely have thyroid function studies, complete blood counts, and liver function and metabolic panels at each treatment and at intervals of 6 to 12 weeks for the first 6 months after finishing treatment. Herein, we report a rare case who had two grade 3-4 irAEs consecutively occurring after PD-1 induction therapy and surgery. A 59-year-old man with stage IIIA squamous cell lung cancer receiving 3 cycles of neoadjuvant nab-paclitaxel, carboplatin, and nivolumab was reevaluated for resectability. The patient experienced acute serum transaminase elevation right after induction therapy. Seven days after surgery he had severe pneumonia. These two serious complications were both eventually relieved by a month long treatment of corticosteroids but not regular medicine which verified the diagnosis of irAEs. Although results of clinical trials of neoadjuvant immunotherapy are worth expecting, our case calls attention to careful surveillance and timely management of irAEs during the perioperative use of PD-(L)1 inhibitors. We also further discuss the standard use of corticosteroids for irAEs based on a review of literature.", "affiliations": "Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.;Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.", "authors": "Zhao\|Hang\|H\|;Ning\|Junwei\|J\|;Gu\|Yu\|Y\|;Zhang\|Xiaocheng\|X\|;Yu\|Wen\|W\|;Chen\|Tianxiang\|T\|;Luo\|Qingquan\|Q\|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/tlcr-21-603", "fulltext": "\n==== Front\nTransl Lung Cancer Res\nTransl Lung Cancer Res\nTLCR\nTranslational Lung Cancer Research\n2218-6751\n2226-4477\nAME Publishing Company\n\n34584866\ntlcr-10-08-3682\n10.21037/tlcr-21-603\nCase Report\nConsecutive severe immune-related adverse events after PD-1 inhibitor induction and surgery in locally advanced non-small cell lung cancer: a case report\nZhao Hang 1 2 #\nNing Junwei 1 # ^\nGu Yu 3 #\nZhang Xiaocheng 1 4\nYu Wen 5\nChen Tianxiang 1\nLuo Qingquan 1\n1 Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China;\n2 Thoracic Surgery Department, Dongyang People’s Hospital, Dongyang, China;\n3 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China;\n4 Department of Pulmonary Medicine, Ruian People’s Hospital, Wenzhou, China;\n5 Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China\n# These authors equally contributed to this work.\n\nCorrespondence to: Qingquan Luo; Tianxiang Chen. Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huai Hai Road, Shanghai 200030, China. Email: luoqingquan@hotmail.com; txchen@shsmu.edu.cn.\n^ ORCID: 0000-0002-0032-0026.\n\n8 2021\n8 2021\n10 8 36823688\n22 6 2021\n16 8 2021\n2021 Translational Lung Cancer Research. All rights reserved.\n2021\nTranslational Lung Cancer Research.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.\nNeoadjuvant PD-(L)1 inhibitors may be promising for locally advanced non-small cell lung cancer (NSCLC) with potential pathological and survival benefits. But severe immune-related adverse events (irAEs) may cause fatal consequences which require early identification and timely intervention. The basis for most of these adverse events is a reactive hyperactivated T-cell response to normal tissues that results in the production of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells in normal tissues. It is recommended that all patients receiving PD-(L)1 inhibitors routinely have thyroid function studies, complete blood counts, and liver function and metabolic panels at each treatment and at intervals of 6 to 12 weeks for the first 6 months after finishing treatment. Herein, we report a rare case who had two grade 3–4 irAEs consecutively occurring after PD-1 induction therapy and surgery. A 59-year-old man with stage IIIA squamous cell lung cancer receiving 3 cycles of neoadjuvant nab-paclitaxel, carboplatin, and nivolumab was reevaluated for resectability. The patient experienced acute serum transaminase elevation right after induction therapy. Seven days after surgery he had severe pneumonia. These two serious complications were both eventually relieved by a month long treatment of corticosteroids but not regular medicine which verified the diagnosis of irAEs. Although results of clinical trials of neoadjuvant immunotherapy are worth expecting, our case calls attention to careful surveillance and timely management of irAEs during the perioperative use of PD-(L)1 inhibitors. We also further discuss the standard use of corticosteroids for irAEs based on a review of literature.\n\nKeywords:\n\nHepatitis\npneumonia\nimmune-related adverse events (irAEs)\nnon-small cell lung cancer (NSCLC)\ncase report\n==== Body\npmcIntroduction\n\nIn recent years, immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 for advanced non-small cell lung cancer (NSCLC) have shown promising results in clinical trials, and are recognized as the standard treatment (1-3). Recent clinical studies like Checkmate-816 also proved that neoadjuvant immunotherapy for locally advanced NSCLC achieve satisfactory rate of major pathologic response (MPR) and pathologic complete response (pCR) (4-7).\n\nAmong the immune-related adverse events (irAEs) of PD-(L)1 inhibitor, hepatitis and pneumonia are considered to be occasional and mild, mostly graded 1–2 (8). However, in reality severe irAEs after immune neoadjuvant therapy not only caused delays or difficulty of surgery, but also increased rate of fatal postoperative complications. Therefore, early identification and timely intervention for irAEs is clinically crucial. In this case report, we present the detailed treatment and outcome of a patient with locally advanced NSCLC who manifested ICI-related hepatitis after induction treatment and postoperative life-threatening ICI-related pneumonia. We present the following article in accordance with the CARE reporting checklist (available at https://dx.doi.org/10.21037/tlcr-21-603).\n\nCase presentation\n\nA 59-year-old Chinese man with body mass index of 27.4 kg/m2 who had a 30 pack-year smoking history was admitted to our center due to a pulmonary right lower lobe tumor close to hilum discovered by chest scan without obvious symptoms. Positron emission tomography/computed tomography (PET-CT) in November 2020 showed a mass, which was 25 mm in diameter and had a maximum standard uptake value (SUVmax) of 11.2, with suspected station 4R and 7 lymph node metastasis in the right hilar (Figure 1). Transbronchial biopsy confirmed squamous cell carcinoma and complete obstruction in the right lower bronchus (Figure 2). He had well-controlled depression by regular medication (citalopram hydrobromide tablet), uncontrolled slight blood glucose elevation (6.2 mmol/L), and controlled hypertension for over 20 years by regular medication without other cardiovascular disease or any other comorbidity.\n\nFigure 1 PET-CT images (A) before induction; (B) before surgery. (A) The tumor was observed at the bronchi in the dorsal segment of the lower lobe of the right lung when admitted. The diameter was 2.5 cm, SUVmax 11.2 (standard uptake value, maximum), with lymph nodes metastasis in the group 4R and 7; (B) the tumor 10 days before surgery. It was considered that the malignant lesion still had high metabolic activity. The size was about 1.5 cm × 1.12 cm, and the enhanced SUVmax was 11.8.\n\nFigure 2 Endoscopic view of right lower bronchus after transbronchial biopsy. The right middle bronchial mucosa was hyperemic, swollen, and red in fluorescence, and the right lower bronchus was completely blocked.\n\nBefore any treatment, his liver function tests including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were normal, and laboratory tests ruled out hepatitis A/C virus infection, but indicated that he was an asymptomatic hepatitis B virus carrier. After multidisciplinary team discussion, he was considered inoperable with multiple stage IIIA (N2) disease and an Eastern Cooperative Oncology Group (ECOG) performance status score of 1. Next-generation sequencing (NGS) revealed no classical driver mutations within the tumor cell genome, but the expression of PD-L1 in tumor tissues was over 10%. Given the NGS results and the surgically removable tumor type, targeted therapy was dismissed. Because the patient and his family had a strong desire for surgery, the medical team decided that a tentative induction therapy would be first given to see if there was chance to downstage the patient for surgery. He underwent 3 cycles of neoadjuvant chemoimmunotherapy starting with nab-paclitaxel (475 mg), carboplatin (580 mg), and nivolumab (360 mg) every 3 weeks, and a partial response (shrinkage from 28 to 19 mm in diameter) was achieved (Table 1). Meanwhile, damage of liver function was developed 22 days after the last cycle with elevated serum level of ALT at 294 U/L and AST at 133 U/L.\n\nTable 1 Cycles of chemoimmunotherapy\n\nCycle\tDose\tAE\tTreatment\tResponse\t\n1\tNab-paclitaxel 475 mg, carboplatin 580 mg, nivolumab 360 mg\t–\tPreventative CSF injection\t–\t\n2\tNab-paclitaxel 475 mg, carboplatin 520 mg, nivolumab 360 mg\t–\tPreventative CSF injection\tPR\t\n3\tNab-paclitaxel 475 mg, carboplatin 520 mg, nivolumab 360 mg\tImmune-related hepatitis (22 days after treatment); immune-related pneumonia (64 days after treatment)\t–\tPR\t\nAE, adverse event; CSF, colony-stimulating factor; PR, partial response.\n\nSince patient had hepatitis B, a course of therapy with magnesium isoglycyrrhizinate and reduced glutathione was first used to protect liver function which was regular combination to reduce liver transaminases in China. However, both ALT and AST levels remained high and other laboratory parameters were within normal ranges, immune-related hepatitis might be the possible cause which could not be relieved without corticosteroids. We added methylprednisolone starting from 30 mg to maximum dose at 80 mg to therapy 13 days after transaminases elevation. ALT and AST soon declined to normal within 10 days. Then the dose of methylprednisolone was gradually reduced every 4 days to the minimum oral dose at 8 mg within 10 days. For the preparation of surgery, corticosteroids were suspended 4 days before operation (Figure 3).\n\nFigure 3 Liver parameters and corticosteroids use. Say the admission day of this patient was day 0 (D0, etc.), the ICI induction therapy began on D12, and ended on D53. On D75, it was found that elevated serum level of ALT at 294 U/L and AST at 133 U/L. Intravenous methylprednisolone was started with 30 mg per day (30 mg/d) on D88. And on D91, it reached a maximum dosage of 80 mg/d, then it gradually reduced to 10 mg/d every 4 days until oral methylprednisolone was prescribed at 8 mg/d on D105. Corticosteroids were stopped 4 days before surgery.\n\nPET-CT (Figure 1) after liver function being normal showed that the SUVmax declined to 11.8 without any suspected metastasis of N2 lymph nodes, so the patient was clinically restaged as cT2NxM0, stage IB-IIIA, and the tumor was reconsidered to be resectable. The patient did not have a cough, sputum, chest pain, dyspnea, or other symptoms, and prophylactic antibiotics were prescribed. Sixty days after neoadjuvant therapy, the patient uneventfully received open surgery of right middle and lower bilobectomy with blood loss about 100 mL. On the 5th postoperative day (POD), his highest body temperature was 38.1 °C, and CT showed scattered inflammatory lesions in both lungs that indicated possible postoperative pulmonary infection. His chest tube was unobstructed without air leak, and he was treated with empirical antibiotic treatment of imipenem/cilastatin. On the 7th POD, hypoxia was observed with finger pulse oxygen about 75% saturation when the patient was inhaling oxygen. After oxygen inhalation by face mask delivering oxygen concentration of 40% flowing at 5 L/min, his oxygenation was back to 95–96%. The D-dimer level was tested to be 1.85 mg/L, postoperative deep vein thrombosis could not be easily ruled out, therefore, low-molecular-weight heparin was administered for anticoagulation although without strong evidence. On the 8th POD, the patient was transferred to the intensive care unit for bi-level positive airway pressure (BiPAP) therapy because of severe hypoxia with oxygen saturation of 60–70% with face-mask oxygen inhalation. A bedside X-ray suggested bilateral severe pulmonary infection (Figure 4). The patient was then diagnosed with immune-related pneumonia given the history of preoperative immune-related liver damage, we administered both intravenous methylprednisolone (1 mg/kg) along with gamma globulin (20 g) to bring down the immune related complications. In addition, oxygen therapy by BiPAP and nutritional support were also strengthened. The hypoxia symptom was relieved very soon after corticosteroids treatment, 13th POD chest X-ray indicated greatly improved pulmonary condition (Figure 4), gamma globulin treatment was stopped. The patient were sent back to normal surgery ward and discharged on 25th POD. After 17 days postoperative course of corticosteroids, he continued oral prednisone acetate tablets for 28 days from the day of discharge.\n\nFigure 4 Bedside chest X-ray images (A) after surgery; (B) after steroids. (A) The bedside chest X-ray image 9 days after surgery showed severe bilateral pneumonia; (B) the bedside chest X-ray image cleared 4 days after corticosteroids treatment.\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.\n\nDiscussion\n\nIn the last decade, significant advances have been achieved in the treatment of NSCLC (9,10). Currently, a number of phase III clinical studies of neoadjuvant immunotherapy including CheckMate 816, Keynote-671, and IMPOWER030 among others are under way. Although the potential benefit of neoadjuvant immunotherapy was seen in the early phase I/II clinical studies, some immunotherapy related concerns were also noticed (4,11-13). For example, of 90 patients with resectable stage IB-IIIA NSCLC in the LCMC3 study, 30 patients (30%) had irAEs (1 case grade ≥3) after atezolizumab was administered for 2 cycles preoperatively (14). The NADIM study reported that the incidence of postoperative complications was 29% (12/41) after 3 cycles of preoperative chemotherapy with nivolumab plus carboplatin and paclitaxel (4). Another study reported an approximately 30% (6/20) incidence of atrial arrhythmia, a 5% incidence of myocardial infarction, a 5% incidence of pulmonary infection, a 5% incidence of pulmonary embolism, and a 5% incidence of empyema after 2 cycles of nivolumab alone for NSCLC (15). Therefore, it can be seen from the published data of various studies that some patients suffer from adverse events or other reasons which may lead to a delay in surgery, reduced surgical safety, higher rate of conversion, prolonged hospital stay, increased economic burden, or even perioperative morbidity and mortality.\n\nOur patient developed immune related hepatitis right after induction which could not be relieved by hepatoprotective medicine (Figure 5), and the liver enzyme levels returned back to normal after timely steroids therapy. Unfortunately, he developed immune-related pneumonia one week after surgery, which still could not be improved by antibiotics alone, the patient was sent to intensive care unit to get support with BiPAP therapy and treated with high-dose corticosteroids, immunoglobulin along with antibiotics. With gradually reduced steroid doses and a series of relatively long-term anti-inflammatory maintenance therapies, his condition improved with satisfactory outcomes.\n\nFigure 5 Treatment timeline of our case. Confirmed NSCLC refers to historically confirmed squamous cell lung cancer. The day of admission was set for day 0 (D0). Corticosteroids include methylprednisolone during hospital stay and prednisone after discharge.\n\nirAEs are usually organ specific. Dermatologic, gastrointestinal, endocrine, respiratory, and hepatic adverse reactions are most frequently reported in clinical trials (16). In KEYNOTE-001 (17), patients with a history of chest radiotherapy were more likely to have treatment-related lung injury after pembrolizumab than those without previous chest radiotherapy (13% versus 1%). For grade 3–4 immune-related pneumonia, the American Society of Clinical Oncology/National Comprehensive Cancer Network (ASCO/NCCN) recommends 1–2 mg/kg/d methylprednisolone or prednisolone (18). The time of tapering should be more than 6 weeks. The European Society for Medical Oncology (ESMO) recommends 2–4 mg/kg/d methylprednisolone or prednisolone, and the tapering time is more than 8 weeks (19). The ASCO/NCCN guideline suggests that when pneumonia reverts to grade 1, steroids can be reduced. ESMO indicates that steroids cannot be reduced until lung inflammation has recovered to basal levels. Due to the lack of a direct comparison of these two therapeutic strategies, both can be taken into practice. There is far from consensus as to what subsequent treatment options should be chosen for patients with poor response to corticosteroid therapy. Both the ASCO/NCCN and ESMO guidelines list treatment options such as infliximab, mycophenolate mofetil, and gamma globulin. However, corticosteroids may reduce the efficacy of PD-(L)1 inhibitors, which may negatively affect the efficacy of ICIs. Data supporting this view come from patients with NSCLC and melanoma, who are most often treated with ICIs (20,21). In these patients, steroids are associated with poorer outcomes and reduced progression-free survival, so treatments other than corticosteroids are required. According to a review, the overall incidence of severe or life-threatening irAEs (grade ≥3) ranged from 10% to 15% for patients with PD-1 inhibitors, and toxicities appear to be dose-independent. While rare, ICI-related pneumonitis is considered one of the more serious irAEs (22-24). The incidence of pneumonitis in melanoma patients receiving anti-PD-1 monotherapy and combination therapy is 3.8% and 9.6%, respectively (25). And the occurrence of grade 3 hepatitis after ICIs is about 2% in NADIM study and other trials (4,26).\n\nIn this case, 2 irAEs (one grade 4) affecting different organs occurred during the perioperative period, which is rare. This also provided us with lessons and further thinking: if immune-related hepatitis occurs after induction therapy, would full course of steroids therapy prevent further postoperative irAEs, despite a delay in surgery? Because the long-term steroids therapy might highly increase the risk of bronchial anastomotic leakage, this patient did not further receive sleeve resection to achieve R0 resection after frozen pathology indicated positive bronchial margin. Life-threatening immune-related pneumonia occurred after surgery which also required long-term high-dose steroids therapy. He was lucky to avoid bronchial anastomotic leakage perioperatively, however it was challenging to strategize adjuvant therapy. Whether or not and when to add radiotherapy to cover the positive margin and mediastinal lymph nodes were not easy to decide. Adjuvant immunotherapy would not be suggested since two irAEs occurred in this patient. Though irAEs could be rarely fatal, but the promising survival benefits for lung cancer should not be overlooked. The keys to successfully managing ICIs toxicity are early diagnosis, high suspicion, good patient-provider communication, and rapid and aggressive use of corticosteroids and other immunosuppressants. To date, there are no effective biomarkers to predict the toxicity of immunotherapy and this is an active area of research.\n\nIn conclusion, although neoadjuvant immunotherapy has potential pathological and survival benefits for patients with locally advanced NSCLC, it is difficult to avoid perioperative occurrence of irAEs, which can be fatal and disastrous. Therefore, the proper and timely management of irAEs needs to be further carefully standardized, and relevant therapeutic principles still need to be further explored.\n\nSupplementary\n\nThe article’s supplementary files as\n\n10.21037/tlcr-21-603 10.21037/tlcr-21-603\n\nAcknowledgments\n\nFunding: This article was supported by the National Natural Science Foundation of China (Grant No. 81972176, 81601995), Shanghai Science and Technology Committee (18411966100), Shanghai Talent Development Fund (2019073), Shanghai Natural Science Foundation (Grant No. 18ZR1435100), Shanghai Rising Stars of Medical Talent, Youth Development Program (Specialist Program), Morningstar award program for outstanding young scholars of Shanghai Jiao Tong University.\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.\n\nReporting Checklist: The authors have completed the CARE reporting checklist. Available at https://dx.doi.org/10.21037/tlcr-21-603\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-603). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Borghaei H Paz-Ares L Horn L Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373 :1627-39. 10.1056/NEJMoa1507643 26412456\n2 Rittmeyer A Barlesi F Waterkamp D Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389 :255-65. 10.1016/S0140-6736(16)32517-X 27979383\n3 Gettinger S Rizvi NA Chow LQ Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34 :2980-7. 10.1200/JCO.2016.66.9929 27354485\n4 Provencio M Nadal E Insa A Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020;21 :1413-22. 10.1016/S1470-2045(20)30453-8 32979984\n5 Spicer J, Wang CL, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC) [EB/OL]. ASCO 2021:abstract 8503.\n6 Chen T Ning J Campisi A Neoadjuvant PD-1 inhibitors and chemotherapy for locally advanced NSCLC: A retrospective study. Ann Thorac Surg 2021. [Epub ahead of print]. doi: .10.1016/j.athoracsur.2021.03.041 33781737\n7 Jiang L Huang J Jiang S The surgical perspective in neoadjuvant immunotherapy for resectable non-small cell lung cancer. Cancer Immunol Immunother 2021;70 :2313-21. 10.1007/s00262-021-02847-1 33512555\n8 Ascierto PA Del Vecchio M Mandalá M Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2020;21 :1465-77. 10.1016/S1470-2045(20)30494-0 32961119\n9 Duma N Santana-Davila R Molina JR . Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment. Mayo Clin Proc 2019;94 :1623-40. 10.1016/j.mayocp.2019.01.013 31378236\n10 Chen T Luo J Gu H Impact of Solid Minor Histologic Subtype in Postsurgical Prognosis of Stage I Lung Adenocarcinoma. Ann Thorac Surg 2018;105 :302-8. 10.1016/j.athoracsur.2017.08.018 29162222\n11 Lee J Chaft J Nicholas A P2.04-88 Surgical outcomes of a multicenter phase II trial of neoadjuvant atezolizumab in resectable stages Ib-IIIb NSCLC: Update on LCMC3 clinical trial. J Thorac Oncol 2019;14 :S744. 10.1016/j.jtho.2019.08.1593\n12 Sepesi B Cascone T William W OA13.06 Surgical outcomes following neoadjuvant nivolumab or nivolumab plus ipilimumab in nonsmall cell lung cancer - NEOSTAR study. J Thorac Oncol 2019;14 :S241-S242. 10.1016/j.jtho.2019.08.481\n13 Gao S Li N Gao S Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. J Thorac Oncol 2020;15 :816-26. 10.1016/j.jtho.2020.01.017 32036071\n14 Surgical and Clinical Outcomes With Neoadjuvant Atezolizumab in Resectable Stage IB–IIIB NSCLC: LCMC3 Trial Primary Analysis. Presented at: 2020 World Conference on Lung Cancer Singapore. January 28-31, 2021. PS01.05.\n15 Bott MJ Yang SC Park BJ Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer. J Thorac Cardiovasc Surg 2019;158 :269-76. 10.1016/j.jtcvs.2018.11.124 30718052\n16 Darnell EP Mooradian MJ Baruch EN Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls. Curr Oncol Rep 2020;22 :39. 10.1007/s11912-020-0897-9 32200442\n17 Shaverdian N Lisberg AE Bornazyan K Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 2017;18 :895-903. 10.1016/S1470-2045(17)30380-7 28551359\n18 Brahmer JR Lacchetti C Schneider BJ Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36 :1714-68. 10.1200/JCO.2017.77.6385 29442540\n19 Haanen JBAG Carbonnel F Robert C Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28 :iv119-42. 10.1093/annonc/mdx225 28881921\n20 Arbour KC Mezquita L Long N Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36 :2872-8. 10.1200/JCO.2018.79.0006 30125216\n21 Faje AT Lawrence D Flaherty K High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 2018;124 :3706-14. 10.1002/cncr.31629 29975414\n22 Spain L Diem S Larkin J . Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016;44 :51-60. 10.1016/j.ctrv.2016.02.001 26874776\n23 Kumar V Chaudhary N Garg M Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Front Pharmacol 2017;8 :49. 10.3389/fphar.2017.00049 28228726\n24 Widmann G Nguyen VA Plaickner J Imaging Features of Toxicities by Immune Checkpoint Inhibitors in Cancer Therapy. Curr Radiol Rep 2016;5 :59. 10.1007/s40134-017-0256-2 28959504\n25 Naidoo J Wang X Woo KM Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2017;35 :709-17. 10.1200/JCO.2016.68.2005 27646942\n26 Shu CA Gainor JF Awad MM Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020;21 :786-95. 10.1016/S1470-2045(20)30140-6 32386568\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2218-6751", "issue": "10(8)", "journal": "Translational lung cancer research", "keywords": "Hepatitis; case report; immune-related adverse events (irAEs); non-small cell lung cancer (NSCLC); pneumonia", "medline_ta": "Transl Lung Cancer Res", "mesh_terms": null, "nlm_unique_id": "101646875", "other_id": null, "pages": "3682-3688", "pmc": null, "pmid": "34584866", "pubdate": "2021-08", "publication_types": "D002363:Case Reports", "references": "28959504;26874776;29442540;30125216;32979984;27979383;29975414;32961119;31378236;27646942;32386568;28881921;27354485;33512555;26412456;33781737;28228726;32200442;30718052;32036071;28551359;29162222", "title": "Consecutive severe immune-related adverse events after PD-1 inhibitor induction and surgery in locally advanced non-small cell lung cancer: a case report.", "title_normalized": "consecutive severe immune related adverse events after pd 1 inhibitor induction and surgery in locally advanced non small cell lung cancer a case report" }	[ { "companynumb": "CN-NOVAST LABORATORIES INC.-2021NOV000322", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditio...
{ "abstract": "OBJECTIVE\nTo determine the efficacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH).\n\n\nMETHODS\nRetrospectively, clinical parameters, biochemistry and histology were obtained from patient records.\n\n\nRESULTS\nNine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P=0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P=0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P=0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P=0.016), while the degree of fibrosis tended to decrease (P=0.049).\n\n\nCONCLUSIONS\nThe use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of fibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.", "affiliations": "Department of Hepatology A-2121, Rigshospitalet, University Hospital of Copenhagen, Denmark. stolze@post3.tele.dk", "authors": "Larsen\|Fin Stolze\|FS\|;Vainer\|Ben\|B\|;Eefsen\|Martin\|M\|;Bjerring\|Peter Nissen\|PN\|;Adel Hansen\|Bent\|B\|", "chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.3748/wjg.v13.i23.3232", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "13(23)", "journal": "World journal of gastroenterology", "keywords": null, "medline_ta": "World J Gastroenterol", "mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016559:Tacrolimus", "nlm_unique_id": "100883448", "other_id": null, "pages": "3232-6", "pmc": null, "pmid": "17589903", "pubdate": "2007-06-21", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "10580593;7560864;15030981;16394302;7537444;11019991;11786954;9121257;8690394;15365410;10068099;10796898;6988304;16447290", "title": "Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis.", "title_normalized": "low dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis" }	[ { "companynumb": "DK-ALKEM LABORATORIES LIMITED-DK-ALKEM-2017-01842", "fulfillexpeditecriteria": "2", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, ...
{ "abstract": "Aplastic anemia (AA) is a life-threatening hematological disorder that can be cured by hematopoietic stem cell transplantation. Haploidentical transplantation becomes an alternative choice for patients in the absence of a matched sibling donor. We used a retrospective study aimed to confirm the feasibility of busulfan-based modified post-transplantation cyclophosphamide (PTCY) strategy in haploidentical hematopoietic stem cell transplantation for AA patients. We analyzed the outcomes of 27 patients from 3 clinical centers who had undergone haploidentical transplantation between October 2018 and July 2020. The modified condition regimen consisted of anti-thymoglobulin/antilymphocyte globulin, fludarabine, busulfan and low-dose cyclophosphamide, and high-dose cyclophosphamide, mycophenolate mofetil (MMF) and tacrolimus were administered as graft versus host disease (GVHD) prophylaxis after transplantation. The median follow-up time was 370 (range 65-721) days. One patient developed primary graft failure, and successful engraftment was observed in 96.29% (95% confidence interval [CI], 93.45%-97.91%) of patients. The median times for neutrophil and platelet engraftment were 13 (range 11-18) days and 13 (range 11-28) days, respectively. The most common regimen-related toxicity was bladder toxicity, followed by stomatitis and gastrointestinal toxicity. The cumulative incidence of grade II-IV aGVHD was 25.93% (95% CI, 5.84%-52.64%), whereas the cumulative incidence of grade III-IV aGVHD was 7.4% (95% CI, 0%-52.16%). Chronic GVHD was observed in 3 patients by the end of follow-up. All 27 patients are alive, with a failure-free survival rate of 96.30% (95% CI, 6.49%-99.47%) and GVHD relapse-free survival rate of 88.89% (95% CI, 69.39%-96.28%). Virus reactivation was comparable, with rates of 53.54% for cytomegalovirus (CMV) reactivation and 41.57% for Epstein-Barr virus, but the CMV diseases and post-transplantation lymphoproliferative disorder were rare. Our study using haploidentical transplantation with modified PTCY demonstrated an encouraging result with prolonged survival and reduced complications for aplastic anemia patients.", "affiliations": "Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Wuhan No. 1 Hospital, Wuhan, Hubei, China.;Department of Hematology, Wuhan No. 1 Hospital, Wuhan, Hubei, China.;Department of Hematology, Yichang Central People's Hospital, Yichang, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address: yczhang@tjh.tjmu.edu.cn.", "authors": "Li\|Yun\|Y\|;Wang\|Na\|N\|;Li\|Lin\|L\|;Cao\|Yang\|Y\|;Xu\|Jinhuan\|J\|;Wang\|Jue\|J\|;Huang\|Lifang\|L\|;Wang\|Lanlan\|L\|;Zou\|Liang\|L\|;Wang\|Haiyan\|H\|;Xiao\|Yi\|Y\|;Wei\|Jia\|J\|;Zhang\|Yicheng\|Y\|", "chemical_list": "D003520:Cyclophosphamide", "country": "United States", "delete": false, "doi": "10.1016/j.jtct.2021.01.018", "fulltext": null, "fulltext_license": null, "issn_linking": "2666-6367", "issue": "27(4)", "journal": "Transplantation and cellular therapy", "keywords": "Aplastic anemia; GVHD prophylaxis; Haploidentical; Post-transplantation cyclophosphamide; Transplantation", "medline_ta": "Transplant Cell Ther", "mesh_terms": "D000741:Anemia, Aplastic; D003520:Cyclophosphamide; D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D012189:Retrospective Studies; D000075442:Transplantation, Haploidentical", "nlm_unique_id": "101774629", "other_id": null, "pages": "331.e1-331.e7", "pmc": null, "pmid": "33836879", "pubdate": "2021-04", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Haploidentical Transplantation with Modified Post-transplantation Cyclophosphamide for Patients with Primary Aplastic Anemia: A Multicenter Experience.", "title_normalized": "haploidentical transplantation with modified post transplantation cyclophosphamide for patients with primary aplastic anemia a multicenter experience" }	[ { "companynumb": "CN-VISTAPHARM, INC.-VER202103-000958", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadd...
