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"abstract": "OBJECTIVE\nTo evaluate the rate of major anomalies after first trimester (T1)-metformin exposure.\n\n\nMETHODS\nComparative, observational cohort study done at the Israeli Teratology Information Service between 2000 and 2013.\n\n\nRESULTS\n170 T1-metformin-exposed pregnancies [119 for diabetes and 51 for polycystic ovary syndrome (PCOS)] were prospectively followed-up and compared with 93 pregnancies of T1-insulin treated women and 530 non-teratogenic exposed (NTE) pregnancies. The differences in the rate of major anomalies excluding genetic/cytogenetic, and spontaneously resolved cardiovascular anomalies were not significant [4.4% (2/45) - metformin-PCOS, 1.1% (1/90) - metformin-diabetes, 2.5% (2/80) - insulin, and 1.7% (9/519) - NTE; ORadj metformin/NTE 1.77; 95% CI 0.45-7.01; ORadj insulin/NTE 1.69; 95% CI 0.35-8.11]. The rate of Cesarean section was higher in both the metformin-diabetes 51/90 (56.7%) and insulin 45/79 (57.0%) groups compared with the NTE group [138/503 (27.4%)].\n\n\nCONCLUSIONS\nMetformin-T1-exposure per se is not associated with an increased risk of major anomalies.",
"affiliations": "The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel; The Hebrew University Hadassah Medical School, Jerusalem, Israel. Electronic address: orna.diav-citrin@moh.gov.il.;The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel; The Division of Clinical Pharmacy, the Hebrew University of Jerusalem, Israel.;The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel.;The Hebrew University Hadassah Medical School, Jerusalem, Israel.",
"authors": "Diav-Citrin|Orna|O|;Steinmetz-Shoob|Salit|S|;Shechtman|Svetlana|S|;Ornoy|Asher|A|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.reprotox.2018.05.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "80()",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": "Congenital anomalies; Diabetes mellitus; Metformin; Polycystic ovary syndrome; Pregnancy",
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D018811:Maternal Exposure; D008687:Metformin; D011085:Polycystic Ovary Syndrome; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D011254:Pregnancy in Diabetics; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "85-91",
"pmc": null,
"pmid": "29857030",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: A prospective comparative observational study.",
"title_normalized": "in utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome a prospective comparative observational study"
} | [
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"companynumb": "IL-ALKEM LABORATORIES LIMITED-IL-ALKEM-2018-04765",
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
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"abstract": "Primary cutaneous CD4+ small-/medium-sized T-cell lymphoproliferative disorder is usually characterized by nodules and plaques affecting the upper part of the body. The present case presented with a large, single tumor located on a lower extremity. The patient did not respond to surgical therapy but responded to cyclophosphamide, methotrexate, and radiotherapy.",
"affiliations": "Department of Dermatology and Venereology Medical University of Lodz Lodz Poland.;Department of Dermatology and Venereology Medical University of Lodz Lodz Poland.;Department of Pathology Medical University of Gdańsk Gdańsk Poland.;Department of Dermatology and Venereology Medical University of Lodz Lodz Poland.;Department of Dermatology and Venereology Medical University of Lodz Lodz Poland.",
"authors": "Koper|Monika|M|;Putała-Pośpiech|Małgorzata|M|;Biernat|Wojciech|W|;Woźniacka|Anna|A|;Robak|Ewa|E|https://orcid.org/0000-0002-4633-9160",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2018",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2018CCR32018Case ReportCase ReportsPrimary cutaneous CD4+ small‐/medium‐sized T‐cell lymphoproliferative disorder: A case report KOPER et al.Koper Monika \n1\nPutała‐Pośpiech Małgorzata \n1\nBiernat Wojciech \n2\nWoźniacka Anna \n1\nRobak Ewa https://orcid.org/0000-0002-4633-9160ewarobak@onet.eu \n1\n\n1 \nDepartment of Dermatology and Venereology\nMedical University of Lodz\nLodz\nPoland\n\n2 \nDepartment of Pathology\nMedical University of Gdańsk\nGdańsk\nPoland\n* Correspondence\n\nEwa Robak, Department of Dermatology and Venereology, Medical University of Lodz, Lodz, Poland.\n\nEmail: ewarobak@onet.eu\n22 2 2019 4 2019 7 4 10.1002/ccr3.2019.7.issue-4703 706 15 9 2018 19 12 2018 05 1 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Key Clinical Message\nPrimary cutaneous CD4+ small‐/medium‐sized T‐cell lymphoproliferative disorder is usually characterized by nodules and plaques affecting the upper part of the body. The present case presented with a large, single tumor located on a lower extremity. The patient did not respond to surgical therapy but responded to cyclophosphamide, methotrexate, and radiotherapy.\n\ncyclophosphamideHodgkin lymphomasmall/medium T cellMedical University of Lodz, from statutory funds(503/1‐152‐01/503‐11‐002) source-schema-version-number2.0component-idccr32018cover-dateApril 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:08.04.2019\n\n\nKoper \nM \n, \nPutała‐Pośpiech \nM \n, \nBiernat \nW \n, \nWoźniacka \nA \n, \nRobak \nE \n. Primary cutaneous CD4+ small‐/medium‐sized T‐cell lymphoproliferative disorder: A case report . Clin Case Rep . 2019 ;7 :703 –706 . 10.1002/ccr3.2018 \n\n\n\nFunding information\nThis paper was funded by Medical University of Lodz, from statutory funds (503/1‐152‐01/503‐11‐002)\n==== Body\n1 INTRODUCTION\nPrimary cutaneous CD4+ small‐/medium‐sized T‐cell lymphoproliferative disorder (PCSM‐TCLPD) is a rare and heterogeneous entity, with suggested derivation from follicular T‐helper lymphocytes. Most of the cases present as a solitary lesion in the upper part of the body and good response to surgical excision or local radiotherapy.1, 2, 3, 4, 5, 6 The report describes a case of this rare disease with some peculiarities compared the typical described forms.\n\n2 CASE REPORT\nWe describe the case of a 55‐year‐old man who developed PCSM‐TCLPD 10 years after successful treatment of Hodgkin lymphoma (HL). The PCSM‐TCLPD developed in an atypical site, that is on the lower extremity, relapsed shortly after surgical excision but responded to cyclophosphamide therapy.\n\nA 55‐year‐old man was consulted in our clinic in 2014, with a three‐year history of a progressive 7 × 3‐cm‐sized tumorous infiltration, which affected the dermis and hypodermis and was localized in the upper and medial part of the right thigh. Before our first examination, a diagnosis of panniculitis was rendered based on clinical presentation and histopathology result. He was treated with glucocorticosteroids and antibiotics and showed progression.\n\nThe past medical history was significant for HL, diagnosed in July 2001. The lymphoma was asymptomatic, and ultrasonography performed due to nephrolithiasis revealed some abnormalities. Following computed tomography revealed the presence of a solid tumor (9 × 6 × 4 cm) in the pelvis, on the right side of the urinary bladder and the lymph node packets around the iliac vessels, without infiltration of the surrounding tissue. Exploratory laparotomy with excisional biopsy of the enlarged lymph nodes was performed, and the tissue was subjected to pathological examination. The results of bone marrow examination were normal. The patient was diagnosed with mixed‐cellularity classical HL at stage II A and began treatment in the middle of July 2001. He received six cycles of ABV/COPP (doxorubicin, bleomycin, vinblastine/cyclophosphamide, vincristine, procarbazine, and prednisone). Two months after chemotherapy, radiotherapy of the subdiaphragmatic lymph nodes was initiated using a 9 MeV photon beam; the patient received cumulative doses of 33.6 and 43.2 Gy for the aortic lymph nodes and iliac inguinal‐femoral nodes, respectively. The treatment ended in the end of April 2002 and produced sustained complete remission during a follow‐up period continuing to December 2005.\n\nFamily medical history revealed one case of malignant neoplasm. The patient's father, a long‐term smoker, was diagnosed with lung cancer at the age of 53.\n\nIn July 2014, a second biopsy specimen was taken. Hematoxylin and eosin (H&E) staining revealed intensive infiltration of small to medium‐sized lymphocytes intermingled with scattered histiocytes and plasma cells involving a deep portion of the dermis (Figure 1A,B). Immunohistochemistry demonstrated follicular T‐helper phenotype of the lymphocytes (CD3+, CD4+, CD8−, CD7−, PD1−, CXCL13+ [Figure 1C], bcl6−, and TIA1−/+). No molecular studies have been undertaken to confirm monoclonality; however, loss of CD7, a pan‐T‐cell marker, seemed to be an indirect proof of malignant transformation, although not unequivocal determinant of TCR rearrangement. Epstein‐Barr virus and cytomegalovirus status have not been analyzed.\n\nFigure 1 \nPCSM‐TCLPD. A, H&E stained histopathological image shows lymphocytic infiltration involving deep portion of the dermis. B, Higher magnification shows mixed infiltrate of small‐ and medium‐sized lymphocytes with scattered plasma cells and macrophages. C, Immunophenotyping results show the lymphoma cells are positive for CXCL13\n\nPhysical examination showed neither systemic symptoms nor lymphadenopathy. The results of laboratory examinations, including a complete blood cell count with differential count, liver function tests, renal function tests, and urinalysis, were all within normal limits. Computed tomography examination of the neck, chest, abdomen, and pelvis revealed no abnormalities. Bone marrow aspiration showed no evidence of malignancy. Relapse of HL was excluded.\n\nBased on these findings, the patient was diagnosed as having PCSM‐TCLPD, as it seemed to be most consistent diagnosis with the clinical and histological findings. He underwent surgical excision of the affected area but surgery turned out to be ineffective: The surgical wound was not healing, and the skin lesion developed again at the original site and gradually increased in size.\n\nOne year after surgical treatment, the patient returned to the clinic for assessment. Physical examination revealed a red‐livid, ulcerative, solitary nodular infiltration of the skin, and subcutaneous tissue, 20 × 15 cm in diameter (Figure 2A,B). Due to the infiltration, the right thigh was enlarged twice to its normal size, which impaired his movement. Staging for extracutaneous involvement was negative. The presence of ulcers was a factor which disqualified from radiotherapy. The patient was started on a course of cyclophosphamide (0.9 mg/kg/d po) and methylprednisolone (0.35 mg/kg/d po). After two weeks of treatment, 90% regression of the skin lesion was observed (Figure 2C). As such, a good response was observed during the follow‐up, and methylprednisolone was gradually tapered and discontinued after eight weeks. Cyclophosphamide was tapered to 75 mg per day after 10 weeks.\n\nFigure 2 \nPCSM‐TCLPD. A and B, Before cyclophosphamide use. Note the extent of the lesion. C, Two weeks after cyclophosphamide therapy was commenced\n\nFour months after the initiation of cyclophosphamide therapy, the patient developed hemorrhagic cystitis and the drug had to be discontinued. As a consequence, the lesion relapsed in the same area over a period of two weeks grew up to 10 × 8 cm in size, and hard‐to‐heal wounds formed within the lesion. In May 2016, computed tomography of the abdomen and pelvis and laboratory tests demonstrated no abnormalities. The patient was put on a course of 20 mg oral methotrexate once a week for ten months, resulting in the disease stabilizing. Methotrexate was found to be clearly less effective than the combination of cyclophosphamide and methylprednisolone administered previously, with the 6‐cm‐sized infiltration persisting, despite the wounds within the lesion almost healing. Therefore, in March 2017, methotrexate therapy was interrupted and the patient started radiation therapy. In the third week of radiotherapy, the lesion decreased to 2.5 cm in size. Subsequently, the tumor disappeared and only healing persisted in the place of tumor. The patient has been seen in our outpatient clinic in November 2018 without any symptoms of lymphoma.\n\n3 DISCUSSION\nWe would like to note a possible link between HL treatment and PCSM‐TCLPD in the presented case. Many reports demonstrate over twofold increased risk of subsequent malignancies for HL survivors compared with general population. The relative risk of subsequent malignancy increased between five and nine years after chemotherapy alone and remained elevated for 25 years and longer when combined therapies (with radiotherapy) were used. The risk was markedly higher when a chemotherapy included alkylators, as in our case.7, 8, 9 In addition, in our case the subsequent tumor developed in the area exposed to radiation during HL treatment, which might be responsible for the unusual localization.\n\nThe lesion size in case described herein was larger than other reported cases (1‐2.5 cm), it might be one of the possible reason why the first‐line therapy failed.5, 6\n\n\nCyclophosphamide is believed to be an effective form of second‐line therapy for PCSM‐TCLPD, when given as a single chemotherapeutic agent. Only few reports of this therapy for PCSM‐TCLPD exist in the literature.4, 10 Wawrzycki at al. observed good response in the case presenting with widespread nodules after ineffective PUVA therapy.10 Alberti‐Violetti et al4 described two cases with initial response and relapse in further course, and the third patient demonstrated progression.\n\nNot only is this the first case report of the development of PCSM‐TCLPD as secondary neoplasm in a patient previously treated for HL, it also describes an atypical presentation of this rare entity.\n\nCONFLICT OF INTEREST\nThe authors have no conflict of interests to declare.\n\nAUTHOR CONTRIBUTIONS\nER: involved in conception and case report drafting and design. MK: managed and collected the data and wrote the report. M P‐P: managed and collected the data. WB: involved in pathological diagnosis and interpretation the tissue biopsy slides. AW: peer reviewed and helped in report writing.\n==== Refs\nREFERENCES\n1 \n\nBeltraminelli \nH \n, \nLeinweber \nB \n, \nKerl \nH \n, et al. Primary cutaneous CD4 + small‐/medium‐sized pleomorphic T‐cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases . Am J Dermatopathol . 2009 ;31 (4 ):317 ‐322 .19461234 \n2 \n\nJames \nE \n, \nSokhn \nJG \n, \nGibson \nJF \n, et al. CD4+ primary cutaneous small/medium‐sized pleomorphic T‐cell lymphoma: a retrospective case series and review of the literature . Leuk Lymphoma . 2015 ;56 (4 ):951 ‐957 .24996443 \n3 \n\nVirmani \nP \n, \nJawed \nS \n, \nMyskowski \nPL \n, et al. Long‐term follow‐up and management of small and medium‐sized CD4+ T cell lymphoma and CD8+ lymphoid proliferations of acral sites: a multicenter experience . Int J Dermatol . 2016 ;55 :1248 ‐1254 .27369070 \n4 \n\nAlberti‐Violetti \nS \n, \nTorres‐Cabala \nCA \n, \nTalpur \nR \n, et al. Clinicopathological and molecular study of primary cutaneous CD4+ small/medium‐sized pleomorphic T‐cell lymphoma . J Cutan Pathol . 2016 ;43 :1121 ‐1130 .27550169 \n5 \n\nGrogg \nKL \n, \nJung \nS \n, \nErickson \nLA \n, et al. Primary cutaneous CD4‐positive small/medium‐sized pleomorphic T‐cell lymphoma: a clonal T‐cell lymphoproliferative disorder with indolent behavior . Mod Pathol . 2008 ;21 (6 ):708 ‐715 .18311111 \n6 \n\nGonzález Fernández \nD \n, \nValdés Pineda \nF \n, \nGómez Díez \nS \n, et al. Primary cutaneous CD4+ small/medium‐sized T‐cell lymphoma with spontaneous regression after biopsy . Acta Derm Venereol . 2015 ;106 :767 ‐768 .\n7 \n\nVan Leeuwen \nFE \n, \nNg \nAK \n. Long‐term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment . Hematology Am Soc Hematol Educ Program . 2016 ;2016 :323 ‐330 .27913498 \n8 \n\nBaras \nN \n, \nDahm \nS \n, \nHaberland \nJ \n, et al. Subsequent malignancies among long‐term survivors of Hodgkin lymphoma and non‐Hodgkin lymphoma: a pooled analysis of German cancer registry data (1990–2012) . Br J Haematol . 2017 ;177 :226 ‐242 .28106907 \n9 \n\nSwerdlow \nAJ \n, \nHiggins \nCD \n, \nSmith \nP \n, et al. Second cancer risk after chemotherapy for Hodgkin’s lymphoma: a collaborative British Cohort Study . J Clin Oncol . 2011 ;29 :4096 ‐4104 .21969511 \n10 \n\nWawrzycki \nB \n, \nChodorowska \nG \n, \nPietrzak \nA \n, et al. Therapeutic hotline: primary cutaneous CD4 + small/medium‐sized pleomorphic T cell lymphoma coexisting with myelodysplastic syndrome transforming into chronic myelomonocytic leukemia successfully treated with cyclophosphamide . Dermatol Ther . 2010 ;23 :676 ‐681 .21054711\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "7(4)",
"journal": "Clinical case reports",
"keywords": "Hodgkin lymphoma; cyclophosphamide; small/medium T cell",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "703-706",
"pmc": null,
"pmid": "30997068",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": "18311111;19461234;21054711;21969511;24996443;26093997;27369070;27550169;27913498;28106907",
"title": "Primary cutaneous CD4+ small-/medium-sized T-cell lymphoproliferative disorder: A case report.",
"title_normalized": "primary cutaneous cd4 small medium sized t cell lymphoproliferative disorder a case report"
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"abstract": "OBJECTIVE\nTo report the first documented case of aripiprazole-induced chorioretinopathy.\n\n\nRESULTS\nA 47-year-old schizophrenic patient with loss of vision due to an atypical retinopathy was investigated. She had been treated with aripiprazole for 8 years. Multimodal imaging showed in the right eye a large area of retinal atrophy predominating in the outer retina, including the posterior pole up to the upper temporal periphery, and in the left eye a serous retinal detachment. The electroretinogram exhibited decreased and delayed responses of both the rod and cone systems; the electrooculogram showed no light peak.\n\n\nCONCLUSIONS\nAripiprazole, an atypical antipsychotic, was introduced more recently than the antipsychotics commonly incriminated in chorioretinopathies, such as thioridazine. Optical coherence tomography was not used to document former cases of antipsychotic-related chorioretinopathies. Although pathophysiological mechanisms are poorly understood, imaging of the present case points toward an involvement of the retinal pigmentary epithelium. Clinicians should be aware of the potential chorioretinal toxicity of new atypical antipsychotics.",
"affiliations": "Ophtalmologie, Hôpital Privé Saint Martin, 18 rue des Roquemonts, 14000, Caen, France, celinefaureoph@gmail.com.",
"authors": "Faure|Céline|C|;Audo|Isabelle|I|;Zeitz|Christina|C|;Letessier|Jean-Bernard|JB|;Robert|Matthieu P|MP|",
"chemical_list": "D014150:Antipsychotic Agents; D004396:Coloring Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D007208:Indocyanine Green",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10633-015-9494-x",
"fulltext": null,
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"issn_linking": "0012-4486",
"issue": "131(1)",
"journal": "Documenta ophthalmologica. Advances in ophthalmology",
"keywords": null,
"medline_ta": "Doc Ophthalmol",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D004396:Coloring Agents; D003623:Dark Adaptation; D004585:Electrooculography; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007208:Indocyanine Green; D008875:Middle Aged; D064847:Multimodal Imaging; D010879:Piperazines; D015363:Quinolones; D012160:Retina; D012164:Retinal Diseases; D055213:Retinal Pigment Epithelium; D012559:Schizophrenia; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "0370667",
"other_id": null,
"pages": "35-41",
"pmc": null,
"pmid": "25791769",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3946667;12096981;7663839;16117689;21830909;13843390;2275937;3978494;2282954;15292663;9639463;15104164;8780438;5010315;22684902;17965519;2221706;6531521;7162792;23676993;12152801;16952115;14641163;19220190",
"title": "Aripiprazole-induced chorioretinopathy: multimodal imaging and electrophysiological features.",
"title_normalized": "aripiprazole induced chorioretinopathy multimodal imaging and electrophysiological features"
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"abstract": "BACKGROUND\nPrimary small cell carcinoma (SCC) after renal transplantation is very rare. Here, we reported 1 case of primary SCC after renal transplantation and analyzed its clinical and pathological characteristics.\n\n\nMETHODS\nA 55-year-old female underwent renal transplantation in our hospital 2 years ago and had been using tacrolimus for immunosuppressive therapy. Because of abdominal distention, the patient was admitted to our hospital. Computed tomography (CT) showed a malignant tumor of left kidney. Patient underwent surgical treatment and radical nephrectomy and lymph node dissection were selected. Postoperative pathological diagnosis was primary renal parenchyma and ureteral SCC. The patient has been treated with combination chemotherapy of lowpol (100 mg per day) and etoposide (10 mg per day). His vital signs are stable now, and he is receiving further treatment in our hospital.\n\n\nCONCLUSIONS\nBecause of immunosuppressive drugs use, the incidence of malignancies has increased significantly after renal transplantation. This case highlights the difficulty of diagnosis of primary SCC and the necessity of checking for neuroendocrine tumor after organ transplantation.",
"affiliations": "Department of Pathology, The 8th Medical Center of Chinese PLA General Hospital, Beijing, China.",
"authors": "Wang|Xueli|X|;Wang|Fenghua|F|;Liang|Yumei|Y|;Chen|Wen|W|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
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"doi": "10.1097/MD.0000000000012592",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30544366MD-D-18-0350210.1097/MD.0000000000012592125927300Research ArticleClinical Case ReportPrimary small cell carcinoma after renal transplant A case reportWang Xueli MDWang Fenghua MDLiang Yumei MDChen Wen MD∗NA. Department of Pathology, The 8th Medical Center of Chinese PLA General Hospital, Beijing, China.∗ Correspondence: Wen Chen, The 8th Medical Center of Chinese PLA General Hospital, Beijing, 100091, China (e-mail: 1607283686@qq.com).12 2018 10 12 2018 97 49 e1259229 5 2018 3 9 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nPrimary small cell carcinoma (SCC) after renal transplantation is very rare. Here, we reported 1 case of primary SCC after renal transplantation and analyzed its clinical and pathological characteristics.\n\nCase presentation:\nA 55-year-old female underwent renal transplantation in our hospital 2 years ago and had been using tacrolimus for immunosuppressive therapy. Because of abdominal distention, the patient was admitted to our hospital. Computed tomography (CT) showed a malignant tumor of left kidney. Patient underwent surgical treatment and radical nephrectomy and lymph node dissection were selected. Postoperative pathological diagnosis was primary renal parenchyma and ureteral SCC. The patient has been treated with combination chemotherapy of lowpol (100 mg per day) and etoposide (10 mg per day). His vital signs are stable now, and he is receiving further treatment in our hospital.\n\nConclusion:\nBecause of immunosuppressive drugs use, the incidence of malignancies has increased significantly after renal transplantation. This case highlights the difficulty of diagnosis of primary SCC and the necessity of checking for neuroendocrine tumor after organ transplantation.\n\nKeywords\nimmunosuppressive therapyrenal transplantsmall cell carcinomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nSmall cell carcinoma (SCC) occurs mainly in the lungs. Extrapulmonary SCC accounts for 2.5% to 5.0% of all SCC and their main sites are bladder, prostate, gastrointestinal tract and cervix.[1] Primary renal SCC is rare, primary SCC after renal transplantation is more rare.[2,3] Here, we reported 1 case of primary SCC after renal transplantation and analyzed its clinical and pathological characteristics.\n\n2 Case report\nThis study was approved by the Ethics Committee of 309th hospital of PLA and was performed according to the principles of Declaration of Helsinki. The patient has provided informed consent for publication of this case, and the ethics committee approved the consent procedure. A 55-year-old female underwent renal transplantation in our hospital 2 years ago and had been using tacrolimus for immunosuppressive therapy. Because of abdominal distention and abdominal mass, the patient was admitted to our hospital recently, and computed tomography (CT) showed a malignant tumor of left kidney. The CT showed that left kidney had irregular mass with a diameter of about 9.3 cm, showing low density necrotic foci and a few punctate calcifications (Fig. 1). Radiologists considered the possibility of renal pelvis carcinoma or urothelial carcinoma.\n\nFigure 1 Computed tomography (CT) showed a malignant tumor of left kidney. CT = computed tomography.\n\nPatient underwent surgical treatment, and radical nephrectomy and lymph node dissection are selected. After surgery, patient has been treated with combination chemotherapy of lowpol (100 mg per day) and etoposide (10 mg per day). Hemodialysis is used to replace kidney function. This patient has been followed up for 8 months after surgery. His vital signs are stable now, and he is receiving further treatment in our hospital.\n\nLeft kidney and part of ureter tissues were examined, and the size of kidney was 14 × 9 × 7 cm. A gray white mass can be detected near the renal pelvis, and its size was 10 × 7 × 6 cm. The cutting surface is gray and medium. Another gray white mass appeared in the ureter cavity, 6 × 3.5 × 2.5 cm in size. Some lymph nodes were found in the hilum, and the diameter was 0.3 to 1.4 cm.\n\nTumor consisted of short spindle and small blue round cells. The tumor cells were nested and trabecular arranged, with large foci of necrosis and hemorrhage. Nucleus was deeply dyed, and nuclear division was more common. Tumor tissues grew diffusely and were extensively infiltrated the surrounding renal medulla, cortex, renal pelvis and adipose tissue around the renal hilum. Tumor suppository was formed in pulse tube. Metastatic small cell carcinoma nests can be observed in hilar lymph nodes (Fig. 2).\n\nFigure 2 HE staining. (A) Renal SCC (100×); (B) Renal SCC (400×); (C) Ureter SCC (100×); (D) Ureter SCC (400×). SCC = small cell carcinoma.\n\nImmunohistochemical results were as follows. Positive expression: CK (+), CK18 (+), CK5/6 (a few +), CD56 (++), NSE (++), SCLC (++), Syn (a few +), LCA (a few +), CD34 (blood vessel +), P40 (a few +), p63 (a few +); Negative expression: CD138 (−), CD38 (−), CK20 (−), CK7 (−), CgA (−), S-100 (−), Vimentin (−), CD10 (−), Pax-8 (−); Proliferation index: Ki-67 (+ > 75%) (Fig. 3).\n\nFigure 3 Immunohistochemical staining. CK (+), CK18 (+), CK20 (−), LCA (a few +), NSE (++), SCLC (++), CD56 (++), Syn (a few +), Ki-67 (+ > 75%).\n\nTo sum up, the patient's pathological diagnosis was primary renal and ureteral SCC with obvious hemorrhage and necrosis. Tumor thrombus was found in the vessel. Tumor cell infiltrated ureter into the serosa, invaded focal pelvis, renal sinus fat, renal capsule and perirenal fat capsule. Tumor metastasis (3/7) can be observed in renal hilar lymph nodes.\n\n3 Discussion\nBecause of immunosuppressive drugs use, the incidence of malignancies has increased significantly after renal transplantation.[4] It is generally believed that there are 3 main sources of tumor after renal transplantation: primary tumor after renal transplantation; tumor recurrence before renal transplantation; tumor derived from donor kidney. Urinary tract tumor especially urothelial carcinoma, is the main type of tumor after renal transplantation.[5]\n\nThe proportion of neuroendocrine carcinoma in renal epithelial malignancies is less than 1%. Renal small cell carcinoma (SCC) is a special neuroendocrine carcinoma, which is relatively rare. Since the 1st report of renal SCC in 1984, dozens of cases have been reported in papers. However, primary SCC in transplanted kidney is rarely reported.[6,7] The clinical symptoms of renal SCC are mainly abdominal mass, abdominal pain and gross hematuria. The peak age is mostly middle-ages and elderly, and women are more common than men.\n\nExtrapulmonary SCC can occur in many organs, including ovary, cervix and pancreas. In urogenital organs, the most common primary site is bladder, followed by prostate, kidney, and ureter.[8] The common clinical symptoms were painless gross hematuria, followed by waist and abdominal pain.[1]\n\nRenal SCC can occur in renal cortex, medulla and renal pelvis. Because their symptoms are not obvious, the tumor is very large and often metastases to lymph nodes when patients come to the hospital. The tumor is composed of poorly differentiated small blue round cells or short spindle cells. Tumor cells are arranged in small nests or trabeculae, often accompanied by necrosis and hemorrhage. The nuclei of tumor cells are rich in chromatin, nucleolus is not obvious, cytoplasm is sparse, mitotic figures are abundant, and mitotic index is high. There are many tumor thrombus formation in the vessels, and some patients with renal SCC may also have urothelial carcinoma. Immunohistochemical staining shows that tumor cells have strong positive expression on neuroendocrine markers, and most of them express epithelial markers. In this case, renal SCC had all above characteristics. Immunohistochemical staining showed that tumor cells expressed multiple epithelial and neuroendocrine markers simultaneously.\n\nThe origin of renal SCC is still unclear. Some studies suggested that the SCC of urogenital system may originate from the pluripotent stem cells of urogenital tract. Renal SCC can also be accompanied by urothelial carcinoma, squamous cell carcinoma and adenocarcinoma, which may support the hypothesis that the tumor originates from ureteral pluripotent stem cells.[9,10] Some researchers believed that tumors originate from the normal neuroendocrine cells in genitourinary tract. This view is supported by the expression of neuroendocrine markers in renal SCC.[11,12] Further studies are needed to elaborate its pathogenesis and origin.\n\nRenal SCC is easily misdiagnosed as other small cell tumors, such as undifferentiated carcinoma, Ewing tumor, embryonal rhabdomyosarcoma, lymphoma and primitive neuroectodermal tumor. Immunohistochemistry and electron microscopy are helpful for differential diagnosis. Renal SCC usually has more than 2 neuroendocrine markers (NSE, CD56, Syn, CgA, CD99, etc.) positive expression.[13–15] We should pay attention to the possibility of external metastasis if we diagnose primary renal small cell carcinoma. Poorly differentiated urothelial carcinoma mainly expresses epithelial markers and does not express neuroendocrine markers.[16] Primary lymphoma of the ureter is rare, mainly expressing B lymphocyte markers, such as CD20, CD79a and so on. Metastatic renal SCC is also rare, and preoperative imaging examination helps to exclude the diagnosis.\n\nSurgical resection is the 1st choice of renal SCC.[17,18] Their prognosis is very poor, with an average survival time of 10.5 months. In this case, the tumor volume is very large, and radical nephrectomy and lymph node dissection are selected.\n\nAuthor contributions\nConceptualization: Fenghua Wang.\n\nData curation: Xueli Wang, Wen Chen.\n\nInvestigation: Xueli Wang, Fenghua Wang, Yumei Liang.\n\nMethodology: Yumei Liang.\n\nWriting – original draft: Wen Chen.\n\nWriting – review & editing: Wen Chen.\n\nAbbreviations: CT = computed tomography, SCC = small cell carcinoma.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Lee SS Lee JL Ryu MH \nExtrapulmonary small cell carcinoma: single center experience with 61 patients . Acta Oncol \n2007 ;46 :846–51 .17653910 \n[2] Deng S Zhang B Huang Y \nCase report of primary renal pelvis squamous cell carcinoma coexisting with long-standing calculi in left kidney on 18F-FDG PET/CT . Medicine (Baltimore) \n2017 ;96 :e6341.28296764 \n[3] La Rosa S Bernasconi B Micello D \nPrimary small cell neuroendocrine carcinoma of the kidney: morphological, immunohistochemical, ultrastructural, and cytogenetic study of a case and review of the literature . Endocr Pathol \n2009 ;20 :24–34 .19096940 \n[4] Cognard N Anglicheau D Gatault P \nRecurrence of renal cell cancer after renal transplantation in a multicenter French cohort . Transplantation \n2018 ;102 :860–7 .29215458 \n[5] Dharnidharka VR Naik AS Axelrod D \nClinical and economic consequences of early cancer after kidney transplantation in contemporary practice . Transplantation \n2017 ;101 :858–66 .27490413 \n[6] Halleck F Budde K \nTransplantation: sirolimus for secondary SCC prevention in renal transplantation . Nat Rev Nephrol \n2012 ;8 :687–9 .23026948 \n[7] Lane BR Chery F Jour G \nRenal neuroendocrine tumours: a clinicopathological study . BJU Int \n2007 ;100 :1030–5 .17784891 \n[8] Bandyopadhyay R Biswas S Nag D \nSquamous cell carcinoma of the renal pelvis presenting as hydronephrosis . J Cancer Res Ther \n2010 ;6 :537–9 .21358095 \n[9] Kaplan M Atakan IH Bilgi S \nCase report: subcutaneous metastasis from small cell carcinoma of the prostate . Int Urol Nephrol \n2007 ;39 :157–60 .17268913 \n[10] Borges GT Vencio EF Quek SI \nConversion of prostate adenocarcinoma to small cell carcinoma-like by reprogramming . J Cell Physiol \n2016 ;231 :2040–7 .26773436 \n[11] Janetschek G Daffner P Peschel R \nLaparoscopic nephron sparing surgery for small renal cell carcinoma . J Urol \n1998 ;159 :1152–5 .9507820 \n[12] Prins FM Kerkmeijer LGW Pronk AA \nRenal cell carcinoma: alternative nephron-sparing treatment options for small renal masses, a systematic review . J Endourol \n2017 ;31 :963–75 .28741377 \n[13] Addis BJ Hamid Q Ibrahim NB \nImmunohistochemical markers of small cell carcinoma and related neuroendocrine tumours of the lung . J Pathol \n1987 ;153 :137–50 .2826741 \n[14] de Souza Braga M da Silva Paiva KB Foguer K \nInvolvement of the NF-small ka, CyrillicB/p50/Bcl-3 complex in response to antiangiogenic therapy in a mouse model of metastatic renal cell carcinoma . Biomed Pharmacother \n2014 ;68 :873–9 .25113400 \n[15] McGahan JP Sidhar K Fananapazir G \nRenal cell carcinoma attenuation values on unenhanced CT: importance of multiple, small region-of-interest measurements . Abdom Radiol (NY) \n2017 ;42 :2325–33 .28389785 \n[16] Sun M Shariat SF Cheng C \nPrognostic factors and predictive models in renal cell carcinoma: a contemporary review . Eur Urol \n2011 ;60 :644–61 .21741163 \n[17] Wang XZ Yu ZX Guo RJ \nApplication of laparospic ultrasonography in surgery of small renal cell carcinoma . Asian Pac J Cancer Prev \n2014 ;15 :9113–6 .25422187 \n[18] Sugimoto K Shimizu N Nose K \nClinical outcome of small renal cell carcinoma after delayed surgery versus immediate surgery . J Cancer \n2013 ;4 :514–8 .23901351\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "97(49)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D018288:Carcinoma, Small Cell; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D008875:Middle Aged; D011183:Postoperative Complications; D014516:Ureteral Neoplasms",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e12592",
"pmc": null,
"pmid": "30544366",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary small cell carcinoma after renal transplant: A case report.",
"title_normalized": "primary small cell carcinoma after renal transplant a case report"
} | [
{
"companynumb": "CN-MYLANLABS-2019M1003894",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nRituximab (RTX) has been reported to effectively treat minimal change disease (MCD) in adults. However, the efficacy of RTX as maintenance therapy, especially in older patients, remains unclear. This study aimed to evaluate the efficacy of repeat-dose RTX maintenance therapy regardless of age.\n\n\nMETHODS\nWe retrospectively reviewed the clinical courses of 13 biopsy-proven adult MCD patients receiving RTX and evaluated the relapse rate, concomitant steroid and immunosuppressant use, relationship between B-cell depletion time and relapse, and adverse events.\n\n\nRESULTS\nMean patient age at start of RTX therapy was 51.5 ± 20.1 years. Each RTX induction consisted of a single 375 mg/m2 dose. One patient received two RTX doses with a 1-year interval. The remaining 12 patients received RTX at 6-month intervals up to four times after RTX introduction. The median observation period was 28 (16-60) months after RTX induction, median relapse frequency was significantly decreased from 0.83 (0.18-1.92) to 0 (0-0.71) times/year (P < 0.001), and median prednisolone dose was reduced from 25 (5-40) mg to 2.5 (0-10) mg (P < 0.001). CD19-positive B cells remained depleted during RTX administration in 6-month intervals. No serious adverse events were observed after RTX administration.\n\n\nCONCLUSIONS\nRepeat-dose RTX as maintenance therapy efficiently prevented recurrence and was well tolerated in adult MCD patients including older. This regimen has the potential to maintain prolonged remission. Future studies in larger cohorts are needed to identify the optimal dose and frequency and evaluate the long-term effectiveness and safety of this regimen.",
"affiliations": "Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8553, Japan. shinyataguchi27@gmail.com.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8553, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8553, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8553, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8553, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8553, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8553, Japan.",
"authors": "Taguchi|Shinya|S|http://orcid.org/0000-0002-4540-125X;Ohtake|Takayasu|T|;Mochida|Yasuhiro|Y|;Ishioka|Kunihiro|K|;Moriya|Hidekazu|H|;Hidaka|Sumi|S|;Kobayashi|Shuzo|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-020-01943-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1342-1751",
"issue": "24(12)",
"journal": "Clinical and experimental nephrology",
"keywords": "B-cell depletion; Minimal change disease; Nephrotic syndrome; Relapse; Rituximab; Steroid",
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D001402:B-Lymphocytes; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009402:Nephrosis, Lipoid; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "1132-1139",
"pmc": null,
"pmid": "32761467",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy of repeat-dose rituximab maintenance therapy for minimal change disease in adults.",
"title_normalized": "efficacy of repeat dose rituximab maintenance therapy for minimal change disease in adults"
} | [
{
"companynumb": "JP-ROCHE-2739298",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nDuration of treatment for chronic hepatitis C infection has been shortened since the introduction of highly effective direct-acting antivirals (DAAs). Presented is our experience in successful treatment of veterans with chronic hepatitis C infection, with a shorter than currently recommended duration of therapy.\n\n\nMETHODS\nRetrospective chart review of veterans with chronic hepatitis C infection who received more than 1 week and up to 6 weeks (8-42 days) of DAA therapy with the initiation day between January 1, 2015, and October 15, 2018, at Bay Pines Veterans Affairs Healthcare System. Successful treatment was defined by a sustained virologic response at 12 weeks (SVR-12) since the end of treatment.\n\n\nRESULTS\nOf the 1841 veterans treated, 27 met the criteria for this review. Overall, SVR-12 was achieved in 92.6% of veterans treated for a duration of more than 1 week and up to 6 weeks. Amongst those who completed only 4 weeks of therapy, 93.3% achieved SVR-12. All four veterans (100%) treated for a duration of more than 4 weeks and up to 6 weeks achieved SVR-12.\n\n\nCONCLUSIONS\nAmongst the chronically infected hepatitis C population, a subpopulation who could achieve SVR with a shorter course of treatment than currently recommended does exist. A prospective study of a larger scale will likely provide helpful data in this regard. Our findings could be an impetus for further work.",
"affiliations": "Section of Infectious Disease, Department of Medicine, Bay Pines VA Healthcare System, Bay Pines, Florida, USA.;Department of Pharmacy, Bay Pines VA Healthcare System, Bay Pines, Florida, USA.",
"authors": "Joshi|Prajwol|P|https://orcid.org/0000-0001-5344-7074;Atherton|Amanda|A|",
"chemical_list": "D000998:Antiviral Agents; D004338:Drug Combinations",
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.14703",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "34(12)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "genotype; hepatitis C; sustained virologic response; veterans; viral load",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004334:Drug Administration Schedule; D004338:Drug Combinations; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014728:Veterans; D019562:Viral Load",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "2173-2178",
"pmc": null,
"pmid": "31062412",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sustained virologic response with 6 weeks or less of direct-acting antiviral therapy for chronic hepatitis C: Experience at a veterans affairs healthcare system.",
"title_normalized": "sustained virologic response with 6 weeks or less of direct acting antiviral therapy for chronic hepatitis c experience at a veterans affairs healthcare system"
} | [
{
"companynumb": "US-009507513-2001USA006259",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
"drugadditional"... |
{
"abstract": "WHAT IS KNOWN ON THE SUBJECT?: More people experience withdrawal symptoms when weaning off antidepressants than previously thought; particularly after taking them for a long time. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: I explore my own experience of weaning off antidepressants; detailing conflicting advice I have received from healthcare professionals, and the mental and physical withdrawal symptoms I experienced. I relate my experiences to a growing body of research, which have important implications for improving care. WHAT ARE THE IMPLICATIONS FOR MENTAL HEALTH NURSING?: Healthcare professionals should make patients aware of potential withdrawal symptoms they may experience before they wean off antidepressants; regularly review their progress; consider helping them access psychological support whilst weaning off; and engage in open and collaborative conversations with patients throughout. Clinical guidance needs to be updated to provide appropriate evidence-based information/advice/recommendations for how best to support patients when coming off of antidepressants. ABSTRACT: A significant proportion of the UK population are taking antidepressants, and have been taking them for at least a year. Clinical guidelines have controversially stated that withdrawal symptoms when weaning off antidepressants are mild and resolve after one week, with the proviso that they can be severe only if the drug is stopped abruptly. However, recent evidence suggests this is not the case. I describe my own experiences of tapering the dose of my antidepressants after several years of taking them. I describe my encounters with healthcare professionals throughout this period, detailing conflicting advice I have received, along with describing the mental and physical withdrawal symptoms I have experienced. My experiences relate to a growing body of research, which have important implications for improving care. Potential learning outcomes are that healthcare professionals should make patients aware of potential withdrawal symptoms they may experience before they wean off antidepressants; regularly review their progress; consider helping them access psychological support whilst weaning off; and engage in open and collaborative conversations with patients throughout the process. Clinical guidance needs to be updated to provide appropriate evidence-based information, advice, and recommendations for how best to support patients when coming off of antidepressants.",
"affiliations": "Faculty of Health, Education, Medicine and Social Care, Anglia Ruskin University, Chelmsford, UK.",
"authors": "Wilson|Ceri|C|https://orcid.org/0000-0001-5192-8683",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"country": "England",
"delete": false,
"doi": "10.1111/jpm.12623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1351-0126",
"issue": "27(6)",
"journal": "Journal of psychiatric and mental health nursing",
"keywords": "anxiety; decision making; depression; physical health; psychotropic medications",
"medline_ta": "J Psychiatr Ment Health Nurs",
"mesh_terms": "D000328:Adult; D003866:Depressive Disorder; D005260:Female; D006801:Humans; D017410:Practice Guidelines as Topic; D011369:Professional-Patient Relations; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D013375:Substance Withdrawal Syndrome; D006113:United Kingdom",
"nlm_unique_id": "9439514",
"other_id": null,
"pages": "850-856",
"pmc": null,
"pmid": "32078199",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D062210:Personal Narrative",
"references": null,
"title": "The long and winding road of discontinuing long-term use of antidepressants: Learning from my experience.",
"title_normalized": "the long and winding road of discontinuing long term use of antidepressants learning from my experience"
} | [
{
"companynumb": "GB-MYLANLABS-2021M1064758",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Mycobacterium avium complex (MAC) infections have been reported rarely in renal transplant patients. Consequently the clinical course and optimal treatment of these patients are not well understood. We present 3 patients with MAC infections after receiving a renal transplant (2 with generalized and 1 with localized infection). All patients were treated with combination antibiotic therapy and reduction of immunosuppression. One patient experienced clinical control of disease but a mild cellular rejection that was successfully treated with high-dose corticosteroids. One patient died of disseminated MAC infection. The patient with localized infection died of unrelated causes. In summary, MAC infection, although rare in renal transplant patients, may respond to combination antimicrobial therapy and reduction of immunosuppression.",
"affiliations": "Division of Infectious Disease, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.",
"authors": "Haas|S|S|;Scully|B|B|;Cohen|D|D|;Radhakrishnan|J|J|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3062.2005.00090.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "7(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": null,
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "75-9",
"pmc": null,
"pmid": "16150095",
"pubdate": "2005-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mycobacterium avium complex infection in kidney transplant patients.",
"title_normalized": "mycobacterium avium complex infection in kidney transplant patients"
} | [
{
"companynumb": "US-PFIZER INC-2016218266",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFABUTIN"
},
"drugadditional": null,
... |
{
"abstract": "We present a critically ill patient affected by COVID-19, whose chest computed tomography (CT) scan featured lung consolidations and severe patchy ground-glass opacitie. On day 3 since hospital admission the patient was placed on convalescent plasma treatment. A combined treatment with supportive care, hemoperfusion and convalescent plasma successfully managed to save the patient's life. Convalescent plasma probably contributed to heal this patient and should always be considered in the management of critically ill COVID-19 cases.",
"affiliations": "Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.;Local Health Unit N. 2 \"Marca Trevigiana\", Public Health Department, Treviso, Italy.;Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran and Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.;Student Research Committee (SRC), Baqiyatallah University of Medical Sciences, Tehran, Iran.;Trauma Research Center, School of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.;JC School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, China.;Department of Radiology, Baqiyatallah University of Medical Sciences, Tehran, Iran.;Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran. Electronic address: mhmjvbt81@gmail.com.",
"authors": "Einollahi|Behzad|B|;Cegolon|Luca|L|;Abolghasemi|Hassan|H|;Imanizadeh|Sina|S|;Bahramifar|Ali|A|;Zhao|Shi|S|;Jafari|Ramezan|R|;Javanbakht|Mohammad|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.transci.2020.102995",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-0502",
"issue": "59(6)",
"journal": "Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis",
"keywords": "COVID-19; Convalescent plasma; Critical; PCR",
"medline_ta": "Transfus Apher Sci",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D016638:Critical Illness; D006801:Humans; D007116:Immunization, Passive; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101095653",
"other_id": null,
"pages": "102995",
"pmc": null,
"pmid": "33183986",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32532758;15616839;32361326;32694043;15214887;32585284;32293713;32298745;26674811;32313872;32802787;32052466;32219428;26618098;32487513;32113510;32694044;32253318",
"title": "A patient affected by critical COVID-19 pneumonia, successfully treated with convalescent plasma.",
"title_normalized": "a patient affected by critical covid 19 pneumonia successfully treated with convalescent plasma"
} | [
{
"companynumb": "IR-PFIZER INC-2021600501",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.",
"affiliations": "Genome Diagnostics Program, IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.;Spanish National Cancer Research Center (CNIO) and Spanish Network on Rare Diseases, Madrid, Spain.;Department of Oncology-Pathology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.;Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.;Department of Genetics and Microbiology, Genetics Department of Hospital de les Santes Creus i Sant Pau, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.;Genome Diagnostics Program, IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.;Genome Diagnostics Program, IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.;Genome Diagnostics Program, IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.;Department of Genetics and Microbiology, Genetics Department of Hospital de les Santes Creus i Sant Pau, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.;Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Genome Diagnostics Program, IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.;Genome Diagnostics Program, IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.;Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.;Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.;Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.;Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.;Department of Molecular Medicine and Surgery, Karolinska Institute, and Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.;Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.;Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.;Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Genetics and Microbiology, Genetics Department of Hospital de les Santes Creus i Sant Pau, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.;Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.;Department of Clinical Genetics, Laboratory Medicine, Office for Medical Services, Lund, Sweden.;Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.;Spanish National Cancer Research Center (CNIO) and Spanish Network on Rare Diseases, Madrid, Spain.;Genome Diagnostics Program, IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.",
"authors": "Catucci|Irene|I|;Osorio|Ana|A|;Arver|Brita|B|;Neidhardt|Guido|G|;Bogliolo|Massimo|M|;Zanardi|Federica|F|;Riboni|Mirko|M|;Minardi|Simone|S|;Pujol|Roser|R|;Azzollini|Jacopo|J|;Peissel|Bernard|B|;Manoukian|Siranoush|S|;De Vecchi|Giovanna|G|;Casola|Stefano|S|;Hauke|Jan|J|;Richters|Lisa|L|;Rhiem|Kerstin|K|;Schmutzler|Rita K|RK|;Wallander|Karin|K|;Törngren|Therese|T|;Borg|Åke|Å|;Radice|Paolo|P|;Surrallés|Jordi|J|;Hahnen|Eric|E|;Ehrencrona|Hans|H|;Kvist|Anders|A|;Benitez|Javier|J|;Peterlongo|Paolo|P|",
"chemical_list": "D000970:Antineoplastic Agents; C518295:FANCM protein, human; D004265:DNA Helicases",
"country": "United States",
"delete": false,
"doi": "10.1038/gim.2017.123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-3600",
"issue": "20(4)",
"journal": "Genetics in medicine : official journal of the American College of Medical Genetics",
"keywords": null,
"medline_ta": "Genet Med",
"mesh_terms": "D000483:Alleles; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D002873:Chromosome Fragility; D003241:Consanguinity; D004265:DNA Helicases; D019008:Drug Resistance, Neoplasm; D005199:Fanconi Anemia; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors",
"nlm_unique_id": "9815831",
"other_id": null,
"pages": "452-457",
"pmc": null,
"pmid": "28837162",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25078778;28033443;20117061;24675953;25099575;19423727;19561169;15239132;11705483;21217111;27500492;26130695;28837157;26254775;16116422;25288723;22058428;25010009;18381420;24773018",
"title": "Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility.",
"title_normalized": "individuals with fancm biallelic mutations do not develop fanconi anemia but show risk for breast cancer chemotherapy toxicity and may display chromosome fragility"
} | [
{
"companynumb": "IT-TEVA-2018-IT-972125",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "A previously well woman aged 63 years presents to the emergency department with vomiting, palpitations and 3 presyncopal episodes. She had no previous medical or cardiac history, with the patient stating that she tried a herbal remedy of boiled comfrey leaves for insomnia 18 hours before arrival to the department. Her ECG showed multiple abnormalities, including bradycardia, second-degree atrioventricular node block, Mobitz Type 2, a shortened QT interval, downsloping ST depression and presence of U waves. After viewing the images of comfrey and foxglove, it highlighted the possibility of mistaken ingestion of Digitalis, containing the organic forms of cardiac glycosides, such as digoxin and digitoxin. Raised serum digoxin levels confirmed this. The patient was haemodynamically stable, and given digoxin-binding antibodies. After 5 days of cardiac monitoring, her ECG returned to normal rhythm, and she was discharged home.",
"affiliations": "Department of Accident and Emergency, King's College Hospital, London, UK.;Department of Accident and Emergency, King's College Hospital, London, UK.",
"authors": "Vithayathil|Mathew Kurian|MK|;Edwards|Matthew|M|",
"chemical_list": "D000910:Antibodies, Heterophile; D004077:Digoxin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-216995",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000059:Accidents; D000910:Antibodies, Heterophile; D054537:Atrioventricular Block; D001919:Bradycardia; D020844:Comfrey; D004070:Digitalis; D004077:Digoxin; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008875:Middle Aged; D018515:Plant Leaves; D010939:Plant Poisoning; D010946:Plants, Medicinal; D007319:Sleep Initiation and Maintenance Disorders; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27908913",
"pubdate": "2016-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "4041297;3924193;25089630;17976892;12866383;17968204;20171590",
"title": "Comfrey herbal remedy causing second-degree heart block: do not be outfoxed by digitalis.",
"title_normalized": "comfrey herbal remedy causing second degree heart block do not be outfoxed by digitalis"
} | [
{
"companynumb": "GB-MYLANLABS-2017M1042092",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHigh-dose methotrexate (HDMTX) therapy is a key component of many chemotherapy protocols. However, some patients develop HDMTX-induced nephrotoxicity. Carboxypeptidase-G2 (CPDG2) hydrolyses MTX into 2,4-diamino-N10-methylpteroic acid (DAMPA) and glutamic acid, and is used as a rescue agent in patients with nephrotoxicity and delayed elimination. Despite the frequency of HDMTX-induced renal injury, crystalluria is uncommon. Furthermore, crystals are rarely identified by conventional chemical methods.\n\n\nOBJECTIVE\nTo determine the composition of crystalluria in a patient with osteosarcoma who was treated with CPDG2.\n\n\nMETHODS\nCrystalluria was evaluated by optical microscopy, and chemical identification was performed by Fourier-transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM) and Orbitrap™ high-resolution mass spectrometry (HRMS).\n\n\nRESULTS\nThe HRMS spectra of the patient's urine sediment showed a main peak at m/z 326.13, corresponding to the molecular mass of DAMPA [(C15H15O2N7) + H+]. The FT-IR spectral patterns of the sediment and DAMPA were not identical. SEM was unable to identify the crystal.\n\n\nCONCLUSIONS\nDAMPA crystalluria was identified by Orbitrap™ HRMS in a patient treated with CPDG2 after HDMTX nephrotoxicity. This case reinforces the need to implement adequate measures to prevent nephrotoxicity. In cases of HDMTX-induced nephrotoxicity, urine sediment analysis should be requested.",
"affiliations": "Laboratory of Renal Lithiasis Research, University Institute of Health Sciences Research (IUNICS-IdISBa), University of Balearic Islands, Ctra. de Valldemossa, km 7.5, 07122 Palma de Mallorca, Spain. Electronic address: f.berga@uib.es.;Oncology Department, Hospital Universitari Son Espases, Ctra. de Valldemossa, 79, 07120 Palma de Mallorca, Spain. Electronic address: pablo.luna@ssib.es.;Pharmacy Department, Hospital Universitari Son Espases, Ctra. de Valldemossa, 79, 07120 Palma de Mallorca, Spain. Electronic address: clara.martorell@ssib.es.;Nephrology Department, Hospital Universitari Son Espases, Ctra. de Valldemossa, 79, 07120 Palma de Mallorca, Spain. Electronic address: juan.rey@ssib.es.;Clinical Analysis Department, Hospital Universitari Son Llàtzer, Research Institute of Health Sciences (IdISBa), Ctra. de Manacor, 07198 Palma de Mallorca, Spain. Electronic address: isabel.gomila@hsll.es.;Oncology Department, Hospital Universitari Son Espases, Ctra. de Valldemossa, 79, 07120 Palma de Mallorca, Spain. Electronic address: sandra.gimenez@ssib.es.;Laboratory of Renal Lithiasis Research, University Institute of Health Sciences Research (IUNICS-IdISBa), University of Balearic Islands, Ctra. de Valldemossa, km 7.5, 07122 Palma de Mallorca, Spain. Electronic address: antonia.costa@uib.es.;Clinical Analysis Department, Hospital Universitari Son Espases, Research Institute of Health Sciences (IdISBa), Ctra. de Valldemossa, 79, 07120 Palma de Mallorca, Spain. Electronic address: miguelangel.elorza@ssib.es.;Reference Laboratory, Carrer Pablo Iglesias, 57-59, 08908 L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address: adnaloi2@gmail.com.;Laboratory of Renal Lithiasis Research, University Institute of Health Sciences Research (IUNICS-IdISBa), University of Balearic Islands, Ctra. de Valldemossa, km 7.5, 07122 Palma de Mallorca, Spain. Electronic address: fgrases@uib.es.;Clinical Analysis Department, Hospital Universitari Son Espases, Research Institute of Health Sciences (IdISBa), Ctra. de Valldemossa, 79, 07120 Palma de Mallorca, Spain. Electronic address: bernardino.barcelo@ssib.es.",
"authors": "Berga|Francisco|F|;Luna|Pablo|P|;Martorell|Clara|C|;Rey|Juan|J|;Gomila|Isabel|I|;Gimenez|Sandra|S|;Costa-Bauza|Antonia|A|;Elorza|Miguel Ángel|MÁ|;Sánchez|Iolanda|I|;Grases|Félix|F|;Barceló|Bernardino|B|",
"chemical_list": "C000203:deoxyaminopteroic acid; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.cca.2018.09.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-8981",
"issue": "487()",
"journal": "Clinica chimica acta; international journal of clinical chemistry",
"keywords": "Crystalluria; DAMPA; High-dose methotrexate; Nephrotoxicity",
"medline_ta": "Clin Chim Acta",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007668:Kidney; D008727:Methotrexate; D012516:Osteosarcoma; D010316:Particle Size; D013499:Surface Properties; D011623:gamma-Glutamyl Hydrolase",
"nlm_unique_id": "1302422",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "30205081",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "2,4-Diamino-N10-methylpteroic acid (DAMPA) crystalluria in a patient with osteosarcoma treated with carboxypeptidase-G2 rescue after high-dose methotrexate-induced nephrotoxicity.",
"title_normalized": "2 4 diamino n10 methylpteroic acid dampa crystalluria in a patient with osteosarcoma treated with carboxypeptidase g2 rescue after high dose methotrexate induced nephrotoxicity"
} | [
{
"companynumb": "ES-MYLANLABS-2018M1078285",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "The brain's ability to encode temporal patterns and predict upcoming events is critical for speech perception and other aspects of social communication. Deficits in predictive coding may contribute to difficulties with social communication and overreliance on repetitive predictable environments in individuals with autism spectrum disorder (ASD). Using a mismatch negativity (MMN) task involving rhythmic tone sequences of varying complexity, we tested the hypotheses that (1) individuals with ASD have reduced MMN response to auditory stimuli that deviate in presentation timing from expected patterns, particularly as pattern complexity increases and (2) amplitude of MMN signal is inversely correlated with level of impairment in social communication and repetitive behaviors. Electroencephalography was acquired as individuals (age 6-21 years) listened to repeated five-rhythm tones that varied in the Shannon entropy of the rhythm across three conditions (zero, medium-1 bit, and high-2 bit entropy). The majority of the tones conformed to the established rhythm (standard tones); occasionally the fourth tone was temporally shifted relative to its expected time of occurrence (deviant tones). Social communication and repetitive behaviors were measured using the Social Responsiveness Scale and Repetitive Behavior Scale-Revised. Both neurotypical controls (n = 19) and individuals with ASD (n = 21) show stepwise decreases in MMN as a function of increasing entropy. Contrary to the result forecasted by a predictive coding hypothesis, individuals with ASD do not differ from controls in these neural mechanisms of prediction error to auditory rhythms of varied temporal complexity, and there is no relationship between these signals and social communication or repetitive behavior measures. LAY SUMMARY: We tested the idea that the brain's ability to use previous experience to influence processing of sounds is weaker in individuals with autism spectrum disorder (ASD) than in neurotypical individuals. We found no difference between individuals with ASD and neurotypical controls in brain wave responses to sounds that occurred earlier than expected in either simple or complex rhythms. There was also no relationship between these brain waves and social communication or repetitive behavior scores.",
"affiliations": "The Cognitive Neurophysiology Laboratory, The Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.;The Cognitive Neurophysiology Laboratory, The Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.;Division of Developmental and Behavioral Pediatrics, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA.;The Cognitive Neurophysiology Laboratory, The Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.;The Cognitive Neurophysiology Laboratory, The Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.",
"authors": "Knight|Emily J|EJ|0000-0002-6971-1148;Oakes|Leona|L|;Hyman|Susan L|SL|;Freedman|Edward G|EG|;Foxe|John J|JJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/aur.2362",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1939-3806",
"issue": "13(12)",
"journal": "Autism research : official journal of the International Society for Autism Research",
"keywords": "auditory perceptual disorders; autism spectrum disorder; communication disorders; electroencephalography; evoked potentials, auditory; mismatch negativity",
"medline_ta": "Autism Res",
"mesh_terms": "D000161:Acoustic Stimulation; D000293:Adolescent; D001307:Auditory Perception; D000067877:Autism Spectrum Disorder; D002648:Child; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory; D006801:Humans; D055815:Young Adult",
"nlm_unique_id": "101461858",
"other_id": null,
"pages": "2058-2072",
"pmc": null,
"pmid": "32881408",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Individuals With Autism Have No Detectable Deficit in Neural Markers of Prediction Error When Presented With Auditory Rhythms of Varied Temporal Complexity.",
"title_normalized": "individuals with autism have no detectable deficit in neural markers of prediction error when presented with auditory rhythms of varied temporal complexity"
} | [
{
"companynumb": "US-OTSUKA-2021_021754",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Infection due to species other than Candida albicans is increasing among solid organ transplant recipients. Candida utilis, commonly used in the food industry, is considered as a low-virulence yeast. We report the first case of C. utilis fungaemia involving a solid organ transplant recipient. The infection was triggered by the withdrawal of a ureteral stent and was successfully treated with intravenous micafungin. We also propose a review of all reported cases of infection caused by C. utilis.",
"affiliations": "Nephrology and Transplantation Department, Centre Hospitalier Universitaire, Nantes, France.;Mycology Laboratory, Centre Hospitalier Universitaire, Nantes, France.;Mycology Laboratory, Centre Hospitalier Universitaire, Nantes, France.;Urology Department, Centre Hospitalier Universitaire, Nantes, France.;Nephrology and Transplantation Department, Centre Hospitalier Universitaire, Nantes, France.;Nephrology and Transplantation Department, Centre Hospitalier Universitaire, Nantes, France.;Nephrology and Transplantation Department, Centre Hospitalier Universitaire, Nantes, France.;Nephrology and Transplantation Department, Centre Hospitalier Universitaire, Nantes, France.;Nephrology and Transplantation Department, Centre Hospitalier Universitaire, Nantes, France.;Nephrology and Transplantation Department, Centre Hospitalier Universitaire, Nantes, France.",
"authors": "Gaisne|Raphaël|R|http://orcid.org/0000-0003-3391-6333;Jeddi|Fakhri|F|;Morio|Florent|F|http://orcid.org/0000-0002-5859-6105;Le Clerc|Quentin-Côme|QC|;Hourmant|Maryvonne|M|;Blancho|Gilles|G|;Giral|Magali|M|;Cantarovich|Diego|D|;Dantal|Jacques|J|;Ville|Simon|S|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.12766",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": "61(8)",
"journal": "Mycoses",
"keywords": "\nCandida utilis\n; candiduria; fungaemia; kidney transplantation; ureteral stent",
"medline_ta": "Mycoses",
"mesh_terms": "D061605:Administration, Intravenous; D000935:Antifungal Agents; D002175:Candida; D058387:Candidemia; D054714:Echinocandins; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D055666:Lipopeptides; D000077551:Micafungin; D008875:Middle Aged; D015607:Stents; D066027:Transplant Recipients; D016896:Treatment Outcome; D014513:Ureter",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "594-599",
"pmc": null,
"pmid": "29575315",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Candida utilis fungaemia following endoscopic intervention on ureteral stent in a kidney transplant recipient: Case report and a review of the literature.",
"title_normalized": "candida utilis fungaemia following endoscopic intervention on ureteral stent in a kidney transplant recipient case report and a review of the literature"
} | [
{
"companynumb": "FR-TEVA-2018-FR-950448",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Eltrombopag, a nonpeptide thrombopoietin receptor agonist (TPO-RA), has been reported to be an effective therapy for chronic immune thrombocytopenia (ITP). However, a higher incidence of arterial and venous thromboembolic events was reported after using eltrombopag.\nA 67-year-old man, treated with eltrombopag due to chronic ITP, was admitted due to acute coronary syndrome (ACS). Although coronary angiography revealed no occlusion, cardiac magnetic resonance imaging suggested a myocardial infarction in the territory of the left circumflex coronary artery. Three months after the ACS event, the obtuse marginal branches exhibited significant stenosis; hence, a percutaneous coronary intervention (PCI) was performed to implant a zotarolimus-eluting stent under the treatment of a dual antiplatelet therapy. However, stent thrombosis occurred 3 hours after PCI and required three other PCIs during the eltrombopag treatment.\nWe present a case of an ITP patient, who experienced repeated coronary and stent thrombosis during the treatment with eltrombopag. We propose that the risk of ACS and consequent coronary stent thrombosis should be considered before the introduction of eltrombopag.",
"affiliations": "Department of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Hematology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Hematology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, Japan.",
"authors": "Satoh|Terumori|T|;Saotome|Masao|M|0000-0001-6197-1669;Suwa|Kenichiro|K|;Ohtani|Hayato|H|;Nagata|Yasuyuki|Y|;Ono|Takaaki|T|;Maekawa|Yuichiro|Y|0000-0002-6792-8458",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/2756319",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2019/2756319Case ReportRecurrent Coronary Thrombus in a Patient with Chronic Immune Thrombocytopenia with Treatment Using Eltrombopag Satoh Terumori \n1\nhttp://orcid.org/0000-0001-6197-1669Saotome Masao msaotome@hama-med.ac.jp\n1\nSuwa Kenichiro \n1\nOhtani Hayato \n1\nNagata Yasuyuki \n2\nOno Takaaki \n2\nhttp://orcid.org/0000-0002-6792-8458Maekawa Yuichiro \n1\n\n1Department of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, Japan\n2Department of Hematology, Internal Medicine 3, Hamamatsu University School of Medicine, Hamamatsu, JapanAcademic Editor: Tayfun Sahin\n\n2019 26 3 2019 2019 275631929 11 2018 28 2 2019 Copyright © 2019 Terumori Satoh 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.Background\n Eltrombopag, a nonpeptide thrombopoietin receptor agonist (TPO-RA), has been reported to be an effective therapy for chronic immune thrombocytopenia (ITP). However, a higher incidence of arterial and venous thromboembolic events was reported after using eltrombopag. \n\nCase Presentation\n A 67-year-old man, treated with eltrombopag due to chronic ITP, was admitted due to acute coronary syndrome (ACS). Although coronary angiography revealed no occlusion, cardiac magnetic resonance imaging suggested a myocardial infarction in the territory of the left circumflex coronary artery. Three months after the ACS event, the obtuse marginal branches exhibited significant stenosis; hence, a percutaneous coronary intervention (PCI) was performed to implant a zotarolimus-eluting stent under the treatment of a dual antiplatelet therapy. However, stent thrombosis occurred 3 hours after PCI and required three other PCIs during the eltrombopag treatment. \n\nConclusion\n We present a case of an ITP patient, who experienced repeated coronary and stent thrombosis during the treatment with eltrombopag. We propose that the risk of ACS and consequent coronary stent thrombosis should be considered before the introduction of eltrombopag.\n\nJapan Society for the Promotion of ScienceJP16K09428\n==== Body\n1. Introduction\nChronic immune thrombocytopenia (ITP) is an autoimmune syndrome, which is caused by the development of an autoantibody against structural platelets. Although bleeding is a major symptom of ITP, a thrombophilia condition can be promoted in ITP patients by excess activated platelet function. Since platelets play critical roles in the progression of atherosclerosis, cardiovascular events have often been reported in ITP patients. Thus, the safety and recommended strategy in percutaneous coronary intervention (PCI) and subsequent antiplatelet therapies toward ITP patients have remained a matter of debate.\n\nCurrently available treatments of ITP include corticosteroids, splenectomy, immunosuppressants, and thrombopoietin receptor agonist (TPO-RA). Eltrombopag, a nonpeptide TPO-RA, has been reported to be effective as a second-line therapy for ITP. However, previous reports indicated a higher incidence of arterial and venous thromboembolic events, including myocardial infarction, after using eltrombopag [1]. In this report, we showed a case of recurrent coronary thrombosis in a patient with ITP who was treated with eltrombopag. We also reviewed the previous reports of PCI and antiplatelet therapy, during and after PCI, in ITP patients.\n\n2. Case Presentation\nA 67-year-old man, who was suffering from long-lasting (>2 hours) severe chest pain, was admitted in our hospital. He was an ex-smoker (between the ages of 20 and 25 years) and had been treated for hypertension and hyperlipidemia. He was diagnosed with ITP 6 months before admission and maintained his platelet count between 10.0 × 109/L and 15.0 × 109/L by receiving prednisolone (10 mg daily) and eltrombopag (50 mg daily). He was immediately relieved of chest pain after admission, and there was no significant finding on a 12-lead electrocardiogram except a left axis deviation (Figure 1(a)). However, a cardiac catheterization was performed urgently due to the significant increase of serum myocardial enzymes (troponin-I 1.56 ng/mL, creatine kinase (CK) 233 IU/L, and CK-muscle/brain 20 IU/L). Although coronary angiography (CAG) revealed no artery occlusion (Figure 1(b)), left ventriculography showed mild hypokinesis in the posterior wall, and cardiac magnetic resonance imaging exhibited a delayed gadolinium enhancement in the posterior wall area (Figure 1(c)), suggesting myocardial infarction in the territory of the left circumflex coronary artery (LCX).\n\nBecause the patient persistently complained of chest pain even after discharge, the second CAG was performed 3 months after the discharge. CAG revealed de novo stenosis in the obtuse marginal branches (#12: 75% with haziness, Figure 2(a)), and adenosine stress myocardial perfusion scintigraphy (Tc-99m tetrofosmin) showed myocardial ischemia in the posterior wall area (Figure 2(b)), where the tracer uptake was reduced at stress and restored at rest. Thus, the first PCI was planned for #12, and a dual antiplatelet therapy (aspirin 100 mg daily and clopidogrel 75 mg daily) was started more than 1 month before the procedure, where his platelet was kept at 27.4 × 109/L by eltrombopag (50 mg daily). The first PCI toward #12 was successfully performed by implantation of a zotarolimus-eluting stent (3.0 × 12 mm) and CAG revealed no residual stenosis (Figure 3(a)). However, the patient complained of severe chest pain with significant ST depression after returning to his hospital room (3 hours after the PCI). The emergent CAG demonstrated a stent thrombosis at the proximal edge of the stent (Figure 3(b)). Although the intravascular ultrasound imaging exhibited neither the underexpansion of the prior-implanted stent nor the coronary artery dissection around the stent, it showed new lining thrombus (white arrows) at the proximal edge of the stent (Figure 3(c)). An additional drug-eluting stent (3.0 × 12 mm, everolimus-eluting stent) was implanted at the proximal edge of the prior stent lesion of #12 (Figure 4(a), second PCI) under the support of an intra-aortic balloon pumping. To avoid further stent thrombosis, the antiplatelet agent was changed from clopidogrel (75 mg daily) to prasugrel (3.75 mg daily). However, CAG, performed 3 days after the second PCI, revealed a massive thrombus with 75% stenosis in #12 (Figure 4(b)). Urokinase (UK 240.000 U) was selectively injected into the LCX, instead of balloon inflation for the third PCI, because recurrent coronary thrombosis was occurring at the area of the dual stent implantation. CAG after the UK injection revealed the residual stenosis (50%) in #12. The follow-up CAG, which was performed 14 days after the third PCI, again revealed the recurrence of stent thrombosis with 75% stenosis in #12 (Figure 4(c)). Subsequently, a coronary thrombus aspiration was performed as the fourth PCI. The final CAG after coronary thrombus aspiration exhibited 50% residual stenosis. Since his platelet maintained at >39.3 × 109/L by eltrombopag during all PCIs, the association between a recurrence of coronary thrombosis and inappropriate platelet increase induced by eltrombopag was suspected. Thus, we transiently ceased eltrombopag, and his platelet promptly decreased to 8.0 × 109/L after 7 days of cessations. CAG, after the cessation of eltrombopag, showed 50% of residual stenosis with thrombus; hence, we did not perform further PCI to #12 (Figure 4(d)). In addition, after he received a splenectomy to cease eltrombopag, he has not complained of any chest pain, and CAG after splenectomy revealed no thrombus in #12.\n\n3. Discussion and Conclusions\nWe report a rare case of recurrent coronary thrombosis in a patient with ITP who was treated with eltrombopag. Despite the thrombocytopenic condition, acute coronary syndrome (ACS) events have been reported in ITP patients. ITP patients could experience comorbid thromboembolic events (TEEs) because ITP itself affords an inflammatory condition and promotes an aberrant platelet condition, with larger, younger, and more adherent platelets. In addition, the multifactorial predisposing factors, such as prednisolone treatment and atherosclerotic comorbidities, facilitate the trigger of TEEs.\n\nAlthough eltrombopag has been commonly used as a second-line therapy of ITP, it may enhance the ITP-specific characteristics of thromboembolism, which may increase the incidence of ACS events in ITP patients. Previous reports described cardiac manifestation, such as tachycardia, cyanosis, QT interval prolongation, pulmonary thromboembolism, and ACS after the use of eltrombopag. A pooled data analysis from five eltrombopag RCTs exhibited that the overall TEE rate was 4.5% (27 cases) in the eltrombopag-treated ITP patients, whereas there was none in the placebo groups, and four patients had ACS event [2]. Previously, three ACS events in patients with ITP were reported, which are suspected to be associated with eltrombopag. No association seems to be seen in the ACS event with the treatment duration (1 to 12 months), the platelet counts (107 to 437 × 109/L), and the atherosclerotic risk factors among them [3–5]. Although the mechanism, by which eltrombopag causes ACS event, remains elusive, a rapid platelet increase induced by eltrombopag (0.8 × 109/L to 10.5 × 109/L per month) may affect the ACS events in the present case.\n\nSince platelets play critical roles in the progression of atherosclerosis, as well as vascular healing, after stent implantation, PCI and the antiplatelet therapies in ITP patient have been a matter of debate for a long time [6]. The present case showed recurrent coronary thrombosis in the LCX even under dual antiplatelet therapy (DAPT—both clopidogrel plus aspirin and prasugrel plus aspirin), suggesting that DAPT may not be effective for activated platelets induced by eltrombopag. Thus, when ITP patients using eltrombopag have a coronary event, it might be safe to avoid any nonurgent PCI. If possible, PCI should be performed with other supporting treatments, such as corticosteroids, splenectomy, and immunosuppressants. Even in an evitable condition, such as ACS, it might be better to avoid any implantation of drug-eluting stent because they might have a poor response to DAPT, which results in repetitive coronary thrombosis. Furthermore, even in ITP patients not receiving eltrombopag treatment, adding eltrombopag before PCI is not recommended. The DAPT treatment for ITP patients has been commonly accepted if ITP patients have a sufficient platelet count (>50 × 109/L) [7]. Even in severe thrombocytopenic conditions, major bleeding was rarely reported in the previous cases [6].\n\nAccordingly, when ITP patients present any risk factors for thromboembolism or atherosclerosis, we recommend careful consideration of the risk-benefit balance before the introduction of eltrombopag. Further investigation is required to detect the eltrombopag-specific factors which increase the TEEs.\n\nAcknowledgments\nThis work was supported by JSPS KAKENHI Grant number JP16K09428 (to M. S).\n\nAbbreviations\nACS:Acute coronary syndrome\n\nCAG:Coronary angiography\n\nCK:Creatine kinase\n\nDAPT:Dual antiplatelet therapy\n\nITP:Immune thrombocytopenia\n\nLCX:Left circumflex coronary artery\n\nTPO-RA:Thrombopoietin receptor agonist\n\nTEEs:Thromboembolic events.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interests regarding the publication of this manuscript.\n\nFigure 1 Electrocardiography (ECG), coronary angiography (CAG), and cardiac magnetic resonance imaging (C-MRI) on the first admission. (a) ECG on admission revealed no significant change except a left axis deviation. (b) CAG revealed no coronary artery occlusion either in the right coronary artery (RCA: left anterior oblique 50° view) or the left coronary arteries (LCA: caudal 30° view). (c) C-MRI of short and long axis view. The arrows indicate the delayed enhancement of the myocardium.\n\nFigure 2 Second CAG and adenosine stress myocardial perfusion scintigraphy. (a) The second CAG was performed to investigate the acetylcholine-induced vasospasm. Although the coronary arteries did not exhibit vasospasm induced by acetylcholine, CAG revealed de novo stenosis in #12. (b) The adenosine stress myocardial perfusion scintigraphy (Tc-99m tetrofosmin) showed the myocardial ischemia in the posterior wall area, suggesting myocardial ischemia in #12.\n\nFigure 3 CAG and intravascular ultrasound images during PCI. In the first PCI, a zotarolimus-eluting stent (3.0 × 12 mm) was implanted in #12 (a, between white arrows). Emergent CAG, which was performed 3 hours after the first PCI, revealed massive thrombus in the stent lesion (b, white arrows). The intravascular ultrasound study (c) showed the new lining thrombus (white arrows) in the stent proximal (A and B), whereas not in the distal (C).\n\nFigure 4 CAG findings after second PCI. Although an additional drug-eluting stent sized 3.0 × 12 mm was implanted in #12 (a), CAG performed 3 days after the second PCI revealed the recurrence of thrombus (white arrow) with 75% haziness stenosis in #12 (b). Another CAG performed 14 days after the third PCI again revealed recurrence of stent thrombosis with 75% stenosis in #12 (c). The final CAG, which was performed after the fourth PCI, showed 50% of residual stenosis with thrombus, and we decided not to perform further PCI to #12 (d).\n==== Refs\n1 Catalá-López F. Corrales I. de la Fuente-Honrubia C. Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials Medicina Clínica 2015 145 12 511 519 10.1016/j.medcli.2015.03.014 2-s2.0-84952876095 26051432 \n2 Bussel J. B. Cheng G. Saleh M. N. Mayer B. Vasey S. Y. Brainsky A. Incidence of thromboembolic events across eltrombopag clinical trials in chronic immune thrombocytopenia (ITP) Blood 2010 116 21 p. 70 \n3 Teichman J. Taher A. Hashi A. Bagai A. Sholzberg M. A sticky situation: myocardial infarction in a young woman with immune thrombocytopenia on eltrombopag and a history of mediastinal radiation Journal of Thrombosis and Thrombolysis 2018 45 1 192 195 10.1007/s11239-017-1577-y 2-s2.0-85032826061 29101508 \n4 Sert S. Ozdil H. Sunbul M. Acute myocardial infarction due to eltrombopag therapy in a patient with immune thrombocytopenic purpura Turkish Journal of Haematology 2017 34 1 107 108 10.4274/tjh.2016.0169 2-s2.0-85014475372 27956373 \n5 Gunes H. Kivrak T. Eltrombopag induced thrombosis: a case with acute myocardial infarction Current Drug Safety 2016 11 2 174 176 10.2174/1574886311207040255 2-s2.0-84973618704 26560493 \n6 Li-Sha G. Peng C. Yue-Chun L. Recurrent acute coronary syndrome and restenosis after percutaneous coronary intervention in a patient with idiopathic thrombocytopenic purpura: a case report and literature review BMC Cardiovascular Disorders 2015 15 1 p. 101 10.1186/s12872-015-0092-3 2-s2.0-84961147416 \n7 Russo A. Cannizzo M. Ghetti G. Idiopathic thrombocytopenic purpura and coronary artery disease: comparison between coronary artery bypass grafting and percutaneous coronary intervention Interactive Cardiovascular and Thoracic Surgery 2011 13 2 153 157 10.1510/icvts.2011.271296 2-s2.0-79960973057 21576275\n\n",
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"abstract": "Statins work synergistically with androgen receptor blockers and androgen biosynthesis inhibitors, improving survival in patients with metastatic castration resistant prostate cancers (mCRPCs). Survival improvement is more pronounced for patients receiving androgen biosynthesis inhibitors compared with patients receiving androgen receptor blockers. A rare adverse interaction between simvastatin and abiraterone (Zytiga), an androgen biosynthesis inhibitor, was observed in a patient with mCRPC due to pharmacokinetic changes resulting from obstructive jaundice.",
"affiliations": "White River Health Systems, Batesville, AR, USA.;White River Health Systems, Batesville, AR, USA.;White River Health Systems, Batesville, AR, USA.;White River Health Systems, Batesville, AR, USA.",
"authors": "Desikan|Sai Prasad|SP|0000-0003-1157-6489;Sobash|Phillip|P|;Fisher|Andrew|A|;Desikan|Raman|R|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620947275\n10.1177_2324709620947275\nCase Report\nStatin-Induced Rhabdomyolysis Due to Pharmacokinetic Changes From Biliary Obstruction in a Patient With Metastatic Prostate Cancer\nhttps://orcid.org/0000-0003-1157-6489Desikan Sai Prasad MD1 Sobash Phillip 1 Fisher Andrew 1 Desikan Raman MD1 1 White River Health Systems, Batesville, AR, USA\nSai Prasad Desikan, White River Medical Center, 1710 Harrison Street, Batesville, AR 72501, USA. Email: sdesikan1@wrmc.com\n5 8 2020 \nJan-Dec 2020 \n8 232470962094727518 6 2020 3 7 2020 11 7 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Statins work synergistically with androgen receptor blockers and androgen biosynthesis inhibitors, improving survival in patients with metastatic castration resistant prostate cancers (mCRPCs). Survival improvement is more pronounced for patients receiving androgen biosynthesis inhibitors compared with patients receiving androgen receptor blockers. A rare adverse interaction between simvastatin and abiraterone (Zytiga), an androgen biosynthesis inhibitor, was observed in a patient with mCRPC due to pharmacokinetic changes resulting from obstructive jaundice.\n\nprostate cancerrhabdomyolysisobstructive jaundicedrug-drug interaction(s)cover-dateJanuary-December 2020typesetterts1\n==== Body\nBackground\nProstate cancer is a disease of elderly men, wherein 6 out of 10 patients are over the age of 65. Hypercholesterolemia is another disease that affects this elderly age group and has been associated with increased aggressiveness (Gleason 8-10) of prostate cancer.1 Statin therapy is common in patients predisposed to prostate cancer and has been associated with decreased incidence and aggressiveness of prostate cancer.2 This association was stronger with increased total dose, longer periods of treatment, and hydrophobic statin agents.3 Metastatic castration resistant prostate cancers (mCRPCs) are treated with androgen receptor blockers and androgen biosynthesis inhibitors. Drug-drug interactions between statins and these agents have been studied and associated with improved cancer-specific survival and overall survival.4 Adverse drug interactions are rare between these 2 classes of medication. In this case report, we describe a unique adverse drug interaction between abiraterone and simvastatin in a patient with mCRPC.\n\nCase Presentation\nA 66-year-old male was started on abiraterone acetate and prednisone for mCRPC 3 months prior to hospitalization. The patient had progressed on enzalutamide, which was started for progressive disease after surgical castration. The patient was on vacation after starting a regimen of abiraterone and low-dose prednisone. The patient’s family noticed that he was increasingly jaundiced and he returned home. On his drive back (approximately 2 days prior to presentation), the patient noticed gait disturbances and increasing proximal lower limb weakness while driving. He presented to his primary care physician with increasing jaundice, lower limb weakness, gait difficulty, light colored stool, and itching. He denied any bowel or bladder incontinence. Medications listed included the following: abiraterone, 1000 mg; prednisone, 5 mg daily (started 3 months prior); amlodipine, 5 mg daily; metoprolol, 25 mg BID (twice a day) for hypertension (started 3 years prior); and simvastatin, 20 mg daily for mild hyperlipidemia (started 40 mg 6-7 years prior, but patient reduced dose to 20 mg 3 years prior).\n\nPhysical evaluation was notable for deep icterus and lower limb weakness. Hip flexion and extension were noted to be 3/5 bilaterally. Knee extension and flexion were 4/5. Deep tendon reflexes and Babinski were normal. Sensation was intact in bilateral lower extremities.\n\nInvestigations\nLaboratory Evaluation\nLaboratory evaluation revealed elevated values: total bilirubin 10.6 mg/dL (0.2-1.3 mg/dL), direct bilirubin 4.8 mg/dL (0.0-0.3 mg/dL), aspartate aminotransferase 630 U/L (17-59 U/L), alanine aminotransferase 363 U/L, alkaline phosphatase 587 U/L (38-126 U/L), and creatinine kinase (CK) 6368 U/L (55-170 U/L). Creatinine was normal at 0.9 mg/dL. Additionally, CK peaked at 40 112 U/L (55-170 U/L) and decreased to 589 U/L on discharge 7 days later. After biliary stent placement on day 12, total bilirubin decreased to 6.70 mg/dL (Table 1).\n\nTable 1. Creatinine Kinase Peaked on Day 3 of Admission but Declined With Response to Treatment as Noted on Day 7. AST, ALT, ALP, and Bilirubin (Day 21) Declined After Biliary Stent Placement on Day 12.\n\n\tDay 0\tDay 3\tDay 7\tDay 21 after biliary stent\t\nBUN (9-20 mg/dL)\t25\t18\t18\t9\t\nCr (0.8-1.5 mg/dL)\t0.9\t0.6\t0.7\t0.7\t\nTotal bilirubin (0.2-1.3 mg/dL)\t10.60\t10.20\t11.10\t6.70\t\nAST (17-59 U/L)\t630\t1146\t844\t312\t\nALT (0-49 U/L)\t363\t572\t671\t197\t\nALP (38-126 U/L)\t587\t556\t549\t348\t\nCreatinine kinase (55-170 U/L)\t6368\t40 112\t589\t40\t\nAbbreviations: BUN, blood urea nitrogen; Cr, creatinine; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.\n\nRadiologic Evaluation\nMagnetic resonance imaging of the cervical, thoracic, and lumbar spine revealed bone metastasis without any evidence of cord compression. Hepatic ultrasound was significant for 2 hypoechoic liver lesions, which were concerning for metastasis, intrahepatic duct dilatation, and a borderline enlarged common bile duct measuring 6 to 7 mm. Magnetic resonance cholangiopancreatography showed intrahepatic and extrahepatic bile duct dilatation with abrupt tapering of the common bile duct at the head of the pancreas, which was concerning for extrinsic compression as well as lesions consistent with hepatic metastases (see Figures 1 and 2). Computed tomography–guided biopsy of one liver lesion was consistent with metastatic prostatic adenocarcinoma. Endoscopic retrograde cholangiopancreatography confirmed biliary stricture extending for 22 mm, and irregularity of the opacified pancreatic duct was also noted.\n\nFigure 1. Single shot fast spin echo magnetic resonance image shows intrahepatic and extrahepatic bile duct dilatation (white arrows) with abrupt narrowing at the head of the pancreas (white arrowhead), compatible with biliary obstruction.\n\nFigure 2. Axial T2 HASTE with fat saturation magnetic resonance image shows multiple intrahepatic T2 hyperintense lesions (white arrows), compatible with hepatic metastatic disease. Multiple dilated intrahepatic bile ducts (white arrowheads) noted as well.\n\nDifferential Diagnosis\nDifferential diagnoses on admission included spinal cord compression, jaundice related to liver metastasis, and abiraterone-induced liver injury.\n\nTreatment\nRhabdomyolysis was treated with aggressive intravenous fluids and discontinuation of simvastatin and abiraterone. CK level was 589 U/L on discharge. Weakness improved with physical therapy.\n\nBiliary obstruction was relieved by biliary sphincterotomy, along with stenting of the common bile duct and pancreatic duct on day 12. Biopsy and cytology of the common bile duct were negative for malignant cells. In addition, the patient was initiated on taxotere for mCRPC on account of progression on enzalutamide and abiraterone.\n\nOutcome and Follow-up\nThe patient had increasing prostate-specific antigen levels on taxotere and was, hence, switched to cabazitaxel. Mutational profiling on tissue and peripheral blood was performed to identify any mutation that could be targeted.\n\nDiscussion\nTargeted therapy against specific mutated pathways is increasingly employed in the therapy of malignancies. Many targeted agents are small molecules, which can readily be formulated as oral therapy. While oral drugs offer ease of administration, they increase the odds of drug-drug interaction. Oral medication used to treat cancer may be substrates for, inducers of, or inhibitors of cytochrome P450 (CYP) enzymes involved in drug metabolism.5\n\nAbiraterone is an oral CYP17 (working on 17-α hydroxylase and C17,20 lyase) inhibitor, which inhibits production of dehydroepiandrosterone (DHEA), a testosterone precursor.6 Simvastatin is a hydrophobic/lipophilic, HMG CoA reductase inhibitor.\n\nWhile primarily used for hypercholesterolemia, simvastatin when employed with abiraterone improves overall survival, cancer-free survival, and improves response (prostate-specific antigen levels) in patients with mCRPC. This synergistic interaction is facilitated by a reduction in cholesterol (in and of itself a DHEA precursor), decreased DHEA transport across the cell membrane, and decreased steroid biosynthesis.4\n\nBoth simvastatin and abiraterone are primarily metabolized by CYP3A4 and excreted in bile. In addition to CYP3A4, CYP2D6 may be involved in simvastatin metabolism. Homozygous CYP2D6 mutations result in increased levels of simvastatin, thereby predisposing patients to statin-induced myopathy.7 Abiraterone is an inhibitor of CYP2D6 in addition to being a substrate for CYP3A4.8 Under normal conditions, CYP3A4 activity is adequate and both drugs can be used concomitantly.\n\nStatins inhibit HMG-CoA reductase. HMG-CoA reductase converts HMG-CoA to mevalonate. Mevalonate is an essential precursor for production of isoprenoids, which are important for anchoring small GTPases.5 Inactivation of Rab GTPases, which are essential for intracellular vesicle trafficking, appears to be an important process in the development of rhabdomyolysis.9 Statin-induced rhabdomyolysis is dose dependent, especially when employed with agents that are also myotoxic or increase statin concentration. Pharmacokinetic changes induced by drug-drug interactions cause rhabdomyolysis in the majority of patients receiving statin therapy. Other risk factors for rhabdomyolysis include advanced age, frailty, pre-existent myopathy, hypothyroidism, as well as renal and liver function abnormalities.10\n\nThe patient presented with obstructive jaundice and lower limb weakness. Obstruction of the biliary tree leads to increased concentrations of both simvastatin and abiraterone in the patient. With increasing concentrations of abiraterone, abiraterone-induced CYP2D6 inhibition becomes more prominent. This inhibition in conjunction with competitive CYP3A4 inhibition (due to increased concentration of both drugs and metabolites) results in increased simvastatin levels and rhabdomyolysis.11 While there are a few case reports of abiraterone solely inducing rhabdomyolysis, our patient tolerated abiraterone and simvastatin until the onset of biliary obstruction, which precipitated the rhabdomyolysis. Amlodipine is also known to increase drug levels (area under the curve) of statins and results in dose-dependent myotoxicity when employed with statins.12,13 However, based on the dose and the fact that amlodipine is primarily renally excreted, it is suspected that this interaction did not contribute significantly to rhabdomyolysis.14,15\n\nIn the vast majority of patients, abiraterone and simvastatin do not demonstrate adverse drug-drug interaction and the coadministration of these agents improve survival and cancer-related mortality in mCRPC. This case highlights the importance of pharmacokinetic changes in precipitating drug-drug interactions. Rhabdomyolysis resulting from drug-drug interactions is a dynamic process that is affected by demographics, genetics, drug dosage, and pharmacokinetic changes. Careful attention to co-administered drugs is necessary to avoid drug toxicity when major changes in pharmacokinetics are anticipated.\n\nLearning Points/Take Home Messages\nOral oncology medications are potential inducers/inhibitors of CYP enzymes.\n\nSimvastatin and abiraterone have a synergistic effect in patients with mCRPC.\n\nPharmacokinetics are not static and can vary based on patient physiology.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Written informed consent was obtained from the patient for anonymized information to be published in this article.\n\nORCID iD: Sai Prasad Desikan \nhttps://orcid.org/0000-0003-1157-6489\n==== Refs\nReferences\n1 \nMurtola TJ Kasurinen TVJ Talal K , et al\nSerum cholesterol and prostate cancer risk in the Finnish randomized study of screening for prostate cancer\n. Prostate Cancer Prostatic Dis . 2019 ;22 :66 -76\n.30214034 \n2 \nSchnoeller TJ Jentzmik F Schrader AJ Steinestel J. \nInfluence of serum cholesterol level and statin treatment on prostate cancer aggressiveness\n. Oncotarget . 2017 ;8 :47110 -47120\n.28445145 \n3 \nLustman A Nakar S Cohen A Vinker S. \nStatin use and incident prostate cancer risk: does the statin brand matter? A population-based cohort study\n. Prostate Cancer Prostatic Dis . 2014 ;17 :6 -9\n.24061633 \n4 \nGordon JA Buonerba C Pond G , et al\nStatin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study\n. Oncotarget . 2018 ;9 :19861 -19873\n.29731989 \n5 \nKitzmiller JP Mikulik EB Dauki AM Murkherjee C Luzum JA. \nPharmacogenomics of statins: understanding susceptibility to adverse effects\n. Pharmacogenomics Pers Med . 2016 ;9 :97 -106\n.\n6 \nYin L Hu Q. \nCYP17 inhibitors—abiraterone, C17,20-lyase inhibitors and multi-targeting agents\n. Nat Rev Urol . 2014 ;11 : 32 -42\n.24276076 \n7 \nDuman I. \nRole of pharmacogenetics on response to statins: a genotype-based approach to statin therapy outcome\n. J Cardiol Ther . 2014 ;6 :111 -120\n.\n8 \nBenoist GE Hendriks RJ Mulders PF , et al\nPharmacokinetic aspects of the two novel oral drugs used for metastatic castration-resistant prostate cancer: abiraterone acetate and enzalutamide\n. Clin Pharmacokinet . 2016 ;55 :1369 -1380\n.27106175 \n9 \nGluba-Brzozka A Franczyk B Toth PT Rysz J Banach M. \nMolecular mechanisms of statin intolerance\n. Arch Med Sci . 2016 ;12 :645 -658\n.27279860 \n10 \nMendes P Robles PG Mathur S. \nStatin-induced rhabdomyolysis: a comprehensive review of case reports\n. Physiother Can . 2014 ;66 :124 -132\n. doi:10.3138/ptc.2012-65 24799748 \n11 \nSoldin OP Chung SH Mattison DR. \nSex differences in drug disposition\n. J Biomed Biotechnol . 2011 ;2011 :187103 .21403873 \n12 \nNeyra JA Rocha NA Bhargava R Vaidya OU Hendricks AR Rodan AR. \nRhabdomyolysis-induced acute kidney injury in cancer patient exposed to denosumab and abiraterone: a case report\n. BMC Nephrol . 2015 ;16 :118 .26220655 \n13 \nGhafouri S Drakaki A. \nAbiraterone-induced rhabdomyolysis in prostate cancer: a report of two cases and review of literature\n. Ann Clin Case Rep . 2018 ;3 :1533 .\n14 \nNishio S Watanabe H Kosuge K Uchida S Hayashi H Ohashi K. \nInteraction between amlodipine and simvastatin inpatients with hypercholesterolemia and hypertension\n. Hypertens Res . 2009 ;28 :223 -227\n.\n15 \nBeresford AP McGibney D Humphrey MJ Macrae PV Stopher DA. \nMetabolism and kinetics of amlodipine in man\n. Xenobiotica . 1988 ;18 :245 -254\n.2967593\n\n",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "drug-drug interaction(s); obstructive jaundice; prostate cancer; rhabdomyolysis",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000368:Aged; D000736:Androstenes; D002779:Cholestasis; D003937:Diagnosis, Differential; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D012206:Rhabdomyolysis; D019821:Simvastatin",
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"title": "Statin-Induced Rhabdomyolysis Due to Pharmacokinetic Changes From Biliary Obstruction in a Patient With Metastatic Prostate Cancer.",
"title_normalized": "statin induced rhabdomyolysis due to pharmacokinetic changes from biliary obstruction in a patient with metastatic prostate cancer"
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"abstract": "Itch is a frequent complaint reported by the patients and is usually ascribed to dermatological causes. Central neurogenic pruritus remains an under-recognized complication with an unclear etiology previously described in the patients with stroke or with an intramedullary mass of the spinal cord. We describe a case of a nine-year-old male who developed unilateral pruritus seven days after he underwent right hemicraniectomy due to ruptured arteriovenous malformation. The patient manifested a significant improvement in pruritus after starting gabapentin. This report highlights the need for having a high index of suspicion for central neurogenic pruritus in such patients.",
"affiliations": "Pediatrics, Ascension Sacred Heart Hospital, Pensacola, USA.;Pediatric Medicine, University of Florida College of Medicine, Pensacola, USA.",
"authors": "Agarwal|Ankit|A|;Fernandez Bowman|Adriana|A|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8661\nDermatology\nNeurology\nNeurosurgery\nUnilateral Neurogenic Pruritus Following Intracranial Surgery\nMuacevic Alexander Adler John R Agarwal Ankit 1 Fernandez Bowman Adriana 2 \n1 \nPediatrics, Ascension Sacred Heart Hospital, Pensacola, USA \n\n2 \nPediatric Medicine, University of Florida College of Medicine, Pensacola, USA \n\nAdriana Fernandez Bowman fernandeza86@ufl.edu\n17 6 2020 \n6 2020 \n12 6 e866129 5 2020 17 6 2020 Copyright © 2020, Agarwal et al.2020Agarwal 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/34440-unilateral-neurogenic-pruritus-following-intracranial-surgeryItch is a frequent complaint reported by the patients and is usually ascribed to dermatological causes. Central neurogenic pruritus remains an under-recognized complication with an unclear etiology previously described in the patients with stroke or with an intramedullary mass of the spinal cord. We describe a case of a nine-year-old male who developed unilateral pruritus seven days after he underwent right hemicraniectomy due to ruptured arteriovenous malformation. The patient manifested a significant improvement in pruritus after starting gabapentin. This report highlights the need for having a high index of suspicion for central neurogenic pruritus in such patients.\n\npruritusitchgabapentinintracranialsurgeryThe 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\nItch is a common symptom and is often associated with dermatological etiologies or medication side effect. Metabolic and endocrinologic disorders are often diagnosed in the absence of dermatological diseases.\n\nIn neurological disorders, postherpetic itch after shingles or radiculopathy due to osteoarthritis accounts for most of the part [1,2]. Diseases affecting the central or peripheral nervous system are generally associated with pain and paresthesia rather than pruritus. Central neurogenic pruritus has seldom been reported in the literature with stroke and intramedullary spinal cord masses as the most common etiologies [3]. There is a paucity of information regarding the intracranial surgical procedure as an etiology of central pruritus with no published reports widely available in the literature.\n\nCase presentation\nA nine-year-old male presented with unilateral pruritus seven days after he underwent right hemicraniectomy due to ruptured arteriovenous malformation. The pruritus was unremitting, interfering with daily activities, and refractory to antipruritic medications and emollients. The affected area was localized to the right lower extremity, particularly the L5 dermatome. The patient had no history of renal, liver, endocrine, hematologic, or skin disease. Underlying medical disorders that should be considered in pruritus without a primary cutaneous eruption were excluded by history and physical examination. Laboratory evaluation included complete blood count, liver, and kidney function tests and were all within normal limits. The cutaneous examination was unremarkable. A seizure focus as a cause of paroxysmal pruritus was not identified on an electroencephalogram (EEG). Itching persisted despite discontinuing opioids, which are known to have the side effect of pruritus. The patient was then started on gabapentin tablet 125 mg twice daily. As the patient showed mild improvement in pruritus, the dose was increased to 125 mg three times a day. Two weeks after starting gabapentin, there was a significant improvement in pruritus.\n\nDiscussion\nLocalized pruritus may be a symptom of any focal neurological phenomenon, such as brain tumors, multiple sclerosis, cerebral vascular aneurysms, and peripheral nerve entrapments. Pruritus tends to be continuous, but may also present in paroxysms or bouts [3]. There is limited information present in the published literature reporting unilateral pruritus after the cranial neurosurgical procedure as in our patient. The excellent initial clinical response to gabapentin supports the diagnosis.\n\nSince central neurogenic pruritus goes unassociated with any established syndrome, and due to its progression to advanced dermatological lesions, the majority of the pertinent case reports have been noticed to be published in dermatology journals. Without diligently giving thought towards the secondary causes, the resulting lesion is mistakenly diagnosed as primary pruritus in such cases.\n\nAlthough the exact neuroanatomy and neurophysiology of itch perception have not been clarified, it is suggested that itch perception utilizes many of the same neural pathways used in pain sensation [4]. Case reports demonstrate that any type of brain lesion that affects the brain’s itch neurons can cause central neuropathic pruritus, including trigeminal trophic syndrome (TTS) [5]. Further case reports and research may help to understand the exact pathomechanism of this phenomenon.\n\nTreating neurogenic pruritus is a challenge in most of the cases as the treatment effective for conventional itch such as antihistamines and anti-inflammatory is usually ineffective. No high-quality clinical treatment trials have been conducted and no medication has a U.S. Food and Drug Administration indication for neuropathic pruritus [1]. Conservative treatments such as maintaining good skin hydration, cognitive behavioral therapy, and barriers to reduce scratching should be considered in all the patients. Application of topical anesthetics such as lidocaine patches and eutectic mixture of lidocaine and prilocaine (EMLA) cream have been reported to be effective for the peripheral types of neuropathic pruritus [6]. Oral medications are largely untested for neurogenic pruritus. Case reports, mostly in TTS patients, support carbamazepine, gabapentin, amitriptyline, and pimozide [7-9]. Systemic local anesthetics and analogs such as mexiletine are untested but may be considered as they decrease neuronal action potentials, particularly in unmyelinated axons [10].\n\nConclusions\nPruritus in patients without clear etiology is a diagnostic and therapeutic challenge for the practitioners. If the dermatological and metabolic tests are unyielding, a detailed history, complete physical examination, and relevant brain and spinal cord imaging are necessary to establish a diagnosis. This report highlights the need for having a high index of suspicion for central neurogenic pruritus in patients with intracranial surgery. In addition, the neurophysiologic basis of pruritus has not been fully established. Further research and reports could provide insights into the ill-defined pathomechanisms of central pruritus which would help to determine better treatment options.\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 Common neuropathic itch syndromes Acta Derm Venereol Oaklander AL 118 125 92 2012 22307048 \n2 Notalgia paresthetica associated with nerve root impingement J Am Acad Dermatol Eisenberg E Barmeir E Bergman R 998 1000 37 1997 9418774 \n3 Central neurogenic pruritus: a literature review Acta Neurol Belg Canavero S Bonicalzi V Massa-Micon B 244 247 97 1997 https://pubmed.ncbi.nlm.nih.gov/9478262/ 9478262 \n4 Unilateral pruritus after a stroke Arch Dermatol Shapiro PE Braun CW 1527 1530 123 1987 3674911 \n5 Unilateral neurogenic pruritus: paroxysmal itching associated with central nervous system lesions Ann Intern Med King CA Huff FJ Jorizzo JL 222 223 97 1982 7103281 \n6 Neuropathic and psychogenic itch Dermatol Ther Yosipovitch G Samuel LS 32 41 21 2008 18318883 \n7 Trigeminal trophic syndrome: successful treatment with carbamazepine Br J Dermatol Bhushan M Parry EJ Telfer NR 758 759 141 1999 10583140 \n8 Neurotrophic trigeminal syndrome after pontine stroke Rom J Neurol Psychiatry Macovei M Popa C Alexianu M. E Vulcan P 153 158 29 1991 https://pubmed.ncbi.nlm.nih.gov/1820101/ 1820101 \n9 Improvement of trigeminal neurotrophic ulceration with pimozide in a cognitively impaired elderly woman: a case report Clin Exp Dermatol Mayer RD Smith NP 171 173 18 1993 8482000 \n10 Central neuropathic itch: a new treatment option? Neurology Sandroni P 778 779 59 2002\n\n",
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"keywords": "gabapentin; intracranial; itch; pruritus; surgery",
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"title": "Unilateral Neurogenic Pruritus Following Intracranial Surgery.",
"title_normalized": "unilateral neurogenic pruritus following intracranial surgery"