{ "abstract": "Recent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases.", "affiliations": "Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University Graz, Graz, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University Graz, Graz, Austria.;Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.;Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University Graz, Graz, Austria.", "authors": "Hoenigl\|Martin\|M\|http://orcid.org/0000-0002-1653-2824;Prattes\|Juergen\|J\|;Neumeister\|Peter\|P\|;Wölfler\|Albert\|A\|;Krause\|Robert\|R\|", "chemical_list": "D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C068538:liposomal amphotericin B; C508735:isavuconazole; C101425:posaconazole; D000666:Amphotericin B; D000637:Transaminases; D065819:Voriconazole", "country": "Germany", "delete": false, "doi": "10.1111/myc.12727", "fulltext": null, "fulltext_license": null, "issn_linking": "0933-7407", "issue": "61(3)", "journal": "Mycoses", "keywords": "diagnosis; invasive aspergillosis; isavuconazole; plasma level; treatment", "medline_ta": "Mycoses", "mesh_terms": "D000666:Amphotericin B; D000741:Anemia, Aplastic; D000935:Antifungal Agents; D001230:Aspergillus; D006402:Hematologic Diseases; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D008297:Male; D009503:Neutropenia; D009570:Nitriles; D011725:Pyridines; D000637:Transaminases; D016896:Treatment Outcome; D014230:Triazoles; D065819:Voriconazole; D055815:Young Adult", "nlm_unique_id": "8805008", "other_id": null, "pages": "201-205", "pmc": null, "pmid": "29112326", "pubdate": "2018-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Real-world challenges and unmet needs in the diagnosis and treatment of suspected invasive pulmonary aspergillosis in patients with haematological diseases: An illustrative case study.", "title_normalized": "real world challenges and unmet needs in the diagnosis and treatment of suspected invasive pulmonary aspergillosis in patients with haematological diseases an illustrative case study" }	[ { "companynumb": "AT-TEVA-2018-AT-868829", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", ...
{ "abstract": "Pacemaker lead endocarditis is an uncommon complication after pacemaker implantation, but is associated with high rates of morbidity and mortality. The authors describe the case of a 68-year-old woman with a double-chamber pacemaker since 2007, admitted to an internal medicine department for spondylodiscitis and Staphylococcus aureus bacteremia. During hospitalization, she had an episode of syncope; the 12-lead electrocardiogram showed pacemaker malfunction with ventricular undersensing and loss of capture. A transesophageal echocardiogram showed images compatible with vegetations on the pacemaker leads. After antimicrobial therapy, the patient developed acute renal failure with subsequent multiple organ failure and death. A high index of clinical suspicion is required for early diagnosis and appropriate treatment of cardiac device-related infective endocarditis.", "affiliations": "Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal. Electronic address: henrique.jp.guedes@gmail.com.;Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.;Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.;Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.;Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.;Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.;Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.;Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.;Serviço de Cardiologia, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.", "authors": "Guedes\|Henrique\|H\|;Pereira\|Adriana\|A\|;Pontes Dos Santos\|Rui\|R\|;Marques\|Leonor\|L\|;Moreno\|Nuno\|N\|;Castro\|Alexandra\|A\|;Cunha E Sousa\|Rui\|R\|;Andrade\|Aurora\|A\|;Pinto\|Paula\|P\|", "chemical_list": null, "country": "Portugal", "delete": false, "doi": "10.1016/j.repc.2016.11.010", "fulltext": null, "fulltext_license": null, "issn_linking": "0870-2551", "issue": "36(10)", "journal": "Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology", "keywords": "Ecocardiograma transesofágico; Endocardite infeciosa; Infective endocarditis; Pacemaker; Staphylococcus aureus; Transesophageal echocardiography", "medline_ta": "Rev Port Cardiol", "mesh_terms": "D000368:Aged; D004697:Endocarditis, Bacterial; D005260:Female; D006801:Humans; D010138:Pacemaker, Artificial; D016459:Prosthesis-Related Infections; D013203:Staphylococcal Infections", "nlm_unique_id": "8710716", "other_id": null, "pages": "775.e1-775.e5", "pmc": null, "pmid": "29037831", "pubdate": "2017-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A complex case of pacemaker lead endocarditis.", "title_normalized": "a complex case of pacemaker lead endocarditis" }	[ { "companynumb": "PT-MYLANLABS-2017M1081858", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, ...
{ "abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) is a hypersensitivity reaction characterized by maculopapular rash, exfoliative dermatitis, lymphadenopathy, fever, eosinophilia, and involvement of internal organs. Evidence for reactivation of herpes family viruses has been observed in some DRESS patients, and activated CD8+ T lymphocytes are largely directed against Epstein-Barr virus. Here, we report two cases complicated with this infection. Both patients received antibiotics and non-steroidal anti-inflammatory drugs. These patients manifested clinically with high fever, facial edema, diffuse pruritic erythroderma and maculopapules over the entire body, purpuric rashes in both lower limbs and lymphadenopathy of cervical and inguinal nodes. Laboratory tests revealed abnormal liver function, blood eosinophils, and ferritin levels. The patients recovered completely; however, the female patient developed hemophagocytic syndrome on the 15th day of illness. She developed new itchy rash, and laboratory tests rapidly worsened with fibrinogen levels dramatically reduced to 0.61 g/L. Bone marrow aspiration revealed an increased number of macrophages with hemophagocytosis and a reversed CD4/CD8 ratio of 0.45. These cases suggest that human herpes virus and coagulation function evaluations are necessary in DRESS patients.", "affiliations": "Department of Dermatology, Peking University First Hospital, Beijing, China.;Department of Dermatology, Peking University First Hospital, Beijing, China.;Department of Dermatology, Peking University First Hospital, Beijing, China.;Department of Dermatology, Peking University First Hospital, Beijing, China.;Department of Dermatology, Peking University First Hospital, Beijing, China.;Department of Dermatology, Peking University First Hospital, Beijing, China.;Department of Dermatology, Peking University First Hospital, Beijing, China.;Department of Dermatology, Peking University First Hospital, Beijing, China.", "authors": "Liang\|Jianhua\|J\|;Qu\|Hui\|H\|;Wang\|Xiaowen\|X\|;Wang\|Aiping\|A\|;Liu\|Lingling\|L\|;Tu\|Ping\|P\|;Li\|Ruoyu\|R\|;Wang\|Mingyue\|M\|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.5021/ad.2018.30.1.71", "fulltext": "\n==== Front\nAnn DermatolAnn DermatolADAnnals of Dermatology1013-90872005-3894The Korean Dermatological Association; The Korean Society for Investigative Dermatology 10.5021/ad.2018.30.1.71Case ReportDrug Reaction with Eosinophilia and Systemic Symptoms Associated with Reactivation of Epstein-Barr Virus and/or Cytomegalovirus Leading to Hemophagocytic Syndrome in One of Two Patients Liang Jianhua 12Qu Hui 13Wang Xiaowen 13Wang Aiping 13Liu Lingling 13Tu Ping 13Li Ruoyu 13Wang Mingyue 131 Department of Dermatology, Peking University First Hospital, Beijing, China.2 Department of Dermatology, Liaocheng People's Hospital, Shandong, China.3 Beijing Key Laboratory of Molecular Diagnosis of Dermatoses, Beijing, China.\nCorresponding author: Mingyue Wang, Department of Dermatology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing 100034, China. Tel: 86-10-83573075, Fax: 86-10-66551216, wangmy@pku.edu.cn2 2018 26 12 2017 30 1 71 74 10 11 2016 31 5 2017 05 6 2017 Copyright © 2018 The Korean Dermatological Association and The Korean Society for Investigative Dermatology2018The Korean Dermatological Association and The Korean Society for Investigative DermatologyThis 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.Drug reaction with eosinophilia and systemic symptoms (DRESS) is a hypersensitivity reaction characterized by maculopapular rash, exfoliative dermatitis, lymphadenopathy, fever, eosinophilia, and involvement of internal organs. Evidence for reactivation of herpes family viruses has been observed in some DRESS patients, and activated CD8+ T lymphocytes are largely directed against Epstein-Barr virus. Here, we report two cases complicated with this infection. Both patients received antibiotics and non-steroidal anti-inflammatory drugs. These patients manifested clinically with high fever, facial edema, diffuse pruritic erythroderma and maculopapules over the entire body, purpuric rashes in both lower limbs and lymphadenopathy of cervical and inguinal nodes. Laboratory tests revealed abnormal liver function, blood eosinophils, and ferritin levels. The patients recovered completely; however, the female patient developed hemophagocytic syndrome on the 15th day of illness. She developed new itchy rash, and laboratory tests rapidly worsened with fibrinogen levels dramatically reduced to 0.61 g/L. Bone marrow aspiration revealed an increased number of macrophages with hemophagocytosis and a reversed CD4/CD8 ratio of 0.45. These cases suggest that human herpes virus and coagulation function evaluations are necessary in DRESS patients.\n\nCytomegalovirusDrug hypersensitivity syndromeEpstein-Barr virus infectionsLymphohistiocytosishemophagocyticSulfasalazine\n==== Body\nINTRODUCTION\nDrug reaction with eosinophilia and systemic symptoms (DRESS) affects multiple organs and is occasionally associated with activation of viruses, such as human herpes virus (HHV)-6, HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus, in the setting of drug hypersensitivities1. In some cases, these active viruses can cause further hematological disorders. Here, we report two cases of such complications.\n\nCASE REPORT\nBoth cases were in middle age and suffered from high fever for 9~21 days followed by onset of generalized pruritic eruptions. Before the skin rashes appeared, both patients received antibiotics and non-steroidal anti-inflammatory drugs (Table 1). Dermatological examinations are described in Fig. 1A, B, D, E. Lymphadenopathies were revealed in cervical and inguinal areas, and splenomegaly was also present in both patients. Skin pathology (Fig. 1C, F) and laboratory findings (Table 1) are provided. Due to positive findings of EBV-immunoglobulin M or deoxyribonucleic acid (DNA) copies of EBV, both patients were diagnosed as DRESS complicated with EBV infection. After treatment with methylprednisolone (40 mg/d), ganciclovir (250 mg, every 12 hours), and intravenous immunoglobins (20 g/d) for case 1 or plasma (200 ml/d) for case 2, the second patient recovered with darkening and diminishing of the eruption and a reduction of aminotransferases. However, on the fifteenth day of illness, case 1 developed new itchy rashes over the body and worsened purpura on extremities. Complete blood counts revealed a leukocyte count of 6.26×109/L and a platelet count of 46×109/L. Blood chemistry revealed progressively impaired liver and coagulation function (alanine aminotransferase 1,141 IU/L, aspartate aminotransferase 3,046 IU/L, lactate dehydrogenase 2,807 IU/L, prothrombin time 21.8 seconds (normal range: 9.0~11.5 seconds), activated partial thromboplastin time 49.2 seconds (normal range: 26.9~37.6 seconds), fibrinogen 0.61 g/L (normal range: 2~4 g/L). A bone marrow aspiration revealed an increased number of macrophages with hemophagocytosis and a reversed CD4/CD8 ratio (0.45). Hemophagocytic syndrome was timely diagnosed based on the above characteristics for this case. Methylprednisolone was increased to 60 mg/d, and plasma infusion was continued daily. The patient's organ dysfunctions recovered gradually, and the skin eruptions were eventually reduced the following week.\n\nDISCUSSION\nDRESS is fatal in approximately 10% of cases2. The most culprit drugs are allopurinol, carbamazepine, and sulfasalazine, and the condition is potentially worsened by β-lactam antibiotics3. Concomitantly, DRESS is possibly associated with proliferation of activated CD8+ T lymphocytes directed against viral antigens derived mostly from herpes viruses such as EBV4. Astonishingly, in a French report, 16 out of 38 (42%) patients experienced EBV reactivation5. By contrast, a recent study including 34 Japanese DRESS patients demonstrated that less than 10% of patients presented with increased EBV DNA levels. In addition, EBV DNA loads were significantly reduced in the steroid-treated group compared with the non-treated group, whereas cytomegalovirus and HHV-6 DNA loads were increased after steroid therapy6. Interestingly, our second case developed extensive activations of EBV, cytomegalovirus and herpes simplex virus, which is rarely reported in the literature.\n\nHemophagocytic syndrome is a disorder manifesting overlapping symptoms as DRESS and infectious mononucleosis, including fever, lymphadenopathy, hepatosplenomegaly, and macular rashes78. Infections (especially EBV), malignancies, or autoimmune diseases can induce this severe condition. DRESS and hemophagocytic syndrome was marked by abnormal T-cell activation; however, few DRESS cases developed hemophagocytic syndrome alone9. After seeking potential causes as noted above, we thus believe hemophagocytic syndrome in this case is likely due to the activation of EBV10. Particularly, this patient had a history of rheumatoid arthritis and a flare of this condition immediately before the drug hypersensitivity aroused by sulfasalazine intake, which is very similar to the case reported by Komatsuda et al.10 Although hemophagocytic syndrome contributed to the worsening background of several disorders, whether the condition was accentuated by this specific drug besides viral activation is not fully understood. Given that this complication developed quickly, blood count, coagulation function, and ferritin levels are useful for early diagnosis.\n\nOur cases emphasized the necessities of HHV and coagulation evaluations in all DRESS patients. Early intervention of such complications may lead to a promising prognosis in these patients.\n\nCONFLICTS OF INTEREST: The authors have nothing to disclose.\n\nFig. 1 Diffuse red maculopapules on the trunk and extremities of case 1 (A, B) and confluent erythroderma in case 2 (D, E). Liquefaction of basal cells, lymphocytes and sparse eosinophils in the upper dermis of case 1 (C) and lichenoid dermatitis in case 2 (F) as assessed by skin pathology (H&E; C, F: ×200).\nTable 1 Clinical summary of the 2 cases upon admission\nItem\tCase 1\tCase 2\t\nAge/sex\t38/female\t37/male\t\nCulprit drug\tSulfasalazine for RA\tβ-Lactam antibiotics for fever\t\nWeeks until eruption (wk)\t4\t3\t\nSkin pathology\tLiquefaction of basal cells, lymphocytes and sparse eosinophils in upper dermis\tLichenoid dermatitis\t\nWhite blood cell (<9.5×109, /L)\t18.27×109\t12.82×109\t\nBlood eosinophils (<0.52×109, /L)\t2.81×109\t4.02×109\t\nBlood eosinophils (<8.0, %)\t15.4\t31.4\t\nAtypical lymphocytes (%)\t15\t5\t\nAlanine aminotransferase (<40, IU/L)\t212\t123\t\nAspartate aminotransferase (<35, IU/L)\t95\t53\t\nLactate dehydrogenase (<240, IU/L)\t437\t320\t\nTotal bilirubin (<20, mmol/L)\t25.8\tNormal\t\nDirect bilirubin (<6, mmol/L)\t10.7\tNormal\t\nFerritin (<306.8, ng/ml)\t>1,500\t506.2\t\nAntinuclear antibodies\t1:320+\t1:320+\t\nEBV-IgM (<40, U/ml)\t100\tNormal\t\nEBV-IgG (<25, U/ml)\t399\t332\t\nEBV-DNA (<500, copies/ml)\tNegative\t2.25×104\t\nCMV-DNA (<500, copies/ml)\tNegative\t3.88×103\t\nHSV-2 IgM (<1.1, index)\tNot done\t1.32\t\nRA: rheumatoid arthritis, EBV: Epstein-Barr virus, Ig: immunoglobulin, DNA: deoxyribonucleic acid.\n==== Refs\n1 Nanishi E Hoshina T Ohga S Nishio H Hara T Drug reaction with eosinophilia and systemic symptoms during primary Epstein-Barr virus infection J Microbiol Immunol Infect 2015 48 109 112 25074626 \n2 Kardaun SH Sidoroff A Valeyrie-Allanore L Halevy S Davidovici BB Mockenhaupt M Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007 156 609 611 17300272 \n3 Girelli F Bernardi S Gardelli L Bassi B Parente G Dubini A A new case of DRESS syndrome induced by sulfasalazine and triggered by amoxicillin Case Rep Rheumatol 2013 2013 409152 23936716 \n4 Drago F Cogorno L Broccolo F Ciccarese G Parodi A A fatal case of DRESS induced by strontium ranelate associated with HHV-7 reactivation Osteoporos Int 2016 27 1261 1264 26519419 \n5 Picard D Janela B Descamps V D'Incan M Courville P Jacquot S Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response Sci Transl Med 2010 2 46ra62 \n6 Ishida T Kano Y Mizukawa Y Shiohara T The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome Allergy 2014 69 798 805 24749495 \n7 Nishio D Izu K Kabashima K Tokura Y T cell populations propagating in the peripheral blood of patients with drug eruptions J Dermatol Sci 2007 48 25 33 17601705 \n8 Filipovich AH The expanding spectrum of hemophagocytic lymphohistiocytosis Curr Opin Allergy Clin Immunol 2011 11 512 516 21971331 \n9 Picard M Fernandez MI Des Roches A Bégin P Paradis J Paradis L Ceftazidime-induced drug reaction with eosinophilia and systemic symptoms (DRESS) complicated by hemophagocytic lymphohistiocytosis J Allergy Clin Immunol Pract 2013 1 409 412 24565550 \n10 Komatsuda A Okamoto Y Hatakeyama T Wakui H Sawada K Sulfasalazine-induced hypersensitivity syndrome and hemophagocytic syndrome associated with reactivation of Epstein-Barr virus Clin Rheumatol 2008 27 395 397 17952482\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1013-9087", "issue": "30(1)", "journal": "Annals of dermatology", "keywords": "Cytomegalovirus; Drug hypersensitivity syndrome; Epstein-Barr virus infections; Lymphohistiocytosis; Sulfasalazine; hemophagocytic", "medline_ta": "Ann Dermatol", "mesh_terms": null, "nlm_unique_id": "8916577", "other_id": null, "pages": "71-74", "pmc": null, "pmid": "29386835", "pubdate": "2018-02", "publication_types": "D002363:Case Reports", "references": "17300272;17601705;24565550;25074626;26519419;23936716;17952482;21971331;20739682;24749495", "title": "Drug Reaction with Eosinophilia and Systemic Symptoms Associated with Reactivation of Epstein-Barr Virus and/or Cytomegalovirus Leading to Hemophagocytic Syndrome in One of Two Patients.", "title_normalized": "drug reaction with eosinophilia and systemic symptoms associated with reactivation of epstein barr virus and or cytomegalovirus leading to hemophagocytic syndrome in one of two patients" }	[ { "companynumb": "CN-CHEPLA-C20200329_01", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, ...
{ "abstract": "To describe the relationship between the incidence of age-related macular degeneration (AMD) and nonsteroidal anti-inflammatory drug (NSAIDs) use.\n\n\n\nProspective cohort study.\n\n\n\nThis study consisted of participants in the California Men's Health Study. Those who completed surveys in 2002-2003 and 2006 were included. Men who self-reported use of aspirin, ibuprofen, naproxen, valdecoxib, celecoxib, and/or rofecoxib at least 3 days per week were considered NSAID users. Patients were categorized as non-users, former users, new users, or longer-term users based on survey responses. NSAID use was also categorized by type: any NSAIDs, aspirin, and/or non-aspirin NSAIDs. Age, race/ethnicity, smoking status, education, income, alcohol use, and Charlson comorbidity index score were included in the multivariate analysis as risk factors for AMD.\n\n\n\nA total of 51 371 men were included. Average follow-up time was 7.4 years. There were 292 (0.6%) and 1536 (3%) cases of exudative and nonexudative AMD, respectively. Longer-term use of any NSAID was associated with lower risk of exudative AMD (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.50-0.96, P = .029). New users of any NSAIDs (HR = 0.79, 95% CI 0.68-0.93, P = .0039) and aspirin (HR = 0.82, 95% CI 0.70-0.97, P = .018) had a lower risk of nonexudative AMD, although this trend did not persist in longer-term users. The relationship between exudative or nonexudative AMD and the remaining categories of NSAID use were not significant.\n\n\n\nThe overall impact of NSAIDs on AMD incidence is small; however, the lower risk of exudative AMD in longer-term NSAID users may point to a protective effect and deserves further study as a possible mechanism to modulate disease risk.", "affiliations": "Department of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park, California; Eye Monitoring Center, Kaiser Permanente Southern California, Baldwin Park, California. Electronic address: BobModj@gmail.com.;Department of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park, California; Eye Monitoring Center, Kaiser Permanente Southern California, Baldwin Park, California; Department of Research and Evaluation, Southern California Permanente Medical Group, Pasadena, California.;Division of Research, Kaiser Permanente Northern California, Oakland, California.;Division of Research, Kaiser Permanente Northern California, Oakland, California.;Department of Research and Evaluation, Southern California Permanente Medical Group, Pasadena, California.;Department of Research and Evaluation, Southern California Permanente Medical Group, Pasadena, California.", "authors": "Modjtahedi\|Bobeck S\|BS\|;Fong\|Donald S\|DS\|;Jorgenson\|Eric\|E\|;Van Den Eeden\|Stephen K\|SK\|;Quinn\|Virginia\|V\|;Slezak\|Jeffrey M\|JM\|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal", "country": "United States", "delete": false, "doi": "10.1016/j.ajo.2018.01.012", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9394", "issue": "188()", "journal": "American journal of ophthalmology", "keywords": null, "medline_ta": "Am J Ophthalmol", "mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002140:California; D006801:Humans; D015994:Incidence; D008268:Macular Degeneration; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D011795:Surveys and Questionnaires", "nlm_unique_id": "0370500", "other_id": null, "pages": "111-122", "pmc": null, "pmid": "29360460", "pubdate": "2018-04", "publication_types": "D016428:Journal Article", "references": null, "title": "The Relationship Between Nonsteroidal Anti-inflammatory Drug Use and Age-related Macular Degeneration.", "title_normalized": "the relationship between nonsteroidal anti inflammatory drug use and age related macular degeneration" }	[ { "companynumb": "US-JNJFOC-20180317064", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "d...
{ "abstract": "A 39-year-old Caucasian man with a history of dermatomyositis and diabetes mellitus on a regimen of tacrolimus and methylprednisolone presented to our dermatology outpatient clinic with a painful eruption on his left lower leg. Three months before presentation, he had been admitted to the hospital for cellulitis of the left leg. During admission, a needle aspirate of the left leg cellulitis was performed to obtain fluid for culture to guide therapy. The patient was empirically started on vancomycin 1 g every 12 hours and managed by infectious diseases. The culture yielded no growth, however, and the patient was continued on vancomycin for 2 weeks, with resolution of his cellulitis. Two months later, the patient developed multiple painful nodules on his left leg and returned to the infectious disease physician who had managed him during his inpatient stay. He was initially treated with 2 weeks of clindamycin 300 mg twice daily (bid) without improvement. This was then followed by 2 weeks of erythromycin 500 mg every 6 hours, again without improvement. At this point, he was referred to our clinic.", "affiliations": "Department of Dermatology, University of Florida Gainesville, FL; ssaikaly@knights.ucf.edu.;University of Central Florida College of Medicine, Orlando, FL.", "authors": "Saikaly\|Sami K\|SK\|;Weinstein\|David\|D\|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1540-9740", "issue": "16(5)", "journal": "Skinmed", "keywords": null, "medline_ta": "Skinmed", "mesh_terms": "D000328:Adult; D003882:Dermatomyositis; D006801:Humans; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae", "nlm_unique_id": "101168327", "other_id": null, "pages": "343-345", "pmc": null, "pmid": "30413232", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Disseminated Cutaneous Mycobacterium chelonae Infection in a Patient with Dermatomyositis.", "title_normalized": "disseminated cutaneous mycobacterium chelonae infection in a patient with dermatomyositis" }	[ { "companynumb": "NVSC2019US042441", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", ...
{ "abstract": "Primary central nervous system posttransplantation lymphoproliferative disorder (PCNS-PTLD) is uncommon, especially after heart or lung transplantation. Database analysis from a single heart and lung transplantation centre and a literature review pertaining to PCNS-PTLD was performed. In this study, the prevalence of PCNS-PTLD was 0.18% after heart and/or lung transplants. Of 1674 transplants, three cases of PCNS-PTLD developed 14 months, 9 years and 17 years posttransplant, and all were Epstein-Barr virus driven malignancies. Literature review of the topic revealed predominantly retrospective studies, with most reported cases after renal transplantation. The overall survival is poor, and it may be improved by early diagnosis and treatment. There are no published guidelines on the management of PCNS-PTLD; immune-chemotherapy in conjunction with reduction of immune suppression is preferred based on available evidence.", "affiliations": "Haematology Department, St Vincent's Hospital, Sydney, New South Wales, Australia.;Haematology Department, St Vincent's Hospital, Sydney, New South Wales, Australia.;Haematology Department, Royal North Shore Hospital, Sydney, New South Wales, Australia.;Haematology Department, St Vincent's Hospital, Sydney, New South Wales, Australia.", "authors": "Gifford\|G\|G\|;Fay\|K\|K\|;Jabbour\|A\|A\|;Ma\|D D\|DD\|", "chemical_list": "D007166:Immunosuppressive Agents", "country": "Australia", "delete": false, "doi": "10.1111/imj.12735", "fulltext": null, "fulltext_license": null, "issn_linking": "1444-0903", "issue": "45(5)", "journal": "Internal medicine journal", "keywords": "central nervous system; heart; lung; lymphoma; posttransplant lymhpoproliferative disorder; transplantation", "medline_ta": "Intern Med J", "mesh_terms": "D000368:Aged; D002493:Central Nervous System Diseases; D003586:Cytomegalovirus Infections; D020031:Epstein-Barr Virus Infections; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D015994:Incidence; D016040:Lung Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D066027:Transplant Recipients; D016896:Treatment Outcome", "nlm_unique_id": "101092952", "other_id": null, "pages": "583-6", "pmc": null, "pmid": "25955465", "pubdate": "2015-05", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review", "references": null, "title": "Primary central nervous system posttransplantation lymphoproliferative disorder after heart and lung transplantation.", "title_normalized": "primary central nervous system posttransplantation lymphoproliferative disorder after heart and lung transplantation" }	[ { "companynumb": "PHHY2015AU057409", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "dr...
{ "abstract": "Neuropathic opioid refractory phantom limb pain (PLP) following amputation can be a life long debilitating chronic pain syndrome capable of completely destroying a patient's life. The pain, its associated depression and sleep deprivation can make many patients suicidal. Ever changing and relentless, it is notoriously unresponsive to traditional cocktails of strong opioids, adjuvant pain medications, antidepressants, local anaesthetics, nerve stimulators, hypnotics and psychotropics. Drug effects are seldom more effective than placebo. We describe a successful sustained rescue of a difficult 2-year-long PLP case with sublingual buprenorphine/naloxone using the drug's potent multimodal mechanisms of action: potent long-acting mu agonist/antagonist, kapa receptor antagonist, delta receptor antagonist and novel opioid receptor-like 1 (OR-L1) agonist effects. Traditional escalating pure mu-opioid receptor agonists and adjuvant neuropathic pain cocktails often have disappointing efficacy in the treatment of resistant PLP. We suggest introducing buprenorphine/naloxone as an early effective opioid choice in PLP management.", "affiliations": "Anesthesiology, University of California San Diego, La Jolla, California, USA usrejic@yahoo.com.;Emergency Medicine, University of California Irvine, Irvine, California, USA.", "authors": "Srejic\|Una\|U\|http://orcid.org/0000-0001-8482-4741;Banimahd\|Faried\|F\|", "chemical_list": "D000701:Analgesics, Opioid; D000069479:Buprenorphine, Naloxone Drug Combination", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-237009", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(2)", "journal": "BMJ case reports", "keywords": "anaesthesia; drugs and medicines; foodborne infections; pain; therapeutic indications", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000701:Analgesics, Opioid; D000069479:Buprenorphine, Naloxone Drug Combination; D059350:Chronic Pain; D006801:Humans; D008297:Male; D008875:Middle Aged; D010591:Phantom Limb; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33608331", "pubdate": "2021-02-19", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Haunting of the phantom limb pain abolished by buprenorphine/naloxone.", "title_normalized": "haunting of the phantom limb pain abolished by buprenorphine naloxone" }	[ { "companynumb": null, "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministratio...
{ "abstract": "BACKGROUND\nParadoxical hidradenitis suppurativa (HS) induced by biologic agents (BA) is scarcely reported.\n\n\nOBJECTIVE\nWe sought to describe the clinical characteristics and outcome of patients developing paradoxical HS under BA.\n\n\nMETHODS\nThis was a multicenter nationwide retrospective study asking physicians to report all cases of HS, confirmed by a dermatologist, occurring during treatment of an inflammatory disease by a BA.\n\n\nRESULTS\nWe included 25 patients (15 inflammatory rheumatism, 9 Crohn's disease, 1 psoriasis) treated by 5 BA (adalimumab = 12, infliximab = 6, etanercept = 4, rituximab = 2, tocilizumab = 1). Median duration of BA exposure before HS onset was 12 (range 1-120) months. Patients were mostly Hurley stage I (n = 13) or II (n = 11). Simultaneously to HS or within 1 year, 11 patients developed additional inflammatory diseases, including paradoxical reactions (psoriasis = 9, Crohn's disease = 3, alopecia areata = 1, erythema elevatum diutinum = 1). Complete improvement of HS was more frequently obtained after BA discontinuation or switch (n = 6/10, 60%) rather than maintenance (n = 1/14, 7%). Reintroducing the same BA resulted in HS relapse in 3 of 3 patients.\n\n\nCONCLUSIONS\nRetrospective nature and lack of complete follow-up for some patients are limitations.\n\n\nCONCLUSIONS\nHS is a rare paradoxical adverse effect of BA, but fortuitous association cannot be excluded in some cases. We observed a trend toward better outcome when the BA was discontinued or switched.", "affiliations": "Dermatology Department, Hôpital Edouard Herriot, Université Claude Bernard Lyon I, Lyon, France. Electronic address: coline.faivre@gmail.com.;Dermatology Department, Hôpital Edouard Herriot, Université Claude Bernard Lyon I, Lyon, France.;Dermatology Department, Hôpital Saint-Jacques, Université de Franche-Comté, Besançon, France.;Dermatology Department, Centre Hospitalo-Universitaire (CHU) de Strasbourg, Université de Strasbourg, Strasbourg, France.;Rheumatology Department, Center Hospitalier de Valence, Valence, France.;Rheumatology Department, CHU Lapeyronie, Montpellier, France.;Dermatology Department, Center Hospitalier de Valence, Valence, France.;Dermatology Department, CHU de Dijon, Dijon, France.;Dermatology Department, CHU Henri-Mondor, Créteil, France.;Clinical Investigation Center for Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM) Centre d'Investigation Clinique (CIC) 1431 and Rheumatology, Université de Franche-Comté, Besançon, France.;Rheumatology Department, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Dermatology Department, CHU Hôtel Dieu, Nantes, France.;Dermatology Department, Center Hospitalier Lyon-Sud, Lyon, France.;Dermatology Department, Hôpital Claude-Huriez, Université Lille II, Lille, France.;Hepatogastroenterology Department, Center Hospitalier Loire Vendée Océan, Challans, France.;Rheumatology Department, CHU Lapeyronie, Université de Montpellier, Montpellier, France.;Infectious Diseases Center Necker-Pasteur, Pasteur Institute, Assistance Publique-Hôpitaux de Paris, Paris, France.;Dermatology Department, Hôpital Edouard Herriot, Université Claude Bernard Lyon I, Lyon, France.;Dermatology Department, Hôpital Edouard Herriot, Université Claude Bernard Lyon I, Lyon, France.", "authors": "Faivre\|Coline\|C\|;Villani\|Axel Patrice\|AP\|;Aubin\|François\|F\|;Lipsker\|Dan\|D\|;Bottaro\|Martine\|M\|;Cohen\|Jean-David\|JD\|;Durupt\|François\|F\|;Jeudy\|Géraldine\|G\|;Sbidian\|Emilie\|E\|;Toussirot\|Eric\|E\|;Badot\|Valérie\|V\|;Barbarot\|Sébastien\|S\|;Debarbieux\|Sébastien\|S\|;Delaporte\|Emmanuel\|E\|;Goegebeur\|Guetty\|G\|;Morel\|Jacques\|J\|;Nassif\|Aude\|A\|;Duru\|Gérard\|G\|;Jullien\|Denis\|D\|;\|\|\|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; D000069283:Rituximab; D000069285:Infliximab; D000068879:Adalimumab; C502936:tocilizumab; D000068800:Etanercept", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0190-9622", "issue": "74(6)", "journal": "Journal of the American Academy of Dermatology", "keywords": "biologic agents; hidradenitis suppurativa; paradoxical reactions; tumor necrosis factor-alfa inhibitors", "medline_ta": "J Am Acad Dermatol", "mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D001168:Arthritis; D001688:Biological Products; D003424:Crohn Disease; D003875:Drug Eruptions; D057915:Drug Substitution; D000068800:Etanercept; D005260:Female; D017497:Hidradenitis Suppurativa; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D028761:Withholding Treatment; D055815:Young Adult", "nlm_unique_id": "7907132", "other_id": null, "pages": "1153-9", "pmc": null, "pmid": "26965410", "pubdate": "2016-06", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Hidradenitis suppurativa (HS): An unrecognized paradoxical effect of biologic agents (BA) used in chronic inflammatory diseases.", "title_normalized": "hidradenitis suppurativa hs an unrecognized paradoxical effect of biologic agents ba used in chronic inflammatory diseases" }	[ { "companynumb": "FR-JNJFOC-20160526603", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, ...