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"abstract": "Non-traumatic myelopathies can result from a wide spectrum of conditions including inflammatory, ischemic, and metabolic disorders. Here, we describe the case of a 60-year old immunocompetent woman who developed acute back pain followed by rapidly ascending flaccid tetraparesis, a C6 sensory level, and sphincter dysfunction within 8 h. Acyclovir and steroids were started on day 2 and herpes simplex virus type 2 (HSV-2) was confirmed by polymerase chain reaction in cerebrospinal fluid. Magnetic resonance imaging revealed a bilateral anterior horn tractopathy expanding from C2 to T2 and cervicothoracic cord swelling. Screening for paraneoplastic antibodies and cancer was negative. Neurophysiology aided in the work-up by corroborating root involvement. Recovery was poor despite early initiation of antiviral treatment, adjuvant anti-inflammatory therapy, and neurorehabilitation efforts. The clinical course, bilateral affection of the anterior horns, and early focal atrophy on follow-up magnetic resonance imaging take a necrotizing myelitis potentially caused by intraneuronal spread of the virus into consideration. Further, we summarize the literature on classical and rare presentations of HSV-2 myeloradiculitis in non-immunocompromised patients and raise awareness for the limited treatment options for a condition with frequent devastating outcome.",
"affiliations": "Department of Neurology, Franz Tappeiner Hospital, Merano, Italy.;Department of Neurorehabilitation Ospedale di Vipiteno and Research Department for Neurorehabilitation South Tyrol, Bolzano, Italy.;Department of Neuroscience, Biomedicine and Movement, Section of Clinical Neurology, University of Verona, Verona, Italy.;Department of Neurology, Franz Tappeiner Hospital, Merano, Italy.;Section of Neuroradiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.;Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria.;Department of Psychiatry and Psychotherapy, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria.;Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria.",
"authors": "Nardone|Raffaele|R|;Versace|Viviana|V|;Brigo|Francesco|F|;Tezzon|Frediano|F|;Zuccoli|Giulio|G|;Pikija|Slaven|S|;Hauer|Larissa|L|;Sellner|Johann|J|",
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"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2017.00199NeuroscienceCase ReportHerpes Simplex Virus Type 2 Myelitis: Case Report and Review of the Literature Nardone Raffaele 12Versace Viviana 3Brigo Francesco 4Tezzon Frediano 1Zuccoli Giulio 5Pikija Slaven 2Hauer Larissa 6†Sellner Johann 27*†1Department of Neurology, Franz Tappeiner Hospital, Merano, Italy2Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria3Department of Neurorehabilitation Ospedale di Vipiteno and Research Department for Neurorehabilitation South Tyrol, Bolzano, Italy4Department of Neuroscience, Biomedicine and Movement, Section of Clinical Neurology, University of Verona, Verona, Italy5Section of Neuroradiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA6Department of Psychiatry and Psychotherapy, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria7Department of Neurology, Klinikum rechts der Isar, Technische Universität München, München, GermanyEdited by: Elliot J. Roth, Rehabilitation Institute of Chicago, USA\n\nReviewed by: Mirjam R. Heldner, University of Oxford, UK; Carsten Lukas, Ruhr University Bochum, Germany\n\n*Correspondence: Johann Sellner, j.sellner@salk.at†These authors have contributed equally to this work.\n\nSpecialty section: This article was submitted to Spinal Cord Medicine, a section of the journal Frontiers in Neurology\n\n10 5 2017 2017 8 19910 2 2017 24 4 2017 Copyright © 2017 Nardone, Versace, Brigo, Tezzon, Zuccoli, Pikija, Hauer and Sellner.2017Nardone, Versace, Brigo, Tezzon, Zuccoli, Pikija, Hauer and SellnerThis 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) or licensor 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.Non-traumatic myelopathies can result from a wide spectrum of conditions including inflammatory, ischemic, and metabolic disorders. Here, we describe the case of a 60-year old immunocompetent woman who developed acute back pain followed by rapidly ascending flaccid tetraparesis, a C6 sensory level, and sphincter dysfunction within 8 h. Acyclovir and steroids were started on day 2 and herpes simplex virus type 2 (HSV-2) was confirmed by polymerase chain reaction in cerebrospinal fluid. Magnetic resonance imaging revealed a bilateral anterior horn tractopathy expanding from C2 to T2 and cervicothoracic cord swelling. Screening for paraneoplastic antibodies and cancer was negative. Neurophysiology aided in the work-up by corroborating root involvement. Recovery was poor despite early initiation of antiviral treatment, adjuvant anti-inflammatory therapy, and neurorehabilitation efforts. The clinical course, bilateral affection of the anterior horns, and early focal atrophy on follow-up magnetic resonance imaging take a necrotizing myelitis potentially caused by intraneuronal spread of the virus into consideration. Further, we summarize the literature on classical and rare presentations of HSV-2 myeloradiculitis in non-immunocompromised patients and raise awareness for the limited treatment options for a condition with frequent devastating outcome.\n\ninfectious myelitisherpes simplex virus type 2longitudinally extensive transverse myelitismyeloradiculitistreatmentoutcome\n==== Body\nIntroduction\nLongitudinally extensive transverse myelopathy (LETM) describes the condition of a hyperintense spinal cord lesion extending over three or more vertebral levels on sagittal T2-weighted magnetic resonance imaging (MRI). While neuromyelitis optica spectrum disorder (NMOSD) is among the most frequent causes worldwide, a number of other disorders can manifest as or develop LETM over time and have risk of recurrence (1). Thus, a timely diagnosis is driven by the efforts to provide early and appropriate treatment, set measures to prevent future attacks, and avoid severe disability (2). In this regard, the differential diagnosis of LETM beyond NMOSD included multiple sclerosis, acute disseminated encephalomyelitis, parainfectious disorder, subacute combined degeneration, tuberculous myelitis, spinal arteriovenous malformation, and systemic lupus erythematosus in a recent study (3).\n\nHerpes simplex virus type 2 (HSV-2) is a neurotropic virus which can cause genital herpes, aseptic meningitis, encephalitis and myelitis, and devastating infections of the neonate. The belief that the virus reactivates in lumbosacral ganglia is challenged by animal experiments, which found that autonomic ganglia and the spinal cord could be another latency site. Moreover, Ohashi and coworkers showed that HSV-2 reaches dorsal root ganglia and spinal cord independently (4). Myelitis related to HSV-2 is a rare entity and mostly reported in patients with malignancy and acquired immune deficits (5). The classical course of HSV-2 myelitis is ascending myelopathy with subacute development of cervicothoracic sensorimotor impairment. However, fulminant and less rapidly progressing cases have been reported as well (6).\n\nCase Report\nA 60-year-old woman developed acute back pain and urinary retention. Ascending sensorimotor disturbances developed thereafter and reached a plateau after 8 h. The neurological examination revealed severe tetraparesis and a sensory C6 level. Deep tendon reflexes were absent in the upper limbs and plantar responses were both extensor. The urodynamic study showed atonic contraction. Spinal cord MRI demonstrated a “pencil-like” T2 lesion expanding from C2 to T2 in the anterior part of the sagittal plane and swelling of the cervicothoracic cord (Figure 1A). Follow-up examination continued to demonstrate a cervicothoracic fusiform lesion in addition to focal atrophy and cavitation (Figures 1B,C). Brain MRI was unremarkable. Cerebrospinal fluid (CSF) analysis showed a normal cell count (2 cells/ml), elevated protein (76 mg/dl), normal glucose levels (65 mg/dl), and IgG index 0.49. Bacterial and fungal cultures were negative, and CSF-specific oligoclonal bands were absent. The test for anti-HSV antibody (ELISA) in the CSF showed positive IgM-HSV (2,000 mg/dl) and negative IgG-HSV. HSV-2 DNA was detected by polymerase chain reaction (PCR) in CSF (50 copies/μl). Other PCR examinations including varicella-zoster virus and enterovirus were negative. Dermatological manifestations did not occur during the entire course. Blood testing for antibodies against aquaporin-4, antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, paraneoplastic antibodies, and HIV were negative. Further unremarkable blood tests included serum protein electrophoresis, angiotensin-converting enzyme vitamin B12, and erythrocyte sedimentation rate. Cancer was ruled out by appropriate measures.\n\nFigure 1 (A) Sagittal T2-weighted magnetic resonance imaging (MRI) of the cervicothoracic spinal cord on admission showed a hyperintense “pencil-like” lesion at the level of the anterior horn which extends from the level of the second cervical to second thoracic vertebral level (red arrowheads) and cord swelling in large parts of the affected area. (B,C) Follow-up T2-weighted MRI 9 weeks later revealed a less homogenous hyperintense filiform signal in the anterior region of the cervicothoracic cord and circumscribed medullar atrophy in the sagittal plane (red arrowheads). The axial MRI is at the C5 level and demonstrates bilateral hyperintensive signals involving the anterior horns of both sides (owl’s eye appearance, red arrowheads).\n\nTreatment with intravenous acyclovir (10 mg/kg body weight three times daily) was started on the second day of admission, 4 days in conjunction with betamethasone (8 mg/day). Compound action potentials (cMAPs) and nerve motor conduction velocity were within normal limits on day 2. F-waves were absent in all tested nerves of upper limb and lower limbs, whereas the sensory nerve conduction study was normal. This finding suggested a damage to the anterior horn motor neurons and ventral root fibers. Ten weeks later, neurography showed a severe and inhomogeneous amplitude reduction and absence of cMAPs with relatively preserved conduction velocity in all tested nerves as well as the appearance in some nerves of impersistent and low-voltage F-responses. This confirmed secondary axonal loss in all motor nerves. Electromyography revealed a subacute neuropathic pattern with widespread denervation, minimally altered motor unit action potentials (MUAPs) morphology, and decreased recruitment in the upper limb muscles with different degree of severity. In the examined muscles of the lower limbs, spontaneous activity was less evident and MUAPs recruitment was absent, thus reflecting a reduced central drive.\n\nThe neurological examination 3 months later revealed a moderate degree flaccid weakness of the upper limbs, a severe spastic paraparesis and a distended bladder. Now, a sensory level was not evident.\n\nDiscussion\nInfratentorial, spinal cord, and peripheral nervous system manifestations of HSV-2 are a relative rarity (7). A Pubmed-search for PCR-confirmed HSV-2 myelitis in non-immunosuppressed patients revealed 11 cases with varying clinical presentation, MRI and CSF findings, dermatological manifestations, chances for recurrence, and persistent neurological deficits (Table 1). Acute, subacute, and ascending progressive courses were present, the ascending necrotizing form is presumably the most devastating subtype (8). Most patients received steroids with varying duration and success on outcome. Yet, some authors assume that this treatment is the mainstay for attenuating immune-mediated damage and halting further disease progression (9). This hypothesis goes back to the observation by Klastersky who reported not only large necrotic areas in the anterior horn and posterior fiber tracts but also multiple demyelinated areas in the white matter in an autopsy case of HSV-2 myelitis (10). The literature search for PCR-confirmed HSV-2 myelitis cases revealed that spinal cord lesions are more frequently located within the thoracolumbar section, and genital herpetic skin lesion are found in a few. A report of a patient series with mostly autopsy-confirmed cases corroborated a rare occurrence of a rash and further disclosed that fever is rare during both onset and progression of the disease (6). Cervical MRI lesions have also been reported with HSV-2 and occasionally in form of LETM. However, anterior horn tractopathy as seen in our case has not been observed among the published HSV-2 cases so far. In contrast, a pediatric case with polio-like presentation caused by HSV-1 was published in 1993 (11). HSV-2 myelitis is assumed to result from virus reactivation, which was latent in dorsal root ganglia (12). It is tempting to speculate intraneural spread of HSV-2 along anterior horn over a large area of the cervicothoracic cord may have been involved in the pathophysiology of our case. The subsequent focal spinal cord degeneration despite early initiation of antiviral and anti-inflammatory therapy is impressive and calls for more research in this condition to examine the pathophysiological basis and treatment options.\n\nTable 1 Herpes simplex virus type 2 (HSV-2) myelitis in non-immunocompromised patients: overview of cases studied by polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) specimen.\n\nCase no.\tReference\tDemographics (gender, years of age)\tComorbidity\tHSV-2 PCR in CSF (copies/μl)\tDynamics and clinical syndrome\tAdditional manifestations\tCSF (cells/μl, protein mg/dl)\tLongitudinal and axial magnetic resonance imaging lesion expansion\tHerpetic skin lesions\tTreatment\tOutcome at discharge\t\n1\t(8)\tFemale, 76\tn.r.\tPositive\tSubacute, paraplegia, bladder dysfunction, T10 level\tRadiculitis\t73, 132\tT10-conus, enhancement of meninges and roots\tButtocks, tights, abdomen\tAcyclovir\tDied 21 days from admission\t\n2\t(13)\tFemale, 49\tn.r.\tPositive\tAcute (sudden), paraplegia, back pain, urinary retention, T5/T7 level\tRelapse of myelitis\t30, 79\tC2, posterior (at relapse)\tNo\tAcyclovir, steroids\tComplete recovery\t\n3\t(13)\tMale, 38\tn.r.\tPositive\tSubacute (1 month), paraparesis, bladder dysfunction, T6 level\tRelapse of myelitis\t11, 75\tNormal at relapse\tGenital at relapse\tAcyclovir, steroids\tParaparesis\t\n4\t(9)\tMale, 44\tDiabetes\tPositive\tAcute (1 week), paraparesis, urinary problems, T4 level\t\t105, 122\tNot performed\tGenital\tAcyclovir on day 5, steroids\tParaplegia\t\n5\t(9)\tMale, 69\tn.r.\tPositive\tAcute (1 week), paraparesis, urinary problems, T3 level\tEncephalitis\t52, 72\tT7–L\tNo\tAcyclovir on day 5, vidarabine, steroids, IVIG\tTetraplegia\t\n6\t(9)\tFemale, 50\tn.r.\tPositive\tAcute (1 week), paraparesis, urinary problems, T5 level\t\t39, 51\tT7–L\tNo\tacyclovir on day 7, vidarabine, steroids\tParaplegia\t\n7\t(9)\tFemale, 50\tn.r.\tPositive\tAcute (2 weeks), paraparesis, urinary problems, T4 level\t\t158, 99\tC–L\tNo\tAcyclovir on day 12, steroids\tParaplegia\t\n8\t(9)\tMale, 68\tn.r.\tPositive\tAcute (2 weeks), paraparesis, urinary problems, T10 level\t\t3, 51\tT5–9\tNo\tAcyclovir after 3 months, steroids\tRecovery\t\n9\t(9)\tMale, 38\tn.r.\tPositive\tSubacute (3 months), paresis of left lower limb, urinary problems, T7 level\tRelapse of myelitis\t11, 75\tNot performed\tGenital\tAcyclovir after 4 months, steroid\tParaplegia\t\n10\t(9)\tFemale, 49\tn.r.\tPositive\tSubacute (4 months), paresis of right lower limb, urinary problems, T6 level\tRelapse of myelitis\t196, 90\tC2–4, posterior funiculus\tNo\tAcyclovir on day 7, steroids\tRecovery\t\n11\t(14)\tFemale, 70\tNormal\tNegative (positive from gluteal skin lesion)\tAcute (couple of days),\t3 myelitis episodes, radiculitis\t79, 43\tConus medullaris T11–L1, fusiform lesion, myelomeningeal enhancement and posterior nerve roots\tAnogenitial and gluteal\tAcyclovir on day 1, steroids\tSlight proximal paraparesis\t\n12\tCurrent case\tFemale, 60\tNormal\t50\tAcute (8 h) severe sensomotoric, C6 level\tRadiculitis\t2, 76\tT2 lesion from C2–T2, bilateral anterior horns\tNo\tAcyclovir, steroids\tModerate paresis upper limbs, severe paraparesis lower limbs\t\nC, cervical; T, thoracal; L, lumbar; n.r., not reported.\n\nA more stroke-like presentation as in our case was reported for one other report (case #2). Indeed, our case does share some clinical and radiological features of spinal cord infarction (15). The extent of longitudinal expansion, however, does not fit into the concept for vascular supply of the spinal cord and is not reported in the most comprehensive prospective study on spinal cord infarction (16). HSV-2 can cause cerebral ischemia and hemorrhage due to vasculitis (17). As ischemic necrosis is a known neuropathological feature of HSV-2 myelitis, an involvement of vasculitis could be translated to the pathogenesis of the disease (10). It needs to be stressed that most tractopathies are seen with parainfectious or paraneoplastic disorders, or infections, such as poliomyelitis, West Nile virus encephalomyelitis, and tick-borne encephalitis (18–20). All these conditions were ruled out. Moreover, neurophysiology is crucial for identifying, quantifying, and monitoring radicular involvement. A contrast-enhanced spinal MRI, however, would have been ideal to further characterize the current case and exclude additional differential diagnoses, including primary CNS vasculitis of the spinal cord (21).\n\nThere are efforts to rationalize the PCR testing for HSV based on CSF cell count and protein levels. Our patient had a normal cell count but elevated protein in CSF and met the Hansen criteria with demand elevated CSF leukocyte count (>5/μl) and/or protein levels (>50 mg/dl) (22). The exception to this guidance includes patient’s age (<2 years) and altered host immune status. PCR results need to be interpreted in the context of the patient’s clinical presentation and timing of the CSF sampling (23). Indeed, the low viral load needs to be seen in the context of early admission, relatively small lesion size, and limited direct CSF contact.\n\nConclusion\nWe report the case of a cervicothoracal tractopathy with stroke-like presentation caused by HSV-2. Outcome was poor despite early antiviral and anti-inflammatory treatment. We conclude that there is need for further neuropathological characterization of the condition and international prospective patient registries, ideally including multimodal treatment concepts.\n\nEthics Statement\nEthical approval or patient consent is not required according to national guidelines.\n\nAuthor Contributions\nRN performed the drafting/revising of the manuscript and accepted responsibility for conduct of research and final approval. VV, FB, FT, GZ, and SP performed the revising of manuscript and acquisition of data and accepted responsibility for conduct of research and final approval. LH and JS performed the drafting/revising of the manuscript and acquisition of data and accepted responsibility for conduct of research and final approval.\n\nConflict of Interest Statement\nThe authors RN, VV, FB, FT, GZ, SP, LH, and JS declare that they have no conflict of interest.\n==== Refs\nReferences\n1 Kister I Johnson E Raz E Babb J Loh J Shepherd TM . Specific MRI findings help distinguish acute transverse myelitis of neuromyelitis optica from spinal cord infarction . Mult Scler Relat Disord (2016 ) 9 :62 –7 .10.1016/j.msard.2016.04.005 27645347 \n2 Sellner J Boggild M Clanet M Hintzen RQ Illes Z Montalban X \nEFNS guidelines on diagnosis and management of neuromyelitis optica . Eur J Neurol (2010 ) 17 (8 ):1019 –32 .10.1111/j.1468-1331.2010.03066.x 20528913 \n3 Jain RS Kumar S Mathur T Tejwani S . Longitudinally extensive transverse myelitis: a retrospective analysis of sixty-four patients at tertiary care center of North-West India . Clin Neurol Neurosurg (2016 ) 148 :5 –12 .10.1016/j.clineuro.2016.06.011 27348743 \n4 Ohashi M Bertke AS Patel A Krause PR . Spread of herpes simplex virus to the spinal cord is independent of spread to dorsal root ganglia . J Virol (2011 ) 85 (6 ):3030 –2 .10.1128/JVI.02426-10 21159869 \n5 Widener RW Whitley RJ \nHerpes simplex virus . Handb Clin Neurol (2014 ) 123 :251 –63 .10.1016/B978-0-444-53488-0.00011-0 25015489 \n6 Nakajima H Shoji S \nHerpes simplex myelitis: differences in clinical manifestations between herpes simplex virus type 1 and type 2 . In: Hayasaka D , editor. Pathogenesis of Encephalitis . Rijeka : InTech (2011 ).\n7 Kennedy PG Steiner I . Recent issues in herpes simplex encephalitis . J Neurovirol (2013 ) 19 (4 ):346 –50 .10.1007/s13365-013-0178-6 23775137 \n8 Ellie E Rozenberg F Dousset V Beylot-Barry M \nHerpes simplex virus type 2 ascending myeloradiculitis: MRI findings and rapid diagnosis by the polymerase chain method . J Neurol Neurosurg Psychiatry (1994 ) 57 (7 ):869 –70 .10.1136/jnnp.57.7.869 8021686 \n9 Nakajima H Furutama D Kimura F Shinoda K Ohsawa N Nakagawa T \nHerpes simplex virus myelitis: clinical manifestations and diagnosis by the polymerase chain reaction method . Eur Neurol (1998 ) 39 (3 ):163 –7 .10.1159/000007927 9605393 \n10 Klastersky J Cappel R Snoeck JM Flament J Thiry L \nAscending myelitis in association with herpes-simplex virus . N Engl J Med (1972 ) 287 (4 ):182 –4 .10.1056/NEJM197207272870411 \n11 Kyllerman MG Herner S Bergstrom TB Ekholm SE . PCR diagnosis of primary herpesvirus type I in poliomyelitis-like paralysis and respiratory tract disease . Pediatr Neurol (1993 ) 9 (3 ):227 –9 .10.1016/0887-8994(93)90091-P 8394714 \n12 Kennedy PG Rovnak J Badani H Cohrs RJ . A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation . J Gen Virol (2015 ) 96 (Pt 7 ):1581 –602 .10.1099/vir.0.000128 25794504 \n13 Nakajima H Furutama D Kimura F Shinoda K Nakagawa T Shimizu A \nHerpes simplex virus type 2 infections presenting as brainstem encephalitis and recurrent myelitis . Intern Med (1995 ) 34 (9 ):839 –42 .10.2169/internalmedicine.34.839 8580553 \n14 Gobbi C Tosi C Stadler C Merenda C Bernasconi E \nRecurrent myelitis associated with herpes simplex virus type 2 . Eur Neurol (2001 ) 46 (4 ):215 –8 .10.1159/000050808 11721130 \n15 Pikija S Mutzenbach J Kunz A Nardone R Leis S Deak I \nDelayed hospital presentation and neuroimaging in non-surgical spinal cord infarction . Front Neurol (2017 ) 8 :143 10.3389/fneur.2017.00143 28446898 \n16 Masson C Pruvo JP Meder JF Cordonnier C Touze E De La Sayette V \nSpinal cord infarction: clinical and magnetic resonance imaging findings and short term outcome . J Neurol Neurosurg Psychiatry (2004 ) 75 (10 ):1431 –5 .10.1136/jnnp.2003.031724 15377691 \n17 Zepper P Wunderlich S Forschler A Nadas K Hemmer B Sellner J \nPearls & Oy-sters: cerebral HSV-2 vasculitis presenting as hemorrhagic stroke followed by multifocal ischemia . Neurology (2012 ) 78 (3 ):e12 –5 .10.1212/WNL.0b013e31823fcd4d 22249502 \n18 Steiner I Kennedy PG . Acute disseminated encephalomyelitis: current knowledge and open questions . J Neurovirol (2015 ) 21 (5 ):473 –9 .10.1007/s13365-015-0353-z 26037112 \n19 Sejvar JJ . West Nile virus infection . Microbiol Spectr (2016 ) 4 (3 ).10.1128/microbiolspec.EI10-0021-2016 27337465 \n20 Pichler A Sellner J Harutyunyan G Sonnleitner A Klobassa DS Archelos-Garcia JJ \nMagnetic resonance imaging and clinical findings in adults with tick-borne encephalitis . J Neurol Sci (2017 ) 375 :266 –9 .10.1016/j.jns.2017.02.003 28320144 \n21 Salvarani C Brown RD JrCalamia KT Christianson TJ Huston J IIIMeschia JF \nPrimary CNS vasculitis with spinal cord involvement . Neurology (2008 ) 70 (24 Pt 2 ):2394 –400 .10.1212/01.wnl.0000314687.69681.24 18541872 \n22 Hanson KE Alexander BD Woods C Petti C Reller LB . Validation of laboratory screening criteria for herpes simplex virus testing of cerebrospinal fluid . J Clin Microbiol (2007 ) 45 (3 ):721 –4 .10.1128/JCM.01950-06 17202281 \n23 Tyler KL . Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret’s . Herpes (2004 ) 11 (Suppl 2 ):57A –64A .15319091\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "8()",
"journal": "Frontiers in neurology",
"keywords": "herpes simplex virus type 2; infectious myelitis; longitudinally extensive transverse myelitis; myeloradiculitis; outcome; treatment",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "199",
"pmc": null,
"pmid": "28539913",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "8580553;17202281;8394714;15377691;27337465;4338243;27348743;23775137;11721130;22249502;26037112;28446898;8021686;21159869;25015489;18541872;9605393;28320144;25794504;27645347;15319091;20528913",
"title": "Herpes Simplex Virus Type 2 Myelitis: Case Report and Review of the Literature.",
"title_normalized": "herpes simplex virus type 2 myelitis case report and review of the literature"
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"abstract": "Stiff person syndrome (SPS) is a rare and challenging neuromuscular junction disorder with typical musculoskeletal manifestations associated with anti-GAD65 antibodies, extra rheumatological manifestations, including neuropsychiatric symptoms and severe dysautonomic troubles. Chronic intestinal pseudo-obstruction (CIPO) is also a rare condition corresponding to a sub-occlusive syndrome, resulting from the functional or structural impairment of smooth neuromuscular tissues of the intestinal tract. In the clinical spectrum of SPS, CIPO has rarely been described and dilated biliary tract has never been described. This present report is therefore the first in the context of anti-GAD65 antibodies with the additional involvement of the biliary tract. Here, we report the case of a 44-year-old woman hospitalized for a rapidly progressive CIPO associated with dilated biliary tract, revealing a typical SPS with slowly progressive rheumatologic complaints relegated to the background. The concomitant improvement of the neuromuscular function on skeletal, intestinal and biliary tree systems with the good outcomes of anti-GAD65 titer under immunosuppressant drugs, allowed us to link all three organic involvements to the antibody pathogenicity on the respective neuromuscular junctions. Therefore, we discussed their common pathogeny based on our patient's treatment outcome.",
"affiliations": "Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France.;Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France.;Department of Radiology, Caen University Hospital, France; Normandy University, Caen, France.;Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France.;Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France.",
"authors": "Nguyen|Alexandre|A|;de Boysson|Hubert|H|;Audrey|Fohlen|F|;Yameogo|Seydou|S|;Aouba|Achille|A|",
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"fulltext": "\n==== Front\nJ Musculoskelet Neuronal InteractJ Musculoskelet Neuronal InteractJournal of Musculoskeletal & Neuronal Interactions1108-7161International Society of Musculoskeletal and Neuronal Interactions Greece 31789305JMNI-19-526Case ReportChronic intestinal pseudo-obstruction with dilated biliary tract as a spectrum of stiff person syndrome in a nondiabetic patient Nguyen Alexandre 1de Boysson Hubert 1Audrey Fohlen 2Yameogo Seydou 1Aouba Achille 11 Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France2 Department of Radiology, Caen University Hospital, France; Normandy University, Caen, FranceCorresponding author: Achille Aouba, MD, PhD, Department of Internal Medicine, Caen University Hospital, Avenue de la Côte de Nacre, 14000 Caen, France E-mail: aouba-a@chu-caen.fr2019 19 4 526 530 12 3 2019 Copyright: © Journal of Musculoskeletal and Neuronal Interactions2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 4.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Stiff person syndrome (SPS) is a rare and challenging neuromuscular junction disorder with typical musculoskeletal manifestations associated with anti-GAD65 antibodies, extra rheumatological manifestations, including neuropsychiatric symptoms and severe dysautonomic troubles. Chronic intestinal pseudo-obstruction (CIPO) is also a rare condition corresponding to a sub-occlusive syndrome, resulting from the functional or structural impairment of smooth neuromuscular tissues of the intestinal tract. In the clinical spectrum of SPS, CIPO has rarely been described and dilated biliary tract has never been described. This present report is therefore the first in the context of anti-GAD65 antibodies with the additional involvement of the biliary tract. Here, we report the case of a 44-year-old woman hospitalized for a rapidly progressive CIPO associated with dilated biliary tract, revealing a typical SPS with slowly progressive rheumatologic complaints relegated to the background. The concomitant improvement of the neuromuscular function on skeletal, intestinal and biliary tree systems with the good outcomes of anti-GAD65 titer under immunosuppressant drugs, allowed us to link all three organic involvements to the antibody pathogenicity on the respective neuromuscular junctions. Therefore, we discussed their common pathogeny based on our patient’s treatment outcome.\n\nStiff Person SyndromeChronic Intestinal Pseudo ObstructionBiliary Tract DilatationGABAAnti GAD65\n==== Body\nIntroduction\nStiff person syndrome (SPS) is a rare and challenging neuromuscular junction disorder with a prevalence estimated in approximately 1/1 000 000. The diagnosis is evoked essentially on typical musculoskeletal manifestations, including limb and spinal muscle stiffness or spasms with enhanced lumbar or cervical lordosis. Extra rheumatological manifestations, including neuropsychiatric symptoms and severe dysautonomic troubles[1], may be in the foreground of the clinical picture and delay disease identification[2]. The diagnosis of SPS is supported by electromyographic abnormalities associated with the detection of antibodies against glutamic acid decarboxylase (GAD 65-antibody) in the serum or cerebrospinal fluid of more than 70% of patients. However, in addition to SPS these antibodies can be detected in other autoimmune conditions, such as Myasthenia gravis, thymoma[3], type 1 diabetes mellitus, thyroiditis, adrenal insufficiency, and vitiligo, which may be isolated or associated with one another[4]. SPS may also present as a paraneoplastic condition associated with various tumoural disorders.\n\nChronic intestinal pseudo-obstruction (CIPO) is also a rare condition corresponding to a sub-occlusive syndrome, resulting from the functional or structural impairment of smooth neuromuscular tissues of the intestinal tract. This syndrome may be idiopathic, or it may present as the consequence of connective diseases such as systemic lupus or systemic sclerosis.\n\nHere, we report the case of a 44-year-old woman hospitalized for a rapidly progressive CIPO associated with dilated biliary tract, which revealed a SPS with typical but slowly progressive rheumatologic complaints relegated to the background. In the clinical spectrum of SPS, CIPO has rarely been described and biliary tract dilatation has never been described. Therefore, we discussed their common pathogeny based on our patient’s treatment outcome.\n\nCase report\nA 44-year-old woman was referred for progressive abdominal pain and weight loss consecutive to a worsening condition of chronic constipation. Her medical history included temporal epilepsy treated with lamotrigine for three years. The first symptoms began three years earlier with progressive and increasing muscle pain, stiffness in her legs and lumbar area, associated with chronic increasing constipation, abdominal bloating, occasional nausea and vomiting. Previous hospitalizations with endoscopic exams in the gastroenterology and neurology departments found no obvious anomaly, leading to functional idiopathic constipation diagnosis. At admission, clinical examination retrieved no signs of systemic sclerosis nor inflammatory rheumatism, but a clear hyperlordosis and hyper-contracture of the paraspinal muscles (Table 1, L3-wall distance 10 cm, Schober Index 1.5 cm, occiput-wall distance 9.5 cm), a swaying walk, an asymmetrical diffused and polykinetic patella hyperreflexia that was more pronounced in the right leg, a sub-occlusive digestive syndrome with major abdominal meteorism, and rare but present hydro-air noises. Haemogram, serum electrolytes, calcium, vitamins, lipase, lipids, muscle enzymes, iron, creatinine, thyroid functions, glycaemia, and biologic inflammatory parameters were in normal range. Serum electrophoresis showed polyclonal hypergammaglobulinemia at 20 g/L and hepatic tests found only a slight persistent increase of gamma-GT (GGT), alkaline phosphatase (ALP) and conjugated bilirubin levels (1,2 to 2 times the normal values). Serum extensive tests were also negative for infectious diseases including HIV, HTLV 1 and 2, and Hepatitis B, C, and E virus. Antibody titers including antinuclear, ANCA, anti-mitochondrial, anti-LKM, ASCA, rheumatoid factor, anti-CCP, anti-smooth-muscles, and those against hu, Yo, Rhi, Ma, Ta, Peripherin G, amphiphysin, potassium channel, N-type or P/Q type calcium channel, GM1, GD1b, GQ1b, muscarinic and nicotinic acetylcholine receptor were all negative. However, anti-GAD 65 antibody was positive in blood serum and cerebrospinal fluid (52 UA/ml and 68 UA/mL, respectively; normally <5 mUA/mL). CSF remained normal for other metabolic and infectious explorations. Blood and CSF immunophenotyping were negative for clonal B, T or NK cells disease. The abdominal ultrasonography and abdominopelvic CT-scan revealed abundant stercoral stasis without any obstacles. Cerebral and spinal MRI and electromyographic exams did not reveal abnormalities, and neuromuscular stimulation showed no sign of myasthenia nor Lambert-Eaton syndrome. A MR cholangiography investigating the biologic and hepatic abnormalities found a significant choledochal dilatation with slight and rare stenosis and numerous small intravesicular and accessory bile duct stones.\n\nTable 1 Overview of the spinal parameters, bowel rhythm, hepatic enzymes, antiGAD-65 titres and treatment outcomes in a stiff person syndrome patient exhibiting spinal stiffness, chronic intestinal pseudo-intestinal syndrome and biliary tract dilatation.\n\n\tIgIV (2g/kg)\tCyclophosphamide (1g/month)\tRituximab (Day 1, Day 15 at M12)\t\n\tM0\tM3\tM4\tM8\tM12\tM16\tM24\t\nAnti GAD65 (mUA/mL) (Blood) N:< 5 mUA/mL\t52\t69\t74\t64\t50\t40\t11\t\nAnti GAD65 (mU/mL) (Cerebrospinal Fluid) N: < 5 mU/mL\t68\t-\t74\t74\t-\t67\t-\t\nLiver enzymes AST (U/L) N: 20 - 40 U/L\t20\t24\t16\t21\t31\t20\t22\t\nLiver Enzymes ALT (U/L) N: 20 - 40 U/L\t21\t26\t20\t20\t25\t22\t14\t\nGGT (U/L) N: < 35 U/L\t167\t102\t80\t79\t98\t88\t100\t\nAlkaline Phosphatase (U/L) N: 50 - 130 U/L\t146\t86\t103\t115\t95\t81\t123\t\nConjugated Bilirubin (umol/L) N: 2 - 5 umol/L\t14\t12\t8\t6\t10\t7\t8\t\nSchober’s Index (10 + X cm)\t1.5\t2\t1.5\t2\t2.5\t4\t5\t\nL3 To Wall Distance (cm)\t10\t9\t10\t9\t8\t8\t7\t\nOcciput To Wall Distance (cm)\t4\t3\t3\t3\t3\t1\t1\t\nHand To Floor Distance (cm)\t29\t21\t24\t22\t22\t14\t10\t\nBowel Rhythm\tRare\tRare\tRare\tFew\tFew\tDaily\tDaily\t\nCollectively, the diagnoses of stiff person syndrome and CIPO, both related to the anti-GAD65 antibody, were made while the aetiology of biliary tract involvement remained uncertain. The patient denied other hepatic endoscopy and biopsy procedures while the exploration of antibodies for a coincidental sclerosing cholangitis came back negative. Finally, an 18-FDG PET scan did not find any uptake that could evoke a tumoral and related paraneoplastic syndrome, or inflammatory background.\n\nThe initial treatment combining abundant laxatives, pyridostigmine, sandostatin, bile acid chelators associated with monthly courses of intravenous immunoglobin (IVIG), rapidly tapered oral prednisone (1 mg/kg/day) and mostly oral diazepam or other benzodiazepines showed only slight improvement on the axial muscle and digestive symptoms, respectively, while the anti-GAD65 titres were unchanged at the 4th month (74 mUA/mL in the blood and 74 mUA/mL in the CSF). Thus, IVIG cures were stopped and a second line treatment with intravenous cyclophosphamide (1 g monthly) for 6 months which allowed partial but clear improvement of all axial, digestive and biliary muscular function assessed on the clinical and biologic signs and imaging (Figure 1 and 2). This partial remission was associated with a moderate decrease of anti-GAD65 levels in serum and CSF (Table 1, 4, 8 and 12 months from diagnosis). Finally, two months after the last cyclophosphamide injection, two infusions of anti-CD20 monoclonal antibody were adminisitered (Rituximab, intravenous 1 g at D0 and D15 12 months from diagnosis) and then renewed 12 months later (Month 24 from the diagnosis) since the clinical remission was still only moderate. This allowed a complete resolution of all rheumatologic and intestinal signs, while the GAD65 antibody dramatically decreased to the minimal threshold of its detection (Table 1; 11 mUA/mL; N<5) in the serum. As for the biliary tract dilatation, a slight improvement with attenuation of stenosis has been observed on biliary tract MRI during follow up associated with GGT, ALP and bilirubin levels decrease. This allowed us to reduce the dose of ursodeoxycholic acid to 10 mg/kg/day. The patient denied any new CSF controls. Concomitantly, both signs of anicteric cholestasis and biliary duct imaging improved.\n\nFigure 1 Clinical and CT-scan features revealing a stiff person syndrome patient suffering from lumbar pain and chronic intestinal pseudo-obstruction; A) Clinical hyperlordosis with bloated abdomen; B) Sagittal CT view showing abundant stercoral stasis and hyperlordosis.\n\nFigure 2 Biliary tract MRI showing the slight and rare stenosis of the biliary ducts and choledochal dilatation revealing stiff person syndrome with associated chronic intestinal pseudo-obstruction.\n\nDiscussion\nFor the first time, this case reports CIPO and biliary tract dilatation as concomitant manifestations of anti-GAD65 antibodies in the context of SPS, which also probably includes temporal epilepsy, considering the concomitant chronology. The concomitant improvement of the neuromuscular function on skeletal, intestinal and biliary tree systems with the good outcomes of anti-GAD65 under immunosuppressant drugs, allowed us to link all three organic involvements to the antibody pathogenicity on the respective neuromuscular junctions.\n\nPhenotypic features among patients with SPS are diverse, including clinical syndromes such as the classical pattern as described herein or more challenging clinical picture like the partial pattern and the progressive encephalomyelitis with rigidity and myoclonus (PERM). SPS also includes a large panel of symptoms, including seizures, cognitive symptoms, eye movement disorders, and myoclonus or cerebellar ataxia[5].\n\nCIPO is associated with various other conditions but it is sometimes thought to be idiopathic. Its pathogeny is still unclear[6] and this syndrome is reported in various neurogenic mechanisms, such as diabetic neuropathy involving myenteric ganglia, or myogenic mechanisms and then related to connective or metabolic diseases such as hypothyroidism, ionic disorders, neoplasia, Hirschsprung disease, systemic sclerosis or systemic lupus[7]. Anti-GAD antibodies were first related to diabetes mellitus where the antibodies hindered the conversion of glutamic acid to gamma-amino butyric acid (GABA) by GAD 65[8]. In fact, beyond pancreatic beta-islet cells, GABA is also expressed in the GABAergic nerve terminals in the enteric nervous system, as well as in the central nervous system[8]-[11]. On the other hand, GAD antibodies are also found in cohorts of patients with achalasia (11-fold higher than in controls, P<0.0001)[9] or in patients with predominant enteric dysmotility[12]. Considering all these arguments, Maier et al described a very well documented case of SPS with limb stiffness and CIPO related to anti-GAD antibodies in a non-diabetic patient. This present report is therefore the second in this setting. However, with the additional involvement of the biliary tract, this report is the first in the context of anti-GAD65 antibodies.\n\nAt least three types of GABA receptors have been characterized, named GABAa, GABAb and GABAc receptors. While GABA has an inhibitory effect on the central nervous system, it’s the opposite for the activation of GABAa receptors which has an excitatory effect on the enteric nervous system[13]. Regarding activation of GABAb receptors, it seems to induce a reduction of the amplitude and frequency of jejunal contractions[14] and to promote propulsive duodenal motor activity. Therefore, the enhanced muscular stiffness and hyperexcitability state in SPS is due to the diminution of inhibitory GABA pathways in the neuromuscular junction and central nervous system, which explains the lumbar/legs contractures as well as the epileptic manifestations and cerebellar ataxia[15]-[17]. Dilated biliary tract was also reported in association with CIPO in three other patients in the literature apart from anti-GAD65 antibodies, including two patients with systemic lupus and one patient with hypomotility of the sphincter of Oddi[17,18]. Biliary stone development is therefore a possible consequence of the hypotonia of the biliary tree.\n\nTreatment management is for the most part intended to treat the symptoms with benzodiazepines, physiotherapy and individualised care but also to treat the dysimmunitary background of the syndrome. IvIg and steroids are the classical first-lines treatments for SPS and other auto immune diseases, usually show variable success, with complete failure in the present case. Other possibilities include immunosuppressants drugs such as cyclophosphamide which didn’t show satisfactory result herein. Due to cyclophosphamide cumulative toxicity, rituximab was a seducing alternative to lower auto antibody production[19]. Regular follow up are organized to assess clinical state and surveillance of tumoral occurrence since paraneoplastic syndrome cannot be completely ruled out. Finally, the improvement and clear good outcome of patient ‘s general status and neuromuscular syndrome, respectively under diazepam and immunosuppressants drugs without any dopaminergic treatment, definitely excluded a Segawa ‘s syndrome. Moreover, even though lumbar contracture is a possible rarer manifestation of this inherited rare disease, the absence of another familial case, the late onset of the disease and the absence of typical legs dystonia and/or of associated signs of Parkinson’s syndrome are all clearly in disfavour of other differential diagnosis.\n\nTo conclude, a sooner investigation of anti-GAD antibodies in patients with unclear gastrointestinal or biliary tract dysmotility, notably in the context of skeletal muscle stiffness, would enable a faster nosological diagnosis and adapted treatment, including immunosuppressants.\n==== Refs\n1 Ameli R Snow J Rakocevic G Dalakas MC A neuropsychological assessment of phobias in patients with stiff person syndrome Neurology 2005 64 11 1961 1963 15955955 \n2 Ho CSH Ho RCM Wilder-Smith EP Stiff person syndrome masquerading as panic attacks Lancet Lond Engl 2014 383 9917 668 \n3 Mitsumoto H Schwartzman MJ Estes ML Chou SM La Franchise EF De Camilli P Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome J Neurol 1991 238 2 91 6 1649913 \n4 Nicholas AP Chatterjee A Arnold MM Claussen GC Zorn GL Oh SJ Stiff-persons'syndrome associated with thymoma and subsequent myasthenia gravis Muscle Nerve 1997 20 4 493 8 9121508 \n5 McKeon A Robinson MT McEvoy KM Matsumoto JY Lennon VA Ahlskog JE Stiff-man syndrome and variants:clinical course, treatments, and outcomes Arch Neurol 2012 69 2 230 238 22332190 \n6 De Giorgio R Guerrini S Barbara G Cremon C Stanghellini V Corinaldesi R New insights into human enteric neuropathies Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc 2004 16 Suppl 1 143 7 \n7 Badari A Farolino D Nasser E Mehboob S Crossland D A novel approach to paraneoplastic intestinal pseudo-obstruction Support Care Cancer 2012 20 2 425 8 22072051 \n8 Maier A Mannartz V Wasmuth H Trautwein C Neumann U-P Weis J GAD Antibodies as Key Link Between Chronic Intestinal Pseudoobstruction, Autonomic Neuropathy, and Limb Stiffness in a Nondiabetic Patient:A CARE-Compliant Case Report and Review of the Literature Medicine (Baltimore) 2015 94 31 e1265 26252289 \n9 Kraichely RE Farrugia G Pittock SJ Castell DO Lennon VA Neural autoantibody profile of primary achalasia Dig Dis Sci 2010 55 2 307 11 19499338 \n10 Auteri M Zizzo MG Serio R GABA and GABA receptors in the gastrointestinal tract:from motility to inflammation Pharmacol Res 2015 93 11 21 25526825 \n11 Törnblom H Lang B Clover L Knowles CH Vincent A Lindberg G Autoantibodies in patients with gut motility disorders and enteric neuropathy Scand J Gastroenterol 2007 42 11 1289 93 17918010 \n12 Dhamija R Tan KM Pittock SJ Foxx-Orenstein A Benarroch E Lennon VA Serologic profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 2008 6 9 988 92 \n13 Bettler B Kaupmann K Mosbacher J Gassmann M Molecular structure and physiological functions of GABA(B) receptors Physiol Rev 2004 84 3 835 67 15269338 \n14 Gentilini G Franchi-Micheli S Pantalone D Cortesini C Zilletti L GABAB receptor-mediated mechanisms in human intestine in vitro Eur J Pharmacol 1992 217 1 9 14 1327818 \n15 Meinck H-M Thompson PD Stiff man syndrome and related conditions Mov Disord Off J Mov Disord Soc 2002 17 5 853 66 \n16 Honnorat J [Which role of antineural autoantibodies in central nervous system diseases?] Rev Neurol (Paris) 2008 164 5 403 4 18555871 \n17 Allescher HD Safrany L Neuhaus H Feussner H Classen M Aerobilia and hypomotility of the sphincter of Oddi in a patient with chronic intestinal pseudo-obstruction Gastroenterology 1992 102 5 1782 7 1568590 \n18 Pardos-Gea J Ordi-Ros J Selva A Perez-Lopez J Balada E Vilardell M Chronic intestinal pseudo-obstruction associated with biliary tract dilatation in a patient with systemic lupus erythematosus Lupus 2005 14 4 328 30 15864921 \n19 Sarva H Deik A Ullah A Severt WL Clinical Spectrum of Stiff Person Syndrome:A Review of Recent Reports Tremor Hyperkinetic Mov N Y N 2016 6 340\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7161",
"issue": "19(4)",
"journal": "Journal of musculoskeletal & neuronal interactions",
"keywords": "Anti GAD65; Biliary Tract Dilatation; Chronic Intestinal Pseudo Obstruction; GABA; Stiff Person Syndrome",
"medline_ta": "J Musculoskelet Neuronal Interact",
"mesh_terms": "D000328:Adult; D018450:Disease Progression; D005260:Female; D006801:Humans; D007418:Intestinal Pseudo-Obstruction; D016750:Stiff-Person Syndrome",
"nlm_unique_id": "101084496",
"other_id": null,
"pages": "526-530",
"pmc": null,
"pmid": "31789305",
"pubdate": "2019-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15955955;22072051;26252289;1649913;12360534;24529469;15066021;15864921;19499338;17918010;15269338;22332190;9121508;18599359;26989571;1327818;25526825;1568590;18555871",
"title": "Chronic intestinal pseudo-obstruction with dilated biliary tract as a spectrum of stiff person syndrome in a nondiabetic patient.",
"title_normalized": "chronic intestinal pseudo obstruction with dilated biliary tract as a spectrum of stiff person syndrome in a nondiabetic patient"
} | [
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"companynumb": "FR-MYLANLABS-2020M1020452",
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{
"abstract": "Natalizumab (NTZ) is a highly effective disease modifying therapy for the treatment of relapsing forms of multiple sclerosis (MS). Despite evidence to support its use as first-line therapy, risk of NTZ-associated progressive multifocal leukoencephalopathy (PML) has largely contributed to it being relegated to a second-line position. Recent preliminary data may allow for a more accurate analysis of JC virus (JCV) risk stratification of a given patient's PML risk. Herein we propose an algorithm to help guide clinicians through this decision-making process. We recommend that NTZ be considered for first-line use in JCV antibody negative MS patients, JCV 'low positive' MS patients without prior exposure to immunosuppression and for a limited period (12-24 months) in JCV 'high positive' MS patients with an aggressive disease course . We caution against first-line use in JCV antibody 'high positive' patients beyond 12-24 months and any JCV antibody positive patient with a history of prior immunosuppression.",
"affiliations": "The Ohio State University Multiple Sclerosis Center, 395 W 12th Avenue, 7th Floor, Columbus, OH 43210, USA.;Department of Neurology and Multiple Sclerosis Center, The Ohio State University, Columbus, OH, USA.;Department of Neurology and Multiple Sclerosis Center, The Ohio State University, Columbus, OH, USA.;Department of Neurology and Multiple Sclerosis Center, The Ohio State University, Columbus, OH, USA.",
"authors": "Nicholas|Jacqueline Ann|JA|;Racke|Michael Karl|MK|;Imitola|Jamie|J|;Boster|Aaron Lee|AL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2040622313514790",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2040-6223",
"issue": "5(2)",
"journal": "Therapeutic advances in chronic disease",
"keywords": "JC polyomavirus; multiple sclerosis; natalizumab; progressive multifocal leukoencephalopathy; treatment algorithm",
"medline_ta": "Ther Adv Chronic Dis",
"mesh_terms": null,
"nlm_unique_id": "101532140",
"other_id": null,
"pages": "62-8",
"pmc": null,
"pmid": "24587891",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "15947082;16268663;16634029;15947079;23526716;15596747;12872014;20298967;22054236;15851719;23485407;19201654;16510745;19204159;20737510;15947080;19308305;16510744;15931259;22591293;15947078;16286540;17388952;17030649;21482925;21625938;22204766",
"title": "First-line natalizumab in multiple sclerosis: rationale, patient selection, benefits and risks.",
"title_normalized": "first line natalizumab in multiple sclerosis rationale patient selection benefits and risks"
} | [
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"companynumb": "US-BIOGENIDEC-2014BI060918",
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"activesubstancename": "ASCORBIC ACID"
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"abstract": "Aspirin use is associated with reduced risk of several cancers. A pooled analysis of 12 case-control studies showed a 10% decrease in ovarian cancer risk with regular aspirin use, which was stronger for daily and low-dose users. To prospectively investigate associations of analgesic use with ovarian cancer, we analyzed data from 13 studies in the Ovarian Cancer Cohort Consortium (OC3).\n\n\n\nThe current study included 758 829 women who at study enrollment self-reported analgesic use, among whom 3514 developed ovarian cancer. Using Cox regression, we assessed associations between frequent medication use and risk of ovarian cancer. Dose and duration were also evaluated. All statistical tests were two-sided.\n\n\n\nWomen who used aspirin almost daily (≥6 days/wk) vs infrequent/nonuse experienced a 10% reduction in ovarian cancer risk (rate ratio [RR] = 0.90, 95% confidence interval [CI] = 0.82 to 1.00, P = .05). Frequent use (≥4 days/wk) of aspirin (RR = 0.95, 95% CI = 0.88 to 1.03), nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs; RR = 1.00, 95% CI = 0.90 to 1.11), or acetaminophen (RR = 1.05, 95% CI = 0.88 to 1.24) was not associated with risk. Daily acetaminophen use (RR = 1.28, 95% CI = 1.00 to 1.65, P = .05) was associated with elevated ovarian cancer risk. Risk estimates for frequent, long-term (10+ years) use of aspirin (RR = 1.15, 95% CI = 0.98 to 1.34) or nonaspirin NSAIDs (RR = 1.19, 95% CI = 0.84 to 1.68) were modestly elevated, although not statistically significantly so.\n\n\n\nThis large, prospective analysis suggests that women who use aspirin daily have a slightly lower risk of developing ovarian cancer (∼10% lower than infrequent/nonuse)-similar to the risk reduction observed in case-control analyses. The observed potential elevated risks for 10+ years of frequent aspirin and NSAID use require further study but could be due to confounding by medical indications for use or variation in drug dosing.",
"affiliations": "Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.;Brigham and Women's Hospital and Harvard Medical School, Boston, MA.;Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA.;Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.;Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.;Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA.;Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, OH.;Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.;Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.;Epidemiology Research Program, American Cancer Society, Atlanta, GA.;Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.;Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.;Division of Genetics and Epidemiology and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.;City of Hope, Duarte, CA.;Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.;Department of Nutrition, University of California Davis, Davis, CA.;Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.;National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.;National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.;Epidemiology Research Program, American Cancer Society, Atlanta, GA.;Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA.;Division of Epidemiology and Community Health, School of Public Health, and Masonic Cancer Center, University of Minnesota, Minneapolis, MN.;Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, DC.;University of Southern California, Los Angeles, CA.;Division of Genetics and Epidemiology and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.;Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.;University of Hawaii Cancer Center, Honolulu, HI.;Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.;Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.;Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA.",
"authors": "Trabert|Britton|B|;Poole|Elizabeth M|EM|;White|Emily|E|;Visvanathan|Kala|K|;Adami|Hans-Olov|HO|;Anderson|Garnet L|GL|;Brasky|Theodore M|TM|;Brinton|Louise A|LA|;Fortner|Renee T|RT|;Gaudet|Mia|M|;Hartge|Patricia|P|;Hoffman-Bolton|Judith|J|;Jones|Michael|M|;Lacey|James V|JV|;Larsson|Susanna C|SC|;Mackenzie|Gerardo G|GG|;Schouten|Leo J|LJ|;Sandler|Dale P|DP|;O'Brien|Katie|K|;Patel|Alpa V|AV|;Peters|Ulrike|U|;Prizment|Anna|A|;Robien|Kim|K|;Setiawan|V Wendy|VW|;Swerdlow|Anthony|A|;van den Brandt|Piet A|PA|;Weiderpass|Elisabete|E|;Wilkens|Lynne R|LR|;Wolk|Alicja|A|;Wentzensen|Nicolas|N|;Tworoger|Shelley S|SS|;|||",
"chemical_list": "D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1093/jnci/djy100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0027-8874",
"issue": "111(2)",
"journal": "Journal of the National Cancer Institute",
"keywords": null,
"medline_ta": "J Natl Cancer Inst",
"mesh_terms": "D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States",
"nlm_unique_id": "7503089",
"other_id": null,
"pages": "137-145",
"pmc": null,
"pmid": "29860330",
"pubdate": "2019-02-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "10469746;10695593;11189684;11744517;11801560;12462545;12598417;14575943;14996861;15254653;15668504;15998890;17330846;17674199;19271346;19342401;19910378;20142241;20818651;20861144;21897394;22440946;22517822;22665579;22972000;23880734;23966559;24503200;24599876;25096604;25158036;25538177;25855626;26066328;26673874;27064677;27325851;28342087;28460643;4104488;7662841;9214672;9492970;9696240",
"title": "Analgesic Use and Ovarian Cancer Risk: An Analysis in the Ovarian Cancer Cohort Consortium.",
"title_normalized": "analgesic use and ovarian cancer risk an analysis in the ovarian cancer cohort consortium"
} | [
{
"companynumb": "US-JNJFOC-20190614989",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Cardiac involvement is a major prognostic determinant in patients with primary AL amyloidosis. The clinical results of standard therapeutic approaches are suboptimal. It has been recently shown that bortezomib, an inhibitor of the proteasome, can induce rapid favourable responses in AL amyloidosis improving cardiac function and survival. Herein we report on two patients with cardiac amyloidosis treated by bortezomib who experienced partial or total remission of hematologic disease and of cardiac involvement. However, death of one patient, suffering from chronic kidney disease stage 5, due to fulminant respiratory syndrome suggests the need for caution in bortezomib use if patients have this comorbid condition.",
"affiliations": "Department of Medicine, Nephrology Unit, St. M. Annunziata Hospital, ASL 10, Florence, Italy.;Hematology and Transfusional Service, St. M. Annunziata Hospital, ASL 10, Florence, Italy.;Cardiology Unit, St. M. Annunziata Hospital, ASL 10, Florence, Italy.;Department of Medicine, Nephrology Unit, St. M. Annunziata Hospital, ASL 10, Florence, Italy.;Department of Medicine, Nephrology Unit, St. M. Annunziata Hospital, ASL 10, Florence, Italy.",
"authors": "Nigrelli|Santi|S|;Curciarello|Giuseppe|G|;Ballo|Piercarlo|P|;Michelassi|Stefano|S|;Pizzarelli|Francesco|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/627474",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/627474Case ReportEffectiveness of Bortezomib in Cardiac AL Amyloidosis: A Report of Two Cases Nigrelli Santi \n1\n*Curciarello Giuseppe \n2\nBallo Piercarlo \n3\nMichelassi Stefano \n1\nPizzarelli Francesco \n1\n1Department of Medicine, Nephrology Unit, St. M. Annunziata Hospital, ASL 10, Florence, Italy2Hematology and Transfusional Service, St. M. Annunziata Hospital, ASL 10, Florence, Italy3Cardiology Unit, St. M. Annunziata Hospital, ASL 10, Florence, Italy*Santi Nigrelli: nigrellisanti@hotmail.comAcademic Editor: Michael S. Firstenberg\n\n2014 10 3 2014 2014 6274746 10 2013 3 2 2014 5 2 2014 Copyright © 2014 Santi Nigrelli 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.Cardiac involvement is a major prognostic determinant in patients with primary AL amyloidosis. The clinical results of standard therapeutic approaches are suboptimal. It has been recently shown that bortezomib, an inhibitor of the proteasome, can induce rapid favourable responses in AL amyloidosis improving cardiac function and survival. Herein we report on two patients with cardiac amyloidosis treated by bortezomib who experienced partial or total remission of hematologic disease and of cardiac involvement. However, death of one patient, suffering from chronic kidney disease stage 5, due to fulminant respiratory syndrome suggests the need for caution in bortezomib use if patients have this comorbid condition.\n==== Body\n1. Introduction\nCardiac amyloidosis, which occurs as a complication of primary amyloidosis, is a result of cardiac deposition of insoluble, monoclonal immunoglobulin light chain fragments. This is observed in about 50% of patients with light chain amyloidosis predominantly after 40 years of age with higher prevalence in men than in women. The development of restrictive cardiomyopathy, complicated by progressive left ventricular or biventricular dysfunction, represents a major determinant of adverse outcome for these patients who typically die as a result of progressive heart failure or sudden cardiac death.\n\nA simple staging index for cardiomyopathy, based on levels of N-terminal brain natriuretic peptide (NTproBNP) and troponin I at presentation of disease, has been shown to predict median survival of 27.2, 11.1, and 4.1 months in stages I (normal values of both markers), II (altered values of only one marker), or III (altered values of both markers), respectively [1].\n\nThe aim of cardiac amyloidosis treatment is to reduce the concentration of the amyloidogenic light chains and to induce improvement of cardiac function and survival [2, 3] and it is crucial that treatment is rapidly effective, tolerable, and safe.\n\nThe severity of cardiac involvement and the high toxicity treatment profile, however, have always limited the outcome of traditional treatment options based on high dose melphalan chemotherapy followed by autologous stem cell transplantation.\n\nRecently it has been shown that bortezomib, a proteasome inhibitor, can induce rapid responses in AL amyloidosis improving cardiac function and survival [4].\n\nWe report herein two cases of cardiac amyloidosis in which treatment with bortezomib was associated with partial or complete clinical remission of disease.\n\n2. Case Presentation\n2.1. Case Report 1\nA 54-year-old man was referred to our institution in June 2006 because of clinical signs of congestive heart failure.\n\nHe was a long distance runner and diver but during the last year he had experienced progressive dyspnea and fatigue in his sport activities.\n\nClinical examination at admission showed breathlessness, peripheral edema, distended neck veins, hepatic engorgement, and upper quadrants abdominal pain. Clinostatic arterial pressure was 110/70 mmHg with a heart rate of 80 bpm, and orthostatic arterial pressure was 100/70 mmHg with heart rate of 84 bpm.\n\nThe electrocardiogram showed diffuse low-voltage QRS complexes. Echocardiography showed a left ventricle with normal diameters (end diastolic diameter 41 mm, end systolic diameter 28 mm) and thickened walls (Table 1) and preserved systolic function (EF 59%) but typical “sparkling” texture of the myocardium and a restrictive transmitral pattern (E/A = 3.9) suggestive of advanced left ventricular diastolic dysfunction. Atrial enlargement (43 mm) and mild pericardial effusion were also found (Figure 1). High serum and urinary monoclonal κ light chain was found with high-serum-free κ/λ ratio, as were high levels of serum NTproBNP (5570 ng/mL) and troponin I (0.85 ng/mL) (Table 1). The glomerular filtration rate was normal and the daily proteinuria was absent. Periumbilical fat aspirate sample confirmed amyloidosis.\n\nA bone marrow biopsy showed 25% of plasma cells with interstitial/paratrabecular distribution. K plasma cellular clonal restriction was observed.\n\nAbdominal ultrasound, EMG, nerve conductivity, and total body bone radiographs were normal. A genetic study excluded a transthyretin amyloidosis.\n\nFrom August 2006 to March 2007, the patient received a total of 6 cycles of melphalan (14 mg/day) and dexamethasone (20 mg/day) for 4 days. The therapy was frequently discontinued because of recurrent leucopenia.\n\nAt the end of this period, blood examination showed a significant decrease in free serum κ light chains but NTproBNP and troponin I levels were increased (Table 1) and the patient remained ill.\n\nFrom April to June 2007 the patient performed 3 cycles of therapy with bortezomib (1.3 mg/sqm/day) and dexamethasone (20 mg/day) administered on the 1st, 4th, 8th, and 11th day of every 21 days course followed by 8 infusions of bortezomib (1.3 mg/sqm/day) every 10 days and 3 infusions every 20 days. The treatment was well tolerated and was stopped in January 2008.\n\nSince the first cycle of bortezomib, the patient experienced a progressive improvement in breathlessness with complete remission during the treatment.\n\nAt the end of therapy serum free κ light chains and free κ/λ ratio were normal while NtproBNP and troponin I were markedly reduced. Moreover, a considerable reduction in left ventricular wall thicknesses was found (Table 1, Figure 2). During the following years, all echocardiographic indexes progressively returned to normal values and complete remission of haematological disease was achieved.\n\nIn September 2013, the patient was still asymptomatic and routinely performed his usual sport activities without any significant physical limitations. Serum κ chains (11 mg/dL) NTproBNP (204 ng/mL) and troponin I (0.05 ng/mL) concentrations were normal. Echocardiographic indexes were all within normal ranges, and in periumbilical fat aspirate sample amyloid deposits disappeared (Table 1).\n\nBased on these descriptors, we can consider the patient recovered.\n\n2.2. Case Report 2\nA 67-year-old golf instructor was admitted to our unit in January 2005 because of recent onset of nephrotic syndrome.\n\nHis medical history highlighted renal stones, relapsing bladder papillomatosis, and a progressive, unintentional weight loss (about 20 kg) that occurred between 2003 and 2004.\n\nOn clinical examination diffuse edema and liver and spleen enlargement were observed. Arterial pressure and heart rate were normal.\n\nBlood tests on admission showed serum creatinine levels of 1.33 mg/dL, total serum protein 5.6 gr/dL, monoclonal gammopathy IgGk, YGT 225 U/L (<66 U/L), alkaline phosphatase 253 U/L (<129 U/L), and NT proBNP 1102 pg/mL (n.v. < 227 pg/mL). Urine tests showed daily proteinuria of 16 gr and Bence Jones proteinuria with monoclonal κ light chains (Table 2).\n\nPeriumbilical fat aspirate sample showed amyloidosis confirmed by kidney biopsy. Amyloid deposits were identified by optical microscopy in glomerular mesangium and renal arteriolar walls. Further immunofluorescence microscopy showed monoclonal κ chain deposits in mesangium and capillary walls.\n\nA bone marrow biopsy showed an interstitial plasmacytosis (10%) with clonal plasma cells restriction for κ chains.\n\nEchocardiography showed mild hyperechogenicity of left ventricular myocardium without thickening of walls.\n\nA diagnosis of AL amyloidosis with involvement of kidney, liver, and heart was made.\n\nIn February 2005, the patient started on treatment with melphalan (16 mg for 4 days) and prednisone (75 mg for 7 days) every 6 weeks. Only two cycles of chemotherapy were performed because in April 2005 the patient experienced acute renal failure (serum creatinine up to 12 mg/dL with only partial resolution to serum creatinine 5.7 mg/dL at discharge) and severe arterial hypertension. Only mild reduction of serum free κ light chains was observed with no remission of nephrotic syndrome (Table 2).\n\nFrom July to December 2005, the patient received oral dexamethasone (40 mg for 4 days/monthly) and from September 2005 the patient received also thalidomide (200 mg/day). Treatment continued but was interrupted between January and May 2006 due to serious polyneuropathy, relapsing pulmonary infection, and herpes zoster infection.\n\nIn May 2006, the patient progressively developed clinical signs of heart failure and terminal uremia requiring hemodialysis: thalidomide (200 mg/day) was restarted at this point.\n\nAfter four months, echocardiography showed increased wall thickness (Figure 3), and the patient experienced worsening of heart failure (NYHA class III) and an increase in both free serum κ light chains and BNP. Following this, the patient received 3 cycles of treatment with melphalan (12 mg/day) and dexamethasone (20 mg/day) for 4 days every 28 days without clinical results (Table 2).\n\nClinical conditions, echocardiographic indexes, and laboratory examination worsened further during the following months. A 35-day cycle with bortezomib (1.3 mg/sqm) i.v. and dexamethasone (20 mg/day) on the 1st, 8th, 15th, and 22nd days was then started.\n\nAfter 6 cycles, June 2008, the patient experienced improvement of general conditions and returned to work. Serum free κ ligth chains, κ/λ ratio and BNP levels were markedly reduced (Table 2), whilst echocardiography showed a significant reduction in left ventricular wall thickness (Figure 4). Treatment was interrupted.\n\nIn October 2008, because of progression of organ damage (Figure 5) and increase of serum free κ light chains (Table 2), the patient restarted therapy with bortezomib and dexamethasone. Unfortunately, 10 days after the end of the first cycle, the patient died because of a fulminant syndrome characterized by diffuse infiltrative pulmonary disease with severe respiratory failure, severe hypotension, and lactic acidosis (up to 10.8 mmol/L) without signs of infections.\n\n3. Discussion\nUntil some years ago, treatment of AL amyloidosis consisted only of oral administration of melphalan/prednisone in repeated cycles over several months. The treatment rarely fully eliminated production of monoclonal light chains, and its impact on survival was poor.\n\nA more aggressive approach consisting of melphalan administered in myeloablative doses followed by autologous stem cell transplantation (HDM/SCT) began to be used in the mid-19 90s. Early experiences were encouraging but autologous stem cell transplantation (ASCT) related mortality (21% even at referral centers) and a high toxicity profile limited the practical feasibility of this approach to selected patients.\n\nAn alternative treatment consists of oral melphalan associated with dexamethasone in 4-day cycles each month (MDex) [5, 6]. Early reports of this treatment describe rapid eradication of monoclonal light chain production and improvement in NTproBNP. Unfortunately the need for repeated courses with high dose dexamethasone increases the risk of fluid retention, cardiac failure, and myopathy. Moreover, duration of hematologic response with this treatment is unclear.\n\nRecently identified alternatives to melphalan based treatment such as thalidomide or lenalidomide (a thalidomide analog) combined with dexamethasone may lead to hematologic response in some individuals with persistent plasma cell dyscrasia after initial treatment with HDM/SCT or Mel/Dex; however, the high dose needed to obtain hematologic response and frequent peripheral persistent neurotoxicity discourage their extensive use [7].\n\nIn small retrospective studies, bortezomib, a boronic acid dipeptide, reversible inhibitor of the 26S proteasome, was proven to be able to induce a high rate of rapid response in patients with AL amyloidosis [8]. The high activity of bortezomib in AL amyloidosis could be due to an imbalance between proteasome load and capacity favored by the peculiar conformational instability of amyloidogenic light chains [9, 10].\n\nA large retrospective study of 94 patients with AL amyloidosis treated with bortezomib and dexamethasone confirmed the efficacy of this combination and showed a significant improvement of cardiac performance among patients with heart involvement [4]. The safety and efficacy of bortezomib as a single agent in AL amyloidosis have been prospectively evaluated in a multicenter trial [11].\n\nThe clinical course of our two patients after bortezomib treatment deserves remarks.Both patients received previous treatment with melphalan, dexamethasone, and thalidomide and experienced some significant reduction, if any, of serum light chains but without improvement of cardiac failure.\n\nBoth patients just after the first cycle of bortezomib experienced a rapid significant reduction of serum free light chains and of NTproBNP or BNP associated with improvement of signs of cardiac failure and followed by reduction of cardiac walls thicknesses.The depressive effect of high concentration of light chains on heart function is common knowledge but in our patients speed of reduction appears more important for improvement of cardiac function than absolute light chains concentration reduction (obtained also with traditional therapy but more slowly).\n\nIn our patients, cardiac recovery of normal morphology was obtained later after the end of bortezomib therapy supporting the hypothesis of an indirect effect of bortezomib on tissutal environment whereby solubility or disappearance of amyloid systemic tissutal deposits is favored as shown by normal myocardium wall thicknesses and by lack of amyloid deposits in periumbilical fat 6 years later. This observation is indeed uncommon: there does not exist a similar case even in the large retrospective study of Kastritis et al. [4].\n\nThough bortezomib/dexamethasone combination seems to fulfill many requirements for optimal treatment of AL amyloidosis, polycentric observational study evidenced a high rate of discontinuation of bortezomib (39% of study population) due to adverse events, sometimes as severe as death [9]. Diffuse infiltrative lung disease represents a fatal, uncommon, unexplained adverse event that correlates to use of the drug probably favoured by comorbid conditions. Patient 2 had no previous history of pulmonary involvement but was on hemodialysis and showed an important liver involvement. We speculate that these two conditions are predisposing risk factors for diffuse infiltrative pulmonary disease. Other studies are needed to better define the safety profile of bortezomib in comorbid subjects especially when renal or liver functions are compromised.\n\n\n\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Case 1: echocardiography before bortezomib.\n\nFigure 2 Case 1; echocardiography after bortezomib.\n\nFigure 3 Case 2; echocardiography after the melphalan/dexamethasone cycles.\n\nFigure 4 Case 2: echocardiography after the bortezomib cycles.\n\nFigure 5 Case 2: echocardiography before the last bortezomib cycle.\n\nTable 1 Followup of case report 1.\n\n \tJune 2006 \nBasal \tMarch 2007\nafter mel/dex\tJanuary 2008\nafter bort/dex\tApril \n2008\tOctober \n2008\tApril \n2009\tSeptember \n2009\tSeptember \n2013\t\nSerum free k light chains \nmg/dL (n.v. < 19.4 )\t292\t110\t10.6\t12.07\t12.03\t12.09\t13.05\t7\t\n\n\n\t\n\nk/λ ratio\n(0.26–1.65)\t56.1\t32.16\t1.1\t1.01\t1.00\t2.01\t0.94\t \t\n\n\n\t\nNTproBNP ng/mL \n(n.v. < 227)\t5570\t8593\t840\t695\t521\t482\t423\t204\t\n\n\n\t\nTroponin I ng/mL\n(n.v. < 0.06)\t0.85\t3.23\t0.59\t0.83\t0.85\t0.19\t0.19\t0.05\t\n\n\n\t\nIVS (mm)\t16\t16\t14\t14\t12\t12\t12\t11\t\n\n\n\t\nLVPW (mm)\t16\t15\t14\t14\t12\t12\t12\t11\t\nmel: melphalan; dex: dexamethasone; bort: bortezomib.\n\nTable 2 Followup of case report 2.\n\n \tJanuary 2005\nBasal\tApril 2005\nafter melp/pr 2 cycles\tSeptember 2006\nafter dex/thalidomide\tJanuary 2007\nafter 2 cycles of melp/dex (Figure 3)\tJuly 2007\nbefore bort/dex\n\n\tJune 2008\nafter bort/dexa 6 cycles (Figure 4)\tOctober\n2008 (Figure 5)\t\nSerum free k light chains \nmg/dL (n.v. < 19.4 )\t92\t63\t174\t134\t331\t149\t189\t\n\n\n\t\n\nk/λ ratio \n(0.26–1.65)\t6.13\t2.92\t2.95\t4.4\t7.4\t4.53\t5.57\t\n\n\n\t\nBNP pg/mL \n(n.v. < 50)\t \t81\t2976\t2480\t3138\t484\t1292\t\n\n\n\t\nTroponin I ng/mL \n(n.v. < 0.06)\t \t0.05\t0.04\t0.02\t0.04\t0.04\t0.07\t\n\n\n\t\nIVS (mm)\t9\t11\t13\t17\t \t12\t14\t\n\n\n\t\nLVPPW (mm) \t9\t10\t13\t15\t \t12\t13\t\nmel: melphalan; pr: prednisone; dex: dexamethasone; bort: bortezomib.\n==== Refs\n1 Dispenzieri A Gertz MA Kyle RA Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis Journal of Clinical Oncology 2004 22 18 3751 3757 2-s2.0-4644336052 15365071 \n2 Palladini G Lavatelli F Russo P Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL Blood 2006 107 10 3854 3858 2-s2.0-33646597285 16434487 \n3 Palladini G Barassi A Klersy C The combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) after chemotherapy best predicts survival in AL amyloidosis Blood 2010 116 18 3426 3430 2-s2.0-78149291059 20644111 \n4 Kastritis E Wechalekar AD Dimopoulos MA Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis Journal of Clinical Oncology 2010 28 6 1031 1037 2-s2.0-77949897868 20085941 \n5 Palladini G Russo P Nuvolone M Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis Blood 2007 110 2 787 788 2-s2.0-34547137414 17606766 \n6 Jaccard A Moreau P Leblond V High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis The New England Journal of Medicine 2007 357 11 1083 1093 2-s2.0-34548716992 17855669 \n7 Sanchorawala V Wright DG Rosenzweig M Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial Blood 2007 109 2 492 496 2-s2.0-33846256126 16960148 \n8 Wechalekar AD Lachmann HJ Offer M Hawkins PN Gillmore JD Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease Haematologica 2008 93 2 295 298 2-s2.0-40849139507 18245653 \n9 Bianchi G Oliva L Cascio P The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition Blood 2009 113 13 3040 3049 2-s2.0-63849281664 19164601 \n10 Sitia R Palladini G Merlini G Bortezomib in the treatment of AL amyloidosis: targeted therapy? Haematologica 2007 92 10 1302 1307 2-s2.0-36348934009 18024367 \n11 Reece DE Sanchorawala V Hegenbart U Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study Blood 2009 114 8 1489 1497 2-s2.0-70349575412 19498019\n\n",
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"title": "Effectiveness of bortezomib in cardiac Al amyloidosis: a report of two cases.",
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"abstract": "Cyberlindnera fabianii is a yeast present in soil rarely associated with invasive infection. Due to advanced diagnostic and therapeutic techniques, pathogenicity is increasingly recognized. A 37-year-old male with B cell lymphoma on rituximab developed multiple organ dysfunction syndrome secondary to C. fabianii bacteremia. Specialized species identification techniques were required after failure of standard methods. Despite extracroporeal membrane oxygenation (ECMO) the patient died on day 26 after admission.",
"affiliations": "INOVA Fairfax Medical Campus, 3300 Gallows Rd, Fairfax, VA, 22042, United States.;INOVA Fairfax Medical Campus, 3300 Gallows Rd, Fairfax, VA, 22042, United States.;INOVA Fairfax Medical Campus, 3300 Gallows Rd, Fairfax, VA, 22042, United States.;INOVA Fairfax Medical Campus, 3300 Gallows Rd, Fairfax, VA, 22042, United States.;INOVA Fairfax Medical Campus, 3300 Gallows Rd, Fairfax, VA, 22042, United States.",
"authors": "Desai|Mehul|M|;Nitta|Bradley|B|;Dhanani|Hussain|H|;Djurkovic|Svetolik|S|;Katugaha|Shalika|S|",
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"doi": "10.1016/j.mmcr.2019.07.004",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30049-110.1016/j.mmcr.2019.07.004Case ReportMultiple organ dysfunction syndrome and death secondary to Cyberlindnera fabianii Desai Mehul Nitta Bradley bradley.nitta@inova.org∗Dhanani Hussain Djurkovic Svetolik Katugaha Shalika INOVA Fairfax Medical Campus, 3300 Gallows Rd, Fairfax, VA, 22042, United States∗ Corresponding author. bradley.nitta@inova.org05 7 2019 12 2019 05 7 2019 26 1 4 23 5 2019 4 7 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cyberlindnera fabianii is a yeast present in soil rarely associated with invasive infection. Due to advanced diagnostic and therapeutic techniques, pathogenicity is increasingly recognized.\n\nA 37-year-old male with B cell lymphoma on rituximab developed multiple organ dysfunction syndrome secondary to C. fabianii bacteremia. Specialized species identification techniques were required after failure of standard methods. Despite extracroporeal membrane oxygenation (ECMO) the patient died on day 26 after admission.\n\nKeywords\nCyberlindnera fabianiiFungemiaSeptic shockLymphomaImmunosuppression\n==== Body\n1 Introduction\nOver the last decade there has been a reduction in mortality associated with B cell lymphoma due to improved recognition and treatment. Mortality is often a result of a complication of treatment or development of an infection. Fungemia carries a high risk of mortality in these immunocompromised patients [1,2]. Though less frequently pathogenic than Candida, Cyberlindnera fabianii is a causative organism that is increasingly being recognized. It is an ascomycetous yeast of the Saccharomycetaceae family [3]. Past names for the organism include: Lindnera fabianii and Pichia fabianii [4]. In a review of the literature, we identified nineteen published cases or case series [[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]]. These cases noted the invasive capability of C. fabianii, with associated sepsis often following bacterial infection.\n\n2 Case\nA 37-year-old male with no prior medical history was admitted to the medical ICU on day 0 with septic shock. The patient complained of a toothache on day −4, for which he went to an urgent care on day −1 and was started on amoxicillin clavulanate for a possible tooth abscess. He required vasopressor support and was placed on broad spectrum antimicrobial coverage with vancomycin, meropenem, clindamycin, and micafugin. The initial laboratory work-up was significant for neutropenia (ANC 70/μL), lactic acidosis, acute kidney injury, ischemic hepatitis (shock liver), and coagulopathy.\n\nDue to encephalopathy, the patient required endotracheal intubation and mechanical ventilation on day 0. He was transitioned to veno-arterial ECMO on day 1 due to worsening septic shock with septic cardiomyopathy. Blood and sputum cultures from day 0 were positive for pan-susceptible Escherichia coli. The patient underwent three full volume plasma exchanges on days 1, 2, and 3 with stabilization in coagulation markers, progressive decline in vasopressor requirement, and clearance of lactate. Flow cytometry revealed a clonal expansion of B cells with a phenotype suggesting marginal zone lymphoma. Rituximab was started on day 8, along with intravenous methylprednisolone.The monoclonal B cell population was not present on repeat flow cytometry on day 20.\n\nOn day 16, while still on ECMO, the patient had increasing vasopressor requirements. Blood cultures from day 16 demonstrated yeast despite active treatment with micafungin, so voriconazole was added on day 19. Transthoracic echocardiography (TTE) on day 19 revealed a left ventricular apical thrombus. The yeast was initially identified as Candida pelliculosa by the Vitek system. Blood cultures were sent to a reference laboratory where Cyberlindnera fabianii was identified by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) on day 24. Amphoteracin B lipid complex was added to the antifungal regimen on day 24 due to species identification and persistent fungemia despite treatment with voriconazole and micafungin. The patient continued to require increasing vasopressor support and eventually died on day 26 after transitioning to comfort care.\n\n3 Discussion\nIn Table 1 we summarize the findings of 20 cases, including our own, of Cyberlindnera fabianii following an English literature search [[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]]. C. fabianii does not appear to demonstrate a predilection for a specific age group. However, severe immunosuppression, major surgery, antimicrobial therapy, and low birth weight appear to be associated with increased propensity for infection. Prior antifungal therapy was present in 7 cases at the time of species identification, suggesting that treatment of C. fabianii requires proper identification and determination of susceptibility. Clinical presentation appears to be relatively nonspecific with fever being the most common presentation. Multiple cases noted nonspecific rises in C reactive protein and variable alterations in the manual differential. Based on review of our case and prior cases, no specific clinical or laboratory data are associated with new onset fungal infection with C. fabianii. In 12 of 20 cases (60%), fungemia was present. In all cases, specialized diagnostic testing was required to identify the correct organism. Therapies included all antifungal classes–azoles, echinocandins, formulations of amphotericin, and flucytosine—as well as source control when possible. Eight of the 20 patients (40%) died of multiple organ dysfunction syndrome.Table 1 Comparison of prior published cases of Cyberlindnera fabianii.\n\nTable 1Reference\tAge/Sex\tPredisposing factors\tAntifungal prophylaxis\tSource\tLab Tests\tDiagnostic testing\tTreatment\tOutcome\t\nKatagiri S, 2015\t69/F\tAML s/p umbilical cord blood transplantation with preconditioning therapy, mechanical ventilation, antibacterial therapy\tmicafungin\tblood cultures\tBeta D Glucan level (150)\trRNA gene amplification\tamphotericin B\tmulti-organ failure\t\nH.Hof, 2017\tNeonate/F\tECMO, antibiotic prophylaxis, open heart surgery, peritoneal dialysis, mechanical ventilation\tfluconazole\tperitoneal dialysis\tCRP (98)\tPCR analysis\tcaspofungin with liposomal amphotericin B, followed by fluconazole\tmulti-organ failure\t\nMinaric-Missoni, 2015\t3/F\tNeutropenia, Leukemia, antibacterial therapy\tfluconazole\tstool\tCRP (24), thrombocytopenia\tPCR amplification and sequence analysis\tfluconazole for 5 days then inhaled amphotericin B for 14 days\tsurvived\t\nMinaric-Missoni, 2015\t2months/M\tHydronephrosis, surgery, antibacterial therapy\tnone\turine\tCRP (21)\tPCR amplification and sequence analysis\tfluconazole for 27 days, urinary catheter removal\tsurvived\t\nMinaric-Missoni, 2015\tNeonate/F\tGastroschisis, surgery, mechanical ventilation, parenteral nutrition, antibacterial therapy\tnone\turine\tCRP(123)\tPCR amplification and sequence analysis\tfluconazole for 27 days, urinary catheter removal and CVC removal\tsurvived\t\nMinaric-Missoni, 2015\tNeonate/M\tHydronephrosis, surgery, parenteral nutrition, antibacterial therapy\tnone\turine\tCRP (31)\tPCR amplification and sequence analysis\tfluconazole for 27 days, followed by caspofungin for 10 days\tsurvived\t\nMinaric-Missoni, 2015\tNeonate/F\tIntestinal atresia, surgery, parenteral nutrition, antibacterial therapy\tfluconazole\tblood cultures\tCRP (30)\tPCR amplification and sequence analysis\tfluconazole for 15 days, CVC removal\tsurvived\t\nMinaric-Missoni, 2015\tNeonate/F\tPulmonary cyst, antibacterial therapy, mechanical ventilation, parenteral nutrition\tfluconazole\tblood cultures\tCRP (30), thrombocytopenia\tPCR amplification and sequence analysis\tfluconazole for 2 days, followed by caspofungin for 21 days\tsurvived\t\nBaghdadi J, 2015\t49/F\tConsumption of com ruou, ventriculoperitoneal shunt\tnone\tCSF\tWBC 7810 cells/mm3 with 66.6% polymorphonuclear cells\tSequencing of the D1/D2 region of the large subunit of 28S ribosomal RNA gene\tintravenous liposomal amphotericin B 5mg/kg daily with oral flucytosine 25mg/kg QID\tsurvived\t\nJindal N, 2014\t5/M\tPreceding antitubercular treatment, ventriculoperitoneal shunt\tnone\turine\t300 leukocytes/mm3 with 24% neutrophils\t26S rRNA gene sequencing\tamphotericin B\tmulti organ failure\t\nGrenouillet F, 2010\t24 weeks/F\tExtremely low birth weight, antibiotic therapy\tnone\tblood cultures, pleural fluid aspirate\tnonspecific\tSequencing of 26 S ribosomal DNA and internal transcribed spacer\tintravenous fluconazole, followed by liposomal amphotericin B and flucytosine\tmulti organ failure\t\nBhally HS, 2006\t5 week/F\tPremature birth (25 and 3/7 weeks)\tnone\tblood culture\tnon specific\tSequencing of D1/D2 domain of the large subunit rDNA\tamphotericin B, with removal of vascular cath\tsurvived\t\nYun JW, 2013\t47/F\tPlasma cell myeloma, lenalidomid, high dose dexamethasone\tnone\tblood culture\tpancytopenia\trRNA gene amplification\tintravenous amphotericin B for 8 days, followed by caspofungin\tmulti organ failure\t\nValenza G, 2006\t46/M\tMechanical ventilation, arteriovenous ECCO2R, dialysis, acute cholecystitis, antimicrobial therapy\tnone\tblood cultures\tnon specific\tGenomic DNA amplification\tfluconazole, followed by caspofungin due to repeat growth in bronch\tmulti organ failure\t\nWu y, 2013\t33 weeks/F\tPremature, LBW (1760g), peripheral venous hyperalimentation, mechanical ventilation, antimicrobial therapy\tnone\tblood cultures\tnon specific\t26S ribosomal DNA amplification\tfluconazole\tsurvived\t\nHamal P, 2008\t40/M\tDecompressive craniotomy\tfluconazole\tblood cultures, and infected valve\televated CRP\tSequencing of the ITS2 of one of the isolates\tfluconazole, followed by voriconazole due to failure to clear cultures, followed by amphotericin B due to persistent fungemia\tsurvived\t\nGabriel F, 2012\t53/W\tAKI requiring dialysis, mesenteric ischemia, antimicrobial therapy\tnone\toropharyngeal swab, rectal, stool cultures\televated CRP\tSequencing of the 18S rDNA gene\tIV caspofungin\tsurvived\t\nLee J, 2015\t87/M\tAntimicrobial therapy, hemodialysis\tnone\tblood cultures\tCRP (9.65), LDH (287), leukocyte count 15,700/mm3\tSequencing of the large subunit (26S) rDNA gene\tanidulafungin\tmulti organ failure secondary to relapse of bacterial infection\t\nFernández-Ruiz, 2016\t48/M\tCirrhosis, autoimmune disease, corticosteroids, rituximab\tnone\tblood cultures, CVC\tnon specific\tPCR-based identification\tcaspofungin\tsurvived\t\nOur case\t37/M\tAntimicrobial therapy, ECMO, hemodialysis, mechanical ventilation, chemotherapy\tmicafungin\tblood cultures\televated vasopressor requirements\tMALDI-TOF\tmicafungin with addition of voriconazole\tmulti organ failure\t\n\n\nOur patient had many of the risk factors identified in previous cases including immunosuppression (new diagnosis of B-cell lymphoma), neutropenia, chemotherapy (rituximab), mechanical ventilation, ECMO support, and antibiotic therapy (for preceding E. coli bacteremia). Classically, cellular immune mechanisms prevent cellular invasion by yeast with modest contribution from the humoral immune response [1]. There is no clear theory to explain B-cell lymphoma or rituximab, a chimeric anti-CD20 monoclonal antibody that induces B cell depletion through lysis, phagocytosis, and cell cycle arrest, would result in increased risk of rare opportunistic fungemia. Based on prior research the influence of rituximab on fungal infections remains unclear [[19], [20], [21]].\n\nThe presence of macro disruptive procedures (mechanical ventilation, ECMO, CRRT) seems to increase the likelihood of Cyberlindnera to cause systemic disease. Our patient presented with gram negative septic shock requiring salvage therapy with veno-arterial ECMO. Because of the high incidence and mortality of Candida sepsis, it is a strong recommendation of the Extracorporeal Life Support Organization (ELSO) Infectious Disease task force that clinicians lower the threshold for antifungal therapy for critically ill septic patients on ECMO [22]. Our case demonstrates that we should extend this vigilance to include rare non-Candida yeast species that may require different therapy in this population.\n\nGrowth of C. fabianii on Dalmau plate culture produces spherical ovoid budding yeast cells with occasional pseudohyphae. Microscopy demonstrates spheroidal to ellipsoidal budding blastoconidia with an absence of pseudohyphae [3]. The use of routine diagnostic kits for the identification of yeast has limited ability to identify Cyberlindnera [9,11,23]. We suspect Cyberlindnera infections are often undiagnosed due to a failure to complete definitive fungal identification. In our case, the organism was initially misidentified as Candida pelliculosa by the Vitek system. Cultures were sent to a reference lab for further identification due to the rarity of that species. Prior cases have also demonstrated misidentification as Candida utilis [9]. Diagnosis of our yeast required use of MALDI-TOF MS.\n\nC. fabianii has been described as a yeast with low virulence and a rare cause of blood stream infection and sepsis. However, our case as well as others (Table 1) have noted the organism to grow from multiple sites with a poor response to treatment with antifungal therapy. Antifungal susceptibility testing should be pursued as strains of the yeast can have varied minimum inhibitory concentrations. Prior cases also noted the rapid development of resistance in isolates following the initiation of therapy, particularly to azoles [6,16]. In our case, fungemia developed while on micafungin and persisted while on both micafungin and voriconazole. Harboring of the fungus in the intra-atrial thrombus and ECMO circuit were presumably also barriers to clearance of the blood. Past C. fabianii isolates demonstrated strong biofilm production [9], which likely contributed to the organism’s persistence in ECMO recipients.\n\n4 Conclusion\nA high index of suspicion is necessary for rare opportunistic yeast species in immunocompromised, critically ill patients, especially in those requiring life support devices such as ECMO. Cyberlindnera fabianii is an emerging pathogen that can be associated with fungemia, sepsis and multiple organ dysfunction syndrome. Antibiotic therapy is a risk factor, and C. fabianii has the ability to breakthrough antifungal prophylaxis and empiric treatment. Given that automated identification systems can misidentify this organism as a Candida species, we emphasize the importance of reference testing, either with MALDI-TOF MS or fungal sequencing. Accurate identification of the yeast is essential in treatment, as Cyberlindnera has varying antifungal susceptibilities, which must guide therapy. It requires source control due to its resistance pattern and biofilm production. In certain patients, C. fabianii can be highly virulent with infection resulting in considerable mortality.\n\nConflict of interest\nThere are none.\n\nAcknowledgements\nThere were no contributors to acknowledge who did not meet the criteria for authorship.\n==== Refs\nReferences\n1 Polonelli L. Casadevall A. Han Y. Bernardis F. Kirkland T. Matthews R. The efficacy of acquired humoral and celular immunity in the prevention and therapy of experimental fungal infections Med. Mycol. 38 1 2000 281 292 11204156 \n2 Netea M.G. Joosten L.A. van der Meer J.W. Kullberg B. van de Veerdonk F.L. Immune defense against Candida fungal infections Nat. Rev. Immunol. 15 2015 630 642 26388329 \n3 [Internet] Mycology Online 2016 The University of Adelaide Adelaide Cyberlindnera fabianii; [revised 2016 Dec; cited 2017 Dec 16];[2 screens]. Available from: https://mycology.adelaide.edu.au/descriptions/yeasts/cyberlindnera \n4 Freel K.C. Sarilar V. Neuvéglise C. Devillers H. Friedrich A. Schacherer J. Genome sequence of the yeast Cyberlindnera fabianii (hansenula fabianii) Genome Announc. 2 4 2014 1 2 \n5 Katagiri A. Gotoh M. Tone K. Akahane D. Ito Y. Ohyashiki K. Fatal Cyberlindnera fabianii fungemia in a patient with mixed phenotype acute leukemia after umbilical cord blood transplantation Int. J. Hematol. 103 5 2016 592 595 26879198 \n6 Hof H. Amann V. Tauber C. Paulun A. Peritonitis in a neonate due to Cyberlindnera fabianii , an ascomycetic yeast Infection 45 6 2017 921 924 28825212 \n7 Minaric-Missoni E. Hatvani L. Kocsubé S. Vágvölgyi C. Škarić I. Lukić-Grlić A. Cyberlindnera fabianii in the neonatal and pediatric intensive care unit: case reports J. Med. Microbiol. Case Rep. 2 2015 1 8 \n8 Baghdadi J. Hemarajata P. Humphries R. Kelesidis T. First Report of ventriculoperitoneal shunt Infection due to Cyberlindnera fabianii [Internet] Case Rep. Infect. Dis. 2015 Oct [cited 2017 Dec 16];2015:1-6. Available from: https://www.hindawi.com/journals/criid/2015/630816/ \n9 Jindal N. Arora S. Dhuria N. Arora D. Cyberlindnera (Pichia) fabianii infection in a neutropenic child: importance of molecular identification J. Med. Microbiol. Case Rep. 2 4 2015 1 3 \n10 Grenouillet F. Millon L. Abdourahim C. Thiriez G. Schulze O. Leroy J. Pichia fabianii fungemia in a neonate Pediatr. Infect. Dis. J. 29 2 2010 191 20118752 \n11 Bhally H.S. Jain S. Shields C. Halsey N. Cristofalo E. Merz W. Infection in a neonate caused by Pichia fabianii : importance of molecular identification Med. Mycol. 44 2 2006 185 187 16519022 \n12 Yun J. Park K. Ki C. Lee N.J. Catheter-related bloodstream infection by Lindnera fabianii in a neutropenic patient J. Med. Microbiol. 62 6 2013 922 925 23475905 \n13 Valenza V. Valenza R. Brederlau J. Frosch M. Kurzai O. Identification of Candida fabianii as a cause of lethal septicemia Mycoses 49 4 2006 331 334 16784449 \n14 Wu Y. Wang J. Li W. Pichia fabianii blood infection in a premature infant in China: case report BMC Res. Notes 6 77 2013 1 4 23281703 \n15 Hamal P. Ostransky J. Dendis M. Horváth R. Ruzicka F. Buchta V. A case of endocarditis caused by the yeast Pichia fabianii with biofilm production and developed in vitro resistance to azoles in the course of antifungal treatment Med. Mycol. 46 6 2008 601 605 18608935 \n16 Gabriel F. Noël T. Accoceberry I. Lindnera (Pichia) fabianii blood infection after mesenteric ischemia Med. Mycol. 50 3 2012 310 314 21671831 \n17 Lee J.I. Yu S. Park J.S. Joo E. Shin J.H. Kwon M. Successful treatment of fungemia caused by Cyberlindnera fabianii with anidulafungin: a case report Ann. Clin. Microbiol. 18 3 2015 94 97 \n18 Fernández-Ruiz M. Guinea J. Puig-Asensio M. Zaragoza O. Almirante B. Cuenca-Estrella M. Fungemia due to rare opportunistic yeasts: data from a population-based surveillance in Spain Med. Mycol. 55 2 2017 125 136 27495321 \n19 Cooper N. Arnold D.M. The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases Br. J. Haematol. 149 1 2010 3 13 20151975 \n20 van Oers M.H. Klasa R. Marcus R.E. Wolf M. Kimby E. Gascoyne R.D. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial Blood 108 10 2006 3295 3301 16873669 \n21 Rafailidis P. Kakisi O. Vardakas K. Falagas M.E. Infectious complications of monoclonal antibodies used in cancer therapy: a systematic review of the evidence from randomized controlled trials Cancer 109 11 2007 2182 2189 17429839 \n22 Annich G. Lynch W. MacLaren G. Wilson J. Bartlett R. ECMO: Extracorporeal Cardiopulmonary Support in Critical Care fourth ed. 2012 Extracorporeal Life Support Ann Arbor \n23 Svobodova L. Bednarova D. Ruzicka F. Chrenkova V. Dobi as R. Mallatova N. High frequency of Candida fabianii among clinical isolates biochemically identified as Candida pelliculosa and Candida utilis Mycoses 59 4 2016 241 246 26763103\n\n",
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"title": "Multiple organ dysfunction syndrome and death secondary to Cyberlindnera fabianii.",
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"abstract": "Although calciphylaxis generally occurs in patients with chronic renal failure, we present a patient with widespread calciphylaxis in the setting of normal renal function following renal transplant. IV and IL sodium thiosulfate injections were not beneficial in our patient.",
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"mesh_terms": "D000328:Adult; D001706:Biopsy; D002115:Calciphylaxis; D002614:Chelating Agents; D051799:Delayed Graft Function; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006801:Humans; D007275:Injections, Intravenous; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D006435:Renal Dialysis; D012867:Skin; D012871:Skin Diseases; D013885:Thiosulfates",
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"title": "Widespread calciphylaxis and normal renal function: no improvement with sodium thiosulfate.",
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"abstract": "We aimed to define the clinical presentations, course and outcome of cholestasis in infants with Down syndrome (trisomy 21) who presented to the Pediatric Hepatology Clinic, New Children Hospital, Cairo University, Egypt.\nRetrospective analysis of data of cohort of infants with Down syndrome and cholestasis who followed up during 2005-2015.\nAmong 779 infants with cholestasis who presented during 2005-2015, 61 (7.8%) had Down syndrome. Six dropped out. Among the 55 who followed-up for a mean duration +SD = 12.1 ± 16.7 months, none had extrahepatic biliary atresia (EHBA), 37 (63.3%) had neonatal hepatitis and 18 (32.7%) had non-syndromic paucity of intrahepatic biliary radicals. Fourteen (25.4%) had associated congenital heart disease. Only 35 (63.3%) cleared the jaundice. Twenty-nine (52.7%) received ursodeoxycholic acid (UDCA); of them, 13 cleared the jaundice, one improved, 14 progressed and one died, compared to 22 who cleared the jaundice of the 26 who did not receive UDCA. Only three of those who did not receive UDCA progressed and none died. UDCA carried a 3.4-fold risk of poor prognosis (p= 0.001). UDCA use was associated with more complications (p= 0.016) in those with Down syndrome and cholestasis.\nWe did not come across EHBA among neonates and infants with Down syndrome in 10 years. Non-syndromic paucity is associated with favorable outcome in infants with Down syndrome. UDCA use in cholestasis with Down syndrome is associated with poor outcome.",
"affiliations": "Pediatrics Department, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt.;Pediatrics Department, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt.;Pediatrics Department, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt.;Pediatrics Department, Public Mounira Hospital, Cairo, Egypt.;Department of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Department of Pediatric Surgery, Cairo University, Cairo, Egypt.;Pediatrics Department, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt.;Pediatrics Department, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt.",
"authors": "Kotb|Magd A|MA|0000-0001-5928-8684;Draz|Iman|I|;Basanti|Christine Ws|CW|0000-0002-3149-9233;El Sorogy|Sally Tm|ST|;Abd Elkader|Hesham M|HM|0000-0002-5612-1157;Esmat|Haytham|H|;Abd El Baky|Hend|H|;Mosallam|Dalia Sayed|DS|",
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"fulltext": "\n==== Front\nClin Exp GastroenterolClin Exp GastroenterolCEGcegClinical and Experimental Gastroenterology1178-7023Dove 21618910.2147/CEG.S216189Original ResearchCholestasis In Infants With Down Syndrome Is Not Due To Extrahepatic Biliary Atresia: A Ten-Year Single Egyptian Centre Experience Kotb et alKotb et alhttp://orcid.org/0000-0001-5928-8684Kotb Magd A 1Draz Iman 1http://orcid.org/0000-0002-3149-9233Basanti Christine WS 1El Sorogy Sally TM 2http://orcid.org/0000-0002-5612-1157Abd Elkader Hesham M 3Esmat Haytham 4Abd El Baky Hend 1Mosallam Dalia Sayed 11 Pediatrics Department, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt2 Pediatrics Department, Public Mounira Hospital, Cairo, Egypt3 Department of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt4 Department of Pediatric Surgery, Cairo University, Cairo, EgyptCorrespondence: Dalia Sayed Mosallam Pediatrics Department, Faculty of Medicine, Cairo University, Al Manial, Cairo11562, EgyptTel +20 2 33386592 Email daliamosalam@kasralainy.edu.eg22 10 2019 2019 12 401 408 17 5 2019 03 9 2019 © 2019 Kotb et al.2019Kotb et al.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).Purpose\nWe aimed to define the clinical presentations, course and outcome of cholestasis in infants with Down syndrome (trisomy 21) who presented to the Pediatric Hepatology Clinic, New Children Hospital, Cairo University, Egypt.\n\nMethods\nRetrospective analysis of data of cohort of infants with Down syndrome and cholestasis who followed up during 2005–2015.\n\nResults\nAmong 779 infants with cholestasis who presented during 2005–2015, 61 (7.8%) had Down syndrome. Six dropped out. Among the 55 who followed-up for a mean duration +SD = 12.1 ± 16.7 months, none had extrahepatic biliary atresia (EHBA), 37 (63.3%) had neonatal hepatitis and 18 (32.7%) had non-syndromic paucity of intrahepatic biliary radicals. Fourteen (25.4%) had associated congenital heart disease. Only 35 (63.3%) cleared the jaundice. Twenty-nine (52.7%) received ursodeoxycholic acid (UDCA); of them, 13 cleared the jaundice, one improved, 14 progressed and one died, compared to 22 who cleared the jaundice of the 26 who did not receive UDCA. Only three of those who did not receive UDCA progressed and none died. UDCA carried a 3.4-fold risk of poor prognosis (p= 0.001). UDCA use was associated with more complications (p= 0.016) in those with Down syndrome and cholestasis.\n\nConclusion\nWe did not come across EHBA among neonates and infants with Down syndrome in 10 years. Non-syndromic paucity is associated with favorable outcome in infants with Down syndrome. UDCA use in cholestasis with Down syndrome is associated with poor outcome.\n\nKeywords\ncholestasisextrahepatic biliary atresiaEHBAneonatal hepatitisDown syndrometrisomy 21ursodeoxycholic acidUDCA\n==== Body\nIntroduction\nDown syndrome (trisomy 21) is associated with congenital anomalies in 64% of cases. The cardiac anomalies are commonest, followed by digestive system, musculoskeletal system, urinary system, respiratory and other system anomalies.1 Estimated worldwide incidence of Down syndrome is 1:1,000–1:1,100, 0.827:1000 in USA2 and 1.8:1000–1.6:1000 in Egypt.3 Cholestasis was reported to affect 3.9% of neonates and infants with Down syndrome in a population-based study.4 The cholestasis in Down syndrome was reported to be due to the probability of a smaller circulating bile acid pool size, a lower rate of synthesis, reduced recirculation of bile acids and immature function of the canalicular bile acid transporting system.5 The increased susceptibility of cholestasis in Down syndrome was not mapped to chromosome 21, i.e. major genes controlling the uptake, synthesis, or secretion of bile acids in human hepatocytes, synthesis, or ileal enterocytes.6 The aim of this study was to define the spectrum of clinical presentations, course and outcome of cholestasis in infants with Down syndrome.\n\nSubjects And Methods\nSubjects\nThis is an observational study that included a retrospective analysis of data of a cohort of infants with Down syndrome and cholestasis who followed up during 2005–2015 at the Pediatric Hepatology Clinic, New Children Hospital, Cairo University, Egypt. The study was approved by the Pediatric Department Committee for Post-Graduate Studies and Research, and by the Post-Graduate Studies and Research Administration, Faculty of Medicine, Cairo University, Egypt. Parental approval was not applicable to this retrospective, observational, non-interventional cohort study.7 The study complies with the Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects.8\n\nMethods\nWe revised all files of neonates and infants who presented with cholestasis and clinical features of Down syndrome (trisomy 21) during 2005–2015. We analyzed all data of recruited children, including the history of age at onset of symptoms, age at presentation, presenting symptom, complications and/or associations of liver disease, neurologic disease, age of the patient at the time of the study, weight and height percentiles, and outcome. Anthropometric measures were plotted against Egyptian percentiles for children with Down syndrome weight and height3 and recorded as percentiles for age.\n\nEtiology of cholestasis was studied according to clinical judgment, i.e., virology, bile acids, metabolic screen, imaging and liver biopsy.\n\nThe outcome was graded into resolved, improved, stationary, progressive and death. The resolved outcome was when the cholestasis resolved without sequelae; improved, with an improvement of cholestasis but did not resolve completely; stationary was coined to those who did not improve or deteriorate; while progressive was coined to those where cholestasis increased.\n\nStatistical Analysis\nAll the statistical analyses in this study were conducted using the Statistical Package for Social Sciences version 19 (SPSS, Chicago, IL). Simple frequency, cross-tabulation, descriptive analysis, tests of significance (t-test for parametric data and χ2 tests for non-parametric numbers N5), and correlations were employed.\n\nResults\nDuring 2005–2015 only 61 infants with Down syndrome presented to the Pediatric Hepatology Clinic, Cairo University. Six (9.2%) dropped out and did not show up for a second visit; they were all females (Figure 1). The other 55 were followed up for 12.1 ± 16.7 months. Of them, 28 (51%) were females and 27 (49%) males. Mean ± SD age at onset of cholestasis was 1.23 ± 11.78 months, and at presentation to our medical attention was 2.1 ± 9.2 months. Seventeen (30.1%) were the product of a consanguineous marriage. Fifteen (27.3%) had a history of another family member affected by cholestasis. The symptoms, signs of the studied cohort, their serum bilirubin and liver enzymes are shown in Tables 1 and 2, respectively. Liver biopsy was performed in 32 (58.2%) subjects and the findings are shown in Table 2.Table 1 Clinical Findings In Down Syndrome Cohort With Cholestasis\n\n\tNumber Of Affected Children\tPercent\t\nVomiting\tPresent\t2\t3.6\t\nAbsent\t53\t96.4\t\nDiarrhea\tPresent\t1\t1.8\t\nAbsent\t54\t98.2\t\nAbdominal Distension\tPresent\t22\t40\t\nAbsent\t3\t5.5\t\nSepsis\tPresent\t1\t1.8\t\nAbsent\t54\t98.2\t\nDark Urine\tPresent\t25\t45.5\t\nAbsent\t30\t54.5\t\nClay-Colored Stools\tPresent\t8\t14.5\t\nAbsent\t47\t85.5\t\nPruritus\tPresent\t6\t10.9\t\nAbsent\t49\t89.1\t\nScratch Marks\tPresent\t7\t12.7\t\nAbsent\t48\t87.3\t\nHepatomegaly\tPresent\t20\t36.36\t\nAbsent\t35\t63.6\t\nSplenomegaly\tPresent\t22\t40\t\nAbsent\t33\t60\t\nCardiac Anomalies\tPFO\t3\t5.5\t\nASD\t3\t5.5\t\nVSD\t2\t3.6\t\nCombined ASD + VSD\t6\t10.9\t\nTotal\t14\t25.5\t\nAbsent\t41\t74.5\t\n\nTable 2 Laboratory And Liver Biopsy Findings In Down Syndrome Cohort With Cholestasis\n\nLaboratory Findings\t\n\tRange\tMean ± SD\t\nTotal bilirubin (mg%)\t4–10.7\t6.48± 1.81\t\nDirect bilirubin (mg%)\t3–9.7\t4.1± 1.67\t\nALT\t0.65–18.15\t5.45± 3.99\t\nAST\t0.97–26.21\t7.55± 5.14\t\nLiver Biopsy Findings in 32 Children\t\n\tNumber\tPercent\t\nHepatocytes\tNormal\t7\t21.9\t\nDiffuse Ballooning\t25\t78.1\t\nInfiltration by Inflammatory Cells\tPresent\t28\t87.5\t\nAbsent\t4\t12.5\t\nBile Duct Proliferation\tPresent\t23\t71.8\t\nAbsent\t9\t28.1\t\nPaucity of Intrahepatic Biliary Radicals\tPresent\t18\t56.26\t\nAbsent\t14\t43.75\t\nKupffer Cells (Stellate Macrophages)\tNormal\t11\t20\t\nHyperplastic\t21\t38.2\t\nArchitecture\tIntact\t32\t100\t\nDistorted\t0\t0\t\nFibrosis\tPresent\t2\t6.25\t\nAbsent\t30\t93.75\t\nHepatic Veins\tNormal\t5\t15.62\t\nDistended\t27\t84.37\t\nNote: ALT and AST were calculated in folds of the upper level of normal.\n\nAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Number, number of affected children; SD, standard deviation.\n\n\nFigure 1 Flowchart of studied cohort of neonates and infants with Down syndrome and cholestasis.\n\n\n\nAssociated congenital cardiac anomalies were encountered in 14 (25.4%) children (Table 1). No other anomalies were encountered in our studied cohort. None had any bone marrow-associated disease.\n\nEtiology and outcome of cholestasis in the studied cohort of neonates and infants with down syndrome are shown in Figures 2 and 3, respectively.\n\nNone of the affected infants had EHBA, 37 (67.3%) had neonatal hepatitis and 18 (32.7%) suffered from non-syndromic paucity of intrahepatic biliary radicals. Cholestasis resolved in 35 (63.6%). None tested positive for viral screening known to cause neonatal hepatitis or metabolic workup and none had progressive familial intrahepatic cholestasis (Figure 2). One child had massive fibrosis, with unidentified underlying pathology, suggesting congenital hepatic fibrosis. Figure 1 depicts the diagnosis and outcome of the studied cohort. They all received fat-soluble vitamin supplements and 29 (52.72%) received UDCA also. Of them, 21 (72.4%) suffered from complications. Both those who received UDCA and those who did not were matched as regards severity of cholestasis (p= 0.17). UDCA use was associated with poorer outcome (p= 0.000) and complications (p= 0.016) (Table 3). UDCA in neonates with Down syndrome and cholestasis carried a 3.4-fold risk of poor prognosis (p= 0.001) (95% confidence interval) (Figure 3).Table 3 Outcome And Associated Complications Of The Cohort With Down Syndrome And Cholestasis According To Etiology, UDCA Intake And Association Of Congenital Heart Disease\n\nOutcome\tPvalue\t\nAccording to Etiology of Cholestasis\t\n\tHepatitis N= 37\tPIBD N= 18\t\t\nResolved Cholestasis\t35\t18\t17\t0.012\t\nImproved\t2\t2\t0\t\nProgression\t17\t16\t1\t\nDeath\t1\t1\t0\t\nAccording to Intake of UDCA\t\n\tReceived UDCA\nN= 29\tNo UDCA\nN= 26\t\t\nResolved Cholestasis\t35\t13\t22\t0.016\t\nImproved\t2\t1\t1\t\nProgression\t17\t14\t3\t\nDeath\t1\t1\t0\t\t\nAssociated Cardiac Anomaly\t\n\tYes\nN= 14\tNone\nN= 41\t\t\nResolved Cholestasis\t35\t6\t29\t0.215\t\nImproved\t1\t1\t0\t\nProgression\t17\t7\t10\t\nDeath\t1\t0\t1\t\t\nComplications in Studied Cohort of Down Syndrome\tP\t\n\tTotal\tReceived UDCA\nN= 29\tNo UDCA\nN= 26\t\t\nRecurrent Diarrhea\tYes\t10\t10\t0\t0.001\t\nNone\t45\t19\t26\t\nTotal\t55\t29\t26\t\nOtitis Media\tYes\t2\t2\t0\t0.2\t\nNone\t53\t27\t26\t\nTotal\t55\t29\t26\t\nPneumonia\tYes\t6\t6\t0\t0.016\t\n\tNone\t49\t23\t26\t\t\n\tTotal\t55\t29\t26\t\t\nBronchitis\tYes\t9\t0\t9\t0.002\t\nNone\t20\t26\t46\t\nTotal\t29\t26\t55\t\nIntractable Pruritus\tYes\t1\t0\t1\t0.33\t\nNone\t28\t26\t54\t\nTotal\t29\t26\t55\t\nNote: All neonates with congenital cardiac anomaly had neonatal hepatitis.\n\n\nFigure 2 Etiology of Cholestasis in Down syndrome. None had biliary atresia.\n\nFigure 3 The outcome of Cholestasis in Down syndrome. UDCA use was associated with poor outcome (p= 0.000).\n\n\n\nDiscussion\nDuring 2005–2015, 7.8% of the neonates and infants who presented with cholestasis to the Pediatric Hepatology Clinic, Faculty of Medicine, Cairo University had the Down syndrome (trisomy 21) phenotype. Clinically, cholestasis was mostly without organomegaly, where only 36.5% and 40% had hepatomegaly and splenomegaly, respectively. The outcome was generally favorable unless UDCA was given.\n\nCongenital Heart Disease Was Encountered In Only 25% Of Cases And None Had Cyanotic Heart Disease\nDown syndrome is associated with congenital heart disease (CHD) in 40–60%,9–11 with a dramatic increase from about 20% in the early 1970s to more than 50% in the late 1980s (p = 0.0001) in certain areas.12 In Egypt, studies of the prevalence of CHD in Down syndrome are limited, but the reported range was almost 40%.13,14 It is not clear why our cohort had less CHD compared to other populations of Down syndrome. More studies are required to establish or refute a protective effect of placental metabolism of environmental factors that are responsible for the development of CHD in a developing fetus with Down syndrome and/or cholestasis. The sample size is small, however, to draw sound conclusions, yet it remains an observation that CHD is less prevalent among Down syndrome with cholestasis, and the CHD spectrum did not include cyanotic heart disease.\n\nWe Did Not Come Across A Single Case Of EHBA In Down Syndrome During The 10 Years 2005–2015\nThis comes in congruence with previous literature, as we failed to find any previous reports of Down syndrome associated with EHBA. Kotb recently defined EHBA as aflatoxin-induced cholangiopathy in neonates with GST M1 null deficiency, while damage to bile ducts was mediated through neutrophil elastase. Damage control of the aflatoxin-induced cholangiopathy through neutrophil elastase ends in fibrosis and obliteration of extrahepatic bile ducts.15 Factors involved in the etiology of EHBA were not sought in this cohort, i.e., aflatoxins, glutathione S transferase M1, p53 and neutrophil functions. It seems that Down syndrome protects against the development of biliary atresia. This protective role might be due to compromised neutrophil function in Down syndrome,16,17 which might arrest the inflammatory process of EHBA.\n\nPaucity Of Intrahepatic Biliary Radicals Has Excellent Prognosis In Down Syndrome\nGenerally, paucity of intrahepatic biliary radicals has a 69% chance of clearance of cholestasis in absence of UDCA intake,18 yet 94.4% of our cohort of neonates and infants with Down syndrome with paucity of intrahepatic biliary radicals cleared the cholestasis. Again, it seems that Down syndrome enhances clearance of cholestasis. This effect could be attributed to the compromised immunity in Down syndrome; this compromise will not mount massive destructive effect in the cholestasis inflammatory process.19\n\nWe Could Not Identify The Etiology Of Neonatal Hepatitis In Down Syndrome\nThe etiology of cholestasis of all of our studied neonates and infants with Down syndrome was idiopathic hepatitis, despite undergoing the battery of investigations to identify etiology (metabolic, congenital and infectious) when appropriate according to clinical situation.18 The etiology of neonatal cholestasis in our studied cohort remained idiopathic, with no overlap in etiology. We did not come across any cases of cystic fibrosis, infections, or galactosemia or any other etiology in our cohort with Down syndrome.\n\nUDCA Is Not Effective And Is Not Safe In Cholestasis In Down Syndrome\nUDCA was found to be ineffective in clearing cholestasis in neonates and infants with Down syndrome, and its use was associated with significantly worse outcome. UDCA compromised the outcome of those with Down and cholestasis – only 44.8% of those who received UDCA resolved the cholestasis, compared to 84.6% of those who did not receive UDCA. UDCA generally impedes resolution of cholestasis in neonatal hepatitis compared to no UDCA (44.8% compared to 70.2%, respectively).18 The discouraging effect of UDCA is exaggerated in our studied cohort. It is not clear why UDCA is more toxic in neonates with Down syndrome and cholestasis. The UDCA toxicity in cholestasis in Down syndrome might be attributed to their compromised detoxification of medications, e.g., methotrexate, glucocorticoids, anthracyclines, etc.20 It might be related to trisomy 21 type karyotyping or other genetic makeup that needs further investigation.\n\nConclusion\nCholestasis complicates Down syndrome. We did not come across EHBA among our studied cohort in 10 years. Down syndrome seems to protect against the development of EHBA. Use of UDCA in cholestasis associated with Down syndrome compromises resolution of cholestasis and its use is associated with poor prognosis. UDCA use in cholestasis associated with Down syndrome should be contraindicated.\n\nAcknowledgments\nWe acknowledge all Pediatric Hepatology Team Members and archiving secretaries of the Pediatric Hepatology Clinic, New Children Hospital, Cairo University Hospital, Cairo University. There was no funding source for this study. The trial was approved by the Pediatric Department Committee for Post-Graduate Studies and Research, and by Post-Graduate Studies and Research Administration, Faculty of Medicine, Cairo University, Cairo, Egypt. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and statistical analysis.\n\nAbbreviations\nALT, alanine aminotransferase; AST, aspartate aminotransferase; CHD, congenital heart disease; D.Bil, direct bilirubin; EHBA, extrahepatic biliary atresia; SD, standard deviation; T.Bil, total bilirubin; UDCA, ursodeoxycholic acid.\n\nCompliance With Ethical Statements\nThis article does not contain any studies with human participants or animals performed by any of the authors. It is a retrospective study including all files of neonates and infants who presented with cholestasis and clinical features of Down syndrome (trisomy 21) during 2005–2015. The study was approved by The Pediatric Department Committee for Post-Graduate Studies and Research, and by Post-Graduate Studies and Research Administration, Faculty of Medicine, Cairo University, Egypt.\n\nWhat Is Known?\nExclusion of surgical causes of cholestasis is invasive, yet it is part of workup in every neonate with cholestasis as surgical portoenterostomy should not be delayed beyond 3 months of age to halt the march of biliary cirrhosis.\n\nCholestasis associated with trisomy 21 (Down syndrome) has been reported previously.\n\n\n\n\nWhat Is New?\nCholestasis in Down syndrome was never found to be due to biliary atresia; we did not come across a single obstructive cholestasis in Down syndrome in 10 years of practice.\n\nGenerally, the outcome of cholestasis is favorable in Down syndrome, especially if the etiology of cholestasis is non-syndromic paucity, unless they receive ursodeoxycholic acid, as its' use is associated with poor outcome, complications and fatality.\n\n\n\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Stoll \nC , Dott \nB , Alembik \nY , Roth \nMP . Associated congenital anomalies among cases with Down syndrome . Eur J Med Genet . 2015 ;58 :674 –680 . doi:10.1016/j.ejmg.2015.11.003 26578241 \n2. Presson \nAP , Partyka \nG , Jensen \nKM , et al. Current estimate of Down Syndrome population prevalence in the United States . J Pediatr . 2013 ;163 (4 ):1163 –1168 . doi:10.1016/j.jpeds.2013.06.013 23885965 \n3. Afifi \nHH , Aglan \nMS , Zaki \nME , Thomas \nMM , Tosson \nAM . Growth charts of Down syndrome in Egypt: a study of 434 children 0–36 months of age . Am J Med Genet A . 2012 ;158A (11 ):2647 –2655 . doi:10.1002/ajmg.a.35468 22811286 \n4. Arnell \nH , Fischler \nB . Population-based study of incidence and clinical outcome of neonatal cholestasis in patients with Down syndrome . J Pediatr . 2012 ;161 :899 –902 . doi:10.1016/j.jpeds.2012.04.037 22658787 \n5. Suchy \nFJ , Balistreri \nWF , Heubi \nJE , Searcy \nJE , Levin \nRS . Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants . Gastroenterology . 1981 ;80 :1037 –1041 . doi:10.1016/0016-5085(81)90078-0 7202962 \n6. Halilbasic \nE , Claudel \nT , Trauner \nM . Bile acid transporters and regulatory nuclear receptors in the liver and beyond . J Hepatol . 2013 ;58 :155 –168 . doi:10.1016/j.jhep.2012.08.002 22885388 \n7. WHO International Standards for Clinical Trial Registries . ISBN 978 92 4 150429 4 (NLM classification: QV 771.4) ; 2012 \nAvailable from : https://apps.who.int/iris/bitstream/handle/10665/76705/9789241504294_eng.pdf;jsessionid=2DA15341BDC67DFDEDE8FC1E1F8B93D5?sequence=1\nAccessed 9 12 , 2019. doi:10.1094/PDIS-11-11-0999-PDN \n8. WMA DECLARATION OF HELSINKI . WMA declaration of Helsinki - ethical principles for medical research involving human subjects, 64th. WMA general assembly ; 2013 \nAvailable from \nhttps://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/\nAccessed 9 12 , 2019.\n9. Elmagrpy \nZ , Rayani \nA , Shah \nA , Habas \nE , Aburawi \nEH . Down syndrome and congenital heart disease: why the regional difference as observed in the Libyan experience? \nCardiovasc J Afr . 2011 ;22 :306 –309 . doi:10.5830/CVJA-2010-072 22159317 \n10. Kim \nMA , Lee \nYS , Yee \nNH , Choi \nJS , Choi \nJY , Seo \nK . Prevalence of congenital heart defects associated with down syndrome in Korea . J Korean Med Sci . 2014 ;29 :1544 –1549 . doi:10.3346/jkms.2014.29.11.1544 25408587 \n11. Morsy \nMM , Algrigri \nOO , Salem \nSS , Abosedera \nMM , Abutaleb \nAR , Al-Harbi \nKM . The spectrum of congenital heart diseases in down syndrome: a retrospective study from Northwest Saudi Arabia . Saudi Med J . 2016 ;37 :767 –772 . doi:10.15537/smj.2016.7.14536 27381537 \n12. Khoury \nMJ , Erickson \nJD . Improved ascertainment of cardiovascular malformations in infants with Down’s syndrome, Atlanta, 1968 through 1989. Implications for the interpretation of increasing rates of cardiovascular malformations in surveillance systems . Am J Epidemiol . 1992 ;136 :1457 –1464 . doi:10.1093/oxfordjournals.aje.a116466 1288275 \n13. Afifi \nHH , Abdel Azeem \nAA , El-Bassyouni \nHT , Gheith \nME , Rizk \nA , Bateman \nJB . Distinct ocular expression in infants and children with down syndrome in Cairo . EgyptMyopia Heart Dis JAMA Ophthalmol . 2013 ;131 :1057 –1066 . doi:10.1001/jamaophthalmol.2013.644 \n14. Mokhtar \nMM , Abdel-Fattah \nM . Major birth defects among infants with Down’s syndrome in Alexandria, Egypt (1995–2000) . J Trop Pediatr . 2002 ;48 :247 –249 . doi:10.1093/tropej/48.4.247 12200989 \n15. Kotb \nMA , Kotb \nA . Extrahepatic biliary atresia is an aflatoxin induced cholangiopathy in infants with null GSTM1 genotype with disrupted P53 and GSTPi to mothers heterozygous for GSTM1 polymorphism: damage control is mediated through neutrophil elastase and CD14+ activated monocytes: kotb disease . Med J Cairo Univ . 2015 ;83 :137 –145 .\n16. Rascón Trincado \nMV , Lorente Toledano \nF , Villalobos \nVS . A study of the functions of polymorphonuclear neutrophil in patients with Down’s syndrome . Allergol Immunopathol (Madr) . 1988 ;16 :339 –345 .2976258 \n17. Novo \nE , García \nMI , Lavergne \nJ . Nonspecific immunity in Down syndrome: a study of chemotaxis, phagocytosis, oxidative metabolism, and cell surface marker expression of polymorphonuclear cells . Am J Med Genet . 1993 ;46 :384 –391 . doi:10.1002/ajmg.1320460408 7689298 \n18. Kotb \nMA . Ursodeoxycholic acid in neonatal hepatitis and infantile paucity of intrahepatic bile ducts: review of a historical cohort . Dig Dis Sci . 2009 ;54 :2231 –2241 . doi:10.1007/s10620-008-0600-8 19082720 \n19. Ram \nG , Chinen \nJ . Infections and immunodeficiency in Down syndrome . Clin Exp Immunol . 2011 ;164 :9 –16 . doi:10.1111/j.1365-2249.2011.04335.x 21352207 \n20. Alaama \nJY , Ahmad \nMS , Ahmad \nS , Damanhouri \nZA . Altered Metabolism in down Syndrome, Health Problems in down Syndrome . Subrata Dey, IntechOpen ; 2015 \nAvailable from \nhttps://www.intechopen.com/books/health-problems-in-down-syndrome/altered-metabolism-in-down-syndrome. doi:10.5772/60638\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7023",
"issue": "12()",
"journal": "Clinical and experimental gastroenterology",
"keywords": "Down syndrome; EHBA; UDCA; cholestasis; extrahepatic biliary atresia; neonatal hepatitis; trisomy 21; ursodeoxycholic acid",
"medline_ta": "Clin Exp Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101532800",
"other_id": null,
"pages": "401-408",
"pmc": null,
"pmid": "31695469",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "27381537;7202962;22658787;22811286;21352207;7689298;25408587;19082720;22885388;23885965;22159317;23764677;12200989;26578241;1288275;2976258",
"title": "Cholestasis In Infants With Down Syndrome Is Not Due To Extrahepatic Biliary Atresia: A Ten-Year Single Egyptian Centre Experience.",
"title_normalized": "cholestasis in infants with down syndrome is not due to extrahepatic biliary atresia a ten year single egyptian centre experience"
} | [
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"abstract": "Intravenous lipid emulsion (ILE) is an emerging therapy for refractory cardiotoxicity due to lipid-soluble drugs. The purpose of this study was to assess survival to hospital discharge, effects on hemodynamic parameters, and adverse event occurrence for patients who were treated with ILE as part of the resuscitative effort for drug-induced cardiotoxicity. This is a multicenter retrospective chart review of inpatients at three tertiary referral medical centers receiving ILE for drug-induced cardiotoxicity between November 2007 and March 2009. Nine cases with drug-induced cardiovascular collapse, defined as cardiac arrest or refractory shock, were selected for review if patients received either bolus or infusion of ILE in any combination. No interventions were done. The main outcome measures were survival to hospital discharge, effect on hemodynamic parameters, and adverse event. Hemodynamic vital signs (heart rate, systolic blood pressure, diastolic blood pressure, calculated mean arterial pressure [MAP]) were measured before administration of ILE and up to five measurements (if available) were recorded after administration of ILE. Attribution of adverse events was determined by assignment of Naranjo adverse drug reaction (ADR) likelihood score (3) with adjudication of three medical toxicologists; disagreements were settled by majority consensus. Of nine cases identified based on inclusion criteria (three cardiac arrest, six refractory shock), five (55%) survived to hospital discharge. ILE regimens were bolus alone in five patients and bolus plus infusion in four patients. Hemodynamic trends in response to ILE demonstrated no difference in MAP immediately pre- and post-administration of ILE (p = NS). Administration of infusion (versus boluses alone) did not demonstrate a statistically significant improvement in MAP. Adverse events due to ILE therapy that were categorized as \"possible\" or \"probable\" based on Naranjo scores included lipemia, digit amputation, lung injury, renal failure, and deep venous thrombosis. ILE administered to patients with drug-induced cardiovascular collapse was associated with 55% survival but with clinically significant adverse effects. At this time, ILE should be restricted to cardiotoxicity involving cardiac arrest or refractory shock until further prospective studies can better evaluate risks and benefits of ILE therapy.",
"affiliations": "Medical Toxicology Program, Department of Emergency Medicine, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. ajgeib@hotmail.com",
"authors": "Geib|Ann-Jeannette|AJ|;Liebelt|Erica|E|;Manini|Alex F|AF|;|||",
"chemical_list": "D005217:Fat Emulsions, Intravenous",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-011-0187-x",
"fulltext": null,
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"issue": "8(1)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012769:Shock",
"nlm_unique_id": "101284598",
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"pages": "10-4",
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"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "20095812;7249508;16029240;9579517;19252304;14656749;17259402;19845549;19704251;18769973;2403233;18950612",
"title": "Clinical experience with intravenous lipid emulsion for drug-induced cardiovascular collapse.",
"title_normalized": "clinical experience with intravenous lipid emulsion for drug induced cardiovascular collapse"
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{
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"activesubstancename": "LISINOPRIL"
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{
"abstract": "For extracranial malignant germ cell tumours (MGCTs) in the UK, the GCII study used carboplatin-based chemotherapy (JEb) and demonstrated equivalent survival to cisplatin-containing protocols. GCIII, a single-arm observational study, used new risk stratification, replaced consolidation chemotherapy with a standard number of cycles and introduced surveillance for all stage I MGCTs. Pure teratomas were registered to understand their natural history.\n\n\n\nPatients with MGCTs were stratified to three risk groups - low risk (LR), intermediate risk (IR) and high risk (HR), using stage and prognostic factors. Patients with alpha fetoprotein (AFP) >10,000 kU/L, stage IV disease (except testis <5 years and all germinomas) or stage II-IV mediastinal tumour were classified HR. Stage I tumours (LR) received chemotherapy only if disease progressed. IR and HR patients received 4 and 6 JEB cycles, respectively. Carboplatin dose was calculated using glomerular filtration rate to give an area under the curve of 7.9 ml/m2.min.\n\n\n\nEighty-six patients with MGCTs were enrolled from 2005 to 2009: 59% female, median age, 5.7 years. Twenty-five patients were LR, 21 IR and 38 HR. Seven LR patients had disease progression; all were successfully treated with chemotherapy. Overall survival (OS) for the whole group was 97%; 5-year event-free survival for JEb-treated patients was 92%, and OS, 95%. JEb was well tolerated with no observed significant hearing or renal side-effects. There was no discernible difference in carboplatin dose whether calculated by body surface area or creatinine clearance. Forty-seven patients with teratoma were managed with surgery and one had malignant transformation.\n\n\n\nCarboplatin-based chemotherapy as part of a risk-stratified approach leads to excellent survival in paediatric MGCTs, minimising potential burden of long-term effects.",
"affiliations": "Children's Cancer Team, Cancer Research Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham, UK. Electronic address: s.depani@bham.ac.uk.;Children and Young Persons Cancer Services, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London, UK. Electronic address: Sara.stoneham@nhs.net.;Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Statistics and Data Centre, Children's Oncology Group, Monrovia, CA, USA. Electronic address: mkrailo@childrensoncologygroup.org.;Statistics and Data Centre, Children's Oncology Group, Monrovia, CA, USA. Electronic address: cxia@childrensoncologygroup.org.;Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. Electronic address: james.nicholson@addenbrookes.nhs.uk.",
"authors": "Depani|Sarita|S|;Stoneham|Sara|S|;Krailo|Mark|M|;Xia|Caihong|C|;Nicholson|James|J|",
"chemical_list": "D016190:Carboplatin; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2019.05.001",
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"issue": "118()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Carboplatin; Germ cell; Late effects; Paediatric",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal; D009919:Orchiectomy; D010051:Ovarian Neoplasms; D010052:Ovariectomy; D000077982:Progression-Free Survival; D018570:Risk Assessment; D012307:Risk Factors; D013724:Teratoma; D013736:Testicular Neoplasms; D013997:Time Factors; D006113:United Kingdom",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "49-57",
"pmc": null,
"pmid": "31306943",
"pubdate": "2019-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Results from the UK Children's Cancer and Leukaemia Group study of extracranial germ cell tumours in children and adolescents (GCIII).",
"title_normalized": "results from the uk children s cancer and leukaemia group study of extracranial germ cell tumours in children and adolescents gciii"
} | [
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"companynumb": "GB-TEVA-2019-GB-1090772",
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"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
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"drugadditional": "3",
... |
{
"abstract": "Trimethoprim-sulfamethoxazole (TMP/SMX) is a bactericidalantibiotic. The most common adverse effect of TMP/SMX is skinrashes and gastrointestinal symptoms. Although hyperkalemia canoccur with TMP/SMX component but hyponatremia is uncommon. A55- year old woman, known case of rheumatoid arthritis, presentedwith fever and mild dyspnea. According to diagnostic work upthe infection with pneumocystis jirovecii was confirmed. TMP/SMX was started but after 10 days the patient acutely representedwith nausea and became lethargic. The laboratory studies showedmoderate hyperkalemia and severe hyponatremia. TMP/SMX wasstopped and alternative treatment started. Upon discontinuation ofthe drug, serum sodium and potassium levels were both changed tonormal. Hyponatremia as a life threatening adverse effect appearsto be rare with TMP-SMX therapy, but clinicians should be awareof electrolyte disturbances developed with this drug and electrolytemonitoring should always be considered.",
"affiliations": "Department of Infectious Diseases, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. a.hakamifard@med.mui.ac.ir.",
"authors": "Khorvash|Farzin|F|;Moeinzadeh|Firouzeh|F|;Saffaei|Ali|A|;Hakamifard|Atousa|A|",
"chemical_list": "D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1735-8582",
"issue": "13(4)",
"journal": "Iranian journal of kidney diseases",
"keywords": null,
"medline_ta": "Iran J Kidney Dis",
"mesh_terms": "D005260:Female; D006801:Humans; D006947:Hyperkalemia; D007010:Hyponatremia; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "101316967",
"other_id": null,
"pages": "277-280",
"pmc": null,
"pmid": "31422395",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trimethoprim-sulfamethoxazole Induced Hyponatremia and Hyperkalemia, The Necessity of Electrolyte Follow-up in Every Patient.",
"title_normalized": "trimethoprim sulfamethoxazole induced hyponatremia and hyperkalemia the necessity of electrolyte follow up in every patient"
} | [
{
"companynumb": "IR-VISTA PHARMACEUTICALS INC.-2081338",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "BACKGROUND\nAlemtuzumab is a treatment for highly active multiple sclerosis (MS). Immunosuppression is considered a risk factor for SARS-CoV-2 infection and there is still lack of evidence to guide MS practice.\n\n\nRESULTS\nWe describe the clinical and immunological evolution of two MS patients under alemtuzumab treatment who were affected by COVID-19, one of them only one week after receiving her last dose, and both recovered without sequelae.\n\n\nCONCLUSIONS\nIn selected patients (young, without comorbidities, and with high activity), MS itself could be more dangerous than COVID-19, so we should consider continuing MS treatment as previously planned, including alemtuzumab.",
"affiliations": "Neurology Department, Complejo Hospitalario Universitario de Albacete, Hermanos Falcó 37, Albacete, Castilla-La Mancha 02006, Spain. Electronic address: evafdezdiaz@gmail.com.;Neurology Department, Complejo Hospitalario Universitario de Albacete, Hermanos Falcó 37, Albacete, Castilla-La Mancha 02006, Spain.;Ophthalmology Department, Complejo Hospitalario Universitario de Albacete, Castilla-La Mancha, Spain.;Neurology Department, Complejo Hospitalario Universitario de Albacete, Hermanos Falcó 37, Albacete, Castilla-La Mancha 02006, Spain.;Neurology Department, Complejo Hospitalario Universitario de Albacete, Hermanos Falcó 37, Albacete, Castilla-La Mancha 02006, Spain.;Professor of Neurology (Universidad de Castilla-La Mancha), Chair of Neurology Department, Complejo Hospitalario Universitario de Albacete, Castilla-La Mancha, Spain.",
"authors": "Fernández-Díaz|Eva|E|;Gracia-Gil|Julia|J|;García-García|Jose Gregorio|JG|;Palao|María|M|;Romero-Sánchez|Carlos M|CM|;Segura|Tomás|T|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000074323:Alemtuzumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2020.102402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "45()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Alemtuzumab; COVID-19; Immunosuppression; Multiple sclerosis; SARS-CoV-2",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D000074322:Antineoplastic Agents, Immunological; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102402",
"pmc": null,
"pmid": "32711297",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "32359409;32593959;28604916;32463329;32329046;30289355;23759318;32241953;32554284;32303837;32334820;32464584",
"title": "COVID-19 and multiple sclerosis: A description of two cases on alemtuzumab.",
"title_normalized": "covid 19 and multiple sclerosis a description of two cases on alemtuzumab"
} | [
{
"companynumb": "ES-FRESENIUS KABI-FK202008190",
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
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... |
{
"abstract": "Cerebrospinal fluid (CSF) rhinorrhea is rarely reported as the first presenting feature of giant invasive macroprolactinomas. Cerebrospinal fluid rhinorrhea is usually reported as a complication of trauma, neurosurgical, and skull-based procedures (such as pituitary surgery or radiations), and less frequently after medical treatment with dopamine agonists (DAs) for macroprolactinomas. This phenomenon results from fistula creation that communicates between the subarachnoid space and the nasal cavity. Meanwhile, pneumocephalus is another well-recognized complication after transsphenoidal surgery for pituitary macroadenomas. This entity may present with nausea, vomiting, headache, dizziness, and more seriously with seizures and/or a decreased level of consciousness if tension pneumocephalus develops. Case reports about the occurrence of spontaneous pneumocephalus after medical treatment with DAs without prior surgical interventions are scarce in the literature. Our index case is a young man who was recently diagnosed with a giant invasive prolactin-secreting pituitary macroadenoma with skull base destruction. A few months before this diagnosis, he presented with spontaneous CSF rhinorrhea with no history of previous medical or surgical treatment. In this case report, we report an uncommon presentation for giant invasive macroprolactinoma with a CSF leak treated with cabergoline that was subsequently complicated by meningitis and pneumocephalus. This is a very rare complication of cabergoline therapy, which occurred approximately 1 month after treatment initiation.",
"affiliations": "Obesity, Endocrine, and Metabolism Center, King Fahad Medical City, Riyadh, Saudi Arabia.;Obesity, Endocrine, and Metabolism Center, King Fahad Medical City, Riyadh, Saudi Arabia.;King Hussein Medical City,Internal Medicine Department, Amman, Jordan.;Obesity, Endocrine, and Metabolism Center, King Fahad Medical City, Riyadh, Saudi Arabia.",
"authors": "Elabd|Souha S|SS|;Ahmad|Maswood M|MM|;Qetab|Sameer Q|SQ|;Almalki|Mussa Hussain|MH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1179551418758640",
"fulltext": "\n==== Front\nClin Med Insights Endocrinol DiabetesClin Med Insights Endocrinol DiabetesENDspendClinical Medicine Insights. Endocrinology and Diabetes1179-5514SAGE Publications Sage UK: London, England 10.1177/117955141875864010.1177_1179551418758640END-0043905Case ReportCabergoline-Induced Pneumocephalus Following Treatment for Giant Invasive Macroprolactinoma Presenting With Spontaneous Cerebrospinal Fluid Rhinorrhea Elabd Souha S 1Ahmad Maswood M 1Qetab Sameer Q 2Almalki Mussa Hussain 131 Obesity, Endocrine, and Metabolism Center, King Fahad Medical City, Riyadh, Saudi Arabia2 King Hussein Medical City,Internal Medicine Department, Amman, Jordan3 King Fahad Medical City and College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaMussa Hussain Almalki, Obesity, Endocrine, and Metabolism Center, King Fahad Medical City, P.O. Box 59046, Riyadh 11525, Saudi Arabia. Email: m2malki@yahoo.com13 2 2018 2018 11 117955141875864012 11 2017 19 1 2018 © The Author(s) 20182018SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Cerebrospinal fluid (CSF) rhinorrhea is rarely reported as the first presenting feature of giant invasive macroprolactinomas. Cerebrospinal fluid rhinorrhea is usually reported as a complication of trauma, neurosurgical, and skull-based procedures (such as pituitary surgery or radiations), and less frequently after medical treatment with dopamine agonists (DAs) for macroprolactinomas. This phenomenon results from fistula creation that communicates between the subarachnoid space and the nasal cavity. Meanwhile, pneumocephalus is another well-recognized complication after transsphenoidal surgery for pituitary macroadenomas. This entity may present with nausea, vomiting, headache, dizziness, and more seriously with seizures and/or a decreased level of consciousness if tension pneumocephalus develops. Case reports about the occurrence of spontaneous pneumocephalus after medical treatment with DAs without prior surgical interventions are scarce in the literature. Our index case is a young man who was recently diagnosed with a giant invasive prolactin-secreting pituitary macroadenoma with skull base destruction. A few months before this diagnosis, he presented with spontaneous CSF rhinorrhea with no history of previous medical or surgical treatment. In this case report, we report an uncommon presentation for giant invasive macroprolactinoma with a CSF leak treated with cabergoline that was subsequently complicated by meningitis and pneumocephalus. This is a very rare complication of cabergoline therapy, which occurred approximately 1 month after treatment initiation.\n\nGiant invasive macroprolactinomaCSF leakpneumocephalushyperprolactinemiacabergolinetranssphenoidal surgerymeningitiscover-dateJanuary-December 2018\n==== Body\nIntroduction\nCerebrospinal fluid (CSF) rhinorrhea is a serious entity that is defined as the pathological leak of the CSF through the nose; this occurs due to a bone defect in the skull base, coupled with disruption of the dura and arachnoid membrane. It is typically classified as traumatic and nontraumatic.1,2 Giant invasive macroprolactinomas constitute one of the rare causes of nontraumatic CSF leak.3 Furthermore, this life-threatening condition is rarely documented as the main presenting symptom of invasive macroprolactinomas.4 Cerebrospinal fluid leakage may result in catastrophic complications, including meningitis, intracranial abscess formation, pneumocephalus, and intracranial hypotension. Pneumocephalus, which is known as a pneumatocele or intracerebral aerocele as well, is a term used to describe the presence of air within the intracranial compartments—the epidural, subdural, subarachnoid, intracerebral, and/or intraventricular spaces. Pneumocephalus very scarcely presents as a clinical feature of giant invasive macroprolactinoma; it can also complicate the treatment course. Pneumocephalus results from a fistula created by the invasion of a giant macroprolactinoma, which destroys the surrounding bony tissues. The fistula enables the communication between extracranial and intracranial spaces and allows the ambient air to enter the intracerebral compartments when the tumor size has reduced following medical treatment with dopamine agonists (DAs). Very few sporadic cases of pneumocephalus arising from the complication of a giant invasive macroprolactinoma—particularly following the initiation of medical treatment with cabergoline—have been described in the medical literature. Pneumocephalus was first described in 1866 by Thomas5 following the autopsy in a patient with trauma, and the term was subsequently used in 1914 by Wolff.6 In addition to neurosurgical and otorhinolaryngological procedures,7 there are other causes of such complications including trauma, parasellar or paranasal sinus malignancies, infection by gas-forming organisms, and other rarer causes.8 Postoperative pneumocephalus is usually suspected soon after transsphenoidal surgery and it is confirmed by neuroimaging; conversely, spontaneous pneumocephalus occurs a few weeks after the initiation of treatment with DAs and requires a high index of suspicion.\n\nCase Report\nA 24-year-old male patient attended the neurosurgery clinic at our hospital with a history of clear-fluid nasal discharge for 8 months. He was evaluated at a peripheral health care facility where he underwent a computed tomographic (CT) scan of the brain. He was found to have a large suprasellar mass and hyperprolactinemia, at which point he was referred to endocrinology clinic for further evaluation.\n\nThe patient was immediately admitted for further assessment and management in our hospital. The nasal discharge was watery, continuous, and worsened when bending forward; the nasal discharge was associated with occasional mild to moderate headaches with mild retro-orbital pain, which rarely required analgesics. A history of decreased libido, occasional morning penile erections, and a few incidents of spontaneous galactorrhea were present along with the loss of facial and axillary hair. However, there was no history of fever, severe headache, vomiting, diplopia, or other visual disturbances. The patient had no complaints of impaired hearing, tinnitus, disorientation, incontinence, hemiparesis, postural symptoms, loss of consciousness, drowsiness, and/or convulsions.\n\nOn physical examination, the patient was conscious, oriented to time and place, and looking well. He was morbidly obese with a body mass index of 52 kg/m2 with absent facial and axillary hair. The patient’s vital signs were stable with no postural hypotension. Neuro-ophthalmologic examination revealed no visual field deficit with a full range of extraocular muscle movements. Galactorrhea and gynecomastia were noticeable on breast examination. The cranial nerve examination was normal, and the patient had a normal gait and no cerebellar signs.\n\nGenital examination revealed small bilateral testes with size of 6 ml on right and 10 ml on left side and a small phallus. The remaining systemic examination was unremarkable.\n\nAnalysis of the nasal fluid confirmed the presence of β2-transferrin and low glucose, indicating CSF rhinorrhea. The pituitary profile was remarkable for central hypothyroidism, hypogonadotropic hypogonadism, and growth hormone (GH) deficiency, but normal for adrenocorticotropic hormone (ACTH) and morning serum cortisol (Table 1).\n\nTable 1. Laboratory assessment.\n\nBiomarker\tValue\tNormal references\t\nProlactin\t292 396 mIU/L (13 792.2 μg/L)\t86-324 mIU/L (5-26 μg/L)\t\nGH\t<0.150 mIU/L\t0.00-9.00 mIU/L\t\nIGF-1\t10.6 nmol/L\t15.1-46.5 nmol/L\t\nACTH\t11.8 pmol/L\t1.6-13.9 pmol/L\t\nFSH\t<0.1 IU/L\t1.5-12.4 IU/L\t\nLH\t<0.1 IU/L\t1.7-8.6 IU/L\t\nSerum cortisol (AM)\t486 nmol/L\t\t\nTotal serum testosterone\t0.87 nmol/L\t8.60-29.00 nmol/L\t\nTSH\t1.2 mIU/L\t0.270-4.200 mIU/L\t\nFree T4\t11.7 pmol/L\t12-22 pmol/L\t\nAbbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; TSH, thyrotropin.\n\nMagnetic resonance imaging of the brain and pituitary (Figures 1 to 3) showed an expansive, irregular lesion in the sellar and suprasellar region, measuring 5.5 cm × 4.4 cm × 5.2 cm, enclosing the right optic nerve and eroding the cavernous sinus and clivus. It extended anteriorly to the posterior ethmoid sinus and superiorly to the right middle cranial fossa, encasing both the internal carotid artery and right middle cerebral artery.\n\nFigure 1. A contrast-enhanced, T1-weighted, sagittal magnetic resonance image showing a huge suprasellar mass (white shaded arrows) extending anteriorly to the posterior ethmoid sinus.\n\nFigure 2. A contrast-enhanced, T1-weighted, axial magnetic resonance image showing the mass (white shaded arrow) encasing the right optic nerve.\n\nFigure 3. A contrast-enhanced, T1-weighted, axial magnetic resonance image showing the tumor encasing both the internal carotid arteries (the long, white arrows, bilateral).\n\nA final diagnosis of giant invasive macroprolactinoma was made and treatment initiated with 0.25 mg of oral cabergoline twice weekly. Levothyroxine 50 μg once daily started orally after ensuring a normal cortisol response to Synacthen stimulation test. He was discharged home in clinically stable condition with instructions to attend emergency department in case of worsening CSF leak, headache, visual disturbances or fever and given 6 week outdoor follow-up appointment.\n\nPatient was readmitted after 5 weeks of cabergoline therapy with severe headache, nausea and worsening of CSF leak. An urgent CT scan revealed extensive pneumocephalus in addition to the previously noted invasive and destructive giant macroprolactinoma, with no evidence of acute territorial infarction or intracerebral hemorrhage (Figures 4 and 5).\n\nFigure 4. Axial computed tomographic images of the brain without contrast showing extensive pneumocephalus (the arrows are pointing to very-low-density areas, representing air) in the basal and suprasellar cisterns extending to the ventricular system and cerebrospinal fluid spaces.\n\nFigure 5. Sagittal computed tomographic images of the brain without contrast showing extensive pneumocephalus (the arrows are pointing to very low-density areas, representing air) in the basal and suprasellar cisterns extending to the ventricular system and cerebrospinal fluid spaces.\n\nThe patient was started on prophylactic antibiotics and hydrocortisone, and he underwent endoscopic transsphenoidal pituitary macroadenoma debulking and skull base reconstruction using neuronavigation, fascia latae, and a fat graft.\n\nImmunostaining for pituitary hormones was positive for prolactin with no expression of GH, ACTH, thyrotropin, luteinizing hormone, or follicle-stimulating hormone, whereas p53 staining was negative. The Ki67 (MIB-1) labeling index was weakly positive.\n\nCabergoline therapy was continued at a dose of 0.25 mg twice weekly. The patient had an unremarkable recovery but was continued on hydrocortisone and discharged home without complications.\n\nOne month later, the patient had his third admission for recurrent CSF leak and meningitis necessitating antibiotics and endoscopic skull base repair. However, the patient recovered fully with no neurological sequelae. His clinical course remained uneventful without any further recurrence of the CSF leak. At 9-month follow-up visit at the endocrinology clinic, he was stable with a prolactin level of 6600 mIU/L (311.3 μg/L).\n\nDiscussion\nGiant invasive macroprolactinomas are very rare types of pituitary adenomas that require special attention due to the challenges they pose in diagnosis and management.9 These macroprolactinoma subtypes account for 0.5% to 4.4% of all pituitary tumors. Giant invasive macroprolactinomas are predominantly found in young men.10,11 They are defined as pituitary adenomas with a diameter of 4 cm or more,12 remarkable extrasellar extension, and significantly elevated prolactin levels (usually >1000 µg/L),13 with no concomitant GH or ACTH secretion. Prolactinomas typically present with features of hyperprolactinemia and/or hypogonadism, but these symptoms are usually overlooked in men. Men usually present with larger tumor sizes, more aggressive tumors, and they might present very late with symptoms of space-occupying lesions.14\n\nSpontaneous CSF rhinorrhea is considered an atypical presentation for giant invasive macroprolactinoma,15 indicating a large tumor size and extension to the surrounding intracranial structures with the invasion of the sphenoid and/or ethmoid sinuses. It is very uncommon in patients with untreated giant prolactinomas and is mostly induced by transsphenoidal surgery or by DA therapy, which causes rapid tumor shrinkage.15,16\n\nIn a literature review, Lam et al17 reported 52 patients (between 1980 and 2011) with a pituitary adenoma and with nonsurgically-induced CSF leaks. Of these patients, 42 (81%) had prolactin-secreting tumors. There were no reports on the exact sizes of the tumors, except for a few cases, but the prolactin concentrations were >1000 µg/L in 37 cases and >10 000 µg/L in 13 cases, thus suggesting the presence of a giant prolactinoma in many of these patients. Interestingly, a large proportion of the prolactinoma-associated CSF rhinorrheas (86%) occurred following the initiation of DA treatment with bromocriptine or cabergoline, and only 6 patients had CSF rhinorrhea as the presenting symptom of their prolactinoma. The average initial prolactin level in patients with spontaneous CSF leakage was 9169 ng/mL compared with 4917 ng/mL in those with DA-induced leakage.\n\nIn another large retrospective review, Suliman et al4 reviewed 114 patients with macroprolactinoma (from 1985 to 2004). The incidence of spontaneous CSF rhinorrhea in those cases was 8.7%. Among those patients, 6.1% (7 patients) developed a DA-induced CSF leak, whereas 2.6% (3 patients) developed spontaneous rhinorrhea. In this review, it was found that DA resistance was more common in macroprolactinomas with CSF leak compared with those without rhinorrhea (30% [n = 10] versus 5% [n = 104], P = .003).4\n\nThe CSF rhinorrhea in our patient can be explained by the direct extension of the tumor through the diaphragma sellae and erosion of the skull base into the sphenoid sinus, resulting in communicating fistula. Unfortunately, the rhinorrhea had recurred and was complicated with bacterial meningitis. It is estimated that meningitis may develop in approximately 15% to 25% of patients with unrepaired CSF leak, and 10% of them consequently die.18,19\n\nOur patient was initially started on a low dose of cabergoline (0.25 mg twice weekly) to avoid worsening of CSF leak. Considering long history of CSF leak along with patients refusal for surgical intervention, Neurosurgery team opted for close monitoring and observation. Cabergoline is a widely used and relatively safe DA. Its therapeutic effect in treating prolactinomas is well-documented in the literature.20 Generally, it has well-tolerated side effects, even at larger doses. Cabergoline is the first-line medication used to treat microprolactinomas, nearly all cases of macroprolactinomas, and most of the cases of giant invasive macroprolactinomas.21\n\nGiant invasive macroprolactinomas can have a remarkable response following the initiation of cabergoline treatment, which can be associated with tumor shrinkage and a significant reduction in or normalization of prolactin levels.9,22,23 Cerebrospinal fluid leaks can occur in cases of invasive macroprolactinoma following treatment with DA17,24 or, spontaneously, as either the primary symptom or an associated symptom,4,17 as occurred in our case. Although the standard management of CSF rhinorrhea is surgical repair in 71% of cases,4 cases of spontaneous resolution following medical treatment with DA have also been reported in the medical literature.24,25 However, our patient did not undergo surgical repair initially and was not started on prophylactic antibiotics due to the debatable data pertaining to the rules of preventing meningitis development.26\n\nIn addition, the pneumocephalus that occurred in this case represents a rare and serious complication of DA treatment for invasive prolactinomas. Cabergoline-induced tumor shrinkage exposes the erosion of the sella floor and allows the CSF leakage and/or pneumocephalus to occur.\n\nPneumocephalus can develop due to the disruption of the skull base and CSF fistulas,27 and two hypotheses may explain its development. The first pertains to the one-way valve, otherwise known as the “ball-valve” mechanism, which requires positive pressure events, such as coughing, sneezing, and Valsalva maneuvers. This event allows the air to enter through the cranial defect where it is trapped, leading to tension pneumocephalus.28 The second hypothesis is the inverted bottle theory, according to which CSF drainage creates a negative intracranial pressure gradient, which is relieved by the influx of air.29\n\nTension pneumocephalus, which is a more serious form of this phenomenon, is the collection of air that increases intracranial pressure and mimics features of space occupying lesion. It may manifest as a wide range of clinical presentations, including severe restlessness, deteriorating consciousness, focal neurological deficits, and even cardiac arrest.8 It is an unusual neurosurgical emergency that can lead to severe neurological damage and disastrous consequences and can be life threatening if it goes unnoticed.\n\nThe detection of pneumocephalus with evidence of its mass effect on the surrounding structures is the primary feature that differentiates tension pneumocephalus from benign pneumocephalus. The “Mount Fuji” sign is the most widely reported radiologic sign that specifically indicates the presence of tension pneumocephalus.30 It is observed when the presence of subdural free air causes compression and separation of the frontal lobes. The displacement of the frontal lobes and the widening of the interhemispheric space simulate the silhouette of Mount Fuji. Although this sign is specific to the pressure effect of subdural air, a large volume of free air might also accumulate in other intracranial compartments (eg, in the subarachnoid and intraventricular spaces) and cause similar mass effects.31 Postoperative pneumocephalus is usually suspected in soon after transsphenoidal surgery and is confirmed by neuroimaging. A very high index of clinical suspicion is required for its prompt diagnosis and management. Overall, the management of pneumocephalus requires urgent neurosurgical evaluation and/or intervention to decrease intracranial pressure and repair the skull base disruption to prevent further morbidity and mortality.\n\nConclusions\nSpontaneous CSF rhinorrhea and pneumocephalus are rare and unusual types of complications related to the presence of giant invasive macroprolactinomas. Pneumocephalus and CSF rhinorrhea can occur after neurosurgical approaches or they rarely ensue following the initiation of DA, such as cabergoline, and rarely as an initial presenting feature, as in this reported case. Although the patient was initially declined the surgical procedure, it is thought that if this treatment option had been employed, they might have decreased the risk of meningitis and pneumocephalus development. We believe that a low threshold of suspicion for these complications and watchful monitoring could help in the early assessment and prompt management of this phenomenon while also preventing serious neurologic sequelae. A multidisciplinary care team is essential, and close follow-up after any treatment is necessary.\n\nEnglish language editing of this manuscript was done by Journal Prep.\n\nFunding:The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nDeclaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nAuthor Contributions: SSE wrote the first draft of the manuscript. MMA, MHA, and SQQ contributed to the writing of the manuscript. SSE and MHA made contributions to the acquisition of the clinical data. SSE, MMA, MHA, and SQQ agreed with the manuscript results and conclusions. SSE, MMA, and MHA jointly developed the structure and arguments of the paper. SSE and MHA made critical revisions and approved the final version of the manuscript. All authors reviewed and approved the final manuscript.\n==== Refs\nReferences\n1 \nBrisman R Hughes JE Mount LA. \nCerebrospinal fluid rhinorrhea . Arch Neurol . 1970 ;22 :245 –252 .5411680 \n2 \nHubbard JL McDonald TJ Pearson BW Laws ERJ \nSpontaneous cerebrospinal fluid rhinorrhea: evolving concepts in diagnosis and surgical management based on the Mayo Clinic experience from through . Neurosurgery . 1985 ;16 :314 –321 .3982609 \n3 \nOmmaya AK Di Chiro G Baldwin M Pennybacker JB. \nNon-traumatic cerebrospinal fluid rhinorrhoea . J Neurol Neurosurg Psychiatry . 1968 ;31 :214 –225 .5303103 \n4 \nSuliman SG Gurlek A Byrne JV et al \nNonsurgical cerebrospinal fluid rhinorrhea in invasive macroprolactinoma: incidence, radiological, and clinicopathological features . J Clin Endocrinol Metab . 2007 ;92 :3829 –3835 . doi:10.1210/jc.2007-0373. 17623759 \n5 \nThomas L. \nDu pneumatocele du crane . Arch Gen Med (Paris) . 1866 ;1 :34 –55 .\n6 \nWolff E. \nLuftansammlung im rechten Seitenventrikel des Gehirns (Pneumozephalus) . Münch Med Wochenschr . 1914 ;61 :899 .\n7 \nGore PA Maan H Chang S Pitt AM Spetzler RF Nakaji P. \nNormobaric oxygen therapy strategies in the treatment of postcraniotomy pneumocephalus . J Neurosurg . 2008 ;108 :926 –929 . doi:10.3171/JNS/2008/108/5/0926. 18447708 \n8 \nMarkham JW. \nThe clinical features of pneumocephalus based upon a survey of cases with report of additional cases . Acta Neurochir (Wien) . 1967 ;16 :1 –78 .6032371 \n9 \nShrivastava RK Arginteanu MS King WA Post KD. \nGiant prolactinomas: clinical management and long-term follow up . J Neurosurg . 2002 ;97 :299 –306 . doi:10.3171/jns.2002.97.2.0299. 12186457 \n10 \nDelgrange E Trouillas J Maiter D Donckier J Tourniaire J. \nSex-related difference in the growth of prolactinomas: a clinical and proliferation marker study . J Clin Endocrinol Metab . 1997 ;82 :2102 –2107 . doi:10.1210/jcem.82.7.4088. 9215279 \n11 \nMindermann T Wilson CB. \nAge-related and gender-related occurrence of pituitary adenomas . Clin Endocrinol (Oxf) . 1994 ;41 :359 –364 .7893282 \n12 \nMurphy FY Vesely DL Jordan RM Flanigan S Kohler PO. \nGiant invasive prolactinomas . Am J Med . 1987 ;83 :995 –1002 .3674103 \n13 \nAstaf’eva LI Kadashev BA Kalinin PL et al \nClinical presentation, diagnostics and results of primary conservative treatment of large and giant prolactin-secreting pituitary adenomas . Zh Vopr Neirokhir Im N N Burdenko . 2008 ;4 :36 –38 (discussion 39).\n14 \nColao A Sarno A Di Cappabianca P et al \nGender differences in the clinical features and response to cabergoline in hyperprolactinemia . Eur J Endocrinol . 2003 ;148 :325 –331 .12611613 \n15 \nGrozinsky-Glasberg S Shimon I. \nUnusual clinical presentations of giant prolactinomas . Pituitary . 2011 ;14 :340 –344 . doi:10.1007/s11102-008-0160-0. 19104942 \n16 \nChattopadhyay A Bhansali A Masoodi SR. \nLong-term efficacy of bromocriptine in macroprolactinomas and giant prolactinomas in men . Pituitary . 2005 ;8 :147 –154 . doi:10.1007/s11102-005-5111-4. 16379032 \n17 \nLam G Mehta V Zada G. \nSpontaneous and medically induced cerebrospinal fluid leakage in the setting of pituitary adenomas: review of the literature . Neurosurg Focus . 2012 ;32 :E2 . doi:10.3171/2012.4.FOCUS1268. \n18 \nCappabianca P Lodrini S Felisati G et al \nCabergoline-induced CSF rhinorrhea in patients with macroprolactinoma. Report of three cases . J Endocrinol Invest . 2001 ;24 :183 –187 . doi:10.1007/BF03343840. 11314748 \n19 \nAarabi B Leibrock LG. \nNeurosurgical approaches to cerebrospinal fluid rhinorrhea . Ear Nose Throat J . 1992 ;71 :300 –305 .1505377 \n20 \nCho EH Lee SA Chung JY et al \nEfficacy and safety of cabergoline as first line treatment for invasive giant prolactinoma . J Korean Med Sci . 2009 ;24 :874 –878 . doi:10.3346/jkms.2009.24.5.874. 19794986 \n21 \nFerrari CI Abs R Bevan JS et al \nTreatment of macroprolactinoma with cabergoline: a study of patients . Clin Endocrinol (Oxf) . 1997 ;46 :409 –413 .9196602 \n22 \nWu ZR Zhang Y Cai L et al \nLong-term clinical outcomes of invasive giant prolactinomas after a mean year followup . Int J Endocrinol . 2016 ;2016 :8580750 . doi:10.1155/2016/8580750. 27999593 \n23 \nCorsello SM Ubertini G Altomare M et al \nGiant prolactinomas in men: efficacy of cabergoline treatment . Clin Endocrinol (Oxf) . 2003 ;58 :662 –670 .12699451 \n24 \nNetea-Maier RT van Lindert EJ Timmers H Schakenraad EL Grotenhuis JA Hermus AR. \nCerebrospinal fluid leakage as complication of treatment with cabergoline for macroprolactinomas . J Endocrinol Invest . 2006 ;29 :1001 –1005 . doi:10.1007/BF03349214. 17259798 \n25 \nBarlas O Bayindir C Hepgul K et al \nBromocriptine-induced cerebrospinal fluid fistula in patients with macroprolactinomas: report of three cases and a review of the literature . Surg Neurol . 1994 ;41 :486 –489 .8059328 \n26 \nBrodie HA. \nProphylactic antibiotics for posttraumatic cerebrospinal fluid fistulae: a meta-analysis . Arch Otolaryngol Head Neck Surg . 1997 ;123 :749 –752 .9236597 \n27 \nWalker FO Vern BA. \nThe mechanism of pneumocephalus formation in patients with CSF fistulas . J Neurol Neurosurg Psychiatry . 1986 ;49 :203 –205 .3950639 \n28 \nDelGaudio JM Ingley AP. \nTreatment of pneumocephalus after endoscopic sinus and microscopic skull base surgery . Am J Otolaryngol . 2010 ;31 :226 –230 . doi:10.1016/j.amjoto.2009.02.012. 20015750 \n29 \nLunsford LD Maroon JC Sheptak PE Albin MS. \nSubdural tension pneumocephalus. Report of two cases . J Neurosurg . 1979 ;50 :525 –527 . doi:10.3171/jns.1979.50.4.0525. 423011 \n30 \nRyan J Shields G Finegan E Moughty A. \nPost traumatic tension pneumocephalus: the Mount Fuji sign . Ir Med J . 2017 ;110 :550 .28665089 \n31 \nSadeghian H. \nMount Fuji sign in tension pneumocephalus . Arch Neurol . 2000 ;57 :1366 .\n\n",
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"issn_linking": "1179-5514",
"issue": "11()",
"journal": "Clinical medicine insights. Endocrinology and diabetes",
"keywords": "CSF leak; Giant invasive macroprolactinoma; cabergoline; hyperprolactinemia; meningitis; pneumocephalus; transsphenoidal surgery",
"medline_ta": "Clin Med Insights Endocrinol Diabetes",
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"pages": "1179551418758640",
"pmc": null,
"pmid": "29467589",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "3674103;10987907;18447708;9215279;9196602;7893282;6032371;5411680;3982609;20015750;3950639;16379032;11314748;27999593;12611613;19104942;19794986;1505377;5303103;28665089;22655691;12699451;423011;8059328;19230480;17623759;12186457;9236597;17259798",
"title": "Cabergoline-Induced Pneumocephalus Following Treatment for Giant Invasive Macroprolactinoma Presenting With Spontaneous Cerebrospinal Fluid Rhinorrhea.",
"title_normalized": "cabergoline induced pneumocephalus following treatment for giant invasive macroprolactinoma presenting with spontaneous cerebrospinal fluid rhinorrhea"
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"abstract": "We retrospectively reviewed outcomes of treatments with cisplatin and topotecan in patients with previously-treated uterine cervix cancer.We analyzed the medical records of patients with advanced (stage IVB) or recurrent or persistent squamous or non-squamous cell carcinoma of the cervix, who were treated with cisplatin and topotecan as a second-line chemotherapy between January 2000 and December 2015. The patients were treated with a combination of cisplatin (50 mg/m for 1 day) and topotecan (0.75 mg/m for 3 days) once every 3 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and non-responder groups (responders showed at least a partial response to prior systemic chemotherapy).Thirty-nine patients with a median age of 47 years (range, 32-73 years) were treated with cisplatin and topotecan. The median PFS was 4.6 months (95% confidence interval [CI], 1.2-7.9 months) and the median OS was 14.1 months (95% CI, 10.0-18.2 months). The overall response rate (ORR) was 30.8%, and the disease control rate was 56.4%. The ORR was significantly better in the responder group compared with the non-responder group (50.0% vs 10.5%; P = .008). All patients reported some grade of hematological toxicity. The most frequently encountered toxicity was anemia, with a rate of 59.7% for any grade and 13.2% for grade 3 or 4.The combination of cisplatin and topotecan was effective as second-line chemotherapy in patients with advanced/recurrent uterine cervix cancer.",
"affiliations": "Department of Internal Medicine, Cheongju Saint Mary's Hospital, Cheongju Department of Internal Medicine Department of Obstetrics and Gynecology Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea.",
"authors": "Moon|Ji Young|JY|;Song|Ik-Chan|IC|;Ko|Young Bok|YB|;Lee|Hyo Jin|HJ|",
"chemical_list": "D019772:Topotecan; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000010340",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29620661MD-D-17-0628710.1097/MD.0000000000010340003405700Research ArticleObservational StudyThe combination of cisplatin and topotecan as a second-line treatment for patients with advanced/recurrent uterine cervix cancer Moon Ji Young MDaSong Ik-Chan MDbKo Young Bok MD, PhDc∗Lee Hyo Jin MD, PhDbd∗Liu. Yuxuan a Department of Internal Medicine, Cheongju Saint Mary's Hospital, Cheongjub Department of Internal Medicinec Department of Obstetrics and Gynecologyd Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea.∗ Correspondence: Hyo Jin Lee, Department of Internal Medicine, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, South Korea (e-mail: cymed@cnu.ac.kr); Young Bok Ko, Department of Obstetrics and Gynecology, Chungnam National University College of Medicine, Daejeon 35015, South Korea (e-mail: koyoung@cnuh.co.kr).4 2018 06 4 2018 97 14 e034011 10 2017 27 2 2018 15 3 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nWe retrospectively reviewed outcomes of treatments with cisplatin and topotecan in patients with previously-treated uterine cervix cancer.\n\nWe analyzed the medical records of patients with advanced (stage IVB) or recurrent or persistent squamous or non-squamous cell carcinoma of the cervix, who were treated with cisplatin and topotecan as a second-line chemotherapy between January 2000 and December 2015. The patients were treated with a combination of cisplatin (50 mg/m2 for 1 day) and topotecan (0.75 mg/m2 for 3 days) once every 3 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and non-responder groups (responders showed at least a partial response to prior systemic chemotherapy).\n\nThirty-nine patients with a median age of 47 years (range, 32–73 years) were treated with cisplatin and topotecan. The median PFS was 4.6 months (95% confidence interval [CI], 1.2–7.9 months) and the median OS was 14.1 months (95% CI, 10.0–18.2 months). The overall response rate (ORR) was 30.8%, and the disease control rate was 56.4%. The ORR was significantly better in the responder group compared with the non-responder group (50.0% vs 10.5%; P = .008). All patients reported some grade of hematological toxicity. The most frequently encountered toxicity was anemia, with a rate of 59.7% for any grade and 13.2% for grade 3 or 4.\n\nThe combination of cisplatin and topotecan was effective as second-line chemotherapy in patients with advanced/recurrent uterine cervix cancer.\n\nKeywords\nchemotherapycisplatintopotecanuterine cervical carcinomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nCancer of the cervix is one of the most common worldwide malignancies. Fortunately, the frequency of occurrence of cervical cancer has decreased because of cytological screening (e.g., the Pap smear test), DNA testing for high risk human papillomavirus (HPV) types, and HPV vaccination. HPV types 16 and 18 cause cervical and anal cancer, and reduction in these HPV types could prevent >70% of cervical cancers worldwide.[1] However, cervical cancer remains a significant problem, with 12,990 new cases and 4120 deaths annually in the United States[2] and 3500 new cases and 960 deaths annually in the Republic of Korea.[3]\n\nCisplatin is the most active, cytotoxic, systemic, single chemotherapeutic agent for advanced carcinomas of the cervix. Its efficacy was first reported as an objective response rate (ORR) of 44% in previously untreated patients.[4] Since its initial use, cisplatin-based combination therapy has been reported to result in a higher response than that of cisplatin single-agent therapy. The combination of cisplatin and ifosfamide showed an improvement compared with cisplatin alone, with an ORR of 13.3% and progression-free survival (PFS) of 1.4 months, although there was no improvement in overall survival (OS). In the report, the significantly increased leukopenia toxicity, renal toxicity, peripheral neurotoxicity, and central nervous system toxicity in the combination regimen were a concern.[5] In another regimen, cisplatin plus paclitaxel showed an improvement compared with cisplatin alone, with an ORR of 17%, PFS of 2 months, and a sustained quality of life, although no significant difference in the median OS was observed.[6] Because cisplatin-based combination therapy showed better results, another study evaluated 4 cisplatin-based regimens, including combinations with paclitaxel, vinorelbine, gemcitabine, and topotecan. The combination of cisplatin and paclitaxel showed a better median OS compared with the other combination regimens (12.9 months vs 10–10.5 months).[7,8] Recently, a phase III randomized trial of bevacizumab plus combination chemotherapy was performed for patients with recurrent, persistent, or metastatic cervical cancer. Bevacizumab, compared with chemotherapy alone, showed a significantly increased OS (17.0 months vs 13.3 months).[9] After that study, a combination of platinum and paclitaxel with/without bevacizumab was accepted as the standard treatment for patients with recurrent or metastatic cervical cancer.\n\nUnfortunately, most responses to chemotherapy are partial and short in duration, and more effective treatments for patients with progressive disease after standard first-line chemotherapy have yet to be identified. Finding enough patient subjects to obtain sufficient power to test novel strategies is also a challenge.\n\nTopotecan is one of the most effective drugs for the treatment of cervical cancer. Furthermore, the combination of cisplatin 50 mg/m2 day 1 and topotecan 0.75 mg/m2 days 1 to 3 every 3 weeks, when compared with cisplatin alone, has been shown to improve OS from 6.5 to 9.4 months in patients who were unsuitable candidates for curative treatment with advanced/recurrent and metastatic cervical cancer.[10] The Gynecologic Oncology Group (GOG) has reported on the phase III trial of 4 cisplatin-containing doublet combinations in stage IV, recurrent, or persistent cervical cancer; paclitaxel and cisplatin, vinorelbine and cisplatin, gemcitabine and cisplatin, and topotecan and cisplatin. The topotecan and cisplatin combination was not superior to paclitaxel and cisplatin in terms of OS, whereas trends in RR, PFS, and OS favored paclitaxel and cisplatin.[7] However, the efficacy of topotecan and cisplatin doublet was not reported in patients with progressive disease after front-line palliative chemotherapy although it could be used as one of several systemic therapy regimens in second-line setting.\n\nBased on these results, we assessed the clinical benefit of cisplatin and topotecan in patients with incurable cervical cancer who showed failure after first-line chemotherapy and for whom no further treatment has been established yet. We describe the results of retrospective analyses of cisplatin plus topotecan, including the treatment outcomes of these patients\n\n2 Methods\n2.1 Patients\nWe collected and reviewed the medical records of patients diagnosed with recurrent or metastatic cervical cancer who were treated with cisplatin plus topotecan as a second-line therapy from January 2000 to December 2015 at Chungnam National University Hospital, Daejeon, Republic of Korea.\n\nWe included patients ≥18 years of age with histologically proven advanced (stage IVB) or recurrent or persistent squamous or non-squamous cell carcinoma of the cervix who were treated with cisplatin plus topotecan. Other inclusion criteria included having >1 measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1),[11] an Eastern Cooperative Oncology Group performance score ≤2, treatment with 1 prior systemic chemotherapy regimen, an absolute neutrophil count ≥1500/μL and platelet count (as hematological parameters) ≥100,000/μL, serum creatinine level (as a renal parameter) ≤1.5-fold the institutional upper limit of normal (ULN), serum bilirubin level (as a hepatic parameter) ≤1.5-fold the ULN, and both aspartate aminotransferase and alkaline phosphatase levels ≤2.5-fold the ULN.\n\nWe excluded patients who had other malignancies within the last 5 years, patients with prior non-cytotoxic therapies, and patients requiring hospital admission for active bleeding, central nervous system diseases, or severe infections. Patients were also excluded for significant cardiovascular diseases (e.g., uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure, or uncontrolled arrhythmias within 6 months of registration), pregnancy or nursing, or major surgical procedures within the last 30 days. This study was approved by the Institutional Review Board of Chungnam National University Hospital.\n\n2.2 Treatment\nThe patients were treated with cisplatin (50 mg/m2 for 1 day) and topotecan (0.75 mg/m2 for 3 days). The drugs were infused separately, and the cycles were repeated every 21 days. The cycles were delayed if the absolute neutrophil count (ANC) was <1500/μL, and/or the platelet count was <100,000/μL on the proposed day of treatment. All patients received prophylactic medication for chemotherapy-induced nausea/vomiting. Granulocyte colony stimulating factor (G-CSF) was administered to patients with febrile neutropenia or with an ANC <500/μL. Chemotherapy was continued until disease progression, unacceptable toxicity, or patient refusal, with a maximum of 6 cycles.\n\n2.3 Response assessment\nResponse evaluations were performed according to clinical assessments and imaging studies after every 2 or 3 cycles in the absence of overt progression. The treatment response was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to the RECIST criteria, version 1.1, and toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, version 4.0 (http://www.eortc.be/services/doc/ctc).\n\n2.4 Statistical analysis\nBasic descriptive statistics included medians with/without ranges. Differences between 2 groups were tested using the t-test or Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables. PFS was defined as the time between the first administration of chemotherapy and the date of tumor progression. OS was defined as the time between the first administration of chemotherapy and the date of last contact or death. PFS and OS were estimated using the Kaplan–Meier method with the log-rank test. A P-value <.05 was considered significant. SPSS statistical software for Windows, version 22 (SPSS, Chicago, IL) was used for all statistical analyses.\n\n3 Results\n3.1 Patient population\nThirty-nine patients with advanced, recurrent, or persistent cervical cancer were treated with a combination of cisplatin and topotecan as second-line chemotherapy between January 2000 and December 2015. The median patient age was 47 years (range, 32–73 years). The distribution of the histological subtypes was as follows: adenocarcinoma (n = 4), squamous cell carcinoma (n = 29), adenosquamous cell carcinoma (n = 4), and undifferentiated carcinoma (n = 2). All patients had previously received platinum-based cytotoxic chemotherapy before the study treatment: 32 (82.1%) a combination of paclitaxel and cisplatin, 6 (15.4%) a combination of paclitaxel and carboplatin, and 1 (2.6%) a bevacizumab-containing regimen as first-line chemotherapy. Twenty (51.3%) patients showed at least a PR to prior systemic chemotherapy (responders), and 19 (48.3%) patients did not show any tumor response to prior chemotherapy (non-responders) (Table 1).\n\nTable 1 Baseline patient characteristics.\n\n3.2 Tumor responses\nA CR was not observed, and a PR was observed in 12 (30.8%) patients. The ORR was 30.8%, and the disease control rate (DCR) was 56.4% (Table 2).\n\nTable 2 Best response to combination of cisplatin and topotecan.\n\nThe ORR was significantly better in the responder group compared with the non-responder group (50.0% vs 10.5%; P = .008), and the DCR was also better in the responder group (75.0% vs 36.8%; P = .016) (Table 3).\n\nTable 3 Best response to combination of cisplatin and topotecan according to response status to prior systemic treatment.\n\n3.3 Survival outcomes\nIn all patients, the median PFS was 4.6 months (95% confidence interval [CI], 1.2–7.9) (Fig. 1) and the median OS was 14.1 months (95% CI, 10.0–18.2) (Fig. 2).\n\nFigure 1 Progression free survival for all patients (n = 39).\n\nFigure 2 Overall survival for all patients (n = 39).\n\nThe median PFS was longer in the responder group compared with the non-responder group (6.5 months vs 2.4 months; P = .244; hazard ratio [HR], 0.66; 95% CI, 0.33–1.32) (Fig. 3), and the median OS was also longer in the responder group (15.4 months vs 9.2 months; P = .201; HR, 0.58; 95% CI, 0.25–1.34) (Fig. 4). The estimated PFS and OS rates at 6 months were 44.7% and 80.0% for all patients, 60.0% and 80.0% for responders, and 28.1% and 73.1% for non-responders, respectively.\n\nFigure 3 Progression free survival between responder (n = 20) and non-responder (n = 19) groups.\n\nFigure 4 Overall survival between responder (n = 20) and non-responder (n = 19) groups.\n\n3.4 Safety profiles\nA total of 159 treatment cycles were administered (median, 4.0 cycles/patient; range, 1–6 cycles/patient). All patients reported some grade of hematological toxicity. The most frequent toxicity was anemia, with a rate of 59.7% for any grade and 13.2% for grade 3 or 4. The rate of neutropenia was 55.3% for any grade and 49.1% for grade 3 or 4, and that of thrombocytopenia was 39.6% for any grade and 16.3% for grade 3 or 4. The tolerable non-hematological toxicities were increased levels of creatinine in 8.1% of the cycles, alanine aminotransferase in 1.2% of the cycles, and bilirubin in 1.8% of any grade and 0.6% of grade 3 or 4. Febrile neutropenia developed in 10 (6.2%) cycles (Table 4).\n\nTable 4 Laboratory toxicities (total 159 cycles with combination of cisplatin and topotecan).\n\n4 Discussion\nEarly-stage and locally advanced cervical cancers are managed with radical surgery or chemoradiotherapy. For the vast majority of patients with recurrent or advanced disease, palliative chemotherapy is the only treatment option.[12–15] Historically, cisplatin has been considered the most effective drug,[16] and numerous studies have assessed platinum-based combination chemotherapy regimens. Recently, based on the GOG 240 study, a combination of bevacizumab and platinum-based chemotherapy was accepted as the first-line treatment.[9] Patients with advanced or recurrent cervical cancer who progress to first-line chemotherapy have poor prognoses because of the overall unsatisfactory outcomes of further chemotherapy. Some studies of conventional chemotherapy involving capecitabine, vinorelbine, pemetrexed, or docetaxel have only shown partial efficacies of short duration, with an ORR of 8.7% to 15.4% and an OS of only approximately 7 months.[17–21] Novel agents such as lapatinib, pazopanib, and temsirolimus have been assessed as treatments for cervical cancer after the failure of standard chemotherapy. Pazopanib and lapatinib, which are multitargeted tyrosine kinase inhibitors, had an ORR of 9% and 5%, a PFS of 4.5 months and 4.3 months, and an OS of 12.6 months and 9.8 months, respectively.[22] Temsirolimus, targeting the PI3K/AKT/mTOR pathway, had an ORR of 3% and a PFS of 3.5 months.[23] The efficacy of these novel agents was also shown to be unsatisfactory.\n\nTopotecan is a specific S phase cytotoxic agent that cleaves double-stranded DNA during replication, which leads to cell death. Topotecan exerted a significant cytotoxic effect on several squamous cell lines of the cervix and vulva, including C-33, CaSki, and CAL-39.[24,25] Noda et al[26] first reported the anti-tumor activity of topotecan against cervical cancer, and clinical benefits were also reported for a combination of topotecan and cisplatin in patients with recurrent/persistent cervical cancer as first-line chemotherapy.[10] However, based on the GOG 204 study, a combination of paclitaxel and cisplatin showed better survival outcomes and quality of life compared with a combination of topotecan and cisplatin.[7] Therefore, the combination of cisplatin and topotecan is only one of several alternative treatment options and is not accepted as a first-line standard treatment for patients with recurrent/advanced cervical cancer. Previous studies of single-agent topotecan as second-line chemotherapy for cervical cancer have been reported, with an ORR of 12.5% to 17%, a PFS of 2.1 to 3.5 months, and an OS of 4.6 to 7.0 months.[25,27–29]\n\nOur study is the first to report a clinical benefit of combination of topotecan and cisplatin as a second-line treatment for patients with advanced/recurrent/persistent cervical cancer. After this treatment, we found an ORR of 30.8%, a median PFS of 4.6 months, and a median OS of 14.1 months. The outcomes were better or comparable with those of previous reports evaluating topotecan-alone treatment as second-line or subsequent chemotherapy. In addition, patients who responded to previous chemotherapy before topotecan and cisplatin showed a significantly better ORR and DCR compared with those of non-responders. The median PFS (6.5 months vs 2.4 months) and median OS (15.4 months vs 9.2 months) were numerically better in the responder than in the non-responder group although their improvement did not reach statistical significance.\n\nWe evaluated laboratory toxicities because of the retrospective nature of this study. All patients reported some grade of hematological toxicity; 49.1% had grade 3/4 neutropenia, 13.2% had grade 3/4 anemia, 16.3% had grade 3/4 thrombocytopenia, and 6.2% had febrile neutropenia. These toxicity profiles were comparable with those of previously reported well-controlled trials using the same dosages of cisplatin and topotecan.[10] Most complications were manageable with antibiotics, G-CSF, and dose modifications and there was no difference of toxicity profile between the responders and the non-responders. There were 2 cases of treatment discontinuation due to toxicities; 1 patient showed severe pancytopenia and the other experienced prolonged thrombocytopenia. Both patients had previously undertaken curative radiotherapy for localized cervical cancer.\n\nThere were some limitations of the present study. First, it was a retrospective analysis and thus subject to potential selection biases. Second, the small sample size precluded definitive conclusions. Furthermore, only 1 patient was treated with a previous regimen including bevacizumab, which is currently the standard chemotherapy, because most enrolled patients were treated before the efficacy of this drug was confirmed. Hence, a prospective, well-designed, and controlled trial is needed, particularly involving patients treated with first-line chemotherapy involving bevacizumab.\n\nIn conclusion, the combination of topotecan and cisplatin was effective in patients with previously treated recurrent/metastatic cervical cancer. This combination is, therefore, a possible treatment for patients showing at least a partial response to prior chemotherapy.\n\nAuthor contributions\nConceptualization: Hyo Jin Lee, Young Bok Ko.\n\nData curation: Ik-Chan Song, Ji Young Moon.\n\nFunding acquisition: Hyo Jin Lee.\n\nInvestigation: Young Bok Ko.\n\nMethodology: Ji Young Moon.\n\nSupervision: Hyo Jin Lee, Young Bok Ko.\n\nWriting – original draft: Hyo Jin Lee, Ik-Chan Song, Ji Young Moon, Young Bok Ko.\n\nWriting – review & editing: Hyo Jin Lee, Ik-Chan Song, Ji Young Moon, Young Bok Ko.\n\nAbbreviations: ANC = absolute neutrophil count, CI = confidence interval, CR = complete response, DCR = disease control rate, DNA = deoxyribonucleic acid, ECOG = Eastern Cooperative Oncology Group, G-CSF = granulocyte colony stimulating factor, GOG = Gynecologic Oncology Group, HPV = human papillomavirus, HR = hazard ratio, ORR = overall response rate, OS = overall survival, Pap = papanicolaou, PD = progressive disease, PFS = progression-free survival, PR = partial response, PS = performance status, RECIST = Response Evaluation Criteria in Solid Tumor, SD = stable disease, UNL = upper limit of normal.\n\nJYM and I-CS have contributed equally to this work.\n\nThis work was in part supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP)(No. 2017R1A5A2015385) and a research fund of Chungnam National University.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Thaxton L Waxman AG \nCervical cancer prevention: immunization and screening 2015 . Med Clin North Am \n2015 ;99 :469 –77 .25841595 \n[2] Siegel RL Miller KD Jemal A \nCancer statistics, 2016 . CA Cancer J Clin \n2016 ;66 :7 –30 .26742998 \n[3] Jung KW Won YJ Oh CM \nCancer statistics in Korea: incidence, mortality, survival, and prevalence in 2014 . Cancer Res Treat \n2017 ;49 :292 –305 .28279062 \n[4] Thigpen T Shingleton H Homesley H \ncis-Dichlorodiammineplatinum(II) in the treatment of gynecologic malignancies: phase II trials by the Gynecologic Oncology Group . Cancer Treat Rep \n1979 ;63 :1549 –55 .498154 \n[5] Omura GA Blessing JA Vaccarello L \nRandomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study . J Clin Oncol \n1997 ;15 :165 –71 .8996138 \n[6] Moore DH Blessing JA McQuellon RP \nPhase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study . J Clin Oncol \n2004 ;22 :3113 –9 .15284262 \n[7] Monk BJ Sill MW McMeekin DS \nPhase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study . J Clin Oncol \n2009 ;27 :4649 –55 .19720909 \n[8] Peiretti M Zapardiel I Zanagnolo V \nManagement of recurrent cervical cancer: a review of the literature . Surg Oncol \n2012 ;21 :e59 –66 .22244884 \n[9] Tewari KS Sill MW Long HJ 3rd \nImproved survival with bevacizumab in advanced cervical cancer . N Engl J Med \n2014 ;370 :734 –43 .24552320 \n[10] Long HJ IIIBundy BN Grendys EC Jr \nRandomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study . J Clin Oncol \n2005 ;23 :4626 –33 .15911865 \n[11] Eisenhauer EA Therasse P Bogaerts J \nNew response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer \n2009 ;45 :228 –47 .19097774 \n[12] Pignata S Silvestro G Ferrari E \nPhase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix . J Clin Oncol \n1999 ;17 :756 –60 .10071263 \n[13] Monk BJ Tewari KS Koh WJ \nMultimodality therapy for locally advanced cervical carcinoma: state of the art and future directions . J Clin Oncol \n2007 ;25 :2952 –65 .17617527 \n[14] Lorusso D Petrelli F Coinu A \nA systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer . Gynecol Oncol \n2014 ;133 :117 –23 .24486604 \n[15] duPont NC Monk BJ \nChemotherapy in the management of cervical carcinoma . Clin Adv Hematol Oncol \n2006 ;4 :279 –86 .16728939 \n[16] Thigpen JT Vance R Puneky L \nChemotherapy as a palliative treatment in carcinoma of the uterine cervix . Semin Oncol \n1995 ;22 (2 Suppl 3) :16 –24 .\n[17] Boussios S Seraj E Zarkavelis G \nManagement of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: where do we stand? A literature review . Crit Rev Oncol Hematol \n2016 ;108 :164 –74 .27931835 \n[18] Garcia AA Blessing JA Darcy KM \nPhase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: a gynecologic oncology group study . Gynecol Oncol \n2007 ;104 :572 –9 .17049588 \n[19] Garcia AA Blessing JA Vaccarello L \nPhase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study . Am J Clin Oncol \n2007 ;30 :428 –31 .17762444 \n[20] Miller DS Blessing JA Bodurka DC \nEvaluation of pemetrexed (Alimta, LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group . Gynecol Oncol \n2008 ;110 :65 –70 .18455781 \n[21] Muggia FM Blessing JA Method M \nEvaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study . Gynecol Oncol \n2004 ;92 :639 –43 .14766259 \n[22] Monk BJ Mas Lopez L Zarba JJ \nPhase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer . J Clin Oncol \n2010 ;28 :3562 –9 .20606083 \n[23] Tinker AV Ellard S Welch S \nPhase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199) . Gynecol Oncol \n2013 ;130 :269 –74 .23672928 \n[24] Boabang P Kurbacher CM Kohlhagen H \nAnti-neoplastic activity of topotecan versus cisplatin, etoposide and paclitaxel in four squamous cell cancer cell lines of the female genital tract using an ATP-Tumor Chemosensitivity Assay . Anticancer Drugs \n2000 ;11 :843 –8 .11142692 \n[25] Fiorica JV Blessing JA Puneky LV \nA Phase II evaluation of weekly topotecan as a single agent second line therapy in persistent or recurrent carcinoma of the cervix: a Gynecologic Oncology Group study . Gynecol Oncol \n2009 ;115 :285 –9 .19726073 \n[26] Noda K Sasaki H Yamamoto K \nPhase II trial of topotecan for cervical cancer of uterus (abstract) . Proc Am Soc Clin Oncol \n1996 ;15 :280 .\n[27] Bookman MA Blessing JA Hanjani P \nTopotecan in squamous cell carcinoma of the cervix: a Phase II study of the Gynecologic Oncology Group . Gynecol Oncol \n2000 ;77 :446 –9 .10831357 \n[28] de Oliveira LN Alves FVG Mora PAR \nTopotecan use for second-line treatment in patients with recurrent or metastatic cervical cancer at brazilian national cancer institute (INCA) . J Cancer Ther \n2013 ;4 :1095 –9 .\n[29] Coronel J Cetina L Candelaria M \nWeekly topotecan as second- or third-line treatment in patients with recurrent or metastatic cervical cancer . Med Oncol \n2009 ;26 :210 –4 .19016011\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "97(14)",
"journal": "Medicine",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D019772:Topotecan; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms",
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"pages": "e0340",
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"pubdate": "2018-04",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": "19097774;24486604;10071263;15911865;19016011;26742998;17762444;14766259;7537898;20606083;25841595;10831357;22244884;24552320;11142692;18455781;15284262;16728939;19726073;17049588;8996138;23672928;28279062;19720909;17617527;27931835;498154",
"title": "The combination of cisplatin and topotecan as a second-line treatment for patients with advanced/recurrent uterine cervix cancer.",
"title_normalized": "the combination of cisplatin and topotecan as a second line treatment for patients with advanced recurrent uterine cervix cancer"
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{
"abstract": "A 47-year-old man was referred to our hospital for epigastric pain and cough, and was given a diagnosis of left clear cell renal carcnoma with multiple pulmonary metastases based on the results of renal tumor biopsy (cT3aN0M1). He received nivolumab/ipilimumab combination therapy, but developed diarrhea (grade 3) on day71, and treatment was discontinued. However, a deep and durable response after discontinuation of treatment was shown, and we were able to perform nephrectomy on day336. He is undergoing nivolumab therapy for pulmonary metastases.",
"affiliations": "The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.;The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.;The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.;The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.;The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.;The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.;The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.;The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.;The Department of Urology, Ohara Health Care Foundation Kurashiki Central Hospital.",
"authors": "Tsuruta|Masafumi|M|;Shibasaki|Noboru|N|;Iguch|Ryo|R|;Yamaguchi|Takahiro|T|;Ota|Hideto|H|;Fuchigami|Yasushi|Y|;Magaribuchi|Toshihiro|T|;Naito|Hirohito|H|;Terai|Akito|A|",
"chemical_list": "D000074324:Ipilimumab; D000077594:Nivolumab",
"country": "Japan",
"delete": false,
"doi": "10.14989/ActaUrolJap_66_12_443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "66(12)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell; D006801:Humans; D000074324:Ipilimumab; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "443-448",
"pmc": null,
"pmid": "33435655",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Deep and Durable Response After Discontinuation of Nivolumab/Ipilimumab Combination Therapy for Metastatic Renal Cell Carcinoma : A Case Report.",
"title_normalized": "deep and durable response after discontinuation of nivolumab ipilimumab combination therapy for metastatic renal cell carcinoma a case report"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-033762",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "A 60-year-old woman with a 5-year history of anxiolytic use, a diazepam-equivalent daily dose of 15 mg, was scheduled for esophageal stent removal. She was given remimazolam (0.5 mg/kg) but remained fully alert. She only lost consciousness with propofol (40 mg). A 61-year-old man with a 1-year history of anxiolytic use, diazepam-equivalent daily dose of 20 mg, was scheduled for hand tumor resection. He was given remimazolam (0.3 mg/kg) but remained fully alert. He only lost consciousness after desflurane inhalation. In a patient with a history of long-term benzodiazepine use, anesthetic or sedative agents aside from remimazolam should be considered.",
"affiliations": "From the Department of Anesthesiology, Showa University School of Medicine, Tokyo, Japan.;From the Department of Anesthesiology, Showa University School of Medicine, Tokyo, Japan.;From the Department of Anesthesiology, Showa University School of Medicine, Tokyo, Japan.;From the Department of Anesthesiology, Showa University School of Medicine, Tokyo, Japan.;From the Department of Anesthesiology, Showa University School of Medicine, Tokyo, Japan.",
"authors": "Yoshikawa|Haruka|H|;Hosokawa|Maiko|M|;Kashima|Yuki|Y|;Oki|Sayaka|S|;Masui|Kenichi|K|",
"chemical_list": "D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; C522201:remimazolam; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001460",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "15(5)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D001569:Benzodiazepines; D003243:Consciousness; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008875:Middle Aged; D015742:Propofol",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01460",
"pmc": null,
"pmid": "33988524",
"pubdate": "2021-05-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Remimazolam Tolerance in Long-term Benzodiazepine Users: A Case Report of 2 Cases.",
"title_normalized": "remimazolam tolerance in long term benzodiazepine users a case report of 2 cases"
} | [
{
"companynumb": "JP-ACACIA PHARMA LIMITED-2108217",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN\\TENELIGLIPTIN"
},
"dru... |
{
"abstract": "We aimed to study the association between use of antihistamines in early pregnancy and congenital heart defects (CHD) in the offspring.\n\n\nMETHODS\nTwo case-control studies.\n\n\nMETHODS\nHAVEN study, Erasmus MC, University Medical Centre, Rotterdam, and Eurocat Northern Netherlands (NNL), University Medical Center Groningen, Groningen, the Netherlands. We studied 361 children with CHD and 410 controls without congenital malformations from the HAVEN study and replicated the analyses in 445 children with CHD and 530 controls from the Eurocat NNL registry. Information about antihistamine use in early pregnancy and potential confounders was obtained from questionnaires postpartum. We calculated the association between antihistamines and CHD risk by multivariable logistic regression analysis.\n\n\nMETHODS\nOdds ratios (OR) with 95% confidence intervals (CI). In the HAVEN study, 25 of 771 mothers used antihistamines that were associated with an increased CHD risk (OR 3.0, 95% CI 1.2-7.3), particularly atrioventricular septal defects (AVSD) (OR 5.1, 95 % CI 1.3-20.5) and perimembranous ventricular septal defects (pVSD) (OR 5.1, 95% CI 1.8-14.4). Mothers with severe nausea who did not use antihistamines had a reduced risk (OR 0.7, 95% CI 0.5-0.98), whereas nauseous mothers using antihistamines showed an almost fivefold increased risk of pVSD (OR 4.8, 95% CI 1.1-21.8). The association between antihistamines and AVSD was confirmed in the Eurocat cohort (OR 3.5, 95% CI 1.4-8.7), but we could not replicate the association with overall CHD risk. We found a positive association between antihistamine use in early pregnancy and CHD risk, particularly AVSD, which seemed to be independent of nausea/vomiting.",
"affiliations": "Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Dr. Molewaterplein 40, Room Ee 2271a, 3015 GD, Rotterdam, The Netherlands.",
"authors": "Smedts|Huberdina P M|HP|;de Jonge|Linda|L|;Bandola|Sarah J G|SJ|;Baardman|Marlies E|ME|;Bakker|Marian K|MK|;Stricker|Bruno H C|BH|;Steegers-Theunissen|Régine P M|RP|",
"chemical_list": "D006633:Histamine Antagonists",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10654-014-9925-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-2990",
"issue": "29(9)",
"journal": "European journal of epidemiology",
"keywords": null,
"medline_ta": "Eur J Epidemiol",
"mesh_terms": "D016022:Case-Control Studies; D016001:Confidence Intervals; D005260:Female; D006330:Heart Defects, Congenital; D006633:Histamine Antagonists; D006801:Humans; D008297:Male; D048968:Morning Sickness; D009035:Mothers; D009426:Netherlands; D016017:Odds Ratio; D011247:Pregnancy; D011295:Prenatal Care; D011297:Prenatal Exposure Delayed Effects; D012042:Registries; D012307:Risk Factors; D011795:Surveys and Questionnaires",
"nlm_unique_id": "8508062",
"other_id": null,
"pages": "653-61",
"pmc": null,
"pmid": "24947638",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16637899;17099293;23863575;8723120;14269616;12952140;17519397;19736223;12551774;10858967;7974252;6627167;17519398;17136550;9643709;15548781;2144945;19161158;16470733;9369870;12084585;17081182;21321151;23335187;10775746;9259911;14269614;18571373",
"title": "Early pregnancy exposure to antihistamines and risk of congenital heart defects: results of two case-control studies.",
"title_normalized": "early pregnancy exposure to antihistamines and risk of congenital heart defects results of two case control studies"
} | [
{
"companynumb": "NL-MYLANLABS-2019M1113197",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Patients with lymphoma are immunocompromised because of the disease per se and its treatments. We aimed to describe the characteristics of patients with lymphoma hospitalized for Coronavirus Disease 2019 (Covid-19) and to analyze pre-Covid-19 determinants of mortality.\nThis retrospective multicentric cohort study used the Programme de Médicalisation des Systèmes d'Information database to identify all adult patients with lymphoma, hospitalized for Covid-19 in March and April 2020, in 12 hospitals of three French regions with pandemic outbreaks. The characteristics of lymphoma and Covid-19 were collected from medical charts.\nEighty-nine patients were included. The median age was 67 years (range, 19-92), 66% were male and 72% had a comorbidity. Most patients had B-cell non-Hodgkin lymphoma (86%) and had received a lymphoma treatment within one year (70%). With a median follow-up of 33 days from admission, 30-day overall survival was 71%, (95% confidence interval, 62-81%). In multivariable analysis, having an age ≥ 70 years (hazard ratio 2·87, 1·20-6·85, p = 0·02) and relapsed/refractory lymphoma (hazard ratio 2·54, 1·14-5·66, p = 0·02) were associated with mortality. Recent bendamustine treatment (n = 9) was also pejorative (hazard ratio 3·20, 1·33-7·72, p = 0·01), but was strongly associated with relapsed/refractory lymphoma. Remarkably, 30-day overall survival for patients < 70 years of age without relapsed/refractory lymphoma was 88% (78% - 99%).\nThirty-day mortality was associated with being older and relapsed/refractory lymphoma. Survival of patients younger than 70 years without relapsed/refractory lymphoma was comparable to that of the general population.\nThere have been no specific funds to run this study.",
"affiliations": "Département d'Hématologie Clinique, CHU de Montpellier, UMR-CNRS 5535, Université de Montpellier, Montpellier, France.;Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, Assistance Publique - Hôpitaux de Paris, Inserm UMRs 938, Sorbonne Université, Paris, France.;Service d'Hématologie-Oncologie, Hôpital St Louis, Assistance Publique - Hôpitaux de Paris ; Université de Paris - Diderot, Paris, France.;Service d'Hématologie, CHRU de Besançon, Besançon, France.;Service d'Hématologie Oncologie, Centre Hospitalier de Versailles, 177, rue de Versailles, 78157 Le Chesnay Cedex, France.;Service d'Hématologie Clinique, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France.;Département d'Hématologie Groupe Hospitalier de Mulhouse Sud Alsace, Mulhouse, France.;Département d'Oncologie médicale - Hématologie, Institut Curie, Saint Cloud, France.;Service d'Hématologie Clinique, CHU de Dijon Bourgogne, Dijon, France.;Service de Médecine Interne - Immunologie, Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris, Le Kremlin-Bicêtre, France.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris, France.;Service d'Hématologie, Centre d'Oncologie de Gentilly, Nancy, France.;Service d'Hématologie, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France.;Service d'Hématologie Oncologie, Centre Hospitalier de Versailles, 177, rue de Versailles, 78157 Le Chesnay Cedex, France.;Département d'Oncologie médicale - Hématologie, Institut Curie, Saint Cloud, France.;Service d'Hématologie Clinique, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France.;Service d'Hématologie, CHRU de Besançon, Besançon, France.;Service d'Hématologie-Oncologie, Hôpital St Louis, Assistance Publique - Hôpitaux de Paris ; Université de Paris - Diderot, Paris, France.;Service d'Hématologie-Oncologie, Hôpital St Louis, Assistance Publique - Hôpitaux de Paris ; Université de Paris - Diderot, Paris, France.;Département d'Hématologie Clinique, CHU de Montpellier, UMR-CNRS 5535, Université de Montpellier, Montpellier, France.;Sorbonne Université, Inserm IPLESP, Service des Maladies Infectieuses et Tropicales, Hôpital Saint Antoine, Assistance Publique - Hôpitaux de Paris, Paris, France.;Service d'Hématologie Oncologie, Centre Hospitalier de Versailles, 177, rue de Versailles, 78157 Le Chesnay Cedex, France.",
"authors": "Lamure|Sylvain|S|;Duléry|Rémy|R|;Di Blasi|Roberta|R|;Chauchet|Adrien|A|;Laureana|Cécile|C|;Deau-Fischer|Bénédicte|B|;Drenou|Bernard|B|;Soussain|Carole|C|;Rossi|Cédric|C|;Noël|Nicolas|N|;Choquet|Sylvain|S|;Bologna|Serge|S|;Joly|Bertrand|B|;Kohn|Milena|M|;Malak|Sandra|S|;Fouquet|Guillemette|G|;Daguindau|Etienne|E|;Bernard|Sophie|S|;Thiéblemont|Catherine|C|;Cartron|Guillaume|G|;Lacombe|Karine|K|;Besson|Caroline|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.eclinm.2020.100549",