{ "abstract": "Herein we present our experience with abatacept in a patient diagnosed with primary focal segmental glomerulosclerosis (FSGS) and resistant to steroid and other immunosuppressives.\n\n\n\nA 17-year-old girl was diagnosed with idiopathic nephrotic syndrome (NS) at the age of 8 years. Kidney biopsy was performed when she did not respond to 6-weeks of steroid (2mg/kg) therapy followed by three doses of pulse methylprednisolone (PMP) and considered as steroid resistant NS. The biopsy revealed focal segmental glomerulosclerosis (FSGS) and cyclophosphamide was added to the steroid treatment but the patient had no response. The genetic analysis revealed G34G/A318A compound homozygous synonym aminoacid variation in NPHS2 gene, thus all immunosuppressive regimes were stopped and she was put on supportive treatment. Throughout this period, she had nephrotic range of proteinuria, however serum albumin levels were > 3g/dl. At the end of two years, the patient had NS with severe edema and hypoalbuminemia. When the genetic analysis was interpreted again, it was found to be consistent with a polymorphism rather than a mutation. Following 3 doses of PMP, oral steroid treatment was resumed and cyclosporine (CsA) was added to the treatment at the fifth year of follow up. However, she was unresponsive to CsA at the end of the first year as well as mycophenolate mofetil used for 12 months and rituximab used for 6 months, respectively. Then abatacept was instituted and proteinuria decreased below 1 gr/day and serum albumin levels increased to 3 g/dl at the end of 6 doses. Serum albumin levels remained stable in the following 7 months.\n\n\n\nPartial remission including the decrease in proteinuria and increase in albumin levels achieved in our patient encourages the usage of abatacept in patients who do not respond to multiple immunosuppressive therapies.", "affiliations": "Department of Pediatric Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, İzmir, Turkey.;Department of Pediatric Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, İzmir, Turkey.;Department of Pediatric Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, İzmir, Turkey.;Department of Pediatric Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, İzmir, Turkey.;Department of Pediatric Nephrology, İstanbul Medipol University Faculty of Medicine, İstanbul Turkey.;Department of Pediatric Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, İzmir, Turkey.", "authors": "Soyaltın\|Eren\|E\|;Demir\|Belde Kasap\|BK\|;Alparslan\|Caner\|C\|;Çamlar\|Seçil Arslansoyu\|SA\|;Alaygut\|Demet\|D\|;Yavaşcan\|Önder\|Ö\|;Mutlubaş\|Fatma\|F\|", "chemical_list": "D007166:Immunosuppressive Agents; D000069594:Abatacept; D016572:Cyclosporine; D008775:Methylprednisolone", "country": "Turkey", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0041-4301", "issue": "62(4)", "journal": "The Turkish journal of pediatrics", "keywords": "abatacept; focal segmental glomerulosclerosis; nephrotic syndrome", "medline_ta": "Turk J Pediatr", "mesh_terms": "D000069594:Abatacept; D000293:Adolescent; D002648:Child; D016572:Cyclosporine; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007166:Immunosuppressive Agents; D008775:Methylprednisolone; D009404:Nephrotic Syndrome", "nlm_unique_id": "0417505", "other_id": null, "pages": "663-667", "pmc": null, "pmid": "32779421", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": null, "title": "A partial response to abatacept in a patient with steroid resistant focal segmental glomerulosclerosis.", "title_normalized": "a partial response to abatacept in a patient with steroid resistant focal segmental glomerulosclerosis" }	[ { "companynumb": "TR-CELLTRION INC.-2020TR025437", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", ...
{ "abstract": "BACKGROUND\nPatients requiring an interruption in dual-antiplatelet therapy (DAPT) within 6 months of cardiac stenting are at risk for thrombotic events. Bridging with short-acting intravenous antiplatelet agents has been proposed to minimize the risk of thrombotic and hemorrhagic complications.\n\n\nMETHODS\nThis retrospective analysis of a tirofiban bridging strategy did not use an initial bolus loading dose. Tirofiban infusions were initiated 24-48 hours after the last oral antiplatelet dose at a rate of 0.1 μg/kg/min (or 0.05 μg/kg/min if renal dysfunction) and continued until 4-8 hours before surgery or until DAPT could be resumed. Coprimary end points were occurrence of major adverse cardiac events (MACE) and bleeding.\n\n\nRESULTS\nTwenty patients requiring DAPT interruption within 6 months of cardiac stenting for either a surgical procedure or who were unable to take any medications by mouth were included. The median time from stent implantation to DAPT interruption was 33 days (range 3-146 days). Two patients experienced a MACE during their hospital stay. No major bleeding events occurred; minor bleeding occurred in four patients during tirofiban therapy. Five patients in this analysis had end-stage renal disease requiring hemodialysis. Of these patients, no MACE or major bleeding events occurred.\n\n\nCONCLUSIONS\nThis analysis observed that a tirofiban bridging strategy without an initial bolus loading dose has comparable efficacy and safety as previously published reports. A tirofiban infusion without bolus dosing may be a safe option for antiplatelet bridging in patients with a recent cardiac stent implant to prevent stent thrombosis.", "affiliations": "Department of Pharmacy, University of California Davis Medical Center, Sacramento, California.;Department of Pharmacy, University of California Davis Medical Center, Sacramento, California.", "authors": "Walker\|Elizabeth A\|EA\|http://orcid.org/0000-0002-0354-3559;Dager\|William E\|WE\|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D014443:Tyrosine; D000077466:Tirofiban", "country": "United States", "delete": false, "doi": "10.1002/phar.1956", "fulltext": null, "fulltext_license": null, "issn_linking": "0277-0008", "issue": "37(8)", "journal": "Pharmacotherapy", "keywords": "antiplatelet agents; bridging; cardiac stents; hemodialysis; perioperative; tirofiban", "medline_ta": "Pharmacotherapy", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003324:Coronary Artery Disease; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007430:Intraoperative Care; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010975:Platelet Aggregation Inhibitors; D019106:Postoperative Hemorrhage; D006435:Renal Dialysis; D012189:Retrospective Studies; D015607:Stents; D000077466:Tirofiban; D016896:Treatment Outcome; D014443:Tyrosine", "nlm_unique_id": "8111305", "other_id": null, "pages": "888-892", "pmc": null, "pmid": "28543216", "pubdate": "2017-08", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Bridging with Tirofiban during Oral Antiplatelet Interruption: A Single-Center Case Series Analysis Including Patients on Hemodialysis.", "title_normalized": "bridging with tirofiban during oral antiplatelet interruption a single center case series analysis including patients on hemodialysis" }	[ { "companynumb": "US-BAYER-2017-170383", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TIROFIBAN" }, "drugadditional": null, "...
{ "abstract": "The use of immune checkpoint inhibitors (CPIs), such as pembrolizumab, for the treatment of cancer, is now prevalent. CPIs are associated with a significant side effect profile, termed immune-related adverse events (irAEs). Renal irAEs, such as interstitial nephritis, are rare, and CPI-related glomerulonephritis even rarer. This is a case report of a 72-year-old man with mesothelioma of the left lung, whose serum creatinine rose during pembrolizumab treatment. Renal biopsy revealed IgA nephropathy. Withdrawal of therapy for 2 months saw no improvement in renal function, and following recommencement, serum creatinine fluctuated at approximately 1.4 times original baseline. This report will highlight the renal irAEs to be the aware of when starting CPIs, and the importance of early renal biopsy in management.", "affiliations": "Medical Oncology, Weston Park Hospital, Sheffield, UK ryan.wang@nhs.net.;Medical Oncology, Weston Park Hospital, Sheffield, UK.;Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.", "authors": "Wang\|Ryan\|R\|;Das\|Tathagata\|T\|;Takou\|Anna\|A\|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors; D003404:Creatinine; C582435:pembrolizumab", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-237008", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(11)", "journal": "BMJ case reports", "keywords": "acute renal failure; respiratory cancer; unwanted effects / adverse reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D003404:Creatinine; D005922:Glomerulonephritis, IGA; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007668:Kidney; D008175:Lung Neoplasms; D008297:Male; D008654:Mesothelioma; D008854:Microscopy, Electron", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33257374", "pubdate": "2020-11-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "IgA nephropathy after pembrolizumab therapy for mesothelioma.", "title_normalized": "iga nephropathy after pembrolizumab therapy for mesothelioma" }	[ { "companynumb": "GB-009507513-2012USA010752", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": "2", ...
{ "abstract": "Hypotension occurred following a combined beta blocker (atenolol), angiotensin converting enzyme inhibitor (quinapil) and selective serotonin reuptake inhibitor (fluvoxamine) overdose. In another instance heart block and hypotension was noted in association with a diltiazem and atenolol adverse interaction. Crystalloid infusion was ineffective in both cases, but toxicity was rapidly reversed with aminophylline administration. Aminophylline's recognized inotropic and chronotropic properties make it a potentially valuable therapeutic agent in the treatment of antihypertensive medication toxicity.", "affiliations": "Department of Emergency Medicine and the Internal Medicine Residency Program, St Francis Medical Center, Pittsburgh, PA 15202, USA.", "authors": "Roberge\|R J\|RJ\|;Rossetti\|M L\|ML\|;Rosetti\|J M\|JM\|", "chemical_list": "D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D002316:Cardiotonic Agents; D007546:Isoquinolines; D017367:Serotonin Uptake Inhibitors; D044005:Tetrahydroisoquinolines; D000628:Aminophylline; D001262:Atenolol; D016666:Fluvoxamine; D000077583:Quinapril", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0145-6296", "issue": "43(5)", "journal": "Veterinary and human toxicology", "keywords": null, "medline_ta": "Vet Hum Toxicol", "mesh_terms": "D000319:Adrenergic beta-Antagonists; D000628:Aminophylline; D000806:Angiotensin-Converting Enzyme Inhibitors; D001262:Atenolol; D002316:Cardiotonic Agents; D062787:Drug Overdose; D005260:Female; D016666:Fluvoxamine; D006801:Humans; D007022:Hypotension; D007546:Isoquinolines; D008875:Middle Aged; D000077583:Quinapril; D017367:Serotonin Uptake Inhibitors; D044005:Tetrahydroisoquinolines; D016896:Treatment Outcome", "nlm_unique_id": "7704194", "other_id": null, "pages": "285-7", "pmc": null, "pmid": "11577934", "pubdate": "2001-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Aminophylline reversal of antihypertensive agent toxicity.", "title_normalized": "aminophylline reversal of antihypertensive agent toxicity" }	[ { "companynumb": "US-BAUSCH-BL-2017-023025", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, ...
{ "abstract": "Isavuconazole (ISA) is a triazole antifungal agent recommended for treatment of invasive aspergillosis or mucormycosis. The objective of this study was to evaluate ISA levels in a real world setting in a mixed patient cohort including patients with non-malignant diseases and extracorporeal treatments, and to correlate findings with efficacy and safety outcomes. We investigated 33 ISA treatment courses in 32 adult patients with hematological and other underlying diseases and assessed the clinical response, side effects and ISA trough plasma concentrations. ISA treatment led to complete and partial response in 87% of patients and was well tolerated. The median ISA plasma concentration was 3.05 µg/mL (range 1.38-9.1, IQR 1.93-4.35) in patients without renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) and significantly lower in patients with RRT including cases with additional ECMO or Cytosorb® adsorber therapy (0.88 µg/mL, range 0.57-2.44, IQR 0.71-1.21). After exclusion of values obtained from four patients with ECMO or Cytosorb® adsorber the median concentration was 0.91 µg/mL (range 0.75-2.44, IQR 0.90-1.36) in the RRT group. In addition to previous recommendations we propose to monitor ISA trough plasma concentrations in certain circumstances including RRT, other extracorporeal treatments and obesity.", "affiliations": "Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.;Department for Anaesthesiology and Intensive Care Medicine, Landesklinikum Baden, 2500 Baden, Austria.;Department of Internal Medicine, Landeskrankenhaus Graz 2, 8020 Graz, Austria.;Department of Internal Medicine, Landeskrankenhaus Hartberg, 8230 Hartberg, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.;Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.;Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, 8036 Graz, Austria.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.;Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE.;Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.", "authors": "Zurl\|Christoph\|C\|0000-0003-0623-0360;Waller\|Maximilian\|M\|;Schwameis\|Franz\|F\|;Muhr\|Tina\|T\|;Bauer\|Norbert\|N\|;Zollner-Schwetz\|Ines\|I\|;Valentin\|Thomas\|T\|;Meinitzer\|Andreas\|A\|;Ullrich\|Elisabeth\|E\|;Wunsch\|Stefanie\|S\|;Hoenigl\|Martin\|M\|0000-0002-1653-2824;Grinschgl\|Yvonne\|Y\|;Prattes\|Juergen\|J\|0000-0001-5751-9311;Oulhaj\|Abderrahim\|A\|;Krause\|Robert\|R\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/jof6020090", "fulltext": "\n==== Front\nJ Fungi (Basel)\nJ Fungi (Basel)\njof\nJournal of Fungi\n2309-608X MDPI \n\n10.3390/jof6020090\njof-06-00090\nArticle\nIsavuconazole Treatment in a Mixed Patient Cohort with Invasive Fungal Infections: Outcome, Tolerability and Clinical Implications of Isavuconazole Plasma Concentrations\nhttps://orcid.org/0000-0003-0623-0360Zurl Christoph 123 Waller Maximilian 1 Schwameis Franz 4 Muhr Tina 5 Bauer Norbert 6 Zollner-Schwetz Ines 1 Valentin Thomas 1 Meinitzer Andreas 7 Ullrich Elisabeth 18 Wunsch Stefanie 1 https://orcid.org/0000-0002-1653-2824Hoenigl Martin 19 Grinschgl Yvonne 10 https://orcid.org/0000-0001-5751-9311Prattes Juergen 13 Oulhaj Abderrahim 11 Krause Robert 13* 1 Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; christoph.zurl@medunigraz.at (C.Z.); maximilian.waller@stud.medunigraz.at (M.W.); ines.schwetz@medunigraz.at (I.Z.-S.); thomas.valentin@klinikum-graz.at (T.V.); elisabeth.ullrich@medunigraz.at (E.U.); stefanie.wunsch@medunigraz.at (S.W.); mhoenigl@health.ucsd.edu (M.H.); juergen.prattes@medunigraz.at (J.P.)\n2 Division of General Paediatrics, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, 8036 Graz, Austria\n3 BioTechMed-Graz, 8010 Graz, Austria\n4 Department for Anaesthesiology and Intensive Care Medicine, Landesklinikum Baden, 2500 Baden, Austria; franz.schwameis@baden.lknoe.at\n5 Department of Internal Medicine, Landeskrankenhaus Graz 2, 8020 Graz, Austria; tina.muhr@kages.at\n6 Department of Internal Medicine, Landeskrankenhaus Hartberg, 8230 Hartberg, Austria; norbert.bauer@lkh-hartberg.at\n7 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria; andreas.meinitzer@medunigraz.at\n8 Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, 8036 Graz, Austria\n9 Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, San Diego, CA 92093, USA\n10 Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, 8036 Graz, Austria; yvonne.grinschgl@medunigraz.at\n11 Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE; aoulhaj@uaeu.ac.ae\n* Correspondence: robert.krause@medunigraz.at; Tel.: +43-316-385-81796\n22 6 2020 \n6 2020 \n6 2 9013 5 2020 19 6 2020 © 2020 by the authors.2020Licensee 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/).Isavuconazole (ISA) is a triazole antifungal agent recommended for treatment of invasive aspergillosis or mucormycosis. The objective of this study was to evaluate ISA levels in a real world setting in a mixed patient cohort including patients with non-malignant diseases and extracorporeal treatments, and to correlate findings with efficacy and safety outcomes. We investigated 33 ISA treatment courses in 32 adult patients with hematological and other underlying diseases and assessed the clinical response, side effects and ISA trough plasma concentrations. ISA treatment led to complete and partial response in 87% of patients and was well tolerated. The median ISA plasma concentration was 3.05 µg/mL (range 1.38–9.1, IQR 1.93–4.35) in patients without renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) and significantly lower in patients with RRT including cases with additional ECMO or Cytosorb® adsorber therapy (0.88 µg/mL, range 0.57–2.44, IQR 0.71–1.21). After exclusion of values obtained from four patients with ECMO or Cytosorb® adsorber the median concentration was 0.91 µg/mL (range 0.75–2.44, IQR 0.90–1.36) in the RRT group. In addition to previous recommendations we propose to monitor ISA trough plasma concentrations in certain circumstances including RRT, other extracorporeal treatments and obesity.\n\nisavuconazolefungal infectionstherapeutic drug monitoringanti-infective agentsantifungal therapy\n==== Body\n1. Introduction\nIsavuconazole (ISA) is a triazole antifungal agent recommended for treatment of invasive aspergillosis or mucormycosis [1,2,3]. In the SECURE trial, ISA was non-inferior to voriconazole for primary treatment of suspected invasive mould disease including mostly patients with invasive aspergillosis, but also cases of non-aspergillus mould or mixed mould infections, and was associated with fewer drug related adverse events [4]. Recently, a post hoc analysis of 36 patients from SECURE showed no relationship between drug exposure (expressed as area under the curve) related to minimum inhibitory concentration (MIC) values of cultured fungi and outcome parameters (i.e., mortality, response of treatment) or safety endpoints (e.g., elevation of liver transaminases). The authors concluded that without a clear relationship of ISA drug exposure and outcome or side effects there is no clinical evidence for recommending routine therapeutic drug monitoring (TDM) compared to, e.g., voriconazole or posaconazole [5,6,7]. Another post hoc analysis of the SECURE trial showed that more than 97% of patients had ISA plasma concentrations >1 µg/mL and <7 µg/mL. Again, no concentration-dependent relationship for efficacy or safety was observed [8].\n\nOne larger study investigated 283 plasma concentrations from real world ISA use, and found ISA plasma concentrations of >1 µg/mL in >90% of patients, resembling findings from the SECURE trial [9]. However, no clinical data were available, and therefore the study could not assess potential associations between ISA levels and efficacy and safety events [9]. This limitation was overcome by a second recent study showing that prolonged administrations and high serum levels of ISA may be associated with adverse events [10]. However, that study was limited by a relatively small sample size (19 patients), all with underlying malignant diseases (18 hematological and one solid), necessitating validation of these findings in other trials and other patient cohorts. The need for additional data on ISA TDM is also emphasized in recent TDM guidelines, where only preliminary recommendations for TDM were made pending further published data [11,12].\n\nThe objective of this study was to evaluate ISA levels in a real world setting in a mixed patient cohort including patients with non-malignant diseases and extracorporeal treatments, and to correlate findings with efficacy and safety outcomes.\n\n2. Materials and Methods\nThis observational national multicenter cohort study prospectively included patients aged 18 years or older undergoing treatment with ISA at four centers in the Southern and Eastern part of Austria, the Medical University of Graz, the Landeskrankenhaus (LKH) Graz 2, LKH Hartberg, and the Klinikum Baden from November 2016 to October 2019.\n\nBased on recommendations of the local drug advisory committees ISA was allowed to be administered in patients with possible/probable/proven invasive aspergillosis using revised EORTC MSG criteria and/or Blot criteria in case of invasive aspergillosis in critical ill patients [13,14]. Patients were eligible for ISA treatment if fulfilling criteria of probable/proven mucormycosis with contraindications to liposomal Amphotericin B (lipAmpB), adverse events under lipAmpB treatment, lack of clinical response, or in other probable/proven invasive fungal infections based on antifungal susceptibility testing favoring Isavuconazole over alternative antifungals. Treatment consisted of 200 mg q8 h for 48 h followed by 200 mg once daily.\n\nPatients’ medical records were reviewed individually by using a standardized data collection template in order to collect demographic information and clinical data, mycological laboratory test results, ISA trough plasma concentrations, as well as ISA formulation, dosing information, termination of ISA treatment as well as other antifungal therapy, clinical response, serious adverse events, and breakthrough infections. Treatment success, failure and death were classified according to EORTC/MSG criteria [15]. Breakthrough infections under ISA were defined according to revised ECMM/MSG criteria [13,16,17]. Possible side effects like QT abnormalities, neutropenia and hepatotoxicity were observed by electrocardiograms (ECG) and laboratory assessment of blood cell count and liver enzymes such as alanine aminotransferase (AST), aspartate aminotransferase (ALT) and alkaline phosphatase (AP), respectively. Other possible adverse events like headache, abdominal pain, nausea or vomiting were documented by daily assessment during hospitalization or at outpatient visits. Indications of ISA treatments differed between individual patients, so efficacy assessment could not be performed at given time points. As data were extracted from real word clinical cases efficacy was assessed throughout the treatment following by an observational time period including radiological assessments as clinically indicated. This observation was up to two months after end of treatment. Safety was assessed concomitantly.\n\nThe day of the first administration of ISA was considered as day 0. Samples for determination of ISA trough plasma concentrations were obtained in the morning immediately prior to scheduled ISA infusion or intake as ordered by the treating physician. As no routine TDM algorithm for ISA was available by the current literature [5,6,7], plasma samples for ISA TDM were obtained as ordered by the treating physicians and adjusted to, e.g., scheduled outpatient visits. ISA plasma concentrations were measured with electrospray ionization tandem mass spectrometry on a Voyager TSQ Quantum triple quadrupole instrument equipped with an Ultimate 3000 chromatography system (Thermo Instruments, San Jose, California, USA) as reported recently [18]. The laboratory investigating ISA plasma concentrations participated in international ISA round-robin tests [18].\n\nThe study was approved by the local ethics committee, Medical University Graz, Austria (protocol number 29–444 ex 16/17). All statistical analyses were performed using R version 3.5.1. Continuous data (i.e., ISA plasma concentrations) are presented as medians (inter-quartile ranges [IQR]). The data at patient level were summarized by calculating the median (alternatively maximum) of Isavuconazole levels. More specifically, in patients with more than one single measurement, the median and maximum levels of Isavuconazole were calculated. By doing so, each patient is represented by one single summary measurement (median or maximum) and standard statistical tests can be applied. We used the median as the main variable for comparison between groups and the maximum value was used for sensitivity analysis. Measurements of patients assigned to specified groups (i.e., with or without extracorporal treatments) were considered independent. Group comparisons were performed by Wilcoxon-rank-sum test. A p-value of <0.05 was considered significant.\n\n3. Results\n3.1. Study Cohort\nA total of 33 courses of ISA treatment were administered to 32 patients (23 (72%) male, nine (28%) female; median age 60 years, range 24 to 85 years, IQR 46–69). Study patients had a median body mass index of 24.6 kg/m2 (range 18.5 to 39.6, IQR 23.3–28.5). A total of 14 patients (44%) had hematological diseases (13 malignant), whereas the 18 other patients (56%) had mixed underlying diseases (Table 1).\n\nFourteen of 32 patients (44%) had proven invasive fungal disease, nine (28%) had probable and nine (28%) had possible invasive fungal disease. One patient with two courses of ISA was classified as suffering from probable invasive fungal disease on both occasions. The median duration of ISA administration was 45 days (min 1, max 441 days, IQR 16–106 days). In 12/33 (36%) ISA courses the patients received only the intravenous and in 6/33 (18%) courses only the oral formulation of ISA. In 15/33 (45%) ISA courses patients received the intravenous and oral formulation. The intravenous ISA formulation was used for a median of 13 days (range 1–54 days, IQR 8–21) whereas the tablet was used for a median of 70 days (range 8–414 days, IQR 34–201). In a total of 20/33 courses (61%) the patients received antifungal therapy or prophylaxis prior to ISA, in six of these 20 courses (30%) ISA was used due to failure and in 13/20 courses (65%) ISA was used due to side effects of preceding antifungals. A total of 11/32 patients (34%) were on renal replacement therapy (RRT; continuous hemodialysis, continuous hemofiltration, or a combination of both), while three of these patients additionally had extracorporeal membrane oxygenation (ECMO) and one additionally had Cytosorb® adsorber therapy (CytoSorbents Europe, Berlin, Germany).\n\n3.2. Isavuconazole Efficacy and Safety\nComplete response occurred in 18/30 (60%) ISA courses, partial response in 8/30 (27%), and stable disease in 1/30 (3%) ISA courses. Assessment was not possible in three cases. Three out of 32 patients (9%) had a fatal outcome during hospitalization attributable to fungal disease. One patient with pulmonal and cerebral aspergillosis died on day 4 and had no ISA plasma concentrations measured. One patient with possible invasive mould disease died on day 10 of ISA treatment and had 1.36 µg/mL ISA plasma concentration on day 3 (without RRT) and 1.69 µg/mL on day 6 while on continuous hemodialysis. The remaining patient received six days of ISA, was switched to lipAmpB plus voriconazole after receiving the antifungal susceptibility testing of a Fusarium solani blood stream isolate and died six weeks later (minimal inhibitory concentrations were 2 µg/mL for Amphotericin B, 1.5 µg/mL for voriconazole and >32 µg/mL for ISA). ISA plasma concentrations were 1.51 µg/mL on day 4, 1.32 µg/mL on day 6 of ISA treatment, and 1.36 µg/mL two days after termination of ISA treatment. In 3/33 (9%) ISA courses no classification was possible (one patient with only one dose of ISA, one patient with acute aortic valve avulsion, one patient with secondary sclerosing cholangitis). Overall, a total of 11/32 patients (34%) had a fatal outcome during hospitalization including the three IFI related deaths. No breakthrough infection during ISA administration was observed.\n\nSix of 33 (18%) ISA treatments led to adverse events including one case with an anaphylaxis (including dyspnea and generalized erythema), one with leucopenia (1.52G/L), two with elevated liver enzymes, one with paraesthesia and one with erythema and elevated liver enzymes. All of these patients had concomitant medication, thus the role of ISA in the reported adverse events remains unclear. All patients recovered fully from adverse events.\n\n3.3. Isavuconazole TDM\nA total of 145 ISA plasma concentrations were measured. Five ISA plasma concentrations were excluded due to erroneous sampling time points (three samples were not trough levels as samples were obtained after ISA intake, two samples were obtained after termination of ISA treatment). Thus, 140 ISA plasma concentrations were analyzed from 29 courses of ISA treatment with a median of three measurements per patient (range 1–18). There was no change in the dosage due to the measured plasma levels. In three out of four patients with missing ISA plasma concentrations ISA was administered for less than 5 days (single dose, 3 days and 4 days, respectively) while it was administered for one month in one patient. Median time of first measurement after initiation was 2.28 days (range 0.74–9.08, IQR 1.51–2.86). The median plasma concentration was 2.35 µg/mL (range 0.66 to 9.1 IQR 1.49–3.71). After exclusion of values during RRT or ECMO the median ISA concentration was 3.05 µg/mL (range 1.38–9.1, IQR 1.93–4.35) (Figure 1). The median level of seven patients receiving RRT was 0.91 µg/mL (range 0.66–2.44, IQR 0.82–1.36). Compared to values without RRT ISA concentration remained at a lower level over treatment period (Figure 2). After exclusion of values from four patients obtained during RRT and additional extracorporeal treatments (ECMO or Cytosorb® adsorber therapy) the median concentration was 0.91 µg/mL (range 0.75–2.44, IQR 0.90–1.36) in the RRT group. Patients without extracorporal treatments also had higher maximum Isavuconazole trough levels compared to the groups with extracorporal treatments (p < 0.001 for RRT; and <0.003 for RRT plus ECMO). Two patients (body mass index 23 and 26 kg/m2) with influenza and ARDS received ECMO (iLA activve®, Novalung, Heilbronn, Germany) for pulmonary support and continuous RRT. One ECMO patient was treated with a standard dose of ISA for invasive aspergillosis since preceding and dose escalated intravenous voriconazole did not reach target levels of >1 µg/mL. On day 12 after initiation of intravenous ISA the plasma concentration was measured and was 1.79 µg/mL. The patient died 2 days later due to a gangrenous bowel. The other ECMO patient had a standard dose of ISA for treatment of probable intraabdominal Candida parapsilosis infection after failure of caspofungin. On day 1 and 4 after initiation of intravenous ISA the plasma concentration was 0.74 µg/mL (during loading dose) and 0.57 µg/mL, respectively. ECMO was terminated on day 6. Subsequent ISA plasma concentration during the second ISA treatment course of this particular patient was 2.44 µg/mL while receiving RRT. The patient died 5 weeks later due to secondary sclerosing cholangitis. The third patient was treated with a Cytosorb® cytokine adsorber within a continuous RRT circuit for 4 days and had an ISA plasma concentration of 1.3 µg/mL immediately prior and 0.82 µg/mL on the last day of adsorber treatment. Subsequent ISA plasma concentrations determined 14 and 32 days after the adsorber treatment but during ongoing RRT were 0.62 µg/mL and 0.91 µg/mL. This patient suffered from pulmonary invasive aspergillosis and had a favorable response after 56 days of ISA treatment. The fourth patient developed ARDS after major cardiac surgery and was treated for pulmonary invasive aspergillosis. ISA concentration was measured daily during a period of 18 days. During ECMO the median ISA concentration was 1.7 µg/mL. On day 12 additional RRT was initiated and ISA concentration decreased to 0.8 µg/mL. ECMO was discontinued on day 15 but RRT was still ongoing and ISA concentration remained below 0.9 µg/mL. Boxplots of ISA plasma concentrations with and without extracorporeal treatments are shown in Figure 1. Overall, there was no correlation of ISA plasma concentrations and complete response or body mass index and ISA plasma concentrations.