"fulltext": "\n==== Front\nEClinicalMedicine\nEClinicalMedicine\nEClinicalMedicine\n2589-5370\nElsevier\n\nS2589-5370(20)30293-5\n10.1016/j.eclinm.2020.100549\n100549\nResearch Paper\nDeterminants of outcome in Covid-19 hospitalized patients with lymphoma: A retrospective multicentric cohort study\nLamure Sylvain a1\nDuléry Rémy b1\nDi Blasi Roberta c\nChauchet Adrien d\nLaureana Cécile e\nDeau-Fischer Bénédicte f\nDrenou Bernard g\nSoussain Carole h\nRossi Cédric i\nNoël Nicolas j\nChoquet Sylvain k\nBologna Serge l\nJoly Bertrand m\nKohn Milena e\nMalak Sandra h\nFouquet Guillemette f\nDaguindau Etienne d\nBernard Sophie c\nThiéblemont Catherine c\nCartron Guillaume a\nLacombe Karine n\nBesson Caroline cbesson@ch-versailles.fr\neo⁎\na Département d'Hématologie Clinique, CHU de Montpellier, UMR-CNRS 5535, Université de Montpellier, Montpellier, France\nb Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, Assistance Publique - Hôpitaux de Paris, Inserm UMRs 938, Sorbonne Université, Paris, France\nc Service d'Hématologie-Oncologie, Hôpital St Louis, Assistance Publique - Hôpitaux de Paris ; Université de Paris – Diderot, Paris, France\nd Service d'Hématologie, CHRU de Besançon, Besançon, France\ne Service d'Hématologie Oncologie, Centre Hospitalier de Versailles, 177, rue de Versailles, 78157 Le Chesnay Cedex, France\nf Service d'Hématologie Clinique, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France\ng Département d'Hématologie Groupe Hospitalier de Mulhouse Sud Alsace, Mulhouse, France\nh Département d'Oncologie médicale – Hématologie, Institut Curie, Saint Cloud, France\ni Service d'Hématologie Clinique, CHU de Dijon Bourgogne, Dijon, France\nj Service de Médecine Interne – Immunologie, Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris, Le Kremlin-Bicêtre, France\nk Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris, France\nl Service d'Hématologie, Centre d'Oncologie de Gentilly, Nancy, France\nm Service d'Hématologie, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France\nn Sorbonne Université, Inserm IPLESP, Service des Maladies Infectieuses et Tropicales, Hôpital Saint Antoine, Assistance Publique - Hôpitaux de Paris, Paris, France\no Université Paris-Saclay, UVSQ, Montigny le Bretonneux; Inserm U1018, CESP, Villejuif, France\n⁎ Corresponding author at: Service d'Hématologie Oncologie, Center Hospitalier de Versailles, 177, rue de Versailles, 78157 Le Chesnay Cedex, France. cbesson@ch-versailles.fr\n1 These authors contributed equally.\n\n13 10 2020\n10 2020\n13 10 2020\n27 10054923 7 2020\n29 8 2020\n3 9 2020\n© 2020 The Author(s)\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nPatients with lymphoma are immunocompromised because of the disease per se and its treatments. We aimed to describe the characteristics of patients with lymphoma hospitalized for Coronavirus Disease 2019 (Covid-19) and to analyze pre-Covid-19 determinants of mortality.\n\nMethods\n\nThis retrospective multicentric cohort study used the Programme de Médicalisation des Systèmes d'Information database to identify all adult patients with lymphoma, hospitalized for Covid-19 in March and April 2020, in 12 hospitals of three French regions with pandemic outbreaks. The characteristics of lymphoma and Covid-19 were collected from medical charts.\n\nFindings\n\nEighty-nine patients were included. The median age was 67 years (range, 19–92), 66% were male and 72% had a comorbidity. Most patients had B-cell non-Hodgkin lymphoma (86%) and had received a lymphoma treatment within one year (70%). With a median follow-up of 33 days from admission, 30-day overall survival was 71%, (95% confidence interval, 62–81%). In multivariable analysis, having an age ≥ 70 years (hazard ratio 2·87, 1·20–6·85, p = 0·02) and relapsed/refractory lymphoma (hazard ratio 2·54, 1·14–5·66, p = 0·02) were associated with mortality. Recent bendamustine treatment (n = 9) was also pejorative (hazard ratio 3·20, 1·33–7·72, p = 0·01), but was strongly associated with relapsed/refractory lymphoma. Remarkably, 30-day overall survival for patients < 70 years of age without relapsed/refractory lymphoma was 88% (78% - 99%).\n\nInterpretation\n\nThirty-day mortality was associated with being older and relapsed/refractory lymphoma. Survival of patients younger than 70 years without relapsed/refractory lymphoma was comparable to that of the general population.\n\nFunding\n\nThere have been no specific funds to run this study.\n==== Body\nResearch in context\n\nEvidence before this study\n\nThere is a lack of data describing in detail the natural history of patients with lymphoma who have Covid-19. As of June 26, 2020, literature concerning patients with cancer in general or hematological malignancies and Covid-19 is growing. Data describing cancer patients demonstrate a worse outcome for older patients, patents with progressive disease and patients with hematological malignancies within 5 years. However, no analyses were performed on the specific population of patients with lymphoma.\n\nAdded value of this study\n\nWe report a large series of consecutive patients with lymphoma and hospitalized for Covid-19, including 89 patients from French regions with an outbreak of the pandemic. The population is homogeneous, lymphoma sub-types are representative of the known epidemiology: most of them had B-cell non-Hodgkin lymphoma, and had been treated for lymphoma within 1 year. We found significant associations between 30-day mortality and increasing age and relapsed/refractory lymphoma. Remarkably, in absence of those factors, mortality was comparable to the French Covid-19 population. There was no significant impact of active lymphoma treatment within one year, except for bendamustine which was associated with mortality.\n\nImplications of all the available evidence\n\nWe identified factors that are associated with increased 30-day mortality in patients with lymphoma hospitalized for Covid-19. In absence of those factors, mortality appears comparable to the general population, encouraging health-care providers to treat them with the standard of care.\n\nAlt-text: Unlabelled box\n\n1. Introduction\n\nThe first cases of coronavirus disease 2019 (Covid-19) were reported to the World Health Organization (WHO) in December 2019 in China with an unprecedented impact on the entire worldwide oncology community reducing healthcare activities for a duration that cannot yet be accurately estimated. The incubation period of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is two to 14 days [1]. During this period, SARS-CoV-2 invades epithelial cells using angiotensin conversion enzyme (ACE) receptor 2 [2]. Then, most patients develop upper respiratory symptoms and fever. Innate and adaptive immune responses lead to recovery for 80–85% of patients, but symptoms worsen for the remaining 1520%. Hospitalization is required in 14 to 39% of symptomatic cases due to hypoxemia, evolution toward acute respiratory distress syndrome, and/or cytokine release syndrome, which occurs in 5–13% of cases, leading to death in approximately 2–9% of cases [3,4]. Risk of death is higher in patients aged above ≥ 60 years and/or with existing comorbidities, including obesity, hypertension, diabetes, or a past history of cancer [5]. Among patients with hematological malignancies, an over-risk of death has been reported with hazard ratios (HRs) ranging from 1·9 to 3·5, depending on the time since diagnosis of the malignancy [5].\n\nThe one-year incidence of lymphoma in France is estimated to be approximately 30,000 [6]. Several factors contribute to immunosuppression in patients with lymphoma: hypogammaglobulinemia, neutropenia and lymphopenia are frequent biological features of lymphoma per se, lymphoma treatment, chemotherapy and/or immunotherapy also contributes to immune deficiency leading to an over incidence of infections [7,8]. Among chemotherapy regimen, bendamustine is a strong inducer of T-cell immune deficiency [9]. Anti-CD20 monoclonal antibodies, such as rituximab or obinutuzumab, induce rapid depletion of more than 95% of CD20-positive mature B-cells. This alters the generation of antibody responses, including memory responses to new pathogens, increasing the incidence of infections [10,11]. However, data on the impact of Covid-19 in lymphoma patients are scarce. In a study from the Covid-19 and Cancer Consortium (CCC19) on 1035 patients with Covid-19 and various cancers, no analysis was conducted specifically on the 81 patients with lymphoma [12]. In other studies on Covid-19, few patients with lymphoma were described [[13], [14], [15]].\n\nWe conducted a retrospective multicentric cohort study in French regions with an outbreak of the pandemic to characterize the clinical presentation and outcomes of patients with lymphoma hospitalized for Covid-19. The analysis of the determinants of survival focused on pre-Covid-19 demographics, comorbidity, and lymphoma characteristics.\n\n2. Methods\n\n2.1. Setting\n\nThis retrospective multicenter study was conducted in 12 hospitals in three French regions: Île-de-France, Grand-Est and Bourgogne-Franche-Comté. Adult patients with a past or current diagnosis of lymphoma (with any known lymphoma code since September 1st, 2019) and admitted for Covid-19 between March 1st and April 30th, 2020 were identified, in each hospital, by the local Programme de Médicalisation des Systèmes d'Information (PMSI), which is a centralized repository of administrative and medical data of every hospital stay in France. PMSI data includes the main diagnosis leading to hospitalization, as well as the associated diseases of each patient, coded according to the 10th edition of the International Classification of Diseases [16,17]. After extraction of the list of putative patients, each local investigator confirmed the cases with a diagnosis of Covid-19 based on a positive polymerase chain reaction (PCR) test result for SARS-CoV-2 from nasopharyngeal or oropharyngeal swabs or a typical clinical history associated with chest computed tomography (CT) with Covid-19 lesions [18]. Patients with any lymphoma subtype could be enrolled in the study, except those with lymphoblastic and lymphocytic lymphomas, which are being investigated in other specific ongoing studies.\n\nPatients or their relatives (for those who were sedated) were informed according to French law on biomedical research. The ethics committee for research of the Université Paris-Saclay approved this study (CER-Paris-Saclay-2020–045) and it was conducted in accordance with the Declaration of Helsinki. Information on the study is available at clinicaltrials.gov (NCT 04386512).\n\n2.2. Data sources and assessment of variables\n\nData were extracted from the medical charts in each hospital by the local investigator. The following data were obtained for each patient: age, sex, body mass index (BMI), patient-reported smoking status, past and current comorbidities and medications; the physical examination, recorded symptoms and vital signs, and inpatient laboratory test results at admission; the most relevant chest computed tomography (CT) scan interpretation, specific medications for Covid-19, including experimental antiviral or immunomodulatory drugs, oxygenation supply modality including ventilator use, and hospital discharge modality. The data obtained concerning lymphoma history included the date of diagnosis, pathological classification according to the WHO classification for lymphoid neoplasms [19], number of treatment lines, past autologous or allogeneic stem cell transplant, chimeric antigen receptor (CAR) T-cell therapy, detailed bendamustine and anti-CD20 monoclonal antibody use (date of first and last administration), and lymphoma status at admission for Covid-19 (complete or partial remission, diagnosed at admission, under first or second line treatment, in watch and wait follow-up, or refractory/relapsed). Refractory/relapsed lymphoma was defined as progressive disease after more than two lines of treatment or progressive disease and palliative care due to comorbidities, regardless of the number of lines of treatment.\n\n2.3. Statistical analysis\n\nContinuous variables are given as their median and range and categorical variables as their frequency and percentage. Follow-up was measured from hospitalization for Covid-19 to the last follow-up or date of death. Data were censored on May 26th, 2020. Overall survival (OS) was measured from hospitalization to last follow-up or death. The probability of OS was estimated using the Kaplan-Meier method, and differences compared using the log-rank test. Cox proportional hazard regression models were used to identify predictors of OS. Covariates considered in this analysis were age (≥ 70 years versus below), gender, BMI (≥ 30 kg/m2 versus below), smoking status, presence of comorbidities (overall or hypertension, diabetes, chronic lung disease, or past history of cancer) and ongoing antihypertensive treatment with an ACE inhibitor or angiotensin-receptor blocker (ARB), main lymphoma subtypes (Hodgkin lymphoma, B-cell non-Hodgkin lymphoma (NHL), or T-cell NHL), recent administration of corticosteroids (within one month), use of bendamustine (within one year), or anti-CD20 monoclonal antibody (within one year), time between diagnosis of lymphoma and hospitalization for Covid-19 (< 2 years versus ≥ 2 years), past history of autologous stem cell transplant, and lymphoma status (refractory/relapsed versus others). Covariates with P-values < 0·10 by univariable analysis were included in the multivariable analysis. Statistical tests were two-tailed and P values < 0·05 and P-values < 0·05 were considered to denote statistical significance. Analyses were performed using Epi Info V7.1.5 (CDC, Atlanta, USA) and Kaplan Meier survival curves with SPSS software V26 (IBM, New York, USA).\n\n2.4. Role of the funding source\n\nThere have been no specific funds to run this study.\n\n3. Results\n\n3.1. Characteristics of patients at admission\n\nThe data of 98 patients were collected. Nine patients were excluded because they were not admitted during the time period of the study (n = 6), had lymphocytic lymphoma (n = 2) or had SARS-CoV-2 infection without overt Covid-19 disease (n = 1). Characteristics of the 89 included patients are summarized in Table 1. Their median age was 67 years (range, 19–92) and 66% were male. Sixty-four patients (72%) had at least one significant comorbidity, including 39 (44%) with hypertension, 20 (22%) with diabetes, and 12 (13%) with a history of previous cancer (including 3 with prostate, 3 with lung, and 2 with breast cancer). Moreover, four patients had an ongoing autoimmune disease (Gougerot-Sjögren, rheumatoid polyarthritis, giant cell arteritis, and hemorrhagic rectocolitis), one had a previous renal transplantation, and two were treated for human immunodeficiency virus infection.Table 1 Baseline characteristics of patients with lymphoma and Covid-19.\n\nTable 1Characteristics\tEntire population\tAdmitted to an ICU\tFatal events\t\n\t(n = 89)\t(n = 25)\t(n = 30)\t\nDemographic characteristics\t\nAge, years\t\t\t\t\nMedian (range)\t67 (19–92)\t61 (52–77)\t75 (63–92)\t\n≥ 70, n (%)\t38 (43)\t4 (16)\t21 (70)\t\nMale gender, n (%)\t59 (66)\t17 (68)\t21 (70)\t\nBody mass index (kg/m2)\t\t\t\t\nMedian (range)\t23·9 (15·9–41·6)\t25 (19·4–41·6)\t24·4 (16·7–38·6)\t\n≥ 30, n (%)\t13 (15)\t5 (20)\t4 (13)\t\nData missing, n (%)\t4 (4)\t1 (4)\t3 (10)\t\nSmoking status, n (%)\t\nNever smoked\t43 (48)\t15 (60)\t12 (41)\t\nFormer smoker\t29 (33)\t5 (20)\t13 (43)\t\nCurrent smoker\t5 (6)\t1 (4)\t1 (3)\t\nUnknown\t12 (13)\t4 (16)\t4 (13)\t\nComorbidities\t\nComorbidity ≥ 1, n (%)\t64 (72)\t12 (48)\t25 (83)\t\nPast diagnoses, n (%)\t\nHypertension\t39 (44)\t6 (24)\t18 (60)\t\nDiabetes\t20 (22)\t3 (12)\t9 (30)\t\nChronic lung disease†\t8 (9)\t2 (8)\t3 (10)\t\nCancer\t12 (13)\t1 (4)\t7 (23)\t\nHIV infection\t2 (2)\t0 (0)\t0 (0)\t\nMedication at baseline, n (%)\t\nACE inhibitor or ARB\t22 (25)\t5 (20)\t10 (33)\t\nSystemic glucocorticoid\t11 (12)\t2 (8)\t4 (13)\t\nLymphoma characteristics\t\nHistologic subtypes, n (%)\t\nHodgkin lymphoma\t5 (6)\t2 (8)\t1 (3)\t\nDiffuse large B-cell lymphoma\t34 (38)\t9 (36)\t15 (50)\t\nFollicular lymphoma\t16 (18)\t7 (28)\t2 (7)\t\nMarginal zone lymphoma\t14 (16)\t1 (4)\t5 (17)\t\nMantle cell lymphoma\t10 (11)\t4 (16)\t4 (13)\t\nHairy cell leukemia\t2 (2)\t0 (0)\t0 (0)\t\nLymphoplasmacytic lymphoma\t1 (1)\t1 (4)\t1 (3)\t\nT-cell lymphoma\t7 (8)\t1 (4)\t2 (7)\t\nLymphoma treatment, n (%)\t\nAnti-CD20 monoclonal antibody#\t47 (53)\t16 (64)\t19 (63)\t\nBendamustine#\t9 (10)\t1 (4)\t7 (23)\t\nAny chemotherapy#\t62 (70)\t19 (76)\t22 (73)\t\nAutologous stem cell transplant\t17 (19)\t8 (32)\t8 (27)\t\nAllogeneic stem cell transplant\t3 (3)\t1 (4)\t1 (3)\t\nCAR T-cell\t4 (4)\t2 (8)\t1 (3)\t\nLymphoma status, n (%)\t\t\t\t\nComplete remission\t39 (44)\t16 (64)\t10 (33)\t\nPartial remission\t1 (1)\t0 (0)\t0 (0)\t\nOngoing therapy < 3 lines\t24 (26)\t4 (16)\t9 (30)\t\nWatch and wait\t12 (14)\t3 (12)\t2 (7)\t\nRelapsed/refractory\t13 (15)\t2 (8)\t9 (30)\t\nTime between diagnosis of lymphoma and hospitalization for Covid-19 (months), median (range)\t26 (0–300)\t25 (0–289)\t26 (1–289)\t\nHIV: human immunodeficiency virus, ACE: angiotensin-converting enzyme, ARB: angiotensin-receptor blocker, CAR: chimeric antigen receptor.\n\n† Chronic lung disease was defined as chronic obstructive pulmonary disease, asthma, or chronic bronchitis.\n\n# Treatment administrated within the last 12 months before hospitalization for Covid-19.\n\nLymphoma histological subtypes were Hodgkin lymphoma in for five patients (6%), B-cell NHL for 77 (86%), and T-cell NHL for seven (8%). The median time between diagnosis of lymphoma and admission in hospital for Covid-19 was 26 months (range, 0–25 years). Lymphoma had been diagnosed for less than one month before Covid-19 for three patients and two were diagnosed with lymphoma concomitantly with Covid-19. Within the last 12 months before hospitalization for Covid-19, 62 patients (70%) received treatment for their lymphoma, including anti-CD20 monoclonal antibody for 47 (53%) and bendamustine for nine (10%). At admission, lymphoma was in complete/partial remission for 40 patients (45%), in first- or second-line therapy for 24 (26%), in watch and wait surveillance for 12 (14%), and relapsed/refractory for 13 (15%).\n\nThe clinical, radiological and biological characteristics at admission to hospital are detailed in Supplemental Table 1. The most common symptoms were dyspnea (n = 58, 65%), cough (n = 53, 60%), fever (n = 43, 48%), and diarrhea (n = 21, 24%). The median duration of symptoms before admission was six days (range, 0–43). Lymphopenia was observed in 66% of patients, neutropenia in 18%, anemia in 66% and thrombocytopenia in 39%. The albumin level was < 30 g/L for 42% evaluable patients and the gamma globulin level < 6·5 g/L for 48%. Chest CT was performed on 75 patients (84%) and bilateral ground-glass opacities evocative of Covid-19 were observed for 67 (75%). Eight patients had negative PCR tests, although they all had evocative clinical symptoms: the diagnosis of SARS-CoV-2 pneumonia was confirmed by chest CT and infectiology expertise in all eight cases.\n\n3.2. Clinical evolution after admission\n\nAs of May 26, 2020, 48 patients (54%) had been discharged from hospital, 30 had died (34%), and 11 (13%) were still hospitalized (including six patients in an intensive care unit (ICU)). During hospitalization, 18 patients (20%) did not require supplemental oxygen, 44 (49%) received low-dose supplemental oxygen, six (7%) non-invasive ventilation or high-flow oxygen, and 21 (24%) invasive mechanical ventilation. Including these last patients, 25 patients (28%) were admitted to the ICU during the study time period (Table 1): 17 (68%) were male and their median age was 61 years (range 52–77), four patients being older than 70 (16%). Overall, 20 patients (22%) were hospitalized for more than 30 days and three (3%) for more than 60.\n\nTwenty-one patients were prescribed a treatment against SARS-CoV-2: chloroquine and hydroxychloroquine were given to 11 patients, either alone (n = 5) or associated with azithromycin (n = 3), nicotine (n = 1), lopinavir + ritonavir (n = 1), or remdesivir (n = 1). Of note, one patient was already receiving chronic hydroxychloroquine treatment for Gougerot-Sjögren's syndrome before Covid-19 and it was not interrupted during the infection. Five other patients received lopinavir + ritonavir, associated with interferon beta for one, and five had remdesivir. Six patients received treatment for cytokine shock (tocilizumab, anakinra, and eculizumab for two patients each). Seventeen patients (19%) developed a documented co-infection and three an (3%) acute pulmonary embolism.\n\n3.3. Overall survival and its determinants\n\nWith a median follow-up of 33 days from admission (range, 3–72), the Kaplan-Meier estimate of 30-day OS was 71% (95% confidence interval (CI), 62%−81%) (Fig. 1A). According to histological type of the lymphoma, 30-day OS were 80% (45%−100%) for Hodgkin lymphoma, 71% (95% CI, 61%−82%) for B-cell NHL and 71% (95% CI, 38%−100%) for T-cell NHL (Fig. 1B). Among the 30 patients who died during the study period, 22 died in standard care units after do-not-resuscitate orders for all of them. Their median age was 77 (range, 53–92) years, 14 were male, and they all had at least one significant comorbidity. Lymphoma status distribution was refractory/relapsed (n = 7), under ongoing therapy (n = 7), in complete remission (n = 6) and on a ‘watch and wait’ policy (n = 2). Eight other patients died in the ICU (Table 2). Six deaths were directly related to Covid-19: All were men, aged 55 to 77 years, four were in complete remission after first (n = 3) or second line therapy (n = 1) while two patients were under ongoing first line chemotherapy with R-CHOP for a DLBCL or autologous transplant for a relapsed follicular lymphoma. Two deaths were directly related to refractory lymphomas. The case fatality rate was 13% in the 55 patients without do-not-resuscitate orders.Fig. 1 Overall survival of patients with Covid-19 and lymphoma in (A) the whole population (N = 89), (B) according to lymphoma subtype, (C) to age group, and (D) lymphoma status.\n\nA) 30-day OS, 71% (95% CI, 62–81%).\n\nB) 30-day OS of five patients with Hodgkin lymphoma, 80% (95% CI, 45–100%); of 77 patients with B-cell non-Hodgkin lymphoma, 71% (95% CI, 61–82%); and of seven patients with T-cell non-Hodgkin lymphoma, 71% (95% CI, 38–100%).\n\nC) 30-day OS of 51 patients aged < 70 years, 85% (95% CI, 76–95%); and of 38 patients aged ≥ 70 years, 53% (95% CI, 37–70%).\n\nD) 30-day OS of 76 patients with non-refractory/relapsed lymphoma 73% (95% CI, 63–84%); and of 13 patients with relapsed/refractory lymphoma 61% (95% CI, 35–88%).\n\nMedian follow-up from admission for Covid-19, 33 days (range, 3–72). CI: confidence interval, OS: overall survival.\n\nFig. 1\n\nTable 2 Description of Covid-19 patients with lymphoma who died while in intensive care.\n\nTable 2Age (year)\tGender\tComorbidity\tLymphoma subtype\tLast treatment\tInterval between last treatment and Covid-19\tLymphoma Status\tLymphocyte count (/µL)\tCRP (mg/L)\tFerritin (ng/L)\tIntubation\tComplication\tInterval from ICU admission and death (days)\t\nPatients who died from Covid-19 in complete remission\t\n57\tM\tNo\tMantle cell lymphoma\tObinutuzumab\t2 months\tComplete remission\t80\t72\t5565\tYes\tVentilator associated\t7\t\npneumonia\t\n59\tM\tPulmonary embolism\tFollicular lymphoma\tBEAM\t9 months\tComplete remission\t170\t238\t3\tYes\tCatheter thrombosis\t30\t\n61\tM\tAtrial fibrillation\tDLBCL\tR-CHOP\t5 months\tComplete remission\t400\t352\t2566\tYes\tNA\t9\t\n77\tM\tDiabetes\tDLBCL\tR-CHOP\t12 months\tComplete remission\t500\t96\t1388\tNo\tNA\t11\t\n\t\tHypertension\t\t\t\t\t\t\t\t\t\t\t\n\t\tCardiopathy\t\t\t\t\t\t\t\t\t\t\t\n\t\nPatients who died from Covid-19 while being treated for lymphoma\t\n55\tM\tLung cancer\tFollicular lymphoma\tBEAM\t6 days\tOngoing consolidation\tNA\tNA\tNA\tYes\tAspergillosis\t29\t\n\t\t\t\t\t\ttreatment\t\t\t\t\t\t\t\n\t\tEmphysema\t\t\t\t\t\t\t\t\t\t\t\n71\tM\tNo\tDLBCL\tR-CHOP\t13 days\tOngoing induction\t840\t62\t2053\tYes\tNA\t25\t\n\t\nPatients who died from lymphoma progression while having Covid-19\t\n60\tF\tNo\tT-cell lymphoma\tBEAM\t5 months\tRelapse\t730\t45\tNA\tNo\tNA\t13\t\n72\tM\tNo\tLymphoplasmacytic\tR-Bendamustine\t7 days\tRefractory\t630\t39\t2271\tNo\tPulmonary embolism\t15\t\n\t\t\tlymphoma\t\t\t\t\t\t\t\t\t\t\nCRP:C-reactive protein, DLBCL: diffuse large B-cell lymphoma, BEAM: autologous stem cell transplantation with carmustine - etoposide - cytarabine and melphalan conditioning regimen, ICU: intensive care unit, NA not available.\n\nIn univariable analysis, there was no significant impact of the patients’ gender, BMI, diabetes status, smoking status, medications at baseline, use of any treatment, including anti-CD20 monoclonal antibody within 12 months, or history of autologous stem cell transplant on OS (Table 3). The main factors associated with mortality were age ≥ 70 years (HR 3·78, 95% CI 1·73–8·25, p = 0·0009), hypertension (HR 2·20, 95% CI 1·06–4·59, p = 0·03), previous cancer (HR 2·11, 95% CI 0·90–4·92, p = 0·08), use of bendamustine within 12 months before admission to hospital (HR 3·05, 95% CI 1·31–7·11, p = 0·01), and refractory/relapsed lymphoma (HR 2·62, 95% CI 1·20–5·72, p = 0·02). Since there was a strong interaction between recent bendamustine administration and refractory/relapsed lymphoma (Odds-ratio: 20·0, p < 0·001), we performed two multivariable analyses to account for these factors. In the first multivariable analysis, combining age subgroup, hypertension, previous cancer, and recent bendamustine use, age ≥ 70 years (HR 2·94, 95% CI 1·26–6·83, p = 0·01) and recent bendamustine use (HR 3·20, 95% CI 1·33–7·72, p = 0·01) were both associated with mortality. In the second multivariable model, combining age subgroup, hypertension, previous cancer, and refractory/relapsed lymphoma, age ≥ 70 years (HR 2·87, 95% CI 1·20–6·85, p = 0·02) and having refractory/relapsed lymphoma (HR 2·54, 95% CI 1·14–5·66, p = 0·02) were significantly associated with the risk of death (Table 3). Overall, the Kaplan-Meier estimate of 30-day OS was 61% (95% CI, 35%−88%) for patients with refractory/relapsed lymphoma, 52% (95% CI, 34%−70%) in patients ≥ 70 years of age with non-refractory/relapsed lymphoma, and 88% (95% CI, 78%−99%) for patients < 70 years old with non-refractory/relapsed lymphoma (Fig. 2).Table 3 Cox univariable and multivariable analyses of overall survival among patients with lymphoma and Covid-19.\n\nTable 3Characteristics\tStudy population\tUnivariate analysis\tMultivariable analysis (model 1)\tMultivariable analysis (model 2)\t\n\tN\tFatal events, n\tHR\t95% CI\tP value*\tHR\t95% CI\tP value*\tHR\t95% CI\tP value*\t\nAge ≥ 70 years\t38\t21\t3·78\t1·73–8·25\t9·10e-4\t2·94\t1·26–6·83\t0·01\t2·87\t1·20–6·85\t0·02\t\nGender\t\t\t\t\t0·68\t\t\t\t\t\t\t\nFemale\t30\t9\t1\t\t\t\t\t\t\t\t\t\nMale\t59\t21\t1·18\t0·54–2·57\t\t\t\t\t\t\t\t\nBody mass index (kg/m2)\t\t\t\t\t0·61\t\t\t\t\t\t\t\n< 30\t72\t23\t1\t\t\t\t\t\t\t\t\t\n≥ 30\t13\t4\t1·25\t0·53–2·91\t\t\t\t\t\t\t\t\nData missing\t4\t3\t\t\t\t\t\t\t\t\t\t\nSmoking status\t\t\t\t\t\t\t\t\t\t\t\t\nNever smoked\t43\t12\t1·51\t0·20–11·61\t0·69\t\t\t\t\t\t\t\nFormer smoker\t29\t13\t2·84\t0·37–21·75\t0·31\t\t\t\t\t\t\t\nCurrent smoker\t5\t1\t1\t\t\t\t\t\t\t\t\t\nUnknown\t12\t4\t1·90\t0·21–17\t0·57\t\t\t\t\t\t\t\nComorbidities (1 or more)\t64\t25\t2·17\t0·83–5·67\t0·11\t\t\t\t\t\t\t\nPast diagnoses\t\t\t\t\t\t\t\t\t\t\t\t\nHypertension\t39\t18\t2·20\t1·06–4·59\t0·03\t1·45\t0·66–3·20\t0·36\t1·45\t0·64–3·29\t0·38\t\nDiabetes\t20\t9\t1·73\t0·79–3·78\t0·17\t\t\t\t\t\t\t\nChronic lung disease†\t8\t3\t1·02\t0·31–3·36\t0·98\t\t\t\t\t\t\t\nCancer\t12\t7\t2·11\t0·90–4·92\t0·08\t2·06\t0·84–5·08\t0·12\t1·97\t0·81–4·80\t0·13\t\nMedication at baseline\t\t\t\t\t\t\t\t\t\t\t\t\nACE inhibitor or ARB\t22\t10\t1·66\t0·77–3·54\t0·19\t\t\t\t\t\t\t\nSystemic glucocorticoids\t11\t4\t0·82\t0·29–2·35\t0·71\t\t\t\t\t\t\t\nHistologic subtypes\t\t\t\t\t\t\t\t\t\t\t\t\nHodgkin lymphoma\t5\t1\t0·43\t0·06–3·19\t0·41\t\t\t\t\t\t\t\nB-cell NHL\t77\t27\t1\t\t\t\t\t\t\t\t\t\nT-cell NHL\t7\t2\t0·81\t0·19–3·42\t0·78\t\t\t\t\t\t\t\nLymphoma treatment\t\t\t\t\t\t\t\t\t\t\t\t\nAnti-CD20 antibody#\t47\t19\t1·41\t0·67–2·97\t0·36\t\t\t\t\t\t\t\nBendamustine#\t9\t7\t3·05\t1·31–7·11\t0·01\t3·20\t1·33–7·72\t0·01\t\t\t\t\nAny therapy#\t62\t22\t1·08\t0·48–2·42\t0·86\t\t\t\t\t\t\t\nAutologous SCT\t17\t8\t1·64\t0·73–3·69\t0·23\t\t\t\t\t\t\t\nLymphoma status\t\t\t\t\t0·02\t\t\t\t\t\t0·02\t\nRelapsed/refractory\t13\t9\t2·62\t1·20–5·72\t\t\t\t\t2·54\t1·14–5·66\t\t\nOthers\t76\t21\t1\t\t\t\t\t\t1\t\t\t\nTime between diagnosis of lymphoma and hospitalization for Covid-19 < 2 years\t76\t21\t1·18\t0·57–2·43\t0·64\t\t\t\t\t\t\t\nACE: angiotensin converting enzyme inhibitors, ARB: angiotensin receptor blockers, CI: confidence interval, HR: hazard ratio, NHL: non-Hodgkin lymphoma, SCT: stem cell transplantation.\n\n† Chronic lung disease was defined as chronic obstructive pulmonary disease, asthma, or chronic bronchitis.\n\n# Treatment administrated within the last 12 months before hospitalization for Covid-19.\n\n* Logrank test.\n\nFig. 2 Overall survival of patients with Covid-19 and lymphoma (N = 89), according to age group and refractory/relapsed lymphoma status.\n\n- 30-day OS for 13 patients with refractory/relapsed lymphoma, 61% (95% CI, 35–88%).\n\n- 30-day OS for 31 patients aged ≥ 70 years with non-refractory/relapsed lymphoma, 52% (95% CI, 34–70%).\n\n- 30-day OS for 45 patients aged < 70 years with non-refractory/relapsed lymphoma, 88% (95% CI, 78–99%).\n\nMedian follow-up from admission for Covid-19: 33 days (range, 3–72); CI: confidence interval, OS: overall survival.\n\nFig. 2\n\n4. Discussion\n\nSARS-CoV-2 infection raises specific concerns in terms of morbidity and mortality for patients with lymphoma due to their immunocompromised status induced by the disease per se and/or its treatment. The present retrospective multicentric cohort study aimed to estimate the mortality rate and to identify preexisting risk factors for Covid-19 related death in the lymphoma population. It focused notably on recent exposition to cytotoxic chemotherapy, including bendamustine and anti-CD20 immunotherapy. Among 89 patients with Covid-19 and lymphoma, one-month OS was 71%. Factors associated with death were advanced age and relapsed/refractory lymphoma. Bendamustine also appeared to be associated with death but most of the patients treated with bendamustine had relapsed/refractory lymphoma. Anti-CD20 treatment within one year was not associated with death. Patients younger than 70 without relapsed or refractory disease had 88% 30-day OS, similar to that of the general population in France [20].\n\nIn the previously mentioned CCC19 study, the death rate for patients with hematological malignancies was 14% during one month [12]. The lower risk of death they reported may have been due to the inclusion of both ambulatory and hospitalized patients with Covid-19 in their study. However, in the UKNHS study, analyzing hospitalized patients only, patients with hematological malignancies diagnosis within five years had a high mortality rate (29%) from Covid-195, similar to our findings. Among well-known risk factors for Covid-19 mortality [5], we report an association with advanced age (above 70 years) (HR 2·94), but no significant association with hypertension (HR 1·46), diabetes (HR 1·73), or obesity (HR 1·25). In accordance with the CCC19 study showing that active cancer was associated with a worse outcome (HR 5·20)(12), refractory/relapsed lymphoma was associated with an increased mortality in our study (HR 2·54).\n\nAlthough recent overall administration of immunochemotherapy was not associated with mortality, a history of treatment with bendamustine within one year was associated with a higher mortality rate (HR 3·20). Bendamustine treatment induces myelosuppression and T-CD4 lymphopenia, and is associated with an increased risk of viral, bacterial or fungal infections [9]. However, among the nine patients who had received this treatment, eight had been given a do-not-resuscitate order and had a refractory/relapsed lymphoma. Further studies are merited to explore the impact of bendamustine on Covid-19 evolution. However, since bendamustine therapy may be associated with a higher risk of mortality, the risk of initiating this therapy in older patients in geographic areas of high prevalence of COVID-19 would warrant careful consideration. Despite the well-known importance of the adaptive immune response to clear SARS-CoV-2 [21], having received an anti-CD20 therapy up to 12 months before Covid-19 was not associated with mortality (HR 1·41). However, B-cell depletion at the time of acute infection may impair the generation of functional primary and memory anti-SARS-CoV-2 T-cell responses. Therefore, there is a concern of whether lymphoma patients on anti-CD20 who contracted SARS-CoV2 and patients who will receive SARS-CoV2 vaccines when available will be effectively protected against re-infection or infection.\n\nOverall, patients younger than 70 without relapsed/refractory lymphoma had outcomes (30-day survival of 88%) comparable to those of the non-cancer population. According to Santé Publique France, in-hospital mortality is 18%, rising from 10% for 45- to 64-year-old patients to 18% for the 65 to 74-year-old group, and 71% for older patients [20]. This encourages the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission. A do-not-resuscitate order was frequently given for patients undergoing advanced lines of treatment and/or with relapsed/refractory disease, limiting the interpretation of data. In patients without do-not-resuscitate order, the case fatality rate was also comparable to comparable to those of the non-cancer population.\n\nA strength of our study was the screening of patients based on the PMSI, which limited selection bias. However, some patients may have been hospitalized for Covid-19 in hospitals other than that of their hematological unit and may have been excluded from the study. Other limitations were the retrospective nature of the study and the study design, which did not allow a direct comparison between lymphoma patients with Covid-19 and Covid-19 patients without lymphoma. Another limitation of selecting only hospitalized patients was the exclusion of patients with mild symptoms, and old patients living in nursing homes that weren't transferred in hospital during the pandemic. Exhaustive inclusion of all patients with Covid-19 and lymphoma, including those with mild symptoms, would have been impossible due to the restricted PCR testing during the first phase of the outbreak in France, but would be recommended in the next epidemic phases, as serological and PCR testing have become largely available.\n\nIn conclusion, this cohort study reports 71% 30-day OS in patients with lymphoma and Covid-19, advanced age and having relapsed/refractory lymphoma being the main risk factors for death. However, patients younger than 70, without relapsed/refractory disease, had 88% 30-day overall survival, which is comparable to that of the general population. Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients.\n\nDeclaration of Interests\n\nThe authors certify that there is no conflict of interest with any organization regarding the material presented in this manuscript.\n\nRémy Duléry reports personal fees from Takeda, non-financial support from Gilead, personal fees from Novartis, outside the submitted work. Roberta Di Blasi reports personal fees from Gilead, personal fees from Novartis, outside the submitted work. Sylvain Choquet reports personal fees from Sanofi, personal fees from Celgene, personal fees from Roche, personal fees from Abbvie, personal fees from Sandoz, personal fees from Janssen, personal fees from Takeda, personal fees from Sandoz, outside the submitted work. Serge Bologna reports personal fees from Janssen, personal fees from Roche, outside the submitted work. Sophie Bernard reports non-financial support from Janssen, outside the submitted work. Guillaume Cartron reports personal fees from Roche, Celgene, Sanofi, Gilead, Janssen, and Abbvie, outside the submitted work. Karine Lacombe reports personal fees and non-financial support from Gilead, personal fees and non-financial support from MSD, personal fees and non-financial support from Abbvie, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Janssen, outside the submitted work. Caroline Besson reports non-financial support from Takeda, outside the submitted work. All other authors have nothing to disclose.\n\nAcknowledgments\n\nWe thank all the clinicians and patients in the participating centers for their contributions to this multicenter study. We are grateful to the Centre Hospitalier de Versailles, in particular Laure Morisset for the research promotion, and for supporting the editing. We thank France Lymphome Espoir for reviewing the study material, LYSA for discussions on the design of this study, Sophie Rigaudeau for her contribution to collection of cases, and Yassine Taoufik for his contributions on the immunological aspects of immunotherapy in Covid-19.\n\nAuthors contributions\n\nSylvain Lamure and Rémy Duléry designed the data collection, collected data, analyzed the data and wrote the article. Roberta Di Blasi, Adrien Chauchet, Bénédicte Deau-Fisher, Bernard Drenou, Carole Soussain, Cédric Rossi, Nicolas Noël, Sylvain Choquet, Serge Bologna, Bertrand Joly, Milena Kohn, Sandra Malak, Guillemette Fouquet, Etienne Daguindau and Sophie Bernard performed the data collection and some data interpretation. Cécile Laureana designed the PMSI analysis and collected data. Catherine Thiéblemont, Guillaume Cartron and Karine Lacombe reviewed the study design and the article. Caroline Besson designed the study, contributed to the analysis and wrote the paper.\n\nData sharing statement\n\nThe dataset supporting this article is available upon demand to the corresponding author and to the promoter (center Hospitalier de Versailles).\n\nFunding\n\nThere have been no specific funds to run this study.\n==== Refs\nReferences\n\n1 Guan W. Ni Z. Hu Y. Liang W. Ou C. He J. Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 382 18 2020 1708 1720 32109013\n2 Zhang H. Penninger J.M. Li Y. Zhong N. Slutsky A.S Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target Intensive Care Med 46 4 2020 586 590 32125455\n3 Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention JAMA 323 13 2020 1239 1242 32091533\n4 Price-Haywood E.G. Burton J. Fort D. Seoane L Hospitalization and mortality among black patients and white patients with Covid-19 N Engl J Med 0 0 2020 null\n5 OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. medRxiv[Internet]. [cited 2020 May 19]. Available from: https://www.medrxiv.org/content/10.1101/2020.05.06.20092999v1\n6 SPF. Estimations nationales de l'incidence et de la mortalité par cancer en France métropolitaine entre 1990 et 2018 - Hémopathies malignes : étude à partir des registres des cancers du réseau Francim [Internet]. [cited 2020 May 21]. Available from: /import/estimations-nationales-de-L-incidence-et-de-la-mortalite-par-cancer-en-france-metropolitaine-entre-1990-et-2018-hemopathies-malignes-etude-a-pa\n7 Averbuch D. Orasch C. Cordonnier C. Livermore D.M. Mikulska M. Viscoli C. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on infections in leukemia Haematologica 98 12 2013 1826 1835 24323983\n8 Maschmeyer G. De Greef J. Mellinghoff S.C. Nosari A. Thiebaut-Bertrand A. Bergeron A. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL) Leukemia 33 4 2019 844 862 30700842\n9 Gafter-Gvili A. Polliack A. Bendamustine associated immune suppression and infections during therapy of hematological malignancies Leuk Lymphoma 57 3 2016 512 519 26696321\n10 Gea-Banacloche J.C. Rituximab-associated infections Semin Hematol 47 2 2010 187 198 20350666\n11 Tudesq J.-.J. Cartron G. Rivière S. Morquin D. Iordache L. Mahr A. Clinical and microbiological characteristics of the infections in patients treated with rituximab for autoimmune and/or malignant hematological disorders Autoimmun Rev 17 2 2018 115 124 29180125\n12 Kuderer N.M. Choueiri T.K. Shah D.P. Shyr Y. Rubinstein S.M. Rivera D.R. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study Lancet 2020 [cited 2020 Jun 5];0(0). Available from https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31187-9/abstract\n13 Malard F. Genthon A. Brissot E. van de Wyngaert Z. Marjanovic Z. Ikhlef S. COVID-19 outcomes in patients with hematologic disease Bone Marrow Transplant 2020 1 5 30914755\n14 Martín‐Moro F. Marquet J. Piris M. Michael B.M. Sáez A.J. Corona M. Survival study of hospitalized patients with concurrent Covid-19 and haematological malignancies Br J Haematol 2020 n/a(n/a). Available from http://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.16801\n15 He W. Chen L. Chen L. Yuan G. Fang Y. Chen W. COVID-19 in persons with haematological cancers Leukemia 2020 [cited 2020 May 21]; Available from http://www.nature.com/articles/s41375-020-0836-7\n16 Cottenet J. Dabakuyo-Yonli T.S. Mariet A.-.S. Roussot A. Arveux P. Quantin C Prevalence of patients hospitalised for male breast cancer in France using the French nationwide hospital administrative database Eur J Cancer Care Engl 28 5 2019 e13117 31231921\n17 Swerdlow S.H. Campo E. Pileri S.A. Harris N.L. Stein H. Siebert R. The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 127 20 2016 2375 2390 26980727\n18 Lei J. Li J. Li X. Qi X CT Imaging of the 2019 novel coronavirus (2019-nCoV) pneumonia Radiology 295 1 2020 18 32003646\n19 Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Stein H. 4th WHO classification of tumours of haematopoietic and lymphoid tissues Vol. 2 2008 IARC 439 p\n20 SPF. COVID-19 : point épidémiologique du 11 juin 2020 [Internet]. [cited 2020 Jun 13]. Available from: /maladies-et-traumatismes/maladies-et-infections-respiratoires/infection-a-coronavirus/documents/bulletin-national/covid-19-point-epidemiologique-du-11-juin-2020\n21 Vabret N. Britton G.J. Gruber C. Hegde S. Kim J. Kuksin M. Immunology of COVID-19: current state of the science Immunity 2020 [cited 2020 May 19]; Available from http://www.sciencedirect.com/science/article/pii/S1074761320301837\n\n",
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"title": "Determinants of outcome in Covid-19 hospitalized patients with lymphoma: A retrospective multicentric cohort study.",
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"abstract": "We are reporting a case of fatal radiation pneumonitis that developed six months following chemoradiation for limited stage small cell lung cancer. The patient was a 67-year-old man with a past medical history of Hashimoto's thyroiditis and remote suspicion for CREST, neither of which were active in the years leading up to treatment. He received 6600 cGy delivered in 200 cGy daily fractions via intensity modulated radiation therapy with concurrent cisplatin/etoposide followed by additional chemotherapy with dose-reduced cisplatin/etoposide and carboplatin/etoposide and then received prophylactic cranial irradiation. The subsequent months were notable for progressively worsening episodes of respiratory compromise despite administration of prolonged steroids and he ultimately expired. Imaging demonstrated bilateral interstitial and airspace opacities. Autopsy findings were consistent with pneumonitis secondary to chemoradiation as well as lymphangitic spread of small cell carcinoma. The process was diffuse bilaterally although his radiation was delivered focally to the right lung and mediastinum.",
"affiliations": "Virginia W Osborn, Andrea Leaf, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, United States.;Virginia W Osborn, Andrea Leaf, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, United States.;Virginia W Osborn, Andrea Leaf, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, United States.;Virginia W Osborn, Andrea Leaf, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, United States.;Virginia W Osborn, Andrea Leaf, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, United States.;Virginia W Osborn, Andrea Leaf, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, United States.;Virginia W Osborn, Andrea Leaf, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, United States.",
"authors": "Osborn|Virginia W|VW|;Leaf|Andrea|A|;Lee|Anna|A|;Garay|Elizabeth|E|;Safdieh|Joseph|J|;Schwartz|David|D|;Schreiber|David|D|",
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"fulltext": "\n==== Front\nWorld J Clin OncolWJCOWorld Journal of Clinical Oncology2218-4333Baishideng Publishing Group Inc jWJCO.v8.i3.pg28510.5306/wjco.v8.i3.285Case ReportBilateral diffuse grade 5 radiation pneumonitis after intensity modulated radiation therapy for localized lung cancer Osborn Virginia W Leaf Andrea Lee Anna Garay Elizabeth Safdieh Joseph Schwartz David Schreiber David Virginia W Osborn, Andrea Leaf, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, United StatesVirginia W Osborn, Anna Lee, Elizabeth Garay, Joseph Safdieh, David Schwartz, David Schreiber, SUNY Downstate Medical Center, Brooklyn, NY 11203, United StatesAuthor contributions: Osborn VW and Schreiber D analyzed case; Osborn VW, Leaf A, Lee A, Garay E, Safdieh J, Schwartz D and Schreiber D wrote and edited the paper.\n\nCorrespondence to: David Schreiber, MD, Attending Physician, Veterans Affairs New York Harbor Healthcare System, 800 Poly Place, 114A, Brooklyn, NY 11209, United States. david.schreiber@va.gov\n\nTelephone: +1-718-6303605 Fax: +1-718-6302857\n\n10 6 2017 10 6 2017 8 3 285 288 9 3 2017 2 5 2017 12 5 2017 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/We are reporting a case of fatal radiation pneumonitis that developed six months following chemoradiation for limited stage small cell lung cancer. The patient was a 67-year-old man with a past medical history of Hashimoto’s thyroiditis and remote suspicion for CREST, neither of which were active in the years leading up to treatment. He received 6600 cGy delivered in 200 cGy daily fractions via intensity modulated radiation therapy with concurrent cisplatin/etoposide followed by additional chemotherapy with dose-reduced cisplatin/etoposide and carboplatin/etoposide and then received prophylactic cranial irradiation. The subsequent months were notable for progressively worsening episodes of respiratory compromise despite administration of prolonged steroids and he ultimately expired. Imaging demonstrated bilateral interstitial and airspace opacities. Autopsy findings were consistent with pneumonitis secondary to chemoradiation as well as lymphangitic spread of small cell carcinoma. The process was diffuse bilaterally although his radiation was delivered focally to the right lung and mediastinum.\n\nRadiationPneumonitisSmall cell lung cancerIntensity modulated radiation therapy\n==== Body\nCore tip: Radiation pneumonitis is an uncommon but serious complication from radiation therapy which can on rare occasions be fatal. This report not only documents the details of such a case but also includes pathologic confirmation and computed tomography images. Although the radiation field was limited to the right lung and mediastinum, the process was also noted to be bilateral and diffuse.\n\nINTRODUCTION\nPneumonitis is an inflammatory lung reaction marked by dyspnea, cough, and occasional fever. It can occur following radiation therapy as a result of cytokine production[1,2], and patients are at increased risk of developing pneumonitis if they have a history of chronic lung disease or smoking[3], or if they received concurrent chemotherapy[3,4]. Rarely, it can be fatal. In the following case report we examine a patient who developed fatal pneumonitis six months after receiving concurrent chemoradiation for small cell lung cancer (SCLC).\n\nCASE REPORT\nA 67-year-old man with a 40 pack-year smoking history initially presented with chills and a productive cough and was given antibiotics for presumed pneumonia. When his condition did not improve, a computed tomography (CT) of the chest was performed and revealed a large right hilar mass with extensive mediastinal adenopathy as well as surrounding infiltrate and atelectasis. Bronchial brushings and a right hilar node FNA were consistent with SCLC. The remainder of the workup, including brain magnetic resonance imaging (MRI), bone scan and positron emission tomography (PET)-CT, was negative for distant metastatic disease, establishing a diagnosis of limited stage (LS) disease. His medical history was significant for numerous coexisting medical conditions including a remote history of suspected but unconfirmed connective tissue disorder (CREST), colitis, esophagitis, duodenitis, livedo reticularis, Hashimoto’s thyroiditis, multinodular goiter, arthritis, glaucoma, hypertension, multifocal motor neuropathy and atrioventricular (AV) nodal reentry tract for which he had undergone AV nodal ablation. Of note, neither the Hashimoto’s nor CREST were active for multiple years leading up to his diagnosis of SCLC. The latter diagnosis had been suspected by the Rheumatology Service but after a negative workup, he was discharged from their clinic.\n\nAfter completion of staging, he was advised to undergo definitive chemoradiation. He was also advised to re-establish follow up with the Rheumatology Service, but declined. After a detailed discussion of the potential for increased risk of complications from radiation with an underlying connective tissue disorder, he elected to proceed. He was treated with intensity modulated radiation therapy to the right lung and mediastinum in 33 daily fractions of 200 cGy to a total dose of 6600 cGy with two cycles of concurrent cisplatin (cis) and etoposide. After 3000 cGy, another CT was performed to allow for decrease in treatment field after initial response. RT was completed in 8 wk and 1 d. A representative image from his intensity modulated radiation therapy (IMRT) radiation plan is presented in (Figure 1). His treatment course was complicated by pancytopenia (for which he received filgrastim and one unit of packed red blood cells), as well as dysphagia and odynophagia. He received two cycles of chemotherapy during the radiation and two cycles in the adjuvant setting after concurrent chemotherapy and radiation therapy, though the last three cycles were dose-reduced because of hematologic toxicities. During chemotherapy he was treated for clostridium difficile colitis and was briefly admitted for generalized weakness. Approximately three months after completion of thoracic RT, he received prophylactic cranial irradiation (PCI) which was given as 10 fractions of 250 cGy.\n\nFigure 1 Intensity modulated radiation therapy radiation plan. The yellow line represents the 100% isodose line, blue lines represent the 90% and 50% isodose lines, and the white line represents the 20% isodose line. The red lines represent the gross tumor and planning treatment volumes (GTV and PTV).\n\nDuring PCI, he required admission due to inability to tolerate daily travel. Shortly after completion of PCI he developed recurrent clostridium difficile colitis and within weeks of completion of PCI he was readmitted and remained hospitalized for two months. While admitted, he experienced episodes of hypoxemic respiratory failure requiring repeated use of a nonrebreather and for which he underwent intubation twice. Chest imaging demonstrated development of worsening bilateral interstitial and airspace opacities (Figure 2). He was aggressively treated with broad spectrum antibiotics and high dose steroids. Eventually he developed tachycardia, respiratory distress, hypotension and suspected disseminated intravascular coagulation. In accordance with his family’s wishes he underwent palliate extubation and expired shortly thereafter.\n\nFigure 2 Chest computed tomography scan images demonstrating bilateral interstitial and airspace opacities.\n\nAn autopsy was performed and the report described extensive, diffuse, bilateral alveolar damage consistent with post-radiation changes, as well as small cell carcinoma in multiple foci within septal capillaries and contiguous alveolar spaces.\n\nDISCUSSION\nRadiation pneumonitis is an uncommon complication of chemoradiation for lung cancer but one which can be fatal in almost 2% of patients[4]. It has been previously been described as having two types of presentations: “Classical” vs “sporadic”. The former is attributed to local cytokine production within the radiated field, while the latter is likened to a hypersensitivity reaction and can be out of proportion to volume irradiated or manifest its effects outside of the treated field. It has even been proposed that the majority of patients develop subclinical lymphocytic alveolitis following lung radiation, but that acute pneumonitis only develops in the fraction that have some genetic or environmental predisposition[5]. Our literature search did not reveal any specific associations between connective tissue disorders and pneumonitis, however in the event that our patient did have a true diagnosis of a connective tissue disorder, one could postulate that it could have served as such a predisposing factor for him.\n\nAlthough certain radiation dose parameters have also been found to be associated with increased risk for radiation pneumonitis, including mean lung dose (MLD), volume of lung receiving 20 Gy (V20) and possibly 5 Gy (V5), this patient’s parameters were within recommendations. His MLD was 1822 cGy, V20 28%, and V5 69.5%. Qualitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines, as well as others, indicate that mean lung dose of 13 Gy results in a 10% rate of symptomatic pneumonitis, MLD of 20 Gy results in 20% risk, and V20 of ≤ 30%-31% keeps the risk below 20%[6,7]. The current Radiation Therapy Oncology Group protocols recommend V20 not to exceed 40% and MLD of no more than 20 Gy[8]. Not only did our patient’s plan meet all of the recommended criteria, it was essentially unilateral, targeted at the right hilar mass and mediastinum. His presentation is therefore more consistent with the development of “sporadic” radiation pneumonitis, given that his ultimate condition was spatially diffuse and out of proportion to what would have been expected from the doses received by his normal tissues.\n\nFurther complicating this patient’s condition was the presence of lymphangitic spread of tumor which may have contributed to compromise of the patient’s lung function. Additionally, he had a history of both a possible CREST and autoimmune disease (Hashimoto’s Thyroiditis). Connective tissue disorders have been described as potential predisposing factors for increased toxicity from radiation therapy, and the mechanism of sporadic radiation pneumonitis itself is in some ways analogous to an autoimmune reaction with cytokine-mediated destruction[9]. However in this case the autoimmune diseases had not been active for years and the collagen vascular disease, though suspected, had not been officially diagnosed, so it is difficult to evaluate whether the patient’s toxicity could be attributed to these medical issues.\n\nThis case is notable for striking imaging findings of diffuse interstitial and alveolar processes (Figure 2) as well as pathologic confirmation of diagnosis of a rare complication from radiation for lung cancer. Limitations are akin to those of any case report, in that it is anecdotal. The patient had multiple processes occurring in the lungs as determined by autopsy, including lymphangitic spread of tumor as well as pneumonia so the fatal respiratory failure may not be entirely attributable to radiation pneumonitis. Furthermore, the patient received concurrent chemotherapy and additional cycles of chemotherapy after radiation which may have resulted in its own toxicity.\n\nThis is a case report of grade 5 radiation pneumonitis in a patient with a potential history of connective tissue disease and/or autoimmune disease who also developed lymphangitic spread of tumor. Standard of care chemoradiation was provided to this patient and all of the radiation dose parameters were well within commonly accepted ranges. Furthermore, connective tissue disorder diagnosis was in question and autoimmune disorder was not active. Despite appropriate precautions, he still developed fatal pneumonitis. Further research is needed to develop a better understanding of the interplay of all of these factors.\n\nCOMMENTS\nCase characteristics\nThis is a case report of grade 5 radiation pneumonitis in a patient with a potential history of connective tissue disease and/or autoimmune disease who also developed lymphangitic spread of tumor after receiving chemoradiation with intensity modulated radiation therapy (IMRT) technique for limited stage small cell lung cancer.\n\nClinical diagnosis\nGrade 5 radiation pneumonitis and lymphangitic spread of tumor developed after chemoradiation for small cell lung cancer.\n\nDifferential diagnosis\nDifferential included pneumonitis, lymphangitic spread of tumor, pneumonia, or other interstitial and/or airspace disease.\n\nImaging diagnosis\nChest X-ray and computed tomography showed worsening bilateral interstitial and airspace opacities.\n\nPathological diagnosis\nAutopsy examination of lung tissue demonstrated extensive, diffuse, bilateral alveolar damage consistent with post-radiation changes, as well as small cell carcinoma in multiple foci within septal capillaries and contiguous alveolar spaces.\n\nTreatment\nInitial therapy consisted of IMRT radiation therapy with concurrent and adjuvant chemotherapy. For his pneumonitis, he was treated with steroids, antibiotics, non-invasive and later mechanical ventilation.\n\nExperiences and lessons\nStandard of care chemoradiation was provided to this patient and all of the radiation dose parameters were well within commonly accepted ranges. Furthermore connective tissue disorder diagnosis was in question and autoimmune disorder was not active. Despite appropriate precautions, he still developed fatal pneumonitis in addition to lymphangic tumor spread. Further research is needed to develop a better understanding of the interplay of all of these factors.\n\nPeer-review\nThe authors present a case report showing a patient with a fatal radiation pneumonitis 6 mo after radiation for limited stage of small cell lung cancer. The article is well explained and implemented.\n\nConflict-of-interest statement: The authors have no conflicts of interest to disclose.\n\nManuscript source: Invited manuscript\n\nSpecialty type: Oncology\n\nCountry of origin: United States\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B, B\n\nGrade C (Good): C, C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nPeer-review started: March 13, 2017\n\nFirst decision: March 27, 2017\n\nArticle in press: May 15, 2017\n\nP- Reviewer: Arcangeli S, Freixinet J, Nacak M, Sugawara I S- Editor: Song XX L- Editor: A E- Editor: Lu YJ\n==== Refs\n1 Anscher MS Marks LB Shafman TD Clough R Huang H Tisch A Munley M Herndon JE Garst J Crawford J Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy Int J Radiat Oncol Biol Phys 2003 56 988 995 12829134 \n2 Anscher MS Thrasher B Zgonjanin L Rabbani ZN Corbley MJ Fu K Sun L Lee WC Ling LE Vujaskovic Z Small molecular inhibitor of transforming growth factor-beta protects against development of radiation-induced lung injury Int J Radiat Oncol Biol Phys 2008 71 829 837 18411002 \n3 Zhang XJ Sun JG Sun J Ming H Wang XX Wu L Chen ZT Prediction of radiation pneumonitis in lung cancer patients: a systematic review J Cancer Res Clin Oncol 2012 138 2103 2116 22842662 \n4 Palma DA Senan S Tsujino K Barriger RB Rengan R Moreno M Bradley JD Kim TH Ramella S Marks LB Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis Int J Radiat Oncol Biol Phys 2013 85 444 450 22682812 \n5 Morgan GW Breit SN Radiation and the lung: a reevaluation of the mechanisms mediating pulmonary injury Int J Radiat Oncol Biol Phys 1995 31 361 369 7836090 \n6 Marks LB Yorke ED Jackson A Ten Haken RK Constine LS Eisbruch A Bentzen SM Nam J Deasy JO Use of normal tissue complication probability models in the clinic Int J Radiat Oncol Biol Phys 2010 76 S10 S19 20171502 \n7 Emami B Lyman J Brown A Coia L Goitein M Munzenrider JE Shank B Solin LJ Wesson M Tolerance of normal tissue to therapeutic irradiation Int J Radiat Oncol Biol Phys 1991 21 109 122 2032882 \n8 CALGB 30610 Phase III Comparison of Thoracic Radiotherapy Regimens in Patients with Limited Small Cell Lung Cancer also Receiving Cisplatin or Carboplatin and Etoposide (Protocol Update #11 4/15/16, Accessed December 12, 2016) Available from: http://www.kccop.org/pdfs/FullProtocol-159116480.pdf \n9 Giaj-Levra N Sciascia S Fiorentino A Fersino S Mazzola R Ricchetti F Roccatello D Alongi F Radiotherapy in patients with connective tissue disorders Lancet Oncology 2016 17 e109 e177 26972857\n\n",
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"keywords": "Intensity modulated radiation therapy; Pneumonitis; Radiation; Small cell lung cancer",
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"title": "Bilateral diffuse grade 5 radiation pneumonitis after intensity modulated radiation therapy for localized lung cancer.",
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"abstract": "Patients with immunodeficiency or immunosuppression are at risk of developing a lymphoproliferative disorder (LPD). Methotrexate (MTX) is an iatrogenic cause of LPD, which in up to 50% cases occurs in extranodal sites. The occurrence of MTX-related LPD with osteonecrosis of the jaw (ONJ) has rarely been reported. Moreover, there are no clear diagnostic criteria and treatment strategies for management of these lesions. In the present cases, discontinuing MTX and debridement of the necrotic bone were effective. This report describes 3 cases of MTX-related LPD in patients with longstanding rheumatoid arthritis (RA) who presented with ONJ. The first patient was a 74-year-old man with RA who had received treatment with MTX for 7 years before presenting with ONJ and submental lymphadenopathy. The second patient was a 79-year-old woman who had been treated for 21 years with MTX and who presented with ONJ. The third patient was a 67-year-old man who had been treated with MTX for more than 15 years. In all 3 cases, biopsy, histology, and immunohistochemistry using a panel of lymphoid markers (Epstein-Barr virus [EBV], CD79a, CD20, PAX-5, CD3, and CD30) resulted in the diagnosis of EBV-driven T-cell, B-cell, and Hodgkin-like LPD. All 3 patients recovered after cessation of MTX and surgical debridement. Biopsy examination, diagnostic immunohistochemistry using lymphoid immune markers, and imaging studies using computed tomography, magnetic resonance imaging, and positron-emission tomographic computed tomography were useful for the correct diagnosis of this condition.",
"affiliations": "Chief, Department of Oral and Maxillofacial Surgery, Tsugaru General Hospital, Goshogawara; Visiting Fellow, Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. Electronic address: furudate@hirosaki-u.ac.jp.;Graduate Student, Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.;Assistant Professor, Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.;Professor, Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.",
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"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D003646:Debridement; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008232:Lymphoproliferative Disorders; D008297:Male; D008336:Mandibular Diseases; D008439:Maxillary Diseases; D008727:Methotrexate; D010020:Osteonecrosis; D012307:Risk Factors",
"nlm_unique_id": "8206428",
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"pages": "97-111",
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"pubdate": "2018-01",
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"title": "Methotrexate-Related Lymphoproliferative Disorder in Patients With Osteonecrosis of the Jaw: A 3-Case Report and Literature Review.",
"title_normalized": "methotrexate related lymphoproliferative disorder in patients with osteonecrosis of the jaw a 3 case report and literature review"
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"abstract": "Pheochromocytoma is a rare neuroendocrine tumor with a highly variable clinical presentation. The serious and potentially lethal cardiovascular complications of these tumors are related to the effects of secreted catecholamines. We describe a case of a 50-year-old woman urgently admitted to our hospital because of symptoms and clinical and instrumental findings consistent with an acute coronary syndrome complicated by acute heart failure. Urgent coronary angiography showed normal coronary arteries. During her hospital stay, the recurrence of episodes characterized by a sudden increase in blood pressure, cold sweating, and nausea allowed us to hypothesize a pheochromocytoma. The diagnosis was confirmed by elevated levels of urinary catecholamines and by the finding of a left adrenal mass on magnetic resonance imaging. The patient underwent left adrenalectomy. Therefore, the initial diagnosis was critically reappraised and reviewed as a cardiac manifestation of a pheochromocytoma during catecholaminergic crisis.",
"affiliations": "Unità Operativa di Cardiologia, Ospedale SS Annunzia, Sassari, aItaly.;Unità Operativa di Cardiologia, Ospedale SS Annunzia, Sassari, aItaly.;Unità Operativa di Cardiologia, Ospedale SS Annunzia, Sassari, aItaly.;Unità Operativa di Cardiologia, Ospedale SS Annunzia, Sassari, aItaly.;Unità Operativa di Cardiologia, Ospedale SS Annunzia, Sassari, aItaly.",
"authors": "Sanna|Giuseppe Damiano|GD|;Talanas|Giuseppe|G|;Fiore|Giuseppina|G|;Canu|Antonella|A|;Terrosu|Pierfranco|P|",
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"fulltext": "\n==== Front\nJ Saudi Heart AssocJ Saudi Heart AssocJournal of the Saudi Heart Association1016-73152212-5043Elsevier S1016-7315(16)00004-X10.1016/j.jsha.2016.02.002Case ReportPheochromocytoma presenting as an acute coronary syndrome complicated by acute heart failure: The challenge of a great mimic Sanna Giuseppe Damiano giuseppedasanna@tiscali.ita⁎Talanas Giuseppe aFiore Giuseppina aCanu Antonella aTerrosu Pierfranco aa Unità Operativa di Cardiologia, Ospedale SS Annunzia, Sassari, aItaly⁎ Corresponding author at: Unità Operativa di Cardiologia, Ospedale SS Annunzia, Via Enrico de Nicola, Sassari 07100, Italy.Unità Operativa di CardiologiaOspedale SS AnnunziaVia Enrico de NicolaSassari07100Italy giuseppedasanna@tiscali.it10 2 2016 10 2016 10 2 2016 28 4 278 282 11 1 2016 30 1 2016 2 2 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Pheochromocytoma is a rare neuroendocrine tumor with a highly variable clinical presentation. The serious and potentially lethal cardiovascular complications of these tumors are related to the effects of secreted catecholamines. We describe a case of a 50-year-old woman urgently admitted to our hospital because of symptoms and clinical and instrumental findings consistent with an acute coronary syndrome complicated by acute heart failure. Urgent coronary angiography showed normal coronary arteries. During her hospital stay, the recurrence of episodes characterized by a sudden increase in blood pressure, cold sweating, and nausea allowed us to hypothesize a pheochromocytoma. The diagnosis was confirmed by elevated levels of urinary catecholamines and by the finding of a left adrenal mass on magnetic resonance imaging. The patient underwent left adrenalectomy. Therefore, the initial diagnosis was critically reappraised and reviewed as a cardiac manifestation of a pheochromocytoma during catecholaminergic crisis.\n\nKeywords\nAcute coronary syndromeArterial hypertensionHeart failurePheochromocytomaDisclosure: Authors have nothing to disclose with regard to commercial support.\n==== Body\nIntroduction\nPheochromocytoma is a neuroendocrine tumor. Clinical presentation is highly variable and pheochromocytoma is often defined as a great mimic.\n\nCase report\nA 50-year-old woman was admitted to the Emergency Room for epigastric pain, dyspnea, nausea, emesis, and cold sweating ongoing for 10 hours. Her medical history included arterial hypertension diagnosed 10 years before, poorly controlled despite combination therapy. A few days prior to hospital admission, electrocardiogram (ECG) and echocardiogram were normal, and antihypertensive therapy (including an angiotensin-converting enzyme inhibitor and a thiazidic diuretic) was enhanced by adding spironolactone 25 mg/d and atenolol 50 mg/d.\n\nAt presentation, physical examination showed cold and sweaty skin, tachycardia, and pulmonary basal rales. Arterial blood pressure (BP) was 170/110 mmHg. ECG showed a sinus tachycardia with negative T waves in precordial leads (Fig.1A). The echocardiogram showed regional wall motion abnormalities (hypokinesia of interventricular septum, anterior wall, and apex) resulting in severe left ventricular systolic dysfunction (ejection fraction 30%).\n\nThe patient was thus admitted to our intensive care unit where the diagnosis of a non-ST elevation myocardial infarction was made due to the presence of ECG abnormalities together with increased cardiac enzymes [troponin I 2.4 ng/mL (normal value 0.00–0.15 ng/mL)]. An urgent invasive strategy was planned. Coronary arteries were normal angiographically (Fig.1B and C).\n\nAfter a first period of clinical stability, the recurrence of paroxysmal episodes characterized by a sudden increase in BP, cold sweating, and nausea allowed us to hypothesize a pheochromocytoma. This diagnostic hypothesis was first supported by elevated urinary catecholamines [noradrenaline 2433 μg/24 h (normal value 15–80 μg/24 h)]. Magnetic resonance imaging showed a left adrenal mass consistent with a pheochromocytoma (Fig.2A). An alpha-adrenergic blocker (doxazosin 4 mg/d) was added to the patient therapy. Thereafter, a progressive improvement of clinical status was observed; left ventricular systolic function returned within normal limits (ejection fraction 55%) and ECG normalized (Fig.2B). The patient underwent left adrenalectomy (Fig.2C). Intraoperative management was based on the lessening of sympathetic tone, avoiding some drugs, and blunting the sympathetic response during anesthesia induction and tracheal intubation. Minor changes in systemic hemodynamics occurred during surgical manipulation of the tumor and they were easily managed. The postoperative hospital stay was uneventful and BP normalized without the use of any drug.\n\nDiscussion\nPheochromocytomas are rare neuroendocrine tumors secreting catecholamines that arise from chromaffin cells of the sympathetic nervous system. Common clinical manifestations include hypertension, tachycardia, and feelings of panic or anxiety, while nausea, fever, and flushing are less common [1]. Cardiovascular complications include myocardial infarction, cardiac arrhythmias, and heart failure due to toxic cardiomyopathy [2]. Although the prevalence of pheochromocytomas in hypertensive patients is reported to be 0.1–0.6% [3], the relatively higher prevalence in necropsy findings suggests that many tumors are undiagnosed.\n\nWe would like to draw attention to certain key aspects of our report, first of all the medical history of the patient. Arterial hypertension was not adequately investigated at the moment of initial diagnosis (the patient was hurriedly labeled as having a primary arterial hypertension). Moreover, the poor BP control during the follow up should have inspired a critical reappraisal of the initial diagnosis.\n\nThe second aspect is related to the changes in drug therapy during the last follow-up visit prior to hospital admission when atenolol and spironolactone were added to the patient therapy. Because atenolol has been introduced, we may presume its pathogenic role in triggering a catecholaminergic crisis. In this setting it is reported that blockade of β-adrenoceptors should never be initiated before blockade of α-adrenoceptors, because the loss of β-adrenoceptor mediated vasodilatation leaves α-adrenoceptors stimulation unopposed resulting in hypertensive crises [1].\n\nWhatever the trigger mechanism of catecholaminergic crises may be, our patient suddenly experienced symptoms consistent with an acute coronary syndrome complicated by a dramatic reduction in left ventricular function (normal before hospital admission). Coronary arteries were normal.\n\nThe recurrence of a sudden increase in BP, nausea, and cold sweating led us to hypothesize a catecholamine excess, confirmed by both elevated levels of urinary catecholamines and by the finding of a large left adrenal mass during magnetic resonance imaging. Therefore, the initial diagnosis of acute coronary syndrome was critically reviewed as a cardiac manifestation of a pheochromocytoma during a catecholaminergic crisis, as previously described by other authors [4], [5], [6].\n\nAlthough the majority of patients with pheochromocytoma have a normal echocardiogram, the pattern of left ventricular dysfunction may be different, sometimes resembling a takotsubo or a reverse takotsubo cardiomyopathy [7], [8]. Similarly to takotsubo syndrome, left ventricular dysfunction is transient and usually recovers within several days [7]. The potential mechanisms for transient left ventricular dysfunction during a catecholaminergic crisis include microvascular impairment of the coronary arteries, multivessel epicardial spasm, impaired fatty acid metabolism, myocarditis, and catecholamine-mediated myocardial dysfunction [8]. Because two patterns of left ventricular dysfunction and a different distribution of sympathetic nerves within the heart have been described, it has been postulated that different segmental involvement may reflect the individual variability in myocardial sympathetic nerve distribution [9].\n\nFinally, we would like to recall some practical aspects concerning the perioperative management of patients with pheochromocytoma. An adequate preoperative pharmacological control of the adverse effects of circulating catecholamines is essential. The most used α-adrenoceptor antagonists include phenoxybenzamine and more recently prazosin, terazosin, and doxazosin, whereas β-adrenoceptor antagonist agents like bisoprolol are preferred over the less selective labetalol and carvedilol. Anesthesia induction is also crucial. The use of drugs that increase sympathetic tone (e.g., ketamine, ephedrine, desflurane, and pancuronium) should be avoided. Anesthesia induction and tracheal intubation must be smooth in order to avoid and limit a sympathetic response with hypertension and tachycardia. Manipulation of the tumor may cause a brisk hemodynamic response. This is usually a pressure response and phentolamine and labetalol are usually sufficient to control and suppress it. The main postoperative complication of surgery for pheochromocytoma is persistent arterial hypotension, which may be refractory to intravascular volume replacement [10].\n\nWe conclude by recalling that in patients with poorly controlled arterial hypertension presenting with an unexpected myocardial event the hypothesis of a pheochromocytoma should be considered in the diagnostic work-up, even in an emergency scenario.\n\nPeer review under responsibility of King Saud University.\n\nFigure 1 (A) Electrocardiogram at hospital admission showing sinus tachycardia 130 bpm and negative T waves from V2 to V6; (B) left coronary angiogram in the antero-posterior caudal view shows the absence of obstructive coronary lesions; and (C) right coronary angiogram in the left cranial view shows the absence of obstructive coronary lesions.\n\nFigure 2 (A) Magnetic resonance imaging showing a huge left adrenal mass (white arrow head) consistent with a pheochromocytoma; (B) electrocardiogram after beginning doxazosin 4 mg/d returns within normal limits; and (C) left adrenalectomy was performed to remove a huge pheochromocytoma.\n==== Refs\nReferences\n1 Lenders J.W.M. Eisenhofer G. Mannelli M. Pacak K. Pheochromocytoma Lancet 366 2005 665 675 16112304 \n2 Liao W.B. Liu C.F. Chiang C.W. Kung C.T. Lee C.W. Cardiovascular manifestations of pheochromocytoma Am J Emerg Med 18 2000 622 625 10999582 \n3 Sinclair A.M. Isles C.G. Brown I. Cameron H. Murray G.D. Robertson J.W. Secondary hypertension in a blood pressure clinic Arch Intern Med 147 1987 1289 1293 3606286 \n4 Mirza A. Myocardial infarction resulting from nonatherosclerotic coronary artery diseases Am J Emerg Med 21 2003 578 584 14655241 \n5 Darze E.S. Von Sohsten R.L. Pheochromocytoma-induced segmental myocardial dysfunction mimicking an acute myocardial infarction in a patient with normal coronary arteries Arq Bras Cardiol 82 2004 178 180 15042254 \n6 Lindsey B. Elsner M.D. Mitchell H.K. Clesham G. Adrenaline rush: an unusual presentation of pheochromocytoma BMJ Case Rep 2016 [in press] \n7 Park H.J. Kim K.S. Sul J.Y. Shin S.K. Kim J.H. Lee J.H. Prevalence and patterns of left ventricular dysfunction in patients with pheochromocytoma J Cardiovasc Ultrasound 19 2011 76 82 21860721 \n8 Sharkey S.W. McAllister N. Dassenko D. Lin D. Han K. Maron B.J. Evidence that high catecholamine levels produced by pheochromocytoma may be responsible for takotsubo cardiomyopathy Am J Cardiol 115 2015 1615 1618 25851794 \n9 Kawano H. Okada R. Yano K. Histological study on the distribution of autonomic nerves in the failing human heart Heart Vessels 18 2003 32 39 12644879 \n10 Prys-Roberts C. Pheochromocytoma-recent progress in its management Br J Anaesth 85 2000 44 57 10927994\n\n",
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"issue": "28(4)",
"journal": "Journal of the Saudi Heart Association",
"keywords": "Acute coronary syndrome; Arterial hypertension; Heart failure; Pheochromocytoma",
"medline_ta": "J Saudi Heart Assoc",
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"nlm_unique_id": "9887261",
"other_id": null,
"pages": "278-82",
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"title": "Pheochromocytoma presenting as an acute coronary syndrome complicated by acute heart failure: The challenge of a great mimic.",
"title_normalized": "pheochromocytoma presenting as an acute coronary syndrome complicated by acute heart failure the challenge of a great mimic"
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"abstract": "Some studies suggest higher efficacy of lacosamide (LCM) in status epilepticus (SE) with higher loading doses; however, this weight-adjusted dose has not been evaluated.\n\n\n\nThe objective was to evaluate the relationship between loading weight-adjusted dose and efficacy of LCM in SE.\n\n\n\nA group of patients with SE treated with LCM from Spanish hospitals was examined retrospectively. Demographic data, type of SE, etiology, response rate, last antiepileptic drug (AED) used, treatment line in which LCM was used, total loading dose, and weight-adjusted dose were collected.\n\n\n\nOne hundred sixty-five cases of SE were collected; 87 (52.7%) patients had nonconvulsive SE. Mean age was 64.2 ± 17.2 and 60.6% (n = 100) were men. Regarding etiology, SE was considered as acute symptomatic in 85 (51.5%), remote symptomatic in 51 (30.9%), progressive symptomatic in 10 (6.1%), and cryptogenic in 19 (11.5%). Lacosamide was used as the third drug in 46.1%, and as a second option in 28%. In 115 patients, clonazepam had been used as the first option, and no benzodiazepines had been administered in the remaining 50. The median loading dose was 400 mg (100-600 mg), and the weight-adjusted dose was 5 mg/kg (3-6 mg/kg). The response rate was 63.3%, and 55.1% responded within the first 12 h. Efficacy was significantly higher in patients who had taken benzodiazepines at LCM loading doses >5.3 mg/kg (p = 0.006). This relationship was maintained independent of using other concomitant AEDs. However, if benzodiazepines were not taken, this relationship was not found.\n\n\n\nIn adults with benzodiazepine-resistant SE, the response rate to LCM was higher, with weight-adjusted doses above 5.3 mg/kg.",
"affiliations": "Epilepsy Unit, Hospital Vall d'Hebron, Barcelona, Spain. Electronic address: esantama@vhebron.net.;Epilepsy Unit, Hospital Vall d'Hebron, Barcelona, Spain.;Epilepsy Unit, Hospital Vall d'Hebron, Barcelona, Spain.;Epilepsy Unit, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.;Epilepsy Unit, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.;Department of Neurology, Hospital Arnau de Vilanova, Lleida, Spain.;Department of Neurology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.;Department of Neurology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.;Department of Neurology, Hospital del Bierzo Ponferrada, Ponferrada, León, Spain.;Epilepsy Unit, Hospital Universitario Cruces, Baracaldo Vizcaya, Spain.;Epilepsy Unit, Hospital Vall d'Hebron, Barcelona, Spain.;Epilepsy Unit, Hospital Vall d'Hebron, Barcelona, Spain.",
"authors": "Santamarina|Estevo|E|;González-Cuevas|Montserrat|M|;Toledo|Manuel|M|;Jiménez|Marta|M|;Becerra|Juan Luis|JL|;Quílez|Alex|A|;Suller|Ana|A|;Mauri|J A|JA|;Fernández|Ángel|Á|;Marinas|Ainhoa|A|;Quintana|Manuel|M|;Puig|Xavier Salas|XS|",
"chemical_list": "D000927:Anticonvulsants; D001569:Benzodiazepines; D000078334:Lacosamide",
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"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D001569:Benzodiazepines; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013030:Spain; D013226:Status Epilepticus; D016896:Treatment Outcome; D055815:Young Adult",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacy.",
"title_normalized": "intravenous lacosamide lcm in status epilepticus se weight adjusted dose and efficacy"
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"abstract": "Pulmonary aspergillosis is a condition caused by the fungi Aspergillus. The form of disease depends on the immunological condition of the host organism and other concomitant illnesses that influence the pulmonary tissue. Asthmatic patients, in particular with the severe form of disease, who require the use of systemic glucocorticoids, are predisposed to develop allergic bronchopulmonary aspergillosis. Development of aspergilloma in the lung is preceded by the formation of pathological cavity in the course of another illness. The study reports a case of a severe asthma patient who developed aspergilloma in atypical localisation, without the presence of predisposing anatomical changes and illnesses.",
"affiliations": "Department of Lung Diseases and Tuberculosis, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Poland. michal.zielinski1@interia.pl.",
"authors": "Zieliński|Michał|M|;Mazur-Zielińska|Henryka|H|;Ziora|Dariusz|D|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5603/PiAP.a2016.0004",
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"issue": "84(3)",
"journal": "Pneumonologia i alergologia polska",
"keywords": "aspergilloma; asthma; pulmonary aspergillosis",
"medline_ta": "Pneumonol Alergol Pol",
"mesh_terms": "D001229:Aspergillosis, Allergic Bronchopulmonary; D001230:Aspergillus; D001249:Asthma; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "9302892",
"other_id": null,
"pages": "181-5",
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"pubdate": "2016",
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"references": null,
"title": "Aspergilloma in atypical localisation in severe asthma patient - case report.",
"title_normalized": "aspergilloma in atypical localisation in severe asthma patient case report"
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"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-122607",
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"abstract": "In recent years, immune checkpoint inhibitors (ICIs) have become a standard treatment for patients with advanced lung cancers. With the widespread use of immunotherapy in clinical practice, immune-related adverse events (irAEs) have become increasingly common. This case report details a 72-year-old man with small-cell lung cancer (SCLC) who developed pneumonitis, appendicitis, and biliary obstruction during treatment with toripalimab. The patient was initially diagnosed with limited-stage SCLC in January 2019 and completed 5 sequential cycles of etoposide/cisplatin (EP) and radiotherapy (60 Gy/30 F). The overall response was complete response (CR) after first line treatment. He developed radiation pneumonitis after completion of radiotherapy, which responded well to symptomatic treatment. Due to newly diagnosed bone metastasis, he was administered toripalimab intravenously every 3 weeks and 12 mg anlotinib orally once a day from January 2020. By the third cycle, the patient presented with electrocardiographic abnormalities, gingival swelling and pain, and hoarseness, and consequently, the anlotinib was suspended. After 4 cycles, he developed suppurative appendicitis, which was managed successfully with anti-inflammatory agents. He then presented with shortness of breath on exertion and after a comprehensive examination, he was diagnosed with ICI-related-pneumonitis. After 6 weeks of treatment with methylprednisolone, the shortness of breath was mostly relieved and treatment continued. In June 2020, the patient developed severe vomiting. Computed tomography (CT) indicated biliary obstruction, and at endoscopic retrograde cholangiopancreatography (ERCP) there was edema of the major papilla of the duodenum. The patient's symptoms were relieved after treatment with gastric acid suppression and antiemetics. Re-examination by magnetic resonance imaging (MRI) showed that the biliary obstruction had been resolved. Although the disease progressed after immunotherapy, no tumor tissue related to the biliary obstruction was detected, and this was therefore classified as an irAE.",
"affiliations": "Department of Thoracic Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.;Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.;Department of Radiation Oncology, Fifth People's Hospital of Shenyang, Shenyang, China.;Department of Radiation Oncology, Fifth People's Hospital of Shenyang, Shenyang, China.;Department of Thoracic Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.;Department of Radiation Oncology, Fourth Hospital Afflicted to China Medical University, Shenyang, China.;Department of Radiation Oncology, Fourth Hospital Afflicted to China Medical University, Shenyang, China.;Department of Thoracic Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.;Department of Thoracic Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.;Department of Gastrointestinal and Urinary and Musculoskeletal Cancer Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.;Department of Thoracic Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.",
"authors": "Qu|Yanli|Y|;Wang|Zheng|Z|;Feng|Jilong|J|;Wang|Lijun|L|;Liu|Hangyu|H|;Liu|Dan|D|;Zhao|Yuxia|Y|;Yu|Ruoxi|R|;Li|Wang|W|;Sun|Deyu|D|;Yu|Hong|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000656314:toripalimab",
"country": "China",
"delete": false,
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"issue": "10(8)",
"journal": "Annals of palliative medicine",
"keywords": "Small-cell lung cancer (SCLC); case report; immune checkpoint inhibitors (ICIs); immune-related adverse events (irAEs)",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D001064:Appendicitis; D002779:Cholestasis; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D011014:Pneumonia",
"nlm_unique_id": "101585484",
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"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pneumonitis, appendicitis, and biliary obstruction during toripalimab treatment in a patient with extensive-stage small-cell lung cancer: a case report.",
"title_normalized": "pneumonitis appendicitis and biliary obstruction during toripalimab treatment in a patient with extensive stage small cell lung cancer a case report"
} | [
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"activesubstancename": "CISPLATIN"
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"abstract": "OBJECTIVE\nTo report a case of seizure activity associated with oral codeine phosphate administered for analgesia in an elderly woman with end-stage renal disease.\n\n\nMETHODS\nA 73-year-old Taiwanese woman with end-stage renal disease received oral codeine phosphate 30 mg 4 times daily for her back and rib pain without adjustment of her dosage regimen. Seven days after starting codeine therapy, the woman became stuporous and developed tonic-clonic seizures. After phenytoin initiation, codeine discontinuation, and naloxone administration, the seizures did not recur.\n\n\nCONCLUSIONS\nCodeine is a frequently used opioid analgesic, especially when pain control with acetaminophen or nonsteroidal antiinflammatory drugs fails. Although seizures associated with codeine have been reported, pertinent data are very limited and the exact mechanism is unknown. An objective causality assessment indicated the seizure to be a probable drug-related event in this patient.\n\n\nCONCLUSIONS\nElderly patients with end-stage renal disease may be predisposed to seizures with higher doses of codeine phosphate. It is imperative to adjust the codeine dosage regimen based on patients' renal function to avoid the potential toxicity with overdose.",
"affiliations": "Institute of Clinical Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.",
"authors": "Kuo|Shih-Chen|SC|;Lin|Ya-Chu|YC|;Kao|Shu-Min|SM|;Yang|Yea-Huei Kao|YH|",
"chemical_list": "D000701:Analgesics, Opioid; D000927:Anticonvulsants; D010672:Phenytoin; D003061:Codeine",
"country": "United States",
"delete": false,
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"issue": "38(11)",
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"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D000927:Anticonvulsants; D003061:Codeine; D005260:Female; D006801:Humans; D010672:Phenytoin; D012640:Seizures",
"nlm_unique_id": "9203131",
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"abstract": "Herein, we describe a neovascular age-related macular degeneration patient with retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy (PCV) coexisting in the same eye at the time of diagnosis. A 55-year-old woman presented with a history of decreased vision in her left eye. Fundoscopy, fluorescein and indocyanine green angiography, and optical coherence tomography imaging revealed RAP and PCV lesions in her left eye at first diagnosis. The patient received intravitreal ranibizumab therapy but developed tachyphylaxis after the first dose despite having three monthly doses. Switching to intravitreal aflibercept injection in our case resulted in anatomic and functional improvement.",
"affiliations": "İstanbul University İstanbul Faculty of Medicine, Department of Ophthalmology, İstanbul, Turkey.;İstanbul University İstanbul Faculty of Medicine, Department of Ophthalmology, İstanbul, Turkey.",
"authors": "Cebeci|Zafer|Z|;Kır|Nur|N|",
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"doi": "10.4274/tjo.14602",
"fulltext": "\n==== Front\nTurk J OphthalmolTurk J OphthalmolTJOTurkish Journal of Ophthalmology2149-86952149-8709Galenos Publishing 10.4274/tjo.146023209Case ReportAll Types of Age-related Macular Degeneration in One Patient Cebeci Zafer 1*Kır Nur 1\n1 \nİstanbul University İstanbul Faculty of Medicine, Department of Ophthalmology, İstanbul, Turkey\n* Address for Correspondence: İstanbul University İstanbul Faculty of Medicine, Department of Ophthalmology, İstanbul, Turkey Phone: +90 212 414 20 00/31381 E-mail: zapherman@yahoo.com12 2017 25 12 2017 47 6 355 357 21 2 2017 31 3 2017 © Copyright 2017 by Turkish Ophthalmological Association\n\nTurkish Journal of Ophthalmology, published by Galenos Publishing House.2017This 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 work is properly cited.Herein, we describe a neovascular age-related macular degeneration patient with retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy (PCV) coexisting in the same eye at the time of diagnosis. A 55-year-old woman presented with a history of decreased vision in her left eye. Fundoscopy, fluorescein and indocyanine green angiography, and optical coherence tomography imaging revealed RAP and PCV lesions in her left eye at first diagnosis. The patient received intravitreal ranibizumab therapy but developed tachyphylaxis after the first dose despite having three monthly doses. Switching to intravitreal aflibercept injection in our case resulted in anatomic and functional improvement.\n\nAge-related macular degenerationretinal angiomatous proliferationpolypoidal choroidal vasculopathy\n==== Body\nINTRODUCTION\nNeovascular age-related macular degeneration (nAMD), also known as “wet” or “exudative” AMD, is characterized by the abnormal formation of new choroidal vessels with growth under the retinal pigment epithelium (RPE) or in subretinal spaces, resulting in severe vision loss.1 Polypoidal choroidal vasculopathy (PCV) features clinically distinguishable orange-reddish lesions beneath the RPE which are caused by dilation of abnormal choroidal vessels. PCV was first reported by Yannuzzi et al.2 in 1990, yet there is still debate about whether PCV should be considered a subtype of nAMD or if they are completely distinct entities. Retinal angiomatous proliferation (RAP), a subtype of nAMD, is a pathology in which the vasogenic process of neovascularization starts from the retina to form choroidal neovascularization (CNV) and is strongly associated with soft drusen or reticular pseudodrusen at the macula.3 RAP tends to show bilateral involvement and is more common in older patients.3 The coexistence of PCV and typical nAMD has been reported in the literature, and although the combination of type 1 and type 3 AMD was also reported, the authors did not provide a detailed description of this case.4,5,6,7,8\n\nIn this report, we describe a case of nAMD co-presenting with different types of lesions in a patient who responded to aflibercept treatment after developing tachyphylaxis to ranibizumab.\n\nCASE REPORT\nA 55-year-old white female presented to our clinic with a chief complaint of gradually decreasing vision in her left eye that she had first noticed one month earlier. She had an unremarkable past ocular and systemic history. In her family history, her parents had a diagnosis of AMD but they did not receive any treatment for this pathology. Her best corrected visual acuity was 20/25 in the right and 20/32 in the left eye. Anterior segments were normal bilaterally. Fundoscopic evaluation showed soft drusen on the macula and peripapillary reddish-orange lesions bilaterally. There was also drusenoid retinal pigment epithelial detachment (PED) in the right and serous PED in the left eye (Figure 1a, b). Fluorescein angiography (FA) revealed peripapillary hyperfluorescence in both eyes which increased in late phases and hyperfluorescence in late phases due to serous PED in the left macula (Figure 1c, e, g, i). Indocyanine green angiography (ICGA) showed peripapillary polypoidal hyperfluorescent lesions bilaterally and hyperfluorescent hot-spot in the centre of hypofluorescent PED, suggesting RAP in the left eye (Figure 1d, f, h, j). Spectral domain optical coherence tomography scan of the macula demonstrated drusen and drusenoid PED in the right eye and serous PED with hyperreflective lesion under the RPE and concomitant subretinal fluid in the left eye (Figure 1k, l). Based on examination and imaging findings, we diagnosed the patient with bilateral AMD consisting of different lesion types.\n\nIntravitreal ranibizumab (0.5 mg/0.05 mL) injection with three monthly loading doses was planned for the left eye after diagnosis. One month after the first dose, serous PED had totally regressed (Figure 2a), but reappeared after the second dose (Figure 2b) and increased despite a third dose (Figure 2c). One month after the third dose, we switched treatment from ranibizumab to aflibercept (2 mg/0.05 mL). Serous PED decreased one month after the first aflibercept injection and totally resolved after the second injection (Figure 2d, e). The patient received three monthly loading doses and continued with pro re nata protocol. She received a total of five injections during the nine months follow-up after starting to use aflibercept. At the final examination, her vision was 20/25 in the left eye and OCT showed no PED or intra- or subretinal fluid. The PCV lesions on ICGA had totally resolved but a small area of subfoveal atrophy developed during the follow-up period (Figure 2f).\n\nDISCUSSION\nCombinations of PCV and typical nAMD lesions in the same eye or one in each eye of the same patient have been reported in the literature.4,5,6,7,8 However, the coexistence of PCV and RAP at the time of diagnosis has not been previously described. In a group of newly diagnosed 155 nAMD patients, Liu et al.4 found 3.2% of the cases had mixed lesions, all of them with PCV and typical CNV in the same eye. The authors considered this mixed presentation a third subtype of nAMD. In a series of 289 Japanese patients with PCV, RAP, and typical AMD, Maruko et al.5 found that 5.5% of the patients had combined lesions, all with PCV in one eye and typical AMD in the other eye. However, no combination of RAP and PCV was detected in these cases. Pereira et al.6 reported that 5.3% of their Brazilian nAMD patients had combined lesions with different types of each in one eye, but the combination of RAP and PCV in the same eye was not reported. In a study assessing the newly diagnosed subtypes of nAMD according to FA alone and FA + OCT images, the authors divided subtypes as type 1 (subRPE), type 2 (subretinal), type 3 (intraretinal), and mixed.7 PCV was considered type 1 and RAP as type 3. Using FA + OCT, mixed lesions were detected in 16.9% of 266 eyes and 15.5% of mixed lesions were a combination of type 1 and 3. However, they did not provide further details about the coexistence of PCV and RAP in the same patient or eye. One report included an 86-year-old female patient with unilateral RAP who developed PCV in the fellow eye three years after the initial diagnosis.8 Our patient had RAP and PCV in the same eye at the time of diagnosis and she may have presented in a early phase, enabling us to identify the RAP lesion. If the patient presented us later, progression towards the advanced stages might occured and we could have diagnosed as CNV instead of RAP.\n\nAnother issue that must be emphasized in our case is the development of tachyphylaxis. Binder9 differentiated tolerance from tachyphylaxis and pointed out that tachyphylaxis could occur in a short time when drugs were used repeatedly. There are several potential mechanisms for development of tachyphylaxis in nAMD, including the development of antibodies against anti-VEGF, change in lesion type or neovascular membrane structure, and other pathways of action used by anti-VEGF drugs.9 Another possible explanation could be upregulation of pro-angiogenic factors other than VEGF-A.9\n\nThe combination of PPV, ILM peeling, MB, and gas tamponade may be effective in patients with high myopia and MHRD. However, although the anatomical success is high with this procedure, functional success may be limited due to chorioretinal atrophy resulting from high myopia. In our patient, limited functional improvement was achieved due to chorioretinal atrophy in the macular region. Therefore, the fact that the severity of chorioretinal atrophy in the posterior pole will limit functional success should be considered prior to surgical intervention in these patients.\n\nSwitching to other anti-VEGF drugs is one option for overcoming tachyphylaxis in nAMD treatment. Bevacizumab and ranibizumab have similar protein composition and sites of action. Aflibercept is shown to be effective in patients with large PEDs that were insufficiently responsive to multiple bevacizumab and ranibizumab injections.10 Because of the higher binding affinity of aflibercept, we decided to switch ranibizumab to aflibercept and achieved a favorable anatomical outcome.\n\nIn conclusion, this case study revealed that different types of lesions can be seen not only in the course of nAMD but also at initial diagnosis. ICGA and OCT are the most important tools to diagnose coexisting lesions when suspected clinically.\n\nEthics\n\nInformed Consent: It was taken.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship Contributions\n\nSurgical and Medical Practices: Zafer Cebeci, Nur Kır, Concept: Zafer Cebeci, Nur Kır, Design: Zafer Cebeci, Nur Kır, Data Collection or Processing: Zafer Cebeci, Nur Kır, Analysis or Interpretation: Zafer Cebeci, Nur Kır, Literature Search: Zafer Cebeci, Nur Kır, Writing: Zafer Cebeci, Nur Kır.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n\nFigure 1 Fundus photography of the right (a) and left (b) eye showing drusen and peripapillary orange-red lesions bilaterally and serous pigment epithelial detachment (PED) on the left eye. Early and late fluorescein angiography and indocyanine green angiography (ICGA) images of the right (c, d, g, h) and left (e, f, i, j) eye. ICGA shows peripapillary hyperfluorescent polypoidal lesions bilaterally and hyperfluorescent spot in the center of hypofluorescent PED on the left eye suggesting a retinal angiomatous proliferation lesion. Spectral domain optical coherence tomography scan of the right macula (k) illustrating drusen and drusenoid PED and serous PED, with subretinal fluid and hyperreflective lesion under the pigment epithelium on the left macula (l)\nFigure 2 Spectral domain optical coherence tomography images of the left eye one month after first (a), second (b), and third (c) intravitreal ranibizumab injections. Switching to aflibercept, one month after first (d), second (e) injections and after 9 months (f)\n==== Refs\nReferences\n1 Cook HL Patel PJ Tufail A Age-related macular degeneration: diagnosis and management Br Med Bull. 2008 85 127 149 18334518 \n2 Yannuzzi LA Sorenson J Spaide RF Lipson B Idiopathic polypoidal choroidal vasculopathy (IPCV) Retina. 1990 10 1 8 1693009 \n3 Yannuzzi LA Negrao S Iida T Carvalho C Rodriguez-Coleman H Slakter J Freund KB Sorenson J Orlock D Borodoker N Retinal angiomatous proliferation in age related macular degeneration Retina. 2001 21 416 434 11642370 \n4 Liu Y Wen F Huang S Luo G Yan H Sun Z Wu D Subtype lesions of neovascular age-related macular degeneration in Chinese patients Graefes Arch Clin Exp Ophthalmol. 2007 245 1441 1445 17406882 \n5 Maruko I Iida T Saito M Nagayama D Saito K Clinical characteristics of exudative age-related macular degeneration in Japanese patients Am J Ophthalmol. 2007 144 15 22 17509509 \n6 Pereira FB Veloso CE Kokame GT Nehemy MB Characteristics of Neovascular Age-Related Macular Degeneration in Brazilian Patients Ophthalmologica. 2015 234 233 242 26394133 \n7 Jung JJ Chen CY Mrejen S Gallego-Pinazo R Xu L Marsiglia M Boddu S Freund KB The incidence of neovascular subtypes in newly diagnosed neovascular age-related macular degeneration Am J Ophthalmol. 2014 158 769 779 25034111 \n8 Sawa M Ueno C Gomi F Nishida K Incidence and characteristics of neovascularization in fellow eyes of Japanese patients with unilateral retinal angiomatous proliferation Retina. 2014 34 761 767 24100709 \n9 Binder S Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br J Ophthalmol. 2012 96 1 2 22157632 \n10 Patel KH Chow CC Rathod R Mieler WF Lim JI Ulanski LJ Leiderman YI Arun V Chau FY Rapid response of retinal pigment epithelial detachments to intravitreal aflibercept in neovascular age-related macular degeneration refractory to bevacizumab and ranibizumab Eye (Lond). 2013 27 663 667 23558214\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2149-8709",
"issue": "47(6)",
"journal": "Turkish journal of ophthalmology",
"keywords": "Age-related macular degeneration; polypoidal choroidal vasculopathy; retinal angiomatous proliferation",
"medline_ta": "Turk J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101686048",
"other_id": null,
"pages": "355-357",
"pmc": null,
"pmid": "29326855",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": "17406882;26394133;1693009;24100709;25034111;18334518;11642370;23558214;22157632;17509509",
"title": "All Types of Age-related Macular Degeneration in One Patient.",
"title_normalized": "all types of age related macular degeneration in one patient"
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"abstract": "Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection is associated with accelerated progression to cirrhosis, end-stage liver disease, and liver-associated death. It is fortunate that curative direct-acting antivirals for the treatment of HCV are widely available in the VA healthcare system. We attempted to identify, evaluate, and treat all HIV/HCV-coinfected persons at the Atlanta VA Healthcare System.\nHuman immunodeficiency virus/HCV-coinfected persons at Atlanta VA between 2015 and 2018 were identified using the HIV Atlanta Veterans Affairs Cohort Study and Hepatitis C VA Clinical Case Registry. Retrospective reviews of each electronic medical record were conducted by the hepatitis C clinical team for validation. The primary end point was achieving sustained virologic response.\nOne hundred thirty-eight veterans with HIV and hepatitis C viremia were identified. One hundred twenty-five (90%) were evaluated for treatment and 113 (91%) were initiated on direct-acting antiviral therapy. Median age at initiation of treatment was 60 years and the majority were black race (90%). Genotype 1a was most common (70%) and 41% had compensated cirrhosis. One hundred eight completed treatment and 96% achieved sustained virologic response. Six veterans had virologic relapse; 4 had treatment-emergent resistance mutations in the NS5a gene. Mean CD4 was 580 cells/mm3 with HIV viral suppression in 82% of the cohort. In those not treated, unstable housing (25%), active substance use (31%), and psychiatric conditions (42%) were identified barriers to care.\nThrough a concerted, systematic effort, over 80% of HIV/hepatitis C persons in the Atlanta VA have been initiated on treatment for hepatitis C, 96% of which have been cured.",
"affiliations": "Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.;Atlanta VA Medical Center, Decatur, Georgia, USA.;Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.",
"authors": "Adekunle|Ruth O|RO|;DeSilva|Kathryn|K|;Cartwright|Emily J|EJ|",
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"doi": "10.1093/ofid/ofaa085",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa085\nofaa085\nMajor Article\nAcademicSubjects/MED00290\nHepatitis C Care Continuum in a Human Immunodeficiency Virus (HIV) Positive Cohort: Data From the HIV Atlanta Veterans Affairs Cohort Study\nAdekunle Ruth O 12 DeSilva Kathryn 2 Cartwright Emily J 12 1 \nDepartment of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA\n2 \nAtlanta VA Medical Center, Decatur, Georgia, USA\nCorrespondence: Ruth O. Adekunle, MD, Division of Infectious Diseases, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA 30303 (roadeku@emory.edu).\n4 2020 \n12 3 2020 \n12 3 2020 \n7 4 ofaa08528 2 2020 04 3 2020 06 4 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nHuman immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection is associated with accelerated progression to cirrhosis, end-stage liver disease, and liver-associated death. It is fortunate that curative direct-acting antivirals for the treatment of HCV are widely available in the VA healthcare system. We attempted to identify, evaluate, and treat all HIV/HCV-coinfected persons at the Atlanta VA Healthcare System.\n\nMethods\nHuman immunodeficiency virus/HCV-coinfected persons at Atlanta VA between 2015 and 2018 were identified using the HIV Atlanta Veterans Affairs Cohort Study and Hepatitis C VA Clinical Case Registry. Retrospective reviews of each electronic medical record were conducted by the hepatitis C clinical team for validation. The primary end point was achieving sustained virologic response.\n\nResults\nOne hundred thirty-eight veterans with HIV and hepatitis C viremia were identified. One hundred twenty-five (90%) were evaluated for treatment and 113 (91%) were initiated on direct-acting antiviral therapy. Median age at initiation of treatment was 60 years and the majority were black race (90%). Genotype 1a was most common (70%) and 41% had compensated cirrhosis. One hundred eight completed treatment and 96% achieved sustained virologic response. Six veterans had virologic relapse; 4 had treatment-emergent resistance mutations in the NS5a gene. Mean CD4 was 580 cells/mm3 with HIV viral suppression in 82% of the cohort. In those not treated, unstable housing (25%), active substance use (31%), and psychiatric conditions (42%) were identified barriers to care.\n\nConclusions\nThrough a concerted, systematic effort, over 80% of HIV/hepatitis C persons in the Atlanta VA have been initiated on treatment for hepatitis C, 96% of which have been cured.\n\nThis review describes the HCV care continuum for HIV/HCV-coinfected veterans treated in the Atlanta VA healthcare system between 2015 and 2018. One hundred twenty-five coinfected veterans were evaluated for treatment: 91% initiated HCV therapy, and 96% achieved sustained virologic response.\n\ncare continuumchronic hepatitis C virusdirect-acting antiviralshuman immunodeficiency virusveteransNational Institutes of Health/National Center for Advancing Translational SciencesTL1TR002382UL1TR002378\n==== Body\nHepatitis C virus (HCV) affects over 3 million persons in the United States and is one of the most common causes of end-stage liver disease (ESLD) [1]. Of the 1.2 million persons in the United States living with human immunodeficiency virus (HIV), 25% are coinfected with HCV [2]. There are significant consequences of HIV/HCV coinfection including lower likelihood of spontaneous clearance, faster progression to cirrhosis, greater incidence of decompensated cirrhosis, higher rates of hepatocellular carcinoma, and higher rates of liver-related and all-cause mortality [3–6]. With the advent of direct-acting antivirals (DAAs), these complications can be mitigated, underscoring the necessity of HCV eradication in this population.\n\nBefore 2014, the available therapy for HCV was injectable interferon (pegylated and nonpegylated) in combination with ribavirin. This regimen was poorly tolerated with (1) high rates of treatment limiting adverse events and (2) reported sustained virologic response (SVR) rates less than 50% in HCV-monoinfected persons [7, 8] and less than 25% in HIV/HCV-coinfected persons [9]. During the interferon era, it was reported that only half of the HCV-infected persons in the United States were tested and aware of their diagnosis, approximately one third had been referred for HCV care, and only 5% to 6% had been successfully treated [10].\n\nOral DAAs have allowed for improved ability to treat HCV, resulting in shorter treatment duration, minimal side effects, and significantly higher rates of SVR (>90%) in both monoinfected and coinfected persons [11–13]. With the availability of curative HCV therapy, treatment of HIV/HCV persons should be a priority. However, DAA treatment uptake has been limited by cost and associated insurance coverage restrictions [14].\n\nThe US Veterans Health Administration (VHA) is in a unique position to address challenges posed by chronic HCV infection and has now become the single largest provider of HCV care in the United States [15]. In 2001, the VHA implemented comprehensive screening guidelines inclusive of the Centers for Disease Control and Prevention screening recommendations and additional risk factors such as alcohol use, history of tattoos, multiple sexual partners, intranasal cocaine use, and service during the Vietnam era [16]. By 2013, more than 70% of veterans in the “baby boomer” birth cohort had been screened for HCV [17], and, when DAA therapy became widely available in 2016, the VHA announced a systematic and concerted effort to provide HCV treatment to all veterans with chronic HCV [18]. As of March 2019, 83% of veterans who started treatment for HCV have completed treatment and are cured [19].\n\nAligned with VHA efforts, we aimed to link HIV/HCV-coinfected veterans into care and initiate HCV treatment at the Atlanta VA. We describe the HCV care continuum that was provided to this cohort between 2015 and 2018.\n\nMATERIALS AND METHODS\nStudy Population and Data Sources\nWe performed a retrospective cohort study of HCV care in HIV/HCV-coinfected adults (18 years and older) at the Atlanta VA Healthcare System (AVAHCS) between January 1, 2015 and October 31, 2018. Patient outreach, linkage, and treatment were performed through regular patient care but retrospectively analyzed as an institutional review board-approved research study.\n\nUsing the HIV Atlanta Veterans Affairs Cohort Study (HAVACS) and HCV VA Clinical Case Registries (HCV CCR), all veterans at the AVAHCS that were living with HIV and had either positive HCV serologic testing or ribonucleic acid (RNA)-based testing were identified.\n\nData Collection\nEach electronic medical record was reviewed by an infectious disease physician or infectious disease-trained clinical pharmacist for validation of HCV and HIV status. The HCV clinical team was made up of a physician-led HCV team including a clinical pharmacy specialist, an advanced practice provider, and a registered nurse. The HCV clinical team educated the HIV staff and providers and additionally provided direct patient outreach to link patients into HCV care. Human immunodeficiency virus clinical providers alerted a designated HCV infectious disease physician to an HIV-positive veteran with HCV viremia. This triggered the process for the veteran to be seen and evaluated for treatment in hepatitis clinic. Pretreatment review of appropriateness of HCV treatment and potential drug-drug interaction with DAA therapy were assessed either through an electronic consult or during an in-person evaluation. Medications identified to have an interaction with DAA either were either safely discontinued, antiretroviral (ARV) medications were adjusted, or a different DAA regimen was chosen. Veterans who were not viremic, transferred to a different VA facility, lost to follow up, or died before the study were not included in the analysis.\n\nData elements of interest included age, sex, race, Charlson comorbidity index (CCI), active substance abuse, history of psychiatric condition, and unstable housing. Active substance use was defined as any use of cocaine, heroin, methamphetamines, or abuse of prescription opiates within 6 months of contact regarding HCV treatment and was ascertained via self-report and/or urine drug screens. Psychiatric condition was defined as any documented history of generalized anxiety disorder, posttraumatic stress disorder, major depression, bipolar disorder, or schizophrenia. Unstable housing was defined as lack of housing or requiring the assistance of the US Department of Housing and Urban Development-VA Supportive Housing (HUD-VASH) program within 3 months before or after initiating HCV treatment.\n\nThrough manual chart review, HIV- and HCV-specific factors were collected. These included CD4 lymphocyte count (cells/mm3), HIV RNA (copies/mL), ARV regimen, need for ART switch before initiation of DAA, HCV viral load, HCV genotype, prior HCV treatment experience, presence of cirrhosis (evidenced by fibrosis [FIB]4 score >3.25, aspartate aminotransferase-to-platelet ratio index [APRI] score >1, Fibroscan >12.5 kPa, or biopsy suggestive of cirrhosis), and DAA regimen. The resistance tests that were used included the HCV NS5A Resistance Genotype, the HCV NS5b drug resistance genotype, and the NS3 drug resistance genotype. Two veterans received treatment through the VA Choice Program (the VA Choice Program allowed veterans to see an HCV provider in the private sector and fill the DAA prescription at the VA pharmacy).\n\nStudy Definitions and Outcomes\nThe primary study objective was to identify HIV/HCV chronically coinfected veterans, link them into HCV care, and initiate HCV treatment to achieve an SVR. Chronic HCV was defined as having a detectable viral load at least 3 months before treatment initiation. If veterans were able to be contacted and presented to their scheduled HCV clinic appointment, they were considered to be linked into care. During the evaluation appointment, a pretreatment assessment was performed. This included the following: assessing their comorbidities; determining their fibrosis stage either through FIB4 score, APRI score, or Fibroscan; obtaining baseline laboratory tests including updated HCV viral load and HIV viral load if indicated; and checking for other hepatitis viruses. Veterans were then started on DAAs appropriate for their genotype, fibrosis stage, and renal function. If drug-drug interactions with DAA therapy was anticipated, veteran’s ARV regimen was adjusted before initial HCV treatment. Veterans were also assessed for baseline NS5a mutations before DAA therapy if they were treatment experienced, which assisted in determination of appropriate DAA regimen. Veterans were seen by an infectious disease physician, physician assistant, or infectious disease-trained clinical pharmacist monthly for additional medication and monitoring while on DAAs. Veterans were determined to have achieved SVR if their HCV RNA was undetectable (less than lower limit of quantification target or not detected) at least 12 weeks after completion of treatment. Relapse was defined as a detectable HCV viral load 12 weeks after completing DAA therapy. If a veteran experienced a relapse, resistance testing was performed to assess whether they developed a treatment-emergent mutation to their DAA therapy. Reinfection was defined as detectable HCV viremia after a veteran achieved SVR and with evidence of high-risk behavior and/or genotype switch.\n\nData Analysis\nWe tabulated the number of HIV/HCV veterans that were evaluated for treatment, seen in clinic, started on HCV therapy, and achieved SVR, which defined the HCV care continuum. We performed descriptive statistics on patient-level demographics, clinical characteristics, and treatment regimens. We compared those who were started on treatment to those who were not to identify factors associated with poor linkage into care. The χ 2 test was used for categorical variables, and Student’s t tests or Wilcoxon rank-sum test was used for continuous variables. Two-sided P values were used for all analyses, and P ≤ 0.05 was considered statistically significant. SAS version 9.4 (SAS Institute Inc.) was used for data management and statistical analysis.\n\nRESULTS\nStudy Population\nIn this all male cohort, the median age was 60 years of age, 90% were of black race, and 70% were genotype 1a (Table 1). For clinical variables, cirrhosis was observed in 41% of veterans, median CCI was 3, and median absolute number of comorbidities was 6. In assessing psychiatric-related conditions, 46% had evidence of a psychiatric condition, and 16% had active substance abuse. The untreated group had more active substance use (31% vs 14%, P = .09) and unstable housing (25% vs 5%, P = .01) compared with treated group. Of the 12 veterans who were not treated, 3 (25%) died shortly after evaluation (2 of which were secondary to complications from ESLD), 5 (42%) had psychiatric conditions (3 of whom had active psychosis), 3 (25%) were consistently nonadherent to ARVs, 3 were unstably housed (25%), 1 decided to be treated outside of the VA, and 1 veteran was unable to be contacted for follow up.\n\nTable 1. Baseline Characteristics of HIV/HCV-Coinfected Veterans Evaluated for HCV Treatment at the Atlanta VA\n\nVariables\tEntire Cohort, n (%)\tTreated, n (%)\tUntreated, n (%)\t\nP Valuea\t\nTotal persons (n)\t125\t113\t12\t\t\nMedian age (IQR)\t60 (55–65)\t60 (55–64)\t62 (55–67)\t0.61\t\nRace\t\t\t\t\t\n White\t9 (7)\t8 (7)\t1 (8)\t\t\n Black\t113 (90)\t103 (91)\t10 (83)\t\t\n Unknown\t3 (2)\t2 (2)\t1 (8)\t\t\nGenotype \t\t\t\t0.86\t\n 1a\t88 (70)\t80 (71)\t8 (67)\t\t\n 1b\t32 (26)\t28 (25)\t4 (33)\t\t\n 1a/1b\t2 (2)\t2 (2)\t0\t\t\n 2b\t2 (2)\t2 (2)\t0\t\t\n 3a\t1 (1)\t1 (1)\t0\t\t\nCirrhosis\t48 (41)\t45(40)\t3 (25)\t0.38\t\n Decompensatedb\t4 (3)\t2 (2)\t2 (17)\t\n0.05\n\t\nDeveloped hepatocellular carcinoma\t3 (2)\t1 (1)\t2 (17)\t\n0.01\n\t\nCCI, median (IQR)\t3 (2–5)\t3 (2–5)\t4 (2–6)\t0.48\t\nAbsolute number of comorbidities, median (IQR)\t6 (4–7)\t6 (4–7)\t5 (3–8)\t0.74\t\nPsychiatric condition \t57 (46)\t52 (46)\t5 (42)\t0.57\t\nActive substance use\t20 (16)\t16 (14)\t4 (31)\t0.09\t\nUnstable housing \t9 (6)\t6 (5)\t3 (25)\t\n0.01\n\t\nAbbreviations: CCI, Charlson comorbidity index; HCV, hepatitis C virus, HIV, human immunodeficiency virus; IQR, interquartile range; VA, Veterans Affairs. \n\n\na\nP values compare those initiated on HCV treatment to those who were not.\n\n\nbDecompensated cirrhosis was defined as presence of ascites, hepatic encephalopathy, history of bleeding esophageal varices, or hepatorenal syndrome.\n\nCare Continuum and Virologic Response\nTwo hundred fifty HIV/HCV-coinfected veterans were identified by the HAVACS and HCV CCR (Figure 1). Of those identified, 56 were not viremic, 14 died (2 of whom died from ESLD and 3 died from hepatocellular carcinoma), and 42 were transferred to a different VA facility. This resulted in 138 veterans who were contacted for HCV treatment. The HCV treatment care continuum is summarized in Figure 2. Of the 138 veterans, 13 (9%) could not be engaged in clinic follow up, whereas 125 (91%) presented for an initial evaluation in hepatitis clinic. These veterans were identified to be linked into HCV care between January 2015 and October 2018. Of the 125 persons, 113 (90%) were initiated on HCV treatment. At study end, 3 veterans remained on treatment and 2 veterans had completed treatment, although SVR data had not yet been obtained; thus, of the veterans who were started on treatment, 108 (96%) achieved SVR on either their first or second treatment attempt with documentation of clinical cure. During the study period, 78% of all HIV/HCV-coinfected veterans had achieved SVR. Of the 108 veterans who achieved SVR, there were 8 (7%) veterans who disrupted and discontinued therapy at either 4 or 6 weeks, all of whom were cured.\n\nFigure 1. Study inclusion criteria for human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected veterans at the Atlanta VA Healthcare System. CCR, VA Clinical Case Registries; HAVACS, HIV Atlanta Veterans Affairs Cohort Study; RNA, ribonucleic acid. \n\nFigure 2. Hepatitis C virus (HCV) treatment care continuum model of human immunodeficiency virus/HCV-coinfected veterans at the Atlanta VA Healthcare System, January 2015–December 2018 (n = 138).\n\nAntiretroviral Regimen\nIn general, the treated cohort had well controlled HIV, with a median CD4 of 580, and more than 80% of veterans were virally suppressed at initiation of therapy (Table 2). The most common ARV regimen at the time of HCV treatment start was an integrase-based regimen. Sixty-four percent of veterans were on an integrase-based regimen, 32% of whom required change to an integrase-based regimen before starting HCV treatment. Of those who required ARV regimen change, 69% were secondary to concerns of drug interactions with DAA therapy.\n\nTable 2. HIV Information for Coinfected Veterans Who Initiated HCV Treatment (n = 113)\n\nVariables\tn (%)\t\nMedian CD4 count (IQR, cells/mm3) \t580 (379–765)\t\nHIV viral load undetectable\t110 (82)\t\nARV regimen at time of HCV therapy\t\t\n Integrase-inhibitor-based\t79 (64)\t\n NNRTI-based\t22 (17)\t\n PI-based\t13 (10)\t\n Other\t7 (6)\t\nARV regimen changed for HCV therapy\t36 (32)\t\nARV regimen change reason \t\t\n Medication interaction \t25 (69)\t\n Optimization of regimen \t7 (19)\t\n Other\t3 (8)\t\nAbbreviations: ARV, antiretroviral; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IQR, interquartile range; NNRTI, nonnucleoside reverse-transcriptase inhibitor; PI, protease inhibitor.\n\nHepatitis C Virus Treatment and Virologic Response\n\nTable 3 encompasses the DAA regimens and clinical response. The most common DAA regimen used was ledipasvir/sofosbuvir (59%), followed by elbasvir/grazoprevir (10%) and sofosbuvir/velpatasvir (9%). There were 2 veterans who experienced adverse events leading to treatment discontinuation. One veteran experienced tongue ulcerations while on ledipasvir/sofosbuvir, which was discontinued. Once the tongue ulcerations resolved, he was started on glecaprevir/pibrentasvir, which was well tolerated, and he achieved SVR. Another veteran developed acute renal injury after approximately 6 weeks of sofosbuvir + daclatasvir, which resolved after discontinuation. This veteran also achieved clinical cure without having to be started on another treatment regimen.\n\nTable 3. HCV Treatment Regimen and Response (n = 113)\n\nHCV Treatment Regimen \tn (%)\t\n Ledipasvir/sofosbuvir\t73 (59)\t\n Elbasvir/grazoprevir\t12 (10)\t\n Sofosbuvir/velpatasvir\t11 (9)\t\n Dasabuvir + ombitasvir/paritaprevir/ritonavir\t5 (4)\t\n Simeprevir + sofosbuvir\t4 (3)\t\n Daclatasvir + sofosbuvir\t3 (2)\t\n Glecaprevir/pibrentasvir\t1 (1)\t\n Unknown*\t1 (1)\t\nDAA discontinued early although cured\t8 (7)\t\nRelapsed\t6 (5)\t\n Number with resistance\t4 (66)\t\n Cured with retreatment\t5 (83)\t\nAbbreviations: DAA, direct-acting antiviral; HCV, hepatitis C virus.\n\n*Patient was treated outside of Atlanta VA Healthcare System through the choice program.\n\nIn total, 6 veterans (5%) experienced a virologic relapse, only 1 of whom was treatment experienced. Four veterans had treatment-emergent resistance mutations in the NS5a gene and all were of black race. Five of the 6 veterans had cirrhosis and 4 of the 6 were on ledipasvir/sofosbuvir. One veteran had a 2-week drug interruption, which we believed contributed to developing resistance. One veteran’s genotype changed from 1a to 1b. Two veterans had Q30R mutations, 2 veterans had L31 mutations, and 2 veterans had Y93H mutations. Five of 6 veterans were cured after retreatment, and 1 veteran declined retreatment. Retreatment regimens included sofosbuvir/velpatasvir/voxilaprevir for 12 weeks (1 veteran), sofosbuvir velpatasvir + ribavirin for 24 weeks (1 veteran), and simeprevir + sofosbuvir + ribavirin for 24 weeks (3 veterans). Only 1 of the 6 veterans had a pretreatment CD4 count less than 200, although it improved to greater than 200 at the next check 3 months later. All veterans who experienced a clinical relapse were HIV virally suppressed. To date, only 1 veteran has been reinfected.\n\nDISCUSSION\nIn this study, we successfully identified 100% of HIV/HCV-coinfected veterans at the AVAHCS, saw 91% in HCV clinic, initiated treatment in over 80%, and 78% of the total cohort achieved clinical cure by end of the study. The World Health Organization HCV elimination goals are to diagnose 90% of persons with HCV and treat everyone identified to have HCV viremia. In this study, we were close to achieving these goals [20].\n\nHepatitis C virus treatment in this coinfected population was well tolerated with limited adverse events; supporting the safety and tolerability of DAAs in this population. Our findings are similar to other published data of >90% cure rate in HIV/HCV-coinfected persons [11, 13, 21, 22], further corroborating that HIV/HCV patients can achieve similar cure rates as HCV-monoinfected persons. Although there is growing evidence that HCV regimens shorter than 12 weeks may lead to treatment failure in HIV/HCV-coinfected persons [23], 8 veterans discontinued treatment at 4 or 6 weeks and still achieved SVR.\n\nOur cohort has a higher percentage of persons with cirrhosis than prior HIV/HCV studies [11, 24]. Cirrhosis was determined through noninvasive measures, thus there is a possibility that fibrosis stage was over estimated. Given the risk of complications and sampling error with biopsy, noninvasive measures of fibrosis have become established methods of diagnosing advanced fibrosis. Between 2000 and 2013, the prevalence of cirrhosis in the veteran population increased by approximately 2-fold, largely secondary to HCV-related cirrhosis [25], which could explain the prevalence of cirrhosis in this cohort. In addition, comorbid alcohol use disorder is prevalent in the veteran population and contributes to accelerated fibrosis progression [26].\n\nIn this study, there were 6 veterans who experienced a virologic relapse, and they were all of black race. A study that included over 1000 veterans in the greater Los Angeles area noted that African Americans had a 57% lower odds of achieving SVR [27]. In addition, Naggie et al [11] examined HCV treatment with ledipasvir/sofosbuvir in an HIV/HCV-coinfected population and found that black patients had lower response rates than other races. They also noted that the majority of failures were in persons taking efavirenz therapy, which was not seen in this study. Only 1 of the veterans who relapsed was on efavirenz before HCV treatment. Sixty-seven percent of the relapses were in patients who received ledipasvir/sofosbuvir as their first HCV therapy. Rossi et al [28] noted that of their 23 clinical failures, 65% were in persons who received ledipasvir/sofosbuvir, possibly suggesting that lower cure rates are achieved with ledipasvir/sofosbuvir in the HIV/HCV population. In contrast, in a large Spanish study, ledipasvir/sofosbuvir was not a factor associated with treatment failure [22]. Furthermore, 83% of our virologic relapse occurred in persons with cirrhosis. Several studies have described lower cure rates in persons with cirrhosis, indicating that advanced liver fibrosis may slightly decrease the effectiveness of DAA therapy [21, 22, 28].\n\nThe importance of prior knowledge of potential drug-drug interactions between ARVs and DAAs was underscored in this study. More than 30% of patients required a change in ARV regimen before starting HCV treatment with the majority of these changes secondary to potential drug-drug interaction with DAA therapy. This finding was also noted by Cope et al [29] where more than 60% of patients required a change in their ARV regimen before being started on DAA therapy. Most of the ARV changes were due to patients on older ARV regimens, and as more patients transition to newer INSTI-based regimens, there may be decreases in ARV-DAAs drug interaction.\n\nIt has been previously demonstrated that socioeconomic and psychiatric comorbidities serve as barriers to engaging in care [30, 31], which was also identified in our study [32]. In our cohort, reasons that veterans were not evaluated in clinic or started on HCV treatment included transportation issues, mental health concerns, active substance use, unstable housing, or comorbidities affecting life expectancy (ie, advanced metastatic cancer). Unstably housed veterans suffer from higher rates of chronic disease and comorbidities; often a combination of psychiatric and medical illnesses [33]. Unstable housing and homelessness have previously been shown to reduce the likelihood of initiating HCV treatment and achieving SVR [34, 35]. Although substance abuse was not statistically significant, our study highlights the role that substance abuse and unstable housing can play in preventing engagement into care. In addition, some veterans had medical conditions that limited their HCV treatment initiation. Those who were not started on treatment had a slighter higher CCI (4 vs 3).\n\nA strength of this study is that the integrated VHA system enhanced our ability to identify and treat willing HIV/HCV-coinfected veterans. The pressures of obtaining insurance coverage before initiating treatment are not present, allowing for patients to be quickly initiated on therapy after being evaluated. Even when HIV and HCV clinics are colocated, Rizk et at [36] recently published that 70.5% were linked into care and 56.1% achieved SVR12. Falade-Nwulia [37] had similar findings in inner city Baltimore, Maryland where 72% were initiated on treatment and 62% achieved clinical cure. In both studies, there were high rates of public insurance, and Falade-Nwulia [37] noted that Medicaid was negatively associated with HCV treatment initiation. In addition, this study was multidisciplinary with the involvement of physicians, advanced practitioners, pharmacy, and nursing. Given that our study population was an exclusively male, majority black, veteran population from a single center, there may be decreased generalizability of our findings. In addition, we did not include the risk factor for HCV transmission. As previously mentioned, 1 patient has been reinfected, and people who inject drugs carry the highest risk for reinfection [38]. This highlights the need to identify these individuals and perform additional counseling on reinfection risk. Finally, the small sample size of our study may limit our ability to identify differences between HCV-treated and -untreated groups.\n\nCONCLUSIONS\nTreatment of HCV in HIV/HCV-coinfected persons is critical to decrease progression of fibrosis, development of decompensated cirrhosis, and liver associated-mortality. In this study, we achieved HCV virologic cure in approximately 80% of the Atlanta VA’s HIV/HCV-coinfected population, contributing to the growing knowledge that this population can perform similarly to monoinfected persons. With safe, effective, and widely available HCV DAA therapy, HCV elimination is attainable among HIV/HCV-coinfected persons.\n\nAcknowledgments\n\nFinancial support. Our research activities are funded, in part, by grants from the National Institutes of Health/National Center for Advancing Translational Sciences (TL1TR002382, UL1TR002378).\n\n\nPotential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1. \nHHS.gov. \nHepatitis C. \n2019 Available at: https://www.hhs.gov/opa/reproductivehealth/fact-sheets/sexually-transmitted-diseases/hepatitis-c/index.html. Accessed 8 October 2019. \n2. \nCenters for Disease Control and Prevention. \nCoinfection with HIV and Viral Hepatitis | Division of Viral Hepatitis | CDC. \n2019 Available at: https://www.cdc.gov/hiv/pdf/library/factsheets/hiv-viral-hepatitis.pdf. Accessed 22 May 2019.\n3. \nPineda JA , Romero-Gómez M , Díaz-García F , et al. ; Grupo Andaluz para el Estudio de las Enfermedades Infecciosas; Grupo Andaluz para el Estudio del Hígado \nHIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis\n. Hepatology 2005 ; 41 :779 –89\n.15800956 \n4. \nBica I , McGovern B , Dhar R , et al. \nIncreasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection\n. Clin Infect Dis 2001 ; 32 :492 –7\n.11170959 \n5. \nChen TY , Ding EL , Seage GR III, Kim AY \nMeta-analysis: increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression\n. Clin Infect Dis 2009 ; 49 :1605 –15\n.19842982 \n6. \nDanta M , Semmo N , Fabris P , et al. \nImpact of HIV on host-virus interactions during early hepatitis C virus infection\n. J Infect Dis 2008 ; 197 :1558 –66\n.18419344 \n7. \nButt AA , Yan P , Lo Re V III, Shaikh OS , Ross DB \nTrends in treatment uptake and provider specialty for hepatitis C virus (HCV) infection in the Veterans Affairs Healthcare System: results from the electronically retrieved cohort of HCV-infected veterans (ERCHIVES)\n. Clin Infect Dis 2019 ; 68 :857 –9\n.30137251 \n8. \nFried MW , Shiffman ML , Reddy KR , et al. \nPeginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection\n. N Engl J Med 2002 ; 347 :975 –82\n.12324553 \n9. \nMehta SH , Lucas GM , Mirel LB , et al. \nLimited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic\n. AIDS 2006 ; 20 :2361 –9\n.17117023 \n10. \nHolmberg SD , Spradling PR , Moorman AC , Denniston MM \nHepatitis C in the United States\n. N Engl J Med 2013 ; 368 :1859 –61\n.23675657 \n11. \nNaggie S , Cooper C , Saag M , et al. ; ION-4 Investigators \nLedipasvir and sofosbuvir for HCV in patients coinfected with HIV-1\n. N Engl J Med 2015 ; 373 :705 –13\n.26196665 \n12. \nCollins LF , Chan A , Zheng J , et al. \nDirect-acting antivirals improve access to care and cure for patients with HIV and chronic HCV infection\n. 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Best Practices in Screening, Diagnosis, and Treatment Along the Veteran Health Administration’s Cascade of HCV Care. 2017 Available at: https://www.globalacademycme.com/cme/emergency-medicine/addressing-unique-needs-military-veterans-chronic/best-practices-screening-diagnosis-and-treatment. Accessed 9 February 2019.\n18. \nGraham J \nVA extends new hepatitis C drugs to all veterans in its health system\n. JAMA 2016 ; 316 :913 –5\n.27532279 \n19. \nUS Department of Veteran Affairs. Office of Public and Intergovernmental Affairs . VA on path to cure 100,000 Veterans of hepatitis C. Available at: https://www.va.gov/opa/pressrel/pressrelease.cfm?id=5219. Accessed 16 August 2019.\n20. \nCooke GS , Andrieux-Meyer I , Applegate TL , et al. ; Lancet Gastroenterology & Hepatology Commissioners \nAccelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission\n. 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Liver Int 2012 ; 32 (Suppl 1 ):151 –6\n.22212587 \n31. \nel-Serag HB , Kunik M , Richardson P , Rabeneck L \nPsychiatric disorders among veterans with hepatitis C infection\n. Gastroenterology 2002 ; 123 :476 –82\n.12145801 \n32. \nFargo J , Metraux S , Byrne T , et al. \nPrevalence and risk of homelessness among US veterans\n. Prev Chronic Dis 2012 ; 9 :E45 .22280960 \n33. \nGoldstein G , Luther JF , Haas GL , et al. \nFactor structure and risk factors for the health status of homeless veterans\n. Psychiatr Q 2010 ; 81 :311 –23\n.20532627 \n34. \nBeiser ME , Smith K , Ingemi M , et al. \nHepatitis C treatment outcomes among homeless-experienced individuals at a community health centre in Boston\n. Int J Drug Policy 2019 ; 72 :129 –37\n.30962036 \n35. \nOlafsson S , Tyrfingsson T , Runarsdottir V , et al. \nTreatment as prevention for hepatitis C (TraP Hep C) - a nationwide elimination programme in Iceland using direct-acting antiviral agents\n. J Intern Med 2018 ; 283 :500 –7\n.29512219 \n36. \nRizk C , Miceli J , Shiferaw B , et al. \nImplementing a comprehensive hepatitis C virus (HCV) clinic within a human immunodeficiency virus clinic: a model of care for HCV microelimination\n. Open Forum Infect Dis 2019 ; 6:500–507 .\n37. \nFalade-Nwulia O , Sutcliffe CG, Mehta SH, et al. \nHepatitis C elimination in people living with HIV is contingent on closing gaps in the HIV continuum\n. Open Forum Infect Dis 2019; 6:ofz426. doi:10.1093/ofid/ofz426 .\n38. \nRossi C , Butt ZA , Wong S , et al. ; BC Hepatitis Testers Cohort Team \nHepatitis C virus reinfection after successful treatment with direct-acting antiviral therapy in a large population-based cohort\n. J Hepatol 2018 ; 69 :1007 –14\n.30142429\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "7(4)",