\n\nAmong the six of 33 (18%) ISA treated patients with adverse events, four had ISA plasma concentrations measured, which were always below 5.5 µg/mL (in the two patients who developed anaphylaxis and leucopenia, respectively, no ISA plasma concentrations were measured).\n\n4. Discussion\nIn our cohort ISA was used for treatment of invasive fungal diseases in patients with malignant and non-malignant underlying diseases. Overall, ISA was well tolerated compared to previous studies [4,10]. Eighteen percent had adverse events during treatment including one ISA case with suspected immediate allergic reaction. The rate of side effects in our study was much lower compared to the SECURE trial where systematic prospective assessment revealed that 96% of patients experienced mostly mild treatment-emergent adverse events [4]. In routine clinical setting side effects were previously reported in approximately 30% [10]. ISA treatment led to complete and partial response in 87% of our patients, whereas progression of invasive fungal infection occurred in 9% of ISA treated patients leading to death. Comparable to previous studies no threshold for efficacy could be identified in our study, presumably due to the low number and short term treatments of failure patients.\n\nAs influenza might result in ARDS requiring extracorporeal membrane oxygenation (ECMO) and was reported to be an independent risk factor for invasive pulmonary aspergillosis [19] the selection of antifungal drugs for treatment of invasive fungal infection in ECMO patients is of utmost importance. Difficulties of voriconazole and micafungin dosing in patients receiving ECMO due to drug sequestration by the ECMO circuit was described previously [20,21]. In our cohort two patients required veno-venous ECMO for treatment of influenza-associated ARDS and received ISA for invasive aspergillosis or probable invasive candidiasis. Currently, there is no literature reporting on ISA levels in such patients. In this study, three patients were on ECMO and continuous RRT in parallel. Whereas one patient had an ISA trough level of 1.70 µg/mL measured on day 12 of ISA treatment, the second had constantly low ISA levels <1 µg/mL (measured on day 1 and 4 during ECMO but increased to 2.44 µg/mL after termination of ECMO on day 6 but ongoing RRT). The third patient had a median ISA concentration of 1.7 µg/mL during ECMO but experienced lower levels after initiation of additional RRT.\n\nThese findings are of course limited by low numbers but may highlight the need of ISA TDM in patients with ongoing ECMO, a fact that was also previously reported for other antifungals like voriconazole or caspofungin. Based on ISA concentrations measured in our ECMO patients one might assume that ISA is sequestrated within the ECMO circuit during the first days of treatment leading to low plasma concentrations according to an assumption previously described for voriconazole [20]. As both patients had ISA plasma concentrations >1 µg/mL while RRT was in place, this extracorporeal treatment obviously had no detrimental effect on ISA plasma concentrations in these particular patients. In the remaining group of patients receiving RRT, one patient had ISA plasma concentrations of 0.62 and 0.67 µg/mL while all the other RRT patients had concentrations >1 µg/mL. Previously, ISA levels were significantly lower after Sustained Low-Efficiency Dialysis (SLED) for treatment of renal impairment in critically ill hematology patients suffering from probable invasive aspergillosis (5.73 μg/mL vs. 3.36 μg/mL; p < 0.001; 42% reduction rate of ISA concentration) [22]. Our critically ill patients with RRT received continuous hemodialysis and/or continuous hemofiltration and had a median ISA concentration of 1.12 μg/mL, which was significantly lower compared to patients without RRT. As no ISA was detectable in the ultrafiltrate in the above mentioned study adsorption of ISA to the extracorporeal circuit has to be assumed [22].\n\nCytokine reduction by hemoadsorption aims to attenuate the overwhelming systemic levels of pro-inflammatory and anti-inflammatory mediators released in the early phase of sepsis. One of our ISA treated patient had a Cytosorb® cytokine adsorber four times for 16 h each within a RRT circuit. Whereas no data of this cytokine adsorber are available determination of ISA plasma concentrations in our patient suggest that this particular device might lower ISA plasma concentrations. However, as the patient subsequently showed ISA plasma concentrations of 0.68 µg/mL and 0.91 µg/mL 14 and 32 days after cytokine adsorption the exact effect of the Cytosorb® cytokine adsorber remains unclear.\n\nOne of our patients had a body mass index (BMI) of 39.6 kg/m2 (140 kg body weight) which was outside the BMI and weight standard deviations of published ISA data [23,24]. Previously, a significant relationship between BMI and clearance was found hence the suitable ISA dosage in very obese patients is unknown [23]. Despite the high BMI of 39.6 kg/m2 the patient received the standard dose of ISA for treatment of probable invasive aspergillosis and was closely monitored by ISA plasma concentrations. The obtained ISA plasma concentrations were 1, 2.42, 3.68 and 3.42 µg/mL, respectively. The patient had a complete response.\n\nA post hoc analysis of ISA exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial showed that no statistically significant relationship between ISA exposure and either efficacy or safety endpoints. The authors concluded that lack of association between exposure and efficacy indicates that the ISA exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that side effects were not related to increase in exposures [5]. Comparable ISA plasma concentrations in clinical use and study populations receiving ISA have been observed [9]. However, due to lack of patient-level data assessment of outcome and safety data with regard to ISA concentration was not possible from that study [9]. In an analysis of 19 hematology patients no ISA concentration cut off for efficacy could be identified, but 5 µg/mL was proposed as the upper normal range due to mainly gastrointestinal side effects [10]. In our patient cohort no calculation of treatment failure was possible as deceased patients had ISA treatment durations of only 4–10 days. In patients with adverse events ISA plasma concentrations were always below 5.5 µg/mL. Recently, increased dosage up to 300 mg of ISA per day for treatment of cerebral invasive aspergillosis has been suggested based on two cases [25]. As ISA concentrations within the brain abscess and inflamed meninges were close to ISA plasma concentration but were much lower in normal brain tissue, we assume that ISA TDM might help to adequately dose and manage adverse events in central nervous system aspergillosis cases.\n\n5. Conclusions\nIn summary, ISA was used in patients with and without hematological malignancies for treatment of invasive fungal diseases. ISA was efficacious, well tolerated and showed ISA plasma concentrations comparable to previously successfully treated patients even in cases with high body weight (BMI). Plasma concentrations in patients receiving RRT were significantly lower compared to patients without. However, due to low numbers of patients with high body weight and RRT as well as inconsistent or low levels obtained in patients with ECMO or cytokine adsorber we propose to monitor ISA plasma concentrations in such patients to attain previously suggested but still uncertain target levels of ISA >1 µg/mL [5,9,22].\n\nAuthor Contributions\nConceptualization, R.K., C.Z.; methodology, R.K., C.Z., M.W., A.O.; formal analysis, R.K., C.Z. resources, A.M.; data curation, R.K., C.Z., M.W., F.S., T.M., N.B., I.Z.-S., T.V., E.U., S.W., Y.G., J.P.; writing—original draft preparation, R.K., C.Z., M.H.; writing—review and editing, R.K., C.Z., T.M., I.Z.-S., T.V., E.U., S.W., J.P., M.H., A.O.; All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis study was supported by an investigator initiated research grant provided by Pfizer (grant number WI242120_IIR). The sponsor had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nConflicts of Interest\nR. Krause received research grants from Merck and Pfizer and served on the speakers’ bureau of Pfizer, Gilead, Astellas, Basilea, Merck and Angelini. M. Hoenigl received research funding from Gilead. J. Prattes received consulting fees from Gilead and travel grants from Angelini, Gilead, MSD and Pfizer. All of the mentioned companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nFigure 1 Boxplots showing median Isavuconazole trough plasma concentration in patients with and without extracorporeal treatments. CRRT = renal replacement therapy, ECMO = extracorporeal membrane oxygenation, adsorber = cytosorb adsorber. P-Values are shown above the brackets. Dots represent outliers.\n\nFigure 2 Spaghetti plot of Isavuconazole plasma concentration in patients with and without continuous renal replacement therapy (CRRT).\n\njof-06-00090-t001_Table 1Table 1 Demographics of Isavuconazole (ISA) treated patients.\n\n\n32 ISA Patients\n\t\nAge, median (IQR), years\t60 years (46–69)\t\nFemale sex, No. (%)\t9 (28%)\t\nWeight, median (IQR), kg\t75 (65–84) \t\nBody Mass Index (BMI), median (IQR), kg/m2\t24.6 (23.3–28.5)\t\n<18.5: underweight, No. (%)\t0 (0%)\t\n18.5 to <25: normal, No. (%)\t19 (59%)\t\n25 to <30: overweight, No. (%)\t7 (22%)\t\n≥30: obese, No. (%)\t6 (19%)\t\n\nInvasive fungal infection (IFI), EORTC (33 ISA courses )\n\t\nPossible, No. (%)\t9 (27%)\t\nProbable, No. (%)\t10 (30%) \t\nProven, No. (%)\t14 (42%)\t\n\nUnderlying diseases\n\t\nHematological disease *\t14 (44%)\t\nSolid cancer\t2 (6%)\t\nSolid organ transplantation\t4 (13%)\t\nCollagenosis/autoimmune diseases\t2 (6%)\t\nType 2 diabetes\t2 (6%)\t\nRespiratory tract diseases\t3 (9%)\t\nBacterial infections\t3 (9%)\t\nCoronary heart disease\t1 (3%)\t\nTrauma associated osteomyelitis\t1 (3%)\t\n One patient with two courses of ISA had probable IFI on both occasions. ** Acute myeloid leukemia 5 patients, aplastic anemia 1 patient, acute lymphatic leukemia 2 patients, chronic lymphatic leukemia 1 patient, lymphoma 4 patients, hemophagocytic syndrome 1 patient.\n==== Refs\nReferences\n1. 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European organization for the research and treatment of cancer/mycoses study group (eortc/msg) host factors and invasive fungal infections in patients with haematological malignancies J. Antimicrob. Chemother. 2012 67 2029 2033 10.1093/jac/dks155 22566591 \n17. Cornely O.A. Hoenigl M. Lass-Florl C. Chen S.C. Kontoyiannis D.P. Morrissey C.O. Thompson G.R. 3rd Defining breakthrough invasive fungal infection-position paper of the mycoses study group education and research consortium and the european confederation of medical mycology Mycoses 2019 62 716 729 10.1111/myc.12960 31254420 \n18. Pea F. Krause R. Müller C. Hennart B. Richardson M. Meinitzer A. Wiesen M.H.J. Wiktorowicz T. Spickermann J. Henriksen A.S. Interlaboratory analysis of isavuconazole plasma concentration assays among european laboratories Ther. Drug Monit. 2019 41 657 664 10.1097/FTD.0000000000000632 31568234 \n19. Schauwvlieghe A. Rijnders B.J.A. Philips N. Verwijs R. Vanderbeke L. Van Tienen C. Lagrou K. Verweij P.E. Van de Veerdonk F.L. Gommers D. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: A retrospective cohort study Lancet Respir. Med. 2018 6 782 792 10.1016/S2213-2600(18)30274-1 30076119 \n20. Spriet I. Annaert P. Meersseman P. Hermans G. Meersseman W. Verbesselt R. Willems L. Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation J. Antimicrob. Chemother. 2009 63 767 770 10.1093/jac/dkp026 19218271 \n21. Watt K.M. Cohen-Wolkowiez M. Williams D.C. Bonadonna D.K. Cheifetz I.M. Thakker D. Benjamin D.K. Jr. Brouwer K.L.R. Antifungal extraction by the extracorporeal membrane oxygenation circuit J. Extra-Corporeal Technol. 2017 49 150 159 \n22. Lahmer T. Batres Baires G. Heilmaier M. Schmid R.M. Sorgel F. Kinzig M. Huber W. Mayr U. Rasch S. Influence of sustained low-efficiency dialysis (sled) treatment on isavuconazole plasma levels in critically ill patients Antimicrob. Agents Chemother. 2019 63 e01162-19 10.1128/AAC.01162-19 31427296 \n23. Kovanda L.L. Desai A.V. Lu Q. Townsend R.W. Akhtar S. Bonate P. Hope W.W. Isavuconazole population pharmacokinetic analysis using nonparametric estimation in patients with invasive fungal disease (results from the vital study) Antimicrob. Agents Chemother. 2016 60 4568 4576 10.1128/AAC.00514-16 27185799 \n24. Marty F.M. Ostrosky-Zeichner L. Cornely O.A. Mullane K.M. Perfect J.R. Thompson G.R. 3rd Alangaden G.J. Brown J.M. Fredricks D.N. Heinz W.J. Isavuconazole treatment for mucormycosis: A single-arm open-label trial and case-control analysis Lancet Infect. Dis. 2016 16 828 837 10.1016/S1473-3099(16)00071-2 26969258 \n25. Rouzaud C. Jullien V. Herbrecht A. Palmier B. Lapusan S. Morgand M. Guery R. Dureault A. Danion F. Puget S. Isavuconazole diffusion in infected human brain Antimicrob. Agents Chemother. 2019 63 e02474-18 10.1128/AAC.02474-18 31405852\n\n", "fulltext_license": "CC BY", "issn_linking": "2309-608X", "issue": "6(2)", "journal": "Journal of fungi (Basel, Switzerland)", "keywords": "anti-infective agents; antifungal therapy; fungal infections; isavuconazole; therapeutic drug monitoring", "medline_ta": "J Fungi (Basel)", "mesh_terms": null, "nlm_unique_id": "101671827", "other_id": null, "pages": null, "pmc": null, "pmid": "32580296", "pubdate": "2020-06-22", "publication_types": "D016428:Journal Article", "references": "22517788;29735569;30816967;19218271;28011902;27365388;18637757;31568234;22566591;26684608;30076119;27185799;31427296;18462102;30476108;29750016;29581116;31119272;28923872;31405852;28979038;31254420;26969258;26684607", "title": "Isavuconazole Treatment in a Mixed Patient Cohort with Invasive Fungal Infections: Outcome, Tolerability and Clinical Implications of Isavuconazole Plasma Concentrations.", "title_normalized": "isavuconazole treatment in a mixed patient cohort with invasive fungal infections outcome tolerability and clinical implications of isavuconazole plasma concentrations" }	[ { "companynumb": "AT-ASTELLAS-2019US038076", "fulfillexpeditecriteria": "1", "occurcountry": "AT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DALTEPARIN SODIUM" }, "drugadditional": null,...
{ "abstract": "Brentuximab vedotin (BV), an antibody drug conjugate against CD30, has been increasingly used in clinical practice, and the less common adverse events associated to the drug are not well described. Also, opportunistic infections have been reported, and data on immune reconstitution after use of BV are lacking. The authors describe a case of a 45-year-old man with Hodgkin lymphoma receiving BV as a consolidation therapy after autologous hematopoietic stem cell transplant. After nine months of consolidation with BV, the patient developed a respiratory disorder characterized by fever, chills, dyspnea, and hypoxemia, and pneumonia by Pneumocystis jirovecii (PJ) was confirmed by bronchoscopy with bronchoalveolar lavage. In spite of the fact that there are no specific recommendations about infectious prophylaxis in patients using the drug, we would like to draw the attention of professionals who use the medication in relation to the risk of opportunistic infections, such as pneumonia by PJ.", "affiliations": "Hematology and Bone Marrow Department, Hospital Sirio Libanes, Sao Paulo, Brazil.;Infectious Diseases Department, Hospital Sirio Libanes, Sao Paulo, Brazil.;Hematology and Bone Marrow Department, Hospital Sirio Libanes, Sao Paulo, Brazil.;Hematology and Bone Marrow Department, Hospital Sirio Libanes, Sao Paulo, Brazil.", "authors": "Ferreira\|Aliana Meneses\|AM\|0000-0003-1672-9261;Ramos\|Jessica Fernandes\|JF\|0000-0002-7023-9514;Fatobene\|Giancarlo\|G\|;Rocha\|Vanderson\|V\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2019/8982937", "fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi 10.1155/2019/8982937Case Report\nPneumocystis jirovecii Pneumonia during Brentuximab Vedotin Therapy: A Case Report and Literature Review http://orcid.org/0000-0003-1672-9261Ferreira Aliana Meneses ali_ferreira@hotmail.com\n1\nhttp://orcid.org/0000-0002-7023-9514Ramos Jessica Fernandes \n2\nFatobene Giancarlo \n1\nRocha Vanderson \n1\n\n1Hematology and Bone Marrow Department, Hospital Sirio Libanes, Sao Paulo, Brazil\n2Infectious Diseases Department, Hospital Sirio Libanes, Sao Paulo, BrazilAcademic Editor: Håkon Reikvam\n\n2019 26 3 2019 2019 898293726 9 2018 14 2 2019 4 3 2019 Copyright © 2019 Aliana Meneses Ferreira et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Brentuximab vedotin (BV), an antibody drug conjugate against CD30, has been increasingly used in clinical practice, and the less common adverse events associated to the drug are not well described. Also, opportunistic infections have been reported, and data on immune reconstitution after use of BV are lacking. The authors describe a case of a 45-year-old man with Hodgkin lymphoma receiving BV as a consolidation therapy after autologous hematopoietic stem cell transplant. After nine months of consolidation with BV, the patient developed a respiratory disorder characterized by fever, chills, dyspnea, and hypoxemia, and pneumonia by Pneumocystis jirovecii (PJ) was confirmed by bronchoscopy with bronchoalveolar lavage. In spite of the fact that there are no specific recommendations about infectious prophylaxis in patients using the drug, we would like to draw the attention of professionals who use the medication in relation to the risk of opportunistic infections, such as pneumonia by PJ.\n==== Body\n1. Introduction\n\nPneumocystis jirovecii (PJ) is an opportunistic infection known to cause life-threatening pneumonia in immunocompromised patients and is associated with substantial morbidity and mortality [1, 2]. Its incidence in patients receiving targeted therapies has not been established, although abnormalities in immune cellular function caused by these drugs may be associated with an increased risk for developing PJ pneumonia. Brentuximab vedotin (BV) is an antibody-drug conjugate against CD30 that has increasingly been used for treatment of Hodgkin lymphoma (HL) and other lymphoproliferative diseases [3].\n\nDespite being a well-tolerated drug, opportunistic infections have been reported in patients undergoing BV therapy. PJ pneumonia, however, is rare, and only a few cases have been reported in the literature [4, 5]. Moreover, the role of the drug in the occurrence of this infection and how to best prevent it are largely unknown, while data regarding immune reconstitution after prolonged use of BV are lacking.\n\nHerein, we report a case of PJ pneumonia in a patient with HL undergoing BV therapy, followed by a discussion on BV-related susceptibility to this infection, and suggested approaches to patients exposed to the drug.\n\n2. Case Report\nA 45-year-old man with no relevant medical history presented with complaints of a persistent dry cough, fever, and night sweats in August 2014. He sought urgent medical assistance a couple of times during this period and underwent empirical antibiotic therapy without improvement. A more detailed investigation using chest-computed tomography (CT) revealed thoracic lymphadenopathies; an excisional biopsy of a cervical lymph node was compatible with mixed cellularity classical HL (CD20 negative, CD3 negative, CD30 positive, CD15 negative, and PAX5 positive). Positron emission tomography-computed tomography (PET-CT) was performed for staging, which revealed involvement of the supra- and infradiaphragmatic lymph nodes, with no extranodal involvement, consistent with Ann Arbor stage IIIB disease.\n\nThe patient underwent polychemotherapy consisting of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). After two cycles, an interim PET-CT scan was negative; he underwent a total of six cycles of ABVD treatment; nevertheless, the posttreatment PET-CT scan remained negative.\n\nUnfortunately, five months later, in January 2015, a screening CT scan revealed iliac and retroperitoneal lymphadenopathy. A new biopsy revealed relapse of his HL. He then underwent second-line therapy with ifosfamide, carboplatin, and etoposide (ICE); however, the disease remained refractory after two cycles. A third-line therapy based on gemcitabine was successful, and hematopoietic stem cells were collected by apheresis in April 2015. A PET-CT scan after two cycles revealed complete response (Deauville score, 2), and the patient was referred to the authors' service for autologous hematopoietic stem cell transplant (HSCT) as consolidation therapy.\n\nThe autologous transplant was performed following a conditioning regimen with carmustine, etoposide, cytarabin and melphalan (BEAM) in May 2016. His transplant course was unremarkable, and neutrophil engraftment occurred 10 days later. A posttransplant PET-CT scan revealed persistent complete response.\n\nBecause the disease had relapsed <12 months after the completion of frontline therapy, the patient was started on BV according to the brentuximab vedotin as consolidation therapy after autologous stem cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA) study, as posttransplant consolidation in July 2016 [6]. He received BV 1.8 mg/kg every three weeks, for a total of 16 doses.\n\nIn April 2017, after 10 doses of BV, the patient presented with sneezing, dry cough, and odynophagia, but without dyspnea, thoracic pain, or other associated symptoms. His workup revealed no abnormalities in whole blood count or acute inflammatory markers, and a chest CT scan was normal. Empirical treatment with levofloxacin and oseltamivir for upper respiratory tract infection was started, and he experienced partial improvement of symptoms. A polymerase chain reaction (PCR) assay for respiratory viruses was negative; therefore, oseltamivir was discontinued. Two weeks later, the patient returned to the authors' center with fever, chills, dyspnea, and asthenia. His physical examination was remarkable for a respiratory rate of 28 breaths/min, hypoxemia (arterial oxygen partial pressure 69 mmHg), and crackles on pulmonary auscultation. No adenopathies were observed.\n\nOn admission, a repeat workup revealed a hemoglobin level of 10.8 g/dL (108 g/L), leucocytes 4670/mm3 (neutrophils 3540/mm3 and lymphocytes 650/mm3), a platelet count of 105,000/mm3, and a lactate dehydrogenase level of 740 U/L (normal range, 240–480 U/L). A chest CT scan revealed areas of parenchymal consolidation and diffuse ground-glass opacities in both lungs, with predominantly peribronchovascular distribution in the upper and middle fields (Figure 1). He was started on empirical therapy with piperacillin-tazobactam (4.5 g every 6 h), oseltamivir (75 mg twice per day), and trimethoprim/sulfamethoxazole (trimethoprim 17 mg/kg/day). A bronchoscopy with bronchoalveolar lavage was performed, which was positive for PJ according to toluidine blue staining and to PCR analysis.\n\nProphylaxis against pneumocystis was initiated in the patient at the time of neutrophilic engraftment after the transplant in June 2016 according to institutional guidelines. However, the patient had stopped it on his own due to gastrointestinal adverse effects for the preceding two months. The last CD4 lymphocyte count available from the patient in March 2017 was 317 cells/mm3.\n\nAfter a 21-day course of treatment with trimethoprim/sulfamethoxazole, the patient experienced full clinical recovery and was restarted on prophylaxis.\n\n3. Discussion\nBV is a monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin-E, targeting CD30-positive cells [7]. It was approved by the United States Food and Drug Administration (FDA) in 2011 for treatment of relapsed or refractory classical HL and anaplastic large-cell lymphoma. In 2015, the FDA expanded its indication as consolidation treatment following autologous HSCT in patients with classical HL at high risk for relapse or progression, based on the results of phase III of the AETHERA trial [6, 8].\n\nIt is not well established how BV affects the immune system, aside from its direct tumor cell cytotoxicity. Normal expression of CD30 is highly restricted to a relatively small population of activated B and T cells, and a small portion of eosinophils, suggesting that the use of BV represents a selective treatment strategy with limited interference in immune function [3]. However, we were unable to find data regarding immune abnormalities and immune reconstitution in patients treated with BV. Therefore, the risk for opportunistic infections in this population remains unclear, which necessitates specific antimicrobial prophylaxis during and after treatment.\n\nDespite the warning on the drug label about the risk for serious and/or opportunistic infections, such as oral candidiasis and PJ pneumonia, no specific prophylaxis is recommended. Nevertheless, it is suggested that patients should be carefully monitored during treatment for the emergence of these conditions. In phase III trials of the drug, it was reported in the context of postautologous HSCT that standard international guidelines for infection prophylaxis, including PJ pneumonia, were followed [6].\n\nSince the initial studies, BV has been increasingly used to treat patients with lymphoproliferative diseases and other medical conditions (e.g., graft versus host disease) in clinical trial settings. Because its use has become more frequent, adverse events have been reported with increasing consistency. The most common adverse events reported to date, typically grade 1 or 2 in severity, have been fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. Although upper respiratory infections occur in a proportion of patients, few cases of pneumonia have been reported [7].\n\nTo our knowledge, only two cases of PJ pneumonia possibly related to BV use have been published. In a report published in 2012, involving 25 heavily pretreated patients with relapsed CD30-positive HL after allogeneic HSCT who received BV, infectious adverse events of at least grade 3 were reported in six (24%) patients. One of these patients experienced a grade 3 respiratory infection—presumably PJ pneumonia—but without laboratory confirmation [4]. The second case was reported in a cohort of 11 patients with diffuse large B-cell lymphoma treated with frontline BV-rituximab, cyclophosphamide, doxorubicin, and prednisone therapy; however, the diagnostic method was not described [5]. Unlike these cases, the diagnosis of pneumocytosis in our case was based on two laboratory methods, including toluidine blue stain, with a better positive predictive value, leaving no doubt about the diagnosis. Additionally, there is no information about these previously reported patients regarding use of prophylaxis at the time of diagnosis of the infection.\n\nIn the AETHERA study, the most common treatment-emergent adverse event in the BV group was peripheral sensory neuropathy. Severe infections (grade ≥ 3) were reported in 11 (7%) patients in the BV group and nine (6%) patients in the placebo group, with no cases of pneumocytosis reported. Similarly, no infections were reported in multiple articles, describing the experience with BV in many countries around the world.\n\nCases of progressive multifocal leukoencephalopathy (PML) have been reported since the approval of BV, which prompted the addition of a warning to the drug label highlighting this potential risk [9]. The physiopathology associated with PJ infection, similar to that of the John Cunningham polyomavirus involved in PML, is predominantly related to defects in CD4 T-cell-mediated immunity, although innate and humoral immune mechanisms may also play a role in host defense against these agents [10]. Therefore, it is plausible to hypothesize that patients undergoing BV therapy are at increased risk for both PML and PJ pneumonia.\n\nNevertheless, it is not possible to assert a causal relationship between the use of BV and the development of PJ pneumonia as multiple risk factors concomitantly present in these patients, such as lymphoid malignancies, multiagent chemotherapy, and HSCT, all of which are potential confounders in assessing the association between PJ infection and BV.\n\nTherefore, given the high morbidity and potential mortality of pneumocytosis, this report raises awareness to the continuous risk for pneumocystis infection in patients receiving BV, to define the real need for prophylaxis. A global survey investigating specific cases of pneumocytosis in patients exposed to BV may clarify the actual magnitude of this potential serious adverse event.\n\nConsent\nThe patient described in this case report consented to the publication of anonymized details.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 A chest-computed tomography scan revealing areas of parenchymal consolidation and diffuse ground-glass opacities.\n==== Refs\n1 Maschmeyer G. Helweg-Larsen J. Pagano L. Robin C. Cordonnier C. Schellongowski P. ECIL guidelines for treatment of Pneumocystis jirovecii pneumonia in non-HIV-infected haematology patients Journal of Antimicrobial Chemotherapy 2016 71 9 2405 2413 10.1093/jac/dkw158 2-s2.0-85021787375 27550993 \n2 Cordonnier C. Cesaro S. Maschmeyer G. \nPneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients Journal of Antimicrobial Chemotherapy 2016 71 9 2379 2385 10.1093/jac/dkw155 2-s2.0-85015293304 27550990 \n3 Ansell S. M. Brentuximab vedotin Blood 2014 124 22 3197 3200 10.1182/blood-2014-06-537514 2-s2.0-84911385117 25293772 \n4 Gopal A. K. Ramchandren R. O’Connor O. A. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation Blood 2012 120 3 560 568 10.1182/blood-2011-12-397893 2-s2.0-84864132475 22510871 \n5 Budde L. E. Halwani A. Yasenchak C. A. Results of an ongoing phase 2 study of brentuximab vedotin with RCHP as frontline therapy in patients with high-intermediate/high-risk diffuse large B cell lymphoma (DLBCL) Blood 2016 128 22 p. 104 \n6 Moskowitz C. H. Nademanee A. Masszi T. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial The Lancet 2015 385 9980 1853 1862 10.1016/S0140-6736(15)60165-9 2-s2.0-84929510996 \n7 Younes A. Bartlett N. L. Leonard J. P. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas New England Journal of Medicine 2010 363 19 1812 1821 10.1056/nejmoa1002965 2-s2.0-78049515807 21047225 \n8 de Claro R. A. McGinn K. Kwitkowski V. U.S. food and drug administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma Clinical Cancer Research 2012 18 21 5845 5849 10.1158/1078-0432.CCR-12-1803 2-s2.0-84868561570 22962441 \n9 Carson K. R. Newsome S. D. Kim E. J. Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project Cancer 2014 120 16 2464 2471 10.1002/cncr.28712 2-s2.0-84905667133 24771533 \n10 Gicliotti F. Limper A. H. Wright T. Pneumocystis Cold Spring Harbor Perspectives in Medicine 2014 4 12 a019828 10.1101/cshperspect.a019828 2-s2.0-84923773865\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6579", "issue": "2019()", "journal": "Case reports in hematology", "keywords": null, "medline_ta": "Case Rep Hematol", "mesh_terms": null, "nlm_unique_id": "101576456", "other_id": null, "pages": "8982937", "pmc": null, "pmid": "31049233", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "21047225;22510871;22962441;24771533;25293772;25367973;25796459;27550990;27550993", "title": "Pneumocystis jirovecii Pneumonia during Brentuximab Vedotin Therapy: A Case Report and Literature Review.", "title_normalized": "pneumocystis jirovecii pneumonia during brentuximab vedotin therapy a case report and literature review" }	[ { "companynumb": "BR-SEATTLE GENETICS-2019SGN03245", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BRENTUXIMAB VEDOTIN" }, "drugadditiona...