"journal": "Open forum infectious diseases",
"keywords": "care continuum; chronic hepatitis C virus; direct-acting antivirals; human immunodeficiency virus; veterans",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa085",
"pmc": null,
"pmid": "32280724",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": "31100364;26196665;26066094;23675657;26562129;29512219;28948181;29377274;31074580;30137251;25023159;18419344;29484189;30142429;12145801;30962036;26255044;29308413;27532279;22280960;20532627;31667200;30949539;30882016;17117023;15800956;26111063;22212587;28919834;31412130;30647010;12324553;11170959;19842982",
"title": "Hepatitis C Care Continuum in a Human Immunodeficiency Virus (HIV) Positive Cohort: Data From the HIV Atlanta Veterans Affairs Cohort Study.",
"title_normalized": "hepatitis c care continuum in a human immunodeficiency virus hiv positive cohort data from the hiv atlanta veterans affairs cohort study"
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"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-029294",
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"activesubstancename": "DACLATASVIR DIHYDROCHLORIDE"
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"abstract": "Donor-derived infections with multidrug-resistant gram-negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor-derived, disseminated infection with colistin-resistant, carbapenemase-producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug-resistant infections in immunocompromised hosts.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. millsjo@umich.edu.;Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.;Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.;Division of Transplant Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.;Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.;Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Research Service, Cleveland, Ohio, USA.;Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.",
"authors": "Mills|J P|JP|;Wilck|M B|MB|;Weikert|B C|BC|;Porrett|P M|PM|;Timko|D|D|;Alby|K|K|;Bonomo|R A|RA|;Blumberg|E A|EA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005578:Fosfomycin; D000078304:Tigecycline; D001618:beta-Lactamases; C063912:carbapenemase; D008911:Minocycline; D003091:Colistin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "18(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "carbapenem-resistant Klebsiella pneumoniae (CRKP); extremely drug-resistant (XDR); fosfomycin; orthotopic liver transplantation (OLT)",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D064591:Allografts; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D001426:Bacterial Proteins; D003091:Colistin; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D005355:Fibrosis; D005578:Fosfomycin; D006801:Humans; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D016031:Liver Transplantation; D008826:Microbial Sensitivity Tests; D008911:Minocycline; D000078304:Tigecycline; D001618:beta-Lactamases",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "777-781",
"pmc": null,
"pmid": "27458980",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20375234;21945848;25835018;711653;21939468;22467548;24648559;23880170;18444833;18444827;23464996;24183799",
"title": "Successful treatment of a disseminated infection with extensively drug-resistant Klebsiella pneumoniae in a liver transplant recipient with a fosfomycin-based multidrug regimen.",
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"abstract": "Sodium-glucose linked transporter (SGLT) inhibitors could improve glycaemia and simplify insulin regimens in recent-onset type 1 diabetes (T1D), provided they were well-tolerated and safe. This study aimed to determine the feasibility and safety of a SGLT inhibitor for the treatment of recent-onset T1D.\nAn open label, prospective pilot study in adults with recent-onset T1D was performed. Empagliflozin, 25 mg orally daily, was given in combination with insulin and multidisciplinary care during a 24-week treatment phase, followed by wash-out visits at weeks 30 and 36.\nFourteen participants (4 women; median age 26 years) began and 13 completed the study. No treatment-emergent serious adverse events were observed, with fatigue and genital infection the most common side-effects. Four participants stopped mealtime insulin for at least one month when taking empagliflozin. At week 24, median weight, HbA1c and insulin dose decreased by 4.4 kg, 1.5% (17 mmol/mol) and 0.03 units/kg/day, respectively. Meal-stimulated C-peptide was maintained during the treatment phase and then decreased at 36 weeks.\nTreatment of adults with empagliflozin within 100 days of T1D diagnosis appeared safe and was associated with improved clinical outcomes. These findings justify a definitive trial to determine if SGLT inhibitors simplify treatment regimens and improve clinical outcomes in recent-onset T1D.\nACTRN12617000016336.",
"affiliations": "Royal Melbourne Hospital, Department of Diabetes and Endocrinology, Australia.;Royal Melbourne Hospital, Department of Diabetes and Endocrinology, Australia.;Royal Melbourne Hospital, Department of Diabetes and Endocrinology, Australia.;Royal Melbourne Hospital Department of Medicine, University of Melbourne, Australia.",
"authors": "Wentworth|John M|JM|;Fourlanos|Spiros|S|;Colman|Peter G|PG|;Harrison|Leonard C|LC|",
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"fulltext": "\n==== Front\nMetabol Open\nMetabol Open\nMetabolism Open\n2589-9368 Elsevier \n\nS2589-9368(20)30001-3\n10.1016/j.metop.2020.100021\n100021\nOriginal Research Paper\nA pilot study of the feasibility of empagliflozin in recent-onset type 1 diabetes\nWentworth John M. wentworth@wehi.edu.auabc∗ Fourlanos Spiros ab Colman Peter G. ab Harrison Leonard C. bc a Royal Melbourne Hospital, Department of Diabetes and Endocrinology, Australia\nb Royal Melbourne Hospital Department of Medicine, University of Melbourne, Australia\nc Walter and Eliza Hall Institute of Medical Research, Population Health and Immunity Division, Australia\n∗ Corresponding author. Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville 3050, Australia. wentworth@wehi.edu.au\n03 1 2020 \n3 2020 \n03 1 2020 \n5 1000213 11 2019 24 12 2019 1 1 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nSodium-glucose linked transporter (SGLT) inhibitors could improve glycaemia and simplify insulin regimens in recent-onset type 1 diabetes (T1D), provided they were well-tolerated and safe. This study aimed to determine the feasibility and safety of a SGLT inhibitor for the treatment of recent-onset T1D.\n\nMethod\nAn open label, prospective pilot study in adults with recent-onset T1D was performed. Empagliflozin, 25 mg orally daily, was given in combination with insulin and multidisciplinary care during a 24-week treatment phase, followed by wash-out visits at weeks 30 and 36.\n\nResults\nFourteen participants (4 women; median age 26 years) began and 13 completed the study. No treatment-emergent serious adverse events were observed, with fatigue and genital infection the most common side-effects. Four participants stopped mealtime insulin for at least one month when taking empagliflozin. At week 24, median weight, HbA1c and insulin dose decreased by 4.4 kg, 1.5% (17 mmol/mol) and 0.03 units/kg/day, respectively. Meal-stimulated C-peptide was maintained during the treatment phase and then decreased at 36 weeks.\n\nConclusions\nTreatment of adults with empagliflozin within 100 days of T1D diagnosis appeared safe and was associated with improved clinical outcomes. These findings justify a definitive trial to determine if SGLT inhibitors simplify treatment regimens and improve clinical outcomes in recent-onset T1D.\n\nRegistration\nACTRN12617000016336.\n\nHighlights\n• First report of SGLT inhibitor treatment in recent-onset T1D.\n\n• Empagliflozin was well tolerated and not associated with serious side effects.\n\n• Bolus insulin requirement decreased during empagliflozin treatment.\n\n\n\nKeywords\nType 1 diabetesSGLT-2 inhibitorClinical trialBeta-cell functionFeasibility study\n==== Body\n1 Introduction\nIn people with long-standing type 1 diabetes (T1D), sodium-glucose cotransporter (SGLT) inhibitors improve glucose control, decrease insulin requirement and promote weight loss [1], but also predispose to genital infection and ketoacidosis [2]. SGLT inhibitors have not been widely used in recent-onset T1D, primarily due to concern about the risk of ketoacidosis [3]. This would be an unreasonable burden for patients to manage while they are adjusting to their diagnosis and learning how to manage their diabetes. However, the presence of residual beta cell function at diagnosis of T1D [4] is likely to decrease the risk of ketosis with SGLT inhibitor treatment [3]. Furthermore, improved postprandial glucose control, observed in people with long-standing T1D who received sotagliflozin [5], may be particularly helpful in recent-onset T1D by decreasing bolus insulin requirements and simplifying insulin regimens. An argument can be made to evaluate SGLT inhibition as a treatment adjunct in recent-onset T1D provided side-effects are tolerable. Therefore, as a prelude to a randomised control trial, we first sought to determine the feasibility and safety of the SGLT2 inhibitor, empagliflozin, in patients with recent-onset T1D.\n\n2 Materials and methods\n2.1 Patients and setting\nThe study was conducted at Royal Melbourne Hospital between January 2017 and May 2019 and registered as ACTRN12617000016336. Inclusion criteria were age 18-40 years, T1D diagnosed within 100 days of starting empagliflozin, presence of at least one islet autoantibody and meal-stimulated plasma C-peptide >0.07 nmol/L. Exclusion criteria were a co-morbidity deemed to pose unacceptable risk, pregnancy or planned pregnancy, breast feeding or, if female, refusal to use effective contraception.\n\n2.2 Interventions and data collection\nAt weeks 0, 12, 24 and 36, participants undertook routine biochemistry, completed a diabetes distress survey [6] and wore a Minimed™ iPro™2 continuous glucose monitor (CGM; Medtronic Minimed™, Northridge, CA) for one week. Mixed meal tolerance tests were performed at the same intervals to determine beta-cell function, calculated by dividing the trapezoidal area under the C-peptide curve by 120 min [7]. Empagliflozin was withheld three days prior to meal tests at weeks 12 and 24 to avoid potential effects on C-peptide release.\n\nAt weeks 4, 8, 18 and 30, additional visits were scheduled to review glucose control. Participants accessed dietician and diabetes educator support at all study visits to target fasting and postprandial glucose to 5 mmol/L and 10 mmol/L respectively. They monitored capillary ketone concentrations weekly using an Optium Neo device (Abbott, Doncaster, Australia).\n\nAdherence with empagliflozin (25 mg daily from weeks 0–24) was assessed by urine dipstick testing for glucose and by counting tablets.\n\n2.3 Outcomes\nThe primary outcome of feasibility was assessed as adherence with the study protocol and safety. Secondary outcomes were numbers and severity of adverse events, body weight, stimulated C-peptide, HbA1c, insulin dose, CGM measures and diabetes distress score [6].\n\n2.4 Statistical analyses\nData were complete with the exception of CGM results at week 12 for one participant, which were imputed by averaging the measures at 0 and 24 weeks. Statistical analyses were performed with Prism software (V8, GraphPad, San Diego, CA). The Friedman test was used to assess differences across time, with correction for multiple comparisons by the two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli [8].\n\n3 Results\n3.1 Participant recruitment and baseline characteristics\nSixty-one individuals were referred to the study. Fifteen did not meet eligibility and 32 declined to participate due to perceived treatment risks and the study demands. All 14 participants who enrolled were on multiple daily insulin injections. Their baseline characteristics are presented in Table 1. Median [Q1, Q3] age was 26 [22, 32] years, body mass index 24 [23, 26] kg/m2, disease duration 72 [54, 92] days and HbA1c 7.1 [6.1, 8.5] percentage units (54 [42, 69] mmol/mol).Table 1 Baseline characteristics.\n\nTable 1ID\tSex\tAge (years)\tDiabetes durationa (days)\tWeight (kg)\tBMI (kg/m2)\tDKA at diagnosis\tPolyuria/polydipsia at diagnosis\tAntibody specificity\tHLA-DR genotype\tHbA1c (%)\tHbA1c (mmol/mol)\tInsulin dose (U/kg/day)\tStimulated C-peptide (nmol/l)\t\n1\tM\t31\t58\t95.3\t26.4\tYes\tYes\tGAD, ZnT8\t4/X\t8.3\t67\t0.24\t0.524\t\n2\tF\t18\t92\t84.1\t33.7\tNo\tNo\tGAD, ZnT8\t4/X\t6.0\t42\t0.27\t1.169\t\n3\tM\t22\t92\t63.7\t21.5\tYes\tYes\tGAD\t3/3\t6.0\t42\t0.36\t0.489\t\n4\tF\t34\t94\t77.7\t25.1\tYes\tYes\tGAD\tNP\t6.5\t47\t0.12\t0.640\t\n5\tM\t22\t72\t81.2\t25.9\tNo\tYes\tGAD, IA2\t4/X\t5.9\t41\t0.15\t0.920\t\n6\tM\t27\t80\t84.0\t24.0\tNo\tYes\tGAD, IA2\t4/4\t8.1\t65\t0.18\t0.399\t\n7\tM\t18\t96\t82.9\t26.2\tNo\tYes\tGAD, IA2, ZnT8\t3/3\t5.9\t41\t0.44\t0.493\t\n8\tM\t22\t55\t82.9\t24.2\tNo\tYes\tGAD, IA2, ZnT8\t3/4\t7.6\t60\t0.11\t1.042\t\n9\tM\t27\t72\t80.0\t25.0\tNo\tYes\tGAD\t3/4\t6.5\t48\t0.40\t1.084\t\n10\tF\t37\t28\t64.5\t22.5\tNo\tYes\tZnT8\t4/X\t10.4\t90\t0.22\t0.392\t\n11\tM\t31\t72\t76.1\t24.0\tNo\tYes\tGAD, IA2, ZnT8\t3/4\t6.5\t48\t0.12\t0.435\t\n12\tM\t22\t68\t65.8\t22.8\tNo\tYes\tGAD\t3/X\t9.5\t80\t1.52\t0.283\t\n13\tF\t25\t50\t56.3\t19.7\tNo\tYes\tGAD, ZnT8\t3/3\t8.9\t74\t0.52\t0.865\t\n14\tM\t36\t28\t71.8\t23.3\tNo\tYes\tGAD, ZnT8\t4/X\t7.9\t63\t0.35\t0.552\t\nNP: not performed.\n\na at time of taking first dose of empagliflozin.\n\n\n\n3.2 Medication adherence and safety\nThe median rate of empagliflozin adherence was 0.89 [0.74, 1.0]. Four serious adverse events (SAEs) affecting four participants were observed. One (alcohol intoxication without ketosis) occurred during week 24 and the other three (concussion, finger dislocation and supraventricular tachycardia) occurred during weeks 24–36, after empagliflozin was ceased.\n\n3.3 Other adverse events\nDuring weeks 0–24, 14 episodes of generalised fatigue affected 9 participants. These episodes were associated with capillary blood glucose readings in the lower range (between 3.5 and 6 mmol/l) and resolved after 1-5 days in 7 of the affected participants. However, fatigue was sufficiently severe to prompt 2 participants to stop taking empagliflozin: one noted fatigue in week 1 and withdrew from the trial; the other took the tablet intermittently over the first 10 weeks due to fatigue before stopping it. On re-exposure during week 16, fatigue recurred and no further doses were taken. In addition, 5 episodes of mild to moderate genital infection affected four participants, all of whom received topical or oral anti-fungal treatment for up to a week and continued taking empagliflozin.\n\n3.4 Capillary ketone measures\nDuring the 24-week empagliflozin treatment phase, the 13 participants who completed the study performed a median [Q1, Q3] of 35 [20, 66] home capillary ketone measurements, only one of which exceeded 1 mmol/l. This occurred in week 15 associated with headache, that resolved after 4 h, when ketones were 0.6 mmol/l.\n\n3.5 Diabetes outcomes\nAfter 24 weeks, median body weight decreased by 4.4 kg and median HbA1c by 1.5% units (17 mmol/mol; Fig. 1a and b). Insulin doses decreased to week 24 and then increased (Fig. 1c), with 4 participants stopping bolus insulin for at least a month. Meal-stimulated C-peptide did not change significantly during the first 24 weeks and then decreased (Fig. 1d and e). CGM mean glucose decreased initially and then increased between weeks 12 and 36 (Fig. 1f), while glucose time within and below range, and %CV did not change significantly (Fig. 1g, h, i). Diabetes distress did not change significantly (Fig. 1j).Fig. 1 Clinical outcomes for the 13 participants who completed the study. Weight (a), HbA1c (b), insulin dose (c), meal-stimulated C-peptide (d, e), CGM measures of mean daily glucose (f), time between 3.9 and 10 mmol/L (g), time <3.9 mmol/L (h) and glucose variability %CV (i), and diabetes distress score (j) are shown as median with interquartile range. The grey shaded area corresponds to the empagliflozin treatment phase from weeks 0–24. *, ** and *** depict p < 0.05, <0.01 and < 0.001 respectively.\n\nFig. 1\n\n4 Discussion\nWe demonstrate a high level of treatment adherence and no concerning ketosis or other adverse events when empagliflozin 25 mg daily was combined with basal/bolus insulin therapy within 100 days of T1D diagnosis. Empagliflozin treatment was associated with decreased body weight and improved glucose control despite decreased frequency and doses of insulin injections. Together, these findings demonstrate the feasibility of this approach to T1D therapy, and suggest it may deliver clinical benefit.\n\nStrengths of this study include the prospective collection of measures of capillary ketones, CGM data and beta-cell function (meal-stimulated C-peptide). Ketoacidosis is reported to occur at a rate of 5 events per 100 patient years in established T1D [3]. Our sample size was too small to determine the risk of ketoacidosis but the finding of only one home ketone measurement over 1 mmol/l suggests it was not increased by treatment with empagliflozin. Glucose time in the 3.9–10 mmol/l range did not improve during empagliflozin treatment, in contrast to prior studies of SGLT inhibitors in long-standing T1D [5,9,10]. However, at baseline, the percentage of time in range was much lower in these studies (40-52% compared to 83% in this study), so any change with SGLT inhibitor treatment would have been smaller in magnitude and therefore more difficult to detect. Meal-stimulated C-peptide did not change significantly during the 24-week treatment phase, indicating no substantial effect of empagliflozin on beta-cell function. The significant decrease in C-peptide between weeks 24 and 36 during the washout phase does however raise the possibility that empagliflozin might preserve beta-cell function in recent-onset T1D. Because the visit schedule of this study mirrored that used by trials of disease-modifying therapy in T1D (e.g. Ref. [11]), our outcome data should aid the design of a placebo-controlled trial involving a similar population to determine the effects of SGLT inhibition on beta-cell function.\n\nThis study identified two common adverse events that may limit tolerability of SGLT inhibitors in recent-onset T1D. Genital infection was not unexpected [9,10,12] and was mild to moderate in severity. However, the observation of generalised fatigue affecting 9 participants and causing 2 to stop empagliflozin treatment early was unexpected. Its association with low-normal capillary glucose measures suggests this side-effect might be alleviated by gradual dose escalation of empagliflozin.\n\n5 Conclusion\nOur findings provide support for a definitive trial to determine the effects of SGLT inhibitors on clinical outcomes and on beta-cell function, either alone or in combination with newer non-insulin therapies [11,13].\n\nDeclaration of competing interestCOI\nNone of the authors reports a conflict of interest.\n\nFunding\nFunded by the 10.13039/100008713Diabetes Australia Research Program (Y18G-WENJ), Type One Melbourne and the Royal Melbourne Hospital Foundation.\n\nResearch involving human participants and/or animals and informed consent\nThe study was approved by the Melbourne Health Human Research Ethics Committee and all participants provided written informed consent.\n\nContributor statements\nJMW, PGC and LCH devised the study and drafted the protocol. JMW, PGC and SF oversaw participant recruitment and care. JMW collated and analyzed the data, and drafted the manuscript, which all authors edited.\n\nData availability\nData for this trial are available from Dr Wentworth upon request.\n\nCRediT authorship contribution statement\nJohn M. Wentworth: Conceptualization, Funding acquisition, Project administration, Formal analysis, Writing - review & editing. Spiros Fourlanos: Writing - review & editing. Peter G. Colman: Conceptualization, Writing - review & editing. Leonard C. Harrison: Conceptualization, Funding acquisition, Writing - review & editing.\n\nAcknowledgements\nWe thank Melbourne Health for Sponsoring the study, Medtronic for donating CGM sensors and Danielle Romanes and Type One Melbourne for financial and logistical support.\n==== Refs\nReferences\n1 Riddle M.C. Cefalu W.T. SGLT inhibitors for type 1 diabetes: an obvious choice or too good to be true? Diabetes Care 41 12 2018 2444 2447 30459245 \n2 Wolfsdorf J.I. Ratner R.E. SGLT inhibitors for type 1 diabetes: proceed with extreme caution Diabetes Care 42 6 2019 991 993 31110116 \n3 Danne T. Garg S. Peters A.L. Buse J.B. Mathieu C. Pettus J.H. International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors Diabetes Care 42 6 2019 1147 1154 30728224 \n4 Greenbaum C.J. Beam C.A. Boulware D. Gitelman S.E. Gottlieb P.A. Herold K.C. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data Diabetes 61 8 2012 2066 2073 22688329 \n5 Danne T. Cariou B. Buse J.B. Garg S.K. Rosenstock J. Banks P. Improved time in range and glycemic variability with sotagliflozin in combination with insulin in adults with type 1 diabetes: a pooled analysis of 24-week continuous glucose monitoring data from the inTandem Program Diabetes Care 42 5 2019 919 930 30833371 \n6 Polonsky W.H. Fisher L. Earles J. Dudl R.J. Lees J. Mullan J. Assessing psychosocial distress in diabetes: development of the diabetes distress scale Diabetes Care 28 3 2005 626 631 15735199 \n7 Greenbaum C.J. Mandrup-Poulsen T. McGee P.F. Battelino T. Haastert B. Ludvigsson J. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes Diabetes Care 31 10 2008 1966 1971 18628574 \n8 Benjamini Y. Krieger A.M. Yekutieli D. Adaptive linear step-up procedures that control the false discovery rate Biometrika 93 2006 491 507 \n9 Dandona P. Mathieu C. Phillip M. Hansen L. Griffen S.C. Tschope D. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial Lancet Diabetes Endocrinol 5 11 2017 864 876 28919061 \n10 Rosenstock J. Marquard J. Laffel L.M. Neubacher D. Kaspers S. Cherney D.Z. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials Diabetes Care 41 12 2018 2560 2569 30287422 \n11 Haller M.J. Schatz D.A. Skyler J.S. Krischer J.P. Bundy B.N. Miller J.L. Low-dose anti-thymocyte globulin (ATG) preserves beta-cell function and improves HbA1c in new-onset type 1 diabetes Diabetes Care 41 9 2018 1917 1925 30012675 \n12 Garg S.K. Henry R.R. Banks P. Buse J.B. Davies M.J. Fulcher G.R. Effects of sotagliflozin added to insulin in patients with type 1 diabetes N Engl J Med 377 24 2017 2337 2348 28899222 \n13 Hagopian W. Ferry R.J. Jr. Sherry N. Carlin D. Bonvini E. Johnson S. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protege trial Diabetes 62 11 2013 3901 3908 23801579\n\n",
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"keywords": "Beta-cell function; Clinical trial; Feasibility study; SGLT-2 inhibitor; Type 1 diabetes",
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"abstract": "In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.\n\n\nOBJECTIVE\nThe effect of apixaban on anti-factor Xa (anti-Xa) assays and international normalized ratio (INR) complicates transitions between anticoagulant agents. When switching from apixaban to warfarin, the recommendation is to begin both a parenteral anticoagulant and warfarin at the time of the next apixaban dose and to discontinue the parenteral agent when INR is in an acceptable range. This proves challenging in renal dysfunction, as continued presence of apixaban contributes to both a prolonged effect on the INR and continued therapeutic levels of anticoagulation.\n\n\nCONCLUSIONS\nThis case describes the transition of apixaban to warfarin in a patient with acute on chronic kidney disease and recent deep vein thrombosis, utilizing chromogenic apixaban anti-Xa assays to assess the level of anticoagulation and avoid unnecessary parenteral anticoagulation.\n\n\nCONCLUSIONS\nUtilization of apixaban anti-Xa levels aided in the transition from apixaban to warfarin in a patient with chronic renal failure and avoided need for parenteral bridging therapy.",
"affiliations": "Sanford USD Medical Center, Sioux Falls, SD, USA.;Sanford USD Medical Center, Sioux Falls, SD, USA.",
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"title": "Utilization of apixaban anti-Xa levels in transition from apixaban to warfarin in a patient with chronic renal dysfunction.",
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"abstract": "We report a case of electrocardiographic signature of the Brugada syndrome in a 39-year-old patient with an overdose of diphenhydramine. He was found unconscious and hypotensive. His serum potassium concentration was 8.3 mEq/L and the ECG revealed a coved-type ST-segment elevation in leads V2-V3. These repolarization abnormalities neither normalize with the correction of the hyperkalemia nor with an intravenous infusion of isoproterenol. When he regained consciousness, he was admitted the toxic ingestion of diphenhydramine and progressively the ECG normalized. A negative flecainide test confirmed that the transient ECG abnormalities were the consequence of the drug overdose and ruled out the Brugada syndrome.",
"affiliations": "Intensive Care Unit, Emergency Department and Arrhythmia Section, Institut Clinic de Malalties Cardiovasculars, IDIBAPS, Hospital Clinic, Spain.",
"authors": "López-Barbeito|Beatriz|B|;Lluis|Meritxell|M|;Delgado|Victoria|V|;Jiménez|Sonia|S|;Díaz-Infante|Ernesto|E|;Nogué-Xarau|Santiago|S|;Brugada|Josep|J|",
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"mesh_terms": "D000328:Adult; D016757:Death, Sudden, Cardiac; D004155:Diphenhydramine; D062787:Drug Overdose; D004562:Electrocardiography; D006801:Humans; D008297:Male; D013406:Suicide, Attempted",
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"title": "Diphenhydramine overdose and Brugada sign.",
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"abstract": "We present a case of a child with unilateral group E retinoblastoma (according to the International Classification of Retinoblastoma) who received superselective intra-arterial chemotherapy as primary therapy. Although the tumor showed signs of regression, the patient developed orbital metastases requiring surgical excision and chemotherapy. Eventually the affected eye progressed to total retinal detachment and required enucleation.",
"affiliations": "Department of Ophthalmology, Royal Children's Hospital, Melbourne, Victoria, Australia. Electronic address: mathewaanu@gmail.com.;Department of Ophthalmology, Royal Children's Hospital, Melbourne, Victoria, Australia.;Department of Ophthalmology, Royal Children's Hospital, Melbourne, Victoria, Australia; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Victoria, Australia.;Department of Ophthalmology, Royal Children's Hospital, Melbourne, Victoria, Australia.;Department of Ophthalmology, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.",
"authors": "Mathew|Anu A|AA|;Sachdev|Nisha|N|;Staffieri|Sandra E|SE|;McKenzie|John D|JD|;Elder|James E|JE|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D003520:Cyclophosphamide; D016190:Carboplatin",
"country": "United States",
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"issue": "19(1)",
"journal": "Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus",
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"medline_ta": "J AAPOS",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002675:Child, Preschool; D003520:Cyclophosphamide; D005047:Etoposide; D015353:Eye Enucleation; D006801:Humans; D007261:Infusions, Intra-Arterial; D008279:Magnetic Resonance Imaging; D008297:Male; D033401:Microscopy, Acoustic; D009918:Orbital Neoplasms; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D014750:Vincristine",
"nlm_unique_id": "9710011",
"other_id": null,
"pages": "72-4",
"pmc": null,
"pmid": "25727592",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Superselective intra-arterial chemotherapy for advanced retinoblastoma complicated by metastatic disease.",
"title_normalized": "superselective intra arterial chemotherapy for advanced retinoblastoma complicated by metastatic disease"
} | [
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"companynumb": "AU-GLAXOSMITHKLINE-AU2015GSK128299",
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"abstract": "Coronary artery ectasia (CAE) is an uncommon anomaly, usually found in 1.2-2% of patients undergoing coronary angiography, defined as a segment of the coronary artery that has a diameter of more than 1.5 times the normal adjacent segments. Atherosclerosis is considered as the cause of half of the CAE cases. We herein present a 65-year-old Asian male with past medical history of Kawasaki disease (KD) who developed recurrent episodes of inferior wall ST-elevation myocardial infarction (STEMI) despite treatment with dual antiplatelet therapy (DAPT). Repeat coronary angiogram showed severely ectatic and tortuous coronary arteries more predominant on the right coronary artery (RCA) with diffuse thrombus in its mid segment. Given his unfavorable vascular anatomy, the condition was managed medically with the addition of warfarin to his DAPT with target international normalized ratio (INR) 2 - 3. This case highlights the association of CAE with a prior history of KD and its therapeutic challenge.",
"affiliations": "Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA.;Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA.;Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA.;Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA.",
"authors": "Abugroun|Ashraf|A|;Vilchez|Daniel|D|;Hallak|Osama|O|;Shahrrava|Anahita|A|",
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"country": "Canada",
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"doi": "10.14740/cr641w",
"fulltext": "\n==== Front\nCardiol ResCardiol ResElmer PressCardiology Research1923-28291923-2837Elmer Press 10.14740/cr641wCase ReportA History of Kawasaki Disease From Childhood and Coronary Artery Ectasia With Recurrent ST Elevation Myocardial Infarction: A Therapeutic Challenge KD From Childhood and CAE With Recurrent STEMIAbugroun Ashraf abVilchez Daniel aHallak Osama aShahrrava Anahita aa Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USAb Corresponding Author: Ashraf Abugroun, Department of Internal Medicine, Advocate Illinois Masonic Medical Center, 836 W Wellington Ave, Chicago, IL 60657, USA. Email: ashraf.abugroun@advocatehealth.com12 2017 22 12 2017 8 6 344 348 22 11 2017 8 12 2017 Copyright 2017, Abugroun et al.2017This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Coronary artery ectasia (CAE) is an uncommon anomaly, usually found in 1.2-2% of patients undergoing coronary angiography, defined as a segment of the coronary artery that has a diameter of more than 1.5 times the normal adjacent segments. Atherosclerosis is considered as the cause of half of the CAE cases. We herein present a 65-year-old Asian male with past medical history of Kawasaki disease (KD) who developed recurrent episodes of inferior wall ST-elevation myocardial infarction (STEMI) despite treatment with dual antiplatelet therapy (DAPT). Repeat coronary angiogram showed severely ectatic and tortuous coronary arteries more predominant on the right coronary artery (RCA) with diffuse thrombus in its mid segment. Given his unfavorable vascular anatomy, the condition was managed medically with the addition of warfarin to his DAPT with target international normalized ratio (INR) 2 - 3. This case highlights the association of CAE with a prior history of KD and its therapeutic challenge.\n\nKawasaki diseaseCoronary artery ectasiaMyocardial infarction\n==== Body\nIntroduction\nKawasaki disease (KD, mucocutaneous lymph node syndrome) is an acquired cause of medium sized vasculitis of unknown etiology that commonly affects the coronaries. While the disease is predominantly seen among children, particularly of Asian descent, chronic vascular sequela including diffuse coronary vascular ectasia remains a therapeutic challenge. Coronary artery ectasia (CAE) is an uncommon anomaly, usually found in 1.2-2% of patients undergoing coronary angiography, defined as a segment of the coronary artery that has a diameter of more than 1.5 times the normal adjacent segments [1]. Atherosclerosis is considered as the cause of half of the CAE cases. This case highlights the association of CAE with a prior history of KD and its therapeutic challenge.\n\nCase Report\nA 65-year-old Asian male with past medical history of KD, hypertension, and hyperlipidemia, came for follow-up in the cardiology clinic following a recent hospital admission for inferior wall ST-elevation myocardial infarction (STEMI) in 2016.\n\nThe patient’s history of KD started as early as year 1956 when he was 6 years old. He developed an abnormal clinical symptom-complex characterized with fever and rash. None of his siblings developed similar condition. His condition was mistakenly diagnosed as scarlet fever as during that time KD was not yet described. The patient was informed several years later, that his childhood illness was actually KD. He was not on treatment for the condition.\n\nHis first myocardial infarction (MI) was in 2009, when he was diagnosed with an inferior wall STEMI (Fig. 1). Coronary angiogram revealed diffuse ectatic changes of all coronaries with no suitable lesion identified for angioplasty or stenting, therefore he was medically managed with dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. His vascular lesions were typical for chronic Kawasaki vascular disease. Following discharge, he developed palpitations and frequent unifocal premature ventricular contractions (PVCs) exceeding 10,000 per 24 h. These symptoms were adequately controlled with metoprolol.\n\nFigure 1 EKG done on 2009 showing sinus bradycardia, first degree AV block and ST segment elevations > 0.1mV in the inferior leads II, III, and aVF. EKG: electrocardiogram; AV: atrioventricular.\n\nEchocardiography done 3 years later showed a left ventricular (LV) ejection fraction of 45%. Patient underwent a stress echo that showed stable inferior-posterior wall motion abnormality without new ischemic changes, accordingly the drop of LVEF was attributed to PVC mediated myopathy. Despite the high PVC burden, metoprolol adequately controlled his symptoms and his LV function remained stable for several years. The patient followed a healthy life style, exercised regularly, and never used any tobacco products. He had a normal physical exam with body mass index (BMI) of 27. Despite these healthy measures and compliance with optimum medical therapy, he developed acute inferior wall STEMI on April 2016, followed by another attack by the end of the same year (Fig. 2). Coronary angiogram showed severely ectatic and tortuous coronary arteries (Fig. 3) more predominant in the right coronary artery (RCA) with a diffuse thrombus in its mid segment (Fig. 4). Given his unfavorable vascular anatomy, his condition was managed medically with the addition of warfarin to his DAPT with target international normalized ratio (INR) 2 - 3.\n\nFigure 2 EKG on late 2016 showing sinus rhythm with a prolonged PR interval, left ventricular hypertrophy based on the height of the R wave in aVL and an inferior infarct based on ST elevations in leads II, III, and aVF.\n\nFigure 3 RAO caudal view of left coronary system. Left circumflex artery is a large ectactic vessel. RAO: right anterior oblique.\n\nFigure 4 RAO cranial view of right coronary system. RCA is a severe ectactic vessel with diffuse thrombus in mid-segment. RCA: right coronary artery.\n\nDiscussion\nKD is characterized by an acute necrotizing vasculitis of the medium- and small-sized vessels. It is most prevalent in Japan, followed by Korea, predominantly seen in children aged from 6 months to 5 years, and has a male-to-female ratio of 1.5 - 1.8. The first report of KD was published in 1967. During that time, KD was described as a self-limiting disease without sequela. It wasn’t until 1970 when the association between KD and coronary artery vasculitis was well-established [2]. The etiopathogenesis of the condition is not fully understood, but it is likely multifactorial with possible role of various environmental, infectious, and genetic factors. KD is the most severe vasculitic syndrome affecting children younger than age 5 and has now surpassed rheumatic fever to become the leading cause of acquired heart disease in children living in developed countries [3, 4].\n\nKD is suspected when a patient develops marked coronary artery ectasia or aneurysm formation despite young age and minimum risk factors for atherosclerotic coronary artery disease [5].\n\nThere are few reports in the literature discussing the occurrence of recurrent myocardial infarctions among patients with coexisting CAE. By reporting this case, we would like to highlight an important therapeutic challenge of CAE. We will cover the current proposed pathophysiology of CAE as well as the available diagnostic and therapeutic options.\n\nThe characteristic hallmark of KD is the presence of coronary artery damage. Other complications related to KD include pericardial effusion, myocarditis, valvular dysfunction, and acquired aneurysms of the systemic arteries. Coronary aneurysms, defined as dilation of the coronary artery to a diameter of at least 1.5 times that of normal adjacent segment, caused by KD have variable outcomes. Small lesions are likely to resolve, while larger lesions have potential for a wide range of remodeling changes [6]. Aneurysmal dilation of the coronary can be spherical or saccular in shape, and either diffuse, affecting the entire length of the vessel, or localized. The diffuse form of the disease is referred to as ectasia.\n\nCAE is found in up to 5% of patients undergoing coronary angiography and in 0.22% to 1.4% of autopsy series [7]. CAE commonly coexists with coronary artery disease (CAD). The pathogenesis of CAD induced CAE is not fully understood. It includes an initial endothelial damage that activates a series of inflammatory changes causing degeneration of the medial layer and remodeling of the vessel [8]. Recent researches have revealed a key role of proteases and the inflammatory system in the pathogenesis of CAE. The 5A/5A genotype of MMP-3 was found to be significantly more frequent in patients with CAE compared to those with atherosclerotic heart disease (ASHD) without CAE. Lamblin et al proposed that this increase in proteolysis of the arterial wall may be a susceptibility factor for the development of CAE [9]. Overexpression of matrix metalloproteinases (MMPs) leads to increased proteolysis of extracellular matrix proteins, and concurrent decreased levels of tissue inhibitors of metalloproteinases (TIMPs) strengthen this effect [1]. Others found increased levels of MMP-3, MMP-9, and IL-6 in patients with CAE compared to patients with ASHD and controls with normal coronaries undergoing catheterization. Plasma levels of adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) were also found to be higher in CAE patients, likely due to their role in facilitating the action of immune cells in the inflammatory response [1].\n\nUpon histopathologic evaluation of ectatic arteries, the findings are similar to those in atherosclerotic arteries, including lipid deposition, degradation of medial collagen and elastin fibers, and disruption of internal and external elastic lamina [1]. Sorrell et al suggested that chronic overstimulation of the endothelium by nitric oxide (NO) or NO donors linked between atherosclerosis and CAE [10], whereas an opposing opinion claims that CAE is not truly a variant of atherosclerosis based on studies showing no difference in traditional cardiovascular risk factors of patients with pure CAE and those with CAE and atherosclerosis, except smoking which was more prevalent in the mixed group. Some studies have found a strong correlation between CAE and aortic aneurysms, with angiotensin II, which has a negative effect on vascular wall function and remodeling, being the link between them [1]. This brings us to the theory that increased MMP activity and decreased TIMPs lead to increased proteolysis of extracellular matrix proteins, followed by disruption of the internal elastic lamina as a gateway for inflammatory cells, as well as expansive arterial remodeling, finally leading to the development of coronary artery ectasia.\n\nAll three coronary vessels can be affected by CAE, but in the majority of patients, only a single artery is involved. The most common locations for aneurysmal formation in patients with concomitant CAD are the proximal and mid segments of the RCA, followed by the left anterior descending artery (LAD) and left circumflex (LCX), and least frequently reported along the left main coronary artery [11]. The reason for the higher rates of RCA involvement by CAE is not fully understood. The most common etiology of aneurysmal dilation in adults is atherosclerosis accounting for 50% of cases. In the remainder of cases, it could be congenital or acquired, secondary to inflammatory, infectious diseases, connective tissue diseases, or following invasive coronary interventions and rarely, trauma [7].\n\nAcute coronary syndrome in patients with coronary artery aneurysm is commonly caused by plaque rupture. It can also be caused by sluggish or turbulent blood flow in the ectatic vessel which results in thrombus formation and distal embolization. Other possible complications include vasospasm and vascular wall rupture [7, 12, 13]. Measurement of thrombosis in myocardial infarction (TIMI) frame count helps in evaluation of coronary blood flow. Decreased TIMI frame count correlates with increased ectasia ration and suggests a worse prognosis in patients with CEA [14, 15]. Ectatic vessels have higher rates for structural alterations and TIMI frame count which contribute to the increased risk for thrombosis and vasospasm. This could also worsen by blood reflux due to possible absence of diastolic antegrade flow gradient due to coronary dilation [16].\n\nThe diagnosis of CAE is mainly achieved by X-ray coronary angiography. Characteristic angiographic findings that are suggestive of KD include marked proximal ectasia followed by sudden transition to an angiographically normal distal segment. Another characteristic feature is the presence of calcification of the arterial wall along sites where former aneurysms have remodeled [5]. Better assessment of luminal size and arterial wall changes could be achieved by intravascular ultrasound (IVUS), which helps in evaluation of the severity of intimal hyperplasia, detection of thrombi, calcification, and severity of luminal narrowing [17]. Other diagnostic tests include three-dimensional, non-contrast-enhanced, free-breathing coronary magnetic resonance angiography (MRA) and coronary artery computed tomography (CACT) [7].\n\nThe medical management of CAE is not adequately addressed. The goals of therapy in KD are to control and manage the cardiovascular risk factors that can contribute to disease progression and to administer medications that can improve disease prognosis. According to the Japanese Circulation Society for management of adult KD, patients with KD who develop angina or MI are treated in a similar way to patients with such conditions due to other causes [17].\n\nAmong patients with coronary aneurysms, available therapeutic options include anti-platelet agents such as aspirin, as well as anticoagulant therapy for patients with giant aneurysms or thrombi in their coronary aneurysms [18]. However, these treatment options have not been tested prospectively on wide scale studies. Patients with stenotic coronary artery lesions may benefit from the use of anti-spasmic agents, such as calcium channel blockers (CCB) and nitrates [19], as well as β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and/or angiotensin receptor II blockers for treatment of associated heart failure. However, the use of vasodilating agents, including nitrates, among patients with CAE is discouraged as medication induced coronary vasodilation can result in worsening of MI. Due to the close relationship between CAE and CAD, intense cardiovascular risk factor modification is necessary. ACS caused by acute thrombotic occlusion in patients with CAE can be treated with heparin infusion and fibrinolysis. For patients with coexisting obstructive lesions with ongoing ischemia despite medical therapy, available therapeutic options include percutaneous and/or surgical coronary vascularization. Coronary artery bypass grafting (CABG), as well as various surgical options including proximal and distal ligation, aneurysmectomy and aneurysm resection, are reserved for patients with significant CAD and ectatic changes [7, 20]. For patients with KD who had severe ischemic heart disease and underwent cardiac transplant, there has been no recurrence of coronary lesions in the transplanted heart [21].\n\nConclusions\nLong term adverse cardiovascular outcomes are higher in ectatic infarcted related artery (EIRA) compared with non-ectatic coronary disease. It should be emphasized that coronary artery ectasia is not a benign finding. Dilated ectatic vessels predispose to various complications including thrombus formation, arterial spasm, spontaneous dissection, and MI. Percutaneous intervention and stent placement has limited role in management of EIRA given the unfavorable anatomy. Moreover, there is a lack of clear guidelines regarding the use of dual antiplatelet therapy, triple blood thinning therapy, or their optimal duration. This patient developed recurrent MI despite optimum health measures and dual antiplatelet therapy. A clear guideline on management of this condition is needed.\n==== Refs\nReferences\n1 Eitan A Roguin A Coronary artery ectasia: new insights into pathophysiology, diagnosis, and treatment Coron Artery Dis 2016 27 5 420 428 10.1097/MCA.0000000000000379 27218145 \n2 Burns JC Kushner HI Bastian JF Shike H Shimizu C Matsubara T Turner CL Kawasaki disease: A brief history Pediatrics 2000 106 2 E27 10.1542/peds.106.2.e27 10920183 \n3 Falcini F Capannini S Rigante D Kawasaki syndrome: an intriguing disease with numerous unsolved dilemmas Pediatr Rheumatol Online J 2011 9 17 10.1186/1546-0096-9-17 21774801 \n4 Kontopoulou T Kontopoulos DG Vaidakis E Mousoulis GP Adult Kawasaki disease in a European patient: a case report and review of the literature J Med Case Rep 2015 9 75 10.1186/s13256-015-0516-9 25890055 \n5 Bhagwat A Mukhedkar S Ekbote S Gordon JB Missed Kawasaki disease in childhood presenting as myocardial infarction in adults Indian Heart J 2015 67 4 385 388 10.1016/j.ihj.2015.04.014 26304576 \n6 Senzaki H Long-term outcome of Kawasaki disease Circulation 2008 118 25 2763 2772 10.1161/CIRCULATIONAHA.107.749515 19106401 \n7 Mavrogeni S Coronary artery ectasia: from diagnosis to treatment Hellenic J Cardiol 2010 51 2 158 163 20378518 \n8 Kruger D Stierle U Herrmann G Simon R Sheikhzadeh A Exercise-induced myocardial ischemia in isolated coronary artery ectasias and aneurysms (\"dilated coronopathy\") J Am Coll Cardiol 1999 34 5 1461 1470 10.1016/S0735-1097(99)00375-7 10551693 \n9 Lamblin N Bauters C Hermant X Lablanche JM Helbecque N Amouyel P Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease J Am Coll Cardiol 2002 40 1 43 48 10.1016/S0735-1097(02)01909-5 12103254 \n10 Sorrell VL Davis MJ Bove AA Origins of coronary artery ectasia Lancet 1996 347 8995 136 137 10.1016/S0140-6736(96)90335-9 8544543 \n11 Demopoulos VP Olympios CD Fakiolas CN Pissimissis EG Economides NM Adamopoulou E Foussas SG et al The natural history of aneurysmal coronary artery disease Heart 1997 78 2 136 141 10.1136/hrt.78.2.136 9326986 \n12 Gziut AI Gil RJ Coronary aneurysms Pol Arch Med Wewn 2008 118 12 741 746 19202953 \n13 Papadakis MC Manginas A Cotileas P Demopoulos V Voudris V Pavlides G Foussas SG et al Documentation of slow coronary flow by the TIMI frame count in patients with coronary ectasia Am J Cardiol 2001 88 9 1030 1032 10.1016/S0002-9149(01)01984-1 11704003 \n14 Ozbay Y Akbulut M Balin M Kayancicek H Baydas A Korkmaz H The level of hs-CRP in coronary artery ectasia and its response to statin and angiotensin-converting enzyme inhibitor treatment Mediators Inflamm 2007 2007 89649 10.1155/2007/89649 17497040 \n15 Kosar F Acikgoz N Sahin I Topal E Aksoy Y Cehreli S Effect of ectasia size or the ectasia ratio on the thrombosis in myocardial infarction frame count in patients with isolated coronary artery ectasia Heart Vessels 2005 20 5 199 202 10.1007/s00380-005-0831-y 16160900 \n16 Hirapur I Veeranna R Agrawal N Regurgitation of blood flow from the ectatic LAD artery as a cause of angina demonstrated during coronary angiogram BMJ Case Rep 2014 2014 10.1136/bcr-2013-203172 24554683 \n17 Group JCSJW Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013). Digest version Circ J 2014 78 10 2521 2562 10.1253/circj.CJ-66-0096 25241888 \n18 Yetkin E Waltenberger J Novel insights into an old controversy: is coronary artery ectasia a variant of coronary atherosclerosis? Clin Res Cardiol 2007 96 6 331 339 10.1007/s00392-007-0521-0 17453130 \n19 Sorrell VL Davis MJ Bove AA Current knowledge and significance of coronary artery ectasia: a chronologic review of the literature, recommendations for treatment, possible etiologies, and future considerations Clin Cardiol 1998 21 3 157 160 10.1002/clc.4960210304 9541758 \n20 Manginas A Cokkinos DV Coronary artery ectasias: imaging, functional assessment and clinical implications Eur Heart J 2006 27 9 1026 1031 10.1093/eurheartj/ehi725 16415301 \n21 Checchia PA Pahl E Shaddy RE Shulman ST Cardiac transplantation for Kawasaki disease Pediatrics 1997 100 4 695 699 10.1542/peds.100.4.695 9310527\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1923-2829",
"issue": "8(6)",
"journal": "Cardiology research",
"keywords": "Coronary artery ectasia; Kawasaki disease; Myocardial infarction",
"medline_ta": "Cardiol Res",
"mesh_terms": null,
"nlm_unique_id": "101557543",
"other_id": null,
"pages": "344-348",
"pmc": null,
"pmid": "29317980",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": "27218145;25241888;8544543;16160900;21774801;20378518;9310527;12103254;17497040;10920183;26304576;9541758;19106401;9326986;11704003;25890055;19202953;10551693;16415301;17453130;24554683",
"title": "A History of Kawasaki Disease From Childhood and Coronary Artery Ectasia With Recurrent ST Elevation Myocardial Infarction: A Therapeutic Challenge.",
"title_normalized": "a history of kawasaki disease from childhood and coronary artery ectasia with recurrent st elevation myocardial infarction a therapeutic challenge"
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"activesubstancename": "CLOPIDOGREL BISULFATE"
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"abstract": "BACKGROUND\nGood glycaemic control during pregnancy is key to reduce maternal and foetal complications. Insulin degludec, an ultralong acting analogue with a \"peakless\" and stable pharmacokinetic profile, has the potential advantage of reducing hypoglycaemia and glucose variability compared to other basal insulins. Therefore, degludec could be a reasonable therapeutic option for pregnant women with type 1 diabetes (T1D). However, degludec is not licensed for use during pregnancy owing to the lack of safety data.\n\n\nRESULTS\nWe herein report details on pregnancy and foetal outcomes in three women with uncontrolled T1D treated with insulin degludec during the first trimester or the whole pregnancy. In addition, we report an updated review of similar cases reported in literature. Overall, no congenital neonatal malformation was observed in the six cases described. Three babies required neonatal intensive care unit admission for respiratory distress, apnoeas, bilirubin increase or hypoglycaemia. However, the observed neonatal complications were deemed unlikely to be related to degludec treatment.\n\n\nCONCLUSIONS\nIn summary, while awaiting for the results of an ongoing randomized controlled trial, data on six cases of degludec exposure during pregnancy reassuringly suggest no embryo-foetal toxicity. More information is needed before degludec can be safely recommended during pregnancy.",
"affiliations": "Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.;Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.;Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padua, Italy. gianpaolo.fadini@unipd.it.",
"authors": "Bonora|B M|BM|;Avogaro|A|A|;Fadini|G P|GP|",
"chemical_list": "D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; C517652:hemoglobin A1c protein, human; C571886:insulin degludec",
"country": "Italy",
"delete": false,
"doi": "10.1007/s40618-018-0926-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-4097",
"issue": "42(3)",
"journal": "Journal of endocrinological investigation",
"keywords": "Analogues; Insulin; Pregnancy; Type 1 diabetes",
"medline_ta": "J Endocrinol Invest",
"mesh_terms": "D000328:Adult; D015415:Biomarkers; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D016640:Diabetes, Gestational; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D007231:Infant, Newborn; D049528:Insulin, Long-Acting; D008297:Male; D011247:Pregnancy; D011256:Pregnancy Outcome; D011254:Pregnancy in Diabetics; D055815:Young Adult",
"nlm_unique_id": "7806594",
"other_id": null,
"pages": "345-349",
"pmc": null,
"pmid": "30043095",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15647580;15910635;17392539;17905178;18445730;22594461;22685467;22851598;23489521;23617228;26232910;28767190;29064082;29222384;29594399;29730391;9000705",
"title": "Exposure to insulin degludec during pregnancy: report of a small series and review of the literature.",
"title_normalized": "exposure to insulin degludec during pregnancy report of a small series and review of the literature"
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"companynumb": "IT-SA-2019SA066496",
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"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN LISPRO"
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{
"abstract": "To compare the functional and anatomical outcomes of eyes with chronic central serous chorioretinopathy treated with yellow micropulse (MP) laser versus half-dose verteporfin photodynamic therapy (PDT).\n\n\n\nThis is a multicentre, retrospective comparative study of 92 eyes treated with yellow MP laser (duty cycle of 5%, zero spacing between spots, spot size varied from 100 to 200 µm, power varied from 320 to 660 mW, and the pulse burst duration was 200 ms) and 67 eyes treated with PDT (half-dose verteporfin (3 mg/m2) infused over 10 min), followed by laser activation for 83 s. Spot sizes varied from 400 to 2000 µm.\n\n\n\nIn the MP group, at 12 months of follow-up, the mean best corrected visual acuity (BCVA) improved from the logarithm of the minimum angle of resolution (logMAR) of 0.41±0.27 at baseline to 0.21±0.26 (P<0.0001), 48.9% (45/92) of eyes had an improvement of ≥3 lines of BCVA from baseline, 48.9% (45/92) of eyes remained within 2 lines of baseline BCVA, and only 2.2% (2/92) of eyes lost ≥3 lines of BCVA from baseline. In the PDT group, at 12 months of follow-up, the mean BCVA changed from logMAR of 0.50±0.34 at baseline to 0.47±0.34 (P=0.89), 19% (13/67) of eyes had an improvement of ≥3 lines of BCVA from baseline, 73% (49/67) of eyes remained within 2 lines of baseline BCVA, and 7% (5/67) of eyes lost ≥3 lines of BCVA from baseline. There were no adverse events attributable to the yellow MP laser treatment. One eye in the PDT group developed choroidal neovascularisation, which was treated with three intravitreal bevacizumab injections.\n\n\n\nBoth PDT and MP are effective in restoring the macular anatomy. In places where PDT is not available, yellow MP laser may be an adequate treatment alternative.",
"affiliations": "Clinica Ricardo Palma, Lima, Peru.;Asociados de Macula Vitreo y Retina de Costa Rica, San Jose, Costa Rica.;Macula Retina Consultores, Mexico City, Mexico.;Ophthalmology, Fundación Oftalmológica Nacional, Universidad del Rosario Bogotá, Bogotá, Colombia.;University of Puerto Rico, San Juan, Puerto Rico.;Hospital La Luz, Mexico City, Mexico.;Federal University of Sao Paulo, Sao Paulo, Brazil.;Hospital La Fe, Universidad de Valencia, Valencia, Spain.;LV Prasad Institute, Hyderabad, India.;Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA.;Instituto Oftalmologico Conde de Valenciana, Mexico City, Mexico.;Clinica Oftalmologica Centro Caracas and the Arevalo-Coutinho Foundation for Research in Ophthalmology, Caracas, Venezuela.",
"authors": "Roca|Jose A|JA|;Wu|Lihteh|L|;Fromow-Guerra|Jans|J|;Rodríguez|Francisco J|FJ|;Berrocal|Maria H|MH|;Rojas|Sergio|S|;Lima|Luiz H|LH|;Gallego-Pinazo|Roberto|R|;Chhablani|Jay|J|;Arevalo|J Fernando|JF|;Lozano-Rechy|David|D|;Serrano|Martin|M|",
"chemical_list": "D017319:Photosensitizing Agents; D000077362:Verteporfin; D007208:Indocyanine Green",
"country": "England",
"delete": false,
"doi": "10.1136/bjophthalmol-2017-311291",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1161",
"issue": "102(12)",
"journal": "The British journal of ophthalmology",
"keywords": "macula; retina; treatment lasers",
"medline_ta": "Br J Ophthalmol",
"mesh_terms": "D000328:Adult; D056833:Central Serous Chorioretinopathy; D002908:Chronic Disease; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D006801:Humans; D007208:Indocyanine Green; D053685:Laser Therapy; D008297:Male; D008875:Middle Aged; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D000077362:Verteporfin; D014792:Visual Acuity",
"nlm_unique_id": "0421041",
"other_id": null,
"pages": "1696-1700",
"pmc": null,
"pmid": "29439089",
"pubdate": "2018-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Yellow (577 nm) micropulse laser versus half-dose verteporfin photodynamic therapy in eyes with chronic central serous chorioretinopathy: results of the Pan-American Collaborative Retina Study (PACORES) Group.",
"title_normalized": "yellow 577 nm micropulse laser versus half dose verteporfin photodynamic therapy in eyes with chronic central serous chorioretinopathy results of the pan american collaborative retina study pacores group"
} | [
{
"companynumb": "PE-BAUSCH-BL-2019-001864",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERTEPORFIN"
},
"drugadditional": "3",
... |
{
"abstract": "We present case of a girl deceased due to Candida albicans breakthrough invasive infection during the echinocandin treatment after undergoing allogeneic haematopoietic stem cell transplant for relaps of acute myeloid leukaemia. Candida albicans generally susceptible to all antifungal drugs wasn't considered for potential resistance and conventional blood culture positivity was too late to reveal the resistance to echinocandins. Due to severe organ toxicities (liver, kidneys) she received echinocandin as an antifungal prophylaxis, no change was made for the treatment of Candida albicans infection. Later, the molecular analysis proved the mutation S645P known as being responsible for the echinocandin resistance. The post mortem analysis of fungal burden in autopsy samples showed very high levels of Candida DNA in gut, liver, spleen and kidneys.",
"affiliations": null,
"authors": "Chrenkova|V|V|;Hubacek|P|P|;Sedlacek|P|P|;Riha|P|P|;Kodetová|D|D|;Bébrová|E|E|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins",
"country": "Czech Republic",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1210-7913",
"issue": "63(2)",
"journal": "Epidemiologie, mikrobiologie, imunologie : casopis Spolecnosti pro epidemiologii a mikrobiologii Ceske lekarske spolecnosti J.E. Purkyne",
"keywords": null,
"medline_ta": "Epidemiol Mikrobiol Imunol",
"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D002176:Candida albicans; D002177:Candidiasis; D025141:Drug Resistance, Fungal; D054714:Echinocandins; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute",
"nlm_unique_id": "9431736",
"other_id": null,
"pages": "121-4",
"pmc": null,
"pmid": "25025677",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Post-mortem analysis of Candida albicans breakthrough infection during echinocandin treatment in haematopoietic stem cell transplant recipient.",
"title_normalized": "post mortem analysis of candida albicans breakthrough infection during echinocandin treatment in haematopoietic stem cell transplant recipient"
} | [
{
"companynumb": "CZ-MYLANLABS-2015M1010734",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Infantile hemangiomas (IHs) are the most common benign tumor of infancy, characterized by a natural history of early proliferation in the first months of life to eventual involution during childhood, often with residual fibrofatty tissue. Once involution has been achieved, IHs do not typically recur. We present two cases of exogenous growth hormone therapy resulting in the recurrence of IHs in late childhood, supported by radiological, immunohistochemical, in vitro, and in vivo evidence.",
"affiliations": "Division of Plastic Surgery, Columbia University Medical Center, New York-Presbyterian Hospital, New York.;Division of Plastic Surgery, Columbia University Medical Center, New York-Presbyterian Hospital, New York.;Division of Pediatric Dermatology, Columbia University Medical Center, New York-Presbyterian Hospital, New York.;Division of Pediatric Radiology, Columbia University Medical Center, New York-Presbyterian Hospital, New York.;Department of Obstetrics and Gynecology, Columbia University Medical Center, New York-Presbyterian Hospital, New York.;Division of Plastic Surgery, Columbia University Medical Center, New York-Presbyterian Hospital, New York.",
"authors": "Munabi|Naikhoba C O|NC|;Tan|Qian Kun|QK|;Garzon|Maria C|MC|;Behr|Gerald G|GG|;Shawber|Carrie J|CJ|;Wu|June K|JK|",
"chemical_list": "D019382:Human Growth Hormone",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12530",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "32(4)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D001706:Biopsy; D002648:Child; D005260:Female; D006391:Hemangioma; D019382:Human Growth Hormone; D006801:Humans; D009364:Neoplasm Recurrence, Local; D012878:Skin Neoplasms",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "539-43",
"pmc": null,
"pmid": "25690955",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "18225592;15901933;17560503;24602073;22010790;18535669;17138012;23096601",
"title": "Growth Hormone Induces Recurrence of Infantile Hemangiomas After Apparent Involution: Evidence of Growth Hormone Receptors in Infantile Hemangioma.",
"title_normalized": "growth hormone induces recurrence of infantile hemangiomas after apparent involution evidence of growth hormone receptors in infantile hemangioma"
} | [
{
"companynumb": "US-PFIZER INC-2014357826",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SOMATROPIN"
},
"drugadditional": null,
... |
{
"abstract": "The emergence of resistance to available antiviral drugs may cause higher Cytomegalovirus (CMV)-associated morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Few novel antiviral drugs are being developed with potential effect against refractory or resistant CMV infections. Brincidofovir, an oral nucleotide analog and prodrug of cidofovir, has shown in vitro activity against CMV.\n\n\n\nWe reviewed data of 4 cancer patients with resistant CMV or herpes simplex virus (HSV) infections and were treated with brincidofovir under emergency IND application.\n\n\n\nThree out of the 4 patients with resistant CMV or HSV infections responded to brincidofovir. Brincidofovir achieved virological response in 2 patients with confirmed UL97 mutation (ganciclovir-resistant CMV infection), but failed to control CMV when a specific UL54 mutation was present (conferring resistance to foscarnet and cidofovir), as seen with patient 3. Furthermore, brincidofovir was effective for treatment of acyclovir resistant HSV infection, as described in patient 4 which is in alignment with the high in vitro potency of brincidofovir (about 100-fold more than acyclovir) for inhibition of HSV replication. Only one patient had brincidofovir-related diarrhea without any evidence of concurrent gastrointestinal GVHD.\n\n\n\nWithout the nephrotoxicity of cidofovir, brincidofovir could be an effective alternative for CMV-resistant and HSV-resistant infections. Combination therapy of brincidofovir with other antiviral agent, at a conventional or a lower dose, could be considered to potentiate efficacy and minimize side effects of the approved antiviral agents.",
"affiliations": "Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA. Electronic address: elchaer.firas@gmail.com.;Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: rfchemaly@mdanderson.org.",
"authors": "El-Haddad|Danielle|D|;El Chaer|Firas|F|;Vanichanan|Jackapat|J|;Shah|Dimpy P|DP|;Ariza-Heredia|Ella J|EJ|;Mulanovich|Victor E|VE|;Gulbis|Alison M|AM|;Shpall|Elizabeth J|EJ|;Chemaly|Roy F|RF|",
"chemical_list": "D000998:Antiviral Agents; D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.antiviral.2016.08.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0166-3542",
"issue": "134()",
"journal": "Antiviral research",
"keywords": "Brincidofovir; Cancer; Cytomegalovirus; Herpes simplex virus; Resistance",
"medline_ta": "Antiviral Res",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D002986:Clinical Trials as Topic; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D003596:Cytosine; D024882:Drug Resistance, Viral; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006561:Herpes Simplex; D006566:Herpesviridae Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D063065:Organophosphonates",
"nlm_unique_id": "8109699",
"other_id": null,
"pages": "58-62",
"pmc": null,
"pmid": "27582067",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Brincidofovir (CMX-001) for refractory and resistant CMV and HSV infections in immunocompromised cancer patients: A single-center experience.",
"title_normalized": "brincidofovir cmx 001 for refractory and resistant cmv and hsv infections in immunocompromised cancer patients a single center experience"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201905510",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BRINCIDOFOVIR"
},
"drugadditional": null... |
{
"abstract": "We evaluated the real-life treatment outcomes of elderly patients with diffuse large B-cell lymphoma from a homogenous Asian population and defined the cutoff age for \"elderly.\"\n\n\n\nThe medical records of 192 DLBCL patients aged > 60 years who had received first-line immunochemotherapy were retrospectively evaluated. The treatment schedule, adverse events, and survival outcomes were analyzed overall and stratified by 4 age groups (> 60-64, 65-69, 70-74, and ≥ 75 years).\n\n\n\nPatient age of ≥ 75 years was associated with a significantly lower complete remission rate (86.5% vs. 81.4% vs. 82.0% vs. 51%; P < .001) and greater treatment-related mortality (5.4% vs. 9.3% vs. 13.1% vs. 33.3%; P = .001). Advanced age was also related to dose reductions (24.3% vs. 39.5% vs. 73.8% vs. 100%; P < .001) and a lower likelihood of completing the planned chemotherapy cycle (73% vs. 79.1% vs. 78.7% vs. 51%, P = .005). Significantly poorer progression-free survival (3-year rate, 73.5% vs. 61.5% vs. 65.2% vs. 38.3%; P < .001) and overall survival (3-year rate, 77.9% vs. 74.1% vs. 70.9% vs. 43.6%; P < .001) were observed for patients aged ≥ 75 years. Multivariate regression analyses identified age ≥ 75 years and initial Eastern Cooperative Oncology Group performance status as potential risk factors associated with overall survival.\n\n\n\nElderly patients aged < 75 years were able to tolerate standard immunochemotherapy, with acceptable survival profiles. In an Asian population, 75 years seems to be a judicious cutoff for predicting treatment outcomes.",
"affiliations": "Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Electronic address: jeongok77@gmail.com.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.",
"authors": "Byun|Ja Min|JM|;Lee|Jeong-Ok|JO|;Kang|Beodeul|B|;Kim|Ji-Won|JW|;Kim|Se Hyun|SH|;Kim|Jin Won|JW|;Kim|Yu Jung|YJ|;Lee|Keun-Wook|KW|;Bang|Soo-Mee|SM|;Lee|Jong Seok|JS|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2016.06.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "16(9)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Asian; DLBCL; Immunochemotherapy; Older patients; Prognosis",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D015897:Comorbidity; D003520:Cyclophosphamide; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance; D011241:Prednisone; D012008:Recurrence; D056910:Republic of Korea; D012189:Retrospective Studies; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "503-510.e3",
"pmc": null,
"pmid": "27375158",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Diffuse Large B-Cell Lymphoma in the Elderly: Real World Outcomes of Immunochemotherapy in Asian Population.",
"title_normalized": "diffuse large b cell lymphoma in the elderly real world outcomes of immunochemotherapy in asian population"
} | [
{
"companynumb": "KR-JNJFOC-20170106109",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Mycobacterium abscessus surgical site infections are rare, but notoriously difficult to treat. Eradication requires aggressive surgical resection, removal of foreign material, prolonged antibiotics, and consideration of delayed reconstruction.",
"affiliations": "Division of Cardiothoracic Surgery Department of Surgery University of Colorado Aurora CO USA.;Division of Cardiothoracic Surgery Department of Surgery University of Colorado Aurora CO USA.;Division of Plastic Surgery Department of Surgery University of Colorado Aurora CO USA.;Division of Cardiothoracic Surgery Department of Surgery University of Colorado Aurora CO USA.",
"authors": "Wojcik|Brandon M|BM|https://orcid.org/0000-0001-9639-470X;Mitchell|John D|JD|;Chong|Tae|T|;Rove|Jessica Y|JY|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4027",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4027\nCCR34027\nCase Report\nCase Reports\nManagement of refractory Mycobacterium abscessus sternal infection following reoperative cardiac surgery\nWOJCIK et al.\nWojcik Brandon M. https://orcid.org/0000-0001-9639-470X\n1 brandon.wojcik@cuanschutz.edu\n\nMitchell John D. 1\nChong Tae 2\nRove Jessica Y. 1\n1 Division of Cardiothoracic Surgery Department of Surgery University of Colorado Aurora CO USA\n2 Division of Plastic Surgery Department of Surgery University of Colorado Aurora CO USA\n* Correspondence\nBrandon M. Wojcik, Cardiothoracic Surgery Fellow, University of Colorado Hospital, 12631 E. 17th Avenue, Mail Stop C‐291, Aurora, CO 80045.\nEmail: brandon.wojcik@cuanschutz.edu\n\n09 3 2021\n4 2021\n9 4 10.1002/ccr3.v9.4 23282331\n15 1 2021\n09 11 2020\n22 2 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nMycobacterium abscessus surgical site infections are rare, but notoriously difficult to treat. Eradication requires aggressive surgical resection, removal of foreign material, prolonged antibiotics, and consideration of delayed reconstruction.\n\nMycobacterium abscessus surgical site infections are rare, but notoriously difficult to treat. Eradication requires aggressive surgical resection, removal of foreign material, prolonged antibiotics, and consideration of delayed reconstruction.\n\ncardiothoracic surgery\ninfectious diseases\nmycobacterium abscessus\nnontuberculous mycobacteria\npostoperative infection\nsource-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:27.04.2021\nWojcik BM , Mitchell JD , Chong T , Rove JY . Management of refractory Mycobacterium abscessus sternal infection following reoperative cardiac surgery. Clin Case Rep. 2021;9 :2328–2331. 10.1002/ccr3.4027\n==== Body\n1 INTRODUCTION\n\nMycobacterium abscessus is a rare cause of surgical site infections, but is notoriously drug‐resistant. Providers must understand the guideline‐directed therapy required to prevent recurrence. We present a case of recurrent postoperative Mycobacterium abscessus sternal infection that was eradicated with aggressive surgical resection, topical/systemic antibiotic therapy, and delayed sternal reconstruction.\n\nNontuberculous mycobacteria (NTM) are a heterogenous group of over 150 species found ubiquitously in the environment. 1 They are opportunistic pathogens, with a subset causing disease in humans with impaired host defenses and in areas of pre‐existing tissue injury. NTM are emerging causes of healthcare‐associated infections following contact with contaminated water, aerosols, or medical equipment. During the last decade, contamination of heater‐cooler units used in cardiac bypass surgery was implicated in a global outbreak of over 100 postoperative infections from Mycobacterium chimaera. 1 Mycobacterium abscessus is a rapid‐growing species that is notoriously drug‐resistant and requires aggressive surgical and medical management. 2 This report describes a novel management strategy to treat a patient with a refractory postoperative Mycobacterium abscessus sternal infection.\n\n2 CASE REPORT\n\nA 67‐year‐old man with a history of coronary artery bypass grafting underwent a mitral and tricuspid valve repair through a redo sternotomy performed at an outside hospital. He was readmitted one month following surgery with serous drainage from his wound. Imaging demonstrated inferior sternal widening with fractured wires and a substernal fluid collection. Operative exploration revealed no purulent fluid, cultures were obtained, and the fluid collection was felt to be a result of the dehiscence. The sternum was closed with wires, reinforced with lower sternal plates under myocutaneous flaps, and the skin was left open with a wound vac. While undergoing vac changes, his sternal and soft tissue cultures grew Mycobacterium abscessus that was macrolide sensitive. Infectious disease was consulted, and he was placed on an appropriate triple antibiotic regimen. 3 The patient returned to the operating room with the assistance of plastic surgery for removal of the lower sternal hardware, sternal debridement, bilateral pectoralis advancement flaps, and skin closure. Cultures taken during this final operation eventually grew Mycobacterium abscessus. After extensive multidisciplinary discussions, further chest wall resection was felt to be high‐risk. A referral was placed to a center with expertise and he was discharged on oral azithromycin, intravenous amikacin, and intravenous imipenem. 3\n\nDuring the ensuing months, he was monitored closely as an outpatient. Drainage from the inferior wound recurred four months following discharge, prompting referral to our institution. Imaging revealed a substernal fluid collection with a draining sinus tract, three upper sternal wires, and sternal sclerosis (Figure postoperative1). Transthoracic echocardiogram demonstrated competent valve repairs and no vegetations. Coronary angiography demonstrated a patent left internal mammary artery (LIMA) graft crossing directly beneath the left upper sternum. The case was reviewed with colleagues in infectious disease and plastic surgery. The decision was made to pursue radical surgical resection, removal of all hardware, serial debridements, and delayed sternal reconstruction after operative cultures cleared. Preoperative nutritional assessment demonstrated adequate nourishment. His antibiotic regimen was expanded to four agents including oral azithromycin, intravenous imipenem, intravenous tigecycline, and intravenous clofazimine.\n\nFIGURE 1 Chest computed tomography axial (A) and sagittal (B) sections demonstrating recurrent infection. White arrow indicates sternal sclerosis. White asterisk indicates substernal fluid collection tracking to the inferior wound. White dashed arrow demonstrates a retained sternal wire\n\nHe was taken to the operating room seven months following his initial valve repair. The sternal scar was excised. An abscess was encountered in the soft tissue at the lower third of the sternal incision that tracked through the pectoralis muscle flaps, inferior sternum, and into the mediastinum (Figure 2A). The inferior sternum was sclerotic and grossly diseased. Tissue cultures were obtained, the remaining sternal wires were removed, and a redo sternotomy with nearly complete sternectomy was performed. The left manubrium and upper sternum were not removed as they were remote from the nidus of infection, appeared normal, and we did not want to risk injury to the patent LIMA graft adherent to its underside (Figure 2B). The abscess cavity was debrided to bleeding tissue except for that directly over the heart. A pulse lavage system (Stryker Inc, Mahwah, NJ) was used to irrigate all exposed mediastinal surfaces with bacitracin (50,000 U/3 L 0.9% normal saline). Absorbable synthetic calcium sulfate beads (Stimulan, Biocomposites, UK) infused with amikacin (5 g in 50 cc of beads) were placed in the wound bed (Figure 2B). A temporary wound vac was placed, and the patient was admitted to the cardiac surgery ward.\n\nFIGURE 2 Intraoperative images demonstrating the (A) inferior sternal abscess and (B) near complete sternectomy with placement of amikacin antimicrobial beads. Microscopic histopathology findings demonstrating (C) granuloma formation in the fibrotic tissue surrounding inferior sternum and (D) acid‐fast stain positive for microorganisms within the granuloma\n\nTissue staining revealed granulomas with acid‐fast bacilli in the connective tissue surrounding the lower sternum, but no active infection of the bone (Figure 2C‐D). Weekly operative debridements were performed while obtaining new cultures and replacing the amikacin beads. At five weeks following initial sternectomy, cultures showed no growth. Wound closure required an omental flap to fill the spatial defect. A pedicled omental flap supplied by the right gastroepiploic artery was tunneled through the diaphragm into the mediastinum (Figure 3A‐B). Plastic surgery elevated bilateral full thickness skin flaps to the level of the remaining pectoralis major fascia. Indocyanine green fluorescence angiography confirmed vascularization of both omental and skin flaps. The skin flaps were advanced over the omentum and closed primarily over drains (Figure 3C).\n\nFIGURE 3 Intraoperative images from delayed sternal reconstruction demonstrating the (A) omental flap tunneled into the mediastinum and (B) positioned in the surgical bed prior to (C) closure of bilateral skin advancement flaps\n\nThe remainder of the patient's hospital course was uncomplicated, and he was discharged home after removal of both drains. He was monitored closely as an outpatient on the aforementioned guideline‐directed antibiotic regimen. 3 This was continued for four months following sternectomy, the recommended course for serious complex soft tissue infections. 3 At one year following surgery, he has no evidence of recurrent infection.\n\n3 COMMENT\n\nPostcardiotomy NTM infections are rare, but when diagnosed, the infections are associated with high morbidity and mortality. 1 Diagnosis is often delayed given their slow growth in cultures and a low index of suspicion. This case emphasizes several important considerations in the management of this complex condition.\n\nFirst, successful management of sternal and mediastinal NTM infection requires a multidisciplinary approach including infectious disease expertise for optimal medical therapy and surgeons for both resection and reconstruction. There should be a low threshold for referral to a center with experience in the management of complex NTM infections.\n\nSecond, guideline‐directed antimicrobial therapy for NTM infections requires multidrug regimens and a combination of oral and intravenous agents to obtain appropriate tissue concentrations. 3 In an effort to deliver a higher concentration of antimicrobials to the affected site, we utilized amikacin beads in addition to systemic therapy. While amikacin beads have previously been described in the treatment of NTM infections, this is, to the best of our knowledge, the first reported use in a NTM sternal infection. 4\n\nFinally, optimal treatment requires aggressive surgical debridement and removal of foreign material. The surgical bed should be monitored with cultures and reconstruction delayed until after the infection has cleared. Large defects are best filled using autologous tissue flaps. The omentum was an excellent choice for our patient given the size of the defect and failure of prior pectoralis muscle flaps.\n\nIn conclusion, we report a rare case of refractory Mycobacterium abscessus sternal infection following reoperative cardiac surgery. A treatment plan was devised by a multidisciplinary team and the infection was eradicated with aggressive surgical resection, a combination of local and systemic antimicrobial therapy, and delayed sternal reconstruction.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nBW, JM, TC, and JR: were actively involved in the clinical care of the patient. BW and JR: wrote the manuscript. JM and TC revised the manuscript.\n\nETHICAL APPROVAL\n\nCase reports of 3 or less patients are not subject to IRB regulations at our institution and were found by our COMIRB to exempt after submission.\n\nPATIENT CONSENT\n\nWritten consent was obtained by the patient and a formal waiver was signed.\n\nACKNOWLEDGMENTS\n\nPublished with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nNo data were generated or analyzed in the presented research.\n==== Refs\nREFERENCES\n\n1 Hasse B , Hannan MM , Keller PM , et al. International society of cardiovascular infectious diseases guidelines for the diagnosis, treatment and prevention of disseminated mycobacterium chimaera infection following cardiac surgery with cardiopulmonary bypass. J Hosp Infect. 2020;104 (2 ):214‐235.31715282\n2 Baker AW , Maziarz EK , Lewis SS , et al. Invasive mycobacterium abscessus complex infection after cardiac surgery: epidemiology, management, and clinical outcomes. Clin Infect Dis. 2020.Online ahead of print\n3 Griffith DE , Aksamit T , Brown‐Elliott BA , et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175 (4 ):367‐416.17277290\n4 Goldstein N , St Clair JB , Kasperbauer SH , Daley CL , Lindeque B . Nontuberculous Mycobacterial musculoskeletal infection cases from a tertiary referral center, Colorado, USA. Emerg Infect Dis. 2019;25 (6 ):1075‐1083.31107224\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(4)",
"journal": "Clinical case reports",
"keywords": "cardiothoracic surgery; infectious diseases; mycobacterium abscessus; nontuberculous mycobacteria; postoperative infection",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2328-2331",
"pmc": null,
"pmid": "33936688",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "17277290;31107224;31715282;32133489",
"title": "Management of refractory Mycobacterium abscessus sternal infection following reoperative cardiac surgery.",
"title_normalized": "management of refractory mycobacterium abscessus sternal infection following reoperative cardiac surgery"
} | [
{
"companynumb": "US-009507513-2105USA002463",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional"... |
{
"abstract": "Continuous renal replacement therapy (CRRT) may be associated with thrombocytopenia in critically ill patients. A confounding factor is concomitant use of unfractionated heparin (UFH) and suspicion for heparin-induced thrombocytopenia (HIT).\n\n\n\nTo determine the impact of CRRT on platelet count and development of thrombocytopenia.\n\n\n\nRetrospective analyses evaluated the intrapatient change in platelet count following CRRT initiation. Critically ill adult patients who received CRRT for at least 48 hours were included. The primary outcome was intrapatient change in platelet count from CRRT initiation through the first 5 days of therapy. Secondary outcomes included thrombocytopenia incidence, identification of concomitant factors associated with thrombocytopenia, and frequency of HIT.\n\n\n\n80 patients were included. Median platelet count at CRRT initiation (D0) was 128000/µL (81500-212500/µL), which was higher than those on subsequent post-CRRT days (D1: 104500/µL [63000-166750/µL]; D2: 88500/µL [53500-136750/µL]; D3: 91000/µL [49000-138000/µL]; D4: 93000/µL [46000-134000/µL]; and D5: 76000/µL [45500-151000/µL]; P < 0.05 for all). Twenty-five (35%) patients had thrombocytopenia on CRRT D0 compared with D2 (56.3%), D3 (58.7%), and D5 (59.1%); P < 0.05 for all. Controlling for potential confounders, Sequential Organ Failure Assessment score at the time of CRRT initiation was the only independent factor associated with thrombocytopenia. One (1.3%) patient had confirmed HIT. Conclusion and Relevance: This study is the first to demonstrate serial decreases in platelet count across multiple days after CRRT initiation. These data may provide additional insight to thrombocytopenia development in critically ill patients receiving heparin while on CRRT that is not associated with HIT.",
"affiliations": "1 University of Cincinnati Medical Center, OH, USA.;1 University of Cincinnati Medical Center, OH, USA.;2 University of Cincinnati James L. Winkle College of Pharmacy, OH, USA.;1 University of Cincinnati Medical Center, OH, USA.;1 University of Cincinnati Medical Center, OH, USA.",
"authors": "Droege|Christopher A|CA|;Ernst|Neil E|NE|;Messinger|Nicholas J|NJ|;Burns|Allison M|AM|;Mueller|Eric W|EW|",
"chemical_list": "D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028018779200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "52(12)",
"journal": "The Annals of pharmacotherapy",
"keywords": "critical care; dialysis; hemofiltration; heparin; renal failure; thrombocytopenia",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D016638:Critical Illness; D005260:Female; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D017582:Renal Replacement Therapy; D012189:Retrospective Studies; D013921:Thrombocytopenia; D055815:Young Adult",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1204-1210",
"pmc": null,
"pmid": "29871503",
"pubdate": "2018-12",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Evaluation of Thrombocytopenia in Critically Ill Patients Receiving Continuous Renal Replacement Therapy.",
"title_normalized": "evaluation of thrombocytopenia in critically ill patients receiving continuous renal replacement therapy"
} | [
{
"companynumb": "US-TEVA-2018-US-986387",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Droxidopa is a norepinephrine precursor that improves symptoms of neurogenic orthostatic hypotension in conditions such as Parkinson disease, multiple system atrophy, and pure autonomic failure by inducing a pressor effect. Unlike other pressor agents, droxidopa crosses the blood-brain barrier; however, its central effects are, as of yet, uncharacterized.\n\n\n\nWe present the results of a retrospective cohort study examining cognitive and behavioral side effects linked to droxidopa therapy.\n\n\n\nWe performed a review of 101 patients who had been treated with droxidopa at an academic tertiary care center and identified cases of cognitive and behavioral changes associated with the therapy.\n\n\n\nWe identified six patients who had developed cognitive and behavioral symptoms, including memory difficulties, confusion, mania, and irritability, shortly after droxidopa initiation. All six patients displayed symptoms of synucleinopathy, manifesting with autonomic failure, rapid eye movement sleep behavior disorder, and parkinsonism. Patients had no significant cognitive or behavioral symptoms before droxidopa initiation. Behavioral disturbances were observed early in the droxidopa titration period and at relatively low doses. Symptoms resolved with dose reduction in four patients, and droxidopa was discontinued in two patients due to persistent irritability. No other medical comorbidities or alternative etiologies were identified to explain the symptoms.\n\n\n\nDroxidopa is designed to act peripherally as a pressor agent but may also exert important central effects. We hypothesize that the cognitive and behavioral manifestations observed in the patients with orthostatic hypotension resulted from an \"overdose\" of key noradrenergic networks linking orbitofrontal and mesolimbic regions.",
"affiliations": "Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.;Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.;Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.;Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.;Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.;Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.",
"authors": "McDonell|Katherine E|KE|;Shibao|Cyndya A|CA|;Biaggioni|Italo|I|;Hartman|Adam|A|;Robertson|David|D|;Claassen|Daniel O|DO|",
"chemical_list": "D000978:Antiparkinson Agents; D015103:Droxidopa",
"country": "United States",
"delete": false,
"doi": "10.1097/WNN.0000000000000198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1543-3633",
"issue": "32(3)",
"journal": "Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology",
"keywords": null,
"medline_ta": "Cogn Behav Neurol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents; D003071:Cognition; D015103:Droxidopa; D005260:Female; D006801:Humans; D007024:Hypotension, Orthostatic; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "101167278",
"other_id": null,
"pages": "179-184",
"pmc": null,
"pmid": "31517701",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "26092297;6421112;8439390;25107282;24494808;22045363;25350981;28596922;24326693;23064099;20571380;15342872;12498954;24800114;24944260;23592075;3982644;27614923;22451506",
"title": "Cognitive and Behavioral Changes in Patients Treated With Droxidopa for Neurogenic Orthostatic Hypotension: A Retrospective Review.",
"title_normalized": "cognitive and behavioral changes in patients treated with droxidopa for neurogenic orthostatic hypotension a retrospective review"
} | [
{
"companynumb": "US-009507513-1911USA005951",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DROXIDOPA"
},
"drugadditional": "1",
... |
{
"abstract": "While most case reports to date are radiation recall dermatitis, radiation recall myositis, which is a distinct form of radiation recall phenomenon caused by carboplatin plus paclitaxel, has not been reported. We treated a 57-year-old female patient who suffered from recurrent cervical cancer. When the patient developed a new left sacral metastasis, salvage radiotherapy (total dose 60 Gy) was administered. Four weeks later, chemotherapy using carboplatin plus paclitaxel was initiated. Four months after chemotherapy, the patient complained of severe pain in her left buttock. On magnetic resonance imaging (MRI), edematous changes and increased signal densities of left gluteus maximus and medius muscles were noted suggesting myositis. The border of the high signal intensity territory of the muscles was sharp and clearly corresponded with the recent irradiation field. We concluded that the patient had radiation recall myositis triggered by paclitaxel-carboplatin. Symptoms were controlled by analgesics, and there was no recurrence.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Korea.",
"authors": "Maeng|Chi Hoon|CH|;Park|Jun Sang|JS|;Lee|Seung Ah|SA|;Kim|Dong Hwan|DH|;Yun|Dong Hwan|DH|;Yoo|Seung-Don|SD|;Kim|Hee-Sang|HS|;Chon|Jinmann|J|",
"chemical_list": "D000700:Analgesics; D016190:Carboplatin; D017239:Paclitaxel",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.146090",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "10(4)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000700:Analgesics; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002294:Carcinoma, Squamous Cell; D005260:Female; D006801:Humans; D007249:Inflammation; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009220:Myositis; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D011832:Radiation Injuries; D016879:Salvage Therapy; D012867:Skin; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "1093-7",
"pmc": null,
"pmid": "25579560",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016422:Letter; D016454:Review",
"references": null,
"title": "Radiation recall phenomenon presenting as myositis triggered by carboplatin plus paclitaxel and related literature review.",
"title_normalized": "radiation recall phenomenon presenting as myositis triggered by carboplatin plus paclitaxel and related literature review"
} | [
{
"companynumb": "KP-CIPLA LTD.-2015KP01308",
"fulfillexpeditecriteria": "1",
"occurcountry": "KP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Ramucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting.\n\n\n\nTo compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer.\n\n\n\nThis phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018.\n\n\n\nPatients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m2, on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m2, on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle).\n\n\n\nThe primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events.\n\n\n\nIn total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]).\n\n\n\nIn this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified.\n\n\n\nClinicalTrials.gov identifier: NCT02539225.",
"affiliations": "Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.;Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, South Korea.;Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.;Osaka University Graduate School of Medicine, Osaka, Japan.;The Cancer Institute Hospital of the Japanese Foundation of Cancer Research, Tokyo, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Keio University School of Medicine, Tokyo, Japan.;Chiba Cancer Center, Chiba, Japan.;Graduate School of Medicine, Gifu University, Gifu, Japan.;Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Division of Hematology and Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan.;Eli Lilly Japan KK, Kobe, Japan.;Eli Lilly Japan KK, Kobe, Japan.;Eli Lilly Japan KK, Kobe, Japan.;Keio University School of Medicine, Tokyo, Japan.",
"authors": "Yoshikawa|Takaki|T|;Muro|Kei|K|;Shitara|Kohei|K|;Oh|Do-Youn|DY|;Kang|Yoon-Koo|YK|;Chung|Hyun Cheol|HC|;Kudo|Toshihiro|T|;Chin|Keisho|K|;Kadowaki|Shigenori|S|;Hamamoto|Yasuo|Y|;Hironaka|Shuichi|S|;Yoshida|Kazuhiro|K|;Yen|Chia-Jui|CJ|;Omuro|Yasushi|Y|;Bai|Li-Yuan|LY|;Maeda|Kaijiro|K|;Ozeki|Akichika|A|;Yoshikawa|Reigetsu|R|;Kitagawa|Yuko|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000077150:Oxaliplatin; C543333:ramucirumab; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1001/jamanetworkopen.2019.8243",
"fulltext": "\n==== Front\nJAMA Netw Open\nJAMA Netw Open\nJAMA Netw Open\nJAMA Network Open\n2574-3805\nAmerican Medical Association\n\n10.1001/jamanetworkopen.2019.8243\nzoi190329\nResearch\nOriginal Investigation\nOnline Only\nGastroenterology and Hepatology\nEffect of First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab on Advanced Gastric Cancer in East Asia\nThe Phase 2 RAINSTORM Randomized Clinical Trial\nS-1 Plus Oxaliplatin With vs Without Ramucirumab in Advanced Gastric Cancer\nS-1 Plus Oxaliplatin With vs Without Ramucirumab in Advanced Gastric Cancer\nYoshikawa Takaki MD PhD 12\nMuro Kei MD 3\nShitara Kohei MD PhD 4\nOh Do-Youn MD PhD 5\nKang Yoon-Koo MD PhD 6\nChung Hyun Cheol MD PhD 7\nKudo Toshihiro MD PhD 89\nChin Keisho MD 10\nKadowaki Shigenori MD PhD 3\nHamamoto Yasuo MD PhD 11\nHironaka Shuichi MD PhD 1213\nYoshida Kazuhiro MD PhD 14\nYen Chia-Jui MD PhD 15\nOmuro Yasushi MD 16\nBai Li-Yuan MD 17\nMaeda Kaijiro MPharm 18\nOzeki Akichika PhD 18\nYoshikawa Reigetsu MD PhD 18\nKitagawa Yuko MD PhD 11\n1 Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan\n2 currently affiliated with Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan\n3 Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan\n4 Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan\n5 Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea\n6 Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, South Korea\n7 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea\n8 Osaka University Graduate School of Medicine, Osaka, Japan\n9 currently affiliated with Osaka International Cancer Institute, Osaka, Japan\n10 The Cancer Institute Hospital of the Japanese Foundation of Cancer Research, Tokyo, Japan\n11 Keio University School of Medicine, Tokyo, Japan\n12 Chiba Cancer Center, Chiba, Japan\n13 currently affiliated with Oita University Faculty of Medicine, Oita, Japan\n14 Graduate School of Medicine, Gifu University, Gifu, Japan\n15 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan\n16 Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan\n17 Division of Hematology and Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan\n18 Eli Lilly Japan KK, Kobe, Japan\nArticle Information\n\nAccepted for Publication: June 8, 2019.\n\nPublished: August 2, 2019. doi:10.1001/jamanetworkopen.2019.8243\n\nOpen Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2019 Yoshikawa T et al. JAMA Network Open.\n\nCorresponding Author: Takaki Yoshikawa, MD, PhD, Department of Gastric Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, Japan (tayoshik@ncc.go.jp).\nAuthor Contributions: Dr T. Yoshikawa had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nConcept and design: Muro, Shitara, Hamamoto, Yoshida, Maeda, R. Yoshikawa, Kitagawa.\n\nAcquisition, analysis, or interpretation of data: T. Yoshikawa, Muro, Shitara, Oh, Kang, Chung, Kudo, Chin, Kadowaki, Hamamoto, Hironaka, Yoshida, Yen, Omuro, Bai, Maeda, Ozeki, R. Yoshikawa.\n\nDrafting of the manuscript: Oh, Chin, Kadowaki, Hamamoto, Hironaka, Yoshida, R. Yoshikawa, Kitagawa.\n\nCritical revision of the manuscript for important intellectual content: T. Yoshikawa, Muro, Shitara, Oh, Kang, Chung, Kudo, Chin, Kadowaki, Hamamoto, Hironaka, Yoshida, Yen, Omuro, Bai, Maeda, Ozeki, R. Yoshikawa.\n\nStatistical analysis: Oh, Ozeki.\n\nObtained funding: Yen.\n\nAdministrative, technical, or material support: Muro, Kang, Chung, Chin, Hamamoto, Bai, Maeda, R. Yoshikawa.\n\nSupervision: T. Yoshikawa, Oh, Chung, Yoshida, Maeda, R. Yoshikawa, Kitagawa.\n\nConflict of Interest Disclosures: Dr T. Yoshikawa reported honoraria from Eli Lilly, Abbott Nutrition, Ajinomoto, Chugai Pharmaceutical, Daiichi Sankyo, Johnson & Johnson, Medtronic, Nippon Kayaku, Olympus, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha; a consulting/advisory role for Chugai Pharmaceutical, MSD Oncology, and Novartis; research funding from Chugai Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha; and personal fees from Taiho, Ono, BMS, MSD, Chugai Pharmaceutical, Daiichi Sankyo, Nippon Kayaku, TERUMO, Covidien Japan, and Olympus as well as grants and personal fees from Lilly outside of the submitted work. Dr Muro reported honoraria from Eli Lilly, Chugai Pharmaceutical, Merck Serono, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha; research funding from Daiichi Sankyo, Gilead Sciences, Kyowa Hakko Kirin, MSD, Ono Pharmaceutical, and Shionogi; grants and personal fees from Eli Lilly during the conduct of the study; grants from Gilead Sciences, Merck Serono, MSD, Daiichi Sankyo, Shionogi, Pfizer, Kyowa Hakko Kirin; personal fees from Chugai Pharmaceutical, Takeda, Taiho, Bayer, and Bristol-Myers Squibb outside of the submitted work; and grants and personal fees from Sanofi and Ono. Dr Shitara reported honoraria from AbbVie, Novartis, and Yakult Honsha; a consulting/advisory role for Eli Lilly, Astellas Pharma, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer, and Takeda Pharmaceutical; research funding from Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; grants and personal fees from Astellas Pharma, Lilly, Ono Pharmaceutical, and MSD; personal fees from Bristol-Myers Squibb, Takeda, Pfizer, Novartis, AbbVie, and Yakult Honsha; and grants from Dainippon Sumitomo Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, and Medi Science outside of the submitted work. Dr Oh reported a consulting/advisory role with AstraZeneca, Baxalta, and Merck and research funding from Array BioPharma, AstraZeneca, and Threshold Pharmaceuticals. Dr Kang reported a consulting/advisory role with Eli Lilly/ImClone, Bristol-Myers Squibb, DAE HWA Pharmaceutical, Merck Serono, Ono Pharmaceutical, Roche/Genetech, and Taiho Pharmaceutical; research funding from DAE HWA Pharmaceutical and LSK Biopharma; nonfinancial support from Eli Lilly; personal fees from Taiho, Ono, BMS, Blueprint, Daehwa, LSK Biopharma, and Merck Serono outside of the submitted work; and grants from Novartis. Dr Chung reported a consulting/advisory role with Eli Lilly, Bristol-Myers Squibb, Celltrion Pharma, Merck, MSD, Quintiles, and Taiho Pharmaceutical; participation in speakers’ bureaus for Eli Lilly, Foundation Medicine, and Merck Serono; research funding from Eli Lilly, Bristol-Myers Squibb, GlaxoSmithKline, Merck Serono, MSD, and Taiho Pharmaceutical; and grants from Eli Lilly, MSD, Merck-Serono, BMS-ONO, Taiho, and GlaxoSmithKline outside of the submitted work. Dr Kudo reported honoraria from Eli Lilly, Bayer, Chugai Pharmaceutical, Merck Serono, Taiho Pharmaceutical, and Takeda Pharmaceutical; research funding from Eli Lilly, Bayer Yakuhin, Chugai Pharmaceutical, Ono Pharmaceutical, and Yakult Honsha; and grants from Yakult Honsha, Chugai Pharmaceutical, and Ono Pharmaceutical outside of the submitted work. Dr Chin reported research funding from Eli Lilly, AstraZeneca, MDS, Ono Pharmaceutical, Shionogi, and Taiho Pharmaceutical. Dr Kadowaki reported honoraria from Eli Lilly, Bayer, Bristol-Myers Squibb, Chugai Pharmaceutical, Ono Pharmaceutical, and Yakult Honsha; research funding from Eli Lilly Japan KK, Boehringer Ingelheim, Bristol-Myers Squibb, Ono Pharmaceutical, and Taiho Pharmaceutical; grants and personal fees from Taiho Pharmaceutical, Ono Pharmaceutical, and Bristol-Myers Squibb; and personal fees from Bayer, Yakult Honsha, and Chugai Pharmaceutical outside of the submitted work. Dr Hamamoto reported honoraria from Eli Lilly, Bristol-Myers Squibb KK, Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha during the conduct of the study. Dr Hironaka reported honoraria from Eli Lilly, Bristol-Myers Squibb KK, Chugai Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha and personal fees from Eli Lilly, Taiho Pharmaceutical, and Yakult Honsha during the conduct of the study. Dr Yoshida reported honoraria from Eli Lilly Japan KK, Bayer Yakuhin, Bristol-Myers Squibb KK, Chugai Pharmaceutical, Covidien, Daiichi Sankyo, Denka, EA Pharma, Eisai, Johnson & Johnson, Merck Serono, MSD KK, Nippon Kayaku, Olympus, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, Terumo Pharmaceutical, and Yakult Honsha; research funding from Eli Lilly, Abbott Laboratories, Asahi Kasei Pharma, Astellas Pharma, Chugai Pharmaceutical, Covidien, Daiichi Sankyo, Eisai, Johnson & Johnson, KCI Pharma, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, Toyama Chemical, Tsumura, and Yakult Honsha; travel grants from Eli Lilly Japan KK, Bayer Yakuhin, Bristol-Myers Squibb KK, Chugai Pharmaceutical, Covidien, Daiichi Sankyo, Denka, EA Pharma, Eisai, Johnson & Johnson, Merck Serono, MSD KK, Nippon Kayaku, Olympus, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, Terumo Pharmaceutical, and Yakult Honsha; grants and personal fees from Eli Lilly during the conduct of the study; grants and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, Yakult Honsha, MSD, Daiichi Sankyo, Ono Pharmaceutical, Merck Serono, Johnson & Johnson, Covidien, Eisai, Otsuka Pharmaceutical, Sanofi, Nippon Kayaku, Asahi Kasei, and Tsumura; grants from Kyowa Hakko Kirin, Astellas, Toyama Chemical, KCI, Abbott Japan, and Toray Medical; and personal fees from EA Pharmaceutical, Bayer Yakuhin, Olympus, Terumo, Bristol Myers Japan, Denka, Teijin, SBI Pharmaceutical, Intuitive Surgical, Novartis, and Pfizer outside of the submitted work. Dr Omuro reported research funding from Eli Lilly, MSD, and Ono Pharmaceutical; grants from Eli Lilly during the conduct of the study; and grants from Astellas Pharma, MSD, Daiichisankyo, and Ono Pharmaceutical outside of the submitted work. Dr Bai reported a consulting/advisory role with Eli Lilly and MSD. Mr Maeda reported employment at and stock ownership in Eli Lilly Japan KK. Dr Ozeki reported employment at Eli Lilly Japan KK as well as research funding and travel, accommodations, and expenses from Eli Lilly Japan KK. Dr R. Yoshikawa reported employment at and stock ownership in Eli Lilly Japan KK during the conduct of the study. Dr Kitagawa reported honoraria from Asahi Kasei Pharma, Chugai Pharmaceutical, Ethicon, Nippon Kayaku, Olympus, Ono Pharmaceutical, and Taiho Pharmaceutical; research funding from Eli Lilly, Ajinomoto, Asahi Kasei Pharma, Astellas Pharma, Boehringer Ingelheim, Chugai Pharmaceutical, CSL Behring, Daiichi Sankyo, Dainippon Sumitomo Pharma, EA Pharma, GlaxoSmithKline, Kaken Pharmaceutical, Kowa Pharmaceutical, Kureha, Kyowa Hakko Kirin, Medicon, Medtronic, Merck Serono, Nippon Kayaku, Novartis, Otsuka Pharmaceutical, Pfizer, Sanofi, Shionogi, Taiho Pharmaceutical, Taisho Toyama Pharma, Takeda Pharmaceutical, Teijin Pharma, Tsumura, and Yakult Honsha; and grants and personal fees from Taiho Pharmaceutical, Yakult Honsha, and Eli Lilly during the conduct of the study. No other disclosures were reported.\n\nFunding/Support: This study was funded by Eli Lilly Japan KK, the manufacturer/licensee of ramucirumab.\n\nRole of the Funder/Sponsor: Eli Lilly was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.\n\nData Sharing Statement: See Supplement 3.\n\nAdditional Contributions: Medical writing assistance was provided by Justine Southby, PhD, CMPP, and Tania Dickson, PhD, CMPP, both of ProScribe – Envision Pharma Group, and was funded by Eli Lilly Japan KK. ProScribe’s services complied with international guidelines for Good Publication Practice. We thank all of the study participants.\n\n2 8 2019\n8 2019\n2 8 2019\n2 8 e19824320 3 2019\n8 6 2019\nCopyright 2019 Yoshikawa T et al. JAMA Network Open.\nThis is an open access article distributed under the terms of the CC-BY-NC-ND License.\njamanetwopen-2-e198243.pdf\n\nKey Points\n\nQuestion\n\nDoes the addition of ramucirumab to S-1 and oxaliplatin improve progression-free survival in patients with metastatic gastric or gastroesophageal junction adenocarcinoma in the first-line setting?\n\nFindings\n\nIn this phase 2 randomized clinical trial of 189 East Asian patients with metastatic gastric or gastroesophageal junction adenocarcinoma, median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 vs 6.74 months).\n\nMeaning\n\nAddition of ramucirumab to first-line S-1 and oxaliplatin treatment did not improve progression-free survival, suggesting that the efficacy of ramucirumab in the second-line setting may not be applicable to the first-line setting when combined with fluoropyrimidine and platinum chemotherapy.\n\nThis randomized clinical trial investigates the efficacy and safety of adding ramucirumab to first-line therapy with S-1 and oxaliplatin among East Asian adults with advanced gastric cancer.\n\nImportance\n\nRamucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting.\n\nObjective\n\nTo compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer.\n\nDesign, Setting, and Participants\n\nThis phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018.\n\nInterventions\n\nPatients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m2, on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m2, on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle).\n\nMain Outcomes and Measures\n\nThe primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events.\n\nResults\n\nIn total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]).\n\nConclusions and Relevance\n\nIn this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified.\n\nTrial Registration\n\nClinicalTrials.gov identifier: NCT02539225\n==== Body\nIntroduction\n\nGlobally, gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer death.1 More than half of the cases in the world occur in East Asia.2 Chemotherapy is the main treatment option for patients with advanced gastric or gastroesophageal junction adenocarcinoma.3,4 The current standard of care in the first-line setting is combination chemotherapy with a fluoropyrimidine (eg, fluorouracil, S-1 [tegafur-gimeracil-oteracil potassium], capecitabine) plus a platinum agent (eg, cisplatin, oxaliplatin).3,4 Among these chemotherapy regimens, S-1 plus oxaliplatin is frequently used in East Asia, according to the phase 3 G-SOX study.5 However, as first-line chemotherapy is associated with median overall survival (OS) times in the range of 6 to 13 months in clinical trials,4 other treatment options with improved clinical outcomes are required for patients with advanced gastric or gastroesophageal junction adenocarcinoma.\n\nRamucirumab is a human IgG 1 monoclonal antibody against vascular endothelial growth factor (VEGF) receptor 2 that blocks the binding of VEGF ligands, thereby preventing receptor activation and inhibiting angiogenesis.6 Ramucirumab has shown promising activity in the treatment of advanced gastric or gastroesophageal junction adenocarcinoma in the second-line setting as monotherapy or in combination with paclitaxel.7,8 In particular, paclitaxel plus ramucirumab has become the standard second-line chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma in East Asia, where paclitaxel monotherapy was a community standard.4 However, the role of an antiangiogenic agent when added to chemotherapy in the first-line setting remains unclear,9,10,11 including the addition of ramucirumab to the global standard of care of fluorouracil-cisplatin or capecitabine-cisplatin or the East Asian standard of care of S-1 plus oxaliplatin. Furthermore, investigation of the continuous use of ramucirumab from the first-line setting to the second-line setting would be of interest, given the finding that the continued use beyond disease progression of bevacizumab (another angiogenesis inhibitor) while switching chemotherapy is beneficial in patients with metastatic colorectal cancer.12\n\nTwo clinical trials have examined these applications of ramucirumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma: (1) the global, randomized, phase 3 RAINFALL (Ramucirumab With Cisplatin and Fluoropyrimidine as First-line Therapy in Patients With Metastatic Gastric or Junctional Adenocarcinoma) study,13 in which the addition of ramucirumab to fluorouracil-cisplatin or capecitabine-cisplatin was evaluated in the first-line setting; and (2) the East Asian, randomized, phase 2 RAINSTORM (First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer) study described here, in which the addition of ramucirumab to S-1 plus oxaliplatin in the first-line setting (part A) and paclitaxel plus ramucirumab treatment in the second-line setting (part B) were evaluated. Given that potential ethnicity-associated differences in efficacy have been observed in the AVAGAST (Avastin in Gastric Cancer)9 and RAINBOW (Ramucirumab Plus Paclitaxel vs Placebo Plus Paclitaxel in Patients With Previously Treated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma)8 studies and S-1 plus oxaliplatin is becoming a mainstay of first-line treatment in Japan, we set up the RAINSTORM study in parallel with the RAINFALL study.\n\nThe primary objective of the RAINSTORM study was to evaluate progression-free survival (PFS). The dose of ramucirumab in part A of this study (8 mg/kg on days 1 and 8 of a 21-day cycle) differed from the approved dose (8 mg/kg every 2 weeks).14 This 3-week schedule was chosen to achieve a higher ramucirumab exposure, on the basis of modeling kinetics that suggested an exposure-response relationship15 and the phase 1b JVCX (Phase 1b Study of Ramucirumab in Combination With Fluoropyrimidines and Platinum-Based Agents in Japanese Patients With Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma) study, conducted in chemotherapy-naive Japanese patients with metastatic gastric or gastroesophageal junction adenocarcinoma, which showed that higher trough levels of ramucirumab were achieved with this schedule without notable increases in toxic effects.16\n\nMethods\n\nStudy Design\n\nThis trial was a randomized, double-blind, phase 2 study of S-1 plus oxaliplatin with or without ramucirumab among East Asian patients with metastatic gastric or gastroesophageal junction adenocarcinoma. It was conducted between October 12, 2015, and April 11, 2018, at a total of 36 sites, with 25 sites in Japan, 6 in South Korea, and 5 in Taiwan. The analysis was performed from November 27, 2017, to June 4, 2018. The trial protocol (Supplement 1) was approved by each site’s ethics review board. All participants provided written informed consent before undergoing any protocol-specific evaluations. The study was conducted in accordance with the Declaration of Helsinki,17 Good Clinical Practice guidelines, and applicable local regulations and followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.\n\nStudy Population\n\nPatients with histologically or cytologically confirmed metastatic gastric or gastroesophageal junction adenocarcinoma who had not received first-line systemic therapy for metastatic gastric or gastroesophageal junction adenocarcinoma (previous neoadjuvant or adjuvant therapy was permitted) were eligible for this study (Figure 1). Patients with esophageal cancer were not eligible. The main inclusion criteria were age 20 years or older; measurable disease or nonmeasurable but evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.118; Eastern Cooperative Oncology Group Performance Status score of 0 or 1; and adequate hepatic, kidney, hematologic, and coagulation function.\n\nFigure 1. CONSORT Flow Diagram\n\nAt the time of data cutoff, 15 patients were still receiving treatment in part A, 2 patients were in the follow-up period after part A, and 17 patients were still receiving treatment in part B. The 2 patients in the ramucirumab plus S-1 and oxaliplatin (RAM+SOX) arm and the 1 patient in the placebo plus S-1 and oxaliplatin (PBO+SOX) arm who discontinued part A for the reason of death are not included in the numbers of patients after part A. In part B, all patients were to receive second-line paclitaxel plus ramucirumab (PTX+RAM) treatment.\n\nThe main exclusion criteria were ERBB2-positive status; significant bleeding disorders, vasculitis, or a significant bleeding episode from the gastrointestinal tract within 12 weeks before randomization; any arterial thromboembolic event within 24 weeks before randomization; and history of gastrointestinal disorders, including perforation and/or fistulae within 24 weeks before randomization, inflammatory bowel disease requiring medical intervention 48 weeks or less before randomization, acute or subacute bowel obstruction, or a history of chronic diarrhea.\n\nRandomization and Masking\n\nPatients were randomized 1 to 1 through an interactive web response system (IWRS) to receive either ramucirumab plus S-1 and oxaliplatin or placebo plus S-1 and oxaliplatin. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status score (0 or 1), region (Japan or other [South Korea or Taiwan]), and disease measurability (measurable or nonmeasurable), with a block size of 4. The treatment arm information for the trial was generated on the basis of a seed number, IWRS chunk size, number of strata, and block size and was then passed on to the IWRS. The IWRS team generated the random allocation sequence, and the study sites were responsible for enrollment and randomization. Only the IWRS team and product delivery team had access to the unblinded information. The investigators, patients, and sponsor personnel remained blinded during part A until database lock for the primary end point analysis.\n\nTreatment Protocol\n\nPart A of the study compared first-line S-1 plus oxaliplatin with and without ramucirumab (eFigure 1 in Supplement 2). In part B, all eligible patients received second-line paclitaxel plus ramucirumab to avoid crossover administration of ramucirumab (ie, first-line ramucirumab to second-line placebo or first-line placebo to second-line ramucirumab).\n\nPart A\n\nPatients received intravenous ramucirumab, 8 mg/kg, or placebo on days 1 and 8 of a 21-day cycle, in combination with oral S-1, 80 to 120 mg, twice daily on days 1 to 14 and intravenous oxaliplatin 100 mg/m2 on day 1. Ramucirumab or placebo and S-1 plus oxaliplatin were continued until disease progression, unacceptable toxic effects developed, or any other discontinuation criteria were met.\n\nPart B\n\nEnrolled patients in both arms of part A who progressed and were eligible for second-line therapy were considered for part B. After the completion of assessments during the pretreatment period of part B, eligible patients received intravenous ramucirumab, 8 mg/kg, on days 1 and 15 plus paclitaxel, 80 mg/m2, on days 1, 8, and 15 every 28 days. Patients who did not meet the initiation criteria for part B (eFigure 1 in Supplement 2) within 12 weeks from the decision to discontinue study treatment in part A did not continue participation in the study.\n\nEfficacy\n\nThe primary end point was PFS (first disease progression) in part A, measured from the date of randomization to the date of radiographic documentation of progression (as assessed by an investigator using the RECIST, version 1.1) or death due to any cause, whichever was earlier. Progression-free survival was censored (1) at the date of the most recent adequate radiologic assessment or the date of randomization (whichever was later) for patients without disease progression or who had not died; (2) at the date of randomization for patients who had missing baseline radiologic tumor assessment and for patients who had missing adequate postbaseline radiologic tumor assessment; (3) at the date of adequate radiologic assessment on or before new anticancer therapy or the date of randomization (whichever was later) for patients receiving new anticancer treatment, including the second-line therapy (paclitaxel plus ramucirumab); and (4) at the date of the most recent adequate radiologic assessment before the missing assessment or the date of randomization (whichever was later) for patients who progressed or for whom death was documented immediately after 2 or more consecutive missing scan intervals after the most recent adequate radiologic tumor assessment or randomization (whichever was later).\n\nSecondary end points included second disease progression (PFS2), OS, overall response rate, and disease control rate. The PFS2 was measured from the date of randomization to the date of radiographic documentation of progression after the start of second-line therapy (paclitaxel plus ramucirumab) or death, using the tumor assessment before starting second-line therapy as the baseline assessment. If second-line therapy was not started, OS was substituted for PFS2. Overall survival was measured from the date of randomization to the date of death from any cause. Overall response rate was the proportion of randomized patients with measurable disease who achieved a best overall response of complete response or partial response in part A according to RECIST, version 1.1. Disease control rate was the proportion of randomized patients with measurable disease who achieved a best overall response of complete response, partial response, or stable disease in part A according to RECIST, version 1.1. Best overall response was the best response recorded from randomization until disease progression.\n\nPharmacokinetics and Safety\n\nIn part A, samples for determining ramucirumab serum trough concentration levels were scheduled before the ramucirumab dose on day 8 of cycle 1 and on day 1 of cycles 2, 3, 5, and 9. Adverse events (AEs) in part A and part B were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.\n\nStatistical Analysis\n\nThe target sample size was 190 patients and 136 PFS events for a power of 80% with a 2-sided significance level of .20, assuming a PFS hazard ratio (HR) of 0.67. The full analysis set for efficacy (based on randomized arm; baseline and efficacy analyses) and the safety population (based on actual arm; safety and exposure analyses) were defined as all randomized patients who received any study medication; in practice, the 2 populations were the same. The PFS was analyzed with the stratified log-rank test, and the PFS HR was estimated using the stratified Cox proportional hazards regression model; both were stratified by the randomization strata. P values were based on stratified log-rank tests. The same statistical methods were used for the analysis of PFS2 and OS. The forest plots (eFigure 2 in Supplement 2) were based on an unstratified Cox proportional hazards regression model for each subgroup. Odds ratios (ORs) for the overall response rate and disease control rate and their P values were based on logistic regression and the Cochran-Mantel-Haenszel test stratified by the randomization strata.\n\nTests for treatment effect were conducted at a 2-sided significance level of .20. Treatment-emergent AEs (TEAEs) were any untoward or worsened medical occurrence any time after baseline that did not necessarily have a causal relationship with the treatment. The AEs of special interest included arterial and venous thromboembolic events, bleeding or hemorrhage, fistula, gastrointestinal hemorrhage events, gastrointestinal perforation, hypertension, infusion-related reaction, proteinuria, and renal failure.\n\nAll results were from the primary database lock (November 27, 2017), except for the PFS2 and OS results, which were from the second database lock (June 4, 2018). Analyses of the full analysis set and safety population were performed using SAS, version 9.4 (SAS Institute).\n\nResults\n\nPatient Disposition\n\nIn total, 191 patients were randomized, of whom 2 did not receive treatment, resulting in 189 patients included in the full analysis set and the safety population in part A. Ninety-six patients were randomized to receive ramucirumab plus S-1 and oxaliplatin, and 93 patients were randomized to receive placebo plus S-1 and oxaliplatin (Figure 1). Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Baseline characteristics were generally similar between the 2 arms in part A (Table 1).\n\nTable 1. Baseline Patient Characteristics in Part A\n\nVariable\tNo. (%)\t\nRAM+SOX Arm (n = 96)\tPBO+SOX Arm (n = 93)\t\nMale\t57 (59.4)\t64 (68.8)\t\nAge, median (range), y\t61.0 (30-82)\t63.0 (26-84)\t\n<65\t57 (59.4)\t53 (57.0)\t\n≥65\t39 (40.6)\t40 (43.0)\t\nRegion\t\t\t\nJapan\t65 (67.7)\t64 (68.8)\t\nKorea\t20 (20.8)\t20 (21.5)\t\nTaiwan\t11 (11.5)\t9 (9.7)\t\nECOG PS\t\t\t\n0\t64 (66.7)\t62 (66.7)\t\n1\t32 (33.3)\t31 (33.3)\t\nPrimary tumor location\t\t\t\nGastric\t91 (94.8)\t88 (94.6)\t\nGastroesophageal junction\t5 (5.2)\t5 (5.4)\t\nHistologic structure\t\t\t\nIntestinal\t17 (17.7)\t22 (23.7)\t\nDiffuse\t60 (62.5)\t53 (57.0)\t\nMixed/unknown\t19 (19.8)\t18 (19.4)\t\nPrevious gastrectomy\t29 (30.2)\t25 (26.9)\t\nPrevious neoadjuvant/adjuvant therapy\t22 (22.9)\t13 (14.0)\t\nMeasurable disease\t55 (57.3)\t54 (58.1)\t\nNo. of metastatic sites\t\t\t\n≤2\t74 (77.1)\t79 (84.9)\t\n≥3\t22 (22.9)\t14 (15.1)\t\nPeritoneal metastases\t63 (65.6)\t56 (60.2)\t\nLiver metastases\t20 (20.8)\t25 (26.9)\t\nAscites\t37 (38.5)\t33 (35.5)\t\nAbbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; PBO+SOX, placebo plus S-1 and oxaliplatin; RAM+SOX, ramucirumab plus S-1 and oxaliplatin.\n\nMost patients discontinued treatment in part A because of progressive disease (ramucirumab plus S-1 and oxaliplatin arm: 71 [74.0%] of 96 patients; placebo plus S-1 and oxaliplatin arm: 71 [76.3%] of 93 patients) (Figure 1). More patients discontinued treatment in part A because of an AE in the ramucirumab plus S-1 and oxaliplatin arm (11 [11.5%] of 96 patients) compared with the placebo plus S-1 and oxaliplatin arm (3 [3.2%] of 93 patients) (Figure 1). Overall, 118 patients (62.4%) received second-line paclitaxel plus ramucirumab treatment in part B (57 patients in the ramucirumab plus S-1 and oxaliplatin arm and 61 patients in the placebo plus S-1 and oxaliplatin arm) (Figure 1). (Patients in part B are referred to according to their treatment arm in part A: that is, ramucirumab plus S-1 and oxaliplatin or placebo plus S-1 and oxaliplatin.)\n\nEfficacy\n\nIn part A, PFS was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (Figure 2A). Median PFS was 6.34 (80% CI, 5.65-6.93) months in the ramucirumab plus S-1 and oxaliplatin arm and 6.74 (80% CI, 5.75-7.13) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.07; 80% CI, 0.86-1.33; P = .70). Overall survival was similar between the 2 arms (Figure 2B). Median OS was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). For PFS and OS, no notable improvements were observed in general in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm across prespecified subgroups (eFigure 2 in Supplement 2).\n\nFigure 2. Progression-Free Survival (PFS), Overall Survival (OS), and Second Disease Progression (PFS2) in Patients Receiving Ramucirumab Plus S-1 and Oxaliplatin (RAM+SOX) or Placebo Plus S-1 and Oxaliplatin (PBO+SOX) in Part A\n\nStratified log-rank test was used to analyze PFS, OS, and PFS2. Hazard ratios (HRs) were estimated with a stratified Cox proportional hazards regression model, and both were stratified by Eastern Cooperative Oncology Group Performance Status, region, and disease measurability. Median PFS was 6.34 (80% CI, 5.65-6.93) months in the RAM+SOX arm and 6.74 (80% CI, 5.75-7.13) months in the PBO+SOX arm (HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median OS was 14.65 (80% CI, 12.39-15.67) months in the RAM+SOX arm and 14.26 (80% CI, 13.83-17.31) months in the PBO+SOX arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). Median PFS2 was 10.94 (80% CI, 9.63-12.52) months in the RAM+SOX arm and 11.99 (80% CI, 9.82-13.83) months in the PBO+SOX arm (HR, 1.11; 80% CI, 0.89-1.39; P = .55).\n\nThe overall response rate was 58% in the ramucirumab plus S-1 and oxaliplatin arm and 50% in the placebo plus S-1 and oxaliplatin arm (OR, 1.37; 80% CI, 0.84-2.24; P = .40). The disease control rate was 91% in the ramucirumab plus S-1 and oxaliplatin arm and 87% in the placebo plus S-1 and oxaliplatin arm (OR, 1.53; 80% CI, 0.68-3.43; P = .50). One patient (1.0%) in the ramucirumab plus S-1 and oxaliplatin arm and 3 patients (3.2%) in the placebo plus S-1 and oxaliplatin arm had a complete response.\n\nThe PFS2 was similar between the 2 arms (Figure 2C). Median PFS2 was 10.94 (80% CI, 9.63-12.52) months in the ramucirumab plus S-1 and oxaliplatin arm and 11.99 (80% CI, 9.82-13.83) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.39; P = .55).\n\nExposure\n\nIn part A, the median (range) relative dose intensity of ramucirumab was 91% (30%-107%) and the median (range) duration of ramucirumab treatment was 22.6 (2.0-99.4) weeks in the ramucirumab plus S-1 and oxaliplatin arm (Table 2). The median (range) relative dose intensities of S-1 (75% [15%-100%] vs 85% [34%-102%]) and oxaliplatin (80% [35%-111%] vs 86% [30%-106%]) were numerically lower in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (Table 2). In addition, the median (range) durations of treatment of S-1 (21.1 [1.9-99.1] weeks vs 25.1 [1.6-102.1] weeks) and oxaliplatin (19.9 [3.0-90.0] weeks vs 22.3 [3.0-104.0] weeks) were numerically shorter in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (Table 2). In part B, the relative dose intensities of ramucirumab were similarly high in the ramucirumab plus S-1 and oxaliplatin and placebo plus S-1 and oxaliplatin arms (99% vs 100%) (eTable 1 in Supplement 2).\n\nTable 2. Dose Intensity, Treatment Duration, and Cumulative Dose of Study Drugs in Part A\n\nStudy Drug\tVariable\tMedian (Range)\t\nRAM+SOX Arm (n = 96)\tPBO+SOX Arm (n = 93)\t\nRAM/PBO\tRelative dose intensity, %\t91 (30-107)\t94 (52-107)\t\nDuration, wk\t22.6 (2.0-99.4)\t24.0 (2.0-103.0)\t\nCumulative dose per body weight, mg/kg\t99.3 (3.2-490.4)\t116.0 (8.0-504.8)\t\nS-1\tRelative dose intensity, %\t75 (15-100)\t85 (34-102)\t\nDuration, wk\t21.1 (1.9-99.1)\t25.1 (1.6-102.1)\t\nCumulative dose, mg\t8120.0 (600.0-44 290)\t10 080.0 (420.0-52 140)\t\nOxaliplatin\tRelative dose intensity, %\t80 (35-111)\t86 (30-106)\t\nDuration, wk\t19.9 (3.0-90.0)\t22.3 (3.0-104.0)\t\nCumulative dose per body surface area, mg/m2\t498.2 (91.9-1905.8)\t583.1 (99.5-3239.8)\t\nAbbreviations: PBO, placebo; PBO+SOX, placebo plus S-1 and oxaliplatin; RAM, ramucirumab; RAM+SOX, ramucirumab plus S-1 and oxaliplatin.\n\nPharmacokinetics and Safety\n\nThe geometric mean trough concentration levels of ramucirumab were as follows: 42.6 μg/mL on day 8 of cycle 1, 41.4 μg/mL on day 1 of cycle 2, 59.4 μg/mL on day 1 of cycle 3, 83.6 μg/mL on day 1 of cycle 5, and 94.6 μg/mL on day 1 of cycle 9 (eTable 2 in Supplement 2).\n\nNo new safety signals for ramucirumab were identified. In part A, the incidences of TEAEs (99% vs 100%) and treatment-related AEs (99% vs 99%) were similar in the ramucirumab plus S-1 and oxaliplatin and placebo plus S-1 and oxaliplatin arms. Serious AEs were reported by 28 patients (29.2%) in the ramucirumab plus S-1 and oxaliplatin arm and by 22 patients (23.7%) in the placebo plus S-1 and oxaliplatin arm. One treatment-related death occurred in the ramucirumab plus S-1 and oxaliplatin arm. The most frequently reported grade 3 or higher TEAEs in the ramucirumab plus S-1 and oxaliplatin arm were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]) (Table 3). The most frequently reported AEs of special interest in the ramucirumab plus S-1 and oxaliplatin arm were bleeding or hemorrhage events (36 patients [37.5%]), hypertension (28 patients [29.2%]), and proteinuria (24 patients [25.0%]) (Table 3).\n\nTable 3. Summary of Treatment-Emergent Adverse Events and Adverse Events of Special Interest in Part A\n\nGrade\tNo. (%)\t\nRAM+SOX Arm (n = 96)\tPBO+SOX Arm (n = 93)\t\nAll\tGrade ≥3\tAll\tGrade ≥3\t\nTEAEa\t\t\t\t\t\n≥1 TEAE\t95 (99.0)\t66 (68.8)\t93 (100.0)\t55 (59.1)\t\nDecreased neutrophil count\t48 (50.0)\t14 (14.6)\t32 (34.4)\t7 (7.5)\t\nHypertension\t28 (29.2)\t10 (10.4)\t12 (12.9)\t5 (5.4)\t\nAnemia\t24 (25.0)\t10 (10.4)\t22 (23.7)\t11 (11.8)\t\nDiarrhea\t50 (52.1)\t9 (9.4)\t28 (30.1)\t3 (3.2)\t\nDecreased appetite\t54 (56.3)\t7 (7.3)\t58 (62.4)\t6 (6.5)\t\nDecreased platelet count\t33 (34.4)\t6 (6.3)\t28 (30.1)\t3 (3.2)\t\nAbdominal pain\t18 (18.8)\t3 (3.1)\t24 (25.8)\t5 (5.4)\t\nAESIb\t\t\t\t\t\n≥1 AESI\t66 (68.8)\t25 (26.0)\t40 (43.0)\t12 (12.9)\t\nBleeding/hemorrhage events\t36 (37.5)\t6 (6.3)\t22 (23.7)\t3 (3.2)\t\nHypertension\t28 (29.2)\t10 (10.4)\t12 (12.9)\t5 (5.4)\t\nProteinuria\t24 (25.0)\t4 (4.2)\t14 (15.1)\t1 (1.1)\t\nGI hemorrhage events\t5 (5.2)\t3 (3.1)\t5 (5.4)\t1 (1.1)\t\nRenal failure\t5 (5.2)\t2 (2.1)\t2 (2.2)\t0\t\nGI perforation\t3 (3.1)\t3 (3.1)\t2 (2.2)\t1 (1.1)\t\nInfusion-related reaction\t2 (2.1)\t1 (1.0)\t3 (3.2)\t0\t\nArterial thromboembolic events\t1 (1.0)\t1 (1.0)\t0\t0\t\nFistula\t1 (1.0)\t0\t0\t0\t\nVenous thromboembolic events\t0\t0\t3 (3.2)\t2 (2.2)\t\nAbbreviations: AESI, adverse event of special interest; GI, gastrointestinal; PBO+SOX, placebo plus S-1 and oxaliplatin; RAM+SOX, ramucirumab plus S-1 and oxaliplatin; TEAE, treatment-emergent adverse event.\n\na Indicates TEAEs of grade 3 or higher occurring in at least 5% of patients in either arm.\n\nb Special interest category term.\n\nIn part B, in both arms, the most frequently reported grade 3 or higher TEAE was decreased neutrophil count, and the most frequently reported AE of special interest was bleeding or hemorrhage events (eTable 3 in Supplement 2).\n\nDiscussion\n\nIn this randomized phase 2 study (RAINSTORM), the addition of ramucirumab to first-line S-1 plus oxaliplatin treatment did not improve PFS, OS, or PFS2 in East Asian patients with metastatic gastric or gastroesophageal junction adenocarcinoma compared with S-1 plus oxaliplatin alone. Overall survival in both the ramucirumab plus S-1 and oxaliplatin and placebo plus S-1 and oxaliplatin arms was relatively longer compared with the OS found in the RAINFALL study,13 which is consistent with previous studies conducted in East Asia.9,19,20 Ramucirumab was associated with a manageable safety profile that was consistent with that reported in previous studies of ramucirumab.7,8,13\n\nTwo other studies11,13 could not show a clinical benefit of adding ramucirumab to first-line chemotherapy for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma. In the randomized phase 3 RAINFALL study, conducted in 645 patients with metastatic gastric or gastroesophageal junction adenocarcinoma, the addition of ramucirumab to first-line fluorouracil-cisplatin or capecitabine-cisplatin chemotherapy resulted in a statistically significant improvement in investigator-assessed PFS (median PFS, 5.7 vs 5.4 months for chemotherapy alone; HR, 0.75; 95% CI, 0.61-0.94).13 However, this improvement in PFS was not confirmed by central independent review of radiologic images (PFS HR, 0.961; 95% CI, 0.768-1.203).13 Moreover, the addition of ramucirumab to first-line chemotherapy did not improve OS in the RAINFALL study.13 In the randomized phase 2 JVBT (Ramucirumab Plus mFOLFOX as First-line Therapy in Patients With Advanced Esophageal, Gastroesophageal Junction, or Gastric Adenocarcinoma) study of first-line ramucirumab in 168 patients with advanced gastric cancer (including patients with esophageal adenocarcinoma), the addition of ramucirumab to mFOLFOX (oxaliplatin plus fluorouracil) did not improve PFS or OS (although in prespecified subgroup analyses, the PFS HR favored the ramucirumab arm in the gastric or gastroesophageal junction cancer subgroup but not in the esophageal cancer subgroup).11\n\nA similar lack of effect on OS in patients with advanced gastric cancer in the first-line setting was observed for other VEGF-targeting agents such as bevacizumab, a monoclonal antibody against VEGF-A.9,10 The chemotherapy backbone to the VEGF-targeting agent may be relevant to its activity. Paclitaxel is well known to show antiangiogenic activity21; therefore, its potential synergy with ramucirumab may have contributed to the improved outcomes observed in advanced gastric cancer in the second-line setting. Taken together, the RAINSTORM, RAINFALL,13 and JVBT11 studies, along with the bevacizumab studies,9,10 suggest that adding an antiangiogenic agent to first-line fluoropyrimidine and platinum chemotherapy does not improve survival in patients with advanced gastric cancer. Further consideration of developing ramucirumab as a combination therapy in the first-line setting includes adding immunotherapeutic interventions.\n\nA strength of this study was that its design incorporated a designated second-line treatment regimen, with the intention of having all patients receive second-line paclitaxel plus ramucirumab treatment. This study design might allow the assessment of the efficacy of continuous antiangiogenic therapy from first-line to second-line treatment. However, of the patients who received first-line treatment in part A, only approximately 60% of patients in both arms received second-line treatment with paclitaxel plus ramucirumab in part B. In total, 26 patients (16 in the ramucirumab plus S-1 and oxaliplatin arm and 10 in the placebo plus S-1 and oxaliplatin arm) received second-line treatment outside of part B because they did not meet the eligibility criteria for part B (4 patients received paclitaxel plus ramucirumab, 1 received ramucirumab monotherapy, and 4 received paclitaxel monotherapy). Furthermore, not all patients in part B received paclitaxel plus ramucirumab: 15 patients (13%) received either ramucirumab or paclitaxel monotherapy. Although the definition of PFS2 in this study took these factors into consideration, interpreting the efficacy of paclitaxel plus ramucirumab in part B of the study was difficult. However, the efficacy of second-line paclitaxel plus ramucirumab seemed to not be lessened because of first-line ramucirumab exposure.\n\nPharmacokinetic analysis showed that ramucirumab serum trough concentration levels in part A exceeded the biological target level (approximately 50 μg/mL16) after day 1 of cycle 3 and were generally consistent with those reported in the RAINFALL13 and JVCX16 studies, which also used a 3-week dose schedule. This schedule was chosen because higher levels of ramucirumab concentration have been associated with longer OS.15 However, factors other than the ramucirumab concentration level, such as the chemotherapy partner to the VEGF-targeting agent, appear to be more influential in prolonging survival in patients who receive ramucirumab with a chemotherapy basis.\n\nThe safety profile of ramucirumab in the current study was manageable and consistent with previously published studies of ramucirumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma.7,8,13 The study treatment was well tolerated. The incidences of neutropenia and thrombocytopenia in the RAINSTORM study were lower compared with the S-1 plus oxaliplatin arm of the G-SOX (S-1 Plus Oxaliplatin Compared With S-1 Plus Cisplatin as First-line Therapy for Advanced or Recurrent Gastric Cancer) study.5 In the RAINSTORM study, the incidence of neutropenia of any grade was 50% and of grade 3 or higher was 15% in the ramucirumab plus S-1 and oxaliplatin arm and was 34% for any grade and 8% for grade 3 or higher in the placebo plus S-1 and oxaliplatin arm, compared with 68.9% for any grade and 19.5% for grade 3 or higher in the S-1 plus oxaliplatin arm of the G-SOX study.5 The incidence of thrombocytopenia of any grade was 34% and of grade 3 or higher was 6% in the ramucirumab plus S-1 and oxaliplatin arm and was 30% for any grade and 3% for grade 3 or higher in the placebo plus S-1 and oxaliplatin arm, compared with 78.4% for any grade and 10.1% for grade 3 or higher in the S-1 plus oxaliplatin arm of the G-SOX study.5 The AEs reported in part B of the study, in which patients received second-line paclitaxel plus ramucirumab, were consistent with those reported in the RAINBOW study of second-line paclitaxel plus ramucirumab.8\n\nLimitations\n\nThis study has some limitations in addition to those discussed above. First, only approximately 60% of patients from part A received treatment in part B. Second, part B was not powered for the evaluation of PFS2.\n\nConclusions\n\nAddition of ramucirumab to first-line S-1 plus oxaliplatin treatment did not improve PFS or OS compared with S-1 plus oxaliplatin alone in this phase 2 randomized clinical trial conducted in East Asian patients with metastatic gastric or gastroesophageal junction adenocarcinoma. The safety profile of ramucirumab observed in this study was consistent with that observed in previous studies of ramucirumab, and no new safety signals were identified. Although ramucirumab has been established as a treatment for advanced gastric cancer in the second-line setting, the RAINSTORM study, in combination with the RAINFALL and JVBT studies, suggest that the efficacy of ramucirumab as a second-line treatment may not be applicable to first-line treatment in combination with fluoropyrimidine and platinum chemotherapy.\n\nSupplement 1. Trial Protocol\n\nClick here for additional data file.\n\nSupplement 2. eTable 1. Dose Intensity, Treatment Duration, and Cumulative Dose of Study Drugs During Part B\n\neTable 2. Summary of RAM Serum Trough Concentrations in Part A\n\neTable 3. Summary of Treatment-emergent Adverse Events and Adverse Events of Special Interest in Part B\n\neFigure 1. Study Design\n\neFigure 2. Forest Plots of PFS (A) and OS (B) by Clinical Characteristics\n\nClick here for additional data file.\n\nSupplement 3. Data Sharing Statement\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Bray F , Ferlay J , Soerjomataram I , Siegel RL , Torre LA , Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68 (6 ):-. doi:10.3322/caac.21492 30207593\n2 GLOBOCAN Cancer fact sheets: stomach cancer. https://gco.iarc.fr/today/data/factsheets/cancers/7-Stomach-fact-sheet.pdf. Published 2018. Accessed October 31, 2018.\n3 Ajani JA , D’Amico TA , Almhanna K , Gastric cancer, version 3.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14 (10 ):1286-1312. doi:10.6004/jnccn.2016.0137 27697982\n4 Japanese Gastric Cancer Association Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20 (1 ):1-19. doi:10.1007/s10120-016-0622-4 27342689\n5 Yamada Y , Higuchi K , Nishikawa K , Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015;26 (1 ):141-148. doi:10.1093/annonc/mdu472 25316259\n6 Fontanella C , Ongaro E , Bolzonello S , Guardascione M , Fasola G , Aprile G Clinical advances in the development of novel VEGFR2 inhibitors. Ann Transl Med. 2014;2 (12 ):123.25568876\n7 Fuchs CS , Tomasek J , Yong CJ , ; REGARD Trial Investigators Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383 (9911 ):31-39. doi:10.1016/S0140-6736(13)61719-5 24094768\n8 Wilke H , Muro K , Van Cutsem E , ; RAINBOW Study Group Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15 (11 ):1224-1235. doi:10.1016/S1470-2045(14)70420-6 25240821\n9 Ohtsu A , Shah MA , Van Cutsem E , Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29 (30 ):3968-3976. doi:10.1200/JCO.2011.36.2236 21844504\n10 Shen L , Li J , Xu J , Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015;18 (1 ):168-176. doi:10.1007/s10120-014-0351-5 24557418\n11 Yoon HH , Bendell JC , Braiteh FS , Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial. Ann Oncol. 2016;27 (12 ):2196-2203. doi:10.1093/annonc/mdw423 27765757\n12 Bennouna J , Sastre J , Arnold D , ; ML18147 Study Investigators Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14 (1 ):29-37. doi:10.1016/S1470-2045(12)70477-1 23168366\n13 Fuchs CS , Shitara K , Di Bartolomeo M , ; RAINFALL Study Group Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20 (3 ):420-435. doi:10.1016/S1470-2045(18)30791-5 30718072\n14 Eli Lilly and Co. Cyramza (ramucirumab): highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477s002lbl.pdf. Revised November 2014. Accessed July 31, 2018.\n15 Tabernero J , Ohtsu A , Muro K , Exposure-response analyses of ramucirumab from two randomized, phase III trials of second-line treatment for advanced gastric or gastroesophageal junction cancer. Mol Cancer Ther. 2017;16 (10 ):2215-2222. doi:10.1158/1535-7163.MCT-16-0895 28716815\n16 Shitara K , Kadowaki S , Nishina T , Safety, pharmacokinetic, and clinical activity profiles of ramucirumab in combination with three platinum/fluoropyrimidine doublets in Japanese patients with chemotherapy-naïve metastatic gastric/gastroesophageal junction cancer. Gastric Cancer. 2018;21 (1 ):106-113. doi:10.1007/s10120-017-0745-2 28667466\n17 World Medical Association World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310 (20 ):2191-2194. doi:10.1001/jama.2013.281053 24141714\n18 Eisenhauer EA , Therasse P , Bogaerts J , New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45 (2 ):228-247. doi:10.1016/j.ejca.2008.10.026 19097774\n19 Muro K , Oh SC , Shimada Y , Subgroup analysis of East Asians in RAINBOW: a phase 3 trial of ramucirumab plus paclitaxel for advanced gastric cancer. J Gastroenterol Hepatol. 2016;31 (3 ):581-589. doi:10.1111/jgh.13153 26317322\n20 Hecht JR , Bang YJ , Qin SK , Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2–positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC—a randomized phase III trial. J Clin Oncol. 2016;34 (5 ):443-451. doi:10.1200/JCO.2015.62.6598 26628478\n21 Bocci G , Di Paolo A , Danesi R The pharmacological bases of the antiangiogenic activity of paclitaxel. Angiogenesis. 2013;16 (3 ):481-492. doi:10.1007/s10456-013-9334-0 23389639\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2574-3805",
"issue": "2(8)",
"journal": "JAMA network open",
"keywords": null,
"medline_ta": "JAMA Netw Open",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001208:Asia; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077150:Oxaliplatin; D017239:Paclitaxel; D013274:Stomach Neoplasms",
"nlm_unique_id": "101729235",
"other_id": null,
"pages": "e198243",
"pmc": null,
"pmid": "31373648",
"pubdate": "2019-08-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "19097774;21844504;23168366;23389639;24094768;24141714;24557418;25240821;25316259;25568876;26317322;26628478;27342689;27697982;27765757;28667466;28716815;30207593;30718072",
"title": "Effect of First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab on Advanced Gastric Cancer in East Asia: The Phase 2 RAINSTORM Randomized Clinical Trial.",
"title_normalized": "effect of first line s 1 plus oxaliplatin with or without ramucirumab followed by paclitaxel plus ramucirumab on advanced gastric cancer in east asia the phase 2 rainstorm randomized clinical trial"
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Hypothyroidism has been associated with quetiapine, but the underlying mechanism is not well understood and has been presumed to result from thyroid gland dysfunction (primary hypothyroidism). We present a case of symptomatic quetiapine-induced hypothyroidism due to hypothalamic/pituitary gland dysfunction (central [secondary] hypothyroidism).",
"affiliations": "National Institute of Child Health and Development (NICHD), Bethesda, MD. Electronic address: anna.zenno@nih.gov.;Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.",
"authors": "Zenno|Anna|A|;Leschek|Ellen|E|",
"chemical_list": "D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaac.2020.01.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-8567",
"issue": "59(5)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": null,
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D006801:Humans; D007037:Hypothyroidism; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "575-576",
"pmc": null,
"pmid": "32036034",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Quetiapine-Induced Central Hypothyroidism.",
"title_normalized": "quetiapine induced central hypothyroidism"
} | [
{
"companynumb": "US-ALEMBIC PHARMACUETICALS LIMITED-2020SCAL000186",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "Phenytoin is a commonly used anti-epileptic drug. Adverse reactions including fever, skin reactions and lymphadenopathy are well known but atypical reactions can also occur. A patient is described with a lag time of only 4 days between onset of phenytoin and the development of a syndrome with acute lung injury and renal failure. The symptoms mimicked a renopulmonary syndrome, and resolved completely after cessation of phenytoin and addition of steroids.",
"affiliations": "Dept of Internal Medicine, University Hospital Groningen, The Netherlands.",
"authors": "Polman|A J|AJ|;van der Werf|T S|TS|;Tiebosch|A T|AT|;Zijlstra|J G|JG|",
"chemical_list": "D000927:Anticonvulsants; D005938:Glucocorticoids; D010672:Phenytoin; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1183/09031936.98.11020501",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0903-1936",
"issue": "11(2)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000927:Anticonvulsants; D001980:Bronchi; D003937:Diagnosis, Differential; D005938:Glucocorticoids; D006801:Humans; D008171:Lung Diseases; D008297:Male; D010672:Phenytoin; D011239:Prednisolone; D013902:Radiography, Thoracic; D012640:Seizures; D013997:Time Factors",
"nlm_unique_id": "8803460",
"other_id": null,
"pages": "501-3",
"pmc": null,
"pmid": "9551761",
"pubdate": "1998-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early-onset phenytoin toxicity mimicking a renopulmonary syndrome.",
"title_normalized": "early onset phenytoin toxicity mimicking a renopulmonary syndrome"
} | [
{
"companynumb": "NL-PFIZER INC-2020460550",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAcetaminophen overuse has been linked to liver injury.\n\n\nOBJECTIVE\nTo identify patterns of medication use associated with exceeding the recommended daily maximum dose of 4 g acetaminophen.\n\n\nMETHODS\nRespondents from a national panel completed a detailed daily medication diary online for 7 days (n = 5649), identifying medications taken from a comprehensive list of over-the-counter (OTC) and prescription (Rx) acetaminophen medications. Respondents were not told the study concerned acetaminophen. Total daily intake was calculated from diary data. Generalized estimating equations assessed the association of medication patterns with exceeding 4 g per day among 3618 respondents who used acetaminophen medications (on 13,852 days) during the diary period.\n\n\nRESULTS\nAcetaminophen intake exceeded 4 g on 3.1% of usage days; median intake on those days was 5.5 g. As expected, days when intake exceeded 4 g were almost always (92%) marked by deviations from label directions-exceeding the one-time dose, re-dosing too soon, and concomitant use of multiple acetaminophen medications. Re-dosing too soon was the most frequent deviation, and concomitant use was most strongly tied to exceeding the daily limit. Use of both an Rx and an OTC medication on the same day also increased the odds of exceeding 4 g on days when concomitant use occurred.\n\n\nCONCLUSIONS\nExcess dosing of acetaminophen is associated with deviations from label directions and by use of both OTC and Rx medications containing acetaminophen within a single concomitant use day.",
"affiliations": "Pinney Associates, Pittsburgh, PA, USA.;Pinney Associates, Pittsburgh, PA, USA.;Pinney Associates, Pittsburgh, PA, USA.;Slone Epidemiology Center at Boston University, Boston, MA, USA.;Appleseed Consumer Insight, Arlington, MA, USA.;Janssen Research & Development, LLC, Titusville, NJ, USA.;Slone Epidemiology Center at Boston University, Boston, MA, USA.",
"authors": "Shiffman|Saul|S|;Rohay|Jeffrey M|JM|;Battista|Deena|D|;Kelly|Judith P|JP|;Malone|Mary K|MK|;Weinstein|Rachel B|RB|;Kaufman|David W|DW|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D004366:Nonprescription Drugs; D000082:Acetaminophen",
"country": "England",
"delete": false,
"doi": "10.1002/pds.3830",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "24(9)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "acetaminophen; dosing behavior; drug safety; epidemiology; pharmacoepidemiology; survey research",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020407:Internet; D008297:Male; D004366:Nonprescription Drugs; D011795:Surveys and Questionnaires",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "915-21",
"pmc": null,
"pmid": "26149538",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Patterns of acetaminophen medication use associated with exceeding the recommended maximum daily dose.",
"title_normalized": "patterns of acetaminophen medication use associated with exceeding the recommended maximum daily dose"
} | [
{
"companynumb": "US-JNJFOC-20150706494",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Besides peripheral cytopenias, bone marrow abnormalities, such as fibrosis, pure red cell aplasia and aplastic anemia have been reported in patients with systemic lupus erythematosus (SLE), suggesting that bone marrow may be a 25 target organ in SLE.\nOur objective was to describe this bone marrow involvement.\nThis registry is a nationwide retrospective study. Centers provided data concerning medical history, SLE manifestations, type of hematologic disorder, treatments and outcome. Bone marrow aspirations and/or biopsies were transferred for centralized review.\nThirty patients from 19 centers were included. Central hematologic manifestations comprised bone marrow fibrosis (n = 17; 57%), pure red cell aplasia (n = 8; 27%), myelodysplastic syndrome (n = 3; 10%), aplastic anemia and agranulocytosis (n = 1; 3% each). Bone marrow involvement was diagnosed concomitantly with SLE in 12 patients. Bone marrow biopsies showed fibrosis in 19 cases, including one case of pure red cell aplasia and one case of agranulocytosis and variable global marrow cellularity. Treatments included corticosteroids (90%), hydroxychloroquine (87%), rituximab (33%), intravenous immunoglobulins (30%), mycophenolate mofetil (20%) and ciclosporine (20%). After a median follow-up of 27 months (range: 1-142), 24 patients manifested complete improvement. No patient died.\nThis registry comprises the largest series of SLE patients with bone marrow involvement. It demonstrates the strong link between SLE and bone marrow fibrosis. Patients with atypical or refractory cytopenia associated with SLE should undergo bone marrow examination to enable appropriate, and often effective, treatment. Long-term prognosis is good.",
"affiliations": "Clinical Investigation Center-CIC 1408, CHU Saint Etienne, France.;Department of Internal Medicine, AP-HP, Referral Center for Rare Auto-Immune and Systemic Diseases, Cochin Hospital, Paris, France.;Department of Internal Medicine, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France.;Department of Internal Medicine Edouard Herriot, Centre Hospitalier Universitaire de Lyon, Lyon, France.;Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.;Department of Rheumatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.;Assistance Publique-Hopitaux de Paris, Hematology Saint Louis, Paris, France.;Department of Internal Medicine, Hopital de Bicetre, Le Kremlin Bicêtre, France.;Department of Biological Hematology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.;Department of Biological Hematology, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France.;Department of Internal Medicine, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France.",
"authors": "Chalayer|E|E|;Costedoat-Chalumeau|N|N|;Beyne-Rauzy|O|O|;Ninet|J|J|;Durupt|S|S|;Tebib|J|J|;Asli|B|B|;Lambotte|O|O|;Ffrench|M|M|;Vasselon|C|C|;Cathébras|P|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/qjmed/hcx102",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1460-2393",
"issue": "110(11)",
"journal": "QJM : monthly journal of the Association of Physicians",
"keywords": null,
"medline_ta": "QJM",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001853:Bone Marrow; D002648:Child; D005260:Female; D005355:Fibrosis; D005602:France; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D010198:Pancytopenia; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9438285",
"other_id": null,
"pages": "701-711",
"pmc": null,
"pmid": "28525589",
"pubdate": "2017-11-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Bone marrow involvement in systemic lupus erythematosus.",
"title_normalized": "bone marrow involvement in systemic lupus erythematosus"
} | [
{
"companynumb": "FR-PFIZER INC-2019164148",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Paradoxical reactions of tuberculosis (TB) in vertebral osteomyelitis are very rarely reported. We experienced four cases of severe paradoxical reactions in tuberculous vertebral osteomyelitis. Four cases of tuberculous vertebral osteomyelitis were confirmed by an acid-fast bacilli smear or culture. The patients were human immunodeficiency virus negative, and were all initially treated with isoniazid, ethambutol, rifampicin and pyrazinamide. Their symptoms improved with anti-TB drugs. However, after 2-12 weeks, their symptoms had recurred, and spinal magnetic resonance imaging at the time of readmission revealed an aggravation of vertebral osteomyelitis. Operations were carried out to relieve severe pain or spinal cord decompression. Through continued anti-TB drug therapy, all patients recovered without sequelae.",
"affiliations": "From the Department of Internal Medicine, Inha University School of Medicine , Incheon , Republic of Korea.",
"authors": "Im|Jae Hyoung|JH|;Baek|Ji Hyeon|JH|;Kwon|Hea Yoon|HY|;Lee|Jin Soo|JS|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "England",
"delete": false,
"doi": "10.3109/00365548.2014.990508",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-4243",
"issue": "47(4)",
"journal": "Infectious diseases (London, England)",
"keywords": "Mycobacterium tuberculosis; osteomyelitis; spinal; tuberculosis; vertebral column",
"medline_ta": "Infect Dis (Lond)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000995:Antitubercular Agents; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D013122:Spinal Diseases; D013131:Spine; D014394:Tuberculosis, Osteoarticular; D055815:Young Adult",
"nlm_unique_id": "101650235",
"other_id": null,
"pages": "271-4",
"pmc": null,
"pmid": "25692354",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Paradoxical reaction of tuberculous vertebral osteomyelitis: a case series.",
"title_normalized": "paradoxical reaction of tuberculous vertebral osteomyelitis a case series"
} | [
{
"companynumb": "KR-SA-2016SA073872",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"drugadditional": null,... |
{
"abstract": "EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed.\n\n\n\nAll patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR).\n\n\n\nWe report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen®) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy.\n\n\n\nAlthough liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.",
"affiliations": "Medical Oncology Unit, University Hospital of Parma, Italy.;Medical Oncology Unit, University Hospital of Parma, Italy.;Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.;Medical Oncology Unit, University Hospital of Parma, Italy.;Department of Medical Oncology, Careggi Hospital of Firenze, Firenze, Italy.;Department of Oncology, University Hospital Policlinico of Modena, Modena, Italy.;Medical Oncology, Versilia Hospital, Lido di Camaiore, Italy.;Department of Experimental and Clinical Medicine, Section of Surgery, Histopathology and Molecular Pathology, University of Florence, Italy.;Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy.;Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy.;Medical Oncology Unit, University Hospital of Parma, Italy.;Medical Oncology Unit, University Hospital of Parma, Italy.;Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.;Department of Medical Oncology, Careggi Hospital of Firenze, Firenze, Italy.;Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy.;Pathology Unit, Azienda USL Valle d'Aosta, Regional Hospital \"Parini\", Aosta, Italy.;Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.;Medical Oncology Unit, University Hospital of Parma, Italy. Electronic address: mtiseo@ao.pr.it.",
"authors": "Minari|R|R|;Bordi|P|P|;Del Re|M|M|;Facchinetti|F|F|;Mazzoni|F|F|;Barbieri|F|F|;Camerini|A|A|;Comin|C E|CE|;Gnetti|L|L|;Azzoni|C|C|;Nizzoli|R|R|;Bortesi|B|B|;Rofi|E|E|;Petreni|P|P|;Campanini|N|N|;Rossi|G|G|;Danesi|R|R|;Tiseo|M|M|",
"chemical_list": "D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2017.11.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "115()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "EGFR; Liquid biopsy; NSCLC; SCLC transformation; T790M; ddPCR",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000178:Acrylamides; D000368:Aged; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung; D002471:Cell Transformation, Neoplastic; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010879:Piperazines; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "21-27",
"pmc": null,
"pmid": "29290257",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy.",
"title_normalized": "primary resistance to osimertinib due to sclc transformation issue of t790m determination on liquid re biopsy"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-067265",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "BACKGROUND\nDrugs and herbal products can induce autoimmune hepatitis. We assessed frequency and clinical outcomes of patients suffering from drug-induced autoimmune hepatitis.\n\n\nMETHODS\nAll patients with drug-induced liver injury admitted between 2000 and 2011 were retrospectively studied. Diagnoses of drug-induced autoimmune hepatitis and idiopathic autoimmune hepatitis were made according to simplified criteria. After discharge, all patients had regular follow-up and were contacted to update outcomes.\n\n\nRESULTS\nAmong 10,270 in-hospital patients, 136 (1.3%) were diagnosed with drug-induced liver injury. Among them, 12 (8.8%) were diagnosed as drug-induced autoimmune hepatitis (41.7% males, age range 17-73); 8 (66.7%) were with jaundice at admission. Liver biopsies showed a pattern compatible with drug-induced autoimmune hepatitis, featured by severe portal inflammation and lymphoplasmacytic infiltrate. Drug-induced autoimmune hepatitis group had a shorter duration of drug intake, and higher values of transaminases and gamma globulins. All patients received immunosuppressive therapy with subsequent clinical remission, and five achieved a steroid-free long-term remission.\n\n\nCONCLUSIONS\nA diagnosis of drug-induced autoimmune hepatitis was quite rare in our cohort, and clinical pattern was similar to idiopathic autoimmune hepatitis. Severe portal inflammation, prominent portal-plasma cells, rosette formation and severe focal necrosis were significantly more frequent in drug-induced autoimmune hepatitis as compared to drug-induced liver injury.",
"affiliations": "Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Italy. Electronic address: anna.licata@unipa.it.;Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Italy.;Section of Anatomical Pathology, University of Palermo, Italy.;Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Italy.;Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Italy.;Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Italy.;Section of Clinical Pathology, University of Palermo, Italy.;Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Italy.;Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Italy.",
"authors": "Licata|Anna|A|;Maida|Marcello|M|;Cabibi|Daniela|D|;Butera|Giuseppe|G|;Macaluso|Fabio S|FS|;Alessi|Nicola|N|;Caruso|Calogero|C|;Craxì|Antonio|A|;Almasio|Piero L|PL|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "46(12)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Autoimmunity; Drug-induced liver injury; Human leucocyte antigens; Liver biopsy",
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005500:Follow-Up Studies; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "1116-20",
"pmc": null,
"pmid": "25224696",
"pubdate": "2014-12",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: a retrospective cohort study.",
"title_normalized": "clinical features and outcomes of patients with drug induced autoimmune hepatitis a retrospective cohort study"
} | [
{
"companynumb": "IT-ROCHE-1603966",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Valproate-induced hyperammonemia is a common side effect of valproate, which may occur either without any symptoms or may rarely cause symptoms of encephalopathy. Different risk factors have been defined for this side effect, including some nutritional deficiencies and polypharmacy (eg, other anticonvulsants). Three cases with psychiatric disorder who showed symptoms of severe hyperammonemia encephalopathy and had taken valproate with antipsychotics, especially risperidone, are presented here. In all cases, the symptoms were improved by discontinuation of valproate. Administration of antipsychotic may be considered as a risk factor for hyperammonemic encephalopathy related to valproate, specifically in some prone populations.",
"affiliations": "Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran; Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Davoudi-Monfared|Effat|E|;Radmehr|Mojan|M|;Ghaeli|Padideh|P|;Mousavi|Maryam|M|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nIran J PsychiatryIran J PsychiatryIJPSIranian Journal of Psychiatry1735-45872008-2215Psychiatry & Psychology Research Center, Tehran University of Medical Sciences Tehran, Iran IJPS-14-248Case SeriesA Case Series of Severe Hyperammonemia Encephalopathy Related to Valproate: Can Antipsychotics Increase the Risk? Davoudi-Monfared Effat 1Radmehr Mojan 1Ghaeli Padideh 2Mousavi Maryam 3*\n1 Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.\n2 Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.\n3 Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran; Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran.* Corresponding Author: Address: Research Center for Rational Use of Drugs, 4th floor, No 92, Karimkhan Zand Avenue, Hafte Tir Square, Tehran, Iran. Tel: 98-2188814157, Fax: 98-2188814157, Email: kh.mousavi@gmail.com7 2019 14 3 248 252 9 4 2019 7 7 2019 14 7 2019 \nCopyright © Psychiatry & Psychology Research Center, Tehran University of Medical Sciences\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Valproate-induced hyperammonemia is a common side effect of valproate, which may occur either without any symptoms or may rarely cause symptoms of encephalopathy. Different risk factors have been defined for this side effect, including some nutritional deficiencies and polypharmacy (eg, other anticonvulsants). Three cases with psychiatric disorder who showed symptoms of severe hyperammonemia encephalopathy and had taken valproate with antipsychotics, especially risperidone, are presented here. In all cases, the symptoms were improved by discontinuation of valproate. Administration of antipsychotic may be considered as a risk factor for hyperammonemic encephalopathy related to valproate, specifically in some prone populations.\n\nKey Words\nAntipsychoticEncephalopathyHyperammonemiaValproate Derivatives\n==== Body\nValproate-induced hyperammonemic encephalopathy (VHE) may occur in 16%-80% of patients receiving valproate. The range of incidence is wide due to variation in definition and setting. This adverse reaction can be either asymptomatic or presented with symptoms such as lethargy, drowsiness, and disorientation (1). Most of the reports have originated from neurology centers, but some recent reports have been received from psychiatric centers. Symptoms of VHE, such as lethargy, retarded motor symptom, or confusion may be misdiagnosed with exacerbation of current mood disorder (2). As a result, the doctor may increase the dose of valproate, which in turn can result in worsening the patient's condition. Hence, medical team awareness may prevent further complications. Various risk factors have been identified that correlate with VHE, which include age younger than two or over 65 years, taking multiple antiepileptics (especially phenytoin, phenobarbital, carbamazepine, and topiramate), developmental disability (such as autistic spectrum), vegetarian or vegan diets, urea cycle disorder, and hypercatabolic state (eg, burn and trauma). \n\nAlso, some other medications may cause hyperammonemia encephalopathy and the exact relevance with valproate may not be possible. However, the correlation of VHE with some factors such as dose and serum medication level still remains unknown (3). Although the exact mortality of this side effect is not determined, some fatalities have been reported, which highlights the importance of early diagnosis and proper treatment of this adverse effect (4). In this article, three cases from Rouzbeh hospital, with symptoms of severe encephalopathy and extremely high serum ammonia levels due to consumption of valproate sodium and antipsychotics, were described.\n\n\nCase 1\n\n\nZ.G., a 35-year-old woman suffering from schizophrenia, was brought to the emergency ward because of her aggressive behavior and thoughts of suicide. At admission, the patient behaved aggressively, was agitated, paranoid and depressed, and felt guilty about how she had been mistreating her husband. She complained about her difficulty falling asleep. \n\nShe also mentioned that she recently heard a voice commanding her to kill herself. Oral valproate 800 mg daily in divided doses and quetiapine 50 mg every night had been started for one week before admission. On the first day of admission, valproate was continued and quetiapine was changed to risperidone 2 mg daily in divided doses. Medication was continued for six days when the patient committed an unsuccessful suicide by cutting her wrist using sharp corners of a metal window. The symptoms of agitation and difficulty falling asleep were also observed. Thus, valproate and risperidone were increased to 1000 mg and 4 mg daily, respectively, and the valproate (VPA) level and liver enzyme were checked the next day. One week later, VPA level was reported to be 128 mg/L, with the normal range being 50-100 mg/L, and liver enzyme was found to stand within the normal limit.\n\nAlthough death wish and auditory hallucination were improving, the nurses reported ataxia and delirious behavior at the ninth day of admission. Therefore, valproate was decreased to 750 mg daily and risperidone was increased to 6 mg daily, both in divided doses. Biperiden was also started at 3 mg daily in divided doses due to extrapyramidal effect induced by risperidone, and the patient was sent for electro-convulsive therapy (ECT). On the 10th day, the patient was delirious and disoriented to place and time. Therefore, valproate was discontinued. However, the patient was still suffering from delirium. She was sometimes unaware of the place and time and sometimes about both.\n\nCarbamazepine 200 mg daily was started on day 17 and ECT was done every other day until day 20, when symptoms of delirium were exacerbated and carbamazepine, risperidone, biperiden, and ECT were all used by the patient. Haloperidol was started on 1 mg daily in divided doses the next day to help treat delirium. After day 20, haloperidol was continued, and the patient experienced severe psychomotor retardation 4 days later for which amantadine and biperiden were ordered. At the same time, serum ammonia was also checked due to the probability of encephalopathy. A few days later, the ammonia level was 297 (with a normal range of 18.7-86.9 mcg/dL) and L-carnitine 250 mg was started. One day later, the patient’s family insisted to discharge the patient from the hospital and she was discharged with legal self-consensus of her family. Other medications that were prescribed during her stay were propranolol, zinc sulfate, ferrous sulfate, folic acid, clonazepam, and acetaminophen. No significant abnormalities were found in the laboratory tests.\n\n\nCase 2\n\n\nG.T., a 54-year-old man, was admitted to the emergency ward due to paranoid delusion, aggressiveness, talkativeness, increased energy, and decreased need for sleep. He was a known case of bipolar disorder with a psychotic feature and had been admitted repeatedly in the same center during the past 30 years. The main etiology for his readmission was that his paranoid thoughts about his wife had returned. He believed that his wife was betraying him and that she intentionally was not giving him the medications to worsen his medical condition. He had also been diagnosed with multiple sclerosis (MS) since 2 years ago and was receiving glatiramer acetate 3 days a week. His medication history consisted of valproate sodium 1500 mg daily in divided doses and propranolol 10 mg thrice daily, which was stopped in the previous week, biperiden 2 mg twice daily that had been discontinued for at least 4 months and haloperidol with unknown order of prescription. Additionally, he was taking opium for several years and was on methadone and buprenorphine intermittently.\n\nThe patient was admitted because of exacerbation of the manic episode; however, it seemed that the underlying disease (MS) and poor adherence to medications caused him such an overwhelming anxiety that resulted in aggressiveness and aggravation of paranoid thoughts in return. The same medications with the same doses were reordered with the exception of haloperidol that was discontinued and replaced by olanzapine 10 mg in 2 divided doses. Also, lorazepam, biperiden, and clonidine (for drawal symptoms) were added to his medication. Due to excess sedation, it was decided to decrease the dose of sodium valproate on the third day, and as sedation continued, haloperidol was started on the seventh day and olanzapine was discontinued. Also, clonidine and buprenorphine use was limited. The patient started to feel better and the paranoid thoughts were disappearing. On the 14th day, the patient presented with a shuffling gate for which neurology consultation was requested. Neurology consultation was done and it was proposed that atypical antipsychotics were better options because of his underlying disease (MS) and probable drug-induced Parkinsonism. Once again, it was decided to replace haloperidol with olanzapine. Moreover, it was proposed that valproate could be discontinued because of excessive sedation. Hence, it was decided to taper down sodium valproate gradually because of mild abnormalities in electroencephalogram. On the 16th day, gait abnormalities, rigidity, and bradykinesia were not improved. At this time, serum valproate and ammonia levels were requested. On day 28, the ammonia level was reported to be 471 (with a normal range of 18.7-86.9 mcg/dL), the valproate level was reported as 94.5 mcg/mL and hepatic enzymes were within normal limits. Valproate was discontinued and L-carnitine 500 mg daily was started because of probable hyperammonemia encephalopathy. Four days later, the patient received methylprednisolone 500 mg for 5 days due to a new lesion on MRI. He had no problem during induction treatment of his MS attack. Other medications that he had received during admission were donepezil, amantadine, folic acid, vitamin B6, and gabapentin. Valproate was not started again for him and his mood was also stable until the next week when he was discharged and prescribed quetiapine 50 mg and carbamazepine 300 mg both in divided doses. Other medications were calcium supplement and folic acid and he was told to visit his neurologist to decide for a proper treatment for his underlying disease. One month later, he came back for a visit and showed no sign of aggressiveness and paranoid thoughts. \n\n\nCase 3\n\n\nS.Y was a 49-year-old woman who was a known case of bipolar disorder for 25 years. She was admitted to the emergency ward because of her aggressive symptoms and tendency to harm herself and others. She was aggressive, agitated, and paranoid about her mother and sister; she was also depressed and had thoughts of suicide and self-injury. She also complained about insomnia and staying awake most of the nights. She was taking valproate 500 mg 3 times a day and risperidone 2 mg at bedtime for many years. On the first day of admission, her valproate was continued and risperidone dose was increased to 1.5 mg twice daily, and on the second day, her risperidone was increased to 2 mg twice daily. Four days later, she lost consciousness and her GCS reduced to 7-8. On day 6, her consciousness did not improve and VPA level was requested. Brain CT scan was performed and there were no signs of end-organ damage. All vital signs were normal except blood pressure that stood above 150/110 mmHg. In the evening of the sixth day of admission, she became conscious but disoriented to time, place, and people. On day 7, she was unconscious again and did not show any responses to painful stimuli. Her VPA level was 201 mcg/mL. Meanwhile, ammonia level was also examined. Her VPA was discontinued and lithium was started. L-carnitine 1000 mg 3 times a day was also started. Risperidone was stopped and replaced by haloperidol 5 mg daily. On day 9, she became alert and oriented. A few days later, her ammonia level was reported at 327mcg/dL. Her hepatic enzyme and other laboratory tests were all within normal limit. Her therapy was continued with lithium and haloperidol; and during her stay in the hospital, she did not experience further loss of consciousness and disorientation. She was discharged and was taking lithium, quetiapine, trifluoperazine, biperiden, and propranolol. She came for a visit 2 weeks later and her only complaint was fatigue, and her other aggressive and agitated symptoms were gone.\n\n The name of hospital is hidden because of regulation of submission to journal\n\nDiscussion\nVHE is a serious adverse effect of valproate that can even lead to death but can be prevented by precautious diagnosis and lowering the dose or discontinuing the medication. Different risk factors may be related to this adverse effect, e.g., urea cycle disorder, immature hepatic function, hereditary or dietary-induced carnitine deficiency, comorbid diseases, increased protein load, and polypharmacy (5). VHE mostly coincides with normal hepatic function (6).\n\nThe mechanism of VHE is related to both renal and hepatic metabolic pathways (7).The renal pathway that has a minor role is related to stimulation of renal glutaminase by one of the metabolites of valproate, sodium 2-propyl 4-pentenoate (4-en-VPA). This may increase renal glutamine uptake and ammonia release [8]. Additionally, the hepatic pathway has a major and complex role in increased ammonia level. One arm is inhibition of the enzyme carbamoyl–phosphate synthetase I (CPS-I) that leads to an increase in ammonia level. Another arm is an increase in omega-oxidation pathway of valproate metabolism to produce 4-en-VPA and propionate that causes hyperammonemia. Propionate also decreases hepatic N-acetyl glutamate level and causes an increase in ammonia level due to CPS-I inhibition. Carnitine deficiency may result in valproate toxicity, especially in long-term.\n\nThe symptoms of VHE vary, although it can also be asymptomatic. VHE can be seen in the form of acute onset of lethargy, impaired consciousness, disorientation, cognitive slowing, and focal neurological deficits (3). The symptoms of the patient in case 1 was disorientation and slowing of cognition; case 2 showed excess sedation and impaired cognition. Both cases showed some degree of extrapyramidal side effects, such as shuffling or bradykinesia. Symptoms of case 3 consisted of sudden loss of consciousness. However, all three cases showed improvement in their symptoms after discontinuation of valproate.\n\nIn fact, VHE is very rare when valproate is used alone and mostly occurs in patients taking valproate with other anticonvulsant drugs, such as carbamazepine or phenytoin (9). Beside anticonvulsants, some other psychotropics, such as risperidone, have been reported to induce VHE (10, 11). \n\nSeveral cases have been reported about risperidone-related VHE and the interaction between risperidone and valproate. Carlson et al reported two pediatric cases with valproate-induced hyperammonemia related to risperidone and suggested that some genetic predisposition (for example, unknown mitochondrial dysregulation) may exist that make children prone to this adverse effect (10).\n\nAnother theory for this interaction may contribute to the ability of risperidone to inhibit CYP2D6 (albeit weekly), and it was proposed that risperidone can increase VPA level (12). Sund et al showed that this may not be true, as in their study, there was no difference between the serum level of valproate in patients who take risperidone and those who do not (13).Another more acceptable theory, although not fully examined, is that valproate extensively binds to plasma proteins. Risperidone may compete with valproate in binding to proteins and may increase the unbound drug in blood, which may lead to further toxicity (10).\n\nThe other mechanism that can lead to risperidone-valproate interaction and valproate toxicity may be related to CYP2D6 polymorphism. One of the most prominent pathways of metabolizing risperidone is CYP2D6, and some studies have shown that CYP2D6 poor metabolizers may have higher risk of side effects (14).Studies have also shown that Caucasians have high poor metabolizer ratios of CYP2D6 (15). It can be assumed that from the overall population, poor metabolizers are at the unpredictable risk of interaction between valproate and risperidone due to the longer half-life of risperidone. \n\nOne concerning aspect of VHE is that it can happen anytime during the treatment, even after years (16). Another concern is misdiagnosis of this side effect with other mood disorder and adverse effects. Likewise, in this study, case two and three have been taking valproate for years. Also, their symptoms were not initially assumed as VHE symptoms. Hence, it may be necessary to request an ammonia level under special conditions or determined interval in prone patients. However, being prone to this side effect should be clarified more precisely in future investigations to prevent overdiagnosis. \n\nBased on the authors' experiences, the incidence of severe hyperammonemia increases when valproate is used with antipsychotics, especially risperidone, in Iranian population. The reason this was not reported before might be attributed to either the limitation in laboratory testing or the lack of proper diagnosis of this side effect. The authors are planning to design new studies to investigate other risk factors for VHE in our ethnic group. \n\nIn these cases, G.T. was diagnosed with hyperammonemia encephalopathy irrespective of risperidone, but it may contribute to olanzapine or haloperidol. Olanzapine administration has never been assumed as a risk factor for VHE; there are some reports of VHE that patients have taken olanzapine with valproate (17, 18), although the exact correlation of VHE and coadministration of olanzapine is not fully explained. Which antipsychotics may be more prominent risk factors for VHE is a question that can be answered in future investigations.\n\nConclusion\nHyperammonemic encephalopathy is a potentially serious side effect of treatment with valproate. Different risk factors, such as age, urea cycle disorder, concomitant administration of some antiepileptic, and nutritional deficiency have been proposed for incidence of VHE. In this case series, 3 cases of severe VHE that may be contributed to coadministration of antipsychotics, especially risperidone, were described. The symptoms of all three cases were improved after discontinuation of valproate. However, this was a hypothesis and needs larger studies to clarify the exact contributors and risk factors for VHE, especially in Iranian populations.\n\nAcknowledgment\nWe like to express our appreciation to the nurses for their patience and cooperation with regard to this case. \n\nConflict of Interest\nWe have no conflicts of interest to declare. We have full control of all primary data and we agree to allow the journal to review the data if requested.\n==== Refs\nReferences\n1 Dealberto MJ Valproate-induced hyperammonaemic encephalopathy: review of 14 cases in the psychiatric setting Int Clin Psychopharmacol. 2007 22 330 7 17917551 \n2 Carr RB Sherwsbury K Hyperammonemia due to valproic acid in the psychiatric setting Am J Psychiatry 2007 164 7 1020 7 17606652 \n3 Lauren M Brown Nicole Cupples Troy A Moore Levocarnitine for valproate-induced hyperammonemia in the psychiatric setting: A case series and literature review Ment Health Clin 2018 8 3 148 54 29955560 \n4 Yue YGW Wai CK Peter WYM Tung WH Yau CK A fatal case of valproate-induced hyperammonemic encephalopathy: An update on proposed pathogenic mechanisms and treatment options Int J Epilep 2017 04 02 181 3 \n5 Lewis C Deshpande A Tesar GE Dale R Valproate-induced hyperammonemic encephalopathy: a brief review Curr Med Res Opin 2012 28 6 1039 42 22587482 \n6 Rath A Naryanan TJ Chowdhary GV Murthy JM Valproate-induced hyperammonemic encephalopathy with normal liver function Neurol India 2005 53 2 226 8 16010067 \n7 Segura-Bruna N Rodriguez-Campello A Puente V Roquer J Valproate-induced hyperammonemic encephalopathy Acta Neurol Scand 2006 114 1 1 16774619 \n8 Lheureux PE Penaloza A Zahir S Gris M Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Crit Care 2005 9 5 431 40 16277730 \n9 Rousseau MC Montana M Villano P Catala A Blaya J Valkov M Valproic acid-induced encephalopathy in very long course treated patients Brain Inj 2009 23 12 981 4 19831495 \n10 Carlson T Reynolds CA Caplan R Case Report: Valproic Acid and Risperidone Treatment Leading to Development of Hyperammonemia and Mania J Am Acad Child Adolesc Psychiatry 2007 46 3 356 61 17314721 \n11 Carr RB Shrewsbury K Hyperammonemia Due to Valproic Acid in the Psychiatric Setting Am J Psychiatry 2007 164 7 1020 7 17606652 \n12 Vitiello B Valproic acid and risperidone: commentary J Am Acad Child Adolesc Psychiatry 2001 40 8 866 7 11501681 \n13 van Wattum PJ Valproic acid and risperidone: a drug interaction? J Am Acad Child Adolesc Psychiatry 2003 42 1 1 2 12500067 \n14 de Leon J Susce MT Pan RM Fairchild M Koch WH Wedlund PJ The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation J Clin Psychiatry 2005 66 1 15 27 15669884 \n15 Mizutani T PM Frequencies of Major CYPs in Asians and Caucasians Drug Metab Rev 2003 35 2-3 99 106 12959412 \n16 Dinçer M Akgün A Bodur S Gül H Taş Torun Y Bolu A C Çetinkaya M Kara H Cöngöloğlu MH Hyperammonemic encephalopathy without hepatic dysfunction due to treatment with valproate: four cases and a mini review Psychiat Clin Psych 2018 28 4 448 460 \n17 Cheng M Tang X Wen S Yue J Wang H Valproate (VPA)-associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012 Compr Psychiatry 2013 54 5 562 7 23246073 \n18 Dixit S Namdeo M Azad S Valproate Induced Delirium due to Hyperammonemia in a Case of Acute Mania: A Diagnostic Dilemma J Clin Diagn Res 2015 9 4 VD01 VD02\n\n",
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"keywords": "Antipsychotic; Encephalopathy; Hyperammonemia; Valproate Derivatives",
"medline_ta": "Iran J Psychiatry",
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"title": "A Case Series of Severe Hyperammonemia Encephalopathy Related to Valproate: Can Antipsychotics Increase the Risk?",
"title_normalized": "a case series of severe hyperammonemia encephalopathy related to valproate can antipsychotics increase the risk"
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"abstract": "Aspergillus species are an important cause of fungal infections in immuncompromised patients and also cause a variety of saprophytic conditions such as pulmonary aspergilloma. Surgical resection alone may be warranted for the treatment of pulmonary aspergilloma; in cases where medical therapy is necessary, the triazole antifungal agents itraconazole, voriconazole, and, presumably, posaconazole are thought to provide therapeutic benefit. The high potential for drug-drug interactions with the \"azole\" antifungal drugs, as well as the possibility for adverse events, while perhaps uncommon, can be problematic. This case describes a 68-year-old patient who developed a pulmonary aspergilloma in the air space of the location of a previous left-upper lobectomy performed five years earlier to treat lung cancer. The patient was initiated on voriconazole, but subsequently developed agitation and hallucinations. The patient was switched to itraconazole and subsequently developed worsening of congestive heart failure. Another switch was made to posaconazole. After an adjustment of his medication regimen for potential drug-drug interactions, the patient was discharged on posaconazole for three to six months, with regular follow-up of liver transaminase monitoring.",
"affiliations": "Virginia Commonwealth University, School of Pharmacy, Medical College of Virginia Campus, Richmond, Virginia 23298-0533, USA. apakyz@vcu.edu",
"authors": "Pakyz|Amy|A|;Bearman|Gonzalo|G|",
"chemical_list": "D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole; D065819:Voriconazole",
"country": "United States",
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"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D001228:Aspergillosis; D004347:Drug Interactions; D005500:Follow-Up Studies; D006212:Hallucinations; D006333:Heart Failure; D006801:Humans; D017964:Itraconazole; D008111:Liver Function Tests; D008172:Lung Diseases, Fungal; D008297:Male; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole",
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"title": "Adverse drug events complicate antifungal therapy for pulmonary aspergilloma.",
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"abstract": "OBJECTIVE\nWe report a case of anaplastic thyroid carcinoma (ATC) with local recurrence and distant metastasis that responded very well to treatment with lenvatinib, a new molecular-targeted anticancer drug.\n\n\nMETHODS\nA 91-year-old Japanese woman presented with a 5-month history of a painless mass in her left anterior neck. She had a past history of total thyroidectomy and neck dissection for papillary carcinoma of the thyroid. Here she underwent neck dissection, and the histopathological diagnosis was lymph node metastasis of papillary carcinoma with anaplastic transformation. Five months later, a cervical lymph node swelled up again. Computed tomography demonstrated an enhanced mass in the neck and multiple nodules in both lungs. Recurrent ATC with multiple lung metastases was diagnosed, and molecular-targeted therapy with lenvatinib was initiated. The neck tumor reduced in 1 week, and the pulmonary nodules became completely hollow within 1 month. However, we had to discontinue lenvatinib because of severe side effects including high blood pressure, hypocalcemia, and hypoalbuminemia. Soon after discontinuation, the side effects subsided, but the tumor rapidly regrew. The patient died of lymphangiosis carcinomatosa 6 days after discontinuation.\n\n\nCONCLUSIONS\nAlthough recent advances in molecular-targeted therapy have provided powerful cancer therapy tools, the negative side of this therapy must be addressed.",
"affiliations": "Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Occupational and Environmental Health.;Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Occupational and Environmental Health.;Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Occupational and Environmental Health.;Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Occupational and Environmental Health.;Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Occupational and Environmental Health.;Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Occupational and Environmental Health.",
"authors": "Ohkubo|Jun-Ichi|JI|;Takahashi|Azusa|A|;Ikezaki|Shoji|S|;Takenaga|Fumiko|F|;Ohkubo|Yufu|Y|;Suzuki|Hideaki|H|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C531958:lenvatinib",
"country": "Japan",
"delete": false,
"doi": "10.2739/kurumemedj.MS6406",
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"issn_linking": "0023-5679",
"issue": "64(1.2)",
"journal": "The Kurume medical journal",
"keywords": "anaplastic thyroid carcinoma; clinical effect; lenvatinib; molecular-targeted therapy; tyrosine kinase inhibitor",
"medline_ta": "Kurume Med J",
"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D065646:Thyroid Carcinoma, Anaplastic",
"nlm_unique_id": "2985210R",
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"title": "Anaplastic Thyroid Carcinoma Treated with Lenvatinib.",
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"abstract": "Decreased abiraterone exposure after introducing carbamazepine.\n\n\n\nAbiraterone acetate and carbamazepine.\n\n\n\nA 65-year-old man with metastatic castration resistant prostate cancer, was treated with abiraterone acetate and prednisolone, and received concomitant carbamazepine for treatment of facial neuropathy.\n\n\n\nThe interaction was confirmed by a decrease in abiraterone exposure >2-fold (area-under-the-curve and trough levels). After discontinuation of carbamazepine therapy, the abiraterone exposure normalized. No alternative causes were found that explain the decrease in abiraterone exposure.\n\n\n\nInduction of CYP3A and potentially phase I metabolism (SULT2A1) by carbamazepine.\n\n\n\nClinicians and pharmacists should be aware of this clinically relevant interaction. The national drug-drug interaction checker does not warn for this interaction, whereas both the Lexicomp® and Micromedex® advice to avoid if possible or to increase the abiraterone dose frequency to twice daily. Carbamazepine should not be combined with abiraterone to avoid underexposure and suboptimal therapy. Therapeutic drug monitoring of abiraterone is useful to guide therapy when drug-drug interactions cannot be avoided.",
"affiliations": "Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Urology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Medical Oncology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.",
"authors": "Benoist|Guillemette E|GE|0000-0002-3432-3575;van der Doelen|Maarten J|MJ|0000-0001-8754-1210;Ter Heine|Rob|R|0000-0003-2185-8201;van Erp|Nielka P|NP|;Mehra|Niven|N|0000-0002-4794-1831",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D065701:Cytochrome P-450 CYP3A Inducers; D002220:Carbamazepine; D011239:Prednisolone; D000069501:Abiraterone Acetate",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "84(5)",
"journal": "British journal of clinical pharmacology",
"keywords": "abiraterone; drug-drug interaction; prostate cancer",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D002220:Carbamazepine; D065701:Cytochrome P-450 CYP3A Inducers; D004347:Drug Interactions; D005155:Facial Nerve Diseases; D006801:Humans; D008297:Male; D011239:Prednisolone; D064129:Prostatic Neoplasms, Castration-Resistant",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "1064-1067",
"pmc": null,
"pmid": "29384591",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": "28881501;17112801;27324190;28027516;29134570;28370076;29384591;17389673;28361167;27138787;29055032;23228172;27128004;25829400;25204404;29149325;29055034;21612468",
"title": "A clinically relevant decrease in abiraterone exposure associated with carbamazepine use in a patient with castration-resistant metastatic prostate cancer.",
"title_normalized": "a clinically relevant decrease in abiraterone exposure associated with carbamazepine use in a patient with castration resistant metastatic prostate cancer"
} | [
{
"companynumb": "NL-ACCORD-064505",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nTo present the characteristics of the AKT1E117K gene variant and a description of the clinical application in a patient with metastatic breast cancer.\n\n\nRESULTS\n63 y/o woman with Stage IV Invasive lobular carcinoma at diagnosis was treated with Palbociclib and aromatase inhibitors (AI). At progression, tissue was sent for comprehensive genomic profiling to Foundation Medicine (FM) which revealed AKT1E17K mutation. In lieu of available clinical data within the patient's tumor type (HR+ HER2- breast cancer), extrapolated data from the Flatiron Health-FM (FH-FMI) Clinico-genomic Database (CGDB) was discussed at our Molecular Tumor Board (MTB). After multidisciplinary discussion, the consensus recommendation was to start treatment with the combination of mTOR inhibitor everolimus, and AI, exemestane. Patient tolerated treatment without major side effects. By the second clinical visit the patient's breast showed signs of improvement. PET/CT showed diminished left axillary uptake, decreased right paratracheal lymph node PET avidity, and stable bone disease consistent with a partial response. The most recent office visit in January 2021, breast exam revealed a normal-appearing skin with only faint erythema. All other skin lesions have resolved. Although, the role of AKT1 variant described here is not well defined and therapeutic significance of M-Tor inhibitors not established in metastatic breast cancers, comprehensive approach to this case unraveled new and successful therapeutic option in this patient.\n\n\nCONCLUSIONS\nThis demonstrates that applying available Precision Medicine tools like MTB and real world data sets from patient populations with similar clinical and genomic profiles may provide more options for treatment.",
"affiliations": "Herbert-Herman Cancer Center, E. W. Sparrow Hospital, Lansing, MI, USA.;Foundation Medicine, Cambridge, MA, USA.;Herbert-Herman Cancer Center, E. W. Sparrow Hospital, Lansing, MI, USA.;Department of Pathology and Laboratory Medicine, Sparrow Hospital System, Lansing, MI, USA.;Foundation Medicine, Cambridge, MA, USA.;Foundation Medicine, Cambridge, MA, USA.;Foundation Medicine, Cambridge, MA, USA.;Foundation Medicine, Cambridge, MA, USA.;Foundation Medicine, Cambridge, MA, USA.;Foundation Medicine, Cambridge, MA, USA; Massachusetts General Hospital, Boston, MS, USA.;Foundation Medicine, Cambridge, MA, USA; Massachusetts General Hospital, Boston, MS, USA.;Foundation Medicine, Cambridge, MA, USA.;Herbert-Herman Cancer Center, E. W. Sparrow Hospital, Lansing, MI, USA. gordan.srkalovic@sparrow.org.",
"authors": "Trivedi|Harsha|H|;Hamdani|Omar|O|;Thomas|Brittani|B|;Richard|James|J|;Shah|Kunal|K|;Raskina|Kira|K|;Zhang|Liang|L|;Madigan|Audrey|A|;Fox|Marshall|M|;Wander|Seth|S|;Frigault|Matthew J|MJ|;Alexander|Brian|B|;Srkalovic|Gordan|G|",
"chemical_list": "C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt",
"country": "Bosnia and Herzegovina",
"delete": false,
"doi": "10.5644/ama2006-124.336",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1840-1848",
"issue": "50(1)",
"journal": "Acta medica academica",
"keywords": "AKT1; Breast Cancer; CGDB – Comprehensive Genomic Data Base; Molecular Tumor Board (MTB)",
"medline_ta": "Acta Med Acad",
"mesh_terms": "D001943:Breast Neoplasms; D018275:Carcinoma, Lobular; D005260:Female; D006801:Humans; D009154:Mutation; D000072078:Positron Emission Tomography Computed Tomography; D051057:Proto-Oncogene Proteins c-akt",
"nlm_unique_id": "101587903",
"other_id": null,
"pages": "209-217",
"pmc": null,
"pmid": "34075774",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patient with Lobular Carcinoma of the Breast and Activating AKT1 E17K Variant.",
"title_normalized": "patient with lobular carcinoma of the breast and activating akt1 e17k variant"
} | [
{
"companynumb": "US-TEVA-2022-US-1997440",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "The rare adverse drug reaction MRONJ (medication-related osteonecrosis of the jaw) can be induced by treatment with antiresorptive, antiangiogenic, or immunomodulating agents. Immune checkpoint inhibitors (ICIs; e.g., pembrolizumab) are the standard care for advanced or metastatic cancer patients. Denosumab directed against receptor activator of NF-kB ligand (RANKL) is approved for preventing skeletal-related events (SREs) in cancer patients with bone metastases. The combination therapy of ICIs + denosumab has shown promising efficacy and no unexpected safety issues in metastatic melanoma and lung cancer patients with bone metastases. We present a rare case of advanced mandibular osteonecrosis in an adult female with metastatic lung cancer and bone metastases who received concomitant pembrolizumab + denosumab.",
"affiliations": "Department of Oral Surgery, Hiroshima Red Cross & Atomic-bomb Survivors Hospital, Hiroshima, Japan. Electronic address: myoken@do5.enjoy.ne.jp.;Department of Oral Surgery, Hiroshima Red Cross & Atomic-bomb Survivors Hospital, Hiroshima, Japan.;Department of Respiratory Disease, Hiroshima Red Cross & Atomic-bomb Survivors Hospital, Hiroshima, Japan.;Department of Molecular Oral Medicine and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.",
"authors": "Myoken|Yoshinari|Y|;Fujita|Yoshinori|Y|;Kawamoto|Kazuma|K|;Toratani|Shigeaki|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D000082082:Immune Checkpoint Inhibitors; D000069448:Denosumab; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1016/j.oraloncology.2020.104874",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1368-8375",
"issue": "111()",
"journal": "Oral oncology",
"keywords": "Bone metastases; Denosumab; Medication-related osteonecrosis of the jaw; Pembrolizumab; Surgical management",
"medline_ta": "Oral Oncol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D001932:Brain Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D000069448:Denosumab; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008175:Lung Neoplasms; D012086:Reoperation; D013290:Streptococcal Infections",
"nlm_unique_id": "9709118",
"other_id": null,
"pages": "104874",
"pmc": null,
"pmid": "32605876",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016422:Letter; D016454:Review",
"references": null,
"title": "Osteonecrosis of the jaw in a metastatic lung cancer patient with bone metastases undergoing pembrolizumab + denosumab combination therapy: Case report and literature review.",
"title_normalized": "osteonecrosis of the jaw in a metastatic lung cancer patient with bone metastases undergoing pembrolizumab denosumab combination therapy case report and literature review"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1874465",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "All nucleoside analogues for treating HIV infection, due to their capacity to integrate into and alter human DNA, are experimentally genotoxic to some extent. The long-term oncogenic risk after in utero exposure remains to be determined. Cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) was evaluated, by cross-checking against the National Cancer Registry, in the French perinatal study of children born to HIV+ mothers. Twenty-one cancers were identified in 15,163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero between 1990 and 2014. Five of these children were exposed to zidovudine monotherapy, and 15 to various combinations, seven of which included didanosine. Overall, the total number of cases was not significantly different from that expected for the general population (SIR = 0.8[0.47-1.24]), but the number of cases after didanosine exposure was twice that expected (SIR = 2.5 [1.01-5.19]). Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In multivariate analysis, didanosine exposure was significantly associated with higher risk (HR = 3.0 [0.9-9.8]). This risk was specifically linked to first-trimester exposure (HR = 5.5 [2.1-14.4]). Three cases of pineoblastoma, a very rare cancer, were observed, whereas 0.03 were expected. Two were associated with didanosine exposure. Despite reassuring data overall, there is strong evidence to suggest that didanosine displays transplacental oncogenicity. These findings cannot be extrapolated to other NRTIs, but they highlight the need for comprehensive evaluations of the transplacental genotoxicity of this antiretroviral class. Environ. Mol. Mutagen., 60:404-409, 2019. © 2017 Wiley Periodicals, Inc.",
"affiliations": "Epidemiology and Population Health Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Le Kremlin-Bicêtre, U1018, France.;Epidemiology of Childhood and Adolescent Cancers Team (EPICEA), Université Paris Descartes, Epidemiology and Biostatistics, INSERM UMR1153, Sorbonne Paris Cité Research Center, Villejuif, France.;Gynecology and Obstetrics Department, Hôpital Louis Mourier, Hôpitaux Universitaires Paris Nord Val de Seine, AP-HP, Colombes, France.;Infectious Diseases Department, Hôpital Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.;Pediatric Department, Hôpital Trousseau, AP-HP, Paris, France.;Pediatric Department, Hôpital Robert Debré, AP-HP, Université Paris Diderot, Sorbonne Paris-Cité, Paris, France.;Gynecology and Obstetrics Department, Hôpital Louis Mourier, Hôpitaux Universitaires Paris Nord Val de Seine, AP-HP, Colombes, France.;Epidemiology of Childhood and Adolescent Cancers Team (EPICEA), Université Paris Descartes, Epidemiology and Biostatistics, INSERM UMR1153, Sorbonne Paris Cité Research Center, Villejuif, France.;Epidemiology and Population Health Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Le Kremlin-Bicêtre, U1018, France.;Immunology Hematology Rheumatology Unit, Pediatric Department, Hôpital Necker-Enfants Malades AP-HP, Université Paris Descartes, Paris, France.",
"authors": "Hleyhel|Mira|M|;Goujon|Stéphanie|S|;Sibiude|Jeanne|J|;Tubiana|Roland|R|;Dollfus|Catherine|C|;Faye|Albert|A|;Mandelbrot|Laurent|L|;Clavel|Jacqueline|J|;Warszawski|Josiane|J|;Blanche|Stéphane|S|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D016049:Didanosine",
"country": "United States",
"delete": false,
"doi": "10.1002/em.22162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-6692",
"issue": "60(5)",
"journal": "Environmental and molecular mutagenesis",
"keywords": "HIV; antiretroviral; cancer; didanosine; foetus; pregnancy",
"medline_ta": "Environ Mol Mutagen",
"mesh_terms": "D000293:Adolescent; D019380:Anti-HIV Agents; D002648:Child; D002675:Child, Preschool; D016049:Didanosine; D005260:Female; D015658:HIV Infections; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D009369:Neoplasms; D009705:Nucleosides; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors; D012306:Risk; D011795:Surveys and Questionnaires; D015215:Zidovudine",
"nlm_unique_id": "8800109",
"other_id": null,
"pages": "404-409",
"pmc": null,
"pmid": "29206312",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Risk of cancer in children exposed to antiretroviral nucleoside analogues in utero: The french experience.",
"title_normalized": "risk of cancer in children exposed to antiretroviral nucleoside analogues in utero the french experience"
} | [
{
"companynumb": "FR-MYLANLABS-2020M1021294",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nLeptospirosis is an underdiagnosed bacterial infection with nonspecific symptoms, hence, a diagnostic challenge. Identifying a case of leptospirosis in Switzerland is uncommon. Although kidney complications are frequent in severe forms, including tubular dysfunction, observing this complication is rare in our country. We report the case of a patient with leptospirosis and kidney dysfunction, which was notable for proximal tubulopathy. This case report describes the diagnosis and management of this patient's tubular dysfunction.\n\n\nMETHODS\nA 34-year-old Caucasian male known for alcohol and drug abuse presented to our emergency department suffering from severe pain in the lower limbs, jaundice, and fever with flu-like symptoms. Physical examination was not contributory. Blood tests showed cytopenia, elevated inflammatory markers, acute kidney injury, and altered liver function tests with predominant cholestasis. Urinalysis showed proteinuria and significant glycosuria without concomitant hyperglycemia. Leptospirosis was suspected and confirmed by both positive serum polymerase chain reaction and elevated immunoglobulin M for Leptospira interrogans. The patient was treated with intravenous amoxicillin-clavulanate and doxycycline for 7 days. After antibiotic treatment, symptoms disappeared, and kidney dysfunction completely resolved.\n\n\nCONCLUSIONS\nOur case focuses on the description of leptospirosis-related acute kidney injury with proximal tubular dysfunction, which is a rare finding in Switzerland.",
"affiliations": "Department of General Internal Medicine, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland. marc.weiner@hcuge.ch.;Department of General Internal Medicine, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Department of General Internal Medicine, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Division of Nephrology, Department of Medicine, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC, Canada.;Department of General Internal Medicine, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.",