{ "abstract": "Because prevalent vertebral fracture (VF) is a strong predictor of future fractures, they are important to identify in clinical practice as osteoporosis medications are effective and can be used to reduce fracture risk in postmenopausal women with VF. Lateral spine imaging (LSI) with dual-energy X-ray absorptiometry (DXA) can be used to diagnose VFs accurately but is not widespread in clinical practice. The prognostic value of grade 1 (20% to 25% compression) VFs diagnosed by LSI with DXA has been insufficiently studied. The aim of this study was to determine if grade 1 VF is associated with incident fracture in older women. Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures (SUPERB) is a population-based study of 3028 older women from Gothenburg, Sweden. Included women were 75 to 80 years of age at baseline, answered questionnaires, and were scanned with DXA (Discovery A, Hologic, Waltham, MA, USA). LSI was used to diagnose VFs, which were classified using the Genant semiquantitative method. Cox regression models were used to estimate the association between VFs at baseline and X-ray-verified incident fractures, with adjustment for confounders. Women with a grade 1 VF (n = 264) or a grade 2-3 VF (n = 349) were compared with women without any fracture (n = 1482). During 3.6 years (median, interquartile range [IQR] 1.5 years) of follow-up, 260 women had any incident fracture and 213 a major osteoporotic fracture (MOF). Women with only grade 1 VF had increased risk of any fracture (hazard ratio [HR] = 1.67; 95% confidence interval [CI] 1.18-2.36) and MOF (HR = 1.86; 95% CI 1.28-2.72). For MOF, this association remained after adjustment for clinical risk factors and femoral neck bone mineral density (BMD). In conclusion, grade 1 VFs were associated with incident MOF, also after adjustment for clinical risk factors and BMD, indicating that all VF identified by DXA should be considered in the evaluation of fracture risk in older women. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..", "affiliations": "Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Clinical Chemistry and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Kungälvs Hospital, Kungälv, Sweden.;Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.", "authors": "Johansson\|Lisa\|L\|;Sundh\|Daniel\|D\|0000-0002-4301-6796;Magnusson\|Per\|P\|0000-0002-2123-7838;Rukmangatharajan\|Komagal\|K\|;Mellström\|Dan\|D\|;Nilsson\|Anna G\|AG\|;Lorentzon\|Mattias\|M\|0000-0003-0749-1431", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/jbmr.4108", "fulltext": null, "fulltext_license": null, "issn_linking": "0884-0431", "issue": "35(10)", "journal": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research", "keywords": "DXA; INCIDENT FRACTURE; MILD VERTEBRAL FRACTURE; OLDER WOMEN; VERTEBRAL FRACTURE ASSESSMENT", "medline_ta": "J Bone Miner Res", "mesh_terms": "D015502:Absorptiometry, Photon; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D005260:Female; D006801:Humans; D058866:Osteoporotic Fractures; D011446:Prospective Studies; D012307:Risk Factors; D016103:Spinal Fractures; D013548:Sweden", "nlm_unique_id": "8610640", "other_id": null, "pages": "1942-1951", "pmc": null, "pmid": "32539162", "pubdate": "2020-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Grade 1 Vertebral Fractures Identified by Densitometric Lateral Spine Imaging Predict Incident Major Osteoporotic Fracture Independently of Clinical Risk Factors and Bone Mineral Density in Older Women.", "title_normalized": "grade 1 vertebral fractures identified by densitometric lateral spine imaging predict incident major osteoporotic fracture independently of clinical risk factors and bone mineral density in older women" }	[ { "companynumb": "SE-AMGEN-SWESP2020196600", "fulfillexpeditecriteria": "2", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DENOSUMAB" }, "drugadditional": "3", ...
{ "abstract": "The diagnosis of human herpesvirus 8 (HHV8)-associated lymphoproliferative disorder (LPD) is challenging because of the rarity and extended spectrum of each entity. A 43-year-old, human immunodeficiency virus seropositive, Japanese man was referred to our department because of persistent fever, generalized lymphadenopathy, jaundice and anasarca. Biopsy of a left axially lymph node demonstrated relatively preserved nodal structure with multicentric Castleman disease (MCD) features. In the germinal center, there were aggregates of HHV8-infected plasmablasts that were diffusely positive for CD38, MUM1/IRF4, LCA, IgM and λ; partially positive for CD30, c-MYC, p53; and negative for CD138, CD20, PAX-5, κ, CD2, CD3 and CD5. A small number of Epstein-Barr virus encoded small RNA (EBER)-positive large cells infiltrated in the outer part of the germinal center and the mantle layer, but the cells copositive for EBER and HHV8 were not evident. We diagnosed the patient as HHV8-positive MCD with germinotropic plasmablastic aggregates, which demonstrated intermediate pathologic features between HHV8-positive MCD and germinotropic lymphoproliferative disorder. The pathogenesis of each HHV8-associated LPD differs in cellular origin, host immune status, cytoplasmic immunoglobulin expression, clonality pattern and EBV infection; however, these factors sometimes overlap and induce extended clinical and pathologic presentations.", "affiliations": "Department of Hematology, Osaka City General Hospital, Osaka, Japan.;Department of Pathology, Osaka City General Hospital, Osaka, Japan.;Department of Infectious Disease, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Hematology, Osaka City General Hospital, Osaka, Japan.;Department of Hematology, Osaka City General Hospital, Osaka, Japan.;Department of Hematology, Osaka City General Hospital, Osaka, Japan.;Department of Hematology, Osaka City General Hospital, Osaka, Japan.;Department of Hematology, Osaka City General Hospital, Osaka, Japan.;Department of Hematology, Osaka City General Hospital, Osaka, Japan.;Department of Hematology, Osaka City General Hospital, Osaka, Japan.;Department of Pathology, Osaka City General Hospital, Osaka, Japan.;Department of Hematology, Osaka City General Hospital, Osaka, Japan.", "authors": "Nakaya\|Yosuke\|Y\|http://orcid.org/0000-0003-3337-1599;Ishii\|Naomi\|N\|;Kasamatsu\|Yu\|Y\|;Shimizu\|Katsujun\|K\|;Tatsumi\|Naoko\|N\|;Tsutsumi\|Minako\|M\|;Yoshida\|Masahiro\|M\|http://orcid.org/0000-0002-5154-189X;Yoshimura\|Takuro\|T\|;Hayashi\|Yoshiki\|Y\|;Nakao\|Takafumi\|T\|;Inoue\|Takeshi\|T\|;Yamane\|Takahisa\|T\|", "chemical_list": null, "country": "Australia", "delete": false, "doi": "10.1111/pin.12951", "fulltext": null, "fulltext_license": null, "issn_linking": "1320-5463", "issue": "70(8)", "journal": "Pathology international", "keywords": "Epstein-Barr virus; germinotropic lymphoproliferative disorder; human herpesvirus 8; human immunodeficiency virus; multicentric Castleman disease; plasmablastic aggregates", "medline_ta": "Pathol Int", "mesh_terms": "D000328:Adult; D005871:Castleman Disease; D003937:Diagnosis, Differential; D020031:Epstein-Barr Virus Infections; D006678:HIV; D006566:Herpesviridae Infections; D004854:Herpesvirus 4, Human; D019288:Herpesvirus 8, Human; D006801:Humans; D016867:Immunocompromised Host; D008198:Lymph Nodes; D008232:Lymphoproliferative Disorders; D008297:Male", "nlm_unique_id": "9431380", "other_id": null, "pages": "574-580", "pmc": null, "pmid": "32449234", "pubdate": "2020-08", "publication_types": "D002363:Case Reports", "references": null, "title": "Human herpesvirus 8-positive multicentric Castleman disease with germinotropic plasmablastic aggregates: Overlapping spectrum of human herpesvirus 8-associated lymphoproliferative disorder.", "title_normalized": "human herpesvirus 8 positive multicentric castleman disease with germinotropic plasmablastic aggregates overlapping spectrum of human herpesvirus 8 associated lymphoproliferative disorder" }	[ { "companynumb": "JP-GILEAD-2020-0499092", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE\\TENOFOVIR" }, "drugadditional": "...
{ "abstract": "We report on a 75-year old woman who presented with acute oliguric renal failure. The kidney biopsy revealed calcium oxalate depositions in the tubular lumen, caused by an overload of intravenous ascorbic acid (cumulative dose of 240 g). Due to a lack of specific therapeutic interventions, the patient remained dialysis-dependent. Iatrogenic causes of kidney failure play an important role in the pathogenesis of kidney diseases and should always be considered in patients with acute renal failure. Detailed evaluation of the patient history is often suggestive, while renal biopsy can establish the diagnosis.", "affiliations": "III. Medizinische Klinik, Abteilung Nephrologie, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland. s.teege@uke.de.;Institut für Pathologie, Sektion Nephropathologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland.;III. Medizinische Klinik, Abteilung Nephrologie, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland.", "authors": "Teege\|S\|S\|;Wiech\|T\|T\|;Steinmetz\|O M\|OM\|", "chemical_list": "D014815:Vitamins; D002129:Calcium Oxalate; D001205:Ascorbic Acid", "country": "Germany", "delete": false, "doi": "10.1007/s00108-016-0175-y", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-9554", "issue": "58(5)", "journal": "Der Internist", "keywords": "Ascorbic acid; Calcium oxalate; Kidney biopsy; Oliguria; Renal insufficiency, iatrogenic disease", "medline_ta": "Internist (Berl)", "mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D001205:Ascorbic Acid; D002129:Calcium Oxalate; D005260:Female; D006801:Humans; D007668:Kidney; D009846:Oliguria; D014815:Vitamins", "nlm_unique_id": "0264620", "other_id": null, "pages": "507-511", "pmc": null, "pmid": "28084501", "pubdate": "2017-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "24163269;22742545;18696123;18324877;24527242;26013423;25812044;26084636;21866092", "title": "Acute renal failure in a 75-year-old woman with a high-output ileostoma.", "title_normalized": "acute renal failure in a 75 year old woman with a high output ileostoma" }	[ { "companynumb": "DE-MYLANLABS-2017M1040281", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASCORBIC ACID" }, "drugadditional": null, ...
{ "abstract": "A 60-year-old man with Addison's disease, primary hypothyroidism and type 2 diabetes mellitus who was treated with stable doses of hydrocortisone and fludrocortisone developed increasing skin pigmentation and a bitemporal hemianopia. The plasma ACTH level was 14,464 pg/mL, and an invasive pituitary macroadenoma with suprasellar extension was found on magnetic resonance imaging leading to transnasal-transsphenoidal adenomectomy. The tumor demonstrated features of an eosinophilic adenoma and stained uniformly for ACTH. Residual tumor was treated with stereotactic radiotherapy. This case and the 13 cases published previously indicate that primary adrenal failure may predispose to corticotroph hyperplasia, and in some patients to the development of an invasive corticotroph adenoma. The ACTH level should be measured, and a pituitary magnetic resonance imaging is indicated when skin pigmentation increases in a patient with primary adrenal failure who is receiving customary treatment with glucocorticoids and mineralocorticoids.", "affiliations": "Division of Endocrinology, Metabolism and Diabetes (SJW), University of Louisville School of Medicine, Louisville, Kentucky; Department of Radiation Oncology (CS), University of Louisville School of Medicine, Louisville, Kentucky; Brain Tumor Center (TV), Norton Neuroscience Institute; and Departments of Pathology (MRN), Radiology (DCC), Norton Health Care, Louisville, Kentucky.", "authors": "Winters\|Stephen J\|SJ\|;Vitaz\|Todd\|T\|;Nowacki\|Michael R\|MR\|;Craddock\|Durrett C\|DC\|;Silverman\|Craig\|C\|", "chemical_list": "D000893:Anti-Inflammatory Agents; D000324:Adrenocorticotropic Hormone; D005438:Fludrocortisone; D006854:Hydrocortisone", "country": "United States", "delete": false, "doi": "10.1097/MAJ.0000000000000305", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9629", "issue": "349(6)", "journal": "The American journal of the medical sciences", "keywords": null, "medline_ta": "Am J Med Sci", "mesh_terms": "D000224:Addison Disease; D000324:Adrenocorticotropic Hormone; D000893:Anti-Inflammatory Agents; D005438:Fludrocortisone; D006801:Humans; D006854:Hydrocortisone; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms; D011859:Radiography", "nlm_unique_id": "0370506", "other_id": null, "pages": "526-9", "pmc": null, "pmid": "25004119", "pubdate": "2015-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Addison's Disease and Pituitary Enlargement.", "title_normalized": "addison s disease and pituitary enlargement" }	[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-97182", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "d...
{ "abstract": "BACKGROUND\nMycobacterium abscessus is a rapidly growing atypical mycobacterium implicated in chronic lung disease, otitis media, surgical site infections, and disseminated cutaneous diseases. It is typically seen in patients with some degree of immunosuppression. Only 1 previous case has been reported in the setting of ventriculoperitoneal (VP) shunt infection. We report a case of M abscessus as the causative organism in a VP shunt infection in an immunocompetent adult.\n\n\nMETHODS\nA 67-year-old woman required VP shunt placement after aneurysmal subarachnoid hemorrhage complicated by hydrocephalus. Her course was complicated by repeat hospitalization for 2 shunt infections, the second of which did not respond to standard antibiotic therapy. Cultures repeatedly grew M abscessus. The patient continued to decline and eventually died after transfer to the palliative care service.\n\n\nCONCLUSIONS\nNontuberculous mycobacteria are rare, atypical organisms in the setting of VP shunt infection. Patients with ventriculitis secondary to atypical mycobacteria may exhibit drug-resistant cerebrospinal fluid pleocytosis in the face of standard antibiotic regimens.", "affiliations": "Department of Emergency Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA; Department of Neurosugery, Hofstra Northwell School of Medicine, Hempstead, New York, USA. Electronic address: zlevy@northwell.edu.;Department of Neurosugery, Hofstra Northwell School of Medicine, Hempstead, New York, USA.;Department of Neurosugery, Hofstra Northwell School of Medicine, Hempstead, New York, USA.;Department of Neurosugery, Hofstra Northwell School of Medicine, Hempstead, New York, USA.;Department of Neurosugery, Hofstra Northwell School of Medicine, Hempstead, New York, USA.", "authors": "Levy\|Zachary D\|ZD\|;Du\|Victor\|V\|;Chiluwal\|Amrit\|A\|;Chalif\|David J\|DJ\|;Ledoux\|David E\|DE\|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1878-8750", "issue": "86()", "journal": "World neurosurgery", "keywords": "Hydrocephalus; Nontuberculous mycobacteria; Subarachnoid hemorrhage; Ventriculitis; Ventriculostomy", "medline_ta": "World Neurosurg", "mesh_terms": "D000368:Aged; D055499:Catheter-Related Infections; D058565:Cerebral Ventriculitis; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006849:Hydrocephalus; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D017287:Ventriculoperitoneal Shunt", "nlm_unique_id": "101528275", "other_id": null, "pages": "510.e1-4", "pmc": null, "pmid": "26546993", "pubdate": "2016-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Ventriculoperitoneal Shunt Infection with Mycobacterium abscessus: A Rare Cause of Ventriculitis.", "title_normalized": "ventriculoperitoneal shunt infection with mycobacterium abscessus a rare cause of ventriculitis" }	[ { "companynumb": "US-BAXTER-2016BAX017458", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "dr...
{ "abstract": "Loperamide is an antidiarrheal agent available as an inexpensive over-the-counter (OTC) medication. In general, it is considered to be safe, but lately, loperamide drug abuse has been reported due to its opioid properties. When used in high doses, several harmful effects including cardiotoxicity, central nervous system (CNS) and respiratory depression have been reported. This prompted the FDA to release a warning in 2016 regarding the arrhythmogenic potential of loperamide. We present a case of a 32-year-old male with a history of polysubstance abuse who presented to the emergency department (ED) requesting \"detoxification\" from loperamide. The patient complained of opiate withdrawal symptoms including chills, nausea, vomiting, constipation, and abdominal cramps thought to be secondary to the abuse of loperamide. He was found to have right bundle branch block (RBBB) and bradycardia with a heart rate (HR) of 51 beats per min (bpm). He also reported an unexplained syncopal episode, one day prior to visiting the ED. In the current case report, we discuss loperamide abuse, its harmful effects, and management.", "affiliations": "Psychiatry, Nassau University Medical Center, East Meadow, USA.;Medicine, Nassau University Medical Center, East Meadow, USA.", "authors": "Palkar\|Pooja\|P\|;Kothari\|Dipti\|D\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.2599", "fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.2599Emergency MedicineInternal MedicinePsychiatryBradycardia and Syncope in a Patient Presenting With Loperamide Abuse Muacevic Alexander Adler John R Palkar Pooja 1Kothari Dipti 2\n1 \nPsychiatry, Nassau University Medical Center, East Meadow, USA \n2 \nMedicine, Nassau University Medical Center, East Meadow, USA \nPooja Palkar poojaypalkar@gmail.com9 5 2018 5 2018 10 5 e259926 3 2018 9 5 2018 Copyright © 2018, Palkar et al.2018Palkar et al.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.This article is available from https://www.cureus.com/articles/11695-bradycardia-and-syncope-in-a-patient-presenting-with-loperamide-abuseLoperamide is an antidiarrheal agent available as an inexpensive over-the-counter (OTC) medication. In general, it is considered to be safe, but lately, loperamide drug abuse has been reported due to its opioid properties. When used in high doses, several harmful effects including cardiotoxicity, central nervous system (CNS) and respiratory depression have been reported. This prompted the FDA to release a warning in 2016 regarding the arrhythmogenic potential of loperamide. We present a case of a 32-year-old male with a history of polysubstance abuse who presented to the emergency department (ED) requesting “detoxification” from loperamide. The patient complained of opiate withdrawal symptoms including chills, nausea, vomiting, constipation, and abdominal cramps thought to be secondary to the abuse of loperamide. He was found to have right bundle branch block (RBBB) and bradycardia with a heart rate (HR) of 51 beats per min (bpm). He also reported an unexplained syncopal episode, one day prior to visiting the ED. In the current case report, we discuss loperamide abuse, its harmful effects, and management.\n\nloperamideabusebradycardiasyncopetoxicityThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nLoperamide is an opioid receptor agonist and acts on peripheral mu receptors in the gastrointestinal tract. It works as an antidiarrheal by slowing down movement of the gut and decreasing the frequency of bowel movements. It is used to treat non-infectious diarrhea and commonly used to treat diarrhea due to opioid withdrawal. It has been proven both effective and safe when used at FDA-approved doses (a maximum 16 mg/day for prescription products and 8 mg/day for over-the-counter (OTC) products) [1-2]. Supratherapeutic doses of loperamide have been associated with QTc prolongation and cardiac dysrhythmias. Since dissemination of its opioid properties in online recreational drug use forums, poison control centers have noticed, since 2014, a doubling in referrals for loperamide overdose [3-4]. An accidental and deliberate overdose of loperamide has been associated with opioid-like euphoria [5-6]. In fact, loperamide was, at one time, a schedule V drug due to its opioid properties [4]. Subsequent studies indicated low risk of physical dependence and abuse with the drug and so it was removed from scheduling. However, with increasing abuse, there has been a concomitant increase in the number of reports of toxicity, particularly cardiac manifestations [2-3]. This prompted the FDA to release a warning in 2016 regarding the arrhythmogenic potential of loperamide [7] and subsequently, in January 2018, the FDA limited the packaging for loperamide to encourage safe use [8]. Loperamide is sometimes referred to as “poor man’s methadone” because of its opioid effects, nonprescription status, and low cost.\n\nCase presentation\nWe present a case report of a 32-year-male with a past medical history of polysubstance abuse, anxiety, depression, and ADHD who presented to the ED requesting “detoxification” from loperamide. The patient reported that he has been consuming at least 50 to 60 pills of loperamide (2 mg tablets) daily for three years. He started using loperamide three years ago for diarrhea to attenuate heroin and other opiate withdrawal symptoms. Initially, it helped him with diarrhea and over the period of the next few months, he started using the medication excessively to attain euphoria that he learned about from the internet. The patient reported a syncopal episode, one day prior to coming to the ED, which was worked up at an outside hospital. A computed tomography (CT) scan of the head done there revealed unremarkable findings. The patient was alert and oriented to time, place, and person. He complained of chills, nausea, vomiting, constipation, and abdominal cramps at the time of admission. He denied chest pain, breathing difficulty, and prior history of cardiac disease. An electrocardiogram (EKG) was done that showed right bundle branch block (RBBB), bradycardia with heart rate (HR) 51 bpm and normal QTc. Cardiac ischemia and other drug toxicities were ruled out. Sodium was 136 mEq/L and glucose was 92 mg/dL on presentation. Electrolytes and thyroid function tests were within normal range. He was admitted to the telemetry floor and placed on a continuous cardiac monitor with normal saline intravenous for hydration. Telemetry strips showed bradycardia with HR ranging from 39 to 58 bpm and RBBB. An abdominal X-Ray was obtained that showed constipation. Patient was given laxatives that helped with constipation. He was seen by cardiology to assess the EKG changes. An echocardiogram was done which was normal; the left ventricular ejection fraction was 55%. The patient was then evaluated by psychiatry and started on venlafaxine and gabapentin for mood and anxiety. He remained asymptomatic and was discharged home with a Holter monitor. The patient was advised to discontinue loperamide use and was briefed of its potential hazards upon using it in such high doses. He was referred to an addiction treatment program.\n\nDiscussion\nLoperamide is an antidiarrheal opioid that can produce life-threatening toxicity at high doses including cardiotoxicity, central nervous system (CNS) depression, respiratory depression, and urinary retention. Cardiac toxicity may present with symptoms ranging from palpitations to sudden cardiac death. Several reports suggest patients presenting with ventricular dysrhythmias, torsades de pointes, and even cardiac arrest. Reported loperamide-induced EKG disturbances include bradycardia, widening of QRS, and QTc prolongation. The ability of high-dose loperamide to block cardiac potassium and sodium channels provides the basis of EKG abnormalities and dysrhythmias [9].\n\nPresyncope, recurrent syncope, dyspnea, and seizure-like activity have also been reported with loperamide abuse. The drug predominantly exhibits peripheral activity, low bioavailability, and poor blood-brain barrier penetration at the FDA-approved doses. However, when ingested in massive doses (40-100 times the usual dose), it can cross the blood-brain barrier and exert CNS activity similar to that of other opioids [3]. Loperamide has a relatively long half-life of 9 to 13 hours. At doses of 16 mg and higher, the half-life has been found to be as high as 41 hours. Our knowledge about drug interactions with loperamide is limited. CYP3A4 inhibitors (e.g., clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, verapamil, cimetidine) and CYP2C8 inhibitors (e.g., gemfibrozil, clopidogrel, grapefruit juice, amitriptyline, trimethoprim) have been reported to increase the plasma concentration of loperamide by about twofold and fourfold, respectively [10]. Inhibitors of P-gp (e.g., clarithromycin, erythromycin, ketoconazole, verapamil, quinidine, ritonavir, ranolazine,) also increase the plasma concentration of loperamide by twofold to threefold and may increase the loperamide CNS concentration by reducing the effectiveness of the blood-brain barrier [11]. Therefore, these should be used cautiously with loperamide.\n\nSupportive care is the mainstay of management. A blood test that specifically measures loperamide levels can be done because a standard drug screening will not detect it. Naloxone has been used to reverse coma and respiratory depression. For treatment of loperamide-induced cardiotoxicity, standard advanced cardiac life support should be followed including cardioversion or defibrillation for shockable rhythms and intravenous magnesium for polymorphic ventricular tachycardia. For QRS interval widening, a trial of sodium bicarbonate is suggested [9]. Even in asymptomatic patients and drug discontinuance, physicians should consider obtaining a consultation with a medical toxicologist, promptly treat ECG abnormalities aggressively, and admit all patients for further monitoring. Also, consider treating underlying opioid use disorder and making a referral to an addiction treatment program.\n\nConclusions\nHealth care providers should counsel patients about the cardiac risks associated with high doses of loperamide, and urge them to stick with the recommended dose. Patients with opioid use disorder should be treated with FDA-approved drugs to reduce opioid withdrawal symptoms. Health care providers should be cautious about prescribing loperamide to patients who are at risk for serious heart problems, are predisposed to QT interval prolongation, or who are already on medications known to inhibit loperamide metabolism.\n\nIn the current age of opioid epidemic in the US and around the world, there is a burgeoning rise in the abuse of loperamide for its euphoric properties and physicians must be aware of potential dangers of abusing this medication. It is vital that, at the time of admission, a review of all the OTC medications taken by patients should be done to help suspect and diagnose loperamide toxicity. Typically, a patient with loperamide abuse will have a history of opioid dependence or discontinuation of prescription opioids. It has become imperative for emergency physicians, internists, and psychiatrists to rule out loperamide abuse in this vulnerable population and identify life-threatening consequences to be treated effectively.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Safety and efficacy of loperamide Am J Med Ericsson CD Johnson PC 10 14 88 1990 https://www.ncbi.nlm.nih.gov/pubmed/2192552 \n2 Adverse event detection using the FDA post-marketing drug safety surveillance system: cardiotoxicity associated with loperamide abuse and misuse J Am Pharmacists Assoc Swank KA Wu E Kortepeter C McAninch J Levin RL 63 67 57 2017 https://www.japha.org/article/S1544-3191(16)30894-9/abstract \n3 Loperamide trends in abuse and misuse over 13 years: 2002-2015 Pharmacotherapy Lasoff DR Koh CH Corbett B Minns AB Cantrell FL 249 253 37 2017 27995643 \n4 Loperamide the “Poor Man’s Methadone:” a brief review J Psychoactive Drugs Stanciu CN Gnanasegaram SA 18 21 49 2017 27918873 \n5 Loperamide: a pharmacological review Rev Gastroenterol Disord Baker DE 11 18 7 2007 https://www.ncbi.nlm.nih.gov/pubmed/?term=Baker+DE.+Loperamide \n6 “I just wanted to tell you that loperamide WILL WORK”: a web-based study of the extra-medical use of loperamide Drug Alcohol Depend Daniulaityte R Carlson R Falck R 241 244 130 2013 23201175 \n7 FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse FDA Safety Announcement FDA Drug Safety Communication 2016 https://www.fda.gov/Drugs/DrugSafety/ucm504617.htm \n8 FDA limits packaging for anti-diarrhea medicine Loperamide (Imodium) to encourage safe use FDA Drug Safety Communication MedWatch The FDA Safety Information and Adverse Event Reporting Program 2018 https://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm594403.htm \n9 Clinical review: loperamide toxicity Ann Emerg Med Wu PE Juurlink DN 245 252 70 2017 28506439 \n10 Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide Eur J Clin Pharmacol Niemi M Tomio A Pasanen MK Fredrikson H Neuvonen PJ Backman JT 463 472 62 2006 16758263 \n11 Increased drug delivery to the brain by P-glycoprotein inhibition Clin Pharmacol Ther Sadeque AJ Wandel C He H Shah S Wood AJ 231 237 68 2000 11014404\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "10(5)", "journal": "Cureus", "keywords": "abuse; bradycardia; loperamide; syncope; toxicity", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e2599", "pmc": null, "pmid": "30013863", "pubdate": "2018-05-09", "publication_types": "D002363:Case Reports", "references": "28073687;16758263;11014404;28506439;27918873;18192961;2192552;23201175;27995643", "title": "Bradycardia and Syncope in a Patient Presenting With Loperamide Abuse.", "title_normalized": "bradycardia and syncope in a patient presenting with loperamide abuse" }	[ { "companynumb": "US-JNJFOC-20210422907", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOPERAMIDE HYDROCHLORIDE" }, "drugadditional": "3...