"authors": "Weiner|Marc|M|http://orcid.org/0000-0001-8778-5485;Coen|Matteo|M|;Serratrice|Jacques|J|;Mavrakanas|Thomas A|TA|;Leidi|Antonio|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02978-0",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n34294111\n2978\n10.1186/s13256-021-02978-0\nCase Report\nAcute kidney injury with partial Fanconi syndrome in a patient with leptospirosis: a case report\nhttp://orcid.org/0000-0001-8778-5485\nWeiner Marc marc.weiner@hcuge.ch\n\n1\nCoen Matteo matteo.coen@hcuge.ch\n\n13\nSerratrice Jacques jacques.serratrice@hcuge.ch\n\n1\nMavrakanas Thomas A. thomas.mavrakanas@mcgill.ca\n\n2\nLeidi Antonio antonio.leidi@hcuge.ch\n\n1\n1 grid.150338.c 0000 0001 0721 9812 Department of General Internal Medicine, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland\n2 grid.63984.30 0000 0000 9064 4811 Division of Nephrology, Department of Medicine, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC Canada\n3 grid.8591.5 0000 0001 2322 4988 Unit of Development and Research in Medical Education (UDREM), Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland\n23 7 2021\n23 7 2021\n2021\n15 35813 4 2021\n18 6 2021\n© The Author(s) 2021, corrected publication 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\nLeptospirosis is an underdiagnosed bacterial infection with nonspecific symptoms, hence, a diagnostic challenge. Identifying a case of leptospirosis in Switzerland is uncommon. Although kidney complications are frequent in severe forms, including tubular dysfunction, observing this complication is rare in our country. We report the case of a patient with leptospirosis and kidney dysfunction, which was notable for proximal tubulopathy. This case report describes the diagnosis and management of this patient’s tubular dysfunction.\n\nCase presentation\n\nA 34-year-old Caucasian male known for alcohol and drug abuse presented to our emergency department suffering from severe pain in the lower limbs, jaundice, and fever with flu-like symptoms. Physical examination was not contributory. Blood tests showed cytopenia, elevated inflammatory markers, acute kidney injury, and altered liver function tests with predominant cholestasis. Urinalysis showed proteinuria and significant glycosuria without concomitant hyperglycemia. Leptospirosis was suspected and confirmed by both positive serum polymerase chain reaction and elevated immunoglobulin M for Leptospira interrogans. The patient was treated with intravenous amoxicillin–clavulanate and doxycycline for 7 days. After antibiotic treatment, symptoms disappeared, and kidney dysfunction completely resolved.\n\nConclusion\n\nOur case focuses on the description of leptospirosis-related acute kidney injury with proximal tubular dysfunction, which is a rare finding in Switzerland.\n\nKeywords\n\nLeptospirosis\nKidney injury\nFanconi syndrome\nProximal tubular dysfunction\nGlucose\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nLeptospirosis is a zoonotic bacterial infection caused by the spirochete Leptospira interrogans. It is transmitted to humans through water or soil contaminated by the urine of infected mammals, most commonly rodents. Contamination occurs by inhalation or ingestion, or through a breach in the skin. Symptoms vary from mild illness with self-limited fever to life-threatening multiorgan dysfunction [1]. Antibiotic therapy with beta-lactams, doxycycline, or macrolides is the mainstay of treatment [2]. In Switzerland, infections mostly occur during summer and fall, probably because the climate favors spirochete growth, and aquatic activities in rivers or lakes increase during the warm season [3]. In Switzerland, 2–13 cases were reported yearly between 1988 and 1996, corresponding to the last year of mandatory reporting for human infections [4]. According to the Swiss Federal Food Safety and Veterinary Office, mortality rate is about 20% for severe forms [5], referred to as Weil’s disease, which occurs in 5–10% of patients. Clinical manifestations include jaundice, thrombocytopenia, respiratory symptoms, myocarditis, conjunctival suffusion, and kidney impairment [6].\n\nKidney complications include acute kidney injury (44–67% of patients [7]), commonly due to tubulointerstitial nephritis, and tubular dysfunction. The latter has been associated with hypophosphatemia, hypokalemia, hypouricemia, and metabolic acidosis, mimicking Fanconi syndrome [8, 9], which represents impaired reabsorption in the proximal tubule of the nephron, resulting in loss of bicarbonate, glucose, phosphate, uric acid, and amino acids [10]. We report herein a case of acute kidney injury with partial Fanconi syndrome in a leptospirosis-infected patient.\n\nCase presentation\n\nA 34-year-old Caucasian male presented to the emergency department complaining of a 4-day history of unbearable leg pain with diffuse arthralgia, fluctuating low-grade fever with profuse sweating, vomiting and diarrhea without abdominal pain, odynophagia, dry cough, headaches, and fatigue. He denied any contact with animals or travel abroad, had not consumed unpasteurized food, and had his last unprotected sexual intercourse 4 months earlier.\n\nHe was taking no medications and was known for alcohol abuse (mainly beer and spirit, approximately 185 alcohol units/week), drug abuse (cocaine, ecstasy, cannabis, methylphenidate, clonazepam, lorazepam), and smoking tobacco. On physical examination, he was afebrile and hypotensive (blood pressure 94/50 mmHg) with a normal heart rate (77 beats/minute). Oral examination revealed dry mucosa and erythematous tonsils without exudate, cardiopulmonary examination was normal, abdominal palpation was unremarkable, and no cutaneous rash was noted. Testing of the lower limbs revealed preserved strength and sensitivity as well as symmetric deep tendon reflexes.\n\nLaboratory findings showed normocytic, normochromic, hypoproliferative anemia (hemoglobin 99 g/l, normal range 140–180 g/l) with thrombocytopenia (24 G/l, normal range 150–350 G/l), left shift without leukocytosis, elevated C-reactive protein (213 mg/l, normal range < 10 mg/l), elevated transaminases (three times the upper limit of normal) with cholestasis and elevated conjugated bilirubin (29 µmol/l on admission, 190 µmol/l on hospital day 8, normal range 0.5–9.5 µmol/l). There was a stage 3 acute kidney injury according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria with a serum creatinine of 112 µmol/l on admission and 247 µmol/l on hospital day 3 (patient’s baseline value 70 µmol/l), a serum urea of 11.4 mmol/l on admission (12 mmol/l on hospital day 3), and preserved urine output. Urinalysis revealed proteinuria (spot urine: protein 1.4 g/l, creatinine 11.5 mmol/l, urine protein–creatinine ratio 1.076 g/g), albuminuria (2+ on semiquantitative analysis), presence of 97 M/l leukocytes, 25 M/l erythrocytes, and renal tubular cells (1+ on semiquantitative analysis). Sodium excretion was high (fractional excretion of sodium on spot urine 3.56%). Due to the context of sepsis, hypovolemic status of the patient, and urinalysis findings, acute tubular necrosis was the suspected mechanism of acute kidney injury.\n\nAnalysis of serum electrolytes showed mild hyperphosphatemia (1.53 mmol/l, normal range 0.80–1.45 mmol/l), hyponatremia (131 mmol/l, normal range 136–144 mmol/l), mild hypouricemia (246 µmol/l, normal range 286–518 µmol/l), low serum chloride (94 mmol/l, normal range 98–106 mmol/l), hypokalemia (2.8 mmol/l, normal range 3.6–4.6 mmol/l), and an anion gap of 10 mmol/l. The transtubular potassium gradient was elevated (16.4). Albumin level was 29 g/l (normal range 35–48 g/l), and creatinine kinase level was 312 U/l on admission, rising to 404 U/l the next day and normalizing on hospital day 4. Blood gas analysis showed a pH of 7.49 (normal range 7.35–7.45) with elevated bicarbonates (29.3 mmol/l, normal range 22–26 mmol/l) and normal pCO2 (5.25 kPa, normal range 4.7–6.4 kPa). Urine pH was 6 (normal range 5–6.5). Presence of glycosuria (7 mmol/l, normal range 0.1–0.9 mmol/l), with concomitant euglycemia (6.6 mmol/l, normal range 4.1–11 mmol/l) and a hemoglobin A1c of 5.1% was highly suspicious of proximal tubular dysfunction.\n\nUpon admission, Streptococcus A rapid test was negative, chest radiograph was normal, and an abdominal ultrasound showed hepatomegaly, a heterogeneous parenchyma with hyperechogenicity around periportal spaces and lymph nodes, liver parenchymal arterialization, and a layer of perihepatic fluid, all consistent with hepatitis. The bile ducts were not dilated. Kidneys were of normal size and morphology, without any urinary tract dilatation. On the second day after admission, the patient developed drowsiness and confusion with high fever (exceeding 40 °C). Normal cerebral magnetic resonance imaging and lumbar puncture excluded central nervous system infection. Clinical features were suggestive of bacterial sepsis [sequential organ failure assessment [SOFA] score of 10], justifying empiric broad spectrum antibiotic therapy with intravenous ceftriaxone and oral clarithromycin.\n\nDetailed history revealed that the patient swam in a river in the Geneva lake area 1 week before hospital admission, raising the diagnostic suspicion of leptospirosis in this clinical setting. Serum polymerase chain reaction (PCR) for Leptospira interrogans was positive, and specific serologies revealed elevated IgM levels (> 100 U/ml, normal range < 15 U/ml). Although IgG levels were below the positive threshold, the values increased from < 2 U/ml initially to 6 U/ml 1 week later (normal range < 10 U/ml). Unfortunately, no ulterior dosage was performed. Antibiotic therapy was changed to intravenous amoxicillin–clavulanate and doxycycline for 7 days with clinical improvement. Serology for hantavirus was performed, revealing an indeterminate result due to nonspecific reactions. Considering the positive results for Leptospira interrogans, additional tests for hantavirus were not performed.\n\nAlong with clinical improvement, kidney function recovered with creatinine normalizing to 87 μmol/l on the sixth hospital day, and all electrolyte abnormalities resolved. Liver tests also normalized as confirmed by a routine blood sample 1 year after discharge. In addition, glycosuria significantly decreased from 7 to 0.5 mmol/l on the 12th day of hospital stay.\n\nDiscussion and conclusion\n\nWe report the case of a patient with leptospirosis who developed acute kidney injury and partial Fanconi syndrome diagnosed on the basis of euglycemic glycosuria. The patient also had proteinuria, although its tubular origin cannot be definitely proven in the absence of a urine albumin-to-creatinine ratio. There was no evidence of proximal renal tubular acidosis. The patient also had mild hyperphosphatemia, but this could be attributed to severe acute kidney injury. Concerning hypokalemia with an increased transtubular gradient, it is most likely explained by an elevated aldosterone level in the context of sepsis and hypovolemia.\n\nThe alkalosis observed is unusual in the setting of proximal tubulopathy and acute kidney injury. Considering the context of hypovolemia and sepsis, without hypocapnia, contraction alkalosis is an explanation. Hypokalemia and metabolic alkalosis may also have been caused by the vomiting.\n\nIn humans, leptospirosis-induced kidney tubular dysfunction is mostly observed in the proximal tubule [8]. Some reports of proximal tubular dysfunction in leptospirosis-infected patients described hypokalemia, hypophosphatemia, hypouricemia, glycosuria, and metabolic acidosis [11–14].\n\nAnimal models have confirmed that Leptospira interrogans can infect kidney proximal tubular epithelial cells through hematogenous spread. Spirochetes enter cells through the basal membrane and then translocate to the apical membrane where they form a biofilm-like structure enabling them to resist the urinary stream [15]. Leptospirosis also inhibits expression of electrolytes transporters in nephrons. The outer membrane protein (OMP) of spirochetes inhibits mRNA synthesis of the sodium, potassium, and chloride cotransporter (NKCC2) [16]. Antibiotic treatment results in an increased activity of the transporters [17]. Other molecular mechanisms of tubular injury in leptospirosis involve the sodium–hydrogen exchanger type 3 (NHE3) [17], Toll-like receptor-dependent pathway [18], and nuclear factor kappa-B (NFkB) [19]. A detailed description of these mechanisms is beyond the scope of this manuscript.\n\nAs glucose is reabsorbed in the proximal tubule by the sodium–glucose cotransporter 2 and, to a lesser extent, sodium–glucose cotransporter 1 (SGLT2, SGLT1) (Fig. 1A), the euglycemic glycosuria developed by our patient suggests a potential inhibition of SGLT2 and/or SGLT1 by spirochetes (Fig. 1B).Fig. 1 Mechanism of glucose reabsorption in the proximal tubule of the nephron (A) and its impairment in leptospirosis (B). The mechanism is similar for SGLT1 in the distal segment of the proximal tubule\n\nAlthough acute interstitial nephritis is part of the differential diagnosis of tubulopathy, we do not think it is the most likely explanation owing to the clinical presentation, the urine sediment findings (tubular cells), and the absence of white blood cell casts.\n\nAlthough alcohol and drug abuse are known to induce Fanconi syndrome [20], our patient was reportedly abstinent during the week prior to hospital admission, and a toxicology screening at the beginning of the hospitalization was only positive for benzodiazepines, which the patient was given in hospital previously to the screening. Moreover, glycosuria resolved after antibiotic treatment, thus favoring our hypothesis that the partial Fanconi syndrome was secondary to leptospirosis rather than substance abuse.\n\nTo conclude, the clinical manifestations of leptospirosis are numerous and nonspecific, which possibly leads to misdiagnosis, especially in Switzerland, where this infection is seldom reported. Among the known clinical manifestations, we focused on kidney tubular dysfunction—specifically, impaired proximal reabsorption of glucose. Our case illustrates the occurrence of transient euglycemic glycosuria in the setting of leptospirosis, which resolved after appropriate antibiotic therapy.\n\nAbbreviations\n\nPCR Polymerase chain reaction\n\nIgM/IgG Immunoglobulin M/immunoglobulin G\n\nKDIGO Kidney Disease Improving Global Outcomes\n\npCO2 Partial pressure of carbon dioxide\n\nSOFA Sequential organ failure assessment\n\nOMP Outer membrane protein\n\nmRNA Messenger ribonucleic acid\n\nNKCC2 Sodium, potassium, and chloride cotransporter\n\nNHE3 Sodium–hydrogen exchanger type 3\n\nNFkB Nuclear factor kappa-B\n\nSGLT1 and 2 Sodium–glucose cotransporter 1 and 2\n\nAcknowledgements\n\nWe would like to thank Jonathan Weiner for his help with the English language.\n\nAuthors’ contributions\n\nMW: analyzing the patient’s clinical findings, medical literature reviewing, writing and revision of the case report. AL: direct supervision during elaboration and revision of the case report, medical literature reviewing. TM, MC, JS: medical literature reviewing, revision of the case report. All authors read and approved the final manuscript.\n\nFunding\n\nThomas A. Mavrakanas received salary support from the McGill University Health Centre Department of Medicine.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nTM reports personal fees from Daiichi Sankyo and Pfizer, outside the submitted work.\n\nThe original version of this article was revised: the paragraph in the top right part and the paragraph in bottom right part of the page 3 have been interchanged due to a typesetting error. This error was fixed\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nChange history\n\n8/16/2021\n\nA Correction to this paper has been published: 10.1186/s13256-021-03040-9\n==== Refs\nReferences\n\n1. Lane AB Dore MM Leptospirosis: a clinical review of evidence based diagnosis, treatment and prevention World J Clin Infect Dis 2016 6 61 66 10.5495/wjcid.v6.i4.61\n2. Johnson RC, Faine S. Leptospira. In: Bergey’s manual of systematic bacteriology, vol. 1. 1984:62–7.\n3. Schreiber PW Aceto L Korach R Cluster of leptospirosis acquired through river surfing in Switzerland Open Forum Infect Dis 2015 2 ofv102 10.1093/ofid/ofv102 26269796\n4. Giulieri S Tissot F A short journey through spirochetal infections Rev Med Suisse 2010 6 721 726 20432993\n5. Federal Food Safety and Veterinary Office. La leptospirose chez l'homme et chez l'animal. 2017. https://www.blv.admin.ch/blv/fr/home/tiere/tierseuchen/uebersicht-seuchen/alle-tierseuchen/leptospirose.html. Accessed 14 Sept 2020.\n6. Levett PN Leptospirosis Clin Microbiol Rev 2001 14 296 326 10.1128/CMR.14.2.296-326.2001 11292640\n7. Cetin BD Harmankaya O Hasman H Acute renal failure: a common manifestation of leptospirosis Ren Fail 2004 26 655 661 10.1081/jdi-200037154 15600257\n8. Khositseth S Sudjaritjan N Tananchai P Renal magnesium wasting and tubular dysfunction in leptospirosis Nephrol Dial Transplant 2008 23 952 958 10.1093/ndt/gfm698 17951309\n9. Picardeau M Virulence of the zoonotic agent of leptospirosis: still terra incognita? Nat Rev Microbiol 2017 15 297 307 10.1038/nrmicro.2017.5 28260786\n10. Izzedine H Launay-Vacher V Isnard-Bagnis C Drug-induced Fanconi's syndrome Am J Kidney Dis 2003 41 292 309 10.1053/ajkd.2003.50037 12552490\n11. Liamis G Rizos E Elisaf MS Reversible proximal tubular dysfunction in a patient with acute febrile illness and normal renal function: an evidence towards leptospirosis Clin Nephrol 2000 53 316 10809424\n12. Liberopoulos E Bairaktari E Elisaf M Reversible proximal tubular dysfunction in a patient with acute febrile illness, marked hyperbilirubinemia and normal renal function: evidence of leptospirosis Nephron 2002 91 532 533 10.1159/000064304 12119494\n13. Yang CW Pan MJ Wu MS Leptospirosis: an ignored cause of acute renal failure in Taiwan Am J Kidney Dis 1997 30 840 845 10.1016/s0272-6386(97)90091-3 9398130\n14. Krishnan A Karnad DR Medhekar TP Paralysis due to renal potassium wasting: an unusual presentation of leptospirosis Nephrol Dial Transplant 2003 18 2454 2455 10.1093/ndt/gfg350 14551392\n15. Yamaguchi T Higa N Okura N Characterizing interactions of Leptospira interrogans with proximal renal tubule epithelial cells BMC Microbiol 2018 18 64 10.1186/s12866-018-1206-8 29973159\n16. Wu MS Yang CW Pan MJ Reduced renal Na+-K+-Cl- co-transporter activity and inhibited NKCC2 mRNA expression by Leptospira shermani: from bed-side to bench Nephrol Dial Transplant 2004 19 2472 2479 10.1093/ndt/gfh452 15388818\n17. Spichler A Ko AI Silva EF Reversal of renal tubule transporter downregulation during severe leptospirosis with antimicrobial therapy Am J Trop Med Hyg 2007 77 1111 1119 10.4269/ajtmh.2007.77.1111 18165532\n18. Yang CW Leptospirosis renal disease: understanding the initiation by Toll-like receptors Kidney Int 2007 72 918 925 10.1038/sj.ki.5002393 17687261\n19. Yang CW Wu MS Pan MJ Leptospira outer membrane protein activates NF-kappaB and downstream genes expressed in medullary thick ascending limb cells J Am Soc Nephrol 2000 11 2017 2026 10.1681/ASN.V11112017 11053477\n20. Werion A Lengele JP Fanconi syndrome in alcoholic patients: old concept new idea Nephron 2019 141 201 202 10.1159/000496035 30602151\n\n",
"fulltext_license": "CC BY",
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"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Case report; Fanconi syndrome; Glucose; Kidney injury; Leptospirosis; Proximal tubular dysfunction",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D005198:Fanconi Syndrome; D006801:Humans; D007921:Leptospira interrogans; D007922:Leptospirosis; D008297:Male; D013557:Switzerland",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "358",
"pmc": null,
"pmid": "34294111",
"pubdate": "2021-07-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26269796;20432993;11292640;28260786;12552490;10809424;12119494;9398130;14551392;29973159;15388818;30602151",
"title": "Acute kidney injury with partial Fanconi syndrome in a patient with leptospirosis: a case report.",
"title_normalized": "acute kidney injury with partial fanconi syndrome in a patient with leptospirosis a case report"
} | [
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"companynumb": "CH-BAUSCH-BL-2022-006836",
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"abstract": "OBJECTIVE\nTo report a single case of donor-derived conjunctival-limbal melanoma that occurred after a keratolimbal allograft (KLAL).\n\n\nMETHODS\nCase report and literature review.\n\n\nRESULTS\nA 56-year-old white woman with a history of bilateral limbal stem cell deficiency developed a donor-related melanoma after a KLAL. Three months after undergoing an uncomplicated KLAL, the patient presented with hemorrhagic nodules within her conjunctiva and transplanted tissue. Excisional biopsy was performed, and the pathology results revealed melanoma cells. Although the donor of the KLAL had a history of metastatic melanoma, the ocular tissue was in compliance with all eye bank requirements for donation. After discovery of the tumor, the patient's systemic immunosuppression was stopped. Within 1 week, the patient demonstrated a dramatic improvement in the size of the lesion. One month after the initial biopsy, the KLAL tissue was excised, and a pathology report revealed that there were no viable tumor cells on the ocular surface. As the limbal stem cell deficiency recurred, the eye underwent placement of a Boston type 1 keratoprosthesis.\n\n\nCONCLUSIONS\nWe present a case of conjunctival-limbal melanoma after a KLAL from a donor who had a history of metastatic melanoma. In response to this case, the US eye banking guidelines were amended to include stricter parameters for vascularized ocular tissue transplantation.",
"affiliations": "*Cincinnati Eye Institute, Cincinnati, OH; †Department of Ophthalmology, University of Cincinnati, Cincinnati, OH; and ‡Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, OH.",
"authors": "Sepsakos|Lorena|L|;Cheung|Albert Y|AY|;Nerad|Jeffrey A|JA|;Mogilishetty|Gautham|G|;Holland|Edward J|EJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000001331",
"fulltext": null,
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"issn_linking": "0277-3740",
"issue": "36(11)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D064591:Allografts; D003230:Conjunctival Neoplasms; D003316:Corneal Diseases; D005260:Female; D006801:Humans; D016850:Limbus Corneae; D008545:Melanoma; D008875:Middle Aged; D013508:Ophthalmologic Surgical Procedures; D033581:Stem Cell Transplantation; D013234:Stem Cells; D014019:Tissue Donors; D014792:Visual Acuity",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1415-1418",
"pmc": null,
"pmid": "28834816",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Donor-Derived Conjunctival-Limbal Melanoma After a Keratolimbal Allograft.",
"title_normalized": "donor derived conjunctival limbal melanoma after a keratolimbal allograft"
} | [
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"companynumb": "US-TEVA-2018-US-921849",
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"abstract": "Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) improves progression-free survival in patients with advanced Hodgkin lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPPescalated to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring.\n\n\n\nAHL2011 is a randomised, non-inferiority, phase 3 study done in 90 centres across Belgium and France. Eligible patients were aged 16-60 years and had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0·33 or greater than or extranodal localisation, and had received no previous treatment for Hodgkin lymphoma. Randomisation was unmasked and done centrally by the permuted block method. Patients were randomly assigned to standard treatment (BEACOPPescalated given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPPescalated, after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPPescalated induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPPescalated and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy. In both treatment groups, PET at the end of induction therapy was used to decide whether to continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPPescalated). BEACOPPescalated consisted of bleomycin 10 mg/m2 and vincristine 1·4 mg/m2 intravenously on day 8, etoposide 200 mg/m2 intravenously on days 1-3, doxorubicin 35 mg/m2 and cyclophosphamide 1250 mg/m2 intravenously on day 1, 100 mg/m2 oral procarbazine on days 1-7, and 40 mg/m2 oral prednisone on days 1-14. ABVD was given every 28 days (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 intravenously on days 1 and 15). The primary endpoint was investigator-assessed progression-free survival. Non-inferiority analyses were done by intention to treat and per protocol. The study had a non-inferiority margin of 10%, to show non-inferiority of PET-guided treatment versus standard care with 80% power and an alpha of 2·5% (one-sided). This study is registered with ClinicalTrials.gov, number NCT01358747.\n\n\n\nFrom May 19, 2011, to April 29, 2014, 823 patients were enrolled-413 in the standard care group and 410 in the PET-driven group. 346 (84%) of 410 patients in the PET-driven treatment group were assigned to receive ABVD and 51 (12%) to continue receiving BEACOPPescalated after PET2. With a median follow-up of 50·4 months (IQR 42·9-59·3), 5-year progression-free survival by intention to treat was 86·2%, 95% CI 81·6-89·8 in the standard treatment group versus 85·7%, 81·4-89·1 in the PET-driven treatment group (hazard ratio [HR] 1·084, 95% CI 0·737-1·596; p=0·65) and per protocol the values were 86·7%, 95% CI 81·9-90·3 and 85·4%, 80·7-89·0, respectively (HR 1·144, 0·758-1·726; p=0·74). The most common grade 3-4 adverse events were leucopenia (381 [92%] in the standard treatment group and 387 [95%] in the PET-driven treatment group), neutropenia (359 [87%] and 366 [90%]), anaemia (286 [69%] vs 114 [28%]), thrombocytopenia (271 [66%] and 163 [40%]), febrile neutropenia (145 [35%] and 93 [23%]), infections (88 [22%] and 47 [11%]), and gastrointestinal disorders (49 [11%] and 48 [11%]). Serious adverse events related to treatment were reported in 192 (47%) patients in the standard treatment group and 114 (28%) in the PET-driven treatment group, including infections (84 [20%] of 412 vs 50 [12%] of 407) and febrile neutropenia (21 [5%] vs 23 [6%]). Six (1%) patients in the standard care group died from treatment-related causes (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukaemia), as did two (<1%) in the PET-driven treatment group (one from septic shock and one from acute myeloblastic leukaemia).\n\n\n\nPET after two cycles of induction BEACOPPescalated chemotherapy safely guided treatment in patients with advanced Hodgkin lymphoma and allowed the use of ABVD in early responders without impairing disease control and reduced toxicities. PET staging allowed accurate monitoring of treatment in this trial and could be considered as a strategy for the routine management of patients with advanced Hodgkin lymphoma.\n\n\n\nProgramme Hospitalier de Recherche Clinique.",
"affiliations": "Department of Haematology, University Hospital F Mitterrand and Inserm UMR 1231, Dijon, France. Electronic address: olivier.casasnovas@chu-dijon.fr.;Department of Haematology, Institut P Calmette, Marseille, France.;Department of Haematology, APHP, Hôpital Saint Louis, Université Paris Diderot, Paris, France.;Department of Haematology, Université Paris-Saclay, Gustave Roussy, Villejuif, France.;Department of Haematology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud and Université Claude Bernard Lyon-1, Pierre Bénite, France.;Department of Haematology, Centre H Becquerel, Rouen, France.;Department of Haematology, Hôpital H Mondor, Creteil, France.;Department of Haematology, Institut d'hématologie de Basse Normandie, Caen, France.;Department of Haematology, University Hospital of Nantes, Nantes, France.;Department of Haematology, Hospital Sud Francilien, Corbeille-Essonnes, France.;Department of Haematology, University Hospital of Bordeaux, Bordeaux, France.;Department of Haematology, Centre L Bérard, Lyon, France.;Department of Haematology, University Hospital of Nancy, Vandoeuvre les Nancy, France.;EA 7365 Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA), Department of Haematology, CHU Lille, Université de Lille, Lille, France.;Department of Haematology, Hôpital Necker, Paris, France.;Department of Haematology, Hôpital Mignot, Versailles, France.;Department of Haematology, University Hospital of Montpellier, Montpellier, France.;Department of Nuclear Medicine, Centre G F Leclerc, Dijon, France.;Department of Haematology, University Hospital of Brest, Brest, France.;Department of Nuclear Medicine, Hôpital R Huguenin, Institut Curie, St-Cloud, France.;Department of Haematology, Centre Hospitalier Départemental de Vendée, Hôpital de La Roche sur Yon, La Roche sur Yon, France.;Department of Haematology, University Hospital of Strasbourg, Strasbourg, France.;Department of Haematology, University Hospital of Rennes, Rennes, France.;Department of Haematology, University Hospital of Reims, Reims, France.;Department of Pathology, Institut Gustave Roussy, Villejuif, France.;Department of Pathology, University Hospital F Mitterrand and Inserm UMR 1231, Dijon, France.;Department of Haematology, CHU UCL Namur, Université Catholique de Louvain, Yvoir, Belgium.;Department of Haematology, University Hospital of Nice, Nice, France.;Department of Pathology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud and Université Claude Bernard Lyon-1, Pierre Bénite, France.;LYSA Imaging, Hôpital H Mondor, Creteil, France.",
"authors": "Casasnovas|René-Olivier|RO|;Bouabdallah|Reda|R|;Brice|Pauline|P|;Lazarovici|Julien|J|;Ghesquieres|Hervé|H|;Stamatoullas|Aspasia|A|;Dupuis|Jehan|J|;Gac|Anne-Claire|AC|;Gastinne|Thomas|T|;Joly|Bertrand|B|;Bouabdallah|Krimo|K|;Nicolas-Virelizier|Emmanuelle|E|;Feugier|Pierre|P|;Morschhauser|Franck|F|;Delarue|Richard|R|;Farhat|Hassan|H|;Quittet|Philippe|P|;Berriolo-Riedinger|Alina|A|;Tempescul|Adrian|A|;Edeline|Véronique|V|;Maisonneuve|Hervé|H|;Fornecker|Luc-Matthieu|LM|;Lamy|Thierry|T|;Delmer|Alain|A|;Dartigues|Peggy|P|;Martin|Laurent|L|;André|Marc|M|;Mounier|Nicolas|N|;Traverse-Glehen|Alexandra|A|;Meignan|Michel|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(18)30784-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "20(2)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D004360:Drug Therapy, Computer-Assisted; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D055815:Young Adult",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "202-215",
"pmc": null,
"pmid": "30658935",
"pubdate": "2019-02",
"publication_types": "D017428:Clinical Trial, Phase III; D000073843:Equivalence Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study.",
"title_normalized": "pet adapted treatment for newly diagnosed advanced hodgkin lymphoma ahl2011 a randomised multicentre non inferiority phase 3 study"
} | [
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"companynumb": "FR-PFIZER INC-2019033751",
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"actiondrug": "6",
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"activesubstancename": "ETOPOSIDE"
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{
"abstract": "BACKGROUND\nPeripheral blood stem cells (PBSCs) are the preferred source in autologous transplantation. We assessed prospectively the efficacy of mobilization in pediatric patients and risk factors associated with its failure.\n\n\nMETHODS\nPatients, aged 0 to 17 years, needing a first collection of PBSCs for autologous stem cell transplantation were eligible. The study period was from July 2008 to September 2010. A blood peak of fewer than 20 × 10(6) CD34+ cells/L was used as the cutoff to define a poor mobilizer.\n\n\nRESULTS\nA total of 145 patients, 57% male (82) and 43% female (63), with a median age of 7 years, affected by solid tumor, 79% (114), and acute leukemia or lymphoma, 21% (31), were enrolled. Granulocyte-colony-stimulating factor used was filgrastim in 69%, lenograstim in 26%, and pegfilgrastim in 5% of patients. A total of 83% (121) of patients mobilized successfully, the median CD34+ count being 120 × 10(6) /L (range, 23 × 10(6) -1840 × 10(6) /L). A single leukapheresis procedure was sufficient to achieve the target CD34+ cell dose in 82% (99/121) of patients. Among 24 poor mobilizer patients, 15 underwent a second mobilizing course and nine required a marrow harvest. Factors associated with poor mobilization were metastatic disease and relapse. Among 99 patients who underwent autologous stem cell transplantation, the median times to neutrophil and platelet engraftment and of hospitalization were longer by 2, 12, and 6 days in poor versus good mobilizer group.\n\n\nCONCLUSIONS\nIn pediatric patients undergoing a first mobilization, the incidence of poor mobilization was 17%. Failure of mobilization resulted in an increase in health costs and a longer hospitalization for those who underwent autologous stem cell transplantation.",
"affiliations": "Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. simone.cesaro@ospedaleuniverona.it",
"authors": "Cesaro|Simone|S|;Tintori|Veronica|V|;Nesi|Francesca|F|;Schiavello|Elisabetta|E|;Calore|Elisabetta|E|;Dallorso|Sandro|S|;Migliavacca|Maddalena|M|;Capolsini|Ilaria|I|;Desantis|Raffaella|R|;Caselli|Desirèe|D|;Fagioli|Franca|F|;Luksch|Roberto|R|;Panizzolo|Irene|I|;Tridello|Gloria|G|;Prete|Arcangelo|A|",
"chemical_list": "D018952:Antigens, CD34",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1537-2995.2012.03911.x",
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"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "53(7)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000293:Adolescent; D018952:Antigens, CD34; D002648:Child; D002675:Child, Preschool; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009369:Neoplasms; D011446:Prospective Studies; D012307:Risk Factors; D014182:Transplantation, Autologous",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "1501-9",
"pmc": null,
"pmid": "23034006",
"pubdate": "2013-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A prospective study on the efficacy of mobilization of autologous peripheral stem cells in pediatric oncohematology patients.",
"title_normalized": "a prospective study on the efficacy of mobilization of autologous peripheral stem cells in pediatric oncohematology patients"
} | [
{
"companynumb": "IT-AMGEN-ITASP2019089306",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "Immunoablation and autologous hematopoietic stem cell transplantation (IA/aHSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration.\n\n\n\nTo model GM and WM volume changes after IA/aHSCT to further understand the effects seen on WB atrophy.\n\n\n\nGM and WM volume changes were calculated from serial baseline and follow-up magnetic resonance imaging (MRI) ranging from 1.5 to 10.5 years in 19 MS patients treated with IA/aHSCT. A mixed-effects model with two predictors (total busulfan dose and baseline T1-weighted WM lesion volume \"T1LV\") characterized the time-courses after IA/aHSCT.\n\n\n\nAccelerated short-term atrophy of 2.1% and 3.2% occurred in GM and WM, respectively, on average. Both busulfan dose and T1LV were significant predictors of WM atrophy, whereas only busulfan was a significant predictor of GM atrophy. Compared to baseline, a significant reduction in GM atrophy, not WM atrophy, was found. The average rates of long-term GM and WM atrophy were -0.18%/year (standard error (SE): 0.083) and -0.07%/year (SE: 0.14), respectively.\n\n\n\nChemotherapy-related toxicity affected both GM and WM. WM was further affected by focal T1-weighted lesion-related pathologies. Long-term rates of GM and WM atrophy were comparable to those of normal-aging.",
"affiliations": "McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.;McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada/Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.;McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.;McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.;Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.;Ottawa Hospital Blood and Marrow Transplant Program, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.;Department of Medicine (Neurology), The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.;McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.",
"authors": "Lee|Hyunwoo|H|;Nakamura|Kunio|K|;Narayanan|Sridar|S|;Brown|Robert|R|;Chen|Jacqueline|J|;Atkins|Harold L|HL|;Freedman|Mark S|MS|;Arnold|Douglas L|DL|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1352458517715811",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "24(8)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Multiple sclerosis; atrophy; axonal loss; magnetic resonance imaging",
"medline_ta": "Mult Scler",
"mesh_terms": "D000328:Adult; D001284:Atrophy; D001921:Brain; D005260:Female; D066128:Gray Matter; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D019172:Transplantation Conditioning; D066127:White Matter; D055815:Young Adult",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "1055-1066",
"pmc": null,
"pmid": "28617152",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis.",
"title_normalized": "impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis"
} | [
{
"companynumb": "CA-OTSUKA-2018_019151",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nInflammatory bowel disease (IBD) is recognized as an independent risk factor for thrombosis. First, we investigate whether the concentration of fibrinolysis inhibitors is increased in patients with IBD. Second, we investigate the effect of infliximab induction therapy on the hemostatic profile.\n\n\nMETHODS\nThis prospective study included 103 patients with IBD starting infliximab therapy and 113 healthy controls. Plasma was collected before the first infliximab infusion (wk 0) and after induction therapy (wk 14). Patients not showing a clinical response on induction were considered as primary nonresponders. Fibrinolysis inhibitors were measured by enzyme-linked immunosorbent assay. Using a clot lysis assay, the area under the curve (global marker for coagulation/fibrinolysis), 50% clot lysis time (marker for fibrinolytic capacity), and amplitude (indicator for clot formation) were determined.\n\n\nRESULTS\nPatients with IBD selected for infliximab treatment have higher area under the curve (median 29 [interquartile range, 20-38]) and amplitude (0.4 [0.3-0.5]) compared with healthy controls (18 [13-24] and 0.3 [0.2-0.3], respectively, P < 0.001). Primary nonresponders showed a decrease neither in inflammatory markers nor in hemostatic parameters, whereas in primary responders, a decrease in inflammatory markers was associated with a decrease in both area under the curve (29 [20-38] (wk 0) to 20 [14-28] (wk 14), P < 0.001) and amplitude (0.4 [0.3-0.5] (wk 0) to 0.3 [0.3-0.4] (wk 14), P < 0.001).\n\n\nCONCLUSIONS\nThis is the first prospective study demonstrating that the clot lysis profile differs between patients with IBD and healthy individuals. On infliximab induction treatment, this clot lysis profile normalizes in responders suggesting that infliximab treatment is advisable for patients with IBD with an activated hemostatic profile.",
"affiliations": "*Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Leuven, Belgium; †Systems and Modeling Unit, Montefiore Institute, University of Liège, Liège, Belgium; ‡Translational Research in Gastrointestinal Disorders, Department of Gastroenterology, Universitair Ziekenhuis Leuven, Leuven, Belgium; and §Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, Universitair Ziekenhuis Leuven, Leuven, Belgium.",
"authors": "Bollen|Lize|L|;Vande Casteele|Niels|N|;Peeters|Miet|M|;Bessonov|Kyrylo|K|;Van Steen|Kristel|K|;Rutgeerts|Paul|P|;Ferrante|Marc|M|;Hoylaerts|Marc F|MF|;Vermeire|Severine|S|;Gils|Ann|A|",
"chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1097/MIB.0000000000000301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "21(3)",
"journal": "Inflammatory bowel diseases",
"keywords": null,
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D005260:Female; D005342:Fibrinolysis; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D013927:Thrombosis; D055815:Young Adult",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "570-8",
"pmc": null,
"pmid": "25659086",
"pubdate": "2015-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Short-term effect of infliximab is reflected in the clot lysis profile of patients with inflammatory bowel disease: a prospective study.",
"title_normalized": "short term effect of infliximab is reflected in the clot lysis profile of patients with inflammatory bowel disease a prospective study"
} | [
{
"companynumb": "BE-PFIZER INC-2016522918",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": null,
... |
{
"abstract": "We present a case of hemorrhagic shock occurred during dienogest therapy for uterine adenomyosis which necessitated an emergency hysterectomy. The patient was a 45-year-old woman with adenomyosis. Magnetic resonance imaging showed type I adenomyosis measuring 10 cm. She had a history of intimal thrombectomy of pulmonary embolism and had been receiving warfarin and aspirin until the onset of the hemorrhagic shock. Following 6-month of gonadotropin-releasing hormone analogue, dienogest was commenced. Nine months after switching to dienogest, the patient experienced a persistent abnormal uterine bleeding for 2 weeks, eventually causing a massive bleeding and was transferred to our emergency room. A diagnosis of hemorrhagic shock with a severe anemia (hemoglobin 3.6 g/dL) was made. Despite blood transfusion and warfarin antagonization, continuous bleeding ≥150 g/h was not controlled. Emergent hysterectomy was opted and enabled hemostasis. Although the number of patients with adenomyosis who can avoid surgery by dienogest is increasing, care must be taken during dienogest therapy, especially in patients with anticoagulants and after gonadotropin-releasing hormone analogue treatment. To prevent such a critical event, careful management including patient education should be carried out.",
"affiliations": "Department of Obstetrics and Gynecology, Saitama Medical University, Saitama, Japan.;Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.",
"authors": "Takamura|Masashi|M|;Koga|Kaori|K|;Harada|Miyuki|M|;Hirota|Yasushi|Y|;Fujii|Tomoyuki|T|;Osuga|Yutaka|Y|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14519",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": null,
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "GnRH analogue; adenomyosis; anticoagulant; dienogest",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": null,
"nlm_unique_id": "9612761",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33090620",
"pubdate": "2020-10-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of hemorrhagic shock occurred during dienogest therapy for uterine adenomyosis.",
"title_normalized": "a case of hemorrhagic shock occurred during dienogest therapy for uterine adenomyosis"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-267116",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIENOGEST"
},
"druga... |
{
"abstract": "Psittacosis, parrot fever, is an infectious disease caused by Chlamydophila psittaci, a common pathogen among birds. The clinical course ranges from a mild flu-like illness to severe disease that requires intensive care in humans. We report three cases of severe pneumonia where C. psittaci was unexpectedly detected during routine validation of a new C. psittaci PCR assay. Psittacosis is a notifiable disease in Sweden and national statistics show that 96% of Swedish psittacosis cases were identified in five of the 24 microbiological laboratories available in the country. These five laboratories perform PCR for C. psittaci routinely in panels with other atypical pneumonia agents and/or Legionella, suggesting that psittacosis is an underdiagnosed infection in Sweden.",
"affiliations": "Danderyds Sjukhus AB - Infektionskliniken Stockholm, Sweden Danderyds Sjukhus AB - Infektionskliniken Stockholm, Sweden.;Clinical Microbiology - Karolinska Universitetssjukhuset Solna, Sweden Clinical Microbiology - Karolinska Universitetssjukhuset Solna, Sweden.;Clinical Microbiology - Karolinska Universitetssjukhuset Solna, Sweden Clinical Microbiology - Karolinska Universitetssjukhuset Solna, Sweden.;Clinical Microbiology - Karolinska Universitetssjukhuset Solna, Sweden Clinical Microbiology - Karolinska Universitetssjukhuset Solna, Sweden.",
"authors": "Marking|Ulrika|U|;Hammas|Berit|B|;Grabbe|Malin|M|;Giske|Christian|C|",
"chemical_list": null,
"country": "Sweden",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-7205",
"issue": "115()",
"journal": "Lakartidningen",
"keywords": null,
"medline_ta": "Lakartidningen",
"mesh_terms": "D000328:Adult; D000368:Aged; D000818:Animals; D001717:Birds; D061387:Chlamydial Pneumonia; D002691:Chlamydophila psittaci; D017714:Community-Acquired Infections; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D009956:Psittacosis; D013548:Sweden",
"nlm_unique_id": "0027707",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30480746",
"pubdate": "2018-11-27",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Psittacosis - a forgotten diagnosis in Sweden?",
"title_normalized": "psittacosis a forgotten diagnosis in sweden"
} | [
{
"companynumb": "SE-MYLANLABS-2019M1053280",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nParacetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both.\n\n\nMETHODS\nWe undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270).\n\n\nRESULTS\nOf 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024).\n\n\nCONCLUSIONS\nIn patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen.\n\n\nBACKGROUND\nChief Scientist Office of the Scottish Government.",
"affiliations": "National Poisons Information Service, Royal Infirmary of Edinburgh, Edinburgh, UK. Electronic address: spib@luht.scot.nhs.uk.;National Poisons Information Service, Royal Infirmary of Edinburgh, Edinburgh, UK; British Heart Foundation Centre for Cardiovascular Science, Edinburgh University, Edinburgh, UK.;Institute of Cellular Medicine, Newcastle University, and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Institute of Cellular Medicine, Newcastle University, and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;National Poisons Information Service, Royal Infirmary of Edinburgh, Edinburgh, UK; British Heart Foundation Centre for Cardiovascular Science, Edinburgh University, Edinburgh, UK.;National Poisons Information Service, Royal Infirmary of Edinburgh, Edinburgh, UK.;Emergency Medicine Research Group, Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.;Emergency Department, Aberdeen Royal Infirmary, Aberdeen, UK.;Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, UK.;Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.;Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.;British Heart Foundation Centre for Cardiovascular Science, Edinburgh University, Edinburgh, UK.;National Poisons Information Service, Royal Infirmary of Edinburgh, Edinburgh, UK.;British Heart Foundation Centre for Cardiovascular Science, Edinburgh University, Edinburgh, UK.;Emergency Medicine Research Group, Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.",
"authors": "Bateman|D Nicholas|DN|;Dear|James W|JW|;Thanacoody|H K Ruben|HK|;Thomas|Simon H L|SH|;Eddleston|Michael|M|;Sandilands|Euan A|EA|;Coyle|Judy|J|;Cooper|Jamie G|JG|;Rodriguez|Aryelly|A|;Butcher|Isabella|I|;Lewis|Steff C|SC|;Vliegenthart|A D Bastiaan|AD|;Veiraiah|Aravindan|A|;Webb|David J|DJ|;Gray|Alasdair|A|",
"chemical_list": "D000932:Antiemetics; D000082:Acetaminophen; D017294:Ondansetron; D000410:Alanine Transaminase; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "383(9918)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase; D000932:Antiemetics; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D009325:Nausea; D017294:Ondansetron; D011041:Poisoning; D016896:Treatment Outcome; D006113:United Kingdom; D014839:Vomiting",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "697-704",
"pmc": null,
"pmid": "24290406",
"pubdate": "2014-02-22",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial.",
"title_normalized": "reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning a randomised controlled trial"
} | [
{
"companynumb": "GB-JNJFOC-20140302275",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Constrictive pericarditis is easily overlooked and can lead to severe problems in hemodynamics and end-organ perfusion, in our patient leading to 98 days of anuria after living kidney transplantation. This was completely reversible after pericardectomy.\n\n\n\nA 43-year-old female caucasian patient received a living kidney donation from her mother. She had developed end-stage renal disease 2 years prior due to nephrotic syndrome linked to graft-versus-host disease after allogenic stem-cell transplantation for aplastic anemia. The graft showed insufficient function already in the early postoperative phase. Dialysis was paused after surgery, but the patient developed hypervolemia with ascites and edema in the lower extremities. Doppler ultrasonography showed scarce perfusion, with intrarenal arterial waveforms without end-diastolic flow. The venous perfusion profiles showed pulsatile retrograde flow. There was no identifiable reason for a primary vascular perfusion problem on ultrasonography or transplant kidney angiography. Kidney transplant biopsy revealed no rejection but extensive acute tubular necrosis. Three weeks after transplantation, the patient developed an acute anuric graft failure caused by severe cardiac decompensation. Echocardiography revealed a previously unnoticed constrictive pericarditis, which could be confirmed in a cardio computed tomography scan. The constrictive pericarditis had not been apparent on previous x-rays, computed tomography scans, or echocardiographies, including those for transplantation evaluation. Conservative management of the constrictive pericarditis was not successful and the graft remained anuric. Eventually, the patient underwent pericardectomy 16 weeks after kidney transplantation. Shortly after surgery, the graft started urine production again, which significantly increased within a few days. The clearance improved and 2 weeks later, the patient was free from dialysis.\n\n\n\nThis case illustrates that special attention should be given to the pericardium during transplant evaluation, especially for patients who previously underwent stem-cell transplantations, chemotherapy or radiation.",
"affiliations": "Department of Nephrology and Hypertension, University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany. caroline.wacker@uk-erlangen.de.;Department of Cardiac Surgery, University Erlangen-Nürnberg, Krankenhausstraße 12, 91054, Erlangen, Germany.;Department of Nephrology and Hypertension, University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.;Department of Nephrology and Hypertension, University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.",
"authors": "Wacker|Caroline|C|;Weyand|Michael|M|;Schiffer|Mario|M|;Opgenoorth|Mirian|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12882-020-01899-2",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369 BioMed Central London \n\n1899\n10.1186/s12882-020-01899-2\nCase Report\nPericardectomy after pericarditis constrictiva led to onset of transplant kidney function after 98 days of anuric kidney graft: a case report\nWacker Caroline caroline.wacker@uk-erlangen.de 1 Weyand Michael 2 Schiffer Mario 1 Opgenoorth Mirian 1 1 grid.5330.50000 0001 2107 3311Department of Nephrology and Hypertension, University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany \n2 grid.5330.50000 0001 2107 3311Department of Cardiac Surgery, University Erlangen-Nürnberg, Krankenhausstraße 12, 91054 Erlangen, Germany \n29 6 2020 \n29 6 2020 \n2020 \n21 24127 2 2020 18 6 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/. 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.Background\nConstrictive pericarditis is easily overlooked and can lead to severe problems in hemodynamics and end-organ perfusion, in our patient leading to 98 days of anuria after living kidney transplantation. This was completely reversible after pericardectomy.\n\nCase presentation\nA 43-year-old female caucasian patient received a living kidney donation from her mother. She had developed end-stage renal disease 2 years prior due to nephrotic syndrome linked to graft-versus-host disease after allogenic stem-cell transplantation for aplastic anemia.\n\nThe graft showed insufficient function already in the early postoperative phase. Dialysis was paused after surgery, but the patient developed hypervolemia with ascites and edema in the lower extremities. Doppler ultrasonography showed scarce perfusion, with intrarenal arterial waveforms without end-diastolic flow. The venous perfusion profiles showed pulsatile retrograde flow. There was no identifiable reason for a primary vascular perfusion problem on ultrasonography or transplant kidney angiography. Kidney transplant biopsy revealed no rejection but extensive acute tubular necrosis. Three weeks after transplantation, the patient developed an acute anuric graft failure caused by severe cardiac decompensation. Echocardiography revealed a previously unnoticed constrictive pericarditis, which could be confirmed in a cardio computed tomography scan. The constrictive pericarditis had not been apparent on previous x-rays, computed tomography scans, or echocardiographies, including those for transplantation evaluation.\n\nConservative management of the constrictive pericarditis was not successful and the graft remained anuric. Eventually, the patient underwent pericardectomy 16 weeks after kidney transplantation. Shortly after surgery, the graft started urine production again, which significantly increased within a few days. The clearance improved and 2 weeks later, the patient was free from dialysis.\n\nConclusions\nThis case illustrates that special attention should be given to the pericardium during transplant evaluation, especially for patients who previously underwent stem-cell transplantations, chemotherapy or radiation.\n\nKeywords\nConstrictive pericarditisKidney transplantDelayed graft functionPericardectomyCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nConstrictive pericarditis (CP) is hard to diagnose in echocardiography and often overlooked. Untreated, it can lead to severe problems in hemodynamic regulation and end-organ perfusion, which can mean a decreased transplant function, as demonstrated in this case.\n\nUp to now, only a few case reports have been published on cases of constrictive pericarditis in kidney transplant patients. These include a case in Sri Lanka where pericardiocentesis had led to onset of graft function in the early phase on the second day after transplantation [1], and a Polish patient who developed CP a year after transplantation and displayed impaired graft function, which could be resolved by pericardectomy [2]. Four more cases of pericardectomy for CP several months to years after transplantation are described in [3] and [4]. All cases had a good prognosis after therapy.\n\nUnique for our case is the long phase of complete anuria (98 days), which required dialysis treatment and was followed by a complete recovery of kidney function after pericardectomy; in all previously described cases, the anuric phase only lasted up to 2 days.\n\nCase presentation\nA 43-year-old female caucasian patient received a living kidney donation from her mother. Two and a half years before, the patient had received high dose chemotherapy and an allogenic stem-cell transplantation due to aplastic anemia and secondary acute myeloic leukemia. Following this, the patient developed chronic graft-versus-host disease and, due to this, severe acute kidney failure with nephrotic syndrome and end-stage renal disease. Regular dialysis treatment was started 6 months before the living kidney donation.\n\nPre-transplant evaluations (including chest x-ray, ECG and echocardiogram) were unremarkable; the only issues were small amounts of ascites and a slightly dilated inferior vena cava (1.8 cm) without inspirational collapse in sonography. Both sonographic findings were attributed to hypervolemic phases in between dialysis treatment. Hypervolemia was also visible in dilated jugular veins.\n\nTuberculosis was ruled out during evaluation via chest x-ray and negative quantiferone test.\n\nDonor nephrectomy and kidney transplantation were performed without surgical complications. The patient showed low immunological risk, i.e. there was no evidence of preformed HLA antibodies, especially no donor specific antibodies. Mismatch was 0–1-0. She was treated with tacrolimus, mycophenolate mofetil and prednisolone and received induction with basiliximab; moreover, she received CMV prophylaxis with valganciclovir and Pneumocystis jirovecii prophylaxis.\n\nAfter kidney transplantation, dialysis was paused. Urinary output in the first 24 h was only 600 ml and remained similar in extent over the next days. Within days, the patient developed hypervolemia with ascites and edema in the lower extremities and high BNP levels (max. 17,395 pg/ml). Serum creatinine remained markedly increased at 3,5 mg/dl, which – in the first place – was attributed to high tacrolimus levels (max. 15 ng/ml). Blood pressure was around 100–110/70 mmHg (measured three times a day) throughout the patient’s stay.\n\nDoppler ultrasonography showed homogeneous perfusion without end-diastolic flow. The venous perfusion profiles showed pulsatile retrograde flow. There was no identifiable reason for a primary vascular perfusion problem on ultrasonography, particularly no sign of renal vein thrombosis; subsequent transplant kidney angiography also did not find any reason.\n\nUrine analysis was performed once to twice a week; the only findings were intermittent slight eumorphic erythrocyturia, which was attributed to the in-situ ureter stent.\n\nAt first, echocardiography did not reveal any reason for the volume overload, but showed normal ejection fraction.\n\nDrinking restriction and lowering of tacrolimus levels to 5 ng/ml led to a slow decrease in serum creatinine (minimum 2,49 mg/dl). Three weeks after transplantation, when serum creatinine stagnated and kidney perfusion still showed end-diastolic no-flow, volume excess was tried and the patient received three liters of intravenuous fluids in order to see if perfusion improved. This led to the development of an acute anuric graft failure, most likely caused by severe cardiac decompensation. Kidney biopsy was performed in order to rule out graft rejection; the report revealed only extensive acute tubular necrosis (see Figs. 1 and 2). Dialysis was started again.\nFig. 1 This figure shows a part of the patient’s renal cortex, displaying acute tubular necrosis while glomeruli are intact\n\nFig. 2 This image of the patient’s renal cortex displays signs of acute tubular necrosis as well (early phase with dense tubuli, but also wide tubuli)\n\n\n\nAnother echocardiography revealed normal right- and leftventricular function, an ejection fraction around 70%, but distinct septal bounce phenomenon and a pronounced respiratory variation in mitral inflow velocity (30%), as often seen in constrictive pericarditis. This diagnosis was confirmed via cardio CT scan.\n\nA conservative approach with optimal volume management and daily hemodialysis was tried for the constrictive pericarditis.\n\nAt last, a change in immunosuppressive therapy free from calcineurin inhibitors was decided and the patient received a belatacept-based medication.\n\nDespite all these actions, the graft remained anuric. Eventually, the patient underwent pericardectomy 16 weeks after kidney transplantation (13 weeks after beginning of anuric phase). Histology of the obtained pericardium was compatible with constrictive pericarditis, showing severely sclerosed pericardium with angiectasias and focal granulocyte infiltration (see Figs. 3 and 4). Within hours after surgery, the graft started urine production again; this significantly increased within days. Intermittently, the patient even showed polyuria. Glomerular filtration rate (GFR) also improved; 2 weeks later, the patient was – after 98 day of anuria – free from dialysis.\nFig. 3 In this part of the pericardium biopsy, fibrosis can be seen as well as invasion of inflammatory cells as a manifestation of pericarditis\n\nFig. 4 The displayed part of the pericardium consists of even more severe sclerosis, contributing to the constrictive part of the pericarditis, and also depicts angiectasias.\n\n\n\nIn the following months, serum creatine levels decreased even further with a serum creatinine of 1,37 mg/dl at its lowest (GFR 47 ml/min).\n\nDiscussion and conclusions\nIn constrictive pericarditis, cardiac filling is impeded by the inelastic pericardium, which leads to an impaired ability to adapt to volume changes. This often results in symptoms related to hypervolemia such as peripheral edema/anasarca and/or symptoms related to diminished cardiac output, such as fatigability or dyspnea. In our case, similar to what the authors described in [3], the constrictive pericarditis and its symptoms were masked by dialysis treatment and only came to full impact when dialysis was stopped.\n\nReasons for development of constrictive pericarditis are manifold. Leading causes, apart from idiopathic CP and post-cardiac surgery, include post-radiation therapy and infectious etiologies [5–8]. Also, cases associated with chronic graft-versus-host-disease [9, 10] and chemotherapy [11, 12] are described, one or more of which might be the cause of CP in our patient.\n\nDiagnosis of CP is often challenging. Electrocardiography is often unobtrusive, with sometimes nonspecific ST and T wave changes and tachycardia or low voltage present [13]. Chest radiograph might show signs for pericardial effusion or, in some cases, even pericardial calcification [13]; however, our patient did not display suspicious findings in both. While there is no single diagnostic echocardiographic parameter, there are a number of suggestive criteria such as presence of increased pericardial thickness, abnormal septal motion, pronounced respiratory variation in ventricular filling, bi-atrial enlargement, and dilated inferior vena cava and hepatic vein, typically in combination [13]. This requires an experienced echocardiographer; in retrospect, some of the clues may already have been present pre-transplant and at the first echocardiogram but were overlooked.\n\nOur patient was lucky to experience a full resolution of symptoms even after delayed diagnosis and prolonged time until pericardectomy, but this may not always be the case. The take-away message is to take constrictive pericarditis into consideration in patients at risk (as described above) and with symptoms of right-sided heart failure, seek establishment of definitive diagnosis by echocardiography and cardiac computed tomography, cardiac magnetic resonance imaging or catheterization and eventually initiate treatment as early as possible.\n\nOn the bright side: While long-term delayed graft function often is highly associated with detrimental impact on graft function and survival [14, 15], our case gives hope concerning recovery, especially in this severe case with anuria over several weeks. This is not only true for allograft kidneys but for kidney function in general.\n\nThere have been rare reports of complete recovery of kidney function after long periods of anuria, including a period of 14 anuric days in a case of acute suprarenal occlusion [16], a period of 72 days after ureteral obstruction [17] and even a period of 315 days in a heart-transplanted 15-year old with hypovolemia [18]. However, our case with 98 days of anuria is the first of such a long period reported in a kidney allograft and also the first in a patient with constrictive pericarditis.\n\nMethods\nFor capturing the microscopy images, an Imager A2 microscope with Axiocam Icc5 (Zeiss, Germany) was used. The acquisition software was ZEN 2.6 (Zeiss, Germany). Images were acquired at 200x magnification with a resolution of 300 dpi (1388 × 1040 pixels).\n\nAbbreviations\nCPConstrictive Pericarditis\n\nCTComputed Tomography\n\nGFRGlomerular Filtration Rate\n\nPro-BNPPro-brain natriuretic peptide\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank our patient for allowing us to publish her case. We thank Dr Frederick Pfister, Department of Nephropathology, University of Erlangen-Nürnberg, for kindly providing the microscopy images. A similar abstract was presented at the 28th Annual Meeting of the German Transplantation Society, Hannover, Germany, 17–19 October 2019 [19].\n\nAuthors’ contributions\nAll authors made substantial contributions to the case. CW wrote the manuscript. MO, MS and MW edited the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nThe datasets used during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Weerakkody RM Lokuliyana PN Sheriff MH Acute renal failure during immediate post transplant period due to a pericardial effusion BMC Res Notes 2015 8 587 10.1186/s13104-015-1571-4 26486858 \n2. Boratyńska M Jezior D Overlooked constrictive pericarditis as a cause of relapsing ascites and impairment of renal allograft function Transplant Proc 2009 41 5 1949 1950 10.1016/j.transproceed.2009.02.083 19545763 \n3. Celebi ZK Keven K Sengul S Sayin T Yazicioglu L Tuzuner A Constrictive pericarditis after renal transplantation: three case reports Transplant Proc 2013 45 3 953 955 10.1016/j.transproceed.2013.02.060 23622596 \n4. Weerakkody RM Perera HD Kularathne C Sheriff R Constrictive pericarditis in a post-renal transplant patient: a case report J Med Case Rep 2014 8 8 10.1186/1752-1947-8-8 24393255 \n5. Cameron J Oesterle SN Baldwin JC Hancock EW The etiologic spectrum of constrictive pericarditis Am Heart J 1987 113 2 Pt 1 354 360 10.1016/0002-8703(87)90278-X 3812191 \n6. Bertog SC Thambidorai SK Parakh K Schoenhagen P Ozduran V Houghtaling PL Constrictive pericarditis: etiology and cause-specific survival after pericardiectomy J Am Coll Cardiol 2004 43 8 1445 1452 10.1016/j.jacc.2003.11.048 15093882 \n7. Szabó G Schmack B Bulut C Soós P Weymann A Stadtfeld S Constrictive pericarditis: risks, aetiologies and outcomes after total pericardiectomy: 24 years of experience Eur J Cardiothorac Surg 2013 44 6 1023 1028 10.1093/ejcts/ezt138 23761416 \n8. George TJ Arnaoutakis GJ Beaty CA Kilic A Baumgartner WA Conte JV Contemporary etiologies, risk factors, and outcomes after pericardiectomy Ann Thorac Surg 2012 94 2 445 451 10.1016/j.athoracsur.2012.03.079 22621875 \n9. Leonard JT Newell LF Meyers G Hayes-Lattin B Gajewski J Heitner S Chronic GvHD-associated serositis and pericarditis Bone Marrow Transplant 2015 50 8 1098 1104 10.1038/bmt.2015.105 25961774 \n10. Karakulska-Prystupiuk E Basak G Dwilewicz-Trojaczek J Paluszewska M Boguradzki P Jędrzejczak W Pericarditis in patients with chronic graft-vs-host disease Transplant Proc 2018 50 7 2218 2222 10.1016/j.transproceed.2018.02.130 30177139 \n11. Hermans C Straetmans N Michaux JL Ferrant A Pericarditis induced by high-dose cytosine arabinoside chemotherapy Ann Hematol 1997 75 1–2 55 57 10.1007/s002770050312 9322684 \n12. Bock J Doenitz A Andreesen R Reichle A Hennemann B Pericarditis after high-dose chemotherapy: more frequent than expected? Onkologie. 2006 29 7 321 324 10.1159/000093528 16874016 \n13. Welch TD Constrictive pericarditis: diagnosis, management and clinical outcomes Heart. 2018 104 9 725 731 10.1136/heartjnl-2017-311683 29175978 \n14. Giral-Classe M Hourmant M Cantarovich D Dantal J Blancho G Daguin P Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys Kidney Int 1998 54 3 972 978 10.1046/j.1523-1755.1998.00071.x 9734625 \n15. Yarlagadda SG Klein CL Jani A Long-term renal outcomes after delayed graft function Adv Chronic Kidney Dis 2008 15 3 248 256 10.1053/j.ackd.2008.04.005 18565476 \n16. Jongkind V Kievit JK Wiersema AM Recovery of renal function after prolonged anuria in acute suprarenal aortic occlusion Ann Vasc Surg 2016 30 307.e11 307.e14 10.1016/j.avsg.2015.07.024 \n17. Hata M Tachibana M Deguchi N Jitsukawa S Recovery of renal function after 72 days of anuria caused by ureteral obstruction J Urol 1983 130 3 537 538 10.1016/S0022-5347(17)51292-6 6887371 \n18. Peng YH Yu XM Yan C Luo L Li TS Xiao J Recovery of renal function in a heart transplantation recipient with over 300 days of iatrogenic anuria: a case report Medicine (Baltimore) 2018 97 17 e0451 10.1097/MD.0000000000010451 29702997 \n19. Wacker C Visconti V Schiffer M Opgenoorth M Pericardectomy after pericarditis constrictiva led to onset of transplant kidney function after 13 weeks of anuric kidney graft – a case report. Transplant international 2019 Hoboken Wiley 49 50\n\n",
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"title": "Pericardectomy after pericarditis constrictiva led to onset of transplant kidney function after 98 days of anuric kidney graft: a case report.",
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"abstract": "This case report comprises three cases of antipsychotic drug-induced hypoglycemia and hypothermia. The mechanisms behind these side-effects are not known, but in hypoglycemia we describe signs of inappropriate insulin secretion. We assume that antipsychotic drug-induced hypoglycemia and hypothermia are underdiagnosed. Antipsychotic drugs are, however, widely used and these rare adverse-effects may occur in the clinical practice. It is of utmost importance to measure blood glucose and body temperature of patients taking these drugs who have unspecific symptoms.",
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"abstract": "Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID-19) complications and deaths. We aimed to describe cases of SARS-CoV-2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID-19 vaccine dose. The SECURE-Liver and COVID-Hep international reporting registries were used to identify laboratory-confirmed COVID-19 in CLD and LT patients who received a COVID-19 vaccination. Of the 342 cases of lab-confirmed SARS-CoV-2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID-19 vaccination, including 12 who were fully vaccinated (≥2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID-19 occurred in patients who had a single vaccine dose within the last 1-2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID-19 infections among patients with CLD and LT recipients who had received the COVID-19 vaccination. Vaccination against SARS-CoV-2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients.",
"affiliations": "Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.;Cambridge Liver Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom.;Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.;Department of Hepatology and Liver Transplantation, Asian Institute of Gastroenterology Hospitals, Gachibowli, Hyderabad, India.;Department of Gastroenterology and Hepatology, University of Health Sciences Istanbul Umraniye Training and Research Hospital, Istanbul, Turkey.;Toronto Center for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.;Department of Medicine and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece.;Liver Transplant Unit, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.;Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.;Oxford Liver Unit, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, United Kingdom.;Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.;Oxford Liver Unit, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, United Kingdom.",
"authors": "Moon|Andrew M|AM|https://orcid.org/0000-0001-7163-2062;Webb|Gwilym J|GJ|https://orcid.org/0000-0002-0710-5644;García-Juárez|Ignacio|I|https://orcid.org/0000-0003-2400-1887;Kulkarni|Anand V|AV|https://orcid.org/0000-0002-1240-1675;Adali|Gupse|G|https://orcid.org/0000-0003-2157-0304;Wong|David K|DK|https://orcid.org/0000-0002-3310-3538;Lusina|Beth|B|;Dalekos|George N|GN|https://orcid.org/0000-0001-7075-8464;Masson|Steven|S|https://orcid.org/0000-0003-1041-9844;Shore|Brandon M|BM|;Barnes|Eleanor|E|https://orcid.org/0000-0002-0860-0831;Barritt|A Sidney|AS|https://orcid.org/0000-0002-4200-3256;Marjot|Thomas|T|https://orcid.org/0000-0002-6542-6323",
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"fulltext": "\n==== Front\nHepatol Commun\nHepatol Commun\n10.1002/(ISSN)2471-254X\nHEP4\nHepatology Communications\n2471-254X\nJohn Wiley and Sons Inc. Hoboken\n\n34708575\n10.1002/hep4.1853\nHEP41853\nOriginal Article\nOriginal Articles\nSARS‐CoV‐2 Infections Among Patients With Liver Disease and Liver Transplantation Who Received COVID‐19 Vaccination\nMoon et al.\nMoon Andrew M. https://orcid.org/0000-0001-7163-2062\n1 * Andrew.Moon@unchealth.unc.edu\n\nWebb Gwilym J. https://orcid.org/0000-0002-0710-5644\n2 *\nGarcía‐Juárez Ignacio https://orcid.org/0000-0003-2400-1887\n3\nKulkarni Anand V. https://orcid.org/0000-0002-1240-1675\n4\nAdali Gupse https://orcid.org/0000-0003-2157-0304\n5\nWong David K. https://orcid.org/0000-0002-3310-3538\n6\nLusina Beth 7\nDalekos George N. https://orcid.org/0000-0001-7075-8464\n8\nMasson Steven https://orcid.org/0000-0003-1041-9844\n9\nShore Brandon M. 10\nBarnes Eleanor https://orcid.org/0000-0002-0860-0831\n11 *\nBarritt A. Sidney IV https://orcid.org/0000-0002-4200-3256\n1 *\nMarjot Thomas https://orcid.org/0000-0002-6542-6323\n11 *\n1 Division of Gastroenterology and Hepatology University of North Carolina Chapel Hill NC USA\n2 Cambridge Liver Unit Addenbrooke’s Hospital Cambridge University Hospitals Cambridge United Kingdom\n3 Department of Gastroenterology Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City Mexico\n4 Department of Hepatology and Liver Transplantation Asian Institute of Gastroenterology Hospitals Gachibowli Hyderabad India\n5 Department of Gastroenterology and Hepatology University of Health Sciences Istanbul Umraniye Training and Research Hospital Istanbul Turkey\n6 Toronto Center for Liver Disease Toronto General Hospital Research Institute University Health Network Toronto ON Canada\n7 Department of Medicine and Oncology Cumming School of Medicine University of Calgary Calgary AB Canada\n8 Department of Medicine and Research Laboratory of Internal Medicine National Expertise Center of Greece in Autoimmune Liver Diseases University Hospital of Larissa Larissa Greece\n9 Liver Transplant Unit Freeman Hospital The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne United Kingdom\n10 Department of Medicine University of North Carolina Chapel Hill NC USA\n11 Oxford Liver Unit, Translational Gastroenterology Unit Oxford University Hospitals NHS Foundation Trust University of Oxford Oxford United Kingdom\n* ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:\nAndrew Moon, M.D., M.P.H.\nDivision of Gastroenterology and Hepatology, University of North Carolina\n8009 Burnett Womack Bldg.\nChapel Hill, NC 27599‐7584, USA\nTel.: +1‐919‐445‐4742\nE‐mail: Andrew.Moon@unchealth.unc.edu\n\n* These authors contributed equally to this work.\n\n09 11 2021\n4 2022\n6 4 10.1002/hep4.v6.4 889897\n12 8 2021\n10 10 2021\n© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nMany safe and effective severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID‐19) complications and deaths. We aimed to describe cases of SARS‐CoV‐2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID‐19 vaccine dose. The SECURE‐Liver and COVID‐Hep international reporting registries were used to identify laboratory‐confirmed COVID‐19 in CLD and LT patients who received a COVID‐19 vaccination. Of the 342 cases of lab‐confirmed SARS‐CoV‐2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID‐19 vaccination, including 12 who were fully vaccinated (≥2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID‐19 occurred in patients who had a single vaccine dose within the last 1‐2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID‐19 infections among patients with CLD and LT recipients who had received the COVID‐19 vaccination. Vaccination against SARS‐CoV‐2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients.\n\nWellcome TrustClinical Research Training Fellowship American Association for the Study of Liver Diseases 10.13039/100005347 Advanced/Transplant Hepatology Award NIH Clinical CenterT32 DK007634 source-schema-version-number2.0\ncover-dateApril 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.2 mode:remove_FC converted:25.03.2022\nSupported by the Wellcome Trust (Clinical Research Training Fellowship), American Association for the Study of Liver Diseases (Advanced/Transplant Hepatology Award), and National Institutes of Health Clinical Center (T32 DK007634).\n\nPotential conflict of interest: Dr. Dalekos advises and received grants from Pfizer, Genkyotex, Novartis, and Sobi. He received grants from AbbVie and Gilead. Dr. Barritt consults for Target RWE.\n==== Body\npmcAbbreviations\n\nCLD chronic liver disease\n\nCOVID‐19 coronavirus disease 2019\n\nGI gastrointestinal\n\nICU intensive care unit\n\nLT liver transplant\n\nMMF mycophenolate mofetil\n\nmRNA messenger RNA\n\nSARS‐CoV‐2 severe acute respiratory syndrome coronavirus 2\n\nSince the onset of the coronavirus disease 2019 (COVID‐19) pandemic, we have learned much about the sequelae of COVID‐19 in patients with liver disease.( 1 ) Patients with decompensated cirrhosis are at increased risk of hospitalization, intensive care unit (ICU) admission, and death from COVID‐19.( 2 , 3 , 4 ) Although liver transplant (LT) recipients may not be at higher risk of COVID‐19 mortality,( 5 , 6 ) some data suggest that these patients might have an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection.( 7 ) Meanwhile, vaccine development has progressed at a rapid rate, and vaccine rollouts have tended to prioritize vulnerable patients, including immunocompromised patients.( 8 ) While the endorsement and potential value of SARS‐CoV‐2 vaccination is well‐established in patients with liver disease,( 9 , 10 , 11 ) more data are needed on vaccine response and sequelae of postvaccine infections in patients with chronic liver disease (CLD) and LT recipients.( 12 )\n\nThere is an excellent immune response to the SARS‐CoV‐2 vaccination in the general population; in vaccinated individuals, complications of COVID‐19, including ICU admission and death, are incredibly rare.( 13 , 14 , 15 , 16 ) However, vaccine immunogenicity may not be as robust for immunocompromised or immunosuppressed patients. Patients with advanced liver disease have deficiencies in innate and humoral immunity, referred to as cirrhosis‐associated immune dysfunction.( 17 , 18 ) Similarly, LT recipients require immunosuppressant medications and have blunted antibody responses following influenza, hepatitis A, hepatitis B, and pneumococcal vaccinations.( 19 , 20 , 21 , 22 ) Early data suggest that the antibody response to the SARS‐CoV‐2 vaccination is attenuated in CLD( 23 ) and solid organ recipients.( 24 , 25 ) However, real‐world data are still lacking on the patterns and outcomes of postvaccination infections in patients with CLD and LT recipients.\n\nWe used data from two large international registries to describe cases of laboratory‐confirmed COVID‐19 among patients with CLD and LT recipients who had received vaccination against SARS‐CoV‐2.\n\nPatients and Methods\n\nWe established an online reporting system for cases of laboratory‐confirmed SARS‐CoV‐2 in patients with CLD or prior LT. For this study, data were collected between March 5, 2021, and August 2, 2021 (era after vaccine licensing), through two collaborating registries (SECURE‐Liver supported by the American Association for the Study of Liver Diseases and COVID‐Hep.net supported by the European Association for the Study of the Liver). These registries were coordinated from the University of North Carolina (United States) and the University of Oxford (United Kingdom). Given that all data submitted to these registries were de‐identified, both the University of Oxford Clinical Trials and Research Governance and the University of North Carolina Office of Human Research Ethics deemed that this project was not human research and did not require formal institutional review board approval.\n\nAs previously described,( 2 , 5 ) clinicians were invited to submit online case report forms providing de‐identified clinical information on cases of laboratory‐confirmed SARS‐Cov‐2 in patients with prior LT or CLD. Case report forms included demographics, liver disease etiology and severity, SARS‐Cov‐2 vaccination details, and COVID‐19 outcomes, including hospitalization, ICU stay, and death. Clinicians were instructed to submit forms after patients had COVID‐19 for a long enough duration to experience recovery from COVID‐19 or death. Here we describe the cases of SARS‐CoV‐2 infection among patients with at least one prior COVID‐19 vaccine dose compared with contemporary (i.e., submitted March 5, 2021, to August 2, 2021) unvaccinated patients with CLD and prior LT.\n\nResults\n\nA total of 342 cases of lab‐confirmed SARS‐CoV‐2 infection among patients with CLD and prior LT were submitted to SECURE‐Liver and COVID‐Hep 2.0 from March 5, 2021, and August 2, 2021. Among these, 40 (12%) patients (n = 21 with CLD, n = 19 with LT) had at least one prior SARS‐CoV‐2 vaccination, 14 had received both doses (all received the same type of vaccine for both doses), and 12 occurred ≥2 weeks after the second vaccine dose (Fig. 1). Characteristics of CLD and LT cases are found in Tables 1 and 2, respectively, and the description of vaccinations received are shown in Fig. 1.\n\nFIG. 1 SARS‐CoV‐2 infection after COVID‐19 vaccination in patients with liver disease and transplantation.\n\nTABLE 1 Patient Characteristics and Information on Vaccination and COVID‐19 Outcomes Among Patients With CLD\n\nAge (years)\tSex\tEtiology\tCLD Severity\tVaccine Type\tVaccine Doses\tWeeks Between v1 & SARS‐CoV‐2\tWeeks Between v2 & SARS‐CoV‐2\tHospitalized\tInvasive Ventilation\tICU\tDeath\t\n60‐69\tM\tHCV\tCP‐A\tOxford‐AstraZeneca\t1\t<1\t–\tNo\t–\t–\tNo\t\n50‐59\tM\tNAFLD\tCP‐B\tOxford‐AstraZeneca\t1\t1\t–\tNo\t–\t–\tNo\t\n40‐49\tM\tNAFLD\tCP‐A\tOxford‐AstraZeneca\t1\t1\t–\tYes\tNo\tNo\tNo\t\n40‐49\tM\tOther\tNoncirrhotic CLD\tPfizer‐BioNTech\t1\t2\t–\tNo\t–\t–\tNo\t\n60‐69\tM\tNAFLD\tCP‐A\tOxford‐AstraZeneca\t1\t2\t–\tYes\tNo\tYes\tNo\t\n50‐59\tF\tNAFLD\tCP‐A\tOxford‐AstraZeneca\t1\t3\t–\tYes\tNo\tNo\tNo\t\n60‐69\tM\tHBV\tCP‐A\tOxford‐AstraZeneca\t1\t3\t–\tNo\t–\t–\tNo\t\n70‐79\tM\tOther\tNoncirrhotic CLD\tPfizer‐BioNTech\t1\t3\t–\tNo\t–\t–\tNo\t\n60‐69\tM\tALD\tCP‐A\tModerna\t1\t4\t–\tNo\t–\t–\tNo\t\n50‐59\tM\tHCV\tCP‐A\tBharat Biotech\t1\t4\t–\tNo\t–\t–\tNo\t\n50‐59\tF\tOther\tCP‐A\tCanSino\t1\t4\t–\tNo\t–\t–\tNo\t\n40‐49\tF\tOther\tCP‐B\tOxford‐AstraZeneca\t1\t6\t–\tNo\t–\t–\tNo\t\n40‐49\tM\tALD\tCP‐B\tOxford‐AstraZeneca\t1\t8\t–\tYes\tNo\tNo\tNo\t\n70‐79\tF\tOther\tCP‐B\tSinovac\t2\t5\t1\tNo\t–\t–\tNo\t\n50‐59\tF\tOther\tCP‐C\tBharat Biotech\t2\t9\t1\tNo\t–\t–\tNo\t\n60‐69\tM\tHCV\tCP‐A\tOxford‐AstraZeneca\t2\t9\t2\tYes\tNo\tNo\tNo\t\n60‐69\tF\tOther\tCP‐B\tOxford‐AstraZeneca\t2\t6\t3\tNo\t–\t–\tNo\t\n50‐59\tM\tNAFLD\tCP‐A\tPfizer‐BioNTech\t2\t9\t3\tNo\t–\t–\tNo\t\n70‐79\tF\tNAFLD\tCP‐A\tPfizer‐BioNTech\t2\t9\t6\tYes\tNo\tNo\tNo\t\n60‐69\tM\tNAFLD\tCP‐B\tOxford‐AstraZeneca\t2\t12\t8\tYes\tNo\tNo\tNo\t\n<40\tM\tOther\tCP‐A\tOxford‐AstraZeneca\t2\t18\t6\tNo\t–\t–\tNo\t\nNote:\n\nFull vaccinated patients in gray.\n\nAbbreviations: ALD, alcohol‐associated liver disease; CP‐A, Child‐Pugh A; CP‐B, Child‐Pugh B; CP‐C, Child‐Pugh C; F, female; HBV, hepatitis B virus; HCV, hepatitis C virus; M, male; NAFLD, nonalcoholic fatty liver disease; v1, first vaccine dose; v2, second vaccine dose.\n\nJohn Wiley & Sons, Ltd\n\nTABLE 2 Patient Characteristics Information on Vaccination and COVID‐19 Outcomes Among LT Recipients\n\nAge (years)\tSex\tTime Since Transplant (years)\tImmunosuppression\tVaccine Type\tVaccine Doses\tWeeks Between Last Dose & SARS‐CoV‐2\tWeeks Between v2 & SARS‐CoV‐2\tHospitalized\tInvasive Ventilation\tICU\tDeath\t\n50‐59\tM\t>10\tTacrolimus, MMF\tModerna\t1\t1\t–\tYes\tYes\tYes\tYes\t\n<40\tM\t5‐10\tTacrolimus\tOxford‐AstraZeneca\t1\t1\t–\tNo\t–\t–\tNo\t\n40‐49\tM\t1‐5\tTacrolimus\tSinovac\t1\t1\t–\tNo\t–\t–\tNo\t\n40‐59\tF\t1‐5\tTacrolimus, MMF\tOxford‐AstraZeneca\t1\t1\t–\tNo\t–\t–\tNo\t\n<40\tM\t5‐10\tTacrolimus\tPfizer‐BioNTech\t1\t2\t–\tNo\t–\t–\tNo\t\n60‐69\tM\t<1\tSirolimus, MMF\tModerna\t1\t2\t–\tYes\tYes\tYes\tYes\t\n70‐79\tF\t>10\tSirolimus\tPfizer‐BioNTech\t1\t2\t–\tYes\tYes\tYes\tNo\t\n60‐69\tF\t>10\tTacrolimus\tPfizer‐BioNTech\t1\t2\t–\tNo\t–\t–\tNo\t\n60‐69\tF\t1‐5\tTacrolimus, Everolimus, MMF\tBharat Biotech\t1\t2\t–\tNo\t–\t–\tNo\t\n60‐69\tM\t1‐5\tTacrolimus\tPfizer‐BioNTech\t1\t2\t–\tNo\t–\t–\tNo\t\n40‐49\tF\t>10\tPrednisone, tacrolimus, MMF\tPfizer‐BioNTech\t1\t3\t–\tNo\t–\t–\tNo\t\n60‐69\tM\t1‐5\tTacrolimus\tModerna\t1\t3\t–\tNo\t–\t–\tNo\t\n70‐79\tM\t6‐10\tTacrolimus, azathioprine\tOxford‐AstraZeneca\t1\t5\t–\tYes\tNo\tNo\tNo\t\n<40\tM\t1‐5\tPrednisone, tacrolimus\tModerna\t2\t6\t2\tNo\t–\t–\tNo\t\n60‐69\tM\t>10\tTacrolimus, MMF\tPfizer‐BioNTech\t2\t12\t2\tYes\tNo\tNo\tNo\t\n60‐69\tF\t1‐5\tNot known\tSinovac\t2\t7\t3\tNo\t–\t–\tNo\t\n50‐59\tF\t5‐10\tTacrolimus\tSinovac\t2\t8\t4\tYes\tNo\tNo\tNo\t\n60‐69\tF\t1‐5\tTacrolimus\tSinovac\t2\t8\t4\tNo\t–\t–\tNo\t\n40‐49\tM\t1‐5\tTacrolimus, MMF\tOxford‐AstraZeneca\t2\t20\t12\tNo\t–\t–\tNo\t\nNote:\n\nFull vaccinated patients in gray.\n\nAbbreviations: F, female; M, male; v1, first vaccine dose; v2, second vaccine dose.\n\nJohn Wiley & Sons, Ltd\n\nCOVID‐19 in Patients with CLD With ≥1 Vaccine Dose Versus Unvaccinated\n\nIn patients with CLD who received at least one vaccination (n = 21), the median age was 59 years (range 28‐72), 67% were male, and cases were from North America (n = 10, 45%), India (n = 6, 27%), the United Kingdom (n = 2, 9%), Turkey (n = 1, 5%), Indonesia (n = 1, 5%), and Greece (n = 1, 5%) (Table 1). The most common CLD etiology reported was nonalcoholic fatty liver disease (n = 7, 33%), and 90% of patients had cirrhosis (Child Pugh A/B/C, 63%/32%/5%). SARS‐CoV‐2 infection was diagnosed after one vaccine dose in 13 (62%) and after two doses in 8 (38%). Viral vector vaccines (Oxford‐AstraZeneca, CanSino) were received by 13 (62%), messenger RNA (mRNA) vaccines (Pfizer‐BioNTech, Moderna) by 5 (24%), and inactivated vaccines (Bharat Biotech, Sinovac) by 3 (14%). Among those who received a single vaccine dose, the median time from vaccination to infection was 3 weeks (range 0‐8), and for those who received both doses, the median time from the second dose to infection was 3 weeks (range 1‐8). Regarding symptoms at presentation, 11 (57%) had respiratory symptoms, 1 (5%) had gastrointestinal (GI) symptoms, 1 (5%) had GI and respiratory symptoms, and 8 (38%) reported no GI or respiratory symptoms (Table 3). Of these 21 patients who received prior vaccination, 7 (33%) were hospitalized, 1 (5%) was admitted to the ICU, 0 required invasive ventilation, and 0 died. Among patients with cirrhosis (n = 19), 9 (47%) developed a new decompensating event (8 new/worsening ascites, 7 hepatic encephalopathy, 4 spontaneous bacterial peritonitis), including 5 patients who were fully vaccinated (≥2 weeks after second dose).\n\nTABLE 3 Symptoms, Hospitalization, ICU Admission, Invasive Ventilation, and Death by Liver Disease and Vaccination Status\n\n\tAll CLDs, ≥1 Vaccine Dose (n = 21)\tAll CLDs, Unvaccinated (n = 225)\tCirrhosis, ≥1 Vaccine Dose (n = 19)\tCirrhosis, Unvaccinated (n = 159)\tPrior LT, ≥1 Vaccine Dose (n = 19)\tPrior LT, Unvaccinated (n = 77)\t\nGI and/or respiratory symptoms (n, %)\t13 (62%)\t172 (76%)\t12 (63%)\t118 (74%)\t17 (89%)\t68 (88%)\t\nHospitalization (n, %)\t7 (33%)\t162 (72%)\t7 (37%)\t118 (74%)\t6 (32%)\t33 (43%)\t\nICU admission (n, %)\t1 (5%)\t20 (9%)\t1 (5%)\t15 (9%)\t3 (16%)*\t7 (9%)\t\nInvasive ventilation (n, %)\t0 (0%)\t12 (5%)\t0 (0%)\t9 (6%)\t3 (16%)*\t9 (12%)\t\nDeath (n, %)\t0 (0%)\t18 (8%)\t0 (0%)\t15 (9%)\t2 (11%)*\t6 (8%)\t\n* All among patients with a single dose within 1‐2 weeks of SARS‐CoV‐2 diagnosis.\n\nJohn Wiley & Sons, Ltd\n\nIn comparison, among the 225 unvaccinated patients with CLD with COVID‐19 (median age 59 years, 62% male, 72% cirrhosis, Child‐Pugh A/B/C 47%/31%/22%), 185 (76%) had respiratory and/or GI symptoms from COVID‐19 compared with 57 (24%) who did not endorse GI or respiratory symptoms. Of these unvaccinated CLD cases, 162 (72%) were hospitalized, 20 (9%) were admitted to the ICU, 12 (5%) required invasive ventilation, and 18 (8%) died, primarily from COVID‐19 lung disease (n = 11 of 18, 61%) (Table 3). Similarly, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated compared to vaccinated patients with cirrhosis (Table 3).\n\nCOVID‐19 in LT Recipients With ≥1 Vaccine Dose Versus Unvaccinated\n\nAmong LT recipients who received at least one vaccination (n = 19), the median age was 60 years (range 32‐79), 58% were male, and most were from North America (n = 14, 74%) followed by Turkey (n = 2, 11%), India (n = 2, 11%), and the United Kingdom (n = 1, 5%) (Table 2). The median time from LT to infection was 4 years (range 1‐24), and the most common immunosuppression regimen prior to diagnosis was tacrolimus monotherapy (n = 8, 42%). A total of 7 (37%) were on mycophenolate mofetil (MMF). The most frequent vaccine type was mRNA (n = 10, 53%), and the remaining patients received inactivated (n = 5, 26%) and viral vector vaccines (n = 4, 21%). Among those who received a single vaccine dose, the median time from the vaccination to infection was 2 weeks (range 1‐5), and for those who received two doses, the median time from the second vaccine dose to infection was 3.5 weeks (range 2‐12). Most (n = 13, 68%) patients had respiratory symptoms at diagnosis, and 1 (5%) had no respiratory or GI symptoms (Table 3). There were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and ICU admission and 2 (11%) resulting in death. Deaths were from COVID‐19 lung disease in 1 patient and cardiogenic shock in 1 patient. Of note, all three cases of severe COVID‐19 occurred in patients who had a single vaccine dose within the last 1‐2 weeks (i.e., not fully vaccinated). Among fully vaccinated LT recipients (n = 5), there were 2 hospitalizations and 0 ICU admissions or deaths.\n\nThere were 77 unvaccinated LT recipients with lab‐confirmed COVID‐19 (median age = 53 years, 55% male, median time from transplant = 6 years [range <1‐31 years], 48% on tacrolimus monotherapy/29% on prednisone/22% on MMF). Respiratory symptoms were reported in 29 (38%), GI symptoms in 3 (4%), both GI/respiratory symptoms in 36 (47%), and neither respiratory nor GI symptoms in 8 (10%). Of these unvaccinated LT recipients, 33 (43%) were hospitalized, 7 (9%) were admitted to the ICU, 9 (12%) required mechanical ventilation, and 6 (8%) died, all from COVID‐19 lung disease (Table 3).\n\nDiscussion\n\nIn the general population, SARS‐CoV‐2 vaccination has demonstrated excellent safety and efficacy, resulting in a robust immune response and significantly reduced risks of COVID‐19 infection and complications.( 16 ) As we have previously shown, patients with decompensated cirrhosis have increased risks of COVID‐19 complications resulting in ICU admission and death.( 2 ) Given the potential for higher risks of COVID‐19 in CLD and LT recipients, guidelines strongly recommend vaccination in patients with liver diseases.( 9 , 10 , 11 ) In patients with CLD and prior LT, there is a lingering concern of low vaccine immunogenicity, given underlying immune dysfunction.( 12 ) This case series adds to recently published literature on breakthrough infections in transplant recipients,( 26 ) demonstrating the potential for breakthrough SARS‐CoV‐2 infections in patients with CLD and LT recipients. Yet, reassuringly, among patients who were fully vaccinated, there were no cases resulting in ICU admission, invasive ventilation, or death. Furthermore, among patients with CLD and cirrhosis, rates of hospitalization, ICU admission, invasive ventilation, and death were numerically lower among patients who had received at least one vaccine dose compared with those who were unvaccinated. These findings are consistent with recently published papers reporting that SARS‐CoV‐2 vaccination reduces severe disease in patients with cirrhosis( 27 ) and solid organ transplant recipients.( 28 )\n\nData on COVID‐19 vaccine response primary consist of reports of postvaccination antibody titers in LT recipients.( 24 ) Antibody titers are not the only correlate of protection against SARS‐CoV‐2 infection and may not be a sufficient measure of protection against COVID‐19 in patients with CLD and LT recipients. It may be that antibodies help prevent infections, which could explain breakthrough infections in our series. However, T‐cell responses, which may be preserved and sufficient in patients with CLD and LT recipients, might help attenuate the COVID‐19 disease course. This could underlie the low rates of ICU admission, mechanical ventilation, and death in patients with CLD who received the full COVID‐19 vaccine series in this data set. Supporting these observations, a recent report suggests that heart and liver transplant recipients develop adequate humoral or cellular responses to an mRNA vaccine.( 29 ) Postvaccination T‐cell responses in patients with CLD have yet to be fully characterized.\n\nThe few cases of severe COVID‐19 resulting in ICU admission and death reported in this series occurred after a single dose of SARS‐CoV‐2 vaccination and were diagnosed within 1‐2 weeks after the vaccine dose. SARS‐CoV‐2 immunity continues to improve beyond 2 weeks of the first mRNA vaccine dose and increases further after a second dose.( 30 ) It is also possible that some of these patients had SARS‐CoV‐2 infection at the time of vaccination. These data are important to inform patients on the need to complete the SARS‐CoV‐2 vaccination series and use other recommended strategies to prevent SARS‐CoV‐2 acquisition.\n\nAmong fully vaccinated patients, there were no cases of COVID‐19 resulting in ICU admission, mechanical ventilation or death, which should provide reassurance to patients and providers. However, there were some cases in our series of liver‐related decompensation events in fully vaccinated individuals, and the potential for breakthrough cases among an immunosuppressed population raises questions about improved strategies of protection against COVID‐19 in vulnerable populations. There has been interest in providing a booster dose to immunosuppressed patients, who may not mount a robust immune response. In a recent case series of vaccinated transplant recipients, a third of patients with negative antibody titers after two doses had increased titers after a third SARS‐CoV‐2 vaccination dose.( 31 ) However, a large proportion of patients had persistently low or negative anti‐spike antibody titers after a third booster dose. Until more data are available on the benefits of this strategy, this suggests that precautions including social distancing and masking should remain in place for patients at the highest risk of severe COVID‐19, including those with decompensated cirrhosis.( 2 )\n\nThis study is strengthened by its large, international, diverse patient data set. Additionally, the use of clinician reporting minimizes the risk of misclassification of liver disease, vaccination details, and COVID‐19 outcomes. However, the findings of this study have to be interpreted in the context of potential limitations. First, this cohort may be subject to selection bias inherent in registry studies, potentially resulting in an overrepresentation of patients with severe COVID‐19. Second, this study design does not allow for the identification of patients with liver disease who were vaccinated but did not test positive for SARS‐CoV‐2. Therefore, while these data demonstrate the potential for breakthrough infections, we are unable to determine the rates of COVID‐19 infections among vaccinated patients with liver disease. Third, as a comparison population, we included cases of SARS‐CoV‐2 among unvaccinated patients with CLD and liver transplant recipients. While these cases were submitted to registries during an identical time period to vaccinated cases (March 5, 2021, to July 22, 2021), it remains possible that some of the infections among unvaccinated individuals occurred before this time (such as before vaccines were available) and were logged after some delay. Finally, we were not able to adjust for potential center‐specific or region‐specific differences in the management of COVID‐19, which could influence hospitalization rates, ICU escalation decisions, and outcomes.\n\nIn summary, this case series demonstrates the potential for breakthrough COVID‐19 infections among patients with CLD and LT recipients. Although some fully vaccinated patients were hospitalized, reassuringly, COVID‐19 resulting in ICU admission or death was limited to patients who had received a recent, single SARS‐CoV‐2 dose. These data reinforce the existing guidelines recommending COVID‐19 vaccination for patients with CLD and LT recipients. However, well‐established strategies for COVID‐19 prevention, including physical distancing and masking, should be considered even for vaccinated patients with CLD and LT recipients. Given the remaining unknowns, ongoing research in these populations on postvaccine immune response and strategies such as booster doses will be important.\n\nSupporting information\n\nTable S1\n\nClick here for additional data file.\n\nAcknowledgment\n\nThe authors thank all of those who submitted cases to the registry (Supporting Table S1). They acknowledge the following endorsing societies: American Association for the Study of Liver Diseases, European Association for Study of the Liver, United European Gastroenterology, British Association for Study of the Liver, International Liver Cancer Association, British Society of Gastroenterology, Gastroenterological Society of Australia, British Liver Trust, European Liver Patients’ Association, Hellenic Association of the Study of the Liver, Hepatology Society of the Philippines, Chinese Portal Hypertension Diagnosis and Monitoring Study Group, and ERN RARE LIVER.\n==== Refs\nReferences\n\n1 Marjot T , Webb GJ , Barritt AS , Moon AM , Stamataki Z , Wong VW , et al. COVID‐19 and liver disease: mechanistic and clinical perspectives. Nat Rev Gastroenterol Hepatol 2021;18 :348‐364.33692570\n2 Marjot T , Moon AM , Cook JA , Abd‐Elsalam S , Aloman C , Armstrong MJ , et al. 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EASL position paper on the use of COVID‐19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients. J Hepatol 2021;74 :944‐951.33563499\n11 American Society of Transplantation . Updated joint AST/ASTS/ISHLT statement about vaccine efficacy in organ transplant recipients. https://www.myast.org/updated‐joint‐astastsishlt‐statement‐about‐vaccine‐efficacy‐organ‐transplant‐recipients. Accessed July 21, 2021.\n12 Marjot T , Webb GJ , Barritt AS , Ginès P , Lohse AW , Moon AM , et al. SARS‐CoV‐2 vaccination in patients with liver disease: responding to the next big question. Lancet Gastroenterol Hepatol 2021;6 :156‐158.33444545\n13 Polack FP , Thomas SJ , Kitchin N , Absalon J , Gurtman A , Lockhart S , et al. Safety and efficacy of the BNT162b2 mRNA Covid‐19 vaccine. N Engl J Med 2020;383 :2603‐2615.33301246\n14 Voysey M , Clemens SAC , Madhi SA , Weckx LY , Folegatti PM , Aley PK , et al. Safety and efficacy of the ChAdOx1 nCoV‐19 vaccine (AZD1222) against SARS‐CoV‐2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397 :99‐111.33306989\n15 Baden LR , El Sahly HM , Essink B , Kotloff K , Frey S , Novak R , et al. Efficacy and safety of the mRNA‐1273 SARS‐CoV‐2 vaccine. N Engl J Med 2021;384 :403‐416.33378609\n16 Team CC‐VBCI . COVID‐19 vaccine breakthrough infections reported to CDC—United States, January 1‐April 30, 2021. MMWR Morb Mortal Wkly Rep 2021;70 :792‐793.34043615\n17 Lebossé F , Gudd C , Tunc E , Singanayagam A , Nathwani R , Triantafyllou E , et al. CD8(+)T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis‐associated immune dysfunction. EBioMedicine 2019;49 :258‐268.31678004\n18 Liaskou E , Hirschfield GM . Cirrhosis‐associated immune dysfunction: novel insights in impaired adaptive immunity. EBioMedicine 2019;50 :3‐4.31727600\n19 Chong PP , Avery RK . A comprehensive review of immunization practices in solid organ transplant and hematopoietic stem cell transplant recipients. Clin Ther 2017;39 :1581‐1598.28751095\n20 Aggeletopoulou I , Davoulou P , Konstantakis C , Thomopoulos K , Triantos C . Response to hepatitis B vaccination in patients with liver cirrhosis. Rev Med Virol 2017;27 :e1942.\n21 McCashland TM , Preheim LC , Gentry MJ . Pneumococcal vaccine response in cirrhosis and liver transplantation. J Infect Dis 2000;181 :757‐760.10669371\n22 Harmala S , Parisinos CA , Shallcross L , O'Brien A , Hayward A . Effectiveness of influenza vaccines in adults with chronic liver disease: a systematic review and meta‐analysis. BMJ Open 2019;9 :e031070.\n23 Hakimian D , Shafrir A , Milgrom Y , Masarwa M , Hazou W , Amer J , et al. Elderly with advanced liver fibrosis had lower response to Pfizer’s SARS‐CoV‐2 vaccine response. In: Proceedings of the European Association for the Study of the Liver International Liver Conference, 2021.\n24 Boyarsky BJ , Werbel WA , Avery RK , Tobian AAR , Massie AB , Segev DL , et al. Antibody response to 2‐dose SARS‐CoV‐2 mRNA vaccine series in solid organ transplant recipients. JAMA 2021;325 :2204‐2206.33950155\n25 Rabinowich L , Grupper A , Baruch R , Ben‐Yehoyada M , Halperin T , Turner D , et al. Low immunogenicity to SARS‐CoV‐2 vaccination among liver transplant recipients. J Hepatol 2021;75 :435‐438.33892006\n26 Qin CX , Moore LW , Anjan S , Rahamimov R , Sifri CD , Ali NM , et al. Risk of breakthrough SARS‐CoV‐2 infections in adult transplant recipients. Transplantation 2021;105 :e265‐e266.34310531\n27 John BV , Deng Y , Scheinberg A , Mahmud N , Taddei TH , Kaplan D , et al. Association of BNT162b2 mRNA and mRNA‐1273 vaccines with COVID‐19 infection and hospitalization among patients with cirrhosis. JAMA Intern Med 2021;181 :1306‐1314.34254978\n28 Ravanan R , Mumford L , Ushiro‐Lumb I , Callaghan C , Pettigrew G , Thorburn D , et al. Two doses of SARS‐CoV‐2 vaccines reduce risk of death due to COVID‐19 in solid organ transplant recipients: preliminary outcomes from a UK registry linkage analysis. Transplantation 2021;105 :e263‐e264.34310530\n29 Herrera S , Colmenero J , Pascal M , Escobedo M , Castel MA , Sole‐González E , et al. Cellular and humoral immune response after mRNA‐1273 SARS‐CoV‐2 vaccine in liver and heart transplant recipients. Am J Transplant 2021 Jul 22. 10.1111/ajt.16768. [Epub ahead of print]\n30 Walsh EE , Frenck RW , Falsey AR , Kitchin N , Absalon J , Gurtman A , et al. Safety and immunogenicity of two RNA‐based Covid‐19 vaccine candidates. N Engl J Med 2020;383 :2439‐2450.33053279\n31 Werbel WA , Boyarsky BJ , Ou MT , Massie AB , Tobian AAR , Garonzik‐Wang JM , et al. Safety and immunogenicity of a third dose of SARS‐CoV‐2 vaccine in solid organ transplant recipients: a case series. Ann Intern Med 2021;174 :1330‐1332.34125572\nAuthor names in bold designate shared co‐first authorship.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2471-254X",
"issue": null,
"journal": "Hepatology communications",
"keywords": null,
"medline_ta": "Hepatol Commun",
"mesh_terms": null,
"nlm_unique_id": "101695860",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34708575",
"pubdate": "2021-10-28",
"publication_types": "D016428:Journal Article",
"references": "34310530;33444545;33306989;33378609;10669371;33892006;32750442;32526252;33035628;28751095;34278287;31494620;34254978;34043615;32866433;34310531;28905444;33577086;31678004;33382671;34291552;33563499;34125572;31727600;33692570;33301246;33053279;33219546;33950155",
"title": "SARS-CoV-2 Infections Among Patients With Liver Disease and Liver Transplantation Who Received COVID-19 Vaccination.",
"title_normalized": "sars cov 2 infections among patients with liver disease and liver transplantation who received covid 19 vaccination"
} | [
{
"companynumb": "US-MYLANLABS-2022M1049077",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nNowadays, pulsed radiofrequency (PRF) is being used to control several types of musculoskeletal pain. Herein, we report a successful application of ultrasound (US)-guided PRF for a patient with refractory sciatic neuropathic pain.\n\n\nMETHODS\nWe applied US-guided PRF to a 50-year-old man, suffering from refractory neuropathic pain on the left foot following sciatic neuropathy for a period of approximately 6 months. We performed PRF on the level of piriformis muscle because the lesion of the sciatic nerve was presented digitally from the level of piriformis muscle on the magnetic resonance images. Under US guidance, the catheter needle was placed close to the left sciatic nerve, and dysesthesia and tingling sensation were reported to be less than 0.2 V. The PRF treatment was administered at 5 Hz and 5 ms pulsed width for 360 seconds at 45 V. After PRF on the left sciatic nerve, pain intensity - based on a numeric rating scale - decreased from 8 to 2. The reduction of pain was sustained for at least 6 months after the PRF procedure.\n\n\nCONCLUSIONS\nWe concluded that the PRF treatment is a very useful treatment technique for patients with refractory sciatic neuropathy.",
"affiliations": "Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Daegu, Korea.;Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Daegu, Korea.;Department of Radiology, College of Medicine, Yeungnam University, Daegu, Korea.;Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Daegu, Korea.",
"authors": "Lee|Dong Gyu|DG|;Cho|Yun Woo|YW|;Cho|Kil-Ho|KH|;Chang|Min Cheol|MC|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.3233/BMR-169724",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8127",
"issue": "30(5)",
"journal": "Journal of back and musculoskeletal rehabilitation",
"keywords": "Sciatic neuropathy; neuropathic pain; pulsed radiofrequency; ultrasound",
"medline_ta": "J Back Musculoskelet Rehabil",
"mesh_terms": "D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009437:Neuralgia; D059408:Pain Management; D061208:Pulsed Radiofrequency Treatment; D012584:Sciatic Nerve; D014463:Ultrasonography",
"nlm_unique_id": "9201340",
"other_id": null,
"pages": "1141-1145",
"pmc": null,
"pmid": "28946529",
"pubdate": "2017-09-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of refractory sciatic neuropathic pain using ultrasound-guided pulsed radiofrequency.",
"title_normalized": "management of refractory sciatic neuropathic pain using ultrasound guided pulsed radiofrequency"
} | [
{
"companynumb": "KR-BAUSCH-BL-2017-031019",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPosterior reversible encephalopathy syndrome (PRES) is a well-recognized complication of hypertensive encephalopathy. Recently, pre-eclampsia, connective tissue disorders, and immunosuppressive drugs have been reported to be the etiologies of this rare syndrome.\n\n\nMETHODS\nWe evaluated 9 cases of PRES whose diagnosis were confirmed based on clinical and radiologic evidence between July 2011 and December 2013 in a tertiary center, Imam Khomeini Hospital, Tehran, Iran.\n\n\nRESULTS\nImmunosuppressive drugs, especially cyclosporine, and hypertension were the main precipitating factors. In this study, seizure was the most common clinical presentation (100%), whereas other common clinical presentations were confusion (78%), visual loss (67%), and headaches (67%). With conservative management and elimination of predisposing factor, the patients improved gradually except for 2 cases who experienced prolonged recovery period because of delayed diagnosis.\n\n\nCONCLUSIONS\nWith timely diagnosis, PRES generally has a good prognosis with complete recovery. However, in missed conditions, it could be associated with catastrophic burden especially in organ transplantation after a prolonged time spending to find matched donors or in chronic immunosuppressive conditions. Thereupon, physicians should be aware of clinical and radiologic manifestations of this preventable but potentially disabling syndrome.",
"affiliations": "Iranian Center of Neurological Research, Neurology Department of Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Iranian Center of Neurological Research, Neurology Department of Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Iranian Center of Neurological Research, Neurology Department of Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Iranian Center of Neurological Research, Neurology Department of Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: b-siroos@razi.tums.ac.ir.",
"authors": "Harirchian|Mohammad Hossein|MH|;Ghaffarpour|Majid|M|;Tabaeizadeh|Mohammad|M|;Siroos|Bahaadin|B|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "24(8)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Posterior reversible encephalopathy syndrome; hypertension; immunosuppressive drugs; organ transplantation",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016572:Cyclosporine; D005260:Female; D006801:Humans; D006973:Hypertension; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "e191-5",
"pmc": null,
"pmid": "26082344",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immunosuppressive Drugs, an Emerging Cause of Posterior Reversible Encephalopathy Syndrome: Case Series.",
"title_normalized": "immunosuppressive drugs an emerging cause of posterior reversible encephalopathy syndrome case series"
} | [
{
"companynumb": "PHHY2015IR099614",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nRadiation-induced tumors are a rare complication of radiation therapy. Here, we describe the first case of a radiation-induced osteosarcoma with a rhabdomyosarcoma component arising from the dura mater after radiation therapy for an astrocytoma.\n\n\nMETHODS\nAn 18-year-old man with generalized seizures presented with a neoplastic lesion in the dura mater of a previously irradiated (56 Gy) region 5 years after the initial radiation therapy. A tumor resection was performed, and histological examination revealed an osteosarcoma with a rhabdomyosarcoma component. The tumor recurred despite eight tumorectomies and the addition of chemotherapy and radiotherapy. The patient died from tumor progression 5 years after the first surgical removal of the radiation-induced tumor.\n\n\nCONCLUSIONS\nThis radiation-induced tumor may have originated from primitive, multipotent mesenchymal cells, as it included both osteosarcoma and rhabdomyosarcoma components.",
"affiliations": "Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. utsuki@med.kitasato-u.ac.jp",
"authors": "Utsuki|S|S|;Oka|H|H|;Sato|K|K|;Shimizu|S|S|;Suzuki|S|S|;Fujii|K|K|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.5414/npp28096",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0722-5091",
"issue": "28(2)",
"journal": "Clinical neuropathology",
"keywords": null,
"medline_ta": "Clin Neuropathol",
"mesh_terms": "D000293:Adolescent; D001254:Astrocytoma; D001921:Brain; D004388:Dura Mater; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008577:Meningeal Neoplasms; D009381:Neoplasms, Radiation-Induced; D012516:Osteosarcoma; D011880:Radiotherapy Planning, Computer-Assisted; D012208:Rhabdomyosarcoma",
"nlm_unique_id": "8214420",
"other_id": null,
"pages": "96-100",
"pmc": null,
"pmid": "19353840",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Radiation-induced osteosarcoma with a rhabdomyosarcoma component arising from the dura mater: a case report.",
"title_normalized": "radiation induced osteosarcoma with a rhabdomyosarcoma component arising from the dura mater a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2021423035",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "Steroid-induced psychosis is a known serious adverse effect seen commonly in adults but less commonly in children. We present a seven-year-old girl with steroid-dependent nephrotic syndrome who developed abnormal behaviour, trichotillomania, alopecia and mood changes. She was investigated to rule out other causes and treated with tapering steroids, fluoxetine and olanzapine. A marked improvement was noted after two months. Patients on long term or high dose steroids should be monitored for adverse psychological effects of steroids, as early recognition and intervention can improve the outcome.",
"affiliations": "Assistant Professor, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Junior Resident, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Associate Professor, Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, India.;Senior Resident, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Associate Professor, Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Assistant Professor, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Dawman|Lesa|L|https://orcid.org/0000-0003-4253-3385;Yadav|Arti|A|;Sharawat|Indar K|IK|https://orcid.org/0000-0002-7003-7218;Srinivasan|Santhiya|S|;Sharma|Akhilesh|A|;Tiewsoh|Karalanglin|K|",
"chemical_list": "D013256:Steroids",
"country": "England",
"delete": false,
"doi": "10.1177/00494755211016126",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-4755",
"issue": "51(4)",
"journal": "Tropical doctor",
"keywords": "Steroids; alopecia; antipsychotics; nephrotic syndrome; psychosis; trichotillomania",
"medline_ta": "Trop Doct",
"mesh_terms": "D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D009404:Nephrotic Syndrome; D013256:Steroids; D014256:Trichotillomania",
"nlm_unique_id": "1301706",
"other_id": null,
"pages": "591-593",
"pmc": null,
"pmid": "34018888",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trichotillomania in a child with nephrotic syndrome: An unusual steroid induced psychiatric manifestation.",
"title_normalized": "trichotillomania in a child with nephrotic syndrome an unusual steroid induced psychiatric manifestation"
} | [
{
"companynumb": "IN-STRIDES ARCOLAB LIMITED-2022SP000211",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nAlthough the ingestion of a dose of colchicine lower than 0.5 mg/kg is usually complicated by a mortality rate less than 5%, severe complications may be associated with drug-drug interactions in case of overdose combining other drugs.\n\n\nMETHODS\nA 33-year-old previously healthy woman was admitted after a drug overdose combining colchicine, atorvastatin, ibuprofen, diclofenac, and furosemide. The amount of colchicine ingested was exactly 20 mg, corresponding to 0.33 mg/kg. Despite this relatively low dose, she presented the clinical course that is usually seen with much larger colchicine ingestions. She developed acute renal and liver failure, acute lung injury, pancytopenia with sepsis, rhabdomyolysis, hypertriglyceridemia, and ultimately died on Day 14 from hyperammonemic encephalopathy, refractory hypoxemia, and cardiac arrhythmias.\n\n\nCONCLUSIONS\nSerious drug-drug interactions may have complicated colchicine poisoning. In particular, atorvastatin, an inhibitor of P-glycoprotein and cytochrome P450 3A4, was likely responsible for an increased severity of rhabdomyolysis. In addition, propofol used for sedation during mechanical ventilation may have induced symptoms consistent with \"propofol infusion syndrome,\" with further muscular injury and hypertriglyceridemia. The mechanism of death was unusual and similar to Reye's syndrome.",