{ "abstract": "Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.", "affiliations": "Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.;Uwe Platzbecker, Christian Thiede, Christoph Röllig, and Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden; Uwe Platzbecker and Gerhard Ehninger, Study Alliance Leukemia, Dresden; Walter Fiedler, University Hospital Hamburg-Eppendorf; Norbert Schmitz, Asklepios Klinik St Georg Hamburg, Hamburg; Peter Brossart, Innere Medizin mit deSchwerpunkten Onkologie, Haematollogie un Rheumatologie, Bonn; Bernd Hertenstein, Klinikum Bremen Mitte, Bremen; Helmut R. Salih, University Hospital Tubingen; Mohammed Wattad, Kliniken Essen Süd, Essen; Michael Lübbert, University Medical Center, Freiburg; Christian H. Brandts, Goethe University Frankfurt, Frankfurt; Mathias Hänel, Klinikum Chemnitz gGmbH, Chemnitz; Hartmut Link, Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern; Konstanze Döhner, Hartmut Döhner, and Richard F. Schlenk, University Hospital Ulm, Ulm; Arnold Ganser, Hannover Medical School, Hannover, Germany; Giuseppe Avvisati, University Campus Bio-Medico; Laura Cicconi, Mariadomenica Divona, Sergio Amadori, and Francesco Lo-Coco, University Tor Vergata; Francesca Paoloni, Marco Vignetti, Fabio Efficace, Paola Fazi, and Franco Mandelli, Gruppo Italiano Malattie Ematologiche dell'Adulto Central Office; Marco Vignetti and Massimo Breccia, Sapienza University, Rome; Felicetto Ferrara, Cardarelli Hospital, Naples; Francesco Albano, University of Bari, Bari; Marco Sborgia, U.O. di Ematologia Clinica, Pescara; Eros Di Bona, San Bortolo Hospital, Vicenza; Erika Borlenghi, U.O. di Ematologia, Spedali Civili, Brescia; Roberto Cairoli, Ospedale Niguarda, Ca' Granda, SC Ematologia; Agostino Cortelezzi, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milano; Alessandro Rambaldi, Azienda Opsedaliera Papa Giovanni XXIII, Bergamo; Lorella Melillo, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo; Giorgio La Nasa, Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari; Chiara Frairia, Hematology, Città della Salute e della Scienza, Torino; Enrico Maria Pogliani, Ospedale San Gerardo, Università degli Studi Milano Bicocca, Monza; Claudio Fozza, University of Sassari, Sassari; Alfonso Maria D'Arco, U.O. Medicina Interna e Onco-Ematologica P.O. \"Umberto I,\" Nocera Inferiore, Nocera Inferiore; Nicola Di Renzo, Ospedale Vito Fazzi, Lecce; and Francesco Fabbiano, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.", "authors": "Platzbecker\|Uwe\|U\|;Avvisati\|Giuseppe\|G\|;Cicconi\|Laura\|L\|;Thiede\|Christian\|C\|;Paoloni\|Francesca\|F\|;Vignetti\|Marco\|M\|;Ferrara\|Felicetto\|F\|;Divona\|Mariadomenica\|M\|;Albano\|Francesco\|F\|;Efficace\|Fabio\|F\|;Fazi\|Paola\|P\|;Sborgia\|Marco\|M\|;Di Bona\|Eros\|E\|;Breccia\|Massimo\|M\|;Borlenghi\|Erika\|E\|;Cairoli\|Roberto\|R\|;Rambaldi\|Alessandro\|A\|;Melillo\|Lorella\|L\|;La Nasa\|Giorgio\|G\|;Fiedler\|Walter\|W\|;Brossart\|Peter\|P\|;Hertenstein\|Bernd\|B\|;Salih\|Helmut R\|HR\|;Wattad\|Mohammed\|M\|;Lübbert\|Michael\|M\|;Brandts\|Christian H\|CH\|;Hänel\|Mathias\|M\|;Röllig\|Christoph\|C\|;Schmitz\|Norbert\|N\|;Link\|Hartmut\|H\|;Frairia\|Chiara\|C\|;Pogliani\|Enrico Maria\|EM\|;Fozza\|Claudio\|C\|;D'Arco\|Alfonso Maria\|AM\|;Di Renzo\|Nicola\|N\|;Cortelezzi\|Agostino\|A\|;Fabbiano\|Francesco\|F\|;Döhner\|Konstanze\|K\|;Ganser\|Arnold\|A\|;Döhner\|Hartmut\|H\|;Amadori\|Sergio\|S\|;Mandelli\|Franco\|F\|;Ehninger\|Gerhard\|G\|;Schlenk\|Richard F\|RF\|;Lo-Coco\|Francesco\|F\|", "chemical_list": "D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide", "country": "United States", "delete": false, "doi": "10.1200/JCO.2016.67.1982", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "35(6)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077237:Arsenic Trioxide; D001152:Arsenicals; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D010087:Oxides; D011446:Prospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D014212:Tretinoin; D055815:Young Adult", "nlm_unique_id": "8309333", "other_id": null, "pages": "605-612", "pmc": null, "pmid": "27400939", "pubdate": "2017-02-20", "publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial", "references": null, "title": "Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial.", "title_normalized": "improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non high risk acute promyelocytic leukemia final results of the randomized italian german apl0406 trial" }	[ { "companynumb": "IT-ROCHE-1430230", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRETINOIN" }, "drugadditional": "3", "drugad...
{ "abstract": "BACKGROUND\nAll antipsychotic medications carry warnings of increased mortality for older adults, but little is known about comparative mortality risks between individual agents.\n\n\nOBJECTIVE\nTo estimate the comparative mortality risks of commonly prescribed antipsychotic agents in older people living in the community.\n\n\nMETHODS\nA retrospective, claims-based cohort study was conducted of people over 65 years old living in the community who had been newly prescribed risperidone, olanzapine, quetiapine, haloperidol, aripiprazole or ziprasidone (n = 136 393). Propensity score-adjusted Cox proportional hazards models assessed the 180-day mortality risk of each antipsychotic compared with risperidone.\n\n\nRESULTS\nRisperidone, olanzapine and haloperidol showed a dose-response relation in mortality risk. After controlling for propensity score and dose, mortality risk was found to be increased for haloperidol (hazard ratio (HR) = 1.18, 95% CI 1.06-1.33) and decreased for quetiapine (HR = 0.81, 95% CI 0.73-0.89) and olanzapine (HR = 0.82, 95% CI 0.74-0.90).\n\n\nCONCLUSIONS\nSignificant variation in mortality risk across commonly prescribed antipsychotics suggests that antipsychotic selection and dosing may affect survival of older people living in the community.", "affiliations": "Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.;Tobias Gerhard, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, and Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Krista Huybrechts, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Mark Olfson, MD MPH, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Sebastian Schneeweiss, MD, ScD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; William V. Bobo, MD, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee; P. Murali Doraiswamy, MD, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina; D. P. Devanand, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York; Judith A. Lucas, EdD RN, Cecilia Huang, PhD, Edmond S. Malka, PhD, MPH, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey; Raisa Levin, MS, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Stephen Crystal, PhD, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, New Jersey, USA.", "authors": "Gerhard\|T\|T\|;Huybrechts\|K\|K\|;Olfson\|M\|M\|;Schneeweiss\|S\|S\|;Bobo\|W V\|WV\|;Doraiswamy\|P M\|PM\|;Devanand\|D P\|DP\|;Lucas\|J A\|JA\|;Huang\|C\|C\|;Malka\|E S\|ES\|;Levin\|R\|R\|;Crystal\|S\|S\|", "chemical_list": "D014150:Antipsychotic Agents", "country": "England", "delete": false, "doi": "10.1192/bjp.bp.112.122499", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1250", "issue": "205(1)", "journal": "The British journal of psychiatry : the journal of mental science", "keywords": null, "medline_ta": "Br J Psychiatry", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D009026:Mortality; D011618:Psychotic Disorders; D012111:Residence Characteristics; D012189:Retrospective Studies; D012306:Risk", "nlm_unique_id": "0342367", "other_id": null, "pages": "44-51", "pmc": null, "pmid": "23929443", "pubdate": "2014-07", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Comparative mortality risks of antipsychotic medications in community-dwelling older adults.", "title_normalized": "comparative mortality risks of antipsychotic medications in community dwelling older adults" }	[ { "companynumb": "US-JNJFOC-20140705910", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nInvasive pulmonary aspergillosis (IPA) after liver transplantation (LT) is most often fatal. We analyzed the outcomes of IPA in a single center.\n\n\nMETHODS\nWe reviewed, retrospectively, the medical records of recipients of living donor LT (LDLT) or deceased donor LT (DDLT) performed between 1995 and 2019 at our institute. We analyzed the incidence of IPA and assessed the treatment courses of patients treated successfully and those not treatment successfully.\n\n\nRESULTS\nAmong 326 recipients, IPA was diagnosed in 6 (1.8%). The incidence of IPA was significantly higher in patients with acute liver failure (ALF, 9.8%) than in those without ALF (0.4%), after DDLT (8.8%) than after LDLT (1.0%), and in recipients who received preoperative steroid pulse therapy (16.0%) than in those who did not (0.7%). Complete cure of IPA was achieved in the most recent three patients, by administering voriconazole immediately after the diagnosis of IPA and performing lung resection, while the IPA lesion was single and localized.\n\n\nCONCLUSIONS\nPatients with risk factors for IPA must be monitored closely. Our three successfully treated cases demonstrate that initiating immediate voriconazole treatment and making a calculated decision about lung resection can contribute to a favorable outcome.", "affiliations": "Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan. masa02114@yahoo.co.jp.;Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.", "authors": "Abe\|Kodai\|K\|http://orcid.org/0000-0002-1138-7437;Shinoda\|Masahiro\|M\|;Uno\|Shunsuke\|S\|;Obara\|Hideaki\|H\|;Kitago\|Minoru\|M\|;Abe\|Yuta\|Y\|;Hishida\|Tomoyuki\|T\|;Yagi\|Hiroshi\|H\|;Hasegawa\|Yasushi\|Y\|;Kitagawa\|Yuko\|Y\|", "chemical_list": "D065819:Voriconazole", "country": "Japan", "delete": false, "doi": "10.1007/s00595-021-02263-z", "fulltext": null, "fulltext_license": null, "issn_linking": "0941-1291", "issue": "51(8)", "journal": "Surgery today", "keywords": "Invasive pulmonary aspergillosis; Liver transplantation; Lung resection", "medline_ta": "Surg Today", "mesh_terms": "D000066491:Clinical Decision-Making; D005260:Female; D006801:Humans; D015994:Incidence; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011013:Pneumonectomy; D011183:Postoperative Complications; D055732:Pulmonary Aspergillosis; D012189:Retrospective Studies; D012307:Risk Factors; D014019:Tissue Donors; D016896:Treatment Outcome; D065819:Voriconazole", "nlm_unique_id": "9204360", "other_id": null, "pages": "1361-1370", "pmc": null, "pmid": "33738584", "pubdate": "2021-08", "publication_types": "D016428:Journal Article; D016454:Review", "references": "28674051", "title": "Invasive pulmonary aspergillosis after liver transplantation: lessons from successfully treated cases and review of the literature.", "title_normalized": "invasive pulmonary aspergillosis after liver transplantation lessons from successfully treated cases and review of the literature" }	[ { "companynumb": "JP-GILEAD-2021-0558293", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": null, ...
{ "abstract": "We report a male newborn who became symptomatic with supraventricular tachycardia on the first day of life. Neither adenosine nor electric cardioversion could terminate the tachycardia, therefore intravenous esmolol (β-receptor blocker) was initiated. Inspite of subsequent administration of various antiarrhythmic medications in increasingly higher doses, repeated supraventricular tachycardic episodes occurred. The electrocardiogram showed typical findings of a multifocal atrial tachycardia as the underlying cause. When tachycardic episodes occurred, they also presented as atrial flutter at 460 bpm and a 2:1 block. Finally, high dosage of amiodarone (10 mg/kgbw/d) led to continuous control of the heart rate without tachycardic episodes. To date our patient is mostly in sinus rhythm but without tachycardic episodes and doing well.", "affiliations": "Kinderklinik und Poliklinik, Universitatsklinikum Würzburg, Würzburg.;Kinderklinik und Poliklinik, Universitatsklinikum Würzburg, Würzburg.;Kinderklinik und Poliklinik, Universitatsklinikum Würzburg, Würzburg.;Kinderklinik und Poliklinik, Universitatsklinikum Würzburg, Würzburg.", "authors": "Braun\|M\|M\|;Siauw\|C\|C\|;Schirrmeister\|J\|J\|;Wirbelauer\|J\|J\|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone", "country": "Germany", "delete": false, "doi": "10.1055/s-0042-109405", "fulltext": null, "fulltext_license": null, "issn_linking": "0948-2393", "issue": "220(6)", "journal": "Zeitschrift fur Geburtshilfe und Neonatologie", "keywords": null, "medline_ta": "Z Geburtshilfe Neonatol", "mesh_terms": "D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D003937:Diagnosis, Differential; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D008297:Male; D013612:Tachycardia, Ectopic Atrial; D016896:Treatment Outcome", "nlm_unique_id": "9508901", "other_id": null, "pages": "265-268", "pmc": null, "pmid": "27723918", "pubdate": "2016-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Perinatal Presentation and Complicated Course of a Multifocal Atrial Tachycardia.", "title_normalized": "perinatal presentation and complicated course of a multifocal atrial tachycardia" }	[ { "companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-154392", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ESMOLOL HYDROCHLORIDE" }, ...
{ "abstract": "Cisplatin and carboplatin are frequently used drugs in the treatment of pediatric hepatoblastoma. Dosing guidelines for these drugs in children requiring peritoneal dialysis are lacking. Here, we describe the case of a 3-year-old boy with pre-existing end-stage renal disease on peritoneal dialysis, requiring treatment with cisplatin and carboplatin for hepatoblastoma.\n\n\n\nPharmacokinetic data were generated to support clinical dosing decisions, with the aim of adequate exposure and minimal toxicity. In the first chemotherapy cycle, 25% of the standard cisplatin dose and 75% of the carboplatin dose, calculated using the pediatric Calvert formula, were administered. Free platinum concentrations were determined in plasma ultrafiltrate and dialysate samples drawn after administration of cis- and carboplatin.\n\n\n\nCisplatin was well tolerated and the observed AUC of cisplatin were 15.3 and 14.3 mg/L h in cycles 1 and 3, respectively. The calculated AUC of carboplatin in cycle 1 (9.8 mg/mL min) exceeded target AUC of 6.5 mg/mL min and toxicity was observed; therefore, the dose was reduced in cycles 2 and 3. The observed AUC in cycles 2 and 3 was 5.4 and 5.7 mg/mL min respectively. Platinum concentrations in the dialysate showed that 3-4% of the total dose of cisplatin and 10-12% of the total dose of carboplatin were excreted via peritoneal dialysis. Chemotherapy enabled extended hemihepatectomy and complete remission was achieved.\n\n\n\nThis report shows that it is feasible to measure AUCs for both drugs and to individualize the dose of these drugs according to the PK results and clinical parameters. Our advice for future cases would be to calculate the starting dose of carboplatin using the (pediatric) Calvert formula, assuming a dialytic clearance of zero, and to adjust the dose if required, based on therapeutic drug monitoring.", "affiliations": "Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. a.l.nijstad-2@umcutrecht.nl.;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.;Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.;Department of Pediatric Nephrology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.", "authors": "Nijstad\|A Laura\|AL\|0000-0003-3448-7665;van Eijkelenburg\|Natasha K A\|NKA\|0000-0002-0526-3737;Kraal\|Kathelijne C J M\|KCJM\|;Meijs\|Marieke J M\|MJM\|;de Kanter\|Clara T M M\|CTMM\|;Lilien\|Marc R\|MR\|0000-0002-8956-0324;Huitema\|Alwin D R\|ADR\|0000-0003-1939-4639", "chemical_list": "D016190:Carboplatin; D002945:Cisplatin", "country": "Germany", "delete": false, "doi": "10.1007/s00280-020-04130-z", "fulltext": "\n==== Front\nCancer Chemother Pharmacol\nCancer Chemother. Pharmacol\nCancer Chemotherapy and Pharmacology\n0344-5704 1432-0843 Springer Berlin Heidelberg Berlin/Heidelberg \n\n4130\n10.1007/s00280-020-04130-z\nShort Communication\nCisplatin and carboplatin pharmacokinetics in a pediatric patient with hepatoblastoma receiving peritoneal dialysis\nhttp://orcid.org/0000-0003-3448-7665Nijstad A. Laura a.l.nijstad-2@umcutrecht.nl 1 http://orcid.org/0000-0002-0526-3737van Eijkelenburg Natasha K. A. 2 Kraal Kathelijne C. J. M. 2 Meijs Marieke J. M. 2 de Kanter Clara T. M. M. 2 http://orcid.org/0000-0002-8956-0324Lilien Marc R. 4 http://orcid.org/0000-0003-1939-4639Huitema Alwin D. R. 13 1 grid.5477.10000000120346234Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands \n2 grid.487647.ePrincess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands \n3 grid.430814.aDepartment of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands \n4 grid.7692.a0000000090126352Department of Pediatric Nephrology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands \n20 8 2020 \n20 8 2020 \n2020 \n86 3 445 449\n28 4 2020 13 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose\nCisplatin and carboplatin are frequently used drugs in the treatment of pediatric hepatoblastoma. Dosing guidelines for these drugs in children requiring peritoneal dialysis are lacking. Here, we describe the case of a 3-year-old boy with pre-existing end-stage renal disease on peritoneal dialysis, requiring treatment with cisplatin and carboplatin for hepatoblastoma.\n\nMethods\nPharmacokinetic data were generated to support clinical dosing decisions, with the aim of adequate exposure and minimal toxicity. In the first chemotherapy cycle, 25% of the standard cisplatin dose and 75% of the carboplatin dose, calculated using the pediatric Calvert formula, were administered. Free platinum concentrations were determined in plasma ultrafiltrate and dialysate samples drawn after administration of cis- and carboplatin.\n\nResults\nCisplatin was well tolerated and the observed AUC of cisplatin were 15.3 and 14.3 mg/L h in cycles 1 and 3, respectively. The calculated AUC of carboplatin in cycle 1 (9.8 mg/mL min) exceeded target AUC of 6.5 mg/mL min and toxicity was observed; therefore, the dose was reduced in cycles 2 and 3. The observed AUC in cycles 2 and 3 was 5.4 and 5.7 mg/mL min respectively. Platinum concentrations in the dialysate showed that 3–4% of the total dose of cisplatin and 10–12% of the total dose of carboplatin were excreted via peritoneal dialysis. Chemotherapy enabled extended hemihepatectomy and complete remission was achieved.\n\nConclusion\nThis report shows that it is feasible to measure AUCs for both drugs and to individualize the dose of these drugs according to the PK results and clinical parameters. Our advice for future cases would be to calculate the starting dose of carboplatin using the (pediatric) Calvert formula, assuming a dialytic clearance of zero, and to adjust the dose if required, based on therapeutic drug monitoring.\n\nKeywords\nCisplatinCarboplatinHepatoblastomaPharmacokineticsPeritoneal dialysisUniversity Medical Center Utrechtissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nHepatoblastoma is the most common malignant liver tumor in the pediatric population [1]. In most of the cases, (neo)adjuvant chemotherapeutic treatment of hepatoblastoma in children consists of platinum-based therapy, such as cisplatin and carboplatin. After administration, these drugs bind irreversibly to proteins and tissue. Free platinum is considered the active form in terms of antitumor effect and toxicity. Free platinum is mainly eliminated by the kidneys.\n\nIn rare cases, children with hepatoblastoma have concomitant kidney failure or a type of kidney disease. Impairment of renal function diminishes platinum clearance, causes an increase of the toxicity of platinum compounds and thereby complicates the treatment of children with hepatoblastoma. Dosing guidelines recommend a reduction of the dose or even omitting therapy with platinum derivatives in patients with renal impairment to prevent further nephrotoxicity. With the exception of a few case reports [2–4], there is no information available on the dosing of cisplatin and carboplatin in children with end-stage renal disease requiring peritoneal dialysis. If platinum drugs are excluded, treatment options are scarce, so more information about the dosing of these agents in patients on renal replacement therapy is needed.\n\nAs recommended by Labaki et al. [5], drugs undergoing significant renal elimination should be administered with caution in peritoneal dialysis patients with close monitoring of adverse events, dose reductions should be applied when using anti-cancer treatments that are typically excreted by the kidneys, and pharmacokinetic studies should be performed when available and dose adjustments applied when necessary, even in the absence of any toxicity.\n\nThis report describes the treatment of hepatoblastoma with cisplatin and carboplatin in a pediatric patient with pre-existing end-stage renal disease on nocturnal intermittent peritoneal dialysis (NIPD).\n\nPatient and methods\nPatient\nThe patient is a 3-year-old boy with end-stage renal disease due to an atypical hemolytic uremic syndrome (HUS) following an influenza A infection. He remained anuric and peritoneal dialysis was started at the age of 5 months. He presented with an unexplained decline of his hemoglobin level for which an abdominal ultrasound was performed. This revealed a large mass in the left lobe of the liver of approximately 12 × 6 × 13 cm. An abdominal CT confirmed the presence of a large hepatic mass involving segments 2, 3 and 5 of the liver, staging to a PRETEXT III. There were no distant metastases detected. Alpha-fetoprotein (AFP) was elevated to 12,500 µg/L (reference range 0.8–4.5 µg/L). Biopsy of the mass revealed epithelial hepatoblastoma.\n\nDialysis prescription\nThe patient was on a nocturnal intermittent cycler-assisted peritoneal dialysis schedule. The dialysis prescription was not changed for the oncological treatment, but dialysate glucose composition was adapted dependent on fluid status of the patient. The total dialysate volume prescribed was 4200 ml/day (9.24–9.35 L/1.73 m2/day). Dialysis time was 12 h/treatment, with seven exchanges per treatment. Daily ultrafiltration varied between 223 and 521 ml/treatment. Dialysis adequacy was monitored during treatment by measurement of K·t/V for urea and creatinine clearance. K·t/V was 2.38/week and creatinine clearance was 36 L/week. The patient had no residual renal function.\n\nTreatment\nHe commenced with chemotherapy according to the intermediate group of the 'Pediatric Hepatic International Tumor Trial' (PHITT) SIOPEL 3 high-risk (HR) treatment regimen, as there was some concern about extrahepatic extension and this regimen was deemed less toxic than others.\n\nThe proposed treatment schedule included cisplatin, carboplatin and doxorubicin. The cisplatin dose according to protocol was 80 mg/m2 on day 1 and the carboplatin dose was 500 mg/m2 on day 15 as an intravenous (iv) infusion. In view of the impaired renal clearance and based on the case report on Sebestyen et al. [4], the dose of cisplatin was reduced to 20 mg/m2 (25% of the recommended dose) and administrated over 6 h. The carboplatin dose was calculated using the formula of Newell et al. [6]. In adults, the carboplatin dose is calculated using the Calvert formula [7]. Calvert showed that the renal clearance of carboplatin is linearly related to the glomerular filtration rate (GFR) and designed a formula to calculate an individual dose using a target area under the curve (AUC). Newell et al. developed a similar formula which is suitable for children: Carboplatindose(mg)=targetAUC×(GFR+(0.36×BW)), where BW equals the body weight in kg. According to Newell et al., a carboplatin dose of 500 mg/m2 equals an AUC of approximately 6.5 mg/ml min. With the formula and an estimated dialysis creatinine clearance of 5 ml/min, a dose of 64 mg was calculated, which was reduced to 75% (48 mg, which equals 75 mg/m2). This was done for extra safety, since it was unknown if the estimated dialysis creatinine clearance exactly corresponded to the carboplatin clearance. Carboplatin was administrated intravenously in 1 h. Free plasma concentrations of cisplatin and carboplatin were measured after the platinum cycles to further individualize the dose. In the first cycle, doxorubicin was given in a 100% dose of 30 mg/m2 on days 15 and 16. Treatment-related toxicities were graded conforming to Common Terminology Criteria for Adverse Events version 5.0 [8], and grade 3 toxicity or higher was recorded.\n\nPharmacokinetic analysis\nBlood samples for the determination of platinum pharmacokinetics were collected at three or four time points after infusion of cis- and carboplatin up to 24 h after administration. For this purpose, an ultrafiltrate was prepared from plasma samples. In addition, samples were taken from the dialysate after the first NIPD cycle after administration of platinum. Free and total platinum concentrations were measured in this ultrafiltrate and dialysate using a validated inductively coupled plasma mass spectrometry (ICP-MS) method as described by Brouwers et al. [9]. AUC0–inf,free for each cycle was calculated using the trapezoid method. R (version 3.6.1) was used for data handling and visualization [10].\n\nResults\nTreatment and dose adjustment\nBlood samples were collected after two cisplatin cycles and three carboplatin cycles. The PK parameters of each cycle are displayed in Table 1. The plasma concentration time curves are displayed in Fig. 1. The AUC0–inf,free of cisplatin following the first dose of 20 mg/m2 was 15.3 mg/L h. No significant side effects were noted after this first cycle of cisplatin. The AUC0–inf,free of carboplatin following the first dose of 48 mg (75 mg/m2) was found to be 9.8 mg/mL min, which exceeds the target AUC of 6.5 mg/mL min. Subsequently, severe clinical toxicity was observed, consisting of grade 3 mucositis.Table 1 Pharmacokinetic parameters and tolerance for cisplatin and carboplatin\n\n\tTotal dose (mg)\tDose (mg/m2)\tAUC0–inf,free\tTolerance\t\nCisplatin\t\nCycle 1\t11.75\t20\t15.3 mg/L h\tNo side effects\t\nCycle 3\t11.75\t20\t14.3 mg/L h\tNo side effects\t\nCarboplatin\t\nCycle 1\t48\t75\t9.8 mg/mL min\tGrade 3 mucositis\t\nCycle 2\t24\t37.5\t5.4 mg/mL min\tNo side effects\t\nCycle 3\t24\t37.5\t5.7 mg/mL min\tNo side effects\t\nFig. 1 Plasma concentration–time curves for cisplatin (a) and carboplatin (b)\n\n\n\nDuring the next chemotherapy cycles, the patient was treated with the same cisplatin dose as the first cycle. The cisplatin dose was not escalated, because the patient had just recovered from the toxicity after the carboplatin dose of cycle 1. For cisplatin, an AUC0–inf,free of 14.3 mg/L h was measured in chemotherapy cycle 3. Because of the high carboplatin AUC and observed clinical toxicity in cycle 1, the dose of carboplatin was reduced to 50% of the previous dose for cycles 2 and 3. After two carboplatin doses of 24 mg (37.5 mg/m2), AUC0–inf,free values of 5.4 and 5.7 mg/mL min were measured in cycles 2 and 3, respectively. The second and third chemotherapy cycles were well tolerated.\n\nDoxorubicin was administered in a dose of 30 mg/m2 on the day of carboplatin and the day after. During the first course, 100% of the recommended doxorubicin dose was administered, since the renal clearance of this drug is minimal. After development of toxicity in cycle 1, the dose of doxorubicin was reduced to 75% in cycles 2 and 3. Plasma concentrations of doxorubicin were not measured.\n\nNIPD was started 3–4 h after end of infusion of cisplatin and 8–9 h after end of infusion of carboplatin. Platinum concentrations in the dialysate showed that platinum can be excreted by peritoneal dialysis. In total, approximately an amount of 0.4–0.5 mg cisplatin and 3–5 mg carboplatin was excreted after the first NIPD course after administration of cisplatin and carboplatin. This equals 3–4% of the total dose of cisplatin and 10–12% of the total dose of carboplatin.\n\nTreatment response and toxicity\nThe first response evaluation was performed using an MRI scan of the liver showing stable disease. Overall, the chemotherapy was well tolerated, but the patient developed grade 3 mucositis after the first cycle of carboplatin/doxorubicin. The AFP was reduced to 16,000 µg/L (after rise before treatment to 51,000 µg/L). Two additional courses of cisplatin and carboplatin/doxorubicin were given, his clinical condition improved during this period and NIPD was continued.\n\nThereafter, an uncomplicated left-sided extended hemihepatectomy was performed. NIPD was converted to continuous venovenous hemodiafiltration for 4 weeks postoperatively, after which NIPD was resumed.\n\nHistology showed multifocal pure epithelial hepatoblastoma with fetal (well differentiated, crowded and pleomorphic) and embryonal differentiation. There was extensive necrosis with also vital tumor tissue (40% approx.) and macroscopic angio-invasion. Radical resection was obtained. Currently, he has finished his hepatoblastoma treatment and is in complete remission. Six months after the end of treatment, no signs of platinum-related neurotoxicity or ototoxicity has been observed.\n\nDiscussion\nThis case report describes the pharmacokinetics of cis- and carboplatin in a child requiring peritoneal dialysis. These results show that it is feasible to measure AUCs for both drugs and to individualize the dose of these drugs according to the clinical parameters and PK results, even though consensus for the target AUC of cisplatin is lacking. In this case, AUCs of cisplatin of 15.3 and 14.3 mg/L h were well tolerated. Previously published, well tolerated, AUCs vary from 5.3 to 79.3 mg/L h in infants with hepatoblastoma (both with and without hemodialysis) [11, 12]. In this case, we chose not to escalate the dose, since the patient had just recovered from severe toxicity following the first carboplatin cycle.\n\nSebestyen et al. [4] reported a case of cisplatin treatment in a 2-year old patient receiving peritoneal dialysis. For this patient, an AUC of 64.1 and 66.6 mg/L h was measured after a dose of 25 mg/m2 and 29.7 mg/L h after a dose of 8.7 mg/m2. According to their data, peritoneal dialysis contributed less than 1% to total body clearance of cisplatin. They compared the values to the data of Dominici et al. [13], who reported an AUC of 15.5 ± 9.1 mg/L h in children with normal kidney function. The results of the AUC in our patient closely match the AUC of Dominici et al. However, the AUC values from the study of Dominici et al. were normalized to a dose of 100 mg/m2, while our patient was supposed to receive a cisplatin dose equal to 80 mg/m2.\n\nCarboplatin was dosed according to the Newell formula [6]. Newell et al. developed a formula suited for GFR-based carboplatin dosing in children. The carboplatin dose is calculated using the target AUC, estimated GFR and body weight. For the first cycle, an estimated creatinine clearance of 5 ml/min was included in the Newell formula. A dose of 48 mg was given. This resulted in an AUC of 9.8 mg/mL min, 1.5-fold higher than the target AUC of 6.5 mg/mL min. At the same time, toxicity (grade 3 mucositis) was observed, so the dose was reduced to 50% of the previous dose. When dialytic clearance was actually measured, it was shown to be 3.6 ml/min (36 L/week).\n\nA previous case report by English et al. [2] also used the Newell formula to calculate the carboplatin dose for a 4.3-year-old girl, diagnosed with Wilms tumor, receiving peritoneal dialysis. This patient had a residual renal clearance of 5 ml/min/1.73 m2 as determined by 51Cr EDTA clearance. According to their data, peritoneal dialysis did not contribute to carboplatin clearance. In our case, assuming no dialytic clearance of carboplatin would have led to a starting dose of 33 mg. In retrospect, this would have been more appropriate in this case; however, it can lead to under-dosing in patients who have residual renal function. Our advice for future cases would be to assume a dialytic clearance of zero to calculate the starting dose of carboplatin, and to adjust the dose if required, based on therapeutic drug monitoring.\n\nThe first carboplatin dose led to severe toxicity, which can be explained by the high AUC. Since carboplatin was administered during the same course as doxorubicin it is hard to distinguish whether the toxicity was caused by carboplatin or doxorubicin. The second and third courses, with reduced doses of carboplatin and doxorubicin, were well tolerated.\n\nIn addition, platinum concentrations in the dialysate were measured. These results show that 3–4% of the total dose of cisplatin and 10–12% of the total dose of carboplatin was excreted by peritoneal dialysis. This supports our hypothesis that free platinum can be excreted via peritoneal dialysis. The difference in amount between these compounds can be explained by the fact that cisplatin rapidly binds to proteins, faster than carboplatin. The half-lives of free cisplatin and carboplatin are approximately 0.5–1 h and 3–5 h, respectively. Furthermore, the time between administration of the platinum drugs and start of peritoneal dialysis is important. If peritoneal dialysis starts directly after end of infusion, it is expected that more free platinum can be excreted than when it starts several hours after end of infusion, since most of the drugs will be bound to proteins.\n\nThe clinical course of this 3-year-old patient with hepatoblastoma on NIPD has been astounding. These ‘tailored made’ and targeted chemotherapy courses enabled extended hemihepatectomy. He is currently off treatment and in complete remission.\n\nIn conclusion, this report shows that treatment with cis- and carboplatin in patients requiring peritoneal dialysis is possible and that pharmacokinetic monitoring contributes to the knowledge about the dosing of these drugs in patients requiring peritoneal dialysis.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor contributions\nNot applicable (is optional).\n\nFunding\nNot applicable.\n\nAvailability of data and material\nNot applicable.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nEthical approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\n\nInformed consent\nInformed consent was obtained from the parents of the patient.\n\nConsent for publication\nInformed consent was obtained from the parents of the patient in this article.\n\nCode availability\nNot applicable.\n==== Refs\nReferences\n1. Kremer N Walther AE Tiao GM Management of hepatoblastoma: an update Curr Opin Pediatr 2014 26 362 369 24759227 \n2. English MW Lowis SP Peng B Pharmacokinetically guided dosing of carboplatin and etoposide during peritoneal dialysis and haemodialysis Br J Cancer 1996 73 776 780 8611379 \n3. Heijns JB van der Burg MEL van Gelder T Continuous ambulatory peritoneal dialysis: pharmacokinetics and clinical outcome of paclitaxel and carboplatin treatment Cancer Chemother Pharmacol 2008 62 841 847 18204842 \n4. Sebestyen J Garg U Lewing KB Cisplatin pharmacokinetics in a child receiving peritoneal dialysis Pediatr Nephrol 2010 25 1185 1189 20084400 \n5. Labaki C Rawadi E Chebel R Anti-neoplastic agents for patients on peritoneal dialysis: a systematic review Crit Rev Oncol Hematol 2020 150 102947 32294609 \n6. Newell DR Pearson AD Balmanno K Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. The United Kingdom Children’s Cancer Study Group J Clin Oncol 1993 11 2314 2323 8246021 \n7. Calvert AH Newell DR Gumbrell LA Carboplatin dosage: prospective evaluation of a simple formula based on renal function J Clin Oncol 1989 7 1748 1756 2681557 \n8. Cancer Therapy Evaluation Program (CTEP) (2017) Common Terminology Criteria for Adverse Events (CTCAE), v.5.0 [5x7]. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed 13 July 2020\n9. Brouwers EEM Tibben MM Rosing H Sensitive inductively coupled plasma mass spectrometry assay for the determination of platinum originating from cisplatin, carboplatin, and oxaliplatin in human plasma ultrafiltrate J Mass Spectrom 2006 41 1186 1194 16929560 \n10. RC Team (2009) R: a language and environment for statistical computing. R Found Stat Comput Vienna\n11. Boucher AA Mizuno T Vinks AA Dose modifications and pharmacokinetics of adjuvant cisplatin monotherapy while on hemodialysis for patients with hepatoblastoma Pediatr Blood Cancer 2019 66 1 5 \n12. Thomas F Veal GJ El Balkhi S Therapeutic drug monitoring and dose adaptation of cisplatin in a newborn with hepatoblastoma: a case report Cancer Chemother Pharmacol 2018 82 361 365 29922990 \n13. Dominici C Petrucci F Caroli S A pharmacokinetic study of high-dose continuous infusion cisplatin in children with solid tumors J Clin Oncol 1989 7 100 107 2909663\n\n", "fulltext_license": "CC BY", "issn_linking": "0344-5704", "issue": "86(3)", "journal": "Cancer chemotherapy and pharmacology", "keywords": "Carboplatin; Cisplatin; Hepatoblastoma; Peritoneal dialysis; Pharmacokinetics", "medline_ta": "Cancer Chemother Pharmacol", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D016190:Carboplatin; D002675:Child, Preschool; D002945:Cisplatin; D018197:Hepatoblastoma; D006801:Humans; D007676:Kidney Failure, Chronic; D008113:Liver Neoplasms; D008297:Male; D010530:Peritoneal Dialysis; D011379:Prognosis; D014018:Tissue Distribution", "nlm_unique_id": "7806519", "other_id": null, "pages": "445-449", "pmc": null, "pmid": "32816154", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "2909663;8611379;30160353;24759227;18204842;8246021;16929560;32294609;20084400;2681557;29922990", "title": "Cisplatin and carboplatin pharmacokinetics in a pediatric patient with hepatoblastoma receiving peritoneal dialysis.", "title_normalized": "cisplatin and carboplatin pharmacokinetics in a pediatric patient with hepatoblastoma receiving peritoneal dialysis" }	[ { "companynumb": "NL-PFIZER INC-2020344061", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, ...
{ "abstract": "Recent successive reports on acute pancreatitis-induced thrombotic thrombocytopenic purpura (TTP) have revealed that TTP-related microvascular damage is an aggravating factor of acute pancreatitis. Here, we report the case of a 26-year-old man diagnosed with acute pancreatitis due to high alcohol consumption. The patient was unconscious as he had taken an overdose of medication, and presented with fever and renal failure due to acute pancreatitis on admission. Although the pancreatitis subsequently improved, the symptoms were still observed; on the next day, he exhibited hemoglobinuria, anemia, and thrombocytopenia. Moreover, general blood examinations indicated the presence of schistocytes and reduced activity of ADAMTS13 (a disintegrin-like metalloproteinase with thrombospondin type 1 motif 13) to 47 %. Thus, the patient was diagnosed with TTP, and plasma exchange was performed. After the development of TTP, the acute pancreatitis recurred, but a severe pathogenesis was prevented by plasma exchange. Thus, ADAMTS13 activity may be useful for predicting a severe pathogenesis of acute pancreatitis. In ADAMTS13-deficient cases, plasma exchange may be an effective technique for preventing aggravation of acute pancreatitis.", "affiliations": "Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan. yfujino-gi@umin.ac.jp.;Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Department of Laboratory Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Department of Blood Transfusion Medicine, Nara Medical University, 840 Shijocho, Kashihara, Nara, 634-8521, Japan.", "authors": "Fujino\|Yasuhisa\|Y\|;Inoue\|Yoshihiro\|Y\|;Onodera\|Makoto\|M\|;Kikuchi\|Satoshi\|S\|;Sato\|Masayuki\|M\|;Kojika\|Masahiro\|M\|;Sato\|Hisaho\|H\|;Suzuki\|Keijiro\|K\|;Matsumoto\|Masanori\|M\|", "chemical_list": "D051722:ADAM Proteins", "country": "Japan", "delete": false, "doi": "10.1007/s12328-016-0632-0", "fulltext": null, "fulltext_license": null, "issn_linking": "1865-7265", "issue": "9(2)", "journal": "Clinical journal of gastroenterology", "keywords": "ADAMTS13 protein; Pancreatitis; Plasma exchange; TTP", "medline_ta": "Clin J Gastroenterol", "mesh_terms": "D051722:ADAM Proteins; D000208:Acute Disease; D000328:Adult; D006801:Humans; D008297:Male; D010195:Pancreatitis; D010951:Plasma Exchange; D011697:Purpura, Thrombotic Thrombocytopenic; D012008:Recurrence", "nlm_unique_id": "101477246", "other_id": null, "pages": "104-8", "pmc": null, "pmid": "26905311", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "20045995;15069598;11586351;22233953;12181489;2062330;2729239;10819702;18609162;12192020;21903475;16607683;12823037;5575492;10071001;15538566;15026315;24678155;17606444;16672704;4734642;19008177;19036107;21716116;22536085;3928249", "title": "Acute pancreatitis-induced thrombotic thrombocytopenic purpura with recurrent acute pancreatitis.", "title_normalized": "acute pancreatitis induced thrombotic thrombocytopenic purpura with recurrent acute pancreatitis" }	[ { "companynumb": "JP-MYLANLABS-2016M1020530", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENOBARBITAL" }, "drugadditional": null, ...
{ "abstract": "We report two patients with bilateral pulmonary embolism who presented to our county hospital reproductive health services clinic. Both patients underwent an uncomplicated first-trimester aspiration abortion while on therapeutic unfractionated heparin therapy. Anticoagulation therapy may be modified to safely perform first-trimester surgical termination without significant blood loss.", "affiliations": "Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Division of Family Planning, Obstetrics and Gynecology, The John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA. Electronic address: jessica-shim@northwestern.edu.;Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Division of Family Planning, Obstetrics and Gynecology, The John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA.", "authors": "Shim\|Jessica Y\|JY\|;Patel\|Ashlesha\|A\|", "chemical_list": "D000925:Anticoagulants; D006493:Heparin", "country": "United States", "delete": false, "doi": "10.1016/j.contraception.2018.01.016", "fulltext": null, "fulltext_license": null, "issn_linking": "0010-7824", "issue": "97(6)", "journal": "Contraception", "keywords": "Abortion; Anticoagulation; Dilation and curettage; Venous thromboembolism", "medline_ta": "Contraception", "mesh_terms": "D000028:Abortion, Induced; D000925:Anticoagulants; D016063:Blood Loss, Surgical; D005260:Female; D006493:Heparin; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011261:Pregnancy Trimester, First; D011655:Pulmonary Embolism; D055815:Young Adult", "nlm_unique_id": "0234361", "other_id": null, "pages": "565-566", "pmc": null, "pmid": "29428851", "pubdate": "2018-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Therapeutic anticoagulation for pulmonary embolism during first-trimester surgical abortion: two case reports.", "title_normalized": "therapeutic anticoagulation for pulmonary embolism during first trimester surgical abortion two case reports" }	[ { "companynumb": "US-TEVA-2019-US-1070466", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ENOXAPARIN" }, "drugadditional": null, ...
{ "abstract": "Fibrolamellar carcinoma is a rare variant of hepatocellular carcinoma not associated with cirrhosis or viral hepatitis. Serum alpha-fetoprotein levels are usually normal; the histology is of a well-differentiated tumor, and the staging is the same as for hepatocellular carcinoma. We describe the case of a female patient in her 4th decade of life with a diagnosis of fibrolamellar hepatocellular carcinoma with a multimodal approach. The rare incidence of this cancer and its unusual clinical presentation justifies reporting this case and highlights the importance of multidisciplinary teams in the treatment of cancer patients.", "affiliations": "Medical Oncology Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal.;General Surgery Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal.;Medical Oncology Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal.;Gastroenterology Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal.;General Surgery Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal.;General Surgery Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal.;Medical Oncology Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal.", "authors": "Barreira\|João Vasco\|JV\|;Silva\|Nádia\|N\|;Parmanande\|Anuraj\|A\|;Rocha\|Manuel\|M\|;Coelho\|João S\|JS\|;Marques\|Hugo Pinto\|HP\|;da Luz\|Ricardo\|R\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000507201", "fulltext": null, "fulltext_license": null, "issn_linking": "2387-1954", "issue": "27(6)", "journal": "GE Portuguese journal of gastroenterology", "keywords": "Fibrolamellar carcinoma; Oncology; Rare tumors", "medline_ta": "GE Port J Gastroenterol", "mesh_terms": null, "nlm_unique_id": "101685861", "other_id": null, "pages": "429-433", "pmc": null, "pmid": "33251292", "pubdate": "2020-11", "publication_types": "D002363:Case Reports", "references": "24917983;26975868;27029710;24578576;22666208", "title": "Fibrolamellar Carcinoma: A Multimodal Approach.", "title_normalized": "fibrolamellar carcinoma a multimodal approach" }	[ { "companynumb": "PT-MYLANLABS-2020M1093499", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", ...
{ "abstract": "Combination therapy regimens containing a proteasome inhibitor, an immunomodulatory drug, and a steroid are an established standard of care for patients with newly diagnosed multiple myeloma (NDMM) regardless of transplant eligibility. Triplet regimens that include lenalidomide/dexamethasone combined with daratumumab or carfilzomib are highly active in multiple myeloma, including NDMM. The aim of this open-label, phase 1b study was to evaluate daratumumab in combination with carfilzomib, lenalidomide, and dexamethasone (D-KRd) in patients with NDMM.\n\n\n\nPatients (n = 22), regardless of transplant eligibility, received treatment with D-KRd for up to thirteen 28-day cycles or until autologous stem cell transplant. The first daratumumab dose was administered as a split infusion (8 mg/kg on days 1 and 2 of cycle 1). The primary end point was safety and tolerability.\n\n\n\nA total of 10 patients discontinued treatment, most frequently because of elective autologous stem cell transplant (n = 8). The most common treatment-emergent adverse events (any grade; grade 3/4) were diarrhea (68%; 18%), lymphopenia (64%; 59%), cough (59%; 5%), and upper respiratory tract infection (55%; 0%). Stem cell collection was successful in most patients (91%). Daratumumab infusion-related reactions occurred in 9 (41%) patients, primarily during the first infusion, and were mild in severity (no grade 3/4 events). The best overall response rate was 95%, including 86% with a very good partial response or better and 67% with a complete response or better.\n\n\n\nD-KRd was well tolerated, and encouraging efficacy results support further investigation of daratumumab-based quadruplet therapies for NDMM.", "affiliations": "University of Chicago Medical Center, Chicago, IL, USA. Electronic address: ajakubowiak@medicine.bsd.uchicago.edu.;Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.;Judy and Bernard Briskin Myeloma Center, City of Hope, Duarte, CA, USA.;Winship Cancer Institute, Emory University, Atlanta, GA, USA.;John C. Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA, USA.;Janssen Research & Development LLC, Raritan, NJ, USA.;Janssen Research & Development LLC, Leiden, The Netherlands.;Janssen Research & Development LLC, Beerse, Belgium.;Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Janssen Research & Development LLC, Raritan, NJ, USA.;Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA.", "authors": "Jakubowiak\|Andrzej\|A\|;Usmani\|Saad Z\|SZ\|;Krishnan\|Amrita\|A\|;Lonial\|Sagar\|S\|;Comenzo\|Raymond L\|RL\|;Wang\|Jianping\|J\|;de Boer\|Carla\|C\|;Deraedt\|William\|W\|;Weiss\|Brendan M\|BM\|;Schecter\|Jordan M\|JM\|;Chari\|Ajai\|A\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.clml.2021.05.017", "fulltext": null, "fulltext_license": null, "issn_linking": "2152-2669", "issue": "21(10)", "journal": "Clinical lymphoma, myeloma & leukemia", "keywords": "Efficacy; Quadruplet regimen; Safety", "medline_ta": "Clin Lymphoma Myeloma Leuk", "mesh_terms": null, "nlm_unique_id": "101525386", "other_id": null, "pages": "701-710", "pmc": null, "pmid": "34274290", "pubdate": "2021-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Daratumumab Plus Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma.", "title_normalized": "daratumumab plus carfilzomib lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma" }	[ { "companynumb": "US-CELGENEUS-USA-20210800119", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": "3", ...
{ "abstract": "Metformin rarely, if ever, causes hypoglycemia when it is used as labeled. A 55-year-old woman presented to the medicine ward with an altered level of consciousness. She had been reviewed in an outpatient department three days earlier and prescribed 500 mg two times per day of metformin immediate-release (Met IR) for newly diagnosed type 2 diabetes mellitus (T2DM), to which she had been adherent; however, she had been experiencing intermittent episodes of hypoglycemia after taking the medication prescribed to treat her T2DM. On physical examination, she was diaphoretic and disoriented but responsive to sensory stimuli. In the ward, she received 25 ml of intravenous dextrose as the initial blood glucose reading was low at 54 mg/dl, and 4 ounces of apple juice additionally two hours later as her blood glucose level fell below 70 mg/dl again. She was no longer hypoglycemic a few hours later, and there was a significant neurological improvement. The remainder of the laboratory results, including serum renal and liver function tests, were normal. Met IR was discontinued, and metformin extended-release (Met XR) 500 mg/day was initiated at discharge. The patient's hypoglycemic episodes resolved within days after the initiation of Met XR. Hypoglycemia is rarely associated with accidental or suicidal overdose of metformin, metabolic dysfunction (e.g., renal insufficiency), exercise, missed meal, acute illness, or the initiation of additional antidiabetic medication. Albeit even uncommon, metformin-associated hypoglycemia may occur with no obvious trigger. In this context, we determine to what extent Met IR may contribute to the development of hypoglycemia in an individual case, but also that the risk could be mitigated by a switch to Met XR. In a preferred embodiment, the Met XR dosage form can be administered once a day, ideally with or after a meal, preferably with or after the evening meal, and it provides therapeutic levels of the drug throughout the day with peak plasma levels being obtained between four to eight hours after the administration (Tmax).", "affiliations": "Internal Medicine, Combined Military Hospital, Rawalpindi, PAK.", "authors": "Akram\|Ayesha\|A\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.16112", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16112\nEndocrinology/Diabetes/Metabolism\nInternal Medicine\nReactive Hypoglycemia From Metformin Immediate-Release Monotherapy Resolved by a Switch to Metformin Extended-Release: Conceptualizing Their Concentration-Time Curves\nMuacevic Alexander\nAdler John R\nAkram Ayesha 12\n1 Internal Medicine, Combined Military Hospital, Rawalpindi, PAK\n2 Internal Medicine, Rawalpindi Medical University, Rawalpindi, PAK\nAyesha Akram ayesha_akram_01@hotmail.com\n2 7 2021\n7 2021\n13 7 e161122 7 2021\nCopyright © 2021, Akram et al.\n2021\nAkram 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/62816-reactive-hypoglycemia-from-metformin-immediate-release-monotherapy-resolved-by-a-switch-to-metformin-extended-release-conceptualizing-their-concentration-time-curves\nMetformin rarely, if ever, causes hypoglycemia when it is used as labeled. A 55-year-old woman presented to the medicine ward with an altered level of consciousness. She had been reviewed in an outpatient department three days earlier and prescribed 500 mg two times per day of metformin immediate-release (Met IR) for newly diagnosed type 2 diabetes mellitus (T2DM), to which she had been adherent; however, she had been experiencing intermittent episodes of hypoglycemia after taking the medication prescribed to treat her T2DM. On physical examination, she was diaphoretic and disoriented but responsive to sensory stimuli. In the ward, she received 25 ml of intravenous dextrose as the initial blood glucose reading was low at 54 mg/dl, and 4 ounces of apple juice additionally two hours later as her blood glucose level fell below 70 mg/dl again. She was no longer hypoglycemic a few hours later, and there was a significant neurological improvement. The remainder of the laboratory results, including serum renal and liver function tests, were normal. Met IR was discontinued, and metformin extended-release (Met XR) 500 mg/day was initiated at discharge. The patient's hypoglycemic episodes resolved within days after the initiation of Met XR. Hypoglycemia is rarely associated with accidental or suicidal overdose of metformin, metabolic dysfunction (e.g., renal insufficiency), exercise, missed meal, acute illness, or the initiation of additional antidiabetic medication. Albeit even uncommon, metformin-associated hypoglycemia may occur with no obvious trigger. In this context, we determine to what extent Met IR may contribute to the development of hypoglycemia in an individual case, but also that the risk could be mitigated by a switch to Met XR. In a preferred embodiment, the Met XR dosage form can be administered once a day, ideally with or after a meal, preferably with or after the evening meal, and it provides therapeutic levels of the drug throughout the day with peak plasma levels being obtained between four to eight hours after the administration (Tmax).\n\nglycemic control\nmetformin immediate release\nmetformin extended release\ntherapeutic indications\nadverse reactions\nhypoglycemia\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nThe term antidiabetic or antihyperglycemic drugs refers to drugs that are useful in managing type 2 diabetes mellitus (T2DM). Preferably, a first-line antidiabetic drug is a biguanide such as metformin or its pharmaceutically acceptable salt such as metformin hydrochloride. Metformin is an oral antihyperglycemic drug that improves glucose tolerance in T2DM by lowering both basal and postprandial plasma glucose [1]. Metformin exerts its metabolic effects by reducing hepatic gluconeogenesis due to the inhibition of mitochondrial glycerophosphate dehydrogenase, decreases hepatic lipogenesis by upregulation of AMP-activated protein kinase, and increases insulin-dependent peripheral glucose uptake and utilization [1,2]. In addition, it reduces appetite and decreases intestinal absorption of glucose [1]. The dosage of metformin is individualized on the basis of both effectiveness and tolerance in adults [1]. Previously, metformin was available as an immediate-release formulation (Met IR) only. Any such formulation is quickly absorbed and then rapidly cleared, necessitating multiple dosing with considerable plasma level fluctuations consisting of peaks and troughs. These fluctuations may account for transient side effects at the peak and a potential fall to subtherapeutic levels at the trough. This ultimately is the rationale behind developing a newer formulation, namely, metformin extended-release (Met XR) [3-5]. Met XR tablets are designed with the active ingredient overlaid with an enteric coat. The active drug is released through hydrated polymers, which expand the safe uptake of fluid, thereby prolonging gastric transit and delaying drug absorption in the upper gastrointestinal tract [1]. Owing to its slower absorption, Met XR can provide non-pulsating, therapeutic levels over a 12- to 24-hour period with less frequent administration, typically once daily [1]. Tolerability and even glycemic control in T2DM have been reported to improve with Met XR. Patient satisfaction and compliance are increased using a reduced dosing interval at one versus two or three times daily [3-5]. The bioavailability of the drug is not decreased by the presence of food, in fact a slight increase in the bioavailability is observed when the Met XR dosage form is administered with food [1]. Circulating levels of endogenous insulin are unchanged or slightly decreased by Met XR, and hence it carries a low risk of hypoglycemia [1]. Adverse events associated with metformin use are often gastrointestinal in nature, e.g., nausea, vomiting, and occasionally diarrhea [1]. However, hypoglycemia due to overdose, decreased drug clearance, nutritional deficits, multiple comorbidities, and drug-drug interactions, is rarely known to occur [6-11]. In this report, the case of a 55-year-old diabetic patient with no known comorbidity who developed metformin-associated hypoglycemia that promptly resolved after stopping Met IR and initiating Met XR is presented. A thorough comparison of the pharmacokinetics of Met IR and Met XR is undertaken in the Discussion section.\n\nCase presentation\n\nA 55-year-old woman with newly diagnosed T2DM was found unresponsive by her family one morning. She had been seen in the outpatient setting three days ago and initiated on Met IR 500 mg twice daily in accordance with two consecutive fasting plasma glucose and hemoglobin A1c (HbA1c) readings of 126 and 155 mg/dl, and 6.3 and 6.8%, respectively, together with an insistence by the patient to \"deliciously\" control diabetes without an excessive cut-down on her favorite dessert. While in the ward, her daughter reported that the patient had experienced three episodes in the past two days characterized by headaches, nausea, sweating, and a feeling that she was going to pass out, despite adequate meals and adherence to Met IR as prescribed. During the most recent episode, her fingerstick glucose was 69 mg/dl and symptoms were relieved by oral fast-acting carbohydrates. Medical history included long-standing obesity only with a body mass index at present of 36 kg/m2. Of note, she had no history of renal insufficiency. When last checked at the outpatient, her urinary albumin-to-creatinine ratio had been 0.22 mg/mmol (normal value: <3.4). On presentation, she was diaphoretic and somnolent, with normal vital signs. Pupils were equal, round, and reactive to light. Further neurologic examination revealed disorientation to time and place but normal deep tendon reflexes and no focal sensory or motor deficits. The cardiopulmonary examination was normal. Her bedside point-of-care capillary blood glucose was checked and it was low, a finding confirmed by a serum blood glucose of 54 mg/dl. The diagnosis prompted intravenous administration of 25 ml of 50% dextrose. Emergent laboratory test results were unremarkable except for low blood glucose and an above-optimal low-density lipoprotein level (Table 1). There was no overt lactic acidosis on arterial blood gas results (pH: 7.4, PaCO2: 36 mmHg, and HCO3-: 24 mEq/L).\n\nTable 1 Blood investigation results\n\nParameter\tValue (reference)\t\nBlood count\t\nLeukocyte count (×109/L)\t6.7 (4.5-11.0)\t\nErythrocyte count (×1012/L)\t4.7 (3.5-5.5)\t\nHemoglobin (g/dL)\t14.9 (12-16)\t\nHematocrit (%) \t42 (36-46)\t\nMean corpuscular volume (fL)\t85.4 (80-100)\t\nMean corpuscular hemoglobin (pg)\t27.6 (25.4-34.6)\t\nMean corpuscular hemoglobin concentration (g/dL)\t33.3 (31.5-34.5)\t\nPlatelet count (×109/L)\t240 (150-400)\t\nLiver function tests\t\nAlanine aminotransferase (U/L)\t22 (8-40)\t\nAspartate aminotransferase (U/L)\t18 (8-40) \t\nAlkaline phosphatase (U/L)\t84 (45-115)\t\nAlbumin (g/L)\t40 (35-50)\t\nTotal bilirubin (μmol/L)\t4 (2-17)\t\nEndocrine/miscellaneous\t\nRandom blood glucose (mg/dL)\t54 (hypoglycemia: ≤70)\t\nVitamin B12 (pmol/L)\t253 (118-701)\t\nThyroid-stimulating hormone (mIU/L)\t2.4 (0.5-5.0)\t\nRenal function tests\t\nUrea (mmol/L)\t4.4 (2.5-7.1)\t\nCreatinine (μmol/L)\t75 (53-106)\t\nSerum electrolytes\t\nSodium (mEq/L)\t138 (136-145)\t\nPotassium (mEq/L)\t4.5 (3.5-5.0) \t\nChloride (mEq/L)\t102 (95-105)\t\nBone profile\t\nCalcium (mmol/L)\t2.3 (2.1-2.7)\t\nPhosphate (mmol/L)\t1.4 (1.0-1.5)\t\nCoagulation profile\t\nProthrombin time (seconds)\t14 (11-15)\t\nPartial thromboplastin time (seconds)\t32 (25-40)\t\nLipid tests\t\nCholesterol (mmol/L)\t4.6 (3.9-6.2)\t\nTriglycerides (mmol/L)\t0.8 (0.4-1.6)\t\nHigh-density lipoprotein (HDL) cholesterol (mmol/L)\t1.2 (desirable: >1.3)\t\nLow-density lipoprotein (LDL) cholesterol (mmol/L)\t3.2 (optimal: <2.6, near/above optimal: 2.6-3.4)\t\nVery-low-density lipoprotein (VLDL) cholesterol (mmol/L)\t0.4 (0.1-1.7)\t\n\nThe patient’s condition improved transiently after the administration of an intravenous bolus of dextrose. However, repeat blood glucose two hours later fell to 67 mg/dl and 4 ounces of apple juice were given at this stage. Subsequently, levels began trending towards the normal range without any recurrence of hypoglycemia, reflected also by her conscious and oriented mental status, till hospital discharge. Serial measurements of blood glucose are documented in Table 2.\n\nTable 2 Blood glucose levels\n\nTime after the morning dose of metformin immediate-release (Met IR)\tBlood glucose levels (mg/dL)\t\n@0400\t54 ➜ intravenous dextrose administered\t\n@0415\t115\t\n@0600\t67 ➜ one 4 oz. apple juice\t\n@0800\t85\t\n@1100\t110\t\n\nThough not very familiar, the temporal association of hypoglycemia with the initiation of Met IR and the fact that there were no other factors to explore caused the medication to be withheld; her therapy was transitioned to Met XR 500 mg once a day. Over the next two weeks, a review of her self-monitored two-hour postprandial blood glucose showed levels of 125-165 mg/dl. Laboratory analysis at follow-up (day 14) revealed the following - fasting plasma glucose: 102 mg/dl, HbA1c: 5.9%. Met XR was now titrated up by 500 mg, i.e., 1000 mg once a day. After three weeks of therapy with Met XR (day 21), the patient is happy because of optimal glycemic control. She has experienced no more hypoglycemic attacks since the new therapy was started. A reasonable alternative is to reduce the dose of Met IR to 250 mg twice a day (the tablet can be cut in half), but this was not experimented on in this particular case.\n\nDiscussion\n\nMetformin is the preferred initial medication for most patients with T2DM due to its overall efficacy and lack of hypoglycemia when used in monotherapy. Overall, the available case reports also suggest that clinically significant hypoglycemia is uncommon in metformin monotherapy and unlikely to occur abruptly in the absence of any predisposing conditions [6-11]. Indeed, there is no previous report of this phenomenon occurring merely due to Met IR, as is evident in this patient by the normal renal and liver function tests, and the absence of risk factors for hypoglycemia that include prolonged fasting, exercise, acute illness, or addition of another antidiabetic [1]. A randomized, multi-center trial compared 24 weeks of treatment with twice-daily Met IR 1000 mg to once-daily Met XR 2000 mg in patients with T2DM and is probably the only one that cites reports of hypoglycemia in 1.1 % of patients exclusively on Met IR. Met XR was well tolerated at a single dose and there was three times less down-titration [12]. Metformin analogs are formulated with different pharmacokinetic properties, with the differences explained by a slower intestinal absorption of Met XR. Met XR provides a delayed mean time to maximum plasma concentration (Tmax), as compared to the Tmax provided by Met IR. The delayed Tmax occurs from four to eight hours after administration [1]. If Met XR is administered at dinner time (when dinner is normally eaten, generally between about 6 p.m. and 8 p.m.), the Tmax would occur during the time when gluconeogenesis is expected to occur at its highest level [13]. The extent of absorption or systemic exposure is equivalent for both formulations, which is ideal especially in patients who switch to a Met XR formulation [1]. Peak plasma levels are about 20% lower as compared to a similar dose of Met IR [1]. In this respect, three parallel studies were conducted on 78 healthy subjects. A sample size of 26 subjects per group provided >80% statistical power to detect a difference in pharmacokinetic parameters between at least one Met XR group and Met IR. Every subject received a one-day dosing of either Met IR 1000 mg in the fed or fasting state or Met XR 750 mg in the fasting state. Both Met XR and Met IR displayed a similar half-life. The maximum plasma concentration (Cmax) of Met XR was much lower than that of Met IR (p<0.05). Additionally, Met XR was generally well-tolerated [14].\n\nThe graph below (Figure 1) shows the plasma drug concentration-time curves of the two different oral formulations. The one represented by the gray curve shows a reduced and delayed peak level relative to the black curve, which is consistent with a sustained-release preparation. The fluctuation index - Cmax minus minimum plasma concentration (Cmin)/average plasma concentration (Cavg) - is of particular interest when comparing drugs with varying release properties. The lower the fluctuation index, the more likely the Cmax is blunted while effectively extending the dosing interval, potentially allowing for up-titration to higher doses if needed for efficacy. This results in flatter concentration-time plots. There is even a benefit to having lower metformin levels in the blood during the afternoon in patients who are under concomitant therapy with at least one additional antidiabetic drug such as glyburide or its equivalents. In contrast to Met XR that does not increase endogenous insulin, a long-acting sulfonylurea, for instance, continues to stimulate pancreatic beta-cell insulin secretion even when blood glucose levels are normal (glucose-independent insulin release) and is therefore prone to causing hypoglycemia [1,15].\n\nFigure 1 Simulated pharmacokinetic comparison of formulations of the same drug to compare immediate- and extended-release properties\n\nbd: twice daily; qd: once daily\n\nSome degree of research has been performed in the area of controlled-release compositions that employ antihyperglycemic drugs. The value of Met XR is further indicated by the results of a randomized, double-blind, active-controlled, six-month clinical trial among adult patients with drug-naive T2DM and HbA1c levels >7.0% and <8.5% [3]. Metformin was given in a randomized sequence at the maximum tolerated dose as Met IR in one group and as Met XR in the other. The efficacy endpoint was glycemic control as determined by the reduction in HbA1C, fasting plasma glucose, and postprandial plasma glucose levels after six months. Accordingly, insulin resistance was also measured. Met XR produced not only a statistically significant and sustained reduction in these measures of glycemic control compared with baseline (p<0.01) but also a more efficacious lowering of levels than Met IR (p<0.05). Secondly, the reduction in insulin resistance was consistent with these changes (p<0.01 vs. baseline, p<0.05 vs. Met IR). Of note, there was no significant increase in adverse events with an average 1000 ± 500 mg/day dose of Met XR, even with improved efficacy at this dose. Although there were no cases of hypoglycemia in either group, the overall incidence of gastrointestinal side effects was lower among those who received Met XR. While there may be other explanations for the improved outcome on Met XR, including enhanced compliance due to less frequent dosing, minimizing fluctuations in serum drug levels or continued glycemic control is likely to have played an important role [3]. In the present case too, Met XR achieved \"therapeutically effective reduction\", which signifies that plasma glucose levels were reduced by an effective amount compared to a Met IR reference standard when the dosage form was orally administered to the patient on a once-daily basis. Further contemplated for the purpose of the present case is that Met IR persisted at its peak plasma levels for approximately two hours, although this claim is directed to the pharmacokinetic parameters of an individual patient. A limitation of this study is that serum metformin levels were not determined. The Naranjo algorithm, a tool used to discern an adverse drug reaction, was used retrospectively to analyze this case presentation. According to the algorithm, this case showed a score of 7, which coincides with a \"probable\" diagnosis of adverse drug reaction. This is supported by clinical improvement and resolution of hypoglycemic symptoms with the discontinuation of Met IR. This patient had symptomatic hypoglycemia, confirmed by the Whipple triad [16], and is by definition \"severe hypoglycemia\" or \"documented symptomatic hypoglycemia\" [17].\n\nConclusions\n\nIn accordance with the dosage forms of the present case, it has been determined that this patient suffering from T2DM achieved improved results (e.g., effectively lowered blood glucose levels, lower risk of hypoglycemia) with Met XR than Met IR administered according to popular protocols, e.g., on a twice-a-day basis. Another clear advantage is a reduction in the frequency of administration with Met XR. All of these findings suggest that Met XR may improve the quality of therapy and the safety profile relative to a conventional dosage form in patients with T2DM.\n\nHuman Ethics\n\nArmed Forces Institute of Pathology (AFIP), for its prompt reporting of laboratory results.\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 GLUCOPHAGE® (metformin hydrochloride tablets) GLUCOPHAGE® XR (metformin hydrochloride extended-release tablets) 62021 2006 https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020357s030,021202s015lbl.pdf\n2 Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase Nature Madiraju AK Erion DM Rahimi Y 542 546 510 2014 24847880\n3 Effects of metformin extended release compared to immediate release formula on glycemic control and glycemic variability in patients with type 2 diabetes Drug Des Devel Ther Derosa G D'Angelo A Romano D Maffioli P 1481 1488 11 2017\n4 Extended release drugs: are they right for you? 62021 2017 https://www.goodrx.com/blog/extended-release-drugs-are-they-right-for-you/\n5 Advantages of extended-release metformin in patients with type 2 diabetes mellitus Postgrad Med Jabbour S Ziring B 15 23 123 2011 21293080\n6 Successful treatment of severe lactic acidosis caused by a suicide attempt with a metformin overdose Kaohsiung J Med Sci Yang PW Lin KH Lo SH Wang LM Lin HD 93 97 25 2009 19321413\n7 Severe lactic acidosis and acute renal failure following ingestion of metformin and kerosene oil: a case report J Med Case Rep Rathnapala A Matthias T Jayasinghe S 18 6 2012 22251748\n8 Metformin overdose-induced hypoglycemia in the absence of other antidiabetic drugs Clin Toxicol (Phila) Al-Abri SA Hayashi S Thoren KL Olson KR 444 447 51 2013 23544622\n9 Severe hypoglycemia in an elderly patient treated with metformin Int J Clin Pharmacol Ther Zitzmann S Reimann IR Schmechel H 108 110 40 2002 11911598\n10 Survival following a metformin overdose of 63 g: a case report Pharmacol Toxicol Gjedde S Christiansen A Pedersen SB Rungby J 98 99 93 2003 12899672\n11 Recurrent hypoglycemia secondary to metformin toxicity in the absence of co-ingestions: a case report J Med Case Rep Aldobeaban S Mzahim B Alshehri AA 223 12 2018 30119705\n12 Metformin extended-release versus immediate-release: an international, randomized, double-blind, head-to-head trial in pharmacotherapy-naïve patients with type 2 diabetes Diabetes Obes Metab Aggarwal N Singla A Mathieu C 463 467 20 2018 28857388\n13 Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study J Clin Invest Magnusson I Rothman DL Katz LD Shulman RG Shulman GI 1323 1327 90 1992 1401068\n14 Metformin IR versus XR pharmacokinetics in humans J Bioequiv Biovailab Idkaidek N Arafat T Melhim M Alawneh J Hakooz N 233 235 3 2011\n15 Sulfonylureas and their use in clinical practice Arch Med Sci Sola D Rossi L Schianca GP 840 848 11 2015 26322096\n16 Hypoglycaemia (Article in Slovak) Vnitr Lek Mokán M 387 394 54 2008 https://pubmed.ncbi.nlm.nih.gov/18630618/ 18630618\n17 Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society Diabetes Care Seaquist ER Anderson J Childs B 1384 1395 36 2013 23589542\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "13(7)", "journal": "Cureus", "keywords": "adverse reactions; glycemic control; hypoglycemia; metformin extended release; metformin immediate release; therapeutic indications", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e16112", "pmc": null, "pmid": "34350076", "pubdate": "2021-07", "publication_types": "D002363:Case Reports", "references": "12899672;18630618;23544622;23589542;11911598;28857388;1401068;21293080;30119705;26322096;19321413;28553078;24847880;22251748", "title": "Reactive Hypoglycemia From Metformin Immediate-Release Monotherapy Resolved by a Switch to Metformin Extended-Release: Conceptualizing Their Concentration-Time Curves.", "title_normalized": "reactive hypoglycemia from metformin immediate release monotherapy resolved by a switch to metformin extended release conceptualizing their concentration time curves" }	[ { "companynumb": "PK-MACLEODS PHARMACEUTICALS US LTD-MAC2021032358", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, ...