"affiliations": "Department of Intensive Care, Université Catholique de Louvain, Cliniques St-Luc, Brussels, Belgium.",
"authors": "Montiel|Virginie|V|;Huberlant|Vincent|V|;Vincent|Marie-Françoise|MF|;Bonbled|Frédéric|F|;Hantson|Philippe|P|",
"chemical_list": "D065692:Cytochrome P-450 CYP3A Inhibitors; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003078:Colchicine; D015742:Propofol",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2010.509101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "48(8)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D000069059:Atorvastatin; D003078:Colchicine; D003422:Critical Care; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D062787:Drug Overdose; D005260:Female; D006538:Heptanoic Acids; D006801:Humans; D009102:Multiple Organ Failure; D015742:Propofol; D011758:Pyrroles; D012206:Rhabdomyolysis",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "845-8",
"pmc": null,
"pmid": "20969505",
"pubdate": "2010-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple organ failure after an overdose of less than 0.4 mg/kg of colchicine: role of coingestants and drugs during intensive care management.",
"title_normalized": "multiple organ failure after an overdose of less than 0 4 mg kg of colchicine role of coingestants and drugs during intensive care management"
} | [
{
"companynumb": "BE-STRIDES ARCOLAB LIMITED-2016SP016655",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional... |
{
"abstract": "Here we report a rare case of late recurrence of pancreatic cancer 8 years after surgery. A woman in her mid-fifties was hospitalized for examination of epigastralgia. Computed tomography (CT) revealed a 4 cm nodule at the pancreatic head with suspected invasion of the superior mesenteric vein. She underwent pancreaticoduodenectomy with wedge resection of superior mesenteric vein and intraoperative radiation therapy. Pathological findings showed moderately differentiated tubular adenocarcinoma and T3N1M0, Stage IIB according to The Union for International Cancer Control (UICC) TNM classification. As adjuvant chemotherapy, 56 courses of gemcitabine (GEM) were administered in 3.5 years. Because of long-term use of GEM, common terminology criteria for adverse events (CTCAE) Grade 3 anemia occurred, and chemotherapy was discontinued. Tumor markers were evaluated every month and CT scans were taken every 6 months for 5 years. Subsequently, CT was performed annually. The patient was hospitalized for high-grade fever, 8.5 years after surgery. CT, magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) detected local recurrence with liver metastases. GEM was administered again, but was ineffective. The patient died 9 years after surgery. In conclusion, even if long-term survival is achieved in pancreatic cancer, follow-ups should not be stopped.",
"affiliations": "Division of Hepato-Biliary-Pancreatic Surgery, Dept. of Surgery, Tohoku University Graduate School of Medicine.",
"authors": "Taniguchi|Hajime|H|;Mizuma|Masamichi|M|;Motoi|Fuyuhiko|F|;Abe|Tomoya|T|;Okada|Ryo|R|;Kawaguchi|Kei|K|;Karasawa|Hideaki|H|;Masuda|Kunihiro|K|;Yabuuchi|Shinichi|S|;Fukase|Koji|K|;Sakata|Naoaki|N|;Okada|Takaho|T|;Nakagawa|Kei|K|;Hayashi|Hiroki|H|;Morikawa|Takanori|T|;Yoshida|Hiroshi|H|;Naito|Takeshi|T|;Katayose|Yu|Y|;Egawa|Shinichi|S|;Unno|Michiaki|M|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "41(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000964:Antimetabolites, Antineoplastic; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D016577:Pancreaticoduodenectomy; D012008:Recurrence; D013997:Time Factors",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2193-5",
"pmc": null,
"pmid": "25731467",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A case of pancreatic cancer with local recurrence and liver metastases eight years after surgery.",
"title_normalized": "a case of pancreatic cancer with local recurrence and liver metastases eight years after surgery"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP03515",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "Cytomegalovirus (CMV) infection risk in the first month after transplantation is felt to be minimal; however, the epidemiology has not been specifically investigated, particularly in the modern era of potent immunosuppressive regimens and universal CMV prophylaxis.\nThe aim of this study was to describe the incidence of and risk factors associated with CMV occurring less than 30 days after transplant and evaluate the effect of very early CMV on outcomes.\nRetrospective, single-center study of adult renal transplant (RTX) recipients between January 1, 1994 and December 31, 2014.\nA total of 5225 patients who received a renal transplant in the study time period were reviewed for the presence of CMV infection occurring less than 30 days after transplant. Of these, only 14 patients demonstrated this finding for an overall incidence of 0.27%. Half of these patients were considered to be at heightened risk due to being a recipient of a non-primary transplant or on chronic immunosuppression. This left seven patients without known risk factors for very early CMV to evaluate. In this group, time from transplant to CMV infection was 13.5 ± 7 days. The majority (57.1%, n = 4) were high-risk serostatus (CMV D+/R-) and occurred in the valganciclovir era (71.4%, n = 5). Lymphocyte-depleting induction predominated (57.1%, n = 4). Average cold ischemic time (CIT) was 19.7 ± 7.7 hours. Three patients had post-operative complications, two required exploratory-laparotomy for hemorrhage. When evaluating outcomes, 43% (n = 3) had subsequent episodes of CMV infection, 28.6% (n = 2) developed rejection, and 28.6% (n = 2) died. Outcomes between patients with CMV infection less than 30 days and those with CMV infection more than 30 days after transplant were not significantly different.\nIn our review of over 5000 kidney transplants, the incidence of CMV infection in the first 30 days after renal transplant is 0.2%. Notable common patient characteristics include hemorrhage requiring re-operation and prolonged CIT. Outcomes were similar to CMV occurring more than 30 days after transplant. This study should provide the clinician with some reassurance; despite potent immunosuppressive therapy, CMV infection in the first 30 days is unlikely.",
"affiliations": "Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Medicine and Population Health Sciences, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.;Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison WI, USA.;Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA.",
"authors": "Jorgenson|M R|MR|https://orcid.org/0000-0001-6088-9727;Descourouez|J L|JL|;Astor|B C|BC|;Smith|J A|JA|;Aziz|F|F|;Redfield|R R|RR|;Mandelbrot|D A|DA|",
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"country": "United States",
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"doi": "10.1177/1178122X19840371",
"fulltext": "\n==== Front\nVirology (Auckl)Virology (Auckl)VRTspvrtVirology : Research and Treatment1178-122XSAGE Publications Sage UK: London, England 10.1177/1178122X1984037110.1177_1178122X19840371Original ResearchVery Early Cytomegalovirus Infection After Renal Transplantation: A Single-Center 20-Year Perspective https://orcid.org/0000-0001-6088-9727Jorgenson MR 1Descourouez JL 1Astor BC 2Smith JA 3Aziz F 3Redfield RR 4Mandelbrot DA 31 Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA2 Department of Medicine and Population Health Sciences, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA3 Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA4 Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison WI, USAMR Jorgenson, Department of Pharmacy, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, USA. Email: MJorgenson@uwhealth.org02 4 2019 2019 10 1178122X1984037110 1 2019 21 2 2019 © The Author(s) 20192019SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background:\nCytomegalovirus (CMV) infection risk in the first month after transplantation is felt to be minimal; however, the epidemiology has not been specifically investigated, particularly in the modern era of potent immunosuppressive regimens and universal CMV prophylaxis.\n\nObjective:\nThe aim of this study was to describe the incidence of and risk factors associated with CMV occurring less than 30 days after transplant and evaluate the effect of very early CMV on outcomes.\n\nMethods:\nRetrospective, single-center study of adult renal transplant (RTX) recipients between January 1, 1994 and December 31, 2014.\n\nResults:\nA total of 5225 patients who received a renal transplant in the study time period were reviewed for the presence of CMV infection occurring less than 30 days after transplant. Of these, only 14 patients demonstrated this finding for an overall incidence of 0.27%. Half of these patients were considered to be at heightened risk due to being a recipient of a non-primary transplant or on chronic immunosuppression. This left seven patients without known risk factors for very early CMV to evaluate. In this group, time from transplant to CMV infection was 13.5 ± 7 days. The majority (57.1%, n = 4) were high-risk serostatus (CMV D+/R−) and occurred in the valganciclovir era (71.4%, n = 5). Lymphocyte-depleting induction predominated (57.1%, n = 4). Average cold ischemic time (CIT) was 19.7 ± 7.7 hours. Three patients had post-operative complications, two required exploratory-laparotomy for hemorrhage. When evaluating outcomes, 43% (n = 3) had subsequent episodes of CMV infection, 28.6% (n = 2) developed rejection, and 28.6% (n = 2) died. Outcomes between patients with CMV infection less than 30 days and those with CMV infection more than 30 days after transplant were not significantly different.\n\nConclusions:\nIn our review of over 5000 kidney transplants, the incidence of CMV infection in the first 30 days after renal transplant is 0.2%. Notable common patient characteristics include hemorrhage requiring re-operation and prolonged CIT. Outcomes were similar to CMV occurring more than 30 days after transplant. This study should provide the clinician with some reassurance; despite potent immunosuppressive therapy, CMV infection in the first 30 days is unlikely.\n\ntransplantationrenal transplantinfectious diseaseviral infectionsantiviralscover-dateJanuary-December 2019\n==== Body\nIntroduction\nCytomegalovirus (CMV), a ubiquitous herpesvirus present in 40% to 70% of the population, is common after solid organ transplantation (SOT) and is an independent risk factor for graft loss and mortality. Iatrogenic immunosuppression targeting T cells may result in uncontrolled CMV replication.1 The risk of CMV infection in the first month after transplantation is generally felt to be minimal, despite the high-intensity immunosuppression used at the time of transplant due to a lack of prolonged immunosuppressive exposure.1–3 Duration of immunosuppressive exposure is thought to be the most significant factor involved in the development of opportunistic infections, such as CMV.1 Indeed, the most respected sources in the field suggest a search for unusual nosocomial exposures or preexisting iatrogenic immunosuppression in the setting of opportunistic infection, such as CMV, occurring less than 1 month after renal transplant.1–3 However, this notion of a required sustained effect of immunosuppression on the development of CMV infection is theoretical and has not been clinically evaluated, particularly in the modern era of potent immunosuppressive regimens and universal CMV prophylaxis.\n\nMethods\nAll adult patients who received a renal transplant at our institution between January 1, 1994 and December 31, 2014 were reviewed for the presence of CMV occurring less than 30 days after transplant (very early CMV). Patients were deemed to have very early CMV if they had evidence of CMV infection defined as any positive CMV detected via molecular diagnostics or biopsy-proven tissue-invasive disease less than 30 days following SOT. Data were collected from the Wisconsin Allograft Recipient Database (WisARD). This study was approved by the local institutional review board.\n\nOur primary objective was to describe the epidemiology of and our experience with very early CMV, including evaluation of possible unknown risk factors associated with very early CMV and response to treatment. Our secondary objective was to describe the patient and graft outcomes after very early CMV and compare these outcomes to the unaffected population (never CMV), and the population with CMV more than 30 days after renal transplant.\n\nThroughout the study period, methodology for detection and quantification of CMV viral load changed. Prior to 2006, CMV was measured via hybrid capture DNA assay at our center due to its significant improvement in sensitivity over blood culture assay. However, quantitative CMV nucleic acid amplification polymerase chain reaction (PCR) testing (CMV QNAT) is more sensitive than the capture assay, with concordance between PCR and capture reported at approximately 79%.4 When PCR values are available, they are reported in copies/mL as the study time period is prior to the adoption of the World Health Organization (WHO) international standard and conversion to the current measurements (IU/mL).\n\nThroughout the study period, CMV prophylaxis protocols at our center changed due to the approval and marketing of the potent antivirals ganciclovir, and its oral prodrug valganciclovir (VGC). Prior to 1996, no effective antiviral medication was available for prophylaxis. From 1996 to 2003, oral ganciclovir at a renally adjusted dose of 3 g/day was used for universal prophylaxis in high-risk patients. After 2003, VGC at a renally adjusted dose of 900 mg daily was used. After publication of a pivotal clinical trial in 2010, duration of prophylaxis was extended from 3 to 6 months in these patients.19 Despite these changes, our CMV prophylactic protocol remained consistent. Preventive antiviral therapy was initiated within 72 hours after renal transplant, and CMV viral load monitoring was not routinely done during prophylactic antiviral therapy.5\n\nRecipients were categorized by CMV status, and baseline characteristics were described by mean, median, and interquartile range (IQR). Outcomes were compared across groups using chi-square and Fisher exact tests.\n\nResults\nA total of 5225 patients who received a renal transplant in the study time period were reviewed for the presence of CMV infection occurring less than 30 days after transplant (very early CMV). Of these, only 14 patients demonstrated this finding for an overall incidence of 0.27%. Median follow-up time of the total cohort was 10 years. Half of these patients (n = 7) were considered to be at heightened baseline risk for very early CMV due to being a recipient of a non-primary transplant or on chronic immunosuppression. This left seven patients without known risk factors for very early CMV to evaluate (Figure 1). In this population, date of transplantation ranged from 1994 to 2009 with a median follow-up time of 6 years. Mean time from transplant to CMV infection was 13.5 ± 7 days. Four patients were high-risk serostatus (CMV D+/R−) and one patient was low-risk serostatus (CMV D−/R−), as defined by the International Consensus Guidelines.5 The majority (71%, n = 5) were receiving dialysis prior to transplant, with a median duration of 27 (range = 17-237) months. Average cold ischemic time (CIT) was 19.7 ± 7.7 hours, with a median of 20 hours. Lymphocyte-depleting induction at the time of transplant predominated (57.1%, n = 4) (Table 1). All patients were on triple drug immunosuppressive therapy with a corticosteroid, antimetabolite, and calcineurin inhibitor (CNI) at the time of CMV infection; 85.7% were receiving mycophenolic acid products (MPA, mycophenolate mofetil, or mycophenolate sodium). Three patients had post-operative complications, two of whom required exploratory laparotomy and hematoma evacuation. One patient required intra-operative donor arterial reconstruction. Mean transplant length of stay was 10 ± 6 days. Almost half were receiving appropriate renal dosing of VGC prophylaxis at the time of CMV infection. Overall, when reported, CMV viral load was relatively low at detection, with the exception of the previously unexposed (CMV D−/R−) patient with new onset (primary) disease, who was above the upper limit of quantification at detection (Table 2). More than half of the patients (57.1%, n = 4) with evidence of very early CMV were symptomatic per chart review; in the others, symptoms were not specifically recorded (Table 2). CMV infection was treated in 71.4% of cases (n = 5) with immunosuppressive reduction ± a ganciclovir derivative (intravenous ganciclovir or oral VGC) for a median of 52 (range = 11-450) days.\n\nFigure 1. Process to identify the incidence of very early CMV.\n\nTable 1. Demographic data.\n\nPt no.\tTXP\nyear\tAge at\nTXP\tCMV\nserostatus\tDonor\ntype\tCIT\n(hours)\tInduction\nimmunosuppression\tMaintenance\nimmunosuppression\tSGF/ DGF\tSignificant post-op complication\tTXP length of stay (days)\tRejection prior to CMV\t\n1\t1994\t33\tD+/R−\tDBD\t33\tOKT3\tCsA, AZA, pred 30/d\tNA\tPneumothorax\t12\tNA\t\n2\t1999\t49\tD+/R−\tDBD\t25\tBasiliximab\tCsA, MPA, pred 30/d\tNA\tNA\t7\tNA\t\n3\t2004\t49\tD+/R−\tDBD\t16\tAlemtuzumab\tCsA, MPA, pred 10/d\tNA\tNA\t5\tNA\t\n4\t2005\t54\tD+/R+\tDCD\t13\tAlemtuzumab\tCsA, MPA, pred 10/d\tNA\tNA\t5\tNA\t\n5\t2006\t50\tD−/R−\tDCD\t21\tAlemtuzumab\tCsA, MPA, pred 10/d\tNA\tRe-operation: RP hematoma\t6\tNA\t\n6\t2008\t51\tD+/R−\tDBD\t20\tBasiliximab\tFK, MPA, pred 30/d\tYes\tDonor IVC interposition with OR reconstruction\t14\tYes\t\n7\t2009\t34\tD−/R+\tDBD\t10\tBasiliximab\tFK, MPA, pred 30/d\tYes\tRe-operation: RP hematoma\t20\tNA\t\nAbbreviations: AZA, azathioprine; CIT, cold ischemic time; CMV, cytomegalovirus; CsA, cyclosporine; D, donor; DBD, donation after brain death; DCD, donation after cardiac death; DGF, delayed graft function; MPA, mycophenolic acid; NA, not applicable; pred, prednisone; Pt, patient; R, recipient; SGF, slow graft function; TXP, transplant.\n\nTable 2. Infection-specific variables.\n\nPt no.\tTXP year\tDays to CMV from TXP\tCMV VL at detection\tCMV PPX\tSymptoms\tInitial CMV treatment\tAnti-CMV DOT (days)\tCMV recurrence after very early CMV (days from TXP)\tRejection after very early CMV (days from TXP)\tAlive at last follow-up\teGFR at last follow-up\t\n1\t1994\t14\tNR\tAcyclovir\tFever\tGCV\t14\t690\tNo\tYes\t37\t\n2\t1999\t17\t1.7a\tPO GCV\tFever\tGCV + CMVIg\t11\tNA\tNo\tYes\t70\t\n3\t2004\t20\t1.7a\tVGC\tGI\tNot treated\tNA\tNA\t67\tNo\t83\t\n4\t2005\t2\t2.8a\tVGC\tNR\tNot treated\tNA\tNA\tNo\tYes\t55\t\n5\t2006\t21\t>100 000 copies/mL\tAcyclovir\tFever\tGCV\t450\t171\t78\tNo\t21\t\n6\t2008\t14\tNR\tVGC\tNR\tNot treated\tNA\t180\tNo\tYes\tNA\t\n7\t2009\t6\t207 copies/mL\tAcyclovir\tNR\tVGC\t90\tNA\tNo\tYes\t56\t\nAbbreviations: CMV, cytomegalovirus; DOT, duration of therapy; GCV, ganciclovir; GI, gastrointestinal symptoms; NA, not applicable; NR, not reported; Pt, patient; VGC, valganciclovir; VL, viral load.\n\na CMV DNA capture: measured in genomes per milliliter. According to the manufacturer’s instructions, a ratio of sample to control value of less than 1.0 was considered positive for CMV DNA.\n\nWhen evaluating outcomes, 43% of patients with very early CMV had a subsequent episode of CMV infection and 28.6% developed rejection, although 85.7% had functional renal allografts at last evaluation, with a mean estimated glomerular filtration rate (eGFR) of 53.7 ± 20.3 at last follow-up (Table 2). The low-risk serotype (D−/R−) patient with de novo infection developed ganciclovir-resistant disease which failed treatment with cidofovir and required prolonged foscarnet administration. Two patients died (n = 28.6%), one of which was due to CMV infection (the patient with drug-resistant CMV). When comparing these outcomes to our entire population of primary renal transplant recipients without early CMV (n = 3404), 15.6% developed CMV infection. The median time to CMV was 163 (IQR = 258) days. In the entire cohort, 27.4% developed rejection, 14% experienced graft failure, and 36.9% died. In the subset with CMV occurring more than 30 days after transplant (n = 532), 39.3% developed rejection, 16% experience graft failure, and 47.6% died (Table 3). Outcomes between the CMV less than 30 day group and the CMV more than 30 day group were not significantly different. However, when comparing the presence of CMV at any time after transplant to those without CMV, rejection and mortality outcomes were less favorable in those with CMV (Table 3).\n\nTable 3. Primary transplant comparative outcomes.\n\n\tCMV < 30 days (n = 7)\tCMV > 30 days (n = 532)\tP-value\tNo CMV (n = 3404)\tP-value\t\nRejection\t28.6% (2)\t39.3% (209)\t.71\t27.4% (932)\t< .00001\t\nGraft failure\t14.3% (1)\t16% (85)\t>.99\t14% (477)\t.23\t\nMortality\t28.6% (2)\t47.6% (253)\t.45\t36.9% (1256)\t.000004\t\nDiscussion\nStudies exist outlining the incidence and risks associated with early CMV, or CMV occurring less than 100 days after transplant.6,7 However, ours is the first to describe very early CMV infection, occurring less than 30 days after transplant. This clinical scenario is postulated to be incredibly uncommon due to a lack of prolonged immunosuppressive exposure, making the population relatively immunocompetent compared with their counterparts with more than 30 days of immunosuppressive exposure.1–3 Still it is possible in the modern era of potent immunosuppression that duration of exposure has less of a profound effect and concern regarding CMV breakthrough despite potent antiviral therapy exists.8 Indeed, clinically, in the setting of fever and leukopenia, the transplant clinician will test for CMV infection regardless of time from transplant. This 20-year analysis, which spans the pre- and post-VGC eras and incorporates a population that would have uniformly received potent immunosuppression with CNIs and MPA as of 2000, suggests that the theoretical historical adage is accurate. In a population exceeding 5000 renal transplants, only 0.27% had CMV infection in the first 30 days.\n\nMany of the widely recognized CMV risk factors were present in our population including high-risk serostatus and lymphocyte-depleting induction.5,8 Interestingly, there was no representation of antithymocyte globulin in our small cohort, with alemtuzumab accounting for most lymphocyte-depleting induction. This may reflect the historical practice of a two-dose induction regimen that was the standard of care in the early 2000s at our center and the resultant potent immunosuppressive effect. Indeed, in a previously published retrospective analysis from our center, alemtuzumab induction was associated with a significantly increased risk of CMV infection.9 Unique risk factors that stand out in the very early CMV cohort are early post-operative complications and bleeding. Although the population is too small to evaluate this statistically, the literature-reported rate of post-operative bleeding after renal transplant is less than 5%; here, in our study population, 25% required return to the operating room for control of post-operative hemorrhage.10 Both of these patients were donor seronegative for CMV, one of which went on to develop de novo CMV infection in the setting of low serologic risk (D−/R−), ganciclovir resistance, and the associated negative sequelae of resistant virus infection.8 While transfusion records were not available, it is possible the receipt of blood products introduced primary CMV in the setting of allograft seronegativity via reactivation of latent virus in donor white blood cells.11 It has been shown that even in CMV seropositive recipients, strain variability can result in a pseudoprimary infection in the setting of donor seropositivity for CMV (D+/R+) and is associated with poorer outcomes than their donor seronegative counterparts (D−/R+).12,13 Another interesting trend in this small population was that of prolonged CIT. A median CIT of 17 hours has been associated with primary CMV infection in D+/R− patients.14 The mean and median CIT of our population exceeded this by 3 hours. It may be prudent for the clinician to watch for signs/symptoms of CMV infection in the first 30 days in patients with prolonged CIT or those receiving blood products who are CMV donor seronegative.\n\nA surprising finding was the incidence of very early CMV infection in the setting of robust CMV prophylaxis. All patients received some form of antiviral prophylaxis, although the majority received less potent suppression with acyclovir or oral ganciclovir. However, three patients were receiving VGC at the time of early CMV infection. It has been postulated that early CMV, and therefore very early CMV, is highly unlikely in the modern era of potent antiviral prophylaxis with VGC; however, this study demonstrates breakthrough in an already low-incidence time period of less than 30 days post transplantation. It is important to note that all patients were receiving renally adjusted doses of VGC that were appropriate per the manufacturer suggestions, but less than the full 900 mg daily.15 There is literature associating CMV breakthrough and viral resistance with low-dose VGC.8,16 This finding of very early CMV despite VGC suggests more aggressive dosing in the setting of early post transplant renal dysfunction and fluctuating renal laboratory markers may be warranted, as this may underestimate true drug clearance capacity.\n\nIt is reassuring that comparative outcomes after very early CMV, and CMV occurring more than 30 days after transplant were not different. While literature exist describing increased risk of negative patient and allograft outcomes when CMV infection or disease occurs in the first 3 months after transplant, it does not appear that less than 30 days is an important clinical breakpoint, although our sample size is small.6,7 However, when comparing those patients with CMV to the unaffected cohort (never CMV), our study again demonstrates the well-published finding that the presence of CMV infection or disease at any time point after transplant is associated with less favorable patient and allograft outcomes after solid organ transplant.17,18\n\nThis study has all the limitations of being a small series from a single center. However, data on all our transplant patients are collected prospectively, we analyzed matched controls, and our database is one of the few in the country that would be large enough to provide this series. The results of this study are striking as they demonstrate clinically the concept of the “net immunosuppressive state” and the importance of the duration of immunosuppressive exposure.1–3 Despite advances in the potency of drug products and the intensification of immunosuppressive regimens after renal transplant, it seems the duration of immunosuppressive exposure is still the most significant risk factor for CMV infection, and it appears that exposure more than 30 days is necessary to create the environment conducive to this clinical scenario.\n\nConclusions\nIn conclusions, in our review of over 5000 kidney transplants, the occurrence of CMV infection in the first 30 days is very uncommon. However, when it occurred, it appeared to be accompanied by the typical symptomatology of fever in most cases. Notable common patient characteristics include hemorrhage requiring re-operation and prolonged CIT. Half of the patients in this series had subsequent episodes of CMV infection more than 30 days after transplant. De novo disease in low-risk serostatus was associated with the worst outcomes, highlighting the importance of leukocyte-reduced irradiated blood products in the CMV unexposed, immunocompromised patient. This study should provide the clinician with some reassurance that the overall risk of CMV infection in the first 30 days is very low.\n\nDeclaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding:The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nAuthor Contributions: MJ and BA developed the study protocol, procured the study data and performed the statistical analysis. All authors contributed to the drafting, review, and final approval of this manuscript.\n\nORCID iD: MR Jorgenson \nhttps://orcid.org/0000-0001-6088-9727\n==== Refs\nReferences\n1 \nFishman JA Rubin RH. \nInfection in organ-transplant recipients . N Engl J Med . 1998 ;338 :1741 –1751 .9624195 \n2 \nRubin RH Wolfson JS Cosimi AB Tolkoff-Rubin NE. \nInfection in the renal transplant patient . Am J Med . 1981 ;70 :405 –411 .6258432 \n3 \nRubin RH \nInfection in the organ transplant recipient . In: Rubin RH Young LS , eds. Clinical Approach to Infection in the Compromised Host . 3rd ed. \nNew York : Plenum Publishing ; 1994 :629 –705 .\n4 \nHebart H Gamer D Loeffler J et al \nEvaluation of Murex CMV DNA hybrid capture assay for detection and quantitation of cytomegalovirus infection in patients following allogeneic stem cell transplantation . J Clin Microbiol . 1998 ;36 :1333 –1337 .9574700 \n5 \nKotton CN Kumar D Caliendo AM et al \nThe third international consensus guidelines on the management of cytomegalovirus in solid organ transplantation . Transplantation . 2018 ;102 :900 –931 .29596116 \n6 \nSagedal S Hartmann A Nordal KP et al \nImpact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival . Kidney Int . 2004 ;66 :329 –337 .15200441 \n7 \nSmedbraten YV Sagedal S Leivestad T et al \nThe impact of early cytomegalovirus infection after kidney transplantation on long-term graft and patient survival . Clin Transplant . 2014 ;28 :120 –126 . doi:10.1111/ctr.12288. 24351078 \n8 \nRolling KE Jorgenson MR Descourouez JL Mandelbrot DA Redfield RR Smith JA. \nGanciclovir-resistant cytomegalovirus infection in abdominal solid organ transplant recipients: case series and review of the literature . Pharmacotherapy . 2017 ;37 :1258 –1271 . doi:10.1002/phar.1987. 28699311 \n9 \nLaMattina JC Mezrich JD Hofmann RM et al \nAlemtuzumab as compared to alternative contemporary induction regimens . Transpl Int . 2012 ;25 :518 –526 . doi:10.1111/j.1432-2277.2012.01448.x. 22394259 \n10 \nHachem LD Ghanekar A Selzner M Famure O Li Y Kim SJ. \nPostoperative surgical-site hemorrhage after kidney transplantation: incidence, risk factors, and outcomes . Transpl Int . 2017 ;30 :474 –483 . doi:10.1111/tri.12926. 28120465 \n11 \nAdler SP. \nTransfusion-associated cytomegalovirus infections . Rev Infect Dis . 1983 ;5 :977 –993 .6318291 \n12 \nStratta R Thacker L Sunderberg A et al \nMultivariate analysis of the influence of donor and recipient cytomegalovirus sero-pairing on outcomes in simultaneous kidney-pancreas transplantation: the South-Eastern Organ Procurement Foundation Experience . Transplant Proc . 2005 ;37 :1271 –1273 .15848692 \n13 \nHughes D Hafferty J Fulton L et al \nDonor and recipient CMV serostatus and antigenemia after renal transplantation: an analysis of 486 patients . J Clin Virol . 2008 ;41 :92 –95 .18032098 \n14 \nSchlott F Steubl D Hoffmann D et al \nPrimary cytomegalovirus infection in seronegative kidney transplant patients is associated with protracted cold ischemic time of seropositive donor organs . PLoS ONE . 2017 ;12 :e0171035 . doi:10.1371/journal.pone.0171035. 28129395 \n15 \nValcyte Prescribing Information . South San Francisco, CA : Hoffmann-La Roche Inc, distributed by Genentech; A Member of the Roche Group .\n16 \nStevens DR Sawinski D Blumberg E Galanakis N Bloom RD Trofe-Clark J. \nIncreased risk of breakthrough infection among cytomegalovirus donor-positive/recipient-negative kidney transplant recipients receiving lower-dose valganciclovir prophylaxis . Transpl Infect Dis . 2015 ;17 :163 –173 . doi:10.1111/tid.12349. 25661673 \n17 \nKanter J Pallardó L Gavela E et al \nCytomegalovirus infection renal transplant recipients: risk factors and outcomes . Transplant Proc . 2009 ;41 :2156 –2158 .19715860 \n18 \nLópez-Oliva MO Flores J Madero R et al \nCytomegalovirus infection after kidney transplantation and long-term graft loss . Nefrología (English Edition) . 2017 ;37 :515 –525 .\n19 \nHumar A Lebranchu Y Vincenti F et al \nThe efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients . Am J Transplant . 2010 ;10 :1228 –1237 .20353469\n\n",
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"issn_linking": "1178-122X",
"issue": "10()",
"journal": "Virology : research and treatment",
"keywords": "antivirals; infectious disease; renal transplant; transplantation; viral infections",
"medline_ta": "Virology (Auckl)",
"mesh_terms": null,
"nlm_unique_id": "101515268",
"other_id": null,
"pages": "1178122X19840371",
"pmc": null,
"pmid": "30983861",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "15200441;15848692;18032098;19715860;20353469;22394259;24351078;25661673;28120465;28129395;28699311;28946964;29596116;6258432;6318291;9574700;9624195",
"title": "Very Early Cytomegalovirus Infection After Renal Transplantation: A Single-Center 20-Year Perspective.",
"title_normalized": "very early cytomegalovirus infection after renal transplantation a single center 20 year perspective"
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"abstract": "Recent case reports have shown that hepatitis E virus (HEV) infection can cause chronic hepatitis in immunosuppressed or immunocompromised patients. A 37-year-old woman suffered from prolonged elevation of aminotransferases after chemotherapy for Burkitt's lymphoma and was diagnosed with chronic hepatitis E due to a transfusion during chemotherapy. After an 8-month administration of ribavirin, complete HEV clearance was not achieved, likely due to prolonged hypogammaglobulinemia. This case indicates that HEV infection should be ruled out during liver dysfunction in immunosuppressed or immunocompromised patients and suggests that an alternative therapeutic strategy for such patients will be needed.",
"affiliations": "Department of Gastroenterology and Hepatology, Yokosuka Kyosai Hospital, Japan.",
"authors": "Miyoshi|Masato|M|;Kakinuma|Sei|S|;Tanabe|Yoko|Y|;Ishii|Koji|K|;Li|Tian-Cheng|TC|;Wakita|Takaji|T|;Tsuura|Yukio|Y|;Watanabe|Hideki|H|;Asahina|Yasuhiro|Y|;Watanabe|Mamoru|M|;Ikeda|Takaaki|T|",
"chemical_list": "D012254:Ribavirin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.7025",
"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.7025Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27725541Case ReportChronic Hepatitis E Infection in a Persistently Immunosuppressed Patient Unable to Be Eliminated after Ribavirin Therapy Miyoshi Masato 12Kakinuma Sei 23Tanabe Yoko 1Ishii Koji 4Li Tian-Cheng 4Wakita Takaji 4Tsuura Yukio 5Watanabe Hideki 1Asahina Yasuhiro 23Watanabe Mamoru 2Ikeda Takaaki 11 Department of Gastroenterology and Hepatology, Yokosuka Kyosai Hospital, Japan2 Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan3 Department for Liver Disease Control, Tokyo Medical and Dental University, Japan4 Department of Virology II, National Institute of Infectious Diseases, Japan5 Department of Pathology, Yokosuka Kyosai Hospital, JapanCorrespondence to Dr. Masato Miyoshi, mmiyoshi.gast@tmd.ac.jp\n\n1 10 2016 55 19 2811 2817 22 12 2015 28 1 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Recent case reports have shown that hepatitis E virus (HEV) infection can cause chronic hepatitis in immunosuppressed or immunocompromised patients. A 37-year-old woman suffered from prolonged elevation of aminotransferases after chemotherapy for Burkitt's lymphoma and was diagnosed with chronic hepatitis E due to a transfusion during chemotherapy. After an 8-month administration of ribavirin, complete HEV clearance was not achieved, likely due to prolonged hypogammaglobulinemia. This case indicates that HEV infection should be ruled out during liver dysfunction in immunosuppressed or immunocompromised patients and suggests that an alternative therapeutic strategy for such patients will be needed. \n\nhepatitis E viruschronic hepatitisblood transfusionimmunocompromised hostrituximabhypogammaglobulinemia\n==== Body\nIntroduction\nHepatitis E virus (HEV) was first identified as a cause of nonA-nonB acute hepatitis in developing countries in the 1980s (1). HEV belongs to the genus Orthohepevirus in the Hepeviridae family. HEV is divided into four genotypes. Genotypes 1 and 2 are prevalent in several developing countries, where they are transmitted through the oral-fecal route and infect only humans. Genotypes 3 and 4 are responsible for sporadic acute hepatitis in developed countries. These viruses are zoonotic and can infect not only humans, but also pigs, deer and other wild mammals (2).\n\nHEV typically causes acute hepatitis and is a self-limiting infection. However, the first case report from France in 2008 showed that HEV can cause chronic hepatitis, referred to as chronic hepatitis E (CH-E), in patients following organ transplantation (3). CH-E has also developed in patients with hematologic diseases and immunocompromised patients such as those receiving chemotherapy or immunosuppressive treatment or individuals infected with human immunodeficiency virus (4-6). Furthermore, CH-E causes relatively rapid fibrosis (7). Previous case reports from Europe have shown that ribavirin administration is effective for CH-E that develops in recipients of organ transplantation (8). We herein report the first case of CH-E in Japan. The patient was treated with intensive chemotherapy for Burkitt's lymphoma and was infected with HEV by a blood transfusion during chemotherapy. The patient started oral ribavirin therapy, however, was unable to eliminate the chronic HEV infection even after 8-month treatment of ribavirin, presumably due to prolonged hypogammaglobulinemia after the end of chemotherapy.\n\nCase Report\nA 37-year-old Japanese woman visited the Department of Gastroenterology and Hepatology, Yokosuka Kyosai Hospital for a workup of prolonged elevation of serum aminotransferases. Her past history included Burkitt's lymphoma that had developed approximately 2.5 years previously. She had no other significant medical history aside from lymphoma. Before her initial treatment for Burkitt's lymphoma, her white blood cell count was 88,300/μL. Serum biochemical data results at this time were: lactate dehydrogenase (LDH) 9,745 U/L, aspartate aminotransferase (AST) 248 U/L, alanine aminotransferase (ALT) 74 U/L, γ-glutamyl transpeptidase (γGTP) 546 U/L, and alkaline phosphatase (ALP) 541 U/L. She subsequently developed multi-organ failure (MOF) due to tumor lysis syndrome and received intensive care against MOF, followed by anti-cancer therapy for lymphoma. She received the curative anti-cancer chemotherapy regimen R-Hyper CVAD, which included rituximab, cyclophosphamide, vincristine, doxorubicin and cytarabine. She received frequent blood transfusions due to serious bone marrow suppression caused by chemotherapy. A total of 36 units of red blood cells and 240 units of platelet concentrates were administered.\n\nThe laboratory data revealed abnormal elevation of serum transaminases after her recovery from bone marrow suppression during the 5th course of chemotherapy. A peak elevation of aminotransferases (AST 98 U/L, ALT 347 U/L) was observed 20 days after the initiation of her 5th chemotherapy course (Fig. 1A). Her transaminase levels then decreased for several days. Similarly, transient liver dysfunction was observed during the 6th and 7th chemotherapy courses (Fig. 1A). After the 7th course, she developed hemorrhagic cystitis due to continuous adenovirus infection. Thus, her bone marrow suppression was considered to be critical and chemotherapy was discontinued after the 7th course.\n\nFigure 1. \nThe clinical course of this patient. (A) The clinical course during chemotherapy after the diagnosis of lymphoma. The x axis represents time from the diagnosis of lymphoma. The normal line and dotted line show ALT and AST, respectively. The arrows, white arrow, and closed square represent transfusion, hepatitis E virus (HEV)-contaminated transfusion, and chemotherapy, respectively. (B) The clinical course after the end of chemotherapy. Black and white arrowheads represent the liver biopsy and supplementation of gamma globulin, respectively. “Consultation” represents the time point when the patient visited the Department of Gastroenterology and Hepatology.\n\n\nThe patient achieved a complete response to the treatment for Burkitt's lymphoma after the 7th chemotherapy course. No evidence of recurrence was detected by blood examinations, including tests for serum soluble IL-2 receptor and computed tomography imaging. After the final course of chemotherapy, she gradually recovered from pancytopenia and her white blood cell counts increased to a normal range. However, her serum gamma globulin concentration gradually decreased, and this was presumed to be a side effect of intensive chemotherapy. Moreover, continuous elevation of aminotransferase was observed (Fig. 1B). Serum HBs antigen and HCV antibody were not detected. Therefore, she was referred to our department.\n\nAt the first visit to our department, she reported no symptoms and no abnormality was detected by a physical examination. There was no candidate for drug-induced liver injury during chemotherapy, because liver dysfunction was persistent after the withdrawal of all drugs. The serum biochemical data were as follows: AST 70 U/L, ALT 111 U/L, γ-GTP 229 U/L, and ALP 196 U/L (Table A). Tests for serological antibodies against hepatitis B virus (HBV), hepatitis C virus (HCV), and autoantibodies such as anti-nuclei antibody and anti-mitochondrial antibody, were negative (Table B). A diagnostic administration of ursodeoxycholic acid was not effective; therefore, a percutaneous liver biopsy was performed. A liver biopsy demonstrated that her histologic findings were consistent with chronic active hepatitis, hepatic activity index (HAI) score 7, and fibrosis stage 2 (Fig. 2). No steatosis was detected in her liver and no serological antibodies against hepatitis A virus (HAV), HEV, Epstein-Barr virus (EBV), or cytomegalovirus (CMV) were detected.\n\nTable. The Test Results of Blood Examinations.\n\n(A) WBC\t3,700\t/µL\t\tLDH\t159\tU/L\t\tIgG\t238.8\tmg/dL\t\nNeutro\t45.5\t%\t\tAST\t70\tU/L\t\tIgA\t3\tmg/dL\t\nEo\t0\t%\t\tALT\t111\tU/L\t\tIgM\t12.7\tmg/dL\t\nBa\t0.5\t%\t\tALP\t196\tU/L\t\tANA\tneg\t\t\nMo\t11\t%\t\tγ-GTP\t229\tU/L\t\tAMA\tneg\t\t\nLy\t43\t%\t\tCK\t18\tU/L\t\tASMA\tneg\t\t\nRBC\t3.89\t×104\t\tT-bil\t0.6\tmg/dL\t\t\t\t\t\nHb\t12.7\tg/dL\t\tD-bil\t0.1\tmg/dL\t\tHBs Ag\tneg\t\t\nPlt\t16.6\t×104\t\tBUN\t8\tmg/dL\t\tHBc Ab\tneg\t\t\n\t\t\t\tCre\t0.45\tmg/dL\t\tHCV Ab\tneg\t\t\nPT%\t>100\t%\t\tCRP\t0.32\tmg/dL\t\tHIV Ab\tneg\t\t\nPT-INR\t0.98\t\t\tNa\t141\tmEq/L\t\t\t\t\t\nAPTT\t30.1\tsec\t\tK\t4.8\tmEq/L\t\t\t\t\t\n\t\t\t\tCl\t103\tmEq/L\t\t\t\t\t\n\t\t\t\tGlu\t109\tmg/dL\t\t\t\t\t\n\t\t\t\tHDL\t64\tmg/dL\t\t\t\t\t\n\t\t\t\tLDL\t61\tmg/dL\t\t\t\t\t\n\t\t\t\tTG\t194\tmg/dL\t\t\t\t\t\n(B) HA-IgM\tneg\t\nHA-IgG\tneg\t\nHEV-IgA\tneg\t\nEBNA\tneg\t\nVCA-IgM\t<10 fold\t\nVCA-IgM\t 10 fold\t\nCMV-IgM\tneg\t\nCMV-IgG\tneg\t\nHBV-DNA\tneg\t\nHCV-RNA\tneg\t\nEBV-DNA\tneg\t\nHEV-RNA\t6.7 Logcopy/mL\t\nHHV6-DNA\tneg\t\nCMV C7HRPAb\tneg\t\n (A) Blood examinations at the time of consultation. (B) Results of viral markers. Antibodies and RNA of hepatitis A virus (HAV), hepatitis E virus (HEV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus (HHV)-6 were investigated. ‘neg’ indicates levels that were under the sensitivity limits for the assays.\n\nFigure 2. \nHistological findings of a liver biopsy. (A) Hematoxylin and Eosin staining shows mild piecemeal necrosis and moderate inflammation around the portal vein, demonstrating chronic hepatitis. Scale bar: 50 μm. (B) Masson’s trichrome staining shows the progression of periportal fibrosis. Scale bar: 200 μm.\n\n\nNext, we speculated that the results for serum viral antibodies may have been inaccurate due to her hypogammaglobulinemia, thus we checked for the presence of hepatitis-related viral genomes in her serum. HBV DNA, HCV RNA, EBV DNA, and human herpes virus (HHV)-6 DNA were undetectable, however, HEV RNA was detected. The amount of viral RNA was 6.7 log copies/mL, and a phylogenetic tree analysis revealed that HEV in her serum was genotype 3 (Fig. 3). We could not retrospectively examine HEV RNA using her serum samples at the beginning of liver dysfunction because such samples were not preserved. She had no history of travel to HEV-endemic areas and no history of eating unsanitary or raw meat from pig, deer or any other known hosts of HEV. In order to clarify the route of infection, we retrospectively tested samples of all blood transfusions she had received during chemotherapy for the presence of HEV RNA. One sample of platelet concentrate administered during her 4th course of chemotherapy was positive for HEV RNA. Parts of open reading frame (ORF) 1 and ORF2 of the HEV-genome sequence were determined by a polymerase chain reaction (PCR)-based direct sequence method in samples from this patient and from the blood donor. The concordance rate of ORF1 and ORF2 sequences in samples obtained from both individuals were 99% (325/326 base) and 100% (412/412 base), respectively. We concluded that the patient had been infected with HEV by the platelet transfusion during the 4th course of chemotherapy, and CH-E then developed due to immunosuppression, including hypogammaglobulinemia that subsequently developed.\n\nFigure 3. \nPhylogenetic analyses. A phylogenetic tree of HEV nucleotide sequences was constructed using the CLUSTAL W version 1.4 and MEGA version 4.0 software programs. For the phylogenetic analysis of HEV nucleotide sequences, we included sequences of several common and/or widespread strains. Each sequence name includes the genotype (Gt) and accession number. The dark box represents the sequence of the present case.\n\n\nAfter the diagnosis of CH-E, the patient's hypogammaglobulinemia was treated by γ-globulin supplementation therapy to allow her to recover from immunosuppression. However, her liver dysfunction did not improve following γ-globulin supplementation therapy and the amount of HEV RNA did not decrease. After obtaining approval for ribavirin therapy according to a previous report from the ethical committee of our hospital, the patient agreed to start ribavirin therapy. According to the previous report, ribavirin was initially administrated at a dose of approximately 8 mg/kg/day (8). Improvement in the patient's liver dysfunction was achieved after the administration of ribavirin for 5 weeks (Fig. 1B). Her serum HEV RNA levels were markedly decreased by -3 log copies/mL (Fig. 4). She developed no adverse events following ribavirin administration, however, tests for IgA antibody against HEV remained negative. Complete clearance of HEV was not achieved after the administration of ribavirin for 6 months, therefore the dose of ribavirin was increased to 10 mg/kg/day. Tests for serum HEV RNA remained positive even after ribavirin had been administered for 8 months.\n\nFigure 4. \nChanges in the serum HEV RNA levels after the diagnosis of HEV viremia. Serum HEV RNA decreased after ribavirin therapy, however, it was not eliminated after 6 months of ribavirin administration. The x axis represents time from the diagnosis of lymphoma. The amounts of serum HEV RNA were quantified by quantitative RT-PCR.\n\n\nDiscussion\nCH-E was first reported in a recipient of organ transplantation in 2008. Other reports also have shown the development of CH-E in immunosuppressed or immunocompromised patients, such as patients with hematologic disorders, HIV-infected patients, and patients with myelosuppression following chemotherapy. To the best of our knowledge, this case is the first confirmed case report of CH-E and one treated with ribavirin in Japan.\n\nDysfunction of the immune system is closely associated with CH-E. The patient described in this case report had two essential immune disorders: bone marrow suppression due to chemotherapy against hematopoietic malignancy and prolonged hypogammaglobulinemia that had still not improved after chemotherapy ended. Following a HEV-contaminated blood transfusion, she developed severe myelosuppression over one week due to her 5th course of chemotherapy, and her white blood cell count was under 500/μL. It is possible that severe immunosuppression at this point contributed to her sustained HEV viremia. Previous reports have shown that HEV infection acquired via blood transfusions can cause acute hepatitis following an incubation period from 3 weeks to 7 months after the transfusion (9). Consistent with these reports, liver dysfunction of this case was noted at 8 weeks following HEV infection, when she had recovered from immunosuppression. Her recovery from immunosuppression initiated an immune response against HEV and led to the onset of hepatitis. However, we could not retrospectively examine her serum for the presence of anti-HEV antibodies or the amount of HEV RNA at the time of chemotherapy because her previous serum samples were unfortunately not preserved.\n\nThe patient developed hypogammaglobulinemia after the end of chemotherapy. Another case of secondary hypogammaglobulinemia after chemotherapy including rituximab has been recently reported (10). In this case, prolonged HEV infection and the onset of CH-E were likely due to secondary hypogammaglobulinemia. A case of CH-E with primary immunodeficiency was also reported (11). These cases indicate that HEV is not a self-limiting infection in immunosuppressed or immunocompromised patient. Thus, we strongly suggest that tests for HEV infection should be performed during the diagnostic workup of liver dysfunction in immunosuppressed or immunocompromised patients.\n\nThere is no well-established treatment for CH-E that is supported by guidelines. If spontaneous clearance of HEV is not observed in a patient's serum, antiviral or anti-inflammatory therapy should be considered to avoid the progression of fibrosis. A reduction of immunosuppressive agents can eliminate HEV in approximately 30% of patients (12). Kamar et al. reported 59 cases of ribavirin therapy against CH-E that developed in organ-transplant patients. The sustained virological response rate of these patients, who had undetectable serum HEV RNA at six months after treatment, was -80% (8). Our patient did not receive any immunosuppressive medicine after the end of chemotherapy, thus ribavirin therapy was started. However, this did not eliminate HEV and we could not discontinue ribavirin therapy. As several reports have shown the efficacy of interferon therapy for CH-E, rescue treatment with interferon would be indicated to achieve HEV clearance in this case (13,14).\n\nThe reasons why HEV is not eradicated from hosts should be investigated in view of both host and viral factors. In this case, hypogammaglobulinemia was sustained, and the patient's CD4/8 ratio was approximately 0.5 when she presented to our department, indicating that she was still immunocompromised. As HEV-specific T-cells may play a role in HEV clearance, the patient's immunocompetence is significantly important (15,16). Previous reports have shown that ribavirin inhibits HEV replication, however, no direct anti-viral effect of ribavirin against HEV was noted (17). A resistant HEV mutation against ribavirin that increases the replication capacity of HEV has been recently reported (18). We analyzed the genomic sequence of HEV in the present case. The analysis showed that several mutations appeared after the administration of ribavirin (data not shown), however, these mutations have not been previously reported to be “resistant mutations”. It is possible that ribavirin monotherapy against an immunocompromised host is insufficient to achieve HEV clearance. Further research is needed to clarify whether the identified mutations in our case are associated with HEV resistance against ribavirin.\n\nIt has been reported that only HEV genotypes 3 and 4 can cause CH-E (3,19). Consistent with these previous reports, our case was genotype 3, however, the mechanism by which these specific genotypes can cause CH-E remains unknown. Although extrahepatic symptoms such as neurological injury and renal diseases have been reported in HEV patients, we observed no extrahepatic symptoms in this case (20). CH-E causes liver fibrosis and cirrhosis as well as CH of other etiology (7,21). Therefore, it is necessary to observe the progression of liver fibrosis carefully, because the natural course and prognosis of HEV-related fibrosis remain unclear.\n\nHEV infection due to a blood transfusion is considered to be a very rare event. In Japan, HEV screening of donated blood using HEV-nucleic acid amplification has been conducted only in Hokkaido, where the incidence rate of hepatitis E is relatively higher than other areas in Japan. In Hokkaido, -0.01% of donated blood samples were positive for HEV-nucleic acid amplification (22). To the best of our knowledge, 13 patients have been infected by HEV via blood transfusion in Japan, including the present case (9). On the other hand, a nationwide study in England revealed that 0.04% of transfused blood contained HEV-RNA, and 18 of 43 patients who received HEV-contaminated blood developed both acute and chronic hepatitis E (23). This study showed that the positive rate for HEV-IgG and/or HEV-IgM antibodies in HEV-infected patients via blood transfusion with immunosuppression was 70%, whereas such rate without immunosuppression was 100%. These data indicated that the detection of HEV antibodies in patients is influenced by immunocompetence in hosts. These data further suggested that HEV screening of donated blood is needed, at least before use in patient with immunodeficiency.\n\nPatients with a hematologic malignancy such as lymphoma or leukemia often require intensive multi-drug chemotherapy, including molecular-targeted drugs. These patients will be immunocompromised and will need to receive frequent blood transfusions. According to the evidence presented in this case report, we recommend that testing for HEV, including HEV RNA detection, should be performed during the diagnostic workup of liver dysfunction in both immunosuppressed and immunocompromised patients. Furthermore, this case suggested that patient immunocompetence could influence the therapeutic efficacy and should be considered in determining the therapy against to CH-E.\n\nThe authors state that they have no Conflict of Interest (COI).\nAcknowledgement\nWe thank Dr. Masahiro Satake (Japanese Red Cross Society Central Blood Center) and the staff of Japanese Red Cross Society for the retrospective survey of transfusion products, excellent technical assistance and insightful discussion.\n==== Refs\n1. \nKamar N , Bendall R , Legrand-Abravanel F , et al \nHepatitis E . Lancet \n379 : 2477 -2488 , 2012 .22549046 \n2. \nTei S , Kitajima N , Takahashi K , Mishiro S \nZoonotic transmission of hepatitis E virus from deer to human beings . Lancet \n362 : 371 -373 , 2003 .12907011 \n3. \nKamar N , Selves J , Mansuy JM , et al \nHepatitis E virus and chronic hepatitis in organ-transplant recipients . N Engl J Med \n358 : 811 -817 , 2008 .18287603 \n4. \nGauss A , Wenzel JJ , Flechtenmacher C , et al \nChronic hepatitis E virus infection in a patient with leukemia and elevated transaminases: a case report . J Med Case Rep \n6 : 334 , 2012 .23031738 \n5. \nOllier L , Tieulie N , Sanderson F , et al \nChronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab . Ann Intern Med \n150 : 430 -431 , 2009 .\n6. \nSellier P , Mazeron MC , Tesse S , et al \nHepatitis E virus infection in HIV-infected patients with elevated serum transaminases levels . Virol J \n8 : 171 , 2011 .21496215 \n7. \nGerolami R , Moal V , Colson P \nChronic hepatitis E with cirrhosis in a kidney-transplant recipient . N Engl J Med \n358 : 859 -860 , 2008 .18287615 \n8. \nKamar N , Izopet J , Tripon S , et al \nRibavirin for chronic hepatitis E virus infection in transplant recipients . N Engl J Med \n370 : 1111 -1120 , 2014 .24645943 \n9. \nFuse K , Matsuyama Y , Moriyama M , et al \nLate onset post-transfusion hepatitis E developing during chemotherapy for acute promyelocytic leukemia . Intern Med \n54 : 657 -661 , 2015 .25786459 \n10. \nCompagno N , Cinetto F , Semenzato G , Agostini C \nSubcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients . Haematologica \n99 : 1101 -1106 , 2014 .24682509 \n11. \nMallet V , Nicand E , Sultanik P , et al \nBrief communication: case reports of ribavirin treatment for chronic hepatitis E . Ann Intern Med \n153 : 85 -89 , 2010 .20547886 \n12. \nKamar N , Garrouste C , Haagsma EB , et al \nFactors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants . Gastroenterology \n140 : 1481 -1489 , 2011 .21354150 \n13. \nHaagsma EB , Riezebos-Brilman A , van den Berg AP , Porte RJ , Niesters HG \nTreatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b . Liver Transpl \n16 : 474 -477 , 2010 .20373458 \n14. \nKamar N , Rostaing L , Abravanel F , et al \nPegylated interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation . Clin Infect Dis \n50 : e30 -e33 , 2010 .20113176 \n15. \nSuneetha PV , Pischke S , Schlaphoff V , et al \nHepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection . Hepatology \n55 : 695 -708 , 2012 .22006345 \n16. \nKamar N , Legrand-Abravanel F , Dalton HR , Izopet J \nHepatitis E virus-specific T-cell response after transplantation . Hepatology \n55 : 1643 ; author reply 1644 , 2012 .22234861 \n17. \nKamar N , Rostaing L , Abravanel F , et al \nRibavirin therapy inhibits viral replication on patients with chronic hepatitis e virus infection . Gastroenterology \n139 : 1612 -1618 , 2010 .20708006 \n18. \nDebing Y , Gisa A , Dallmeier K , et al \nA mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with ribavirin treatment failure in organ transplant recipients . Gastroenterology \n147 : 1008 -1011 .e7 ; quiz e15 -e16 , 2014 .25181691 \n19. \nWu CH , Ho CM , Tsai JH , Sun HY , Hu RH , Lee PH \nFirst case genotype 4 hepatitis E infection after a liver transplant . Exp Clin Transplant (Epub ahead of print).\n20. \nAhmed A , Ali IA , Ghazal H , Fazili J , Nusrat S \nMystery of hepatitis e virus: recent advances in its diagnosis and management . Int J Hepatol \n2015 : 872431 , 2015 .25692043 \n21. \nTamura A , Shimizu YK , Tanaka T , et al \nPersistent infection of hepatitis E virus transmitted by blood transfusion in a patient with T-cell lymphoma . Hepatology Research \n37 : 113 -120 , 2007 .17300706 \n22. \nMatubayashi K \nHEV positives among blood donors in Hokkaido . Byogen Biseibutsu Kenshutsu Joho (IASR) \n35 : 7 -8 , 2014 (in Japanese).\n23. \nHewitt PE , Ijaz S , Brailsford SR , et al \nHepatitis E virus in blood components: a prevalence and transmission study in southeast England . Lancet \n384 : 1766 -1773 , 2014 .25078306\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "55(19)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D005260:Female; D016751:Hepatitis E; D006521:Hepatitis, Chronic; D006801:Humans; D016867:Immunocompromised Host; D012254:Ribavirin",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2811-2817",
"pmc": null,
"pmid": "27725541",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19293084;20708006;20547886;22234861;18287615;25078306;12907011;20373458;25692043;22006345;26221721;17300706;25786459;22549046;23031738;21496215;24645943;24682509;18287603;21354150;25181691;20113176",
"title": "Chronic Hepatitis E Infection in a Persistently Immunosuppressed Patient Unable to Be Eliminated after Ribavirin Therapy.",
"title_normalized": "chronic hepatitis e infection in a persistently immunosuppressed patient unable to be eliminated after ribavirin therapy"
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"companynumb": "US-SAGENTPRD-2016-US-000070",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "VINCRISTINE"
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{
"abstract": "BACKGROUND Lurbinectedin (Lurbi) was first approved in June 2020 for metastatic small cell lung cancer (SCLC) patients with progression following platinum-based chemotherapy. Extrapulmonary small cell neuroendocrine cancers (SCNECs) are treated with regimens used for SCLCs. Tumor lysis syndrome (TLS) in solid SCLCs and SCNECs following Lurbi use has not been reported in the literature so far. CASE REPORT We report a case of Lurbi-induced TLS in a patient with metastatic SCNEC of the cecum following a single intravenous dose of Lurbi 3.2 mg/m2. She presented to the hospital with abdominal pain, anuria, and grade 4 TLS. She required emergent hemodialysis due to acute renal failure. Our patient had a high Ki-67 proliferation index (95%), harbored a huge disease burden, and had bilateral renal metastasis, thus making her more susceptible to develop TLS. CONCLUSIONS Although data regarding the occurrence of TLS due to Lurbi in solid tumors are scarce, it remains a potential complication of Lurbi in neuroendocrine tumors with high proliferation index and large tumor burden.",
"affiliations": "Department of Hospital Medicine/Internal Medicine, Baptist Medical Center South, Montgomery, AL, USA.;Department of Internal Medicine, McLaren Regional Medical Center, Flint, MI, USA.;Department of Hospital Medicine, Northeast Internal Medicine Associates, LaGrange, IN, USA.;UAB Montgomery Internal Medicine Residency, Baptist Medical Center South, Montgomery, AL, USA.;Department of Hematology-Oncology, Alabama Oncology Hematology Associates, Montgomery, AL, USA.",
"authors": "Wahab|Ahsan|A|;Rafae|Abdul|A|0000-0003-4113-3304;Mushtaq|Kamran|K|;Venkata|Krishna|K|;Sarmad|Rehan|R|",
"chemical_list": "D002243:Carbolines; D006576:Heterocyclic Compounds, 4 or More Rings; C568606:PM 01183",
"country": "United States",
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"doi": "10.12659/AJCR.932081",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34125741\n10.12659/AJCR.932081\n932081\nArticles\nLurbinectedin-Induced Tumor Lysis Syndrome in Small Cell Neuroendocrine Cancer of the Cecum: A First-Ever Case Report\nWahab Ahsan AEF1\nRafae Abdul BD2\nMushtaq Kamran BD3\nVenkata Krishna EF4\nSarmad Rehan AEF5\n1 Department of Hospital Medicine/Internal Medicine, Baptist Medical Center South, Montgomery, AL, U.S.A.\n2 Department of Internal Medicine, McLaren Regional Medical Center, Flint, MI, U.S.A.\n3 Department of Hospital Medicine, Northeast Internal Medicine Associates, LaGrange, IN, U.S.A.\n4 UAB Montgomery Internal Medicine Residency, Baptist Medical Center South, Montgomery, AL, U.S.A.\n5 Department of Hematology-Oncology, Alabama Oncology Hematology Associates, Montgomery, AL, U.S.A.\nCorresponding Author: Ahsan Wahab, e-mail: drahsan.wahab@gmail.com\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n14 6 2021\n22 e932081-1e932081-5\n10 3 2021\n12 5 2021\n20 5 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 38-year-old\n\nFinal Diagnosis: Tumor lysis syndrome\n\nSymptoms: Abdominal pain\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Hematology • Oncology\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nLurbinectedin (Lurbi) was first approved in June 2020 for metastatic small cell lung cancer (SCLC) patients with progression following platinum-based chemotherapy. Extrapulmonary small cell neuroendocrine cancers (SCNECs) are treated with regimens used for SCLCs. Tumor lysis syndrome (TLS) in solid SCLCs and SCNECs following Lurbi use has not been reported in the literature so far.\n\nCase Report:\n\nWe report a case of Lurbi-induced TLS in a patient with metastatic SCNEC of the cecum following a single intravenous dose of Lurbi 3.2 mg/m2. She presented to the hospital with abdominal pain, anuria, and grade 4 TLS. She required emergent hemodialysis due to acute renal failure. Our patient had a high Ki-67 proliferation index (95%), harbored a huge disease burden, and had bilateral renal metastasis, thus making her more susceptible to develop TLS.\n\nConclusions:\n\nAlthough data regarding the occurrence of TLS due to Lurbi in solid tumors are scarce, it remains a potential complication of Lurbi in neuroendocrine tumors with high proliferation index and large tumor burden.\n\nKeywords:\n\nAcute Kidney Injury\nCarcinoma, Neuroendocrine\nSmall Cell Lung Carcinoma\nTumor Lysis Syndrome\n==== Body\nBackground\n\nTumor lysis syndrome (TLS) is one of the most common medical emergencies in patients with cancers. It occurs due to the rapid breakdown of tumor cells and subsequent release of their contents into the bloodstream, usually after starting chemo-therapy or spontaneously [1]. TLS is associated with electrolyte abnormalities, including hyperkalemia (≥6 mEq/l), hyper-uricemia (≥8 mg/dl), hyperphosphatemia (≥4.5 mg/dl), and hypocalcemia (≤7 mg/dl), which eventually cause clinical toxicities in the form of acute kidney failure, seizures, arrhythmias, and death [1,2]. A 25% increase in baseline potassium, uric acid, and phosphate levels and a 25% decrease in baseline calcium level are also considered positive lab indicators for TLS [1,2]. The emergence of newer effective targeted therapies may predispose to tumor breakdown and thus release massive breakdown products, overwhelming the body’s homeostasis and disposal mechanisms.\n\nLurbinectedin (PM01183), a derivative of ecteinascidin, attaches to the DNA minor groove and thus promotes double-strand DNA breaks [3]. The drug is a second-generation analog of trabectedin that suppresses RNA-polymerase-II activity and facilitates its breakdown with the help of ubiquitin/proteasome machinery [3]. Lurbinectedin (Lurbi) was first approved by the Food and Drug Administration (FDA) in June 2020 for metastatic small cell lung cancer (SCLC) patients with disease progression following platinum-based chemotherapy [3]. The approval was based on the evidence from a pivotal phase II basket trial (NCT02454972) that showed an overall response rate of 35% (95%CI: 26.2–45.2) when Lurbi was given as a second-line agent among these patients [4]. Hematological toxicity, elevated creatinine, abnormal liver functions, and fatigue were the most common adverse events (AEs), whereas neutropenia (46%), leukopenia (29%), and thrombocytopenia (7%) were the most common grade (G) 3 or 4 toxicities. Ten percent of patients in this trial had serious toxicity, 5% each accounted for neutropenia and febrile neutropenia. No treatment-related deaths occurred in this trial with 2% discontinuations secondary to toxicity. There were no documented reports of TLS [4]. Extrapulmonary small cell neuroendocrine cancers (SCNECs) are treated with regimens used for SCLCs [5]. This recommendation of parallel treatment paradigms is based on similar histology and biological behavior. TLS due to Lurbi has not been reported so far in solid tumors. We report a patient with metastatic SCNEC of cecum who was treated with Lurbi as third-line therapy and she developed TLS.\n\nCase Report\n\nA 38-year-old woman underwent right upper-quadrant ultra-sound for abdominal pain, which showed hypoechoic lesions within the liver, concerning for metastasis. The patient did not have a prior history of cancer. She underwent a computed tomography (CT) scan of abdomen with contrast that showed multiple lesions in the liver measuring up to 3.5 cm, concerning for metastatic disease. The patient underwent a chest CT, which showed a normal CT chest. The left adrenal gland had a 1.8-cm nodule, presumably metastatic, and a 2-cm round soft-tissue nodule located in the left kidney and tail of the pancreas, possibly metastatic as well. The patient was also found to have a cecal mass that was thought to be the primary. Magnetic resonance imaging (MRI) of the brain was negative for brain metastasis. She underwent a CT-guided biopsy of the liver. The pathology was consistent with SCNEC of the cecum with Ki-67 greater than 95% (Figure 1). The patient underwent a positron emission tomography (PET) scan (Figure 2), which showed widespread metastasis involving the supraclavicular area, right breast, both kidneys, cecum, the left iliac ala, and the left ovary.\n\nThe patient was labelled as metastatic SCNEC with its primary in the cecum. She was started on carboplatin, etoposide, and atezolizumab. The patient underwent a PET scan after 3 cycles of the above-mentioned treatment, which showed reduction in size of most of the lesions. The treatment course was complicated by a partial small-bowel obstruction, which improved following conservative measures. She completed 4 cycles of chemoimmunotherapy followed by 3 cycles of maintenance atezolizumab. Follow-up CT of the chest, abdomen, and pelvis showed worsening of disease in all of the lesions as well as a new left ovarian lesion. MRI of the brain was again negative for metastatic disease.\n\nNext-generation sequencing of the blood showed mutations in APC, KRAS, RB1, and TP53 but no targetable mutations. These mutations are seen in patients with colorectal cancers; therefore, the initial biopsy was re-reviewed with pathology to ensure that we were not dealing with colon cancer with neuroendocrine differentiation, but it was concluded that this was clearly a small-cell neuroendocrine tumor. The decision was made to start the patient on FOLFIRI as second-line therapy given the unavailability of a clinical trial. A follow-up CT scan after 3 cycles of FOLFIRI showed progression of disease in all areas in addition to the development of a large right-sided pleural effusion along with compressive atelectasis. There was a small pathologic nondisplaced fracture of the left iliac crest with increase in the size of the cecal mass. The hepatic disease and lymph nodes were also increased in size. She was started on Lurbi 3.2 mg/m2 intravenously every 3 weeks as a third-line therapy. The patient received a single dose of Lurbi and was admitted to the hospital 5 days later with abdominal pain. Upon admission, she was noted to be anuric. Lab tests (reference range in parenthesis) performed in the Emergency Department showed blood urea nitrogen 52 mg/dl (70–20), creatinine 3.97 mg/dl (0.60–1.30), eGFR 15 ml/min/1.73 m2 (>60), sodium 133 mmol/l (135–145), potassium 6.3 mg/dl (3.5–5.5), chloride 100 mmol/l (98–108), and bicarbonate 18 mmol/l (21–32). Phosphorus level was 7.6 mg/dl (2.5–4.9) and uric acid level 19.3 mg/dl. Lactic acid was 4.0 mmol/l (0.4–2.0). AST was 429 IU/L (8–37), ALT 49 IU/L (12–68), ALP 599 IU/L (45–117), total bilirubin 2.3 mg/dl (0.2–1.0), albumin 1.9 mg/dl (3.4–5.0), and total calcium 6.4 mg/dl (8.5–10.1). White blood cell (WBC) count was 9.89×10–3/ul (4.1–10.3), hemoglobin 9.6 gm/dl (11.3–15.3), MCV 69 FL (81–100), MCHC 31 g/dl (32–35), and platelet count 234×10–6/ul (140–400). The patient was diagnosed with TLS secondary to Lurbi. Given her life-threatening electrolyte abnormalities, anuria, and metabolic acidosis, she was initiated on emergent hemodialysis on the same day. After hemodialysis, the lab values improved, with BUN 21 mg/dl, creatinine 1.90 mg/dl, eGFR 36 ml/min/1.73 m2, sodium 136 mmol/l, potassium 4.3 mmol/l, chloride 99 mmol/l, bicarbonate 25 mmol/l, and uric acid 7.1 mg/dl. A plan was made to resume hemodialysis based on the patient’s renal failure and laboratory profile. However, during the hospitalization, the patient developed pancytopenia (WBC count 1.1×10–3/ul, hemoglobin 7.3 g/dl and platelets 33×10–6/ul) and coagulopathy with elevated PT/INR. The coagulopathy was thought to be due to disseminated intravascular coagulation (DIC) and liver dysfunction. She was given packed RBCs, platelets, FFPs, and IV vitamin K. She was also started on filgrastim. On the following day, the patient developed rectal bleeding. CT abdomen did not identify any source. She was treated with broad-spectrum antibiotics, given her pancytopenia and suspected sepsis. She became hemodynamically unstable, precluding invasive gastrointestinal evaluation. Blood cultures grew Escherichia coli and methicillin-sensitive Staphylococcus aureus. She continued to deteriorate afterward despite appropriate antibiotics and developed septic shock, requiring multiple pressors. She went into cardiac arrest, requiring CPR and intubation, and she continued to decline. Her family decided to withdraw care given multiorgan failure and dismal prognosis. The patient died 4 days after admission.\n\nDiscussion\n\nSmall-cell neuroendocrine cancers (SCNECs) are exceedingly rare tumors of the colon, accounting for 0.6% of all types [6]. They exhibit an aggressive clinical behavior, and two-thirds of them are already metastatic at the time of diagnosis, and thus have a dismal prognosis (median survival: 10.4 months, 95%CI: 6.7–18.9). Chemoimmunotherapy is the treatment of choice for metastatic SCNECs. Therefore, we used a platinum-based therapy in our patient due to Ki-67 >55%, as these tumors tend respond well to such therapy [5,7]. However, the patient’s tumor burden continued to build up. She also progressed on FOLFIRI and thus had to be started on Lurbi according to the National Comprehensive Cancer Network (NCCN) guidelines. Following Lurbi, she developed G-4 TLS and acute renal failure and needed emergent hemodialysis.\n\nThere are no published reports on the experience and safety regarding the use of Lurbi in SCNECs. Many clinical trials that evaluated the role of Lurbi alone or in combination with other drugs in solid tumors such as SCLC, non-SCLC, sarcoma, metastatic breast cancer, ovarian cancer, malignant mesothelioma, head and neck cancers, and endometrial cancers did not document any event of TLS [4,8–10]. One phase I trial (NCT01970540) evaluated the safety of escalating doses of Lurbi along with doxorubicin in advanced solid tumors, including 9 patients with neuroendocrine cancers [3,8]. There are no reports of TLS in neuroendocrine cancers or any other solid tumor type. One case of TLS was reported in a phase I trial (n=42) that tested various doses of Lurbi ranging from 1 to 7 mg in non-solid tumor type, ie, acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) [11]. One incident of G-4 TLS was reported in a patient with 3 mg of Lurbi, although there were even higher doses given in other patients without developing TLS.\n\nTLS is a function of a multitude of factors (patient-, tumor-, and therapy-related) such as: (1) patient’s age and predisposing renal factors, eg, renal insufficiency, dehydration, hyperuricemia, renal invasion of tumor; (2) tumor type (solid vs hematologic) and histology such as acute vs chronic leukemia, Burkitt lymphoma, and neuroblastomas and SCLC; (3) tumor bulkiness, staging and proliferation; (4) tumor sensitivity to chemotherapy; and (5) type of chemotherapy used [12,13]. Patients with hematologic malignancies such as AML and acute lymphoblastic leukemia with WBC count ≥100×109/l and lactate dehydrogenase level ≥2 times the upper normal limit are more at risk [12]. Therefore, one TLS case in an AML/MDS patient might be due to such potential factors not documented in the published trial. The co-occurrence of DIC and TLS has been reported in the literature as well, with one acting as a nidus for the other, contributing further to hemodynamic instability [13].\n\nThose solid tumors that have a high proliferation index and show an extreme sensitivity to cytotoxic or targeted drugs may also present with TLS. Our patient had a high Ki-67 proliferation index (95%), harbored a huge disease burden, and had bilateral renal metastasis, thus making her more susceptible to develop TLS. Previously, patients with solid tumors with a high Ki-67 index have been reported to develop TLS [14,15]. Our patient developed abdominal pain from tumor lysis within 5 days of Lurbi and became anuric, along with having metabolite abnormalities. The presentation of such a case demands a proactive prophylactic strategy and high index of suspicion for TLS in neuroendocrine tumors, especially among those that have a high proliferation index. Prophylactic hydration, diuresis, and hypouricemic agents aiming to improve the urinary flow and prevent renal failure should be instituted. Acute renal failure is an oncological emergency and needs emergent hemodialysis.\n\nConclusions\n\nAlthough the data regarding the occurrence of TLS due to Lurbi in solid tumors are limited, it remains a potential complication of Lurbi in patients with neuroendocrine tumors with high proliferation index and large tumor burden. Treating physicians should consider TLS as a potential complication of Lurbi and proactively develop a preventive strategy. TLS can be life-threatening, leading to renal failure and death.\n\nFigure 1. Histopathology of liver biopsy specimen showing (A) hematoxylin and eosin staining and immunohistochemical staining positive for (B) synaptophysin, (C) chromogranin, and (D) Ki-67.\n\nFigure 2. (A, B) PET/CT of the patient showing multiple metastatic lesions in liver, right breast, both kidneys, and iliac bone (arrows).\n\nConflicts of interest\n\nNone.\n==== Refs\nReferences:\n\n1. Abu-Alfa AK Younes A Tumor lysis syndrome and acute kidney injury: Evaluation, prevention, and management Am J Kidney Dis 2010 55 5 Suppl. 3 S1 13 ; quiz S14–19\n2. Howard SC Jones DP Pui C-H The tumor lysis syndrome N Eng J Med 2011 364 19 1844 54\n3. Markham A Lurbinectedin: First approval Drugs 2020 80 13 1345 53 32816202\n4. Trigo J Subbiah V Besse B Lurbinectedin as second-line treatment for patients with small-cell lung cancer: A single-arm, open-label, phase 2 basket trial Lancet Oncol 2020 21 5 645 54 32224306\n5. National Comprehensive Cancer Network Neuroendocrine and Adrenal Tumors (Version 2.2020) [cited 2021 Feb 25] https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine_blocks.pdf\n6. Bernick PE Klimstra DS Shia J Neuroendocrine carcinomas of the colon and rectum Dis Colon Rectum 2004 47 2 163 69 15043285\n7. Sorbye H Welin SF Langer SW Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): The NORDIC NEC study Ann Oncol 2013 24 1 152 60 22967994\n8. Calvo E Moreno V Flynn M Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study Ann Oncol 2017 28 10 2559 66 28961837\n9. Cote GM Choy E Chen T A phase II multi-strata study of lurbinectedin as a single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas Eur J Cancer 2020 126 21 32 31896519\n10. Cruz C Llop-Guevara A Garber JE Multicenter phase II study of lurbinectedin in BRCA-mutated and unselected metastatic advanced breast cancer and biomarker assessment substudy J Clin Oncol 2018 36 31 3134 43 30240327\n11. Benton CB Chien KS Tefferi A Safety and tolerability of lurbinectedin (PM01183) in patients with acute myeloid leukemia and myelodys-plastic syndrome Hematol Oncol 2019 37 1 96 102 30153704\n12. Cairo MS Coiffier B Reiter A Younes A TLS Expert Panel Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus Br J Haematol 2010 149 4 578 86 20331465\n13. Teh RW Tsoi DT Acute disseminated intravascular coagulation in neuroendocrine carcinoma Case Rep Oncol 2012 5 524 29 23139666\n14. Martínez-Sáez O Mezquita L Caravaca-Fontan F Spontaneous tumor lysis syndrome in the setting of small cell lung cancer: Report of two cases and review of the literature Cancer Treatment and Research Communications 2016 9 92 95\n15. Namdari N Azarpira N Spontaneous tumor lysis syndrome in primitive neuroectodermal tumor Middle East Journal of Cancer 2019 10 4 384 88\n\n",
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"mesh_terms": "D002243:Carbolines; D018278:Carcinoma, Neuroendocrine; D002432:Cecum; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D008175:Lung Neoplasms; D015275:Tumor Lysis Syndrome",
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"title": "Lurbinectedin-Induced Tumor Lysis Syndrome in Small Cell Neuroendocrine Cancer of the Cecum: A First-Ever Case Report.",
"title_normalized": "lurbinectedin induced tumor lysis syndrome in small cell neuroendocrine cancer of the cecum a first ever case report"
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"abstract": "BACKGROUND\nMetformin is considered the first choice oral treatment for type 2 diabetes patients in the absence of contraindications. Rarely, life-threatening complications associated with metformin treatment are seen in some patients with underlying diseases. The aim of this study was to further investigate the clinical profiles and risk factors for metformin-associated lactic acidosis (MALA) and the treatment modalities according to survival.\n\n\nMETHODS\nTo identify MALA, we performed a retrospective study in seven diabetic patients who were taking metformin and had been diagnosed with lactic acidosis at Inha University Hospital between 1995 and 2012. For each patient, we recorded the age, sex, daily metformin dosage, laboratory test results, admission diagnosis, and risk factors. Also, concurrent conditions, treatment modalities, and outcomes were evaluated.\n\n\nRESULTS\nSix patients had risk factors for lactic acidosis before admission. All patients had renal impairment on admission as a precipitating risk factor. Five patients survived and two patients died despite early renal replacement therapy. Older patients tended to have a poorer prognosis.\n\n\nCONCLUSIONS\nRenal function must be monitored in elderly type 2 diabetes mellitus patients with underlying diseases and conditions causing renal impairment who begin metformin treatment. Accurate recognition of MALA and initiation of renal replacement are essential for treatment.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea. sbhongmd@inha.ac.kr.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.",
"authors": "Kim|Min Ju|MJ|;Han|Ju Young|JY|;Shin|Jun Young|JY|;Kim|Shin Il|SI|;Lee|Jeong Min|JM|;Hong|Seongbin|S|;Kim|So Hun|SH|;Nam|Moon Suk|MS|;Kim|Yong Seong|YS|",
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"country": "Korea (South)",
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"doi": "10.3803/EnM.2015.30.1.78",
"fulltext": "\n==== Front\nEndocrinol Metab (Seoul)Endocrinol Metab (Seoul)ENMEndocrinology and Metabolism2093-596X2093-5978Korean Endocrine Society 2582746010.3803/EnM.2015.30.1.78Original ArticleMetformin-Associated Lactic Acidosis: Predisposing Factors and Outcome Kim Min Ju Han Ju Young Shin Jun Young Kim Shin Il Lee Jeong Min Hong Seongbin Kim So Hun Nam Moon Suk Kim Yong Seong Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.Corresponding author: Seongbin Hong. Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University School of Medicine, 27 Inhang-ro, Jung-gu, Incheon 400-711, Korea. Tel: +82-32-890-3484, Fax: +82-32-882-6578, sbhongmd@inha.ac.kr3 2015 27 3 2015 30 1 78 83 12 5 2014 26 6 2014 03 7 2014 Copyright © 2015 Korean Endocrine Society2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nMetformin is considered the first choice oral treatment for type 2 diabetes patients in the absence of contraindications. Rarely, life-threatening complications associated with metformin treatment are seen in some patients with underlying diseases. The aim of this study was to further investigate the clinical profiles and risk factors for metformin-associated lactic acidosis (MALA) and the treatment modalities according to survival.\n\nMethods\nTo identify MALA, we performed a retrospective study in seven diabetic patients who were taking metformin and had been diagnosed with lactic acidosis at Inha University Hospital between 1995 and 2012. For each patient, we recorded the age, sex, daily metformin dosage, laboratory test results, admission diagnosis, and risk factors. Also, concurrent conditions, treatment modalities, and outcomes were evaluated.\n\nResults\nSix patients had risk factors for lactic acidosis before admission. All patients had renal impairment on admission as a precipitating risk factor. Five patients survived and two patients died despite early renal replacement therapy. Older patients tended to have a poorer prognosis.\n\nConclusion\nRenal function must be monitored in elderly type 2 diabetes mellitus patients with underlying diseases and conditions causing renal impairment who begin metformin treatment. Accurate recognition of MALA and initiation of renal replacement are essential for treatment.\n\nMetforminAcidosis, lacticDiabetes mellitus, type 2Inha University\n==== Body\nINTRODUCTION\nMetformin is an oral antidiabetic drug in the biguanide class that is widely used, alone or in combination with a sulfonylurea or other drugs, in patients with type 2 diabetes. The drug's glucose-lowering effect results mainly from decreased hepatic glucose output with increased glucose utilization in peripheral tissues [1]. Metformin is absorbed mainly from the small intestine, has 40 to 60% oral bioavailability, and has an estimated plasma half-life of 1.5 to 4.9 hours [2]. Unlike sulfonylureas, metformin is not metabolized and does not bind to plasma proteins. Metformin is eliminated by renal tubular secretion and glomerular filtration. Thus, the serum metformin concentration and toxicity are related to renal function.\n\nThe most common side effects of metformin are gastrointestinal disturbances, including anorexia, nausea, abdominal discomfort, and diarrhea. These mild symptoms are usually reversed after discontinuation or dose reduction. Rarely, a serious condition called metformin-associated lactic acidosis (MALA) can occur in patients with predisposing factors such as renal insufficiency, hepatic disease, congestive heart failure, or sepsis [3].\n\nThe incidence of lactic acidosis in patients on metformin therapy appears to be very low [4,5,6], but it can be fatal when it occurs. In a review of 11,800 patients treated with metformin for a mean duration of approximately 2 years, only two patients developed lactic acidosis (an incidence of nine cases per 100,000 person-years of exposure). In clinical practice, metformin is used for diabetics despite its contraindications in 24.5% to 94% of patients with type 2 diabetes [7,8].\n\nThe aim of this study was to further investigate the clinical profiles and risk factors for MALA and to analyze treatment modalities according to survival.\n\nMETHODS\nWe conducted a retrospective analysis of patients admitted into a single academic hospital due to MALA and analyzed the precipitating causes and prognoses. In this study, patients were defined as having MALA if they had metabolic acidosis (arterial pH <7.35, plasma lactate level >5.0 mmol/L [0.50 to 1.50]) and had been treated with metformin before admission.\n\nWe searched for cases with diabetes and acidosis including lactic acidosis and ketoacidosis between January 1995 and December 2012 and reviewed the medication histories and causes of acidosis. Among 5,558 patients who were admitted due to diabetes, we identified 198 patients with acidosis, including lactic acidosis or ketoacidosis. Patients with diabetic ketoacidosis and an unknown medication history or low lactic acid level (<5 mmol/L) were excluded. For the selected MALA cases, we recorded the age, sex, daily metformin dosage, laboratory tests, admission diagnosis, and risk factors for lactic acidosis. In addition, accompanying diseases, treatments and outcomes were evaluated. Renal dysfunction was defined as a plasma creatinine level >1.49 mg/dL in men and >1.40 mg/dL in women. Glomerular filtration rate was calculated before initiation of continuous renal replacement therapy using the MDRD eGFR equation (estimated glomerular filtration rate mL/min/1.73 m2=175×Scr-1.154×age-0.203×0.742 if female). Impaired liver function was defined as a serum alanine transaminase concentration >3-fold the upper limit of normal. Values are expressed as means±SD. The relationship between clinical parameters and outcome was examined using the Mann-Whitney test for quantitative variables and the Fisher exact test for qualitative variables in patients who both survived and died. A P≤0.05 was considered to be statistically significant.\n\nRESULTS\nOf the 198 diabetic patients reviewed for acidosis, seven patients (five females and two males) were diagnosed with MALA during the study period. Two patients had been misdiagnosed with diabetic ketoacidosis. All patients had been treated with metformin by their primary physicians and had visited the emergency room. Table 1 summarizes the demographics and laboratory data of the seven MALA cases. The patients were 74.5±9.8 years of age (range, 57 to 86), six of whom were older than 70 years except one alcoholic. The mean arterial pH was 6.9±0.2, mean serum lactate was 15.7±8.3 mmol/L, and the mean daily dose of metformin was 1,528±658 mg. Case 1 is described singly here, and the other six cases are summarized in Tables 1, 2.\n\nCase 1\nA 73-year-old woman with a history of hypertension and type 2 diabetes was admitted to the emergency department after 2 days of general weakness, anorexia, vomiting and diarrhea. She was hypotensive, and her mentality was deeply drowsy. She was intubated, ventilated and administered massive fluid resuscitation immediately. Her pharmacologic regimen included metformin 2,000 mg, glimepiride 8 mg, telmisartan/hydrochlorothiazide 80/12.5 mg, amlodipine 10 mg, nifedipine 30 mg, alprazolam 0.5 mg, pantoprazole 20 mg, trimetazidine dihydrochloride 40 mg, and bisoprolol 10 mg. Her physical examination revealed no abnormalities other than severe dehydration. Laboratory results showed leukocytosis (19,660/mm3, 81.4%) with left shift and anemia and levels of hemoglobin of 6.8 g/dL, blood glucose of 419 mg/dL, sodium of 130 mEq/L, potassium of 8 mEq/L, and chloride of 96 mEq/L. Acute renal failure was noted, with a blood urea nitrogen level of 70.6 mg/dL and serum creatinine level of 5.8 mg/dL, and the creatinine clearance was calculated as 7 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula. The last creatinine level measured before admission was 1.6 mg/dL. Analysis of arterial blood gases indicated a high anion gap (31.5 mEq/L), metabolic acidosis (pH 6.9), and bicarbonate 2.5 mEq/L. Liver function tests were within normal ranges. The serum lactate level was elevated at 9.2 mmol/L. Despite forced diuresis after massive rehydration, urine output was absent and acidosis was aggravated. Continuous venovenous hemodialysis was started using bicarbonate buffered solution. Twenty-four hours of renal replacement therapy led to progressive improvement of metabolic acidosis with pH values of 7.16, 7.36, and 7.41 and bicarbonate values of 6, 12, and 24 mEq/L on each subsequent day. The urinary output also increased progressively. Two days later, the patient returned to a normal mental state with stable vital signs without inotropics or ventilator support. Renal function was improved as indicated by a serum creatinine level of 1.63 mg/dL. After 15 days, the patient was discharged.\n\nRisk factors\nAll patients who presented with MALA had impaired renal function on admission. Three patients had chronic kidney disease (CKD) before admission. The admission diagnoses, risk factors, treatments and outcomes (60 days after admission) are summarized in Table 2. Six patients (86%) had risk factors for lactic acidosis in their medical histories. Five patients were dehydrated due to vomiting and diarrhea, indicating that acute renal failure resulted from dehydration secondary to diarrhea and poor oral intake and likely was the cause of MALA. Three patients were diagnosed with pneumonia during the treatment. Two patients had been diagnosed previously with heart failure.\n\nTreatment\nFour patients (58%) received renal replacement therapy, and the remaining three patients (42%) were treated conservatively with sodium bicarbonate and fluid resuscitation. The bicarbonate-buffered renal replacement therapy was maintained for 24 to 48 hours until the patient's lactate level and urine output were normalized. Three cases underwent continuous venovenous hemodialysis and one underwent intermittent hemodialysis.\n\nMortality\nTwo patients (29%) died despite renal replacement therapy on hospitalization days 14 and 60, respectively (Table 3). In case 5, while continuous venovenous hemodialysis improved the acidosis, mental state failed to recover, and the patient was transferred to another hospital. Pneumonia and pulmonary congestion were aggravated in case 7. Both patients who died had acute renal failure with more severe metabolic acidosis (P=0.053) and were older than the patients who survived (P=0.049). Furthermore, their lactate levels were as high as 17 and 32 mmol/L, respectively (P=0.121).\n\nDISCUSSION\nKnown predisposing factors for MALA include impaired renal function, concurrent liver disease, alcoholism, and decreased tissue perfusion due to infection, heart failure, or other causes [8,9]. In our study, most MALA cases occurred in patients with renal impairment with or without other precipitating conditions. Metformin therapy was contraindicated relatively or absolutely in six patients. Three patients had concurrent pneumonia, suggesting decreased tissue perfusion, since infection precipitates MALA. In MALA, metformin's mechanism of action is thought to inhibit hepatic gluconeogenesis from lactate, pyruvate, and alanine, resulting in additional lactate and substrates for lactate production by decreased pyruvate carboxylase activity, a rate limiting enzyme needed for the formation of glucose from lactate [1]. Another mechanism includes a shift in the intracellular redox potential from aerobic to anaerobic metabolism, with conversion of glucose to lactate in the splanchnic bed of the small intestine.\n\nThe main finding in our patients with severe lactic acidosis who were taking metformin was an improvement in shock following a short duration of renal replacement therapy or conservative treatment. Although some of the patients had other diseases such as pneumonia, which could have contributed to the lactic acidosis, this condition alone was not sufficient to cause severe acidosis. The patients recovered from shock rapidly following continuous renal replacement therapy, after which their renal function was normalized.\n\nScale and Harvey [10] reported that diabetes, rather than metformin therapy, is the major risk factor for the development of lactic acidosis. It remains unclear as to whether this is a causative link or is associated with other causes. Since lactic acidosis continues to develop in patients taking metformin, it is important to clarify the clinical findings and to identify and treat these cases appropriately. We also reviewed five cases of metformin-independent lactic acidosis in our hospital. The mortality rate was 80%, which is higher than that for MALA. In addition, the patients had multiple comorbidities (data not shown).\n\nSymptoms of lactic acidosis are nonspecific and may include anorexia, nausea, vomiting, abdominal pain, lethargy, hyperventilation, and hypotension [11]. Five of our patients (71%) complained of diarrhea, which can be an adverse effect of metformin and can aggravate hypovolemia. Metformin toxicity has been reported previously to mimic the clinical picture of abdominal sepsis [12].\n\nPreviously, MALA cases were rare; however, relatively high incidences, such as 47 to 57 cases per 100,000 patient-years, are now being reported [13]. Additionally, the incidence of MALA can be underestimated, because it is not always recorded as acidosis, due to other concomitant diseases, or it can be confused with ketoacidosis. Two of our cases had mildly elevated ketones, and their initial diagnosis at the emergency room was diabetic ketoacidosis. Data from a large clinical trial identified no cases of lactic acidosis [4]. The risk factors of lactic acidosis differ greatly between stable trial patients and those who are acutely unwell or have insufficient renal function.\n\nDosage guidelines for CKD patients have been published recently [14]. The following maximum daily doses have been recommended for specific creatinine clearance rates: 3 g (120 mL/min), 2 g (60 mL/min), 1 g (15 mL/min), and 500 mg (below 15 mL/min).\n\nMost studies on MALA have focused on its incidence and predisposing factors. However, we were interested in the clinical factors that can guide treatment and predict outcome. In our study, age was the most important factor while the metformin dose and pH had no prognostic value. Also, the mortality was lower than that of other studies evaluating patients with similar cases of acidosis. After correction of acidosis, treatment of the underlying disease affects the outcome. Case 7 recovered from acidosis after hemodialysis treatment, but the pneumonia was aggravated. Recently, it was shown that neither the serum lactate concentration nor metformin dosage is related to the prognosis of MALA [13].\n\nRenal replacement therapy was initiated in four of seven patients. Renal replacement therapy corrects acidosis by filtering out anions and efficiently removes metformin from the plasma. Bicarbonate hemodialysis, continuous venovenous high-flow hemofiltration dialysis, or combined modalities have been reported in the treatment of severe MALA cases [15]. Such severe cases should be treated immediately with renal replacement therapy using bicarbonate-buffered fluids and correction of any associated conditions. A recent study demonstrated that prompt recognition of lactic acidosis and early treatment using bicarbonate dialysis can result in a favorable clinical outcome [16]. Another study reported that continuous venovenous high-flow hemofiltration dialysis can be effective in patients with hemodynamic instability or in those who require urgent removal of metformin and lactic acid [17]. Yet, there is no conclusive data available to indicate which dialysis technique is superior. In our cases, patients with pH <7.0 required renal replacement therapy.\n\nOur report has several limitations. First, serum metformin was not measured in our cases, so its prognostic value could not be assessed. In addition, our sample size was relatively small due to the rarity of the condition and the retrospective nature of our study. We were also unable to compare the findings in our sample patients with those in a control group of metformin users who did not develop lactic acidosis. Also, lactic acidosis may often be misdiagnosed in diabetic patients, although in our study all cases of acidosis were reviewed.\n\nThe majority of elderly type 2 diabetes mellitus patients have renal insufficiency and other various comorbidities that increase the risk of lactic acidosis. To prevent MALA in patients at risk of lactic acidosis who are taking metformin, risk factors for MALA should be carefully assessed and renal function monitored. Early recognition of this condition and initiation of renal replacement therapy can improve the outcome.\n\nACKNOWLEDGMENT\nThis study was supported by Inha University.\n\nCONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.\n\nTable 1 Demographic and Laboratory Data of Patients with Metformin-Associated Lactic Acidosis\nBUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; BP, blood pressure.\n\naeGFR was calculated using the modification of diet in renal disease eGFR equation.\n\nTable 2 Risk Factors, Diagnosis on Admission, Treatment and Outcome of Patients with Metformin-Associated Lactic Acidosis\nDF, female; CKD, chronic kidney disease; ARF, acute renal failure; CVVH, continuous venovenous hemodialysis; S, survived; M, male; HHS, hyperglycemic hyperosmolar syndrome; AKA, alcoholic ketoacidosis; HD, hemodialysis; NA; not available; CHF, congestive heart failure; D, died.\n\nTable 3 Clinical and Laboratory Variables according to Outcome\nValues are expressed as median (range).\n\nDM, diabetes mellitus; SBP, Systolic blood pressure; eGFR, estimated glomerular filtration rate.\n\naP<0.05.\n==== Refs\n1 Viollet B Guigas B Sanz Garcia N Leclerc J Foretz M Andreelli F Cellular and molecular mechanisms of metformin: an overview Clin Sci (Lond) 2012 122 253 270 22117616 \n2 Bailey CJ Turner RC Metformin N Engl J Med 1996 334 574 579 8569826 \n3 Wiholm BE Myrhed M Metformin-associated lactic acidosis in Sweden 1977-1991 Eur J Clin Pharmacol 1993 44 589 591 8405019 \n4 Cryer DR Nicholas SP Henry DH Mills DJ Stadel BV Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study Diabetes Care 2005 28 539 543 15735184 \n5 Salpeter SR Greyber E Pasternak GA Salpeter Posthumous EE Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Cochrane Database Syst Rev 2010 20 1 CD002967 \n6 Stang M Wysowski DK Butler-Jones D Incidence of lactic acidosis in metformin users Diabetes Care 1999 22 925 927 10372243 \n7 Sulkin TV Bosman D Krentz AJ Contraindications to metformin therapy in patients with NIDDM Diabetes Care 1997 20 925 928 9167101 \n8 Emslie-Smith AM Boyle DI Evans JM Sullivan F Morris AD DARTS/MEMO Collaboration Contraindications to metformin therapy in patients with type 2 diabetes: a population-based study of adherence to prescribing guidelines Diabet Med 2001 18 483 488 11472468 \n9 Gan SC Barr J Arieff AI Pearl RG Biguanide-associated lactic acidosis. Case report and review of the literature Arch Intern Med 1992 152 2333 2336 1444694 \n10 Scale T Harvey JN Diabetes, metformin and lactic acidosis Clin Endocrinol (Oxf) 2011 74 191 196 21039727 \n11 Sirtori CR Pasik C Re-evaluation of a biguanide, metformin: mechanism of action and tolerability Pharmacol Res 1994 30 187 228 7862618 \n12 Ashall V Dawes T Metformin and lactic acidosis Br J Anaesth 2008 101 876 877 19004915 \n13 van Berlo-van de Laar IR Vermeij CG Doorenbos CJ Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements J Clin Pharm Ther 2011 36 376 382 21545617 \n14 Duong JK Kumar SS Kirkpatrick CM Greenup LC Arora M Lee TC Timmins P Graham GG Furlong TJ Greenfield JR Williams KM Day RO Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function Clin Pharmacokinet 2013 52 373 384 23475568 \n15 Dichtwald S Weinbroum AA Sorkine P Ekstein MP Dahan E Metformin-associated lactic acidosis following acute kidney injury: efficacious treatment with continuous renal replacement therapy Diabet Med 2012 29 245 250 21977945 \n16 Kang BI Kim SJ Kim JH Gil HW Yang JO Lee EY Hong SY Two cases of metformin-induced lactic acidosis successfully treated by hemodialysis Korean J Med 2011 80 473 476 \n17 Choi HS Jung KH Shim JJ Chae MJ Lee SH Lee TW Lim CK Kim MJ A case of metformin-associated lactic acidosis Korean J Nephrol 2004 23 143 146\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2093-596X",
"issue": "30(1)",
"journal": "Endocrinology and metabolism (Seoul, Korea)",
"keywords": "Acidosis, lactic; Diabetes mellitus, type 2; Metformin",
"medline_ta": "Endocrinol Metab (Seoul)",
"mesh_terms": null,
"nlm_unique_id": "101554139",
"other_id": null,
"pages": "78-83",
"pmc": null,
"pmid": "25827460",
"pubdate": "2015-03-27",
"publication_types": "D016428:Journal Article",
"references": "19004915;20091535;1444694;21545617;23475568;7862618;22117616;15735184;8569826;21977945;9167101;8405019;10372243;11472468;21039727",
"title": "Metformin-associated lactic acidosis: predisposing factors and outcome.",
"title_normalized": "metformin associated lactic acidosis predisposing factors and outcome"
} | [
{
"companynumb": "KR-INVENTIA-000044",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Objective: To explore the clinical features of three early-onset infantile epileptic encephalopathy (EIEE) patients with variations in phosphofurin acidic cluster sorting protein 2 (PACS2) gene and to review related literature. Methods: The clinical data and genetic features of three early infantile epileptic encephalopathy 66 (EIEE66) patients with a PACS2 gene variant diagnosed by the Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2019 to January 2020 were retrospectively analyzed. A literature search with \"PACS2 gene\" \"PACS2\" \"epileptic encephalopathy, early infantile, 66\" and\"early infantile epileptic encephalopathy 66\" as key words was conducted at PubMed, China National Knowledge Infrastructure (CNKI), and Wanfang Data Knowledge Service Platform (up to July 2020). Case reports of patients with PACS2 gene variants and related clinical data were chosen and reviewed. Results: Case 1, a girl aged 2 years and 2 months was hospitalized because of repetitive seizures within more than two years and 6 convulsions within 2 days due to fever. The seizures occurred at the age of 7 days, characterized by focal seizures and generalized tonic-clonic seizures. Sometimes, the frequency of seizures increased with high fever. Regular treatment had not been implemented in the early stage, later seizures were controlled by valproic acid treatment. Case 2, a female 5 months of age, was admitted due to recurrent convulsions in nearly five months. Focal seizures occured at the age of 5 days. And the brain magnetic resonance imaging (MRI) confirmed abnormal cerebellar hemispheres and cerebellar vermis, as well as cerebellar dysplasia. Several antiepileptic drugs and ketogenic diet were ineffective in the early months, and later seizures were controlled with the treatment with levetiracetam and valproic acid. Case 3, a five-month-old girl, was admitted because of recurrent convulsions for nearly five months. At the age of 3 days, she had tonic seizures, and showed good response to levetiracetam and valproic acid. All the three cases were accompanied by development delay and dysmorphic facial appearance, and got seizure-free with the treatment with valproic acid. All copy-number variant analysis and trio whole exome sequencing revealed a recurrent heterozygous missense variant (c.625G>A) in PACS2 gene. No related reports were found in Chinese journals, while 4 reports were found in English literature, describing 17 patients in total. With these 3 patients included, 20 cases had only two missense PACS2 gene variants, in whom 19 cases carried the variant c. 625G>A (p.Glu209Lys) and 1 case carried the variant c. 631G>A (p.Glu211Lys). Epilepsy was the first reported symptom in all patients, and 17 cases had seizures during the first week of life. Out of the various seizure types observed, focal seizures were the predominant types (13 cases), whereas tonic, clonic, tonic-clonic seizures and non-motor seizures (such as facial flushing) were also reported. Almost all patients showed facial dysmorphism and developmental delay to different degrees. Total of 16 patients had abnormal brain MRI recordings, and 13 cases had cerebellar hypoplasia. More specifically, 7 cases showed inferior vermian hypoplasia, and 3 cases showed hypothalamic fusion anomaly. The treatment was mainly aimed to control the symptoms. And the recommended effective treatment for epilepsy has not been reported yet. Conclusions: PACS2-related early infantile epileptic encephalopathy is an autosomal dominant disease, characterized by seizure onset within the first week of life in most cases, dysmorphic facial appearance, and various degrees of developmental retardation. Treatment with valproic acid showed good effect.",
"affiliations": "Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.;Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.;Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.;Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.;Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.;Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.",
"authors": "Wu|M J|MJ|;Hu|C H|CH|;Ma|J H|JH|;Hu|J S|JS|;Liu|Z S|ZS|;Sun|D|D|",
"chemical_list": "C499638:PACS2 protein, human; D033921:Vesicular Transport Proteins",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.cn112140-20201122-01047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0578-1310",
"issue": "59(7)",
"journal": "Zhonghua er ke za zhi = Chinese journal of pediatrics",
"keywords": null,
"medline_ta": "Zhonghua Er Ke Za Zhi",
"mesh_terms": "D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006801:Humans; D007223:Infant; D012189:Retrospective Studies; D012640:Seizures; D013036:Spasms, Infantile; D033921:Vesicular Transport Proteins",
"nlm_unique_id": "0417427",
"other_id": null,
"pages": "594-599",
"pmc": null,
"pmid": "34405643",
"pubdate": "2021-07-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Early infantile epileptic encephalopathy caused by PACS2 gene variation: three cases report and literature review.",
"title_normalized": "early infantile epileptic encephalopathy caused by pacs2 gene variation three cases report and literature review"
} | [
{
"companynumb": "CN-LUPIN PHARMACEUTICALS INC.-2021-20261",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nPemphigus is a rare and fatal autoimmune disease for which the treatment options are limited. This study aimed to evaluate the efficacy of autologous peripheral hematopoietic stem cell transplantation (APHSCT) for pemphigus.\n\n\nMETHODS\nWe conducted APHSCT for 12 pemphigus patients (seven males and five females, mean age 23.8 years) with life-threatening complications or who responded poorly to conventional therapy. Peripheral blood stem cells were mobilized with cyclophosphamide, granulocyte colony-stimulating factor, and rituximab, and purified autologous CD34+ stem cells were infused. Overall survival rate, progression-free survival, and adverse events were recorded.\n\n\nRESULTS\nWith a mean follow-up period of 80.3 months, overall survival and complete clinical remission rates were 92% (11/12) and 75% (9/12), respectively. Adverse effects included pyrexia, allergy, infection, and elevation of enzymes. Only one patient died of severe sepsis and multiple organ failure 2 months after APHSCT.\n\n\nCONCLUSIONS\nOverall APHSCT is a promising therapeutic option for pemphigus.",
"affiliations": "Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.;Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.",
"authors": "Wang|Menglei|M|;Cao|Can|C|;Sun|Jing|J|;Peng|Xuebiao|X|;Liu|Qifa|Q|;Huang|Liang|L|;Chai|Yanyan|Y|;Lai|Kuan|K|;Chen|Pingjiao|P|;Liu|Qingxiu|Q|;Li|Qian|Q|;Peng|Yusheng|Y|;Xiong|Hao|H|;Zhang|Jing|J|;Chen|Minghua|M|;Zeng|Kang|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ijd.13461",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "56(3)",
"journal": "International journal of dermatology",
"keywords": "autologous peripheral hematopoietic stem cell transplantation; pemphigus",
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000328:Adult; D018572:Disease-Free Survival; D005260:Female; D005334:Fever; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D006967:Hypersensitivity; D008297:Male; D010392:Pemphigus; D012008:Recurrence; D012074:Remission Induction; D018805:Sepsis; D015996:Survival Rate; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "296-301",
"pmc": null,
"pmid": "28093721",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Application of autologous hematopoietic stem cell transplantation for pemphigus.",
"title_normalized": "application of autologous hematopoietic stem cell transplantation for pemphigus"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1026355",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
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