{ "abstract": "Neonatal sepsis is a major cause of morbidity and mortality in preterm infants. Chorioamnionitis is an important risk factor for the development of sepsis, therefore neonates born to mothers developing signs of amnionitis need to be treated with antibiotics immediately after birth. Ureaplasma spp can be a causative agent of vaginal or intra amniotic infection needing antibiotic treatment. Macrolides are frequently used to treat maternal intrauterine infection, but antibiotic treatment of the neonate should be consciously chosen with consideration of potential side effects. Indeed, macrolides are great purveyors of heart rhythm disorders.\nWe describe the case of a 29 weeks preterm infant born to a mother with Ureaplasma spp infection. The baby was treated with erythromycin immediately after birth. During the second day of life, the baby presented some episodes of tachyarrhythmia with premature ventricular beats (PVBs) that were followed by a non-sustained ventricular tachycardia as high as 270 bpm leading to a cardiac arrest. After resuscitation, tachycardia resolved but the rhythm was characterised by numerous PVBs and an electrocardiogram (ECG) diagnosed a Long QT Syndrome (LQTS). Erythromycin was discontinued, and the rhythm normalised a few days after withdrawal.\nErythromycin should be administered in neonates only if no other choice is available, as although generally well tolerated, its administration can be associated with QTc interval prolongation. When no other option is available, paediatricians should be aware to perform cardiac monitoring or at least serial ECGs before and during erythromycin administration.", "affiliations": "Department of Neonatology, Cliniques Universitaires Saint Luc, Bruxelles, Belgium.;Department of Neonatology, Cliniques Universitaires Saint Luc, Bruxelles, Belgium.;Department of Pediatric Cardiology, Cliniques Universitaires Saint Luc, Bruxelles, Belgium.;Department of Pediatric Cardiology, Cliniques Universitaires Saint Luc, Bruxelles, Belgium.;Department of Neonatology, CHU, Tivoli, Belgium.;Department of Neonatology, Cliniques Universitaires Saint Luc, Bruxelles, Belgium.;Department of Neonatology, Cliniques Universitaires Saint Luc, Bruxelles, Belgium.", "authors": "Fobe\|Caroline\|C\|;Van Grambezen\|Benedicte\|B\|;Moniotte\|Stéphane\|S\|;Vo\|Christophe\|C\|;Dussart\|Anneliese\|A\|;Danhaive\|Olivier\|O\|;Piersigilli\|Fiammetta\|F\|https://orcid.org/0000-0002-6581-2822", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/00015385.2021.1968153", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5385", "issue": null, "journal": "Acta cardiologica", "keywords": "Long QT syndrome; Neonate; erythromycin; preterm", "medline_ta": "Acta Cardiol", "mesh_terms": null, "nlm_unique_id": "0370570", "other_id": null, "pages": "1-5", "pmc": null, "pmid": "34420486", "pubdate": "2021-08-23", "publication_types": "D016428:Journal Article", "references": null, "title": "Torsade de pointe due to QT prolongation following erythromycin administration in a preterm infant.", "title_normalized": "torsade de pointe due to qt prolongation following erythromycin administration in a preterm infant" }	[ { "companynumb": "BE-MLMSERVICE-20210913-3103963-1", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadd...
{ "abstract": "A 56-year-old woman presented with anasarca, hypoalbuminaemia and hypotension following cycle 3 day 1 of adjuvant gemcitabine for stage II pancreatic cancer. Due to the temporal nature of presentation, suspicion for gemcitabine-induced capillary leak syndrome was included in the differential diagnosis. Vascular endothelial growth factor levels were elevated at 707 pg/mL (reference range: 9-86 pg/mL). Corticosteroids were initiated, resulting in complete resolution of symptoms and hypotension. The patient suffered relapse of symptoms on discontinuation of steroids, further supporting chronic capillary leak syndrome.", "affiliations": "Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, Florida, USA.;Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, Florida, USA.;Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, Florida, USA.", "authors": "Bajwa\|Ravneet\|R\|;Starr\|Jason\|J\|;Daily\|Karen\|K\|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-221068", "fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2017-22106810.1136/bcr-2017-221068ArticleFindings That Shed New Light on the Possible Pathogenesis of a Disease or an Adverse Effect15061517Female51-70 yearsWhiteUSA/CanadaCase ReportGemcitabine-induced chronic systemic capillary leak syndrome Bajwa Ravneet Starr Jason Daily Karen Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, Florida, USACorrespondence to Dr Ravneet Bajwa, ravneet.bajwa@medicine.ufl.edu2017 30 8 2017 30 8 2017 2017 bcr201722106816 8 2017 © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2017This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/A 56-year-old woman presented with anasarca, hypoalbuminaemia and hypotension following cycle 3 day 1 of adjuvant gemcitabine for stage II pancreatic cancer. Due to the temporal nature of presentation, suspicion for gemcitabine-induced capillary leak syndrome was included in the differential diagnosis. Vascular endothelial growth factor levels were elevated at 707 pg/mL (reference range: 9–86 pg/mL). Corticosteroids were initiated, resulting in complete resolution of symptoms and hypotension. The patient suffered relapse of symptoms on discontinuation of steroids, further supporting chronic capillary leak syndrome.\n\npancreatic cancercontraindications and precautionsunwanted effects / adverse reactionsspecial-featureunlocked\n==== Body\nBackground\nSystemic capillary leak syndrome (SCLS) is a rare disorder characterised by hypotension, hypoalbuminaemia and haemoconcentration. It can be idiopathic (Clarkson’s disease) or secondary to various conditions, such as monoclonal gammopathy of undetermined significance, engraftment syndrome after haematopoietic stem cell transplantation, viral infections (eg, viral haemorrhagic fever like hantavirus, dengue haemorrhagic fever), snake bites and secondary to treatments, such as chemotherapy medications.1 2 The pathophysiology is thought to be secondary to derangements in the endothelial surface causing leakage of proteins and plasma into the interstitial compartment. High levels of plasma vascular endothelial growth factor (VEGF) levels have been reported during acute, severe episodes.2 Further, elevated levels of VEGF were noted in a series of 23 patients and in several smaller reports.2 3 A chronic form of SCLS has also been described, in which patients present with persistent, non-cyclical, progressive generalised oedema rather than acute attacks and may also have associated pleural and pericardial effusions.4 SCLS has been reported as a rare adverse effect from gemcitabine.5 6 The exact pathophysiology of gemcitabine-induced capillary leak syndrome is unclear.\n\nCase presentation\nWe present here a case of a 56-year-old woman who was diagnosed with stage IIB (pT3pN1M0), moderately differentiated adenocarcinoma of the pancreatic head. In September 2015, the patient underwent a pancreatojejunostomy (Whipple procedure) with resection of a long afferent limb from a previous gastric bypass and placement of a feeding jejunostomy for enteral nutrition. This was followed by adjuvant radiation (50.4 Gy at 1.8 Gy/fraction) to the pancreatic tumour bed with concurrent continuous infusion of 5-fluorouracil. Subsequently the patient began adjuvant gemcitabine (1000 mg/m2) on days 1, 8 and 15 of each 28 day cycle. She received cycle 3, day 1 of gemcitabine in April 2016 and presented to the emergency room (ER) 10 days later with complaints of worsening shortness of breath. Evaluation revealed the patient to have anasarca, bilateral pleural effusions and hypotension (systolic blood pressure ranging from 77 to 87 mm Hg). The patient reported previous episodes of hypotension and oedema with gemcitabine infusions, managed with intravenous fluids in the chemotherapy infusion room and ER.\n\nHer other medical history included hypertension, pancreatitis, gastro-oesophageal reflux disease with Barrett’s oesophagus and insulin dependent diabetes mellitus. Her surgical history included laparoscopic Roux-en-Y gastric bypass, cholecystectomy and total abdominal hysterectomy with salpingo-oophorectomy. She had prior alcohol abuse and a 60-pack year smoking history.\n\nInvestigations\nLaboratory evaluation at the time of hospitalisation described aboverevealed profound hypoalbuminaemia with albumin level of 1.8 g/dL (reference range: 3.5–5.0 g/dL) and total protein of 4.6 g/dL (reference range: 6.4–8.3 g/dL). Complete blood count revealed haematocrit 32%. B-natriuretic peptide prior to starting gemcitabine was 361 pg/mL (reference range: <125 pg/mL). During this hospitalisation, it was 366 pg/mL. Cortisol (drawn the morning following the day of admission) was noted to be 12.7 mcg/dL (reference range: AM 7.0–22.0 mcg/dL, PM 3.0–9.0 mcg/dL). Urinalysis was negative for any proteinuria.\n\nCT scan of the chest, abdomen and pelvis did not show recurrence of cancer but was significant for bilateral pleural effusions and extensive hepatic steatosis with diffuse soft tissue anasarca and simple ascites.\n\nAn echocardiogram on admission revealed an ejection fraction (EF) of 65%. Similarly, an echocardiogram done before initiation of gemcitabine revealed an EF of 65%.\n\nDifferential diagnosis\nSCLS is under-recognised due to its rarity and non-specific presenting symptoms. Many patients presenting with hypotension are presumed to have septic shock and are treated with antibiotics and intravenous fluids.7 Unlike the hypotension associated with anaphylaxis, which usually resolves with administration of subcutaneous epinephrine, the hypotension in SCLS can be resistant to medications including vasopressors.\n\nCongestive heart failure and nephrotic syndrome can present with anasarca but have associated findings of poor EF on echocardiogram and proteinuria on urinalysis, respectively. Our patient had a normal echocardiogram and urinalysis.\n\nAdrenal insufficiency can also mimic SCLS with hypotension, diarrhoea and hypoalbuminaemia. Cortisol levels are typically low in these patients. Cortisol levels in our patient were normal on two separate occasions.\n\nPancreatic insufficiency secondary to pancreas surgery can lead to malabsorption and subsequent hypoalbuminaemia with resultant oedema. This is typically associated with diarrhoea and steatorrhoea, which our patient did not have. Further, our patient was on postoperative supplemental pancreatic enzymes.\n\nHereditary angioedema typically presents in adults with recurrent attacks of cutaneous and gastrointestinal oedema. It is due to deficiency or dysfunction of C1 inhibitor. Unlike the generalised oedema of SCLS, the cutaneous swelling of hereditary angioedema is usually localised.\n\nToxic shock syndrome presents with high fever, hypotension and rash. The presence of skin findings along with infection source and/or blood cultures will help distinguish toxic shock syndrome from SCLS.\n\nGleich syndrome is characterised by recurrent episodes of angioedema, urticaria, pruritus, fever, weight gain, oliguria and eosinophilia. Symptoms occur in cycles of 3–4 weeks and resolve spontaneously. Our patient did not exhibit features of this disease.\n\nTreatment\nInitial evaluation for an infectious aetiology was negative. The patient received several doses of intravenous albumin 25 g along with midodrine. Despite escalating doses of midodrine, the patient continued to have refractory hypotension, requiring intravenous fluid boluses.\n\nOn further review of the patient’s history and records, the episodes of hypotension appeared to be temporally linked to the infusions of gemcitabine. When the patient did not respond to midodrine, we considered the diagnosis of capillary leak syndrome induced by gemcitabine. The patient was started on methylprednisolone (1 mg/kg), and VEGF levels from peripheral blood were sent. The patient responded quickly to treatment with resolution of hypotensive episodes within 24 hours. The albumin gradually increased to 2.2 g/dL over a period of 2 weeks. VEGF levels were elevated at 707 pg/mL (reference range: 9–86 pg/mL). The patient was treated with high-dose steroids prednisone (1 mg/kg) for a week and then discharged on 10 mg daily. Given the above clinical events gemcitabine was permanently discontinued.\n\nOutcome and follow-up\nUnfortunately, the patient stopped taking steroids against medical advice and presented to the hospital with similar complaints approximately 2 months later. It was unclear why the patient discontinued the steroids. A complete workup to rule out other causes of SCLS was performed during the hospitalisation, which included serum protein electrophoresis (SPEP) with immunofixation, quantitative immunoglobulins, kappa/lambda free light chains, serum cortisol and antiphospholipid antibody syndrome testing; all which were negative. A repeat echocardiogram showed again an EF of 65%. Laboratories revealed total protein of 5.5 g/dL, albumin 1.6 g/dL. Haematocrit was 41%. Urinalysis revealed trace (30–50 mg/dL) proteinuria. Given the multiple hospitalisations and the patient’s general decline in health, she opted to forego all treatment, including corticosteroids and pursued hospice care. She passed away shortly thereafter. An autopsy was not performed.\n\nDiscussion\nSCLS is a rare and potentially fatal disorder characterised by recurrent episodes of generalised oedema, haemoconcentration and severe hypotension. Dr Clarkson first described it in 1960 and since then both case reports and case series have been published in literature.1 7 The exact incidence of the disorder is unknown as most cases go undiagnosed. The incidence seems to have increased in the past 15 years, due to increased awareness and successful identification of the disease with the help of classic laboratory findings.8\n\nMost patients present with a prodrome of fatigue, abdominal pain, nausea, myalgias, polydipsia and sudden increase in body weight. Episodes of hypotension presenting as lightheadedness and dizziness are common. The hypotension usually lasts for several days accompanied by massive extravasation of fluid resulting in oedema and anasarca. During quiescent periods between attacks, patients are usually asymptomatic.\n\nAcute attacks are characterised by elevation in haematocrit concentration. The median absolute increase in haematocrit in a retrospective review was seen to be about 19.8%.8 Hypoalbuminaemia is another classic feature of the disease. Presence of a monoclonal protein, usually IgG kappa, is seen in about 80% of patients. This is the only laboratory abnormality which will persist in the quiescent phase of the disease.4 8 Antiphospholipid antibodies as aetiology for SCLS have been reported in case reports.9\n\nThe pathogenesis of the disease remains unclear, but vascular endothelial growth factor, cytokines and complements have been implicated. Whether the monoclonal paraproteins present in SCLS contribute directly to disease pathogenesis is unclear.\n\nIn patients with the chronic form of capillary leak syndrome, there are often pleural and pericardial effusions, as seen in our patient.4 7 Chronic capillary leak syndrome induced by gemcitabine has been reported previously in case reports and may respond to a therapeutic regimen of prednisone, furosemide and theophylline.7\n\nGemcitabine is an S phase specific pyrimidine antimetabolite which impairs DNA synthesis by competitively inhibiting DNA polymerase and gets incorporated in DNA leading to impaired chain elongation.10 Gemcitabine is typically well tolerated and is used in a number of different malignancies including: pancreaticobiliary, bladder, non-small cell lung, Hodgkin lymphoma, breast, ovarian and testicular cancers. Neutropaenia and thrombocytopaenia can be dose limiting. Other adverse effects include transaminitis, peripheral oedema and fever.\n\nThe pathophysiology of capillary leak syndrome induced by gemcitabine is unknown. It is hypothesised that this syndrome occurs along the spectrum with gemcitabine pulmonary toxicity (GPT). GPT is thought to be secondary to endothelial dysfunction subsequently causing capillary leakage.11–13 The incidence of gemcitabine-induced SCLS is unknown, but the overall incidence of GPT is less than 1%.12 Increasing peripheral oedema along with decreasing serum albumin in patients receiving gemcitabine should prompt the clinician to SCLS. Patients with gemcitabine-induced SCLS and/or GPT typically respond to systemic steroids.5 11 14 Cessation of gemcitabine is mandatory.\n\nOur patient’s episodes were closely linked to gemcitabine infusions and there was resolution of symptoms with the addition of steroids. Relapse of disease with the discontinuation of steroids likely reflected chronic capillary leak syndrome which is known to have a relapsing and remitting course. Our patient’s albumin had decreased after the Whipple procedure (2.4–2.7 g/dL) and prior to starting gemcitabine which likely reflected a nutritional deficiency. However, after starting gemcitabine, her albumin decreased to as low as 1.3 g/dL. The rapid response of albumin and her episodes of hypotension to steroids favours capillary leak syndrome as the aetiology of her symptoms and clinical findings.\n\nLearning points\nSystemic capillary leak syndrome (SCLS) is a rare disorder which is often missed at the initial diagnosis due to non-specific symptoms leading to high mortality.\n\nTriad of hypotension, oedema and elevated haematocrit should alert the physician to a possible diagnosis of acute systemic SCLC.\n\nAlthough the aetiology is not well understood, SCLC is thought to be secondary to vascular endothelial damage. Elevated levels of vascular endothelial growth factors are commonly reported in the literature.\n\nGemcitabine-induced capillary leak syndrome is a rare, potentially lethal side effect of gemcitabine. Death can ensue if there is a delay in this diagnosis and thus SCLS should be kept in the differential diagnosis in a patient with unremitting oedema and hypotension.\n\nContributors: RB contributed to writing and drafting the case report, gathering all information and getting informed consent from the patient's family. KD and JS provided critical revisions and added intellectual content.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained from guardian.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Duron L , Delestre F , Amoura Z , et al \nIdiopathic and secondary capillary leak syndromes: a systematic review of the literature . Rev Med Interne \n2015 ;36 :386 –94 . 10.1016/j.revmed.2014.11.005 25600329 \n2 Lesterhuis WJ , Rennings AJ , Leenders WP , et al \nVascular endothelial growth factor in systemic capillary leak syndrome . Am J Med \n2009 ;122 :e5 –e7 . 10.1016/j.amjmed.2009.01.020 \n3 Xie Z , Ghosh CC , Patel R , et al \nVascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome) . Blood \n2012 ;119 :4321 –32 . 10.1182/blood-2011-08-375816 22411873 \n4 Druey KM , Greipp PR \nNarrative review: the systemic capillary leak syndrome . Ann Intern Med \n2010 ;153 :90 –8 . 10.7326/0003-4819-153-2-201007200-00005 20643990 \n5 Biswas S , Nik S , Corrie PG \nSevere gemcitabine-induced capillary-leak syndrome mimicking cardiac failure in a patient with advanced pancreatic cancer and high-risk cardiovascular disease . Clin Oncol \n2004 ;16 :577 –9 . 10.1016/j.clon.2004.06.019 \n6 Baron D , Mayo A , Kluger Y \nGemcitabine-induced chronic systemic capillary leak syndrome: a life-threatening disease . Clin Oncol \n2006 ;18 :90 –1 . 10.1016/j.clon.2005.09.003 \n7 Airaghi L , Montori D , Santambrogio L , et al \nChronic systemic capillary leak syndrome. Report of a case and review of the literature . J Intern Med \n2000 ;247 :731 –5 . 10.1046/j.1365-2796.2000.00693.x 10886496 \n8 Kapoor P , Greipp PT , Schaefer EW , et al \nIdiopathic systemic capillary leak syndrome (Clarkson's disease): the Mayo clinic experience . Mayo Clin Proc \n2010 ;85 :905 –12 . 10.4065/mcp.2010.0159 20634497 \n9 Prete M , Urso L , Fatone MC , et al \nAntiphospholipids syndrome complicated by a systemic capillary leak-like syndrome treated with steroids and intravenous immunoglobulins: a case report . Medicine \n2016 ;95 :e2648\n10.1097/MD.0000000000002648 26844485 \n10 Plunkett W , Huang P , Searcy CE , et al \nGemcitabine: preclinical pharmacology and mechanisms of action . Semin Oncol \n1996 ;23 :3 –15 .\n11 Pavlakis N , Bell DR , Millward MJ , et al \nFatal pulmonary toxicity resulting from treatment with gemcitabine . Cancer \n1997 ;80 :286 –91 . 10.1002/(SICI)1097-0142(19970715)80:2<286::AID-CNCR17>3.0.CO;2-Q 9217042 \n12 Barlesi F , Villani P , Doddoli C , et al \nGemcitabine-induced severe pulmonary toxicity . Fundam Clin Pharmacol \n2004 ;18 :85 –91 . 10.1046/j.0767-3981.2003.00206.x 14748759 \n13 Gupta N , Ahmed I , Steinberg H , et al \nGemcitabine-induced pulmonary toxicity: case report and review of the literature . Am J Clin Oncol \n2002 ;25 :96 –100 .11823707 \n14 Vander Els NJ , Miller V \nSuccessful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy . Chest \n1998 ;114 :1779 –81 . 10.1378/chest.114.6.1779 9872221\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "contraindications and precautions; pancreatic cancer; unwanted effects / adverse reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000964:Antimetabolites, Antineoplastic; D019559:Capillary Leak Syndrome; D003841:Deoxycytidine; D004487:Edema; D005260:Female; D006801:Humans; D034141:Hypoalbuminemia; D007022:Hypotension; D008875:Middle Aged; D010190:Pancreatic Neoplasms", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28855215", "pubdate": "2017-08-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19486705;14748759;20634497;26844485;9872221;16477934;9217042;11823707;25600329;20643990;22411873;8893876;15630853;10886496", "title": "Gemcitabine-induced chronic systemic capillary leak syndrome.", "title_normalized": "gemcitabine induced chronic systemic capillary leak syndrome" }	[ { "companynumb": "US-PFIZER INC-2017386649", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional"...
{ "abstract": "Presented is a case report of a young man dependent on fentanyl who did not receive opioid agonist therapy (OAT) during incarceration. Highlighted are the barriers to accessing OAT in custody, which exacerbates problems with drug-seeking behavior, diversion, and recidivism. Discussed are the implications for correctional healthcare, including the benefits of utilizing telehealth services to maximize accessibility to OAT in correctional institutions that will not only enhance the quality of patient care but also address the growing opioid epidemic across Canada.", "affiliations": "Alberta Health Services.", "authors": "McIntyre\|Jessica L\|JL\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/JFN.0000000000000221", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3693", "issue": "14(4)", "journal": "Journal of forensic nursing", "keywords": null, "medline_ta": "J Forensic Nurs", "mesh_terms": "D006297:Health Services Accessibility; D006801:Humans; D008297:Male; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011329:Prisoners; D000075665:Recidivism; D055815:Young Adult", "nlm_unique_id": "101234500", "other_id": null, "pages": "248-252", "pmc": null, "pmid": "30433912", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Combatting the Opioid Crisis From Prison: Initiating Opioid Agonist Therapy.", "title_normalized": "combatting the opioid crisis from prison initiating opioid agonist therapy" }	[ { "companynumb": "CA-TEVA-2019-CA-997326", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "d...